Clinical trial NCT01964560
Conditions: Epilepsy
Keywords: Lacosamide Vimpat UCB Epilepsy Partial-Onset Seizures Pediatric
Sponsor: UCB BIOSCIENCES, Inc.
Start date: 2014-08-13; Completion date: 2022-04-13
Enrollment: 540 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term safety, tolerability and efficacy of lacosamide (LCM) in pediatric subjects.

Detailed description:

Arms: arm 1: In the first week after enrollment into EP0034 subjects will be dosed according to their weight:

* Lacosamide (LCM) 10 mg/kg/day (oral solution) for subjects weighing \<30 kg
* LCM 6 mg/kg/day (oral solution) for subjects weighing ≥30 kg to \<50 kg
* LCM 300 mg/day (tablets) for subjects weighing ≥50 kg

After 1 week the investigator may adjust the LCM dose during the Treatment Period based on clinical judgment within a range of 2 mg/kg/day to 12 mg/kg/day for the oral solution and 100 mg/day to 600 mg/day for the tablets.
Interventions: intervention 1: Lacosamide intervention 2: Lacosamide
Intervention descriptions: intervention 1: Pharmaceutical form: oral solution

Concentration: 1 mg/kg - 6 mg/kg BID (2 mg/kg/day - 12 mg/ kg/day)

Route of administration: oral use intervention 2: Pharmaceutical form: tablet

Concentration: 50 mg - 300 mg BID (100 mg/day - 600 mg/day)

Route of administration: oral use

Protocol documents:
Prot_000.pdf: 
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EP0034 
 
 
 
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PROTOCOL EP0034 AMENDMENT 3 
A MULTICENTER, OPEN-LABEL, LONG-TERM EXTENSION 
STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF 
LACOSAMIDE AS ADJUNCTIVE THERAPY IN PEDIATRIC 
SUBJECTS WITH EPILEPSY WITH PARTIAL‑ONSET 
SEIZURES 
PHASE 3 
EudraCT Number: 2012-005012-26 
IND Numbers: 73809 (oral solution) and 57939 (tablet) 
Sponsor: 
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
UNITED STATES 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
24 May 2013 
Not applicable 
Protocol Amendment 0.1 (Russia) 
06 Mar 2015 
Substantial 
Protocol Amendment 1 
30 Jun 2015 
Substantial 
Protocol Amendment 2 
24 Mar 2017 
Substantial 
Protocol Amendment 3 
03 Nov 2020 
Nonsubstantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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EP0034 
 
 
 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB BIOSCIENCES Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Str. 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Biopharma SRL 
208 Bath Road 
Slough, Berkshire, SL1 3WE 
UNITED KINGDOM 
Phone: 
 
Email: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Email: 
 
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Clinical Monitoring Contract Research Organization 
Name: 
PRA Health Sciences 
Address: 
4130 Park Lake Avenue, Suite 400  
Raleigh, NC 27612  
UNITED STATES 
Phone: 
+1 919 786 8200 
Fax: 
+1 919 786 8201 
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03 Nov 2020 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
 
Email 
Global: DS_ICT@ucb.com 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 13 
3 
STUDY OBJECTIVES .................................................................................................... 15 
3.1 
Primary objective ......................................................................................................... 15 
3.2 
Secondary objective ..................................................................................................... 15 
3.3 
Other objectives ........................................................................................................... 15 
4 
STUDY VARIABLES ..................................................................................................... 15 
4.1 
Safety variables ............................................................................................................ 15 
4.1.1 
Primary safety variables ...................................................................................... 15 
4.1.2 
Other safety variables .......................................................................................... 16 
4.2 
Efficacy variables......................................................................................................... 16 
4.2.1 
Primary efficacy variables ................................................................................... 16 
4.2.2 
Secondary efficacy variable ................................................................................. 16 
4.2.3 
Other efficacy variables ....................................................................................... 16 
5 
STUDY DESIGN ............................................................................................................. 17 
5.1 
Study description ......................................................................................................... 17 
5.1.1 
Study duration per subject ................................................................................... 19 
5.1.2 
Planned number of subjects and site(s) ............................................................... 19 
5.1.3 
Anticipated regions and countries ....................................................................... 19 
5.2 
Schedule of study assessments..................................................................................... 19 
5.3 
Schematic diagram ....................................................................................................... 30 
5.4 
Rationale for study design and selection of dose ......................................................... 33 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 33 
6.1 
Inclusion criteria .......................................................................................................... 33 
6.2 
Exclusion criteria ......................................................................................................... 33 
6.3 
Withdrawal criteria ...................................................................................................... 34 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 35 
7 
STUDY TREATMENT(S) .............................................................................................. 36 
7.1 
Description of investigational medicinal product ........................................................ 36 
7.2 
Treatment(s) to be administered .................................................................................. 36 
7.2.1 
Treatment Period ................................................................................................. 36 
7.2.2 
Taper Period ......................................................................................................... 37 
7.2.3 
Alternative study treatment supply due to coronavirus disease 2019 pandemic . 38 
7.3 
Packaging ..................................................................................................................... 38 
7.4 
Labeling ....................................................................................................................... 38 
7.5 
Handling and storage requirements ............................................................................. 39 
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7.6 
Drug accountability ...................................................................................................... 39 
7.7 
Procedures for monitoring subject compliance ............................................................ 39 
7.8 
Concomitant medication(s)/treatment(s) ..................................................................... 40 
7.8.1 
Permitted and prohibited concomitant treatments (medications and therapies) .. 40 
7.9 
Blinding........................................................................................................................ 40 
7.10 
Randomization and numbering of subjects .................................................................. 40 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 41 
8.1 
Treatment Period .......................................................................................................... 41 
8.1.1 
Visit 1 (Week 0) ................................................................................................... 41 
8.1.2 
Telephone contact (Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 66, and 78) .............. 43 
8.1.3 
Visit 2 (Week 4) ................................................................................................... 44 
8.1.4 
Visit 3 (Week 8) and Visit 4 (Week 12) .............................................................. 45 
8.1.5 
Visit 5 (Week 20) ................................................................................................. 45 
8.1.6 
Visit 6 (Week 28) ................................................................................................. 47 
8.1.7 
Visit 7 (Week 36) and Visit 8 (Week 44) ............................................................ 47 
8.1.8 
Visit 9 (Week 52) ................................................................................................. 48 
8.1.9 
Visit 10 (Week 60) ............................................................................................... 50 
8.1.10 
Visit 11 (Week 72) ............................................................................................... 50 
8.1.11 
Visit 12 (Week 84) ............................................................................................... 52 
8.1.12 
Visit 13/Termination Visit (Week 96) ................................................................. 52 
8.1.13 
Early Termination Visit ....................................................................................... 54 
8.2 
Taper Period ................................................................................................................. 56 
8.3 
Safety Follow-Up Visit ................................................................................................ 57 
8.4 
Safety Follow-Up Telephone Contact ......................................................................... 58 
8.5 
Unscheduled Visit ........................................................................................................ 58 
8.6 
Study conduct due to coronavirus disease 2019 pandemic .......................................... 59 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 60 
9.1 
Seizure frequency......................................................................................................... 60 
9.2 
Global Impression of Change ...................................................................................... 60 
9.3 
PedsQL ......................................................................................................................... 60 
9.4 
Health care resource use .............................................................................................. 61 
10 ASSESSMENT OF SAFETY .......................................................................................... 61 
10.1 
Adverse events ............................................................................................................. 61 
10.1.1 
Definition of adverse event .................................................................................. 61 
10.1.2 
Procedures for reporting and recording adverse events ....................................... 61 
10.1.3 
Description of adverse events .............................................................................. 61 
10.1.4 
Follow up of adverse events ................................................................................ 62 
10.1.5 
Rule for repetition of an adverse event ................................................................ 62 
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10.1.6 
Pregnancy ............................................................................................................ 62 
10.1.7 
Overdose of IMP .................................................................................................. 63 
10.1.8 
Safety signal detection ......................................................................................... 63 
10.1.9 
Occurrence of COVID-19 .................................................................................... 63 
10.2 
Serious adverse events ................................................................................................. 63 
10.2.1 
Definition of serious adverse event ..................................................................... 63 
10.2.2 
Procedures for reporting serious adverse events ................................................. 64 
10.2.3 
Follow up of serious adverse events .................................................................... 65 
10.3 
Adverse events of special interest ................................................................................ 65 
10.4 
Immediate reporting of adverse events ........................................................................ 66 
10.5 
Anticipated serious adverse events .............................................................................. 66 
10.6 
Laboratory measurements ............................................................................................ 67 
10.6.1 
Liver function tests and evaluation of PDILI ...................................................... 68 
10.6.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 72 
10.6.1.2 
Immediate action: determination of IMP discontinuation ......................... 72 
10.6.1.3 
Testing: identification/exclusion of alternative etiology ........................... 72 
10.6.1.4 
Follow-up evaluation ................................................................................. 74 
10.7 
Pregnancy testing ......................................................................................................... 74 
10.8 
Other safety measurements .......................................................................................... 74 
10.8.1 
Physical examination ........................................................................................... 74 
10.8.1.1 
Complete physical examination ................................................................ 75 
10.8.1.2 
Brief physical examination ........................................................................ 75 
10.8.2 
Neurological examination .................................................................................... 75 
10.8.2.1 
Complete neurological examination .......................................................... 75 
10.8.2.2 
Brief neurological examination ................................................................. 75 
10.8.3 
Tanner Stage ........................................................................................................ 75 
10.8.4 
12-lead ECG ........................................................................................................ 75 
10.8.4.1 
Overall ECG interpretation ....................................................................... 76 
10.8.5 
Vital signs, body weight, and height ................................................................... 76 
10.8.6 
Assessment of suicidality .................................................................................... 76 
10.8.7 
Achenbach CBCL ................................................................................................ 77 
10.8.8 
BRIEF-P and BRIEF ........................................................................................... 77 
10.8.9 
Bayley Scales of Infant and Toddler Development, Third Edition ..................... 78 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 79 
11.1 
Adherence to protocol .................................................................................................. 79 
11.2 
Monitoring ................................................................................................................... 79 
11.2.1 
Definition of source data ..................................................................................... 79 
11.2.2 
Source data verification ....................................................................................... 80 
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11.3 
Data handling ............................................................................................................... 80 
11.3.1 
Case Report form completion .............................................................................. 80 
11.3.2 
Database entry and reconciliation ........................................................................ 80 
11.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 80 
11.4 
Termination of the study .............................................................................................. 81 
11.5 
Archiving and data retention ........................................................................................ 81 
11.6 
Audit and inspection .................................................................................................... 81 
11.7 
Good Clinical Practice ................................................................................................. 82 
12 STATISTICS ................................................................................................................... 82 
12.1 
Definition of analysis sets ............................................................................................ 82 
12.2 
General statistical considerations ................................................................................. 82 
12.3 
Planned safety analyses................................................................................................ 82 
12.4 
Planned efficacy and other analyses ............................................................................ 83 
12.4.1 
Efficacy analyses ................................................................................................. 83 
12.5 
Handling of protocol deviations................................................................................... 83 
12.6 
Handling of dropouts or missing data .......................................................................... 83 
12.7 
Planned interim analysis and data monitoring ............................................................. 83 
12.8 
Determination of sample size ....................................................................................... 83 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 84 
13.1 
Informed consent ......................................................................................................... 84 
13.2 
Subject identification cards .......................................................................................... 84 
13.3 
Institutional Review Boards and Independent Ethics Committees .............................. 84 
13.4 
Subject privacy............................................................................................................. 85 
13.5 
Protocol amendments ................................................................................................... 85 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 86 
15 REFERENCES ................................................................................................................ 86 
16 APPENDICES ................................................................................................................. 88 
16.1 
Protocol Amendment 1 ................................................................................................ 88 
16.2 
Protocol Amendment 2 .............................................................................................. 114 
16.3 
Protocol Amendment 3 .............................................................................................. 129 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 144 
18 SPONSOR DECLARATION ........................................................................................ 145 
 
LIST OF TABLES 
Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 .................. 20 
Table 5-2: 
Schedule of study assessments: Treatment Period from Week 32 to 
Week 96/Termination Visit .............................................................................. 24 
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Table 5-3: 
Schedule of study assessments: Taper Period and Safety Follow-Up 
Period ............................................................................................................... 28 
Table 7-1: 
Minimum and maximum LCM dose during the Treatment Period ................. 37 
Table 7-2: 
Dose taper steps for subjects receiving oral solution ....................................... 37 
Table 7-3: 
Dose taper steps for subjects taking tablets ..................................................... 38 
Table 10‒1: 
Anticipated SAEs for the pediatric epilepsy population .................................. 67 
Table 10‒2: 
Laboratory measurements ................................................................................ 68 
Table 10‒3: 
Required investigations and follow up for PDILI............................................ 70 
Table 10‒4: 
PDILI laboratory measurements ...................................................................... 72 
Table 10‒5: 
PDILI information to be collected ................................................................... 74 
 
LIST OF FIGURES 
Figure 5-1: 
Schematic diagram ........................................................................................... 31 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
Bayley-III® 
Bayley Scales of Infant and Toddler Development, Third Edition 
bid 
twice daily 
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 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DEM 
data evaluation meeting 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EI-AED 
enzyme-inducing antiepileptic drug 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GMP 
Good Manufacturing Practice 
HRQoL 
health-related quality of life 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IXRS 
interactive voice/web response system 
LCM 
lacosamide 
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LFT 
liver function test 
MedDRA® 
Medical Dictionary for Regulatory Activities 
PDILI 
potential drug-induced liver injury 
PedsQL™ 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetic(s) 
QTc 
corrected QT interval 
RDC 
remote data capture 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VNS 
vagus nerve stimulation 
 
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1 
SUMMARY 
EP0034 is a Phase 3, multicenter, open-label, extension study to obtain long-term safety and 
efficacy data in pediatric subjects with epilepsy with partial-onset seizures treated with 
lacosamide (LCM) oral solution or LCM tablets as adjunctive therapy. The study will provide 
continued availability of LCM to subjects who have completed SP0969 (pediatric subjects with 
epilepsy aged ≥4 to <17 years with partial-onset seizures). EP0034 will also be open to subjects 
who participate in SP0967 (pediatric subjects with epilepsy aged 1 month to <4 years with 
partial-onset seizures). Both SP0969 and SP0967 are Phase 3, double-blind, placebo-controlled 
studies for LCM as adjunctive therapy. 
Approximately 500 subjects from SP0967 and SP0969 may be eligible to enroll in this 
open-label extension study, for a maximum duration per subject of approximately 2 years. The 
number of sites is dependent on the number of enrolling centers from SP0967 and SP0969. The 
study will be conducted in North America, Europe, Latin America, and the Asia/Pacific regions, 
with the possibility to expand the study to other countries and regions if deemed necessary. At 
selected sites, subjects may also be able to participate in a substudy without withdrawing from 
EP0034. 
The study medication is LCM in either the oral solution formulation or tablet formulation. 
Subjects may take either oral solution or tablets during the Treatment Period, based on clinical 
judgment, regardless of their weight. Lacosamide will be administered twice daily (bid) at 
approximately 12-hour intervals, once in the morning and once in the evening, in divided doses. 
The oral solution formulation will be measured and administered via a dosing syringe. 
After completion of the Transition Period in the primary study, subjects will have been 
transitioned to a dose of LCM according to their weight. Subjects will receive 
LCM 10mg/kg/day (oral solution) for subjects weighing <30kg, LCM 6mg/kg/day (oral solution) 
for subjects weighing ≥30kg to <50kg, and LCM 300mg/day (tablets) for subjects weighing 
≥50kg during at least their first week in the Treatment Period of EP0034. After 1 week in 
EP0034, the investigator may adjust the LCM dose during the Treatment Period based on clinical 
judgment within a range of 2mg/kg/day to 12mg/kg/day for the oral solution and 100mg/day to 
600mg/day for the tablets. 
During the Treatment Period, study visits are scheduled at Weeks 0, 4, 8, 12, 20, 28, 36, 44, 52, 
60, 72, 84, and 96. Telephone contacts are scheduled at Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 
66, and 78. Subjects who withdraw from treatment during the study should taper off LCM if the 
following doses are achieved: LCM ≥3mg/kg/day (oral solution) for subjects receiving LCM oral 
solution, or LCM ≥150mg/day (tablet) for subjects taking tablets; lower doses will not require a 
taper. An Early Termination Visit must be completed for all subjects who prematurely 
discontinue from the study. Subjects who complete the study or withdraw prematurely from the 
study, and who discontinue use of LCM, should complete a Safety Follow-Up Visit 2 weeks 
(±2 days) after the final dose of LCM. A Safety Follow-Up Telephone Contact will be made 
30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit and the Safety 
Follow-Up Telephone Contact are not required for subjects who participate in EP0151 or 
EP0152. 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 or withdraw from the study 
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prematurely, depending on the treatment option selected by the investigator in consultation with 
the subject and/or legal representative(s). 
Safety will be evaluated based on the occurrence of adverse events (AEs), the results of periodic 
clinical laboratory tests, electrocardiograms (ECGs), physical (Tanner Stage, if applicable, 
depending on subject’s developmental status) and neurological examinations, vital signs (blood 
pressure and pulse rate) monitoring, and body weight and height. 
The efficacy variables will be based on seizure diary data and will include the percentage of 
seizure-free days during the study. The following other efficacy variables based on seizure diary 
data will be computed for subjects from SP0969: the percentage of 50% responders (subjects 
with at least a 50% reduction in total partial-onset seizure frequency per 28 days compared to 
Baseline) and the percentage of 50% responders per seizure type (simple partial, complex partial, 
or secondarily generalized) compared to Baseline, the percentage of 75% responders (subjects 
with at least a 75% reduction in total partial-onset seizure frequency per 28 days compared to 
Baseline) and the percentage of 75% responders per seizure type (simple partial, complex partial, 
or secondarily generalized) compared to Baseline, absolute and percent reduction in total partial-
onset seizures and per partial-onset seizure type (simple partial, complex partial, or secondarily 
generalized) compared to Baseline (Baseline is defined as the period before receiving study 
medication in the previous pediatric study), and partial-onset seizure frequency per 28 days. The 
following other efficacy variables will be computed for all subjects in EP0034: achievement of 
seizure-free status (no seizure) during the study for total partial-onset seizure and per seizure 
type (simple partial, complex partial, or secondarily generalized), Clinical Global Impression of 
Change, and Caregiver’s Global Impression of Change.  
Other evaluations will include behavioral and cognition assessments (Achenbach Child Behavior 
Checklist [CBCL], Behavior Rating Inventory of Executive Function [BRIEF®]/BRIEF 
Preschool Version [BRIEF®-P], and Bayley Scales of Infant and Toddler Development, Third 
Edition [Bayley-III®] for subjects enrolled in English-speaking countries), quality of life 
assessments (Pediatric Quality of Life Inventory [PedsQL™]), health care resource use 
(concomitant medications, medical procedures, and health care provider consultations including 
hospitalizations not foreseen by the protocol). 
2 
INTRODUCTION 
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated that 
almost 70 million people suffer from epilepsy worldwide (Ngugi et al, 2011). Although some 
forms of epilepsy may respond to surgical treatment and others may not require any treatment at 
all, most patients with epilepsy require appropriate pharmacological therapy (Perucca, 1996). 
The Institute of Medicine of the National Academies recently provided a review of the burdens 
of epilepsy, global incidence and prevalence of epilepsy, and general recommendations (Institute 
of Medicine, 2012). Several newer options for the medical treatment of epilepsy have been 
introduced, including novel antiepileptic drugs (AEDs) and vagus nerve stimulation (VNS). The 
classification of epilepsies in children was described in 1989 by the Commission on 
Classification and Terminology of the International League Against Epilepsy (1989; Aicardi, 
1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
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according to a number of criteria, including seizure type, cause, anatomy, precipitating factors, 
age at onset, and sometimes prognosis. 
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and pharmacokinetic (PK) characteristics (Herman and Pedley, 
1998). However, more than 30% of patients have inadequate seizure control on currently 
available AEDs or experience significant adverse drug effects (CHMP/EWP/566/98, 2010). 
Therefore, a need remains for AEDs with improved effectiveness and tolerability (Sander, 1998). 
Among the newer AEDs, only 6 (gabapentin, lamotrigine, oxcarbazepine, topiramate, 
levetiracetam, and perampanel) have successfully demonstrated efficacy as adjunctive therapy in 
children with difficult to treat partial-onset seizures (Rheims and Ryvlin, 2013; Glauser et al, 
2006; Glauser et al, 2000; Appleton et al, 1999; Duchowny et al, 1999; Elterman et al, 1999). 
Despite the availability of new AEDs, more than 25% of pediatric patients have inadequate 
seizure control on currently available AEDs or experience significant adverse drug effects 
(Hadjiloizou and Bourgeois, 2007).  
Lacosamide (VIMPAT®; SPM 927; previously referred to as harkoseride; [R] 2-acetamido-N-
benzyl-3-methoxypropionamide, ADD 234037) belongs to a novel class of functionalized amino 
acids. It has minimal protein binding and effect on cytochrome P450 enzyme system function 
(reducing the risk of drug-drug interactions), high oral bioavailability, and a half-life of 
approximately 13 hours (in adults), which allows a 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 as monotherapy or adjunctive therapy in the treatment of 
partial-onset seizures in patients 17 years of age and older in the United States (tablets, oral 
solution, and solution for intravenous [iv] infusion) and as monotherapy or adjunctive therapy in 
the treatment of partial-onset seizures with or without secondary generalization in patients 16 
years of age and older in the European Union (tablets, oral solution, and solution for iv infusion). 
The oral solution (also referred to as syrup) is a formulation suitable for administration to 
children. Bioequivalence has been shown between the tablet and oral solution formulations, 
comparing 2 tablets of LCM 100mg and the oral solution containing LCM 200mg, after 
single-dose administration in healthy subjects. The PK of LCM and SPM 12809 (major LCM 
metabolite in humans) in plasma, urine, and saliva were identical or very similar after single oral 
doses of LCM 200mg administered as tablets or as oral solution. 
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
LCM 400mg bid (LCM 800mg/day) were evaluated in approximately 800 unique volunteers who 
received LCM in Phase 1 studies. The safety and efficacy of LCM has also been evaluated in 
Phase 2/3 studies as adjunctive oral therapy in over 1300 adult subjects with partial-onset 
seizures and as oral monotherapy in over 2400 adult subjects in other indications (neuropathic 
pain, osteoarthritis, fibromyalgia, and migraine prophylaxis). In addition, LCM solution for 
infusion was evaluated as short-term replacement therapy in a subset of subjects with 
partial-onset seizures (220 patients) who were receiving adjunctive LCM tablets. 
Three double-blind, placebo-controlled, multicenter studies (SP667, SP754, and SP755) in 
1308 adult subjects, aged 16 to 70 years, established the efficacy of oral LCM as adjunctive 
therapy (1 to 3 concomitant AEDs) in subjects with difficult to control partial-onset seizures. In 
these studies, LCM was initiated at a dose of 100mg/day (in 2 divided doses) and escalated to the 
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randomized dose (LCM 200mg/day, LCM 400mg/day, or LCM 600mg/day) in 100mg/day per 
week increments. 
When oral LCM was administered as adjunctive therapy at doses up to 600mg/day in the 
3 double-blind, placebo-controlled, multicenter studies in subjects with partial-onset seizures, the 
most frequently reported treatment-emergent AEs (TEAEs) were central nervous system- and 
gastrointestinal-associated events. A dose relationship was seen for the most frequently reported 
common TEAEs, including dizziness, nausea, and diplopia. The nature and frequency of AEs 
were comparable to adjunctive therapy with other marketed AEDs. Safety evaluations support 
the further development of LCM as an AED. 
Pellock et al have recently conducted a systematic review of AEDs used in the treatment of 
partial-onset seizures (Bourgeois and Goodkin, 2012; Pellock et al, 2012). The AEDs that were 
shown to be superior to placebo for the adjunctive treatment of partial-onset seizures in adult 
clinical studies were also shown to be superior to placebo for adjunctive treatment of 
partial-onset seizures in the pediatric clinical studies (subjects >2 years of age) in which they 
were investigated. The efficacy and safety of LCM observed in clinical studies in adults and 
preclinical data, as well as many additional attributes of LCM, render the drug appropriate to 
investigate in pediatric subjects. These attributes include predictable and linear PK, lack of 
drug-drug interactions, easy twice daily dosing, and the availability of 3 different types of 
formulations in multiple strengths (allowing for flexibility in dose range and individualizing 
treatment). 
EP0034 is a Phase 3, multicenter, open-label, extension study to obtain long-term safety and 
efficacy data in pediatric subjects with epilepsy with partial-onset seizures treated with LCM oral 
solution or LCM tablets as adjunctive therapy. The study will provide continued availability of 
LCM to subjects who have completed SP0969 (pediatric subjects with epilepsy aged ≥4 to 
<17 years with partial-onset seizures). EP0034 will also be open to subjects who participate in 
SP0967 (pediatric subjects with epilepsy aged 1 month to <4 years with partial-onset seizures). 
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
• To assess the long-term safety and tolerability of LCM in pediatric subjects 
3.2 
Secondary objective 
• To assess the efficacy of LCM during long-term exposure in pediatric subjects 
3.3 
Other objectives 
• To assess behavior, cognition, quality of life, and development during long-term LCM 
exposure in pediatric subjects 
4 
STUDY VARIABLES 
4.1 
Safety variables 
4.1.1 
Primary safety variables 
The primary safety variables include the following: 
• Incidence of TEAEs 
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• Incidence of serious TEAEs 
• Incidence of TEAEs leading to study discontinuation 
4.1.2 
Other safety variables 
The other safety variables include the following: 
• Safety laboratory tests (hematology; biochemistry including hepatic monitoring of alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
total bilirubin, and gamma-glutamyltransferase [GGT]; endocrinology for all subjects; and 
urinalysis for subjects ≥5 years of age)  
• Electrocardiograms  
• Physical (Tanner Stage, if applicable depending on subject’s developmental status) and 
neurological examinations  
• Vital signs (blood pressure and pulse rate) 
• Body weight and height 
• Change from Baseline in the Achenbach CBCL score: the Achenbach CBCL/1½-5 for 
children from 1.5 to 5 years of age and the Achenbach CBCL/6-18 for children ≥6 years of 
age 
• Change from Baseline in the BRIEF-P score for subjects ≥2 and <5 years of age 
• Change from Baseline in the BRIEF score for subjects ≥5 years of age 
• Change from Baseline in the Bayley-III scales in subjects <18 months of age at study entry 
(applicable only to subjects enrolled in English-speaking countries)  
4.2 
Efficacy variables 
4.2.1 
Primary efficacy variables 
No primary efficacy variables are defined for this study. 
4.2.2 
Secondary efficacy variable 
The secondary efficacy variable planned for analysis will be based on seizure diary data from 
EP0034 and will include the following for all subjects: 
• Percentage of seizure-free days during the study (presented for the overall Treatment Period 
only) 
4.2.3 
Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969 and include 
the following:  
• Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
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• Percentage of 75% responders (subjects with at least a 75% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure 
type (simple partial, complex partial, or secondarily generalized) compared to Baseline  
• Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034 and include 
the following: 
• Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• Clinical Global Impression of Change 
• Caregiver’s Global Impression of Change 
• Change from Baseline in PedsQL  
• Health care resource use: concomitant medications, medical procedures, and health care 
provider consultations including hospitalizations not foreseen by the protocol 
5 
STUDY DESIGN 
5.1 
Study description 
EP0034 is a Phase 3, multicenter, open-label, extension study to obtain long-term safety and 
efficacy data in pediatric subjects with epilepsy with partial-onset seizures treated with LCM oral 
solution or LCM tablets as adjunctive therapy.  
Subjects who have participated in SP0967 or SP0969, meet the eligibility requirements of this 
open-label extension study, and who consent or whose legal representative consents to 
participation can enroll into EP0034 for a maximum duration of approximately 2 years.  
During the study, LCM will be available in either the oral solution formulation or tablet 
formulation. Subjects who are able and willing to swallow tablets may be dispensed LCM tablets 
during the Treatment Period, based on clinical judgment, regardless of their weight.  
Treatment Period 
After completion of the Transition Period in the primary study, subjects will have been 
transitioned to a dose of LCM according to their weight. Subjects will receive 
LCM 10mg/kg/day (oral solution) for subjects weighing <30kg, LCM 6mg/kg/day (oral solution) 
for subjects weighing ≥30kg to <50kg, and LCM 300mg/day (tablets) for subjects weighing 
≥50kg during at least their first week in the Treatment Period of EP0034. After 1 week in 
EP0034, the investigator may adjust the LCM dose during the Treatment Period according to 
Table 7-1 (refer to Section 7.2.1). Subjects may take either oral solution or tablets during the 
Treatment Period, based on clinical judgment, regardless of their weight.  
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During the Treatment Period, study visits are scheduled at Weeks 0, 4, 8, 12, 20, 28, 36, 44, 52, 
60, 72, 84, and 96. Telephone contacts are scheduled at Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 
66, and 78.  
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 legal representative(s). These 
subjects should complete Visit 13/Termination Visit and then complete the Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit 
is not required for subjects who complete the study and who do not undergo taper of LCM. The 
Safety Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required for 
subjects who participate in EP0151 or EP0152. 
Subjects who complete the study and discontinue use of LCM (as determined by the investigator 
in consultation with the subject and/or legal representative) should taper LCM gradually as 
described in Section 7.2.2. These subjects should complete Visit 13/Termination Visit and enter 
the Taper Period.  
Subjects who prematurely discontinue the study should complete an Early Termination Visit. At 
the time of withdrawal from 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 withdraw from the study prematurely, depending on 
the treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s). These subjects should complete the Safety Follow-Up Telephone Contact 
30 days (-1/+3 days) after the final dose of LCM. 
Subjects who withdraw from the study prematurely and discontinue use of LCM (as determined 
by the investigator in consultation with the subject and/or legal representative) should taper LCM 
gradually as described in Section 7.2.2. These subjects should enter the Taper Period. 
Taper Period 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. Taper of LCM may not be required for some 
subjects who complete the study or withdraw from the study prematurely, depending on the 
treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s) or for subjects who participate in EP0151 or EP0152. 
End of study and Safety Follow-Up Period 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM, should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of 
LCM. A Safety Follow-Up Telephone Contact is required for all subjects (those who complete 
the study as planned or have withdrawn prematurely from the study). This telephone contact will 
occur 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit and the 
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Safety Follow-Up Telephone Contact are not required for subjects who participate in EP0151 or 
EP0152. 
Unscheduled visits may be conducted at the discretion of the investigator. 
Detailed schedules of study procedures are provided in Section 5.2, and a study schematic 
diagram is included in Section 5.3. 
No formal interim analysis or Data Monitoring Committee is planned. 
5.1.1 
Study duration per subject 
The maximum duration of LCM administration during EP0034 will be approximately 2 years. 
The start of the study is defined as the first visit of the first subject entering the study. The end of 
the study is defined as the date of the last telephone contact (or last site visit if telephone contact 
does not happen) of the last subject in the study.  
5.1.2 
Planned number of subjects and site(s) 
Approximately 500 subjects from SP0967 and SP0969 may be eligible to enroll in this 
open-label extension study. The number of sites is dependent on the number of enrolling centers 
from SP0967 and SP0969. 
5.1.3 
Anticipated regions and countries 
The study will be conducted in North America, Europe, Latin America, and the Asia/Pacific 
regions, with the possibility to expand the study to other countries and regions if deemed 
necessary. 
5.2 
Schedule of study assessments 
Table 5-1, Table 5-2 and Table 5-3 present the tabular schedules of study procedures. 
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Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
V1 
TC1 
V2 
TC2 
V3 
TC3 
V4 
TC4 
V5 
TC5 
V6 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W28 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VNS assessmente 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Physical examination (complete) 
Xd 
 
 
 
 
 
 
 
X 
 
 
X 
 
Physical examination (brief) 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
Tanner Stagef 
Xg 
 
 
 
 
 
 
 
X 
 
 
X 
 
Blood pressure and pulse rate 
(including orthostatic assessments in 
ambulatory subjects) 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body weight and height 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Xh 
Head circumference 
Xg 
 
 
 
 
 
 
 
X 
 
 
X 
 
Neurological examination (complete) 
Xd 
 
 
 
 
 
 
 
X 
 
 
X 
 
Neurological examination (brief) 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
12-lead ECGi 
Xg 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xd 
 
 
 
 
 
 
 
X 
 
 
X 
 
Endocrinology blood sample 
Xg 
 
 
 
 
 
 
 
X 
 
 
X 
 
Urinalysis (subjects aged ≥5 years)j 
Xd 
 
 
 
 
 
 
 
X 
 
 
X 
 
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Clinical Study Protocol 
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Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
V1 
TC1 
V2 
TC2 
V3 
TC3 
V4 
TC4 
V5 
TC5 
V6 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W28 
Serum pregnancy testk 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Urine pregnancy testk 
Xd 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
C-SSRSl 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Xm 
Clinical GIC 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Caregiver GIC 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Achenbach CBCLn 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Bayley-IIIo  
Xd 
 
 
 
 
 
 
 
X 
 
 
X 
 
BRIEF/BRIEF-Pp 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
PedsQLq 
Xg 
 
 
 
 
 
 
 
X 
 
 
X 
  
Contact IXRS 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
 
LCM return/compliance 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Dispense LCM 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xs 
 
Subject diaryt  
Xd 
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 
AE reportingu 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF-P/BRIEF=Behavior Rating 
Inventory of Executive Function-Preschool Version/Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; Cmax=maximum plasma 
concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; 
IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; Unsch=Unscheduled; 
V=Visit; VNS=vagus nerve stimulation; W=week 
 
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Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
V1 
TC1 
V2 
TC2 
V3 
TC3 
V4 
TC4 
V5 
TC5 
V6 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W28 
a A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts after Visit 1 during the Treatment Period. 
b An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
c If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion.  
d Assessments may have already been completed during the final Transition Visit of the primary study (SP0969 or SP0967) and should not be repeated at Visit 1 
of EP0034.  
e Only applicable for subjects with an implanted VNS device. 
f The Tanner Stage will be performed only for subjects who are pubescent at V1 or who enter puberty during the course of the study. 
g Assessments may have already been completed during the final Maintenance Visit of the primary study (SP0969 or SP0967) and should not be repeated at 
Visit 1 of EP0034.  
h Height will not be recorded at an Unscheduled Visit. 
i A 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart) will be performed prior to any blood draws and vital signs and, if possible, 
after the subject has been in a supine position for approximately 5 minutes preceding the ECG recording. All subjects will be required to have a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, after subsequent 
dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first 
time a subject reaches a LCM dose of 400mg/day,  500mg/day, etc), or when a new concomitant AED is introduced during the study. This ECG can be 
conducted at an Unscheduled Visit, if necessary. Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new concomitant AED is 
added, will be required to arrive at the clinic prior to taking their morning dose of LCM. Subjects will be administered their morning LCM dose by study 
personnel at the clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to any blood sample collection or vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM. 
j For subjects aged ≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to collect urine (in an appropriate container). 
k For female subjects of childbearing potential.  
l For all subjects ≥6 years of age, the “Since Last Visit” version of the C-SSRS should be completed. 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 at 
subsequent visits. 
m The C-SSRS assessment should be completed if the Unscheduled Visit is due to a safety or efficacy reason. 
n 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 primary 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. 
o The Bayley-III scales should be completed for subjects <18 months of age at study entry if enrolled in English-speaking countries. The same scale should be 
completed for 1 year after the Baseline assessment of the primary study, even if the subject turns >18 months of age during that period. 
p 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 
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Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
V1 
TC1 
V2 
TC2 
V3 
TC3 
V4 
TC4 
V5 
TC5 
V6 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W28 
Baseline assessment of the primary 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 only 
be administered in countries where a validated translated version is available. 
q 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 of the primary study, and subsequently the form consistent with his/her age at the time of assessment should be completed. The PedsQL 
will only be administered in countries where a validated translated version is available. 
r Only if LCM will be dispensed for taper. 
s Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥3mg/kg/day (oral solution) or LCM ≥150mg/day (tablet). It is 
recommended that the dose be tapered gradually in weekly decrements. A slower taper is permitted, if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the Medical Monitor, whenever possible. Taper of LCM may not be required for some subjects who withdraw from the 
study prematurely, depending on the treatment option selected by the investigator in consultation with the subject and/or legal representative(s). 
t Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. 
u Ongoing AEs from the primary study will be followed, as well as recording of new AEs during the current study. 
 
 
 
 
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Table 5-2: 
Schedule of study assessments: Treatment Period from Week 32 to Week 96/Termination Visit 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
TC6 
V7 
TC7 
V8 
TC8 
V9 
TC9 
V10 
TC10 
V11 
TC11 
V12 
V13 / 
TermVd 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W66 
W72 
W78 
W84 
W96 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VNS assessmente 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Physical exam 
(complete) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
Physical exam (brief) 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Tanner Stagef 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
Blood pressure and 
pulse rate (including 
orthostatic 
assessments in 
ambulatory subjects) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Body weight and 
height 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Xg 
Head circumference 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Neurological exam 
(complete) 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
Neurological exam 
(brief) 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
12-lead ECGh 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Clinical chemistry 
and hematology 
blood sample 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
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Table 5-2: 
Schedule of study assessments: Treatment Period from Week 32 to Week 96/Termination Visit 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
TC6 
V7 
TC7 
V8 
TC8 
V9 
TC9 
V10 
TC10 
V11 
TC11 
V12 
V13 / 
TermVd 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W66 
W72 
W78 
W84 
W96 
Endocrinology blood 
sample 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Urinalysis (subjects 
aged ≥5 years)i 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Serum pregnancy testj 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Urine pregnancy testj 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
C-SSRSk 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Xl 
Clinical GIC 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Caregiver GIC 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Achenbach CBCLm 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Bayley-IIIn 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
BRIEF/BRIEF-Po 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
PedsQLp 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Contact IXRS 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xq 
Xp 
 
LCM return/ 
compliance 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Dispense LCM 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
Xq 
 
Subject diarys 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Withdrawal criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 5-2: 
Schedule of study assessments: Treatment Period from Week 32 to Week 96/Termination Visit 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
TC6 
V7 
TC7 
V8 
TC8 
V9 
TC9 
V10 
TC10 
V11 
TC11 
V12 
V13 / 
TermVd 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W66 
W72 
W78 
W84 
W96 
Health care resource 
use 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF-P/BRIEF=Behavior Rating 
Inventory of Executive Function-Preschool Version/Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; Cmax=maximum plasma 
concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; 
IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; TermV=Termination Visit; 
Unsch=Unscheduled; V=Visit; VNS=vagus nerve stimulation; W=week 
 
a A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts after Visit 1 during the Treatment Period. 
b An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
c If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion.  
d Visit 13 will be the treatment Termination Visit for subjects who complete up to 2 years of treatment. 
e Only applicable for subjects with an implanted VNS device.  
f The Tanner Stage will be performed only for subjects who are pubescent at V1 or who enter puberty during the course of the study. 
g Height will not be recorded at an Unscheduled Visit. 
h A 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart) will be performed prior to any blood draws and vital signs and, if possible, 
after the subject has been in a supine position for approximately 5 minutes preceding the ECG recording. All subjects will be required to have a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, after subsequent 
dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first 
time a subject reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new concomitant AED is introduced during the study. This ECG can be 
conducted at an Unscheduled Visit, if necessary. Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new concomitant AED is 
added will be required to arrive at the clinic prior to taking their morning dose of LCM. Subjects will be administered their morning LCM dose by study 
personnel at the clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to any blood sample collection or vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM. 
i For subjects aged ≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to collect urine (in an appropriate container). 
j For female subjects of childbearing potential. 
k For all subjects ≥6 years of age, the “Since Last Visit” version of the C-SSRS should be completed. 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 at 
subsequent visits. 
l The C-SSRS assessment should be completed if the Unscheduled Visit is due to a safety or efficacy reason. 
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Table 5-2: 
Schedule of study assessments: Treatment Period from Week 32 to Week 96/Termination Visit 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
TC6 
V7 
TC7 
V8 
TC8 
V9 
TC9 
V10 
TC10 
V11 
TC11 
V12 
V13 / 
TermVd 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W66 
W72 
W78 
W84 
W96 
m 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 primary 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. 
n The Bayley-III scales should be completed for subjects <18 months of age at study entry if enrolled in English-speaking countries. The same scale should be 
completed for 1 year after the Baseline assessment of the primary study, even if the subject turns >18 months of age during that period. 
o 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 primary study and turn 5 years of age within 1 year after the Baseline assessment of the primary study, the BRIEF-P should be 
completed 1 year after the Baseline assessment of the primary study, and subsequently the BRIEF should be completed. The BRIEF-P and BRIEF will only be 
administered in countries where a validated translated version is available. 
p 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 of the primary study, and subsequently the form consistent with his/her age at the time of assessment should be completed. The PedsQL 
will only be administered in countries where a validated translated version is available. 
q Only if LCM will be dispensed for taper. 
r Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥3mg/kg/day (oral solution) or LCM ≥150mg/day (tablet). It is 
recommended that the dose be tapered gradually in weekly decrements. A slower taper is permitted, if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the Medical Monitor, whenever possible. Taper of LCM may not be required for some subjects who withdraw from the 
study prematurely, depending on the treatment option selected by the investigator in consultation with the subject and/or legal representative(s). 
s Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. For subjects who enter the Safety Follow-Up Period, the subject 
diary will be returned at the Safety Follow-Up Visit. Subjects who do not enter the Safety Follow-Up Period will return the diary at V13/TermV. 
 
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Table 5-3: 
Schedule of study assessments: Taper Period and Safety Follow-Up 
Period 
Assessments 
Taper Period 
Safety Follow-Up Period 
Taper Visita 
Safety Follow-Up 
Visitb 
Safety Follow-Up 
Telephone Callc 
Concomitant medications 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
VNS assessmentd 
X 
X 
 
Physical exam (complete) 
 
X 
 
Physical exam (brief) 
X 
 
 
Tanner Stagee 
 
X 
 
Blood pressure and pulse rate (including orthostatic 
assessments in ambulatory subjects) 
X 
X 
 
Body weight and height 
X 
X 
 
Neurological exam (complete) 
 
X 
 
Neurological exam (brief) 
X 
 
 
12-lead ECGf 
X 
X 
 
Clinical chemistry and hematology blood sample 
X 
X 
 
Endocrinology blood sample 
X 
X 
 
Urinalysis (subjects aged ≥5 years)g 
X 
X 
 
Serum pregnancy testh 
X 
X 
 
C-SSRSi 
X 
X 
 
LCM return/compliance 
X 
 
 
Subject diaryj 
X 
X 
 
AE reporting 
X 
X 
Xk 
Health care resource use 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; IXRS=interactive voice/web response system; LCM=lacosamide; Term=Termination; 
V=Visit; VNS=vagus nerve stimulation 
a The Taper Period (up to 4 weeks, depending on dose level achieved, see Section 7.2.2 for details) will be required 
for subjects who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking tablets. 
The Taper Visit will be performed at the end of the Taper Period. Taper of LCM may not be required for some 
subjects who complete the study or withdraw from the study prematurely, depending on the treatment option 
selected by the investigator in consultation with the subject and/or legal representative(s). 
b Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM, 
should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM (including that from 
LCM taper). The Safety Follow-Up Visit is not required for subjects who complete the study and do not undergo 
taper of LCM. The Safety Follow-Up Visit is not required for subjects who participate in EP0151 or EP0152. 
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Table 5-3: 
Schedule of study assessments: Taper Period and Safety Follow-Up 
Period 
Assessments 
Taper Period 
Safety Follow-Up Period 
Taper Visita 
Safety Follow-Up 
Visitb 
Safety Follow-Up 
Telephone Callc 
c The Safety Follow-Up Telephone Call occurs 30 days (-1/+3 days) after the final dose of LCM. The Safety 
Follow-Up Telephone Call is not required for subjects who participate in EP0151 or EP0152. 
d Only applicable for subjects with an implanted VNS device.  
e The Tanner Stage will be performed only for subjects who are pubescent at V1 or who enter puberty during the 
course of the study. 
f A 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart) will be performed prior to any 
blood draws and vital signs and, if possible, after the subject has been in a supine position for approximately 
5 minutes preceding the ECG recording.  
g For subjects aged ≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to 
collect urine (in an appropriate container). 
h For female subjects of childbearing potential. 
i For all subjects ≥6 years of age, the “Since Last Visit” version of the C-SSRS should be completed. 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 at subsequent visits. 
j Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. For subjects who 
enter the Safety Follow-Up Period, the subject diary will be returned at the Safety Follow-Up Visit. Subjects who 
do not enter the Safety Follow-Up Period will return the diary at V13/TermV. 
k If an AE is reported at this telephone contact, the investigator will follow the AE 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. 
 
 
 
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5.3 
Schematic diagram 
Figure 5-1 presents schematic diagrams of dosing for EP0034. 
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Figure 5-1: Schematic diagram  
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU TC 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 4 weeks) 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
11mg/kg/day 
 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
10mg/kg/day 
 
 
 
 
 
 
 
Subjects 
11mg/kg/day 
 
 
 
9mg/kg/day 
 
 
 
 
 
 
 
<30kg 
10mg/kg/day 
10mg/kg/day 
 
 
8mg/kg/day 
 
 
 
 
 
 
 
 
9mg/kg/day 
 
 
 
7mg/kg/day 
 
 
 
 
 
 
 
 
8mg/kg/day 
 
 
 
6mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
5mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
4mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
3mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
2mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-100 
101-104 
 
 
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU TC 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 4 weeks) 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
11mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
10mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
9mg/kg/day 
 
 
 
 
 
 
 
 
8mg/kg/day 
 
 
 
8mg/kg/day 
 
 
 
 
 
 
 
Subjects 
7mg/kg/day 
 
 
 
7mg/kg/day 
 
 
 
 
 
 
 
≥30kg & 
6mg/kg/day 
6mg/kg/day 
 
 
6mg/kg/day 
 
 
 
 
 
 
 
<50kg 
 
 
 
 
5mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
4mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
3mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
2mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-100 
101-104 
 
 
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V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU TC 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 4 weeks) 
 
 
 
 
 
 
 
600mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
500mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
400mg/day 
 
 
 
400mg/day 
 
 
 
 
 
 
 
Subjects 
350mg/day 
 
 
 
 
 
 
 
 
 
 
 
≥50kg 
300mg/day 
300mg/day 
 
 
300mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
200mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-100 
101-104 
 
 
LCM=lacosamide; SFU=Safety Follow-Up; TC=telephone contact; V=visit 
Note: Taper of LCM may not be required for some subjects who complete the study or withdraw from the study prematurely, depending on the treatment option 
selected by the investigator in consultation with the subject and/or legal representative(s) or for subjects who participate in EP0151 or EP0152. 
 
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5.4 
Rationale for study design and selection of dose 
Epilepsy is a condition for which an improved benefit/risk ratio for medicinal products remains a 
challenge; this is especially true for pediatric patients. 
EP0034 will provide continued availability of LCM to subjects who have completed SP0969, 
which is a Phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of LCM as adjunctive therapy in pediatric subjects with 
epilepsy ≥4 years to <17 years of age with partial-onset seizures. EP0034 will also be open to 
subjects who complete SP0967, which is the planned confirmatory study for LCM as adjunctive 
therapy in pediatric subjects with epilepsy aged ≥1 month to <4 years with partial-onset seizures.  
Dose selection in EP0034 is based on the primary studies (ie, SP0969 and SP0967). During 
EP0034, 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 600mg/day or 12mg/kg/day, whichever is lower based on body weight. 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form (ICF) is signed and dated by the subject or legal representative. The 
ICF or a specific Assent form, where required, will be signed and dated by minors. 
2. Subject has completed the Transition Period of SP0967 or SP0969 for the treatment of 
uncontrolled partial-onset seizures in pediatric epilepsy. 
3. Subject is expected to benefit from participation, in the opinion of the investigator. 
4. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries), visit schedule, and medication intake according 
to the judgment of the investigator. 
5. Subject is male or female aged 1 month to ≤17 years. 
6. Subject has a diagnosis of epilepsy with partial-onset seizures. 
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 a mandatory withdrawal criterion (ie, MUST withdraw criterion) for SP0967 
or SP0969, or is experiencing an ongoing serious AE (SAE). 
3. For subjects ≥6 years of age, 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 Visit 1. 
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5.  Female subject who is pregnant or nursing, and/or a female subject of childbearing potential 
who is not surgically sterile or does not practice 1 highly effective method of contraception 
(according to the International Council for Harmonisation [ICH] guidance defined as those 
that result in a failure rate <1% per year when used consistently and correctly), unless 
sexually abstinent, for the duration of the study. Female subject of childbearing potential 
taking enzyme-inducing antiepileptic drugs (EI-AEDs: carbamazepine, phenytoin, 
barbiturates, primidone, topiramate, oxcarbazepine) who is not surgically sterile or does not 
practice 1 highly effective method of contraception according to the World Health 
Organization recommendation (ie, depot medroxyprogesterone acetate, norethisterone 
enantate, intrauterine devices, combined injectables, and progestogen implants) with 
administration of EI-AEDs OR does not practice 2 combined methods of contraception (ie, 
combined hormonal contraception plus barrier method with spermicidal agent), unless 
sexually abstinent, for the duration of the study. 
6. Subject has >2x the upper limit of normal (ULN) of any of the following: ALT, AST, 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 enrolled subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, a 
Baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
6.3 
Withdrawal criteria 
Subjects are free to withdraw or the subject’s legal representatives are free to withdraw the 
subject from the study at any time, without prejudice to their continued care. 
Participation in this study must be discontinued for any of the following reasons: 
1. Subject experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the investigator, preclude further participation in the study.  
2. The sponsor or a regulatory agency requests withdrawal of the subject. 
3. Subject has a QTc interval ≥500ms that is confirmed by a cardiologist over read on any ECG. 
4. Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block. 
5. For subjects ≥6 years of age, subject has actual suicidal ideation since last visit as indicated 
by a positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study.  
6. Subject is unwilling or unable to continue or legal representative is unwilling or unable to 
allow the subject to continue in the study. 
7. Investigator decides that withdrawal from further participation would be in the subject’s best 
interest.  
9.  Female subject who achieves menarche during the study and does not practice contraception 
as provided in Exclusion Criteria 5 unless sexually abstinent. 
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10. Subject becomes pregnant, as evidenced by a positive pregnancy test. 
Participation in this study may be discontinued for any of the following reasons: 
1. Any clinically relevant change in medical or psychiatric condition (if, in the opinion of the 
investigator, the condition warrants discontinuation from the study). 
2. Subject requires a medication that is not permitted by the protocol (see Section 7.8.1). 
3. Subject and/or legal representative is noncompliant with study procedures or medication, in 
the opinion of the investigator.  
Subjects discontinuing LCM for any reason should taper off medication as described in 
Section 7.2.2. Whenever possible, these cases should be discussed with the Medical Monitor 
prior to withdrawing the subject from the study.  
Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. For subjects considered as lost to follow-up, the investigator should make an 
effort (at least 1 phone call and 1 written message to the subject and/or legal representative), 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. All subjects who withdraw from the study due to an 
AE must be followed until resolution of the event or until the event is considered stable. The 
eCRF must document the primary reason for withdrawal or discontinuation. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (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:  
• Subjects with either of the following: 
− ALT or AST ≥5xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of IMP: 
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator. 
• Subjects with ALT or AST ≥3xULN (and ≥2x Baseline), and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness) 
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Evaluation of PDILI must be initiated as described in Section 10.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
7 
STUDY TREATMENT(S) 
7.1 
Description of investigational medicinal product 
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 one side and “50” on the other. The 100mg 
tablets are dark yellow, oval, film-coated tablets debossed with “SP” on one side and “100” on 
the other.  
7.2 
Treatment(s) to be administered 
Lacosamide will be administered bid (at approximately 12-hour intervals, once in the morning 
and once in the evening) in divided doses. The oral solution formulation will be measured and 
administered via a dosing syringe. 
Oral administration is the preferred route in this study. Feeding tube administration is an 
alternative route in case a subject is unable to swallow the study medication. 
Each subject’s weight will be monitored at every visit, and the LCM dose will be adjusted 
accordingly. 
7.2.1 
Treatment Period 
After completion of the Transition Period in the primary study, all subjects will have been 
transitioned to a dose of LCM according to their weight. Subjects will receive 
LCM 10mg/kg/day (oral solution) for subjects weighing <30kg, LCM 6mg/kg/day (oral solution) 
for subjects weighing ≥30kg to <50kg, and LCM 300mg/day (tablets) for subjects weighing 
≥50kg during at least their first week in the Treatment Period of EP0034. After 1 week in 
EP0034, the investigator may adjust the LCM dose during the Treatment Period based on clinical 
judgment according to Table 7-1. If the investigator wants to adjust the LCM dosage after 
1 week in EP0034, the subject should return to the clinic for an Unscheduled Visit, at the 
discretion of the investigator. Subjects who are able and willing to swallow tablets may be 
dispensed LCM tablets during the Treatment Period, based on clinical judgment, regardless of 
weight. Lacosamide doses may be increased up to a maximum of LCM 600mg/day or 
12mg/kg/day, whichever is lower based on body weight. 
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Table 7-1: 
Minimum and maximum LCM dose during the Treatment Period 
Formulation 
Minimum LCM dose 
Maximum LCM dose 
Oral solution 
2mg/kg/day 
12mg/kg/day 
Tablets 
100mg/day 
600mg/day 
LCM=lacosamide 
Subjects may be allowed to switch from one formulation to the other formulation during the 
Treatment Period based on clinical judgment. Consideration of the current LCM milligram dose 
in the oral solution should occur if/when transitioning to the tablet formulation. In cases where 
the LCM dose received with the oral solution is not supported by the tablet strengths available in 
EP0034 (50mg and 100mg), a clinical decision must be made by the investigator or other study 
physician to either increase or decrease the LCM dose to the next multiple of 50mg with a 
maximum permitted dose of 600mg/day.  
7.2.2 
Taper Period 
Subjects who withdraw during the study should taper off LCM if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving LCM oral solution or LCM ≥150mg/day for 
subjects taking tablets. It is recommended that the dose be tapered gradually in weekly 
decrements (see Table 7-2 and Table 7-3). A slower taper is permitted, if medically necessary. In 
case of an emergency, a faster taper is permitted after discussion with the Medical Monitor, 
whenever possible.  
Table 7-2: 
Dose taper steps for subjects receiving oral solution 
LCM dose 
achieved 
LCM doses for the Taper Period 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
11 to 12mg/kg/day 
9mg/kg/day 
6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
– 
9 to 10mg/kg/day 
8mg/kg/day 
6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
– 
7 to 8mg/kg/day 
6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
– 
5 to 6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
– 
– 
3 to 4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
– 
– 
– 
LCM=lacosamide 
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Table 7-3: 
Dose taper steps for subjects taking tablets 
LCM dose 
achieved 
LCM doses for the Taper Period 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
>500 to 600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
– 
>400 to 500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
– 
>300 to 400mg/day 
300mg/day 
200mg/day 
100mg/day 
100mg/day 
– 
>200 to 300mg/day 
200mg/day 
100mg/day 
100mg/day 
– 
– 
≥150 to 200mg/day 
100mg/day 
100mg/day 
– 
– 
– 
LCM=lacosamide 
Taper of LCM may not be required for some subjects who complete the study or withdraw from 
the study prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or legal representative(s) or for subjects who participate in 
EP0151 or EP0152. 
7.2.3 
Alternative study treatment supply due to coronavirus disease 2019 
pandemic 
When a subject can no longer return to the study site due to general circumstances but will 
continue in the study, the following methods may be used to provide study treatment: 
• Site to subject: In instances where site staff can ship study treatment dispensed from the site 
pharmacy supply directly to the subject. 
• Depot to subject: In instances where it is not possible for the site staff to access study 
treatment in the site pharmacy and/or ship study treatment dispensed from the site pharmacy 
supply directly to the subject. 
7.3 
Packaging 
Lacosamide (tablets and oral solution) is manufactured, packaged, and labeled according to 
Good Manufacturing Practice (GMP) guidelines and applicable laws or regulations. The IMP is 
suitably packaged in such a way as to protect the IMP from deterioration during transport and 
storage. 
Lacosamide 10mg/mL oral solution will be packaged in amber polyethylene terephthalate bottles 
with a white, child-proof, polypropylene screw cap. The LCM dose will be measured and 
administered via a dosing syringe.  
Lacosamide tablets will be packaged in high-density polyethylene bottles with a child-proof, 
polypropylene screw cap. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current ICH guidelines on Good 
Clinical Practice (GCP) and GMP and will include any locally required statements. If necessary, 
labels will be translated into the local language. 
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7.5 
Handling and storage requirements 
Lacosamide is to be stored according to the instructions on the label. 
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 either by controlled room temperature or by 
completion of a temperature log in accordance with local requirements on a regular basis, 
showing minimum and maximum temperatures reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately communicated to the 
sponsor’s designee in accordance with the pharmacy 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 (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. 
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The investigator must ensure that the IMP is used only in accordance with the protocol. 
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. The IMP intended for the study cannot be used for any other 
purpose than that described in this protocol. 
7.7 
Procedures for monitoring subject compliance 
At each visit after IMP is dispensed, subjects must return all used, unused, and empty IMP 
containers. Drug accountability must be done 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 use will be confirmed at each visit and telephone contact. 
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7.8 
Concomitant medication(s)/treatment(s) 
7.8.1 
Permitted and prohibited concomitant treatments (medications and 
therapies) 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(ie, eCRF and source document). 
The following concomitant medications are prohibited during the study: 
• Clozapine 
• Monoamine oxidase-A inhibitors  
• Barbiturates (except as AEDs) 
• Cannabidiols (not approved or indicated for epilepsy by local health authority) 
− Long-term use of narcotic analgesics (the use of short-term [2 to 3 weeks] narcotic 
analgesics may be allowed for management of acute pain (eg, fractures or during the 
perioperative period for subjects requiring surgery). 
Neuroleptics (except for clozapine) are allowed during the study but the investigator should 
make every effort to keep the dose stable. 
The use of amphetamines and sedative antihistamines is allowed during the study. Also, low 
doses of anxiolytics or hypnotics are allowed for nonepilepsy indications.  
If needed to optimize tolerability and seizure reduction in selected subjects, concomitant AEDs 
may be carefully tapered and discontinued to achieve LCM monotherapy. New concomitant 
AEDs may be introduced as treatment if the medication has been approved by the regulatory 
authorities in the country in which the subject lives. New concomitant AEDs should be added 
only when the subject has not optimally or adequately responded to a maximum tolerated dose of 
LCM. 
Implantation of and changes in vagal nerve stimulation settings are permitted.  
The investigator must contact the Medical Monitor if surgery is planned for any subject. In 
general, it is not necessary to discontinue LCM for subjects undergoing surgery, although each 
case must be discussed on a case-by-case basis. The investigator must contact the Medical 
Monitor before re-starting LCM after a surgery. 
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 the frame of this study. The subject's participation in this study may be discontinued 
in such a case. 
7.9 
Blinding 
EP0034 is an open-label study; thus, there will be no blinding. 
7.10 
Randomization and numbering of subjects 
Subjects will not be randomized in this study. The same unique 5-digit identification number 
used in the primary study (ie, SP0967 or SP0969) will be used in EP0034. This subject number 
will be used to identify the subject throughout the study and to maintain subject confidentiality. 
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At study visits, an interactive voice/web response system (IXRS) will assign the applicable LCM 
bottle number. Further instructions will be provided in the IXRS manual. 
8 
STUDY PROCEDURES BY VISIT  
Detailed tabular schedules of study procedures are provided in Section 5.2.  
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone 
contacts after Visit 1 during the Treatment Period. On the mornings of the clinic visits, the 
subject should take the morning LCM dose at the usual time. 
At all visits and telephone contacts, subjects will be instructed to call the investigator if any 
intolerable and/or serious AEs occur before the next visit or contact. 
Subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 to 
30 minutes apart) conducted at LCM maximum plasma concentration (Cmax) 1 week after a LCM 
dose increase to ≥8mg/kg/day, after subsequent dose increases (ie, the first time a subject reaches 
a LCM dose of 8mg/kg/day, 9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day 
(ie, the first time a subject reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new 
concomitant AED is introduced during the study. This ECG can be conducted at an Unscheduled 
Visit (Section 8.5), if necessary. Subjects having a LCM dose increase to ≥8mg/kg/day or to 
≥400mg/day, or when a new concomitant AED is added will be required to arrive at the clinic 
prior to taking their morning dose of LCM. Subjects will be administered their morning LCM 
dose by study personnel at the clinic so that an ECG (2 interpretable recordings approximately 
20 to 30 minutes apart prior to any blood sample collection or vital signs assessment) can be 
performed 30 minutes to 1 hour after the administration of LCM.  
The PedsQL, the Achenbach CBCL, and the BRIEF-P and BRIEF will only be administered in 
countries where a validated translated version is available. The Bayley-III scales should be 
completed only for subjects enrolled in English-speaking countries. 
8.1 
Treatment Period 
8.1.1 
Visit 1 (Week 0) 
For subjects completing the Transition Period of the primary studies and choosing to enroll in 
EP0034, the final Transition Visit (Transition Visit 4 in SP0969 and Final Transition Visit in 
SP0967) will serve as Visit 1 of EP0034. At Visit 1 (Week 0), prior to the conduct of any 
study-related procedures, a complete explanation (both verbal and written) of the nature and 
purpose of the study will be given to the subject (when possible or as required according to local 
IRBs/IECs) and the subject’s legal representative(s) by the investigator (or designee). The 
subject’s parent/legal guardian will be requested to sign and date the IRB/IEC-approved ICF. 
When possible, or as required by the local IRB/IEC, the subject will be requested to give assent 
to participate in the study. 
The subject’s eligibility for the study will be determined at Visit 1 on the basis of the 
inclusion/exclusion criteria, signature of an ICF prior to any study-related procedures or 
evaluations, and the results of the assessments listed below (for further details of the assessments 
and the required procedures and methods, please refer to Section 9 and Section 10 of this 
protocol).  
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At Visit 1 (Week 0), all subjects will have been transitioned to a dose of LCM according to their 
weight and will receive a dose of LCM 10mg/kg/day (oral solution) for subjects weighing 
<30kg, LCM 6mg/kg/day (oral solution) for subjects weighing ≥30kg to <50kg, and 
LCM 300mg/day (tablets) for subjects weighing ≥50kg during at least their first week in the 
Treatment Period of EP0034. After 1 week in EP0034, the investigator may adjust the LCM dose 
according to Table 7-1. During the Treatment Period, subjects may take either oral solution or 
tablets, based on clinical judgment, regardless of their weight. 
During Visit 1 (Week 0), the following assessments will be performed (assessments marked [T] 
may have already been completed during the final Transition Visit of the primary study and 
should not be repeated at Visit 1 of EP0034; assessments marked [M] may have already been 
completed during the final Maintenance Visit of the primary study and should not be repeated at 
Visit 1 of EP0034):  
• Medical history update 
• Concomitant medications assessment (T) 
• Concomitant AEDs assessment (T) 
• VNS assessments (T) (if applicable) 
• Physical examination (complete) (T) 
• Tanner Stage (M) (only for subjects who are pubescent at Visit 1 or who enter puberty during 
the course of the study) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects (T) 
• Body weight and height assessments (T) 
• Head circumference (M) 
• Neurological examination (complete) (T) 
• 12-lead ECG (M) (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
• Blood sample for clinical chemistry and hematology (T) 
• Blood sample for endocrinology (M) 
• Urine sample for urinalysis (T) (for subjects aged ≥5 years) (urine assessments will be based 
on the subject’s ability to void and staff’s ability to collect urine [in an appropriate 
container]) 
• Urine pregnancy test (T) (for female subjects of childbearing potential) 
• C-SSRS (T) (for all subjects ≥6 years of age, the “Since Last Visit” version should be 
completed; if a subject becomes 6 years of age during the study, the “Already Enrolled” 
version should be used at the first visit at which the subject is 6 years of age and the “Since 
Last Visit” version at subsequent visits) 
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• Achenbach CBCL (M) (the CBCL/1½-5 for children from 1.5 to 5 years old and the 
CBCL/6-18 for children 6 years and older; however, the version used in the primary study 
must be used for 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.7) 
• Bayley-III scales (T) (in subjects <18 months of age at study entry; the same scale should be 
completed for 1 year after the Baseline assessment of the primary study, even if the subject 
turns >18 months of age during that period) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) assessment (M) (version 
consistent with age at the visit; however, the version used in the primary study must be used 
for at least 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.8)  
• PedsQL assessment (M) (form consistent with age at the visit; however, the form used in the 
primary study must be used for at least 1 year after the Baseline assessment of the primary 
study, as described in Section 9.3) 
• Contact IXRS 
• Review LCM return and compliance (T) 
• Dispense LCM  
• Reminder to complete subject diary on a daily basis (T) 
• Adverse event reporting (T) (ongoing AEs from the primary study will be followed, as well 
as recording of new AEs during the current study)  
• Health care resource use (T) 
A telephone contact will be made approximately 2 weeks after Visit 1 (end of Week 2, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 4 weeks after Visit 1. If the investigator wants to adjust the LCM dosage after 
1 week in EP0034, the subject should return to the clinic for an Unscheduled Visit, at the 
discretion of the investigator. 
8.1.2 
Telephone contact (Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 66, and 78) 
At the end of Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 66, and 78, between scheduled visits, the 
investigator or designee should contact the subject and/or caregiver (including legal 
representative) by telephone (a time window of ±7 days relative to Visit 1 is allowed). The 
investigator (or designee) should remind the subject and caregiver (including legal 
representative) to bring used and unused LCM to the next clinic visit. The following should be 
performed via telephone: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
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If an AE necessitates the subject’s withdrawal from the study, the subject should return for an 
Early Termination Visit (Section 8.1.13) as soon as possible. 
Lacosamide is supplied so that the subject or caregiver (including legal representative) can 
immediately decrease their dose, if needed, in consultation over the telephone with the 
investigator or subinvestigator. Thus, LCM can be continued at a decreased dose until a clinic 
visit can be scheduled. 
8.1.3 
Visit 2 (Week 4) 
At Visit 2 (end of Week 4 ±7 days relative to Visit 1), subjects will return for a clinic visit and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Neurological examination (brief) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to vital signs assessment and, if possible, after the subject has been in a 
supine position for approximately 5 minutes preceding the ECG recording) 
• Urine pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
A telephone contact will be made approximately 2 weeks after Visit 2 (end of Week 6, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 4 weeks.  
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8.1.4 
Visit 3 (Week 8) and Visit 4 (Week 12) 
Subjects will return to the clinic at Visit 3 (end of Week 8 ±7 days relative to Visit 1) and Visit 4 
(end of Week 12 ±7 days relative to Visit 1), and the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
• Body weight and height assessments 
• Neurological examination (brief) 
• Urine pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
A telephone contact will be made approximately 2 weeks after Visit 3 and approximately 
4 weeks after Visit 4 (end of Weeks 10 and 16, Section 8.1.2). Subjects will be scheduled to 
return to the clinic for the next visit approximately 8 weeks after Visit 4. 
8.1.5 
Visit 5 (Week 20) 
At Visit 5 (end of Week 20 ±7 days relative to Visit 1), subjects will return for a clinic visit and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (complete) 
• Tanner Stage (only for subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study) 
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• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
• Body weight and height assessments 
• Head circumference  
• Neurological examination (complete) 
• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (subjects aged ≥5 years) (urine assessments will be based on the 
subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Clinical Global Impression of Change assessment 
• Caregiver’s Global Impression of Change assessment 
• Achenbach CBCL (the CBCL/1½-5 for children from 1.5 to 5 years old and the CBCL/6-18 
for children 6 years and older; however, the version used in the primary study must be used 
for 1 year after the Baseline assessment of the primary study, as described in Section 10.8.7) 
• Bayley-III scales (in subjects <18 months of age at study entry; the same scale should be 
completed for 1 year after the Baseline assessment of the primary study, even if the subject 
turns >18 months of age during that period) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) assessment (version 
consistent with age at the visit; however, the version used in the primary study must be used 
for at least 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.8)  
• PedsQL assessment (form consistent with age at the visit; however, the form used in the 
primary study must be used for at least 1 year after the Baseline assessment of the primary 
study, as described in Section 9.3) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
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A telephone contact will be made in approximately 4 weeks (end of Week 24, Section 8.1.2). 
Subjects will be scheduled to return to the clinic for the next visit in approximately 8 weeks.  
8.1.6 
Visit 6 (Week 28) 
At Visit 6 (end of Week 28 ±7 days relative to Visit 1), subjects will return for a clinic visit and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
• Body weight and height assessments 
• Neurological examination (brief) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to vital signs assessment and, if possible, after the subject has been in a 
supine position for approximately 5 minutes preceding the ECG recording) 
• Urine pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
A telephone contact will be made approximately 4 weeks after Visit 6 (end of Week 32, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 8 weeks. 
8.1.7 
Visit 7 (Week 36) and Visit 8 (Week 44) 
Subjects will return to the clinic at Visit 7 (end of Week 36 ±7 days relative to Visit 1) and 
Visit 8 (end of Week 44 ±7 days relative to Visit 1), and the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
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• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Neurological examination (brief) 
• Urine pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
A telephone contact will be made approximately 4 weeks after Visit 7 (end of Week 40) and 
approximately 4 weeks after Visit 8 (end of Week 48, Section 8.1.2). Subjects will be scheduled 
to return to the clinic for the next visit approximately 8 weeks after Visit 8. 
8.1.8 
Visit 9 (Week 52) 
At Visit 9 (end of Week 52 ±7 days relative to Visit 1), subjects will return for a clinic visit and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (complete) 
• Tanner Stage (only for subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
• Body weight and height assessments 
• Head circumference 
• Neurological examination (complete) 
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• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (for subjects aged ≥5 years) (urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Clinical Global Impression of Change assessment 
• Caregiver’s Global Impression of Change assessment 
• Achenbach CBCL (the CBCL/1½-5 for children from 1.5 to 5 years old and the CBCL/6-18 
for children 6 years and older; however, the version used in the primary study must be used 
for at least 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.7) 
• Bayley-III scales (in subjects <18 months of age at study entry; the same scale should be 
completed for 1 year after the Baseline assessment of the primary study, even if the subject 
turns >18 months of age during that period) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) assessment (version 
consistent with age at the visit; however, the version used in the primary study must be used 
for at least 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.8)  
• PedsQL assessment (form consistent with age at the visit; however, the form used in the 
primary study must be used for at least 1 year after the Baseline assessment of the primary 
study, as described in Section 9.3) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
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A telephone contact will be made approximately 4 weeks after Visit 9 (end of Week 56, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 8 weeks. 
8.1.9 
Visit 10 (Week 60) 
At Visit 10 (end of Week 60 ±7 days relative to Visit 1), subjects will return for a clinic visit and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Neurological examination (brief) 
• Urine pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
A telephone contact will be made approximately 6 weeks after Visit 10 (end of Week 66, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 12 weeks. 
8.1.10 
Visit 11 (Week 72) 
At Visit 11 (end of Week 72 ±7 days relative to Visit 1), subjects will return for a clinic visit and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
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• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
• Body weight and height assessments 
• Head circumference 
• Neurological examination (brief) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (for subjects aged ≥5 years) (urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Clinical Global Impression of Change assessment 
• Caregiver’s Global Impression of Change assessment 
• Achenbach CBCL (the CBCL/1½-5 for children from 1.5 to 5 years old and the CBCL/6-18 
for children 6 years and older) 
• Bayley-III scales (in subjects <18 months of age) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) assessment (version 
consistent with age at the visit)  
• PedsQL assessment (form consistent with age at the visit) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
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A telephone contact will be made approximately 6 weeks after Visit 11 (end of Week 78, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 12 weeks. 
8.1.11 
Visit 12 (Week 84) 
At Visit 12 (end of Week 84 ±7 days relative to Visit 1), subjects will return for a clinic visit, and 
the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Neurological examination (brief) 
• Urine pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Contact IXRS 
• Review LCM return and compliance 
• Dispense LCM (the investigator may adjust the LCM dose according to Table 7-1) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
• Health care resource use 
Subjects will be scheduled to return to the clinic for the Termination Visit in approximately 
12 weeks. 
8.1.12 
Visit 13/Termination Visit (Week 96) 
Visit 13 (end of Week 96 ±7 days relative to Visit 1) will be the treatment Termination Visit for 
subjects who complete up to 2 years of treatment. Subjects who prematurely discontinue the 
study must return for an Early Termination Visit as soon as possible (Section 8.1.13). 
At Visit 13/Termination Visit, the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
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• VNS assessment (if applicable) 
• Physical examination (complete) 
• Tanner Stage (only for subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Head circumference 
• Neurological examination (complete) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (for subjects aged ≥5 years) (urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Clinical Global Impression of Change assessment 
• Caregiver’s Global Impression of Change assessment 
• Achenbach CBCL (the CBCL/1½-5 for children from 1.5 to 5 years old and the CBCL/6-18 
for children 6 years and older) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) assessment (version 
consistent with age at the visit)  
• PedsQL assessment (form consistent with age at the visit) 
• Contact IXRS (only if LCM will be dispensed for taper, as described below) 
• Review LCM return and compliance 
• Dispense LCM (if applicable for taper, as described below) 
• Reminder to complete subject diary on a daily basis  
• Adverse event reporting  
• Health care resource use 
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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 legal representative(s). These 
subjects should complete Visit 13/Termination Visit and then complete the Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit 
is not required for subjects who complete the study and who do not undergo taper of LCM. The 
Safety Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required for 
subjects who participate in EP0151 or EP0152. 
Subjects who complete the study and discontinue use of LCM (as determined by the investigator 
in consultation with the subject and/or legal representative) should enter the Taper Period after 
the Visit 13/Termination Visit and taper LCM gradually as described in Section 7.2.2. A Taper 
Visit will be performed at the end of the Taper Period, followed by the Safety Follow-Up Visit 
that occurs 2 weeks (±2 days) after the final dose of LCM, and then the Safety Follow-Up 
Telephone Contact that occurs 30 days (-1/+3 days) after the final dose of LCM. 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of 
LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking 
tablets (Section 7.2.2). It is recommended that the dose be tapered gradually in weekly 
decrements. A slower taper is permitted, if medically necessary. In case of an emergency, a 
faster taper is permitted after discussion with the Medical Monitor, whenever possible.  
8.1.13 
Early Termination Visit 
Subjects who prematurely discontinue from the study must complete an Early Termination Visit 
as soon as possible. 
The following will be performed at the Early Termination Visit: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (complete) 
• Tanner Stage (only for subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
• Body weight and height assessments 
• Head circumference 
• Neurological examination (complete) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
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• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (for subjects aged ≥5 years) (urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Clinical Global Impression of Change assessment 
• Caregiver’s Global Impression of Change assessment 
• Achenbach CBCL (the CBCL/1½-5 for children from 1.5 to 5 years old and the CBCL/6-18 
for children 6 years and older; however, the version used in the primary study must be used 
for at least 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.7) 
• Bayley-III scales (in subjects <18 months of age at study entry; the same scale should be 
completed for 1 year after the Baseline assessment of the primary study, even if the subject 
turns >18 months of age during that period) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) assessment (version 
consistent with age at the visit; however, the version used in the primary study must be used 
for at least 1 year after the Baseline assessment of the primary study, as described in 
Section 10.8.8)  
• PedsQL assessment (form consistent with age at the visit; however, the form used in the 
primary study must be used for at least 1 year after the Baseline assessment of the primary 
study, as described in Section 9.3) 
• Contact IXRS (only if LCM will be dispensed for taper, as described below) 
• Review LCM return and compliance 
• Dispense LCM (if applicable for taper, as described below) 
• Reminder to complete subject diary on a daily basis  
• Adverse event reporting  
• Health care resource use 
At the time of withdrawal from 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 withdraw from the study prematurely, depending on 
the treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s). These subjects should complete the Early Termination Visit and then complete 
the Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM, followed by the 
Safety Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. 
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Subjects who withdraw from the study prematurely and discontinue use of LCM (as determined 
by the investigator in consultation with the subject and/or legal representative) should taper LCM 
gradually as described in Section 7.2.2. These subjects should complete the Early Termination 
Visit and enter the Taper Period. A Taper Visit will be performed at the end of the Taper Period, 
followed by the Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM, and then 
the Safety Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of 
LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking 
tablets (Section 7.2.2). It is recommended that the dose be tapered gradually in weekly 
decrements. A slower taper is permitted, if medically necessary. In case of an emergency, a 
faster taper is permitted after discussion with the Medical Monitor, whenever possible. 
8.2 
Taper Period 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from the study prematurely, if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. Taper of LCM may not be required for some 
subjects who complete the study or withdraw from the study prematurely, depending on the 
treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s) or for subjects entering EP0151 or EP0152. 
During the Taper Visit, the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (brief) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Neurological examination (brief) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (for subjects aged ≥5 years) (urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
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• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Review LCM return and compliance 
• Reminder to complete subject diary on a daily basis  
• Adverse event reporting  
• Health care resource use 
Subjects will be scheduled to return to the clinic for the Safety Follow-Up Visit 2 weeks 
(±2 days) after the final dose of LCM. 
8.3 
Safety Follow-Up Visit 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM, should complete the Safety Follow-Up Visit 2 weeks (±2 days) after the final dose 
of LCM (including that from LCM taper). The Safety Follow-Up Visit is not required for 
subjects who complete the study or withdraw prematurely from the study but do not undergo 
taper of LCM. The Safety Follow-Up Visit is not required for subjects who participate in EP0151 
or EP0152. 
During the Safety Follow-Up Visit, the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Physical examination (complete) 
• Tanner Stage (only for subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects 
• Body weight and height assessments 
• Neurological examination (complete) 
• 12-lead ECG (2 interpretable recordings, approximately 20 to 30 minutes apart, to be 
performed prior to any blood draws and vital signs assessment and, if possible, after the 
subject has been in a supine position for approximately 5 minutes preceding the ECG 
recording) 
• Blood sample for clinical chemistry and hematology  
• Blood sample for endocrinology 
• Urine sample for urinalysis (for subjects aged ≥5 years) ( urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
• Serum pregnancy test (for female subjects of childbearing potential) 
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• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
• Subject diary return (for subjects who enter the Safety Follow-Up Period, the subject diary 
will be returned at the Safety Follow-Up Visit, and subjects who do not enter the Safety 
Follow-Up Period will return the diary at Visit 13/Termination Visit) 
• Adverse event reporting  
• Health care resource use 
8.4 
Safety Follow-Up Telephone Contact 
Safety Follow-Up Telephone Contact is required for all subjects (those who complete the study 
as planned or have withdrawn prematurely from the study). This telephone contact will occur 
30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Telephone Contact is 
not required for subjects who participate in EP0151 or EP0152. 
The following should be performed via telephone: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Adverse event reporting (if an AE is reported at this telephone contact, the investigator will 
follow the AE 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 [Section 10.1.4]). 
8.5 
Unscheduled Visit 
An Unscheduled Visit may be performed at the investigator’s discretion. 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 
to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, 
after subsequent dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 
9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first time a subject 
reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new concomitant AED is 
introduced during the study. This ECG can be conducted at an Unscheduled Visit, if necessary. 
Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new 
concomitant AED is added, will be required to arrive at the clinic prior to taking their morning 
dose of LCM. Subjects will be administered their morning LCM dose by study personnel at the 
clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment) can be performed 30 minutes to 1 hour after the administration of LCM. 
If an Unscheduled Visit is needed, then the following assessments will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• VNS assessment (if applicable) 
• Blood pressure and pulse rate, including orthostatic assessments in ambulatory subjects  
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• Body weight assessment 
• C-SSRS (only if the Unscheduled Visit is due to safety or efficacy reasons; for subjects 
≥6 years of age, the “Since Last Visit” version should be completed; if a subject becomes 
6 years of age during the study, the “Already Enrolled” version should be used at the first 
visit at which the subject is 6 years of age and the “Since Last Visit” version at subsequent 
visits) 
• Reminder to complete subject diary on a daily basis  
• Review withdrawal criteria 
• Adverse event reporting  
Additional assessments can be performed at the investigator’s discretion. 
8.6 
Study conduct due to coronavirus disease 2019 pandemic 
The protocol-mandated visit schedule should be followed to the extent possible, considering the 
individual benefit-risk assessment by the investigator. If necessary, remote visits may be 
conducted, and the subjects or caregivers will be contacted by telephone or videoconference. 
Remote follow up, at minimum with a telephone call after 3 months, must be done (preferably 
more frequently and as needed to follow up on subject safety assessments).  
Ad hoc subject contact may be warranted  to understand the current health status of the subjects, 
to follow up on AEs, and inform them of any protective measures taken by the clinical site as a 
result of the coronavirus disease 2019 (COVID-19) pandemic (eg, any measures that may limit 
access to the site or may require additional actions by the subject prior to entry to the site). 
If a subject needs to be discontinued and cannot come into the clinic, then appropriate tapering 
instructions will be provided, and a visit will be scheduled to perform safety assessments as soon 
as possible. 
In situations where a subject is unable to return to the study site, investigators will assess and 
document the subject’s safety via telephone contact. Based on information gathered from the 
telephone contact, investigators will confirm whether the subject could continue the current 
study treatment based upon the outcome of the safety assessments. Subjects’ agreement to 
implement this procedure should be obtained and documented prior to implementing any 
changes. Changes in the study treatment supply in this situation are described in Section 7.2.3.  
If a subject visits another facility for a medical issue (or has to switch sites for a COVID-19-
related reason), the investigator should request contact with the physician providing care to 
provide a detailed explanation of the subject’s condition and his/her participation in the clinical 
study. Subjects or caregivers shall be reminded to completely collect and keep records of this 
visit.  
Deviations to data collection including inability to perform some assessments, such as ECG, 
blood collection for safety laboratory assessments and PK, or alternative methods of assessment, 
such as phone calls, should be recorded in the source documentation and notated as “not done” in 
the eCRF. 
In cases where subjects cannot return to the clinic, and it will not be possible to dispense a new 
seizure diary, subjects will be instructed to continue recording of seizures in a manner that is 
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mutually agreed with the investigator (eg, hand-written notes, recording on a smart device). Any 
recording of seizures in a manner outside of the study seizure diary must be carefully 
documented in the source medical records (copies/print-screen printouts of these recordings will 
be brought to and retained at the site). 
9 
ASSESSMENT OF EFFICACY 
9.1 
Seizure frequency 
Efficacy variables based on seizures will be measured using data obtained from subject diaries. If 
an electronic diary was used in the primary study, the subject will continue to use the same diary 
in EP0034; otherwise, a new diary will be dispensed at admission to EP0034. Subjects or their 
caregivers will keep a diary to record the daily seizure activity from the beginning of the 
Treatment Period (Visit 1) until the last study visit, recording both seizure type and seizure 
frequency. The seizure records will be checked by the investigator with regards to correct and 
thorough daily completion by the subject, and to determine if a dose adjustment is required. At 
each visit and telephone contact subject and/or legal representative should be reminded to 
complete subject diaries on a daily basis. 
9.2 
Global Impression of Change 
The Clinical and Caregiver’s Global Impression of Change will be administered according to the 
tabular schedules of study procedures (Section 5.2). 
The Clinical Global Impression of Change is a 7-point categorical rating scale in which the 
investigator assesses the subject’s change from Baseline in clinical status, including an 
evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional 
status. 
The Caregiver’s Global Impression of Change is a 7-point categorical rating scale in which the 
caregiver assesses the subject’s change from Baseline in clinical status, including an evaluation 
of seizure frequency and intensity, the occurrence of AEs, and subject’s functional status. 
9.3 
PedsQL 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions (Varni et al, 2001). 
The PedsQL will be administered according to the tabular schedules of study procedures 
(Section 5.2). The PedsQL will only be administered in countries where a validated translated 
version is available. 
The PedsQL measurement model consists of developmentally appropriate forms for pediatric 
subjects 1 month to 12 months, 13 months to 24 months, 2 years to 4 years, 5 years to 7 years, 8 
years to 12 years, and 13 years to 18 years of age. 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 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. 
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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. 
9.4 
Health care resource use 
For health care resource use, the following will be evaluated: concomitant medications, medical 
procedures, and health care provider consultations including hospitalizations not foreseen by the 
protocol. 
10 
ASSESSMENT OF SAFETY 
10.1 
Adverse events 
10.1.1 
Definition of adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), 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. For results disclosure, only TEAEs are 
applicable.  
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. 
10.1.2 
Procedures for reporting and recording adverse events 
The subject or subject’s parent(s)/caregiver(s)/legal representative(s) will be given the 
opportunity to report AEs spontaneously. A general prompt will also be given at each study visit 
to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
10.1.3 
Description of adverse events 
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
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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 Adverse Event eCRF (including judgment of relationship to study 
drug) are described in the eCRF Completion Guidelines. 
10.1.4 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the subject is lost to follow up.  
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
investigator must provide a justification. The follow up will usually be continued for 30 days 
after the subject has discontinued his/her IMP. 
10.1.5 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
10.1.6 
Pregnancy 
Should a subject become pregnant after the first intake of any IMP, UCB’s Drug Safety 
department should be informed immediately. The subject should be withdrawn from the study as 
soon as pregnancy is known, and the following should be completed: 
• The subject should return for an Early Termination Visit. 
• The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the Early Termination Visit.  
• A Safety Follow-Up Visit should be scheduled 2 weeks (±2 days) after the subject has 
discontinued IMP. 
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, UCB 
will ask the investigator or designee to contact the subject and his partner to request consent via 
the Partner Pregnancy Consent form. If the partner agrees to provide additional information, the 
Pregnancy Report and Outcome form will be forwarded to the subject’s partner for completion. 
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed-up using the Pregnancy Report and Outcome form in which the investigator has to 
report on the health of the mother and of the child. The health of the child must be followed for 
30 days after birth for any significant medical issues. 
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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. 
10.1.7 
Overdose of IMP 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the Drug Accountability or Study Drug Dosing module of the eCRF. Any SAE or 
nonserious AE associated with excessive dosing must be followed as any other SAE or 
nonserious AE. These events are 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). 
10.1.8 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Drug Safety 
representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study. 
10.1.9 
Occurrence of COVID-19 
Occurrence of COVID-19 in subjects should be reported as either “suspected COVID-19” or 
“confirmed COVID-19” along with all available relevant data including diagnostic and 
laboratory data. For subjects where COVID-19 is still suspected despite a negative viral test, 
please report as “suspected COVID-19” and provide relevant data to support the diagnosis as 
well as the test results. 
10.2 
Serious adverse events 
10.2.1 
Definition of serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
• Death 
• Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
• Significant or persistent disability/incapacity 
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• 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 10.3], 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 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.) 
10.2.2 
Procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database. 
An Investigator SAE report form will be provided to the investigator. The Investigator SAE 
report form must be completed in English.  
It is important for the investigator, when completing the SAE report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information (eg, autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
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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. 
10.2.3 
Follow up of serious adverse events 
An SAE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up.  
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time. 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 10.6.1. 
10.3 
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 
(<45beats/min) 
• Syncope or loss of consciousness (other than seizure-related) 
• Serious suspected multiorgan hypersensitivity reactions 
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the US Food and 
Drug Administration: 
− An AE or laboratory value (as defined in the following text) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system involvement) 
combined with at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
◦ 
Eosinophils % ≥10% 
◦ 
Eosinophils absolute ≥0.5G/L 
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◦ 
Neutrophils absolute <1.5G/L 
◦ 
Platelets ≤100G/L 
◦ 
ALT ≥2×ULN 
◦ 
AST ≥2×ULN 
• 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. 
10.4 
Immediate reporting of adverse events 
The following AEs must be reported immediately: 
• SAE: AE that the investigator classifies as serious by the above definitions regardless of 
causality 
• Suspected transmission of an infectious agent via a medicinal product 
• AE of special interest (see Section 10.3) 
10.5 
Anticipated serious adverse events 
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure. This original list will remain in effect for the duration of the protocol. 
This list does not change the investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 10.2.2. 
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Table 10‒1: Anticipated SAEs for the pediatric epilepsy population 
MedDRA SOC 
MedDRA PT 
Congenital, familial and genetic disorders 
Teratogenicity 
General disorders and administration site conditions 
Sudden unexplained death in epilepsy 
Nervous system disorders 
Convulsion 
 
Incontinence 
 
Status epilepticus 
Pregnancy, puerperium and perinatal disorders 
Abortion spontaneous 
Psychiatric disorders 
Psychotic behaviour 
 
Abnormal behaviour 
 
Anxiety 
 
Sleep disorder 
Reproductive system and breast disorders 
Menstrual disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SOC=system organ class; 
SAE=serious adverse event 
10.6 
Laboratory measurements 
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis testing will be collected according to the tabular schedules of study procedures 
(Section 5.2). Urine assessments will be performed for subjects aged ≥5 years. For subjects aged 
≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to 
collect urine (in an appropriate container). A central laboratory will perform the routine analysis 
of blood and urine specimens. Pregnancy testing will also be performed (see Section 10.7). The 
procedures for handling and shipping these specimens will be provided to the sites. In 
exceptional circumstances, local laboratory analysis may be performed. The medical monitor 
should be contacted beforehand to discuss these circumstances. 
The following laboratory parameters will be measured: 
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Table 10‒2: Laboratory measurements 
Hematology 
Chemistry 
Endocrinology 
Urinalysisa 
Hematocrit 
Calcium 
FSH 
pH 
Hemoglobin 
Phosphorus 
LH 
Ketones 
Platelet count 
Serum electrolytes 
(sodium, potassium, 
chloride, bicarbonate) 
Testosterone 
Glucose 
RBC count 
Creatinine 
TSH 
Albumin 
WBC count 
BUN 
T3 (total and serum free) Specific gravity 
Differential count 
AST 
T4 (total and serum free) Microscopic exam for 
blood cells or casts/hpf 
 
ALT 
 
 
 
Total bilirubin 
 
 
 
Alkaline phosphatase 
 
 
 
GGT 
 
 
 
Glucose 
 
 
 
Albumin 
 
 
 
Total serum protein 
 
 
 
Uric acid 
 
 
 
Total cholesterol 
 
 
 
Triglycerides 
 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle 
stimulating hormone; GGT=gamma-glutamyltransferase; hpf=high power field; LH=luteinizing hormone; RBC=red 
blood cells; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; WBC=white blood cell 
a Urinalysis will be performed for subjects ≥5 years of age only. 
 
10.6.1 
Liver function tests and evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 10.6.1.2, 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 10.3), and, if applicable, also reported as an 
SAE (see Section 10.2).  
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 10.6.1.1). The local 
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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 10.6.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
Table 10‒3 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 10.6.1.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within Baseline 
values.d 
 
≥5xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
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 10.6.1.2). 
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 10.6.1.3). 
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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Table 10‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
.c Details provided in Section 10.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed 
 
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10.6.1.1 
Consultation with Medical Monitor and local hepatologist 
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 10.6.1.3) and SAE report (if applicable). 
10.6.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 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. 
10.6.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 10‒4 (laboratory measurements) and Table 10‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
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 
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Table 10‒4: PDILI laboratory measurements 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
WBC count 
Differential count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
Bilirubin (If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin) 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
AST 
ALT 
ALP 
GGT 
Albumin 
Additional 
Prothrombin time/INRa 
Serum pregnancy test in women of childbearing potential  
PK sample 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine 
phosphokinase; GGT=gamma-glutamyltransferase; HBcAb-IgM=hepatitis B core antibody-IgM; HBsAg=hepatitis 
B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate dehydrogenase; 
PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RBC=red blood cell; RNA=ribonucleic acid; 
ULN=upper limit of normal; WBC=white blood cell 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
The following additional information is to be collected: 
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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 
10.6.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 10‒3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to Baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
10.7 
Pregnancy testing 
Females of childbearing potential will have serum and urine pregnancy tests performed during 
the study according to the tabular schedules of study assessments (Section 5.2). 
10.8 
Other safety measurements 
10.8.1 
Physical examination 
Physical examinations will be performed according to the tabular schedules of study procedures 
(Section 5.2) by a medically qualified clinician licensed to perform the examination. Clinically 
significant physical examination findings are to be reported as AEs. 
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10.8.1.1 
Complete physical examination 
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems. Genitourinary and breast 
examinations will be performed for the assessment of Tanner Stage only. 
10.8.1.2 
Brief physical examination 
The brief physical examination will include review of the following body systems:  
• Cardiovascular 
• Pulmonary 
• Abdominal (hepato-gastrointestinal) 
• Dermatologic 
10.8.2 
Neurological examination 
Neurological examinations will be performed according to the tabular schedules of study 
procedures (Section 5.2) by a medically qualified clinician with documented training in the 
conduct of neurological examinations. If possible, the same clinician should conduct all 
neurological examinations for the same subject during the study. The investigator or 
subinvestigator is responsible for confirming the diagnosis of partial-onset seizures. 
10.8.2.1 
Complete neurological examination  
The complete neurological examination will include selected assessment of general neurological 
status (level of consciousness, mental status, speech), cranial nerves, reflexes, motor system 
(general motor status, muscle strength, muscle tone), coordination/cerebellar function, and 
sensation.  
The head circumference will be measured according to the tabular schedules of study procedures 
(Section 5.2).  
10.8.2.2 
Brief neurological examination 
The brief neurological examination will include selected assessment of general neurological 
status (level of consciousness, mental status, speech), reflexes, muscle strength, and 
coordination/cerebellar function. 
10.8.3 
Tanner Stage 
The investigator or qualified designee will evaluate the subject’s sexual development using the 
3-item Tanner scale, according to the tabular schedules of study procedures (Section 5.2). The 
investigator should use clinical judgment in deciding which subjects are selected for evaluation 
of Tanner Stage (ie, those subjects who are pubescent at Visit 1 or who enter puberty during the 
course of the study).  
10.8.4 
12-lead ECG 
Standard 12-lead ECGs will be performed according to the tabular schedules of study 
assessments (Section 5.2). Two interpretable recordings should be made approximately 20 to 
30 minutes apart. Care should be taken to ensure proper lead placement and quality ECG 
recordings. The ECGs will be performed prior to any blood draws and vital signs assessment. 
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Subjects should rest in a supine position approximately 5 minutes prior to each recording and 
during the recording.  
All subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 
to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, 
after subsequent dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 
9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first time a subject 
reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new concomitant AED is 
introduced during the study. This ECG can be conducted at an Unscheduled Visit, if necessary. 
Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new 
concomitant AED is added will be required to arrive at the clinic prior to taking their morning 
dose of LCM. Subjects will be administered their morning LCM dose by study personnel at the 
clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
any blood sample collection or vital signs assessment) can be performed 30 minutes to 1 hour 
after the administration of LCM. 
10.8.4.1 
Overall ECG interpretation 
Electrocardiograms will be reviewed locally by the investigator, subinvestigator, or qualified 
designated reader and at a central ECG laboratory. If the reading identifies second or third degree 
AV block 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. 
10.8.5 
Vital signs, body weight, and height 
Noninvasive blood pressure (systolic and diastolic) and pulse rate will be measured at clinic 
visits after at least 3 minutes at rest in a supine position, according to the tabular schedules of 
study procedures (Section 5.2). Assessment of orthostatic changes (only in ambulatory subjects) 
will be as follows: after the 3-minute measurement with the subject in a supine position, the 
subject will be asked to stand up, and blood pressure and pulse rate will be taken 1 minute and 
3 minutes after standing up, as feasible. 
Body weight will be determined without shoes and wearing light clothing, and height will be 
measured without shoes. Body weight and height will be assessed according to the tabular 
schedules of study procedures (Section 5.2). 
10.8.6 
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 subject’s eligibility for the study as well as to 
assess suicidal ideation and behavior that may occur during the study.  
The C-SSRS will be completed according to the tabular schedules of study procedures 
(Section 5.2). This scale will be completed for subjects ≥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 
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“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 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. Parents and caregivers should also be advised accordingly and 
effort should be made at clinic visits to specifically assess potential depression. 
10.8.7 
Achenbach CBCL 
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. Behavioral problems will be scored by the 
parent(s)/legal representative(s).  
Depending on the subject’s age, 2 versions of the Achenbach CBCL will be used. The 
CBCL/1½-5 checklist is intended for use in children 18 months to 5 years and 11 months of age 
(Achenbach and Rescorla, 2000). For subjects ≥6 years to <17 years of age, the CBCL/6-18 
version will be used (Achenbach and Rescorla, 2001). 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. 
The Achenbach CBCL will be completed according to the tabular schedules of study procedures 
(Section 5.2). The completion of the Achenbach CBCL will require approximately 45 minutes.  
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
• 0=not true (as far as known) 
• 1=somewhat or sometimes true 
• 2=very true or often true 
Eight syndrome scores will be calculated from these questions, which will in turn be summarized 
by 2 composite scores. Additionally, for each score on the question, syndrome, and total level, 
categorizations based on a normative sample will be used to evaluate normal, borderline, or 
clinically relevant behavior. 
In addition, the CBCL/6-18 includes ratings related to performance in school, activities in leisure 
time, and special interests. 
10.8.8 
BRIEF-P and 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 (Gioia et al, 2000). The BRIEF-P or 
BRIEF appropriate for each subject’s age should be completed, with the following exception: 
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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 
according to the tabular schedules of study procedures (Section 5.2). The BRIEF-P and BRIEF 
will only be administered in countries where a validated translated version is available. 
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. 
10.8.9 
Bayley Scales of Infant and Toddler Development, Third Edition 
The Bayley-III scales are recognized internationally as one of the most comprehensive 
developmental assessment instruments (Sattler and Hoge, 2006) used to examine the major 
facets of a young child’s development (Bayley, 2006). The Bayley-III scales are a standardized, 
individually administered, adaptive assessment that measures the developmental functioning of 
infants and young pediatric subjects from 1 month to 42 months of age (Bayley, 2006). The 
Bayley-III scales measure cognitive, language, motor, social-emotional, and adaptive 
development and are a revision of the predecessor, the Bayley Scales of Infant Development, 
Second Edition (Bayley, 1993). The Bayley-III scales are a technically sound instrument, with 
strong internal consistency, as well as test-retest stability. The Bayley-III scales are validated 
only in English.  
This scale is validated as a tool for assessment of neurological development in young pediatric 
subjects and is therefore considered appropriate for EP0034.  
The Bayley-III scales are an individually administered, adaptive assessment that presents 
pediatric subjects with situations and tasks designed to produce an observable set of behavioral 
responses. They consist of a cognitive scale, a language composite scale with receptive and 
expressive language subscales, and a motor composite scale with fine and gross motor subscales 
to be completed by the investigator or designee. It also has a social emotional scale, comprising 
social-emotional competence, and sensory processing, and an adaptive behavior scale, which 
assesses the attainment of skills necessary for the development of independence, to be completed 
by the child’s parent or caregiver.  
The completion of the Bayley-III scales will require approximately 50 minutes for pediatric 
subjects who are 12 months old or younger and 90 minutes for pediatric subjects aged 12 months 
to 18 months.  
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The scale will be completed according to the tabular schedules of study procedures (Section 5.2). 
The same scale should be completed for 1 year after the Baseline assessment of the primary 
study, even if the subject turns >18 months of age during that period. 
11 
STUDY MANAGEMENT AND ADMINISTRATION  
11.1 
Adherence to protocol 
The investigator should not deviate from the protocol. However, the investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
After implementation of such measure, the investigator must notify the Clinical Project Manager 
of the sponsor within 24 hours and follow any local regulatory requirements. 
11.2 
Monitoring 
UCB (or designee) will monitor the study to meet the sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a contract research organization (CRO) or a contract monitor. 
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The investigator will allow UCB (or designee) to periodically review all CRFs and 
corresponding source documents (eg, hospital and laboratory records for each subject). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of CRFs, ensure that all protocol 
requirements, applicable authorities regulations, and investigator’s obligations are being fulfilled, 
and resolve any inconsistencies in the study records. 
11.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies of CRFs 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 
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by the investigator and become a permanent part of the subject’s source documents. The 
investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
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 study will be performed using remote data capture (RDC). The investigator is responsible 
for prompt reporting of accurate, complete, and legible data in the electronic CRFs and in all 
required reports. 
Any change or correction to the electronic eCRF after saving must be accompanied by a reason 
for the change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the electronic 
eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
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 is performed using RDC; the data are entered into the electronic CRFs 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 Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log. 
The investigator will keep a Subject Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each subject. 
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The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
11.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused study drug and other material in accordance with UCB procedures for the study. 
11.5 
Archiving and data retention 
The investigator will maintain adequate records for the study, including medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with UCB (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 study master file. 
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 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). 
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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 
Analysis sets will be defined as follows: 
• The Safety Set (SS) will consist of all enrolled subjects who took at least 1 dose of LCM in 
this long-term study. All safety analyses will be performed on the SS. 
• The Full Analysis Set will be used for the analysis of seizure data and will consist of all 
subjects in the SS, who have at least 1 completed post-Baseline seizure diary. 
12.2 
General statistical considerations 
Descriptive statistics will be used to provide an overview of the safety and efficacy results. For 
categorical parameters, the number and 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 n, 
mean, standard deviation (SD), median, minimum, and maximum. No statistical hypothesis 
testing will be performed. Baseline values for safety and efficacy variables will be determined 
from Baseline values of the primary study. 
Further methods pertaining to the summary and analysis of the efficacy and safety data are 
presented in the following sections, and will be described in more detail in the SAP. 
12.3 
Planned safety analyses 
The long-term safety of LCM at individualized doses will be evaluated by means of the safety 
analyses. Summary tables will be presented over the Treatment Period by 3-month periods and 
by categories of total duration of exposure. All safety variables will be analyzed by descriptive 
methods on the SS. Treatment-emergent AEs will be defined as those events which started on or 
after the date of first EP0034 dose of LCM, or whose severity worsened on or after the date of 
first EP0034 dose of LCM. Adverse events which occur within 30 days after last dose of LCM 
will be considered treatment emergent. Treatment-emergent AEs will be summarized by 
categories of total duration of exposure, 3-month period, Medical Dictionary for Regulatory 
Activities (MedDRA®) Primary System Organ Class and Preferred Term in incidence tables. 
Separate tables will be provided by categories of total duration of exposure for AEs leading to 
withdrawal from the study and SAEs. 
The safety variables such as changes in ECG, vital signs, laboratory parameters, height, body 
weight measurements, and Tanner Stage scores will be analyzed descriptively. The results for 
occurrence of these variables during long-term treatment will be summarized overall, and by 
visit. Subjects will be grouped by dose for summary purposes. The procedure for grouping 
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subjects by dose will be defined in the SAP. In addition, shift tables may be used to evaluate the 
number and percentage of subjects having a different post-Baseline status when compared to 
their Baseline status. 
Changes from Baseline in laboratory, ECG, and vital sign values will be tabulated. In addition, 
physical and neurological examination abnormalities will be listed by visit. Markedly abnormal 
values will be summarized descriptively for laboratory, vital sign, body weight, and ECG 
parameters. 
Achenbach CBCL scores, BRIEF/BRIEF-P scores, and Bayley-III scores and the respective 
change from primary LCM study Baseline scores will be analyzed in a descriptive manner. 
12.4 
Planned efficacy and other analyses 
12.4.1 
Efficacy analyses 
Efficacy variables will be summarized descriptively. Efficacy evaluation for seizures will be 
based on subject diaries, which include type, date, and number of seizures. 
Descriptive statistics will also be presented for the Clinical and Caregiver’s Global Impression of 
Change, PedsQL scores, and the number of health care resources used (concomitant medications, 
medical procedures, and health care provider consultations including hospitalizations not 
foreseen by the protocol).  
12.5 
Handling of protocol deviations 
After all CRFs have been entered and queries addressed, and prior to locking the clinical 
database, a data evaluation meeting (DEM) will be held. The purpose of this DEM will be to 
assess the quality of the data for subsequent database lock, identify protocol deviations, and 
finalize analysis sets. 
12.6 
Handling of dropouts or missing data 
No imputation of missing values for analysis parameters is planned unless otherwise noted. 
Imputations for missing or partial values for dates for AEs and concomitant medications will be 
applied to determine if an event is to be considered treatment emergent or concomitant. Across 
safety and efficacy analyses, only reported data will be used in each analysis time interval. 
Protocol deviations (eg, missing assessments or visits) related to COVID-19 will be documented. 
12.7 
Planned interim analysis and data monitoring 
No formal 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 
Approximately 500 subjects from the SP0967 and the SP0969 study will be eligible to enroll in 
this open-label extension study. No formal hypothesis testing will be conducted in this study; 
therefore, no formal sample size calculations have been performed. 
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13 
ETHICS AND REGULATORY REQUIREMENTS 
13.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. When possible or as required according to local 
IRB/IEC, assent also has to be obtained from the subject. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the investigator. 
Prior to participation in the study, the written ICF should be signed and personally dated by the 
subject, or his/her legal representative, and by the person who conducted the informed consent 
discussion (investigator or designee). The subject or his/her legal representative must receive a 
copy of the signed and dated ICF. As part of the consent process, each subject must consent to 
direct access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, 
and regulatory inspection. 
If the ICF 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 ICF by 
the IRB/IEC and use of the amended form. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
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 ICF. An eCRF must not be 
started, nor may any study specific procedure be performed for a given subject, without having 
obtained his/her written consent to participate in the study. 
13.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The investigator will fill in the subject identifying information and medical emergency contact 
information. The investigator will instruct the subject to keep the card with him/her at all times. 
13.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The investigator/UCB 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, ICF, 
Investigator’s Brochure, investigator’s curriculum vitae (if applicable), advertisement (if 
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applicable), and all other subject-related documents to be used for the study to the IRB/IEC for 
its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
13.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
13.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
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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. 
15 
REFERENCES 
Achenbach TM, Rescorla LA. Manual for the ASEBA Preschool Forms & Profiles. Burlington, 
Vermont: University of Vermont, Research Center for Children, Youth, & Families; 2000. 
Achenbach TM, Rescorla LA. Manual for the ASEBA School-Age Forms & Profiles. 
Burlington, Vermont: University of Vermont, Research Center for Children, Youth, & Families; 
2001.  
Aicardi J. Syndromic classification in the management of childhood epilepsy. J Child Neurol. 
1994;9(Suppl 2):14-8. 
Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as 
add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, 
placebo-controlled study: Gabapentin Pediatric Study Group. Epilepsia. 1999;40:1147-54. 
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006. 
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: The Psychological 
Corporation; 1993. 
Bourgeois BF, Goodkin HP. Efficacy of antiepileptic drugs in adults vs children: does one size 
fit all? Neurology. 2012;79;1420-1. 
CHMP/EWP/566/98 Guideline on clinical investigation of medicinal products in the treatment of 
epileptic disorders (EMA) Rev 2, 20 Jan 2010. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed 30 Oct 2012. 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 
1989;30:389-99. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, et al. A placebo controlled 
trial of lamotrigine add-on therapy for partial seizures in children: Lamictal Pediatric Partial 
Seizure Study Group. Neurology. 1999;53:1724-31. 
Elterman RD, Glauser TA, Wylie E, Reife R, Wu SC, Pledger G. A double-blind, randomized 
trial of topiramate as adjunctive therapy for partial-onset seizures in children: Topiramate YP 
Study Group. Neurology. 1999;52:1338-44. 
Gioia GA, Isquith PK, Guy SC, Kenworthy L. Behavior rating inventory of executive function. 
Child Neuropsychol. 2000;6:235-8.  
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Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. on behalf of 
the N159b Study Group. Double-blind placebo-controlled trial of adjunctive levetiracetam in 
pediatric partial seizures. Neurology. 2006;66:1654-60. 
Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B, et al. Adjunctive 
therapy with oxcarbazepine in children with partial seizures: the Oxcarbazepine Pediatric Study 
Group. Neurology. 2000;54:2237-44. 
Hadjiloizou SM, Bourgeois BF. Antiepileptic drug treatment in children. Expert Rev Neurother. 
2007;7:179-93. 
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4. 
Institute of Medicine. Epilepsy across the spectrum: promoting health and understanding. 
Washington, DC: The National Academies Press. 2012. 
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence 
ofepilepsy: A systematic review and meta-analysis. Neurology. 2011; 77(10): 1005–12. 
Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of 
antiepileptic drugs in adults predicts efficacy in children: A systematic review. Neurology. 
2012;79;1482-9. 
Perucca E. Established antiepileptic drugs. Baillieres Clin Neurol. 1996;5:693-722. 
Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial onset 
seizures. Neuropsychiatr Dis Treat. 2013;9:629-37. 
Sander JW. New drugs for epilepsy. Curr Opin Neurol. 1998;11:141-8. 
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. 5th ed. 
La Mesa: Jerome M Sattler; 2006. 
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life 
version 4.0 generic core scales in healthy and patient populations. Med Care. 2001;39:800-12. 
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16 
APPENDICES 
16.1 
Protocol Amendment 1 
Rationale for the amendment 
The primary purpose of this substantial amendment is to add further clarification regarding the 
addition of extra procedures (ECGs) in case of LCM dose increases to ≥8mg/kg/day and 
≥400mg/day in accordance with the FDA request and based on program specific guidelines. 
Furthermore, at the request of the Spanish IEC, additional inclusion criteria (Inclusion Criterion 
#5 and #6) were added to clarify age and diagnosis requirements for enrollment.  
Additional changes have been implemented for consistency with other protocols in the LCM 
pediatric program. 
Furthermore, administrative changes including the update of the study team and minor 
corrections, and update of the Sponsor Declaration for electronic signature, have been made.  
 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• Text has been added to clarify the extra ECG assessments related to LCM dose increases of 
≥8mg/kg/day and ≥400mg/day, respectively. 
• Inclusion Criterion #5 has been added to clarify the enrollment requirements for age of 
subjects (1 month to ≤17 years). 
• Inclusion Criterion #6 has been added to clarify the enrollment requirements for diagnosis of 
subjects (epilepsy with partial-onset seizures). 
• Text has been modified to clarify that the C-SSRS needs to be completed at an Unscheduled 
Visit if the visit is scheduled due to safety or efficacy reasons. 
• Text has been added to clarify which C-SSRS versions to use if a subject becomes 6 years of 
age (at that specific visit and all subsequent visits).  
• Text has been updated to clarify protocol adherence.  
• Efficacy variables have been added. 
• Text has been modified to clarify the handling of dropouts or missing data. 
• Exclusion Criterion #2 has been amended and Exclusion Criterion #4 has been deleted to 
clarify that subjects are excluded if they meet the mandatory withdrawal criteria for SP0967 
or SP0969. 
• Text has been added to clarify that the subject’s parent(s)/caregiver(s)/legal representative(s) 
are also given the opportunity to report AEs spontaneously.  
 
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• Text has been added to clarify that urine assessment will be performed on subjects aged ≥5 
years and the assessments will be based on the subject’s ability to void and staff’s ability to 
collect urine (in an appropriate container).  
• Text has been added to clarify that implantation of and changes in vagal nerve stimulation 
settings are permitted.  
• For subjects choosing to enroll in EP0034 from SP0969, the final Transition Visit, which will 
serve as Visit 1 of EP0034, has been corrected from Transition Visit 3 to Transition Visit 4. 
• Text has been corrected to clarify that the LCM doses will be divided between the morning 
and the evening dose (but not equally divided).  
• Text has been modified to correct the duration of the Taper Period from 6 weeks to 4 weeks.  
• The Sponsor Study Physician, Clinical Project Manager, and Clinical Trial Biostatistician 
have changed and their contact details, as well as those of the Clinical Monitoring Research 
Organization, have been updated. 
• The Sponsor Declaration has been updated for electronic signature. 
• Other changes made in this amendment are to provide clarification, are administrative in 
nature, or are to correct errors.  
 
Specific changes 
Change #1 
SPONSOR DECLARATION 
Clinical Project Manager 
 
_____________________________ 
Date/Signature 
Clinical Trial Biostatistician 
 
_____________________________ 
Date/Signature 
Study Physician 
 
_____________________________ 
Date/Signature 
Clinical Program Director 
 
_____________________________ 
Date/Signature 
 
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Has been revised and moved to Section 18: 
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. 
 
Change #2 
STUDY CONTACT INFORMATION 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
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Clinical Monitoring Contract Research Organization 
Name: 
Pharmaceutical Research Associates, Inc. 
Address: 
4130 Park Lake Avenue, Suite 400  
Raleigh, NC 27612  
UNITED STATES 
Phone: 
+1 919 786 8200 
Fax: 
+1 919 786 8201 
 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
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Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH. 
Alfred-Nobel-Str. 10 
40789 Monheim 
GERMANY 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
Clinical Monitoring Contract Research Organization 
Name: 
PRA Health Sciences 
Address: 
4130 Park Lake Avenue, Suite 400  
Raleigh, NC 27612  
UNITED STATES 
Phone: 
+1 919 786 8200 
Fax: 
+1 919 786 8201 
 
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Change #3 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World (except Japan): +32 2 386 24 21 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
Japan: +81 3 6864 7400 
Email 
Global: DS_ICT@ucb.com 
 
Has been changed to: 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
Email 
Global: DS_ICT@ucb.com 
 
Change #4 
LIST OF ABBREVIATIONS 
DRM data review meeting 
 
Has been changed to: 
DEM data evaluation meeting 
 
Change #5 
Section 1 SUMMARY, paragraphs 3, 7, and 8 
The study medication is LCM in either the oral solution formulation or tablet formulation. 
Subjects may take either oral solution or tablets during the Treatment Period, based on clinical 
judgment, regardless of their weight. Lacosamide will be administered twice daily (bid) at 
approximately 12-hour intervals, once in the morning and once in the evening, in equally divided 
doses. The oral solution formulation will be measured and administered via a dosing syringe. 
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The efficacy variables will be based on seizure diary data and will include the percentage of 
seizure-free days during the study. The following other efficacy variables based on seizure diary 
data will be computed for subjects from SP0969: the percentage of 50% responders (subjects 
with at least a 50% reduction in total partial-onset seizure frequency per 28 days compared to 
Baseline) and the percentage of 50% responders per seizure type (simple partial, complex partial, 
or secondarily generalized) compared to Baseline, and absolute and percent reduction in total 
partial-onset seizures and per partial-onset seizure type (simple partial, complex partial, or 
secondarily generalized) compared to Baseline (Baseline is defined as the period before 
receiving study medication in the previous pediatric study). The following other efficacy 
variables will be computed for all subjects in EP0034: achievement of seizure-free status (no 
seizure) during the study for total partial-onset seizure and per seizure type (simple partial, 
complex partial, or secondarily generalized), Clinical Global Impression of Change, and 
Caregiver’s Global Impression of Change. 
Other evaluations will include behavioral and cognition assessments (Achenbach Child Behavior 
Checklist [CBCL], Behavior Rating Inventory of Executive Function [BRIEF®]/BRIEF 
Preschool Version [BRIEF® P], and Bayley Scales of Infant and Toddler Development, Third 
Edition [Bayley-III®] for subjects enrolled in English-speaking countries), quality of life 
assessments (Pediatric Quality of Life Inventory [PedsQL™]), plasma concentrations of LCM, 
and health care resource use (concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays). 
 
Has been changed to: 
The study medication is LCM in either the oral solution formulation or tablet formulation. 
Subjects may take either oral solution or tablets during the Treatment Period, based on clinical 
judgment, regardless of their weight. Lacosamide will be administered twice daily (bid) at 
approximately 12 hour intervals, once in the morning and once in the evening, in divided doses. 
The oral solution formulation will be measured and administered via a dosing syringe. 
The efficacy variables will be based on seizure diary data and will include the percentage of 
seizure-free days during the study. The following other efficacy variables based on seizure diary 
data will be computed for subjects from SP0969: the percentage of 50% responders (subjects 
with at least a 50% reduction in total partial-onset seizure frequency per 28 days compared to 
Baseline) and the percentage of 50% responders per seizure type (simple partial, complex partial, 
or secondarily generalized) compared to Baseline, the percentage of 75% responders (subjects 
with at least a 75% reduction in total partial-onset seizure frequency per 28 days compared to 
Baseline) and the percentage of 75% responders per seizure type (simple partial, complex partial, 
or secondarily generalized) compared to Baseline, absolute and percent reduction in total partial-
onset seizures and per partial-onset seizure type (simple partial, complex partial, or secondarily 
generalized) compared to Baseline (Baseline is defined as the period before receiving study 
medication in the previous pediatric study), and partial-onset seizure frequency per 28 days. The 
following other efficacy variables will be computed for all subjects in EP0034: achievement of 
seizure-free status (no seizure) during the study for total partial-onset seizure and per seizure 
type (simple partial, complex partial, or secondarily generalized), Clinical Global Impression of 
Change, and Caregiver’s Global Impression of Change. 
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Other evaluations will include behavioral and cognition assessments (Achenbach Child Behavior 
Checklist [CBCL], Behavior Rating Inventory of Executive Function [BRIEF®]/BRIEF 
Preschool Version [BRIEF® P], and Bayley Scales of Infant and Toddler Development, Third 
Edition [Bayley-III®] for subjects enrolled in English-speaking countries), quality of life 
assessments (Pediatric Quality of Life Inventory [PedsQL™]), health care resource use 
(concomitant medications, medical procedures, and health care provider consultations including 
hospitalizations not foreseen by the protocol). 
 
Change #6 
Section 4.4 Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969 and include 
the following:  
• Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure 
type (simple partial, complex partial, or secondarily generalized) compared to Baseline 
The following other efficacy variables will be computed for all subjects in EP0034 and include 
the following: 
• Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• Clinical Global Impression of Change 
• Caregiver’s Global Impression of Change 
• Change from Baseline in PedsQL for subjects ≥2 years of age 
• Health care resource use: concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays 
 
Has been changed to: 
The following other efficacy variables will be computed for subjects from SP0969 and include 
the following:  
• Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
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• Percentage of 75% responders (subjects with at least a 75% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure 
type (simple partial, complex partial, or secondarily generalized) compared to Baseline  
• Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034 and include 
the following: 
• Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• Clinical Global Impression of Change 
• Caregiver’s Global Impression of Change 
• Change from Baseline in PedsQL for subjects ≥2 years of age 
• Health care resource use: concomitant medications, medical procedures, and health care 
provider consultations including hospitalizations not foreseen by the protocol 
 
Change #7 
Section 5.1 Study description, Taper Period 
The Taper Period (up to 6 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. 
 
Has been changed to: 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. 
 
Change #8 
Section 5.2 Schedule of study assessments, Table 5-1 footnote i and Table 5-2 footnote h 
A 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart) will be 
performed prior to any blood draws and vital signs and, if possible, after the subject has been in a 
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supine position for approximately 5 minutes preceding the ECG recording. All subjects will be 
required to have a 12 lead ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day or when a new 
concomitant AED is introduced. This ECG can be conducted at an Unscheduled Visit, if 
necessary. Subjects having a LCM dose increase to ≥8mg/kg/day will be required to arrive at the 
clinic prior to taking their morning dose of LCM. Subjects will be administered their morning 
LCM dose by study personnel at the clinic so that an ECG (2 interpretable recordings 
approximately 20 to 30 minutes apart prior to any blood sample collection or vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM 
steady state Cmax). 
 
Has been changed to: 
A 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart) will be 
performed prior to any blood draws and vital signs and, if possible, after the subject has been in a 
supine position for approximately 5 minutes preceding the ECG recording. All subjects will be 
required to have a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, after 
subsequent dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 
9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first time a subject 
reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new concomitant AED is 
introduced during the study. This ECG can be conducted at an Unscheduled Visit, if necessary. 
Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new 
concomitant AED is added will be required to arrive at the clinic prior to taking their morning 
dose of LCM. Subjects will be administered their morning LCM dose by study personnel at the 
clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
any blood sample collection or vital signs assessment) can be performed 30 minutes to 1 hour 
after the administration of LCM. 
 
Change #9 
Section 5.2 Schedule of study assessments, Table 5-1 footnote j, Table 5-2 footnote i, and 
Table 5-3 footnote g 
The following footnote has been added: 
For subjects aged ≥5 years, urine assessments will be based on the subject’s ability to void and 
staff’s ability to collect urine (in an appropriate container). 
 
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Change #10 
Section 5.2 Schedule of study assessments, Table 5-1 footnote k, Table 5-2 footnote j, and 
Table 5-3 footnote h 
For all subjects ≥6 years of age, the “Since Last Visit” version of the C-SSRS should be 
completed. If a subject turns 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. 
 
Has been changed to: 
For all subjects ≥6 years of age, the “Since Last Visit” version of the C-SSRS should be 
completed. 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 at subsequent visits. 
 
Change #11 
Section 5.2 Schedule of study assessments, Table 5-1 footnote l and Table 5-2 footnote k 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
 
Has been changed to: 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to a safety or 
efficacy reason. 
 
Change #12 
Section 5.2 Schedule of study assessments, Table 5-3 footnote a 
The Taper Period (up to 6 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets. The Taper Visit will be performed at the end of the Taper Period. Taper 
of LCM may not be required for some subjects who complete the study or withdraw from the 
study prematurely, depending on the treatment option selected by the investigator in consultation 
with the subject and/or legal representative(s). 
 
Has been changed to: 
The Taper Period (up to 4 weeks, depending on dose level achieved, see Section 7.2.2 for details) 
will be required for subjects who complete the study or withdraw from treatment during the 
study if the following doses are achieved: LCM ≥3mg/kg/day for subjects receiving oral 
solution, or LCM ≥150mg/day for subjects taking tablets. The Taper Visit will be performed at 
the end of the Taper Period. Taper of LCM may not be required for some subjects who complete 
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the study or withdraw from the study prematurely, depending on the treatment option selected by 
the investigator in consultation with the subject and/or legal representative(s). 
 
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Change #13 
Section 5.3 Schematic diagram, Figure 5-1 
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 6 weeks) 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
11mg/kg/day 
 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
10mg/kg/day 
 
 
 
 
 
 
 
Subjects 
11mg/kg/day 
 
 
 
9mg/kg/day 
 
 
 
 
 
 
 
<30kg 
10mg/kg/day 
10mg/kg/day 
 
 
8mg/kg/day 
 
 
 
 
 
 
 
 
9mg/kg/day 
 
 
 
7mg/kg/day 
 
 
 
 
 
 
 
 
8mg/kg/day 
 
 
 
6mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
5mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
4mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
3mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
2mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-101 
102-103 
 
 
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V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 6 weeks) 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
11mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
10mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
9mg/kg/day 
 
 
 
 
 
 
 
 
8mg/kg/day 
 
 
 
8mg/kg/day 
 
 
 
 
 
 
 
Subjects 
7mg/kg/day 
 
 
 
7mg/kg/day 
 
 
 
 
 
 
 
≥30kg & 
6mg/kg/day 
6mg/kg/day 
 
 
6mg/kg/day 
 
 
 
 
 
 
 
<50kg 
 
 
 
 
5mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
4mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
3mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
2mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-101 
102-103 
 
 
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 6 weeks) 
 
 
 
 
 
 
 
600mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
550mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
500mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
450mg/day 
 
 
 
 
 
 
 
 
400mg/day 
 
 
 
400mg/day 
 
 
 
 
 
 
 
Subjects 
350mg/day 
 
 
 
350mg/day 
 
 
 
 
 
 
 
≥50kg 
300mg/day 
300mg/day 
 
 
300mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
250mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
200mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
150mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
100mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-101 
102-103 
 
 
LCM=lacosamide; SFU=Safety Follow-Up; V=visit 
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Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
 
Confidential 
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Has been changed to: 
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU TC 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 4 weeks) 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
11mg/kg/day 
 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
10mg/kg/day 
 
 
 
 
 
 
 
Subjects 
11mg/kg/day 
 
 
 
9mg/kg/day 
 
 
 
 
 
 
 
<30kg 
10mg/kg/day 
10mg/kg/day 
 
 
8mg/kg/day 
 
 
 
 
 
 
 
 
9mg/kg/day 
 
 
 
7mg/kg/day 
 
 
 
 
 
 
 
 
8mg/kg/day 
 
 
 
6mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
5mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
4mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
3mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
2mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-100 
101-104 
 
 
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03 Nov 2020 
Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
 
Confidential 
Page 103 of 145 
 
 
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU TC 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 4 weeks) 
 
 
 
 
 
 
 
12mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
11mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
10mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
9mg/kg/day 
 
 
 
 
 
 
 
 
8mg/kg/day 
 
 
 
8mg/kg/day 
 
 
 
 
 
 
 
Subjects 
7mg/kg/day 
 
 
 
7mg/kg/day 
 
 
 
 
 
 
 
≥30kg & 
6mg/kg/day 
6mg/kg/day 
 
 
6mg/kg/day 
 
 
 
 
 
 
 
<50kg 
 
 
 
 
5mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
4mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
3mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
2mg/kg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-100 
101-104 
 
 
 
V1 
 
 
V2-V12 including Unscheduled Visits 
V13 
 
SFU TC 
 
 
 
 
 
 
 
Transition Period 
(primary study) 
Treatment Period 
(up to 2 years) 
Taper Period 
(up to 4 weeks) 
 
 
 
 
 
 
 
600mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
500mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
400mg/day 
 
 
 
400mg/day 
 
 
 
 
 
 
 
Subjects 
350mg/day 
 
 
 
 
 
 
 
 
 
 
 
≥50kg 
300mg/day 
300mg/day 
 
 
300mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
200mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 1 week in EP0034, the investigator may adjust the LCM dose during the Treatment 
Period based on clinical judgment 
A slower or faster 
taper is permitted 
 
 
 
 
Week 
Weeks 
Weeks 
Weeks 
 
 
 
1 
2-96 
97-100 
101-104 
 
 
 LCM=lacosamide; SFU=Safety Follow-Up; TC=telephone contact; V=visit
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Lacosamide 
EP0034 
 
 
 
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Change #14 
Section 6.1 Inclusion criteria, Criterion #5 and #6 
The following 2 criteria have been added: 
4. Subject is male or female aged 1 month to ≤17 years. 
5. Subject has a diagnosis of epilepsy with partial-onset seizures. 
 
Change #15 
Section 6.2 Exclusion criteria, Criterion #2 
2. Subject is experiencing an ongoing serious AE (SAE). 
 
Has been changed to: 
2. Subject meets a mandatory withdrawal criterion (ie, MUST withdraw criterion) for SP0967 
or SP0969, or is experiencing an ongoing serious AE (SAE). 
 
Change #16 
Section 6.2 Exclusion criteria, Criterion #4 
The following criterion has been deleted: 
4. Subjects with a major protocol deviation during the primary study (or a deviation related to 
enrollment criteria for primary study). 
 
Change #17 
Section 7.2 Treatment(s) to be administered, paragraph 1 
Lacosamide will be administered bid (at approximately 12-hour intervals, once in the morning 
and once in the evening) in equally divided doses. The oral solution formulation will be 
measured and administered via a dosing syringe. 
 
Has been changed to: 
Lacosamide will be administered bid (at approximately 12-hour intervals, once in the morning 
and once in the evening) in divided doses. The oral solution formulation will be measured and 
administered via a dosing syringe. 
 
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Lacosamide 
EP0034 
 
 
 
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Change #18 
Section 7.2.2 Taper Period, Table 7-3  
Table 7-3: 
Dose taper steps for subjects taking tablets 
LCM dose 
achieved 
LCM doses for the Taper Period 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
>500 to 600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
– 
>400 to 500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
– 
>300 to 400mg/day 
300mg/day 
200mg/day 
100mg/day 
100mg/day 
– 
>200 to 300mg/day 
200mg/day 
100mg/day 
100mg/day 
– 
– 
>150 to 200mg/day 
100mg/day 
100mg/day 
– 
– 
– 
 
Has been changed to: 
Table 7-3: 
Dose taper steps for subjects taking tablets 
LCM dose 
achieved 
LCM doses for the Taper Period 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
>500 to 600mg/day 
500mg/day 
300mg/day 
200mg/day 
100mg/day 
– 
>400 to 500mg/day 
400mg/day 
300mg/day 
200mg/day 
100mg/day 
– 
>300 to 400mg/day 
300mg/day 
200mg/day 
100mg/day 
100mg/day 
– 
>200 to 300mg/day 
200mg/day 
100mg/day 
100mg/day 
– 
– 
≥150 to 200mg/day 
100mg/day 
100mg/day 
– 
– 
– 
 
Change #19 
Section 7.8.1 Permitted and prohibited concomitant treatments (medications and 
therapies), after paragraph 4 
The following paragraph has been added: 
Implantation of and changes in vagal nerve stimulation settings are permitted. 
 
Change #20 
Section 8 STUDY PROCEDURES BY VISIT, paragraph 4 
Subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 to 
30 minutes apart) conducted at LCM maximum plasma concentration (Cmax) 1 week after a LCM 
dose increase to ≥8mg/kg/day or when a new concomitant AED is introduced during the study. 
This ECG can be conducted at an Unscheduled Visit (Section 8.5), if necessary. Subjects having 
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Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
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a LCM dose increase to ≥8mg/kg/day will be required to arrive at the clinic prior to taking their 
morning dose of LCM. Subjects will be administered their morning LCM dose by study 
personnel at the clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart prior to any blood sample collection or vital signs assessment) can be performed 30 
minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
 
Has been changed to: 
Subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 to 
30 minutes apart) conducted at LCM maximum plasma concentration (Cmax) 1 week after a LCM 
dose increase to ≥8mg/kg/day, after subsequent dose increases (ie, the first time a subject reaches 
a LCM dose of 8mg/kg/day, 9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day 
(ie, the first time a subject reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new 
concomitant AED is introduced during the study. This ECG can be conducted at an Unscheduled 
Visit (Section 8.5), if necessary. Subjects having a LCM dose increase to ≥8mg/kg/day or to 
≥400mg/day, or when a new concomitant AED is added will be required to arrive at the clinic 
prior to taking their morning dose of LCM. Subjects will be administered their morning LCM 
dose by study personnel at the clinic so that an ECG (2 interpretable recordings approximately 
20 to 30 minutes apart prior to any blood sample collection or vital signs assessment) can be 
performed 30 minutes to 1 hour after the administration of LCM. 
 
Change #21 
Section 8.1.1 Visit 1 (Week 0), paragraph 1, sentence 1 
For subjects completing the Transition Period of the primary studies and choosing to enroll in 
EP0034, the final Transition Visit (Transition Visit 3 in SP0969 and Final Transition Visit in 
SP0967) will serve as Visit 1 of EP0034. 
 
Has been changed to: 
For subjects completing the Transition Period of the primary studies and choosing to enroll in 
EP0034, the final Transition Visit (Transition Visit 4 in SP0969 and Final Transition Visit in 
SP0967) will serve as Visit 1 of EP0034. 
 
Change #22 
Section 8.1.1 Visit 1 (Week 0), Section 8.1.5 Visit 5 (Week 20), Section 8.1.8 Visit 9 (Week 
52), Section 8.1.10 Visit 11 (Week 72), Section 8.1.12 Visit 13/Termination Visit (Week 96), 
Section 8.1.13 Early Termination Visit, Section 8.2 Taper Period, and Section 8.3 Safety 
Follow-Up Visit 
• Urine sample for urinalysis (for subjects aged ≥5 years) 
 
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Lacosamide 
EP0034 
 
 
 
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Has been changed to: 
• Urine sample for urinalysis (for subjects aged ≥5 years) (urine assessments will be based on 
the subject’s ability to void and staff’s ability to collect urine [in an appropriate container]) 
 
Change #23 
Section 8.1.1 Visit 1 (Week 0), Section 8.1.3 Visit 2 (Week 4), Section 8.1.4 Visit 3 (Week 8) 
and Visit 4 (Week 12), Section 8.1.5 Visit 5 (Week 20), Section 8.1.6 Visit 6 (Week 28), 
Section 8.1.7 Visit 7 (Week 36) and Visit 8 (Week 44), Section 8.1.8 Visit 9 (Week 52), 
Section 8.1.9 Visit 10 (Week 60), Section 8.1.10 Visit 11 (Week 72), Section 8.1.11 Visit 12 
(Week 84), Section 8.1.12 Visit 13/Termination Visit (Week 96), Section 8.1.13 Early 
Termination Visit, Section 8.2 Taper Period, and Section 8.3 Safety Follow-Up Visit 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject turns 6 years of age during the study, the “Already Enrolled” version should be 
used once, followed by the “Since Last Visit” version at subsequent visits) 
 
Has been changed to: 
• C-SSRS (for all subjects ≥6 years of age, the “Since Last Visit” version should be completed; 
if a subject becomes 6 years of age during the study, the “Already Enrolled” version should 
be used at the first visit at which the subject is 6 years of age and the “Since Last Visit” 
version at subsequent visits) 
 
Change #24 
Section 8.1.1 Visit 1 (Week 0), last paragraph 
A telephone contact will be made approximately 2 weeks after Visit 1 (end of Week 2, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 4 weeks. If the investigator wants to adjust the LCM dosage after 1 week in 
EP0034, the subject should return to the clinic for an Unscheduled Visit, at the discretion of the 
investigator. 
 
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Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
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Has been changed to: 
A telephone contact will be made approximately 2 weeks after Visit 1 (end of Week 2, 
Section 8.1.2). Subjects will be scheduled to return to the clinic for the next visit in 
approximately 4 weeks after Visit 1. If the investigator wants to adjust the LCM dosage after 
1 week in EP0034, the subject should return to the clinic for an Unscheduled Visit, at the 
discretion of the investigator. 
 
Change #25 
Section 8.2 Taper Period, paragraph 1 
The Taper Period (up to 6 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from the study prematurely, if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. 
 
Has been changed to: 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from the study prematurely, if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. 
 
Change #26 
Section 8.5 Unscheduled Visit, paragraph 2 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 
to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day 
or when a new concomitant AED is introduced during the study. This ECG can be conducted at 
an Unscheduled Visit, if necessary. Subjects having a LCM dose increase to ≥8mg/kg/day will 
be required to arrive at the clinic prior to taking their morning dose of LCM. Subjects will be 
administered their morning LCM dose by study personnel at the clinic so that an ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment) 
can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state 
Cmax). 
 
Has been changed to: 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 
to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, 
after subsequent dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 
9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first time a subject 
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Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
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Page 109 of 145 
 
 
reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new concomitant AED is 
introduced during the study. This ECG can be conducted at an Unscheduled Visit, if necessary. 
Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new 
concomitant AED is added will be required to arrive at the clinic prior to taking their morning 
dose of LCM. Subjects will be administered their morning LCM dose by study personnel at the 
clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment) can be performed 30 minutes to 1 hour after the administration of LCM. 
 
Change #27 
Section 8.5 Unscheduled Visit 
• C-SSRS (only if the Unscheduled Visit is due to an AE; for subjects ≥6  years of age, the 
“Since Last Visit” version should be completed; if a subject turns 6 years of age during the 
study, the “Already Enrolled” version should be used once, followed by the “Since Last 
Visit” version at subsequent visits) 
 
Has been changed to: 
• C-SSRS (only if the Unscheduled Visit is due to safety or efficacy reasons; for subjects 
≥6 years of age, the “Since Last Visit” version should be completed; if a subject becomes 
6 years of age during the study, the “Already Enrolled” version should be used at the first 
visit at which the subject is 6 years of age and the “Since Last Visit” version at subsequent 
visits)  
 
Change #28 
Section 9.4 
Health care resource use 
For health care resource use, the following will be evaluated: concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital stays. 
 
Has been changed to: 
For health care resource use, the following will be evaluated: concomitant medications, medical 
procedures, and health care provider consultations including hospitalizations not foreseen by the 
protocol. 
 
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Change #29 
Section 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. 
 
Has been changed to: 
The subject or subject’s parent(s)/caregiver(s)/legal representative(s) will be given the 
opportunity to report AEs spontaneously. A general prompt will also be given at each study visit 
to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
 
Change #30 
Section 10.6 Laboratory measurements, paragraph 1 
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis testing will be collected according to the tabular schedules of study procedures 
(Section 5.2). Urine assessments will be performed for subjects aged ≥5 years. A central 
laboratory will perform the routine analysis of blood and urine specimens. Pregnancy testing will 
also be performed (see Section 10.8). The procedures for handling and shipping these specimens 
will be provided to the sites. 
 
Has been changed to: 
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis testing will be collected according to the tabular schedules of study procedures 
(Section 5.2). Urine assessments will be performed for subjects aged ≥5 years. For subjects aged 
≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to 
collect urine (in an appropriate container). A central laboratory will perform the routine analysis 
of blood and urine specimens. Pregnancy testing will also be performed (see Section 10.8). The 
procedures for handling and shipping these specimens will be provided to the sites. 
 
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Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
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Change #31 
Section 10.6 Laboratory measurements, Table 10-2 
The following footnote was added: 
Urinalysis will be performed for subjects ≥5 years of age only. 
 
Change #32 
Section 10.9.4 12-lead ECG, paragraph 2 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 
to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day 
or when a new concomitant AED is introduced. This ECG can be conducted at an Unscheduled 
Visit, if necessary. Subjects having a LCM dose increase to ≥8mg/kg/day will be required to 
arrive at the clinic prior to taking their morning dose of LCM. Subjects will be administered their 
morning LCM dose by study personnel at the clinic so that an ECG (2 interpretable recordings 
approximately 20 to 30 minutes apart prior to any blood sample collection or vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM 
steady state Cmax). 
 
Has been changed to: 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings approximately 20 
to 30 minutes apart) conducted at LCM Cmax 1 week after a LCM dose increase to ≥8mg/kg/day, 
after subsequent dose increases (ie, the first time a subject reaches a LCM dose of 8mg/kg/day, 
9mg/kg/day, 10mg/kg/day, etc) or for LCM doses of ≥400mg/day (ie, the first time a subject 
reaches a LCM dose of 400mg/day, 500mg/day, etc), or when a new concomitant AED is 
introduced during the study. This ECG can be conducted at an Unscheduled Visit, if necessary. 
Subjects having a LCM dose increase to ≥8mg/kg/day or to ≥400mg/day, or when a new 
concomitant AED is added will be required to arrive at the clinic prior to taking their morning 
dose of LCM. Subjects will be administered their morning LCM dose by study personnel at the 
clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
any blood sample collection or vital signs assessment) can be performed 30 minutes to 1 hour 
after the administration of LCM. 
 
Change #33 
Section 10.9.6 Assessment of suicidality, paragraph 2 
The C-SSRS will be completed according to the tabular schedules of study procedures 
(Section 5.2). This scale will be completed for subjects ≥6 years of age. The “Since Last Visit” 
version of the C-SSRS should be used. If a subject turns 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. 
 
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Clinical Study Protocol 
Lacosamide 
EP0034 
 
 
 
Confidential 
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Has been changed to: 
The C-SSRS will be completed according to the tabular schedules of study procedures 
(Section 5.2). This scale will be completed for subjects ≥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 at the first visit at which the subject is 
6 years of age and the “Since Last Visit” version at subsequent visits. 
 
Change #34 
Section 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. 
 
Has been changed to: 
The investigator should not deviate from the protocol. However, the investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
After implementation of such measure, the investigator must notify the Clinical Project Manager 
of the sponsor within 24 hours and follow any local regulatory requirements. 
 
Change #35 
Section 12.4.1 Efficacy analyses 
Efficacy variables will be summarized descriptively. Efficacy evaluation for seizures will be 
based on subject diaries, which include type, date, and number of seizures. 
Descriptive statistics will also be presented for the Clinical and Caregiver’s Global Impression of 
Change, PedsQL scores, and the number of health care resources used (concomitant medications, 
medical procedures, health care provider consultations not foreseen by the protocol, and hospital 
stays). 
 
Has been changed to: 
Efficacy variables will be summarized descriptively. Efficacy evaluation for seizures will be 
based on subject diaries, which include type, date, and number of seizures. 
Descriptive statistics will also be presented for the Clinical and Caregiver’s Global Impression of 
Change, PedsQL scores, and the number of health care resources used (concomitant medications, 
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Clinical Study Protocol 
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EP0034 
 
 
 
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medical procedures, and health care provider consultations including hospitalizations not 
foreseen by the protocol). 
 
Change #36 
Section 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.  
Subjects who discontinue from the study prematurely will be evaluated based on the data 
collected at each visit attended. 
 
Has been changed to: 
No imputation of missing values for analysis parameters is planned unless otherwise noted. 
Imputations for missing or partial values for dates for AEs and concomitant medications will be 
applied to determine if an event is to be considered treatment emergent or concomitant. Across 
safety and efficacy analyses, only reported data will be used in each analysis time interval. 
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16.2 
Protocol Amendment 2 
The primary purposes of this substantial amendment are to allow administration of the Pediatric 
Quality of Life Inventory (PedsQL) to subjects under 2 years of age and to implement language 
regarding potential drug-induced liver injury (PDILI) events, based on new standard language 
which is being applied across all protocols at UCB.  Addition of this language is to align with 
FDA guidance regarding monitoring of PDILI events and does not reflect a change in the liver 
safety signal for LCM.  
 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• The PedsQL measurement model text was updated so it consists of developmentally 
appropriate forms for pediatric subjects ≥1 month to ≤12 months, ≥13 months to <24 months. 
• To update the protocol information pertaining to PDILI monitoring in the exclusion criteria, 
withdrawal criteria, adverse events of special interest, and assessment of safety. 
• Minor editorial changes have been made throughout the protocol.  
 
Specific changes 
Change #1 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA: +1 800 880 6949  
Canada: +1 877 582 8842 
Email 
Global: DS_ICT@ucb.com 
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EP0034 
 
 
 
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Has been changed to: 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com 
 
Change #2 
Section 2 INTRODUCTION, paragraphs 1, 3 and 5 
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). 
Among the newer AEDs, only 5 (gabapentin, lamotrigine, oxcarbazepine, topiramate, and 
levetiracetam) have successfully demonstrated efficacy as adjunctive therapy in children with 
difficult to treat partial-onset seizures (Glauser et al, 2006; Glauser et al, 2000; Appleton et al, 
1999; Duchowny et al, 1999; Elterman et al, 1999). Despite the availability of new AEDs, more 
than 25% of pediatric patients have inadequate seizure control on currently available AEDs or 
experience significant adverse drug effects (Hadjiloizou and Bourgeois, 2007). 
Lacosamide has been approved as adjunctive therapy in the treatment of partial-onset seizures in 
patients 17 years of age and older in the United States (tablets, oral solution, and solution for 
intravenous [iv] infusion) and as adjunctive therapy in the treatment of partial-onset seizures 
with or without secondary generalization in patients 16 years of age and older in the European 
Union (tablets, oral solution, and solution for iv infusion). 
 
Has been changed to: 
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated that 
almost 70 million people suffer from epilepsy worldwide (Ngugi et al, 2011). 
Among the newer AEDs, only 6 (gabapentin, lamotrigine, oxcarbazepine, topiramate, 
levetiracetam, and perampanel) have successfully demonstrated efficacy as adjunctive therapy in 
children with difficult to treat partial-onset seizures (Rheims and Ryvlin, 2013; Glauser et al, 
2006; Glauser et al, 2000; Appleton et al, 1999; Duchowny et al, 1999; Elterman et al, 1999). 
Despite the availability of new AEDs, more than 25% of pediatric patients have inadequate 
seizure control on currently available AEDs or experience significant adverse drug effects 
(Hadjiloizou and Bourgeois, 2007). 
Lacosamide has been approved as monotherapy or adjunctive therapy in the treatment of partial-
onset seizures in patients 17 years of age and older in the United States (tablets, oral solution, 
and solution for intravenous [iv] infusion) and as monotherapy or adjunctive therapy in the 
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treatment of partial onset seizures with or without secondary generalization in patients 16 years 
of age and older in the European Union (tablets, oral solution, and solution for iv infusion). 
 
Change #3 
Section 4.4 Other efficacy variables, 10th bullet 
The variable for PedsQL has been amended to include subjects ≤2 years of age. 
• Change from Baseline in PedsQL for subjects ≥2 years of age 
 
Has been changed to: 
• Change from Baseline in PedsQL  
 
Change #4 
Table 5.1  
Superscript ‘g’ has been removed for the Achenbach CBCL and 
BRIEF/BRIEF-P scales 
 
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Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
V1 
TC1 
V2 
TC2 
V3 
TC3 
V4 
TC4 
V5 
TC5 
V6 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W28 
Achenbach CBCLn 
Xg 
 
 
 
 
 
 
 
X 
 
 
X 
 
BRIEF/BRIEF-Pp 
Xg 
 
 
 
 
 
 
 
X 
 
 
X 
 
AE=adverse event; AED=antiepileptic drug; Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF-P/BRIEF=Behavior Rating 
Inventory of Executive Function-Preschool Version/Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; Cmax=maximum plasma 
concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; 
IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; Unsch=Unscheduled; 
V=Visit; VNS=vagus nerve stimulation; W=week 
g Assessments may have already been completed during the final Maintenance Visit of the primary study (SP0969 or SP0967) and should not be repeated at 
Visit 1 of EP0034.  
Has been changed to  
Table 5-1: 
Schedule of study assessments: Treatment Period up to Week 28 
Assessments 
Treatment Perioda 
ETVb 
Unsch 
Visitc 
V1 
TC1 
V2 
TC2 
V3 
TC3 
V4 
TC4 
V5 
TC5 
V6 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W28 
Achenbach CBCLn 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
BRIEF/BRIEF-Pp 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
AE=adverse event; AED=antiepileptic drug; Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF-P/BRIEF=Behavior Rating 
Inventory of Executive Function-Preschool Version/Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; Cmax=maximum plasma 
concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; 
IXRS=interactive voice/web response system; LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; Unsch=Unscheduled; 
V=Visit; VNS=vagus nerve stimulation; W=week 
g Assessments may have already been completed during the final Maintenance Visit of the primary study (SP0969 or SP0967) and should not be repeated at 
Visit 1 of EP0034. 
 
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Change #5 
Section 6.2 Exclusion criteria 
The following new bullet has been added: 
6. Subject has >2x the upper limit of normal (ULN) of any of the following: ALT, AST, 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 enrolled subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, a 
Baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
 
Change #6 
Section 6.3 Withdrawal criteria 
The following “must” criterion has been removed: 
6. In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) ≥3x the 
upper limit of normal (ULN) to <5x ULN and total bilirubin ≥2x ULN or transaminases 
(AST, ALT, or both) ≥5x ULN, the study medication must be immediately discontinued and 
the subject withdrawn from the study. The LFTs will be repeated as soon as possible, and in 
no case more than 1 week later. 
 
And the following “may” criterion has been removed: 
4. Transaminases (AST, ALT, or both) ≥3x ULN to <5x ULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3x ULN to <5x ULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3x ULN or stable condition). The investigator is 
to decide whether or not to stop the study medication. 
 
Change #7 
The following new section has been added:  
Section 6.3.1 Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (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:  
• Subjects with either of the following: 
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• ALT or AST ≥5xULN 
• ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of IMP: 
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator. 
• Subjects with ALT or AST ≥3xULN (and ≥2x Baseline), and <5xULN,  total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness) 
Evaluation of PDILI must be initiated as described in Section 10.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
 
Change #8 
Section 7.8.1, Permitted and prohibited concomitant treatments (medications and 
therapies), paragraphs 1 to 3 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(ie, eCRF and source document). 
The use of neuroleptics, monoamine oxidase inhibitors, barbiturates (except for treatment of 
epilepsy), and long-term narcotic analgesics is prohibited throughout the study. The use of short 
term (2 to 3 weeks) narcotic analgesics may be allowed for management of acute pain (eg, 
fractures or during the perioperative period for subjects requiring surgery). 
The use of amphetamines and sedative antihistamines is allowed during the study. Also, low 
doses of anxiolytics or hypnotics (eg, 5mg/day of diazepam) are allowed for nonepilepsy 
indications. 
 
Have been changed to: 
All concomitant medication and treatment must be recorded in the appropriate study documents 
(ie, eCRF and source document). 
The following concomitant medications are prohibited during the study: 
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• Clozapine 
• Monoamine oxidase-A inhibitors  
• Barbiturates (except as AEDs) 
• Cannabidiols (not approved or indicated for epilepsy by local health authority) 
− Long-term use of narcotic analgesics (the use of short-term [2 to 3 weeks] narcotic 
analgesics may be allowed for management of acute pain (eg, fractures or during the 
perioperative period for subjects requiring surgery). 
Neuroleptics (except for clozapine) are allowed during the study but the investigator should 
make every effort to keep the dose stable. 
The use of amphetamines and sedative antihistamines is allowed during the study. Also, low 
doses of anxiolytics or hypnotics are allowed for nonepilepsy indications. 
 
Change #9 
Sections 8.1.1, 8.1.5, 8.1.8, 8.1.10, 8.1.12, and 8.1.13, Treatment Period Visits 
The PedsQL bullet point has been amended to include patients ≤2years 
• PedsQL assessment (M) (for subjects ≥2 years of age; form consistent with age at the visit; 
however, the form used in the primary study must be used for at least 1 year after the 
Baseline assessment of the primary study, as described in Section 9.3) 
 
Has been changed to: 
• PedsQL assessment (M) (form consistent with age at the visit; however, the form used in the 
primary study must be used for at least 1 year after the Baseline assessment of the primary 
study, as described in Section 9.3) 
 
Change #10 
Section 9.3 PedsQL, 2nd paragraph 
The PedsQL measurement model consists of developmentally appropriate forms for pediatric 
subjects ≥2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 
years of age. Self-report is measured for pediatric subjects ≥5 years to ≤18 years of age, and 
parent proxy report of child health related quality of life (HRQoL) is measured for pediatric 
subjects ≥2 years to ≤18 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. 
 
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Has been changed to: 
The PedsQL measurement model consists of developmentally appropriate forms for pediatric 
subjects 1 month to 12 months, 13 months to 24 months,2 years to 4 years, 5 years to 7 years, 
8 years to 12 years, and 13 years to 18 years of age. 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 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. 
 
Change #11 
Section 10.2.1 Definition of serious adverse event, 5th bullet 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.) 
 
Has been changed to: 
• 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 10.3], 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.) 
 
Change #12 
Section 10.2.3 Follow up of serious adverse events, paragraph 2 
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time. 
 
Has been changed to: 
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time. This follow up requirement applies to AEs, SAEs, 
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and AEs of special interest; further details regarding follow up of PDILI events are provided in 
Section 10.6.1. 
 
Change #13 
Section 10.3 Adverse events of special interest 
The following bullet 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 #14 
Section 10.6.1 Liver function tests 
10.6.1 Liver function tests 
Refer to Section 6.3 for LFT withdrawal criteria. 
Transaminases (AST, ALT, or both) ≥3×ULN but <5×ULN, in the presence of total bilirubin 
≥2×ULN, or transaminases (AST, ALT, or both) ≥5×ULN will result in immediate 
discontinuation of study medication and withdrawal of the subject from the study. The LFTs will 
be repeated as soon as possible, and in no case more than 1 week later. 
Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality (ie, 
transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring of LFTs 
should continue until resolved (ie, <3xULN or stable condition). The investigator is to decide 
whether or not to stop the study medication.  
In all cases of transaminases (AST, ALT, or both) ≥3xULN, testing for hepatitis A, B, and C will 
be done. 
Referral to a specialist (ie, hepatologist or gastroenterologist) is at the discretion of the 
investigator. This is recommended especially if the transaminase abnormalities >3xULN persist 
after discontinuation of the study medication. 
 
Has been changed to: 
Section 10.6.1 Liver function tests and evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 10.6.1.2, 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 
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reported as an AE of special interest (see Section10.3), and, if applicable, also reported as an 
SAE (see Section 10.2).  
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 10.6.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in Section 
10.6.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 2 
laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
Table 10‒3 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 10.6.1.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within Baseline 
values.d 
 
≥5xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
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 10.6.1.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
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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 
≥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 
10.6.1.3). 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within Baseline 
values.d 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
.c Details provided in Section 10.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed 
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10.6.1.1 Consultation with Medical Monitor and local hepatologist 
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 10.6.1.3) and SAE report (if applicable). 
10.6.1.2 Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 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. 
10.6.1.3 Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 10‒4 (laboratory measurements) and Table 10‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
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) 
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Table 10-4: PDILI laboratory measurements 
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 in women of childbearing potential 
PK sample 
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). 
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 
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Table 10-5: PDILI information to be collected 
New or updated information 
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 
10.6.1.4 Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 10‒3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to Baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
 
Change #15 
Section 15 REFERENCES  
The following reference has been removed: 
Dichek B. Epilepsy: an ancient ailment that still eludes a cure. Scrip Magazine. 1999;Feb:9 11. 
 
And the following references have been added: 
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence 
ofepilepsy: A systematic review and meta-analysis. Neurology. 2011; 77(10): 1005–12. 
Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial onset 
seizures. Neuropsychiatr Dis Treat. 2013;9:629-37. 
 
 
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16.3 
Protocol Amendment 3 
Rationale for the amendment 
The primary purpose of this nonsubstantial amendment is to clarify when both the Safety 
Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required. In addition, 
language specifying the use of local laboratories in exceptional circumstances and applicable 
study conduct modifications due to the COVID-19 pandemic have been added. 
Furthermore, minor administrative changes have been made, including the update of the study 
team. 
 
Modifications and changes 
Global changes 
• The name and contact information for the Sponsor Study Physician, Clinical Project 
Manager, and Clinical Trial Biostatistician were updated. 
• Text updated to clarify the Safety Follow-Up Visit and the Safety Follow-Up Telephone 
Contact. 
• Text added to clarify study conduct due the COVID-19 pandemic. 
• Study variables were reorganized to clarify categorization of primary, secondary, and other. 
• Text added to clarify the use of local laboratories in exceptional circumstances. 
• Assessments added for PDILI laboratory measurements. 
• Minor editorial changes have been made throughout the protocol.  
 
Specific changes 
Change #1 
STUDY CONTACT INFORMATION 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
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Clinical Project Manager 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Str. 10 
40789 Monheim 
GERMANY 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Fax: 
 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
UCB BIOSCIENCES GmbH 
Alfred-Nobel-Str. 10 
40789 Monheim 
GERMANY 
Phone: 
 
Email: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Biopharma SRL 
208 Bath Road 
Slough, Berkshire, SL1 3WE 
UNITED KINGDOM 
Phone: 
 
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Email: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc.  
8010 Arco Corporate Drive  
Raleigh, NC 27617  
UNITED STATES 
Phone: 
 
Email: 
 
 
Change #2 
Section 1 SUMMARY, paragraph 5: 
During the Treatment Period, study visits are scheduled at Weeks 0, 4, 8, 12, 20, 28, 36, 44, 52, 
60, 72, 84, and 96. Telephone contacts are scheduled at Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 
66, and 78. Subjects who withdraw from treatment during the study should taper off LCM if the 
following doses are achieved: LCM ≥3mg/kg/day (oral solution) for subjects receiving LCM oral 
solution, or LCM ≥150mg/day (tablet) for subjects taking tablets; lower doses will not require a 
taper. An Early Termination Visit must be completed for all subjects who prematurely 
discontinue from the study. Subjects who complete the study or withdraw prematurely from the 
study, and who discontinue use of LCM, should complete a Safety Follow-Up Visit 2 weeks 
(±2 days) after the final dose of LCM. A Safety Follow-Up Telephone Contact will be made 
30 days (-1/+3 days) after the final dose of LCM. 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 or withdraw from the study prematurely, depending on the treatment option 
selected by the investigator in consultation with the subject and/or legal representative(s). 
Has been changed to: 
During the Treatment Period, study visits are scheduled at Weeks 0, 4, 8, 12, 20, 28, 36, 44, 52, 
60, 72, 84, and 96. Telephone contacts are scheduled at Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 
66, and 78. Subjects who withdraw from treatment during the study should taper off LCM if the 
following doses are achieved: LCM ≥3mg/kg/day (oral solution) for subjects receiving LCM oral 
solution, or LCM ≥150mg/day (tablet) for subjects taking tablets; lower doses will not require a 
taper. An Early Termination Visit must be completed for all subjects who prematurely 
discontinue from the study. Subjects who complete the study or withdraw prematurely from the 
study, and who discontinue use of LCM, should complete a Safety Follow-Up Visit 2 weeks 
(±2 days) after the final dose of LCM. A Safety Follow-Up Telephone Contact will be made 
30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit and the Safety 
Follow-Up Telephone Contact are not required for subjects who participate in EP0151 or 
EP0152. At the completion of the study, investigators should discuss treatment options with the 
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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 or withdraw from the study 
prematurely, depending on the treatment option selected by the investigator in consultation with 
the subject and/or legal representative(s). 
 
Change #3 
Section 4, STUDY VARIABLES, all subsections (4.1, 4.2, 4.3, and 4.4): 
4.1 Safety variables 
The safety variables include the following: 
• Adverse event reporting 
• Safety laboratory tests (hematology; biochemistry including hepatic monitoring of alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
total bilirubin, and gamma-glutamyltransferase [GGT]; endocrinology for all subjects; and 
urinalysis for subjects ≥5 years of age)  
• Electrocardiograms  
• Physical (Tanner Stage, if applicable depending on subject’s developmental status) and 
neurological examinations  
• Vital signs (blood pressure and pulse rate) 
• Body weight and height 
4.2 Other safety variables 
The other safety variables include the following: 
• Change from Baseline in the Achenbach CBCL score: the Achenbach CBCL/1½-5 for 
children from 1.5 to 5 years of age and the Achenbach CBCL/6-18 for children ≥6 years of 
age 
• Change from Baseline in the BRIEF-P score for subjects ≥2 and <5 years of age 
• Change from Baseline in the BRIEF score for subjects ≥5 years of age 
• Change from Baseline in the Bayley-III scales in subjects <18 months of age at study entry 
(applicable only to subjects enrolled in English-speaking countries)  
4.3 Efficacy variables 
The efficacy variables planned for analysis will be based on seizure diary data from EP0034 and 
will include the following for all subjects: 
• Percentage of seizure-free days during the study 
4.4 Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969 and include 
the following:  
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• Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Percentage of 75% responders (subjects with at least a 75% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure 
type (simple partial, complex partial, or secondarily generalized) compared to Baseline  
• Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034 and include 
the following: 
• Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• Clinical Global Impression of Change 
• Caregiver’s Global Impression of Change 
• Change from Baseline in PedsQL  
• Health care resource use: concomitant medications, medical procedures, and health care 
provider consultations including hospitalizations not foreseen by the protocol 
Have been changed to: 
4.1 Safety variables 
4.1.1 Primary safety variables 
The primary safety variables include the following: 
• Incidence of TEAEs 
• Incidence of serious TEAEs 
• Incidence of TEAEs leading to study discontinuation 
4.1.2 Other safety variables 
The other safety variables include the following: 
• Safety laboratory tests (hematology; biochemistry including hepatic monitoring of alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 
total bilirubin, and gamma-glutamyltransferase [GGT]; endocrinology for all subjects; and 
urinalysis for subjects ≥5 years of age)  
• Electrocardiograms  
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• Physical (Tanner Stage, if applicable depending on subject’s developmental status) and 
neurological examinations  
• Vital signs (blood pressure and pulse rate) 
• Body weight and height 
• Change from Baseline in the Achenbach CBCL score: the Achenbach CBCL/1½-5 for 
children from 1.5 to 5 years of age and the Achenbach CBCL/6-18 for children ≥6 years of 
age 
• Change from Baseline in the BRIEF-P score for subjects ≥2 and <5 years of age 
• Change from Baseline in the BRIEF score for subjects ≥5 years of age 
• Change from Baseline in the Bayley-III scales in subjects <18 months of age at study entry 
(applicable only to subjects enrolled in English-speaking countries)  
4.2 Efficacy variables 
4.2.1 Primary efficacy variables 
No primary efficacy variables are defined for this study. 
4.2.2 Secondary efficacy variables 
The efficacy variables planned for analysis will be based on seizure diary data from EP0034 and 
will include the following for all subjects: 
• Percentage of seizure-free days during the study (presented for the overall Treatment Period 
only) 
4.2.3 Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969 and include 
the following:  
• Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Percentage of 75% responders (subjects with at least a 75% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure 
type (simple partial, complex partial, or secondarily generalized) compared to Baseline  
• Partial-onset seizure frequency per 28 days 
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The following other efficacy variables will be computed for all subjects in EP0034 and include 
the following: 
• Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• Clinical Global Impression of Change 
• Caregiver’s Global Impression of Change 
• Change from Baseline in PedsQL  
• Health care resource use: concomitant medications, medical procedures, and health care 
provider consultations including hospitalizations not foreseen by the protocol 
 
Change #4 
Section 5.1, Study description, paragraphs 6, 10, and 11: 
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 legal representative(s). These 
subjects should complete Visit 13/Termination Visit and then complete the Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit 
is not required for subjects who complete the study and who do not undergo taper of LCM. 
… 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period.  
… 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM, should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of 
LCM. A Safety Follow-Up Telephone Contact is required for all subjects (those who complete 
the study as planned or have withdrawn prematurely from the study). This telephone contact will 
occur 30 days (-1/+3 days) after the final dose of LCM.  
Have been changed to: 
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 legal representative(s). These 
subjects should complete Visit 13/Termination Visit and then complete the Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit 
is not required for subjects who complete the study and who do not undergo taper of LCM. The 
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Safety Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required for 
subjects who participate in EP0151 or EP0152. 
… 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from treatment during the study if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. Taper of LCM may not be required for some 
subjects who complete the study or withdraw from the study prematurely, depending on the 
treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s) or for subjects who participate in EP0151 or EP0152. 
… 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM, should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of 
LCM. A Safety Follow-Up Telephone Contact is required for all subjects (those who complete 
the study as planned or have withdrawn prematurely from the study). This telephone contact will 
occur 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit and the 
Safety Follow-Up Telephone Contact are not required for subjects who participate in EP0151 or 
EP0152. 
 
Change #5 
Section 5.2, Schedule of study assessments, Table 5-2, footnote s: 
s Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. 
Has been changed to: 
s  Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. For subjects who 
enter the Safety Follow-Up Period, the subject diary will be returned at the Safety Follow-Up Visit. Subjects who 
do not enter the Safety Follow-Up Period will return the diary at V13/TermV. 
 
Change #6 
Section 5.2, Schedule of study assessments, Table 5-3, footnotes b, c, and j: 
b Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM, 
should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM (including that from 
LCM taper). The Safety Follow-Up Visit is not required for subjects who complete the study and do not undergo 
taper of LCM. 
c The Safety Follow-Up Telephone Call occurs 30 days (-1/+3 days) after the final dose of LCM. 
j Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. The subject diary 
will be returned at the Safety Follow-Up Visit. 
 
Have been changed to: 
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b Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM, 
should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM (including that from 
LCM taper). The Safety Follow-Up Visit is not required for subjects who complete the study and do not undergo 
taper of LCM. The Safety Follow-Up Visit is not required for subjects who participate in EP0151 or EP0152. 
c The Safety Follow-Up Telephone Call occurs 30 days (-1/+3 days) after the final dose of LCM. The Safety 
Follow-Up Telephone Call is not required for subjects who participate in EP0151 or EP0152. 
j  Subjects and/or legal representative(s) will be reminded to complete the diary on a daily basis. For subjects who 
enter the Safety Follow-Up Period, the subject diary will be returned at the Safety Follow-Up Visit. Subjects who 
do not enter the Safety Follow-Up Period will return the diary at V13/TermV. 
 
Change #7 
Section 5.3, Schematic diagram, Figure 5-1, a footnote was added: 
Note: Taper of LCM may not be required for some subjects who complete the study or withdraw 
from the study prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or legal representative(s) or for subjects who participate in 
EP0151 or EP0152. 
 
Change #8 
Section 7.2.2, Taper Period, paragraph 2: 
Taper of LCM may not be required for some subjects who complete the study or withdraw from 
the study prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or legal representative(s). 
Has been changed to: 
Taper of LCM may not be required for some subjects who complete the study or withdraw from 
the study prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or legal representative(s) or for subjects who participate in 
EP0151 or EP0152. 
 
Change #9 
Section 7.2.3, Alternative study treatment supply due to coronavirus disease 2019 
pandemic, was added: 
When a subject can no longer return to the study site due to general circumstances but will 
continue in the study, the following methods may be used to provide study treatment: 
• Site to subject: In instances where site staff can ship study treatment dispensed from the site 
pharmacy supply directly to the subject. 
• Depot to subject: In instances where it is not possible for the site staff to access study 
treatment in the site pharmacy and/or ship study treatment dispensed from the site pharmacy 
supply directly to the subject. 
 
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Change #10 
Section 8.1.12, Visit 13/Termination Visit (Week 96), paragraph 3: 
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 legal representative(s). These 
subjects should complete Visit 13/Termination Visit and then complete the Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit 
is not required for subjects who complete the study and who do not undergo taper of LCM. 
Has been changed to: 
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 legal representative(s). These 
subjects should complete Visit 13/Termination Visit and then complete the Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Visit 
is not required for subjects who complete the study and who do not undergo taper of LCM. The 
Safety Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required for 
subjects who participate in EP0151 or EP0152. 
 
Change #11 
Section 8.2, Taper Period, paragraph 1: 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from the study prematurely, if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period.  
Has been changed to: 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects 
who complete the study or withdraw from the study prematurely, if the following doses are 
achieved: LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for 
subjects taking tablets; lower doses will not require a taper (refer to Section 7.2.2). A Taper Visit 
must be completed at the end of the Taper Period. Taper of LCM may not be required for some 
subjects who complete the study or withdraw from the study prematurely, depending on the 
treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s) or for subjects entering EP0151 or EP0152. 
 
Change #12 
Section 8.3, Safety Follow-Up Visit, paragraph 1 and bullet 15: 
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Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM, should complete the Safety Follow-Up Visit 2 weeks (±2 days) after the final dose 
of LCM (including that from LCM taper). The Safety Follow-Up Visit is not required for 
subjects who complete the study or withdraw prematurely from the study but do not undergo 
taper of LCM. 
… 
• Subject diary return 
Has been changed to: 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM, should complete the Safety Follow-Up Visit 2 weeks (±2 days) after the final dose 
of LCM (including that from LCM taper). The Safety Follow-Up Visit is not required for 
subjects who complete the study or withdraw prematurely from the study but do not undergo 
taper of LCM. The Safety Follow-Up Visit is not required for subjects who participate in EP0151 
or EP0152. 
… 
• Subject diary return (for subjects who enter the Safety Follow-Up Period, the subject diary 
will be returned at the Safety Follow-Up Visit and subjects who do not enter the Safety 
Follow-Up Period will return the diary at Visit 13/Termination Visit) 
 
Change #13 
Section 8.4, Safety Follow-Up Telephone Contact, paragraph 1: 
Safety Follow-Up Telephone Contact is required for all subjects (those who complete the study 
as planned or have withdrawn prematurely from the study). This telephone contact will occur 
30 days (-1/+3 days) after the final dose of LCM. 
Has been changed to: 
Safety Follow-Up Telephone Contact is required for all subjects (those who complete the study 
as planned or have withdrawn prematurely from the study). This telephone contact will occur 
30 days (-1/+3 days) after the final dose of LCM. The Safety Follow-Up Telephone Contact is 
not required for subjects who participate in EP0151 or EP0152. 
 
Change #14 
Section 8.6, Study conduct due to coronavirus disease 2019 pandemic, was added: 
The protocol-mandated visit schedule should be followed to the extent possible, considering the 
individual benefit-risk assessment by the investigator. If necessary, remote visits may be 
conducted, and the subjects or caregivers will be contacted by telephone or videoconference. 
Remote follow up, at minimum with a telephone call after 3 months, must be done (preferably 
more frequently and as needed to follow up on subject safety assessments).  
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Ad hoc subject contact may be warranted  to understand the current health status of the subjects, 
to follow up on AEs, and inform them of any protective measures taken by the clinical site as a 
result of the coronavirus disease 2019 (COVID-19) pandemic (eg, any measures that may limit 
access to the site or may require additional actions by the subject prior to entry to the site). 
If a subject needs to be discontinued and cannot come into the clinic, then appropriate tapering 
instructions will be provided, and a visit will be scheduled to perform safety assessments as soon 
as possible. 
In situations where a subject is unable to return to the study site, investigators will assess and 
document the subject’s safety via telephone contact. Based on information gathered from the 
telephone contact, investigators will confirm whether the subject could continue the current 
study treatment based upon the outcome of the safety assessments. Subjects’ agreement to 
implement this procedure should be obtained and documented prior to implementing any 
changes. Changes in the study treatment supply in this situation are described in Section 7.2.3.  
If a subject visits another facility for a medical issue (or has to switch sites for a COVID-19-
related reason), the investigator should request contact with the physician providing care to 
provide a detailed explanation of the subject’s condition and his/her participation in the clinical 
study. Subjects or caregivers shall be reminded to completely collect and keep records of this 
visit.  
Deviations to data collection including inability to perform some assessments, such as ECG, 
blood collection for safety laboratory assessments and PK, or alternative methods of assessment, 
such as phone calls, should be recorded in the source documentation and notated as “not done” in 
the eCRF. 
In cases where subjects cannot return to the clinic, and it will not be possible to dispense a new 
seizure diary, subjects will be instructed to continue recording of seizures in a manner that is 
mutually agreed with the investigator (eg, hand-written notes, recording on a smart device). Any 
recording of seizures in a manner outside of the study seizure diary must be carefully 
documented in the source medical records (copies/print-screen printouts of these recordings will 
be brought to and retained at the site). 
 
Change #15 
Section 10.1.1, Definition of adverse event, paragraph 2: 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), 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.  
Has been changed to: 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), 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 
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all AEs that recurred or worsened after the initial visit. For results disclosure, only TEAEs are 
applicable.  
 
Change #16 
Section 10.1.9, Occurrence of COVID-19, was added: 
Occurrence of COVID-19 in subjects should be reported as either “suspected COVID-19” or 
“confirmed COVID-19” along with all available relevant data including diagnostic and 
laboratory data. For subjects where COVID-19 is still suspected despite a negative viral test, 
please report as “suspected COVID-19” and provide relevant data to support the diagnosis as 
well as the test results. 
 
Change #17 
Section 10.6, Laboratory measurements, paragraph 1: 
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis testing will be collected according to the tabular schedules of study procedures 
(Section 5.2). Urine assessments will be performed for subjects aged ≥5 years. For subjects aged 
≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to 
collect urine (in an appropriate container). A central laboratory will perform the routine analysis 
of blood and urine specimens. Pregnancy testing will also be performed (see Section 10.7). The 
procedures for handling and shipping these specimens will be provided to the sites. 
Has been changed to: 
Blood and urine specimens for routine assay of hematology, clinical chemistry, endocrinology, 
and urinalysis testing will be collected according to the tabular schedules of study procedures 
(Section 5.2). Urine assessments will be performed for subjects aged ≥5 years. For subjects aged 
≥5 years, urine assessments will be based on the subject’s ability to void and staff’s ability to 
collect urine (in an appropriate container). A central laboratory will perform the routine analysis 
of blood and urine specimens. Pregnancy testing will also be performed (see Section 10.7). The 
procedures for handling and shipping these specimens will be provided to the sites. In 
exceptional circumstances, local laboratory analysis may be performed. The medical monitor 
should be contacted beforehand to discuss these circumstances. 
 
Change #18 
Section 10.6.1.3, Testing: identification/exclusion of alternative etiology, Table 10-4: 
Table 10-4 
PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
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Table 10-4 
PDILI laboratory measurements 
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 in women of childbearing potential  
PK sample 
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) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
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Table 10-4: PDILI laboratory measurements 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
WBC count 
Differential count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
Bilirubin (If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin) 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
AST 
ALT 
ALP 
GGT 
Albumin 
Additional 
Prothrombin time/INRa 
Serum pregnancy test in women of childbearing potential  
PK sample 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine 
phosphokinase; GGT=gamma-glutamyltransferase; HBcAb-IgM=hepatitis B core antibody-IgM; HBsAg=hepatitis 
B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate dehydrogenase; 
PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RBC=red blood cell; RNA=ribonucleic acid; 
ULN=upper limit of normal; WBC=white blood cell 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
 
Change #19 
Section 12.6, Handling of dropouts or missing data, paragraph 2 was added: 
Protocol deviations (eg, missing assessments or visits) related to COVID-19 will be documented. 
 
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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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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:
ep0034-protocol-amend-3
Version:
1. 0
Document Number:
CLIN-000162885
Title:
EP0034 Protocol Amendment 3 Multicentre, Open-label, Long-term Extension Study,
Safety and Efficacy of LCM Adjunctive Therapy in Pediatrics with POS
Approved Date:
05 Nov 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 03-Nov-2020 15:31:35 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 04-Nov-2020 18:05:50 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 04-Nov-2020 23:04:43 GMT+0000
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STATISTICAL ANALYSIS PLAN 
Study: EP0034 
Product: Lacosamide 
 
 
A MULTICENTER, OPEN-LABEL, LONG-TERM EXTENSION STUDY TO INVESTIGATE 
THE EFFICACY AND SAFETY OF LACOSAMIDE AS ADJUNCTIVE THERAPY IN 
PEDIATRIC SUBJECTS WITH EPILEPSY WITH PARTIAL‑ONSET SEIZURES 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 
 
SAP/Amendment Number Date 
Final SAP 
28 May 2015 
SAP – Amendment 1 
10 Feb 2016 
SAP – Amendment 2 
21 Mar 2019 
SAP – Amendment 3 
03 Jun 2021 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF TABLES ..................................................................................................................... 4 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 
Study objectives ............................................................................................................. 7 
2.2 
Study variables ............................................................................................................... 7 
2.3 
Study design and conduct .............................................................................................. 9 
2.4 
Determination of sample size ....................................................................................... 10 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 11 
3.1 
General presentation of summaries and analyses ......................................................... 11 
3.2 
General study level definitions ..................................................................................... 13 
3.3 
Definition of Baseline values ....................................................................................... 20 
3.4 
Protocol deviations ....................................................................................................... 20 
3.5 
Analysis sets ................................................................................................................. 20 
3.6 
Treatment assignment and treatment groups ................................................................ 21 
3.7 
Center pooling strategy ................................................................................................ 21 
3.8 
Coding dictionaries ...................................................................................................... 21 
3.9 
Changes to protocol-defined analyses .......................................................................... 21 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 21 
4.1 
Adjustments for covariates ........................................................................................... 21 
4.2 
Handling of dropouts or missing data .......................................................................... 21 
4.3 
Interim analyses and data monitoring .......................................................................... 23 
4.4 
Multicenter studies ....................................................................................................... 23 
4.5 
Multiple comparisons/multiplicity ............................................................................... 24 
4.6 
Use of an efficacy subset of subjects ........................................................................... 24 
4.7 
Active-control studies intended to show equivalence .................................................. 24 
4.8 
Examination of subgroups ........................................................................................... 24 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 24 
5.1 
Subject disposition ....................................................................................................... 24 
5.2 
Protocol deviations ....................................................................................................... 25 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 25 
6.1 
Demographics and other Baseline characteristics ........................................................ 25 
6.2 
Medical history and concomitant diseases ................................................................... 26 
6.3 
History of epilepsy ....................................................................................................... 26 
6.4 
Prior and concomitant medications .............................................................................. 27 
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7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 27 
8 
SAFETY ANALYSES ..................................................................................................... 27 
8.1 
Extent of exposure ....................................................................................................... 28 
8.2 
Adverse events ............................................................................................................. 28 
8.3 
Clinical laboratory evaluations .................................................................................... 30 
8.4 
Vital signs, physical findings, and other observations related to safety ...................... 31 
9 
EFFICACY ANALYSES ................................................................................................ 41 
9.1 
Efficacy variables based on seizures ............................................................................ 42 
9.2 
Analysis of other efficacy variables ............................................................................. 43 
10 PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 45 
11 REFERENCES ................................................................................................................ 46 
12 APPENDICES ................................................................................................................. 47 
12.1 
Marked abnormality criteria for laboratory data .......................................................... 47 
12.2 
Other Significant AEs .................................................................................................. 52 
12.3 
List of AEs for Potentially Drug Induced Liver Injury (PDILI) .................................. 54 
13 AMENDMENTS TO THE STATISTICAL ANALYSIS PLAN .................................... 57 
13.1 
Amendment 1 ............................................................................................................... 57 
13.2 
Amendment 2 ............................................................................................................... 69 
13.3 
Amendment 3 ............................................................................................................... 89 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 115 
 
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LIST OF TABLES 
Table 3‒1: 
Definition of monthly interval durations during the first year ......................... 14 
Table 8‒1: 
Vital signs abnormality criteria ........................................................................ 31 
Table 8‒2: 
ECG abnormality criteria ................................................................................. 33 
Table 8‒3: 
CBCL/1½-5 ...................................................................................................... 37 
Table 8‒4: 
CBCL/6-18 ....................................................................................................... 37 
Table 8‒5: 
BRIEF-P questionnaire scoring ....................................................................... 38 
Table 8‒6: 
BRIEF questionnaire scoring ........................................................................... 40 
Table 12‒1: 
Hematology abnormality criteria ..................................................................... 47 
Table 12‒2: 
Chemistry abnormality criteria ......................................................................... 49 
Table 12‒3: 
Other significant TEAEs .................................................................................. 52 
Table 12‒4: 
AEs for PDILI .................................................................................................. 54 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
Alanine aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
BMI 
body mass index 
BCR 
borderline or clinical range 
BRIEF® 
Behavior Rating Inventory of Executive Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive Function® - 
Preschool Version 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBCL 
Child Behavior Checklist 
COVID-19 
coronavirus disease 2019 
DBP 
diastolic blood pressure 
DEM 
Data Evaluation Meeting 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ER 
emergency room 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
GGT 
gamma-glutamyl transpeptidase 
HRQoL 
health-related quality of life 
ILAE 
International League Against Epilepsy 
LCM 
Lacosamide 
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LFT 
liver function test 
MA 
markedly abnormal 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDILI 
Potential Drug Induced Liver Injury 
PedsQL 
Pediatric Quality of Life Inventory 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
ULN 
upper limit of normal 
VNS 
vagus nerve stimulation 
WHODD 
World Health Organization Drug Dictionary 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report for EP0034. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
• 
To assess the long-term safety and tolerability of Lacosamide (LCM) in pediatric subjects 
2.1.2 
Secondary objective 
• 
To assess the efficacy of LCM during long-term exposure in pediatric subjects 
2.1.3 
Other objectives 
• 
To assess behavior, cognition, quality of life, and development during long-term LCM 
exposure in pediatric subjects 
2.2 
Study variables 
2.2.1 
Primary Safety variables 
The primary safety variables include the following: 
• 
Incidence of TEAEs 
• 
Incidence of serious TEAEs 
• 
Incidence of TEAEs leading to study discontinuation 
2.2.2 
Other safety variables 
The other safety variables include the following: 
• 
Safety laboratory tests (hematology; biochemistry including hepatic monitoring of alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], total 
bilirubin, and gamma-glutamyl transferase [GGT]; endocrinology for all subjects; and 
urinalysis for subjects ≥5 years of age) 
• 
Electrocardiograms (ECGs) 
• 
Physical (Tanner Stage, if applicable depending on subject’s developmental status) and 
neurological examinations 
• 
Vital signs (blood pressure and pulse rate) 
• 
Body weight and height 
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• Change from Baseline in the Achenbach Child Behavior Checklist (CBCL) score: the 
Achenbach CBCL/1½-5 for children from 1.5 to 5 years of age and the Achenbach 
CBCL/6-18 for children ≥6 years of age 
• 
Change from Baseline in the Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) score for subjects ≥2 and <5 years of age 
• 
Change from Baseline in the Behavior Rating Inventory of Executive Function (BRIEF) 
score for subjects ≥5 years of age 
 
• 
Change from Baseline in the Bayley-III scales in subjects <18 months of age at study 
entry (applicable only to subjects enrolled in English-speaking countries) 
2.2.3 
Efficacy variables 
2.2.3.1 
Primary efficacy variables 
No primary efficacy variables are defined for this study. 
2.2.3.2 
Secondary efficacy variables 
The secondary efficacy variable planned for analysis will be based on seizure diary data from EP0034 
and will include the following for all subjects: 
• 
Percentage of seizure-free days during the study (presented for the overall Treatment Period 
only) 
2.2.3.3 
Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969: 
• 
Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving LCM in the previous pediatric study 
• 
Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Percentage of 75% responders (subjects with at least a 75% reduction in total partial-
onset seizure frequency per 28 days compared to Baseline), with Baseline defined as 
the period before receiving study medication in the previous pediatric study 
• 
Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure type 
(simple partial, complex partial, or secondarily generalized) compared to Baseline 
• 
Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034: 
• 
Achievement of seizure-free status (no seizure) during the study for total partial-onset 
seizure and per seizure type (simple partial, complex partial, or secondarily generalized) 
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• 
Clinical Global Impression of Change 
• 
Caregiver’s Global Impression of Change 
• 
Change from Baseline in Pediatric Quality of Life Inventory (PedsQL)  
• 
Health care resource use: concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and hospital stays 
2.3 
Study design and conduct 
This is a Phase 3, multicenter, open-label, extension study to obtain long-term safety and efficacy data 
in pediatric subjects with epilepsy with partial-onset seizures treated with LCM oral solution or LCM 
tablets as adjunctive therapy. 
Subjects who have participated in SP0967 or SP0969, meet the eligibility requirements of this open-
label extension study, and who consent or whose legal representative consents to participation can 
enroll into EP0034 for a maximum duration of approximately 2 years. The subject’s eligibility for the 
study will be determined at Visit 1 (Week 0). 
During the study, LCM will be available in either the oral solution formulation or tablet formulation. 
Subjects who are able and willing to swallow tablets may be dispensed LCM tablets during the 
Treatment Period, based on clinical judgment, regardless of their weight.  
Approximately 500 subjects from SP0967 and SP0969 may be eligible to enroll in this open- label 
extension study. The number of sites is dependent on the number of enrolling centers from SP0967 and 
SP0969. 
Treatment Period 
After completion of the Transition Period in the previous pediatric study, subjects will have been 
transitioned to a dose of LCM according to their weight. Subjects will receive LCM 10mg/kg/day (oral 
solution) for subjects weighing <30kg, LCM 6mg/kg/day (oral solution) for subjects weighing ≥30kg 
to <50kg, and LCM 300mg/day (tablets) for subjects weighing ≥50kg during at least their first week in 
the Treatment Period of EP0034. After 1 week in EP0034, the investigator may adjust the LCM dose 
during the Treatment Period (see Table 7-1 in the protocol). Subjects may take either oral solution or 
tablets during the Treatment Period, based on clinical judgment, regardless of their weight. 
Investigators will be allowed to increase or decrease the dose of LCM to optimize tolerability and 
seizure reduction in each subject. LCM doses may be increased up to a maximum of LCM 
600mg/day or 12mg/kg/day, whichever is lower based on body weight; LCM doses may be 
decreased to a minimum of LCM 100mg/day (tablet) or 2mg/kg/day (oral solution). 
During the Treatment Period, study visits are scheduled at Weeks 0, 4, 8, 12, 20, 28, 36, 44, 52, 
60, 72, 84, and 96. Telephone contacts are scheduled at Weeks 2, 6, 10, 16, 24, 32, 40, 48, 56, 
66, and 78. 
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 legal representative(s). These subjects should 
complete Visit 13/Termination Visit and then complete the Safety Follow-Up Telephone Contact 30 
days (-1/+3 days) after the last dose of LCM. The Safety Follow-Up Visit is not required for subjects 
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who complete the study and who do not undergo taper of LCM. The Safety Follow-Up Visit and the 
Safety Follow-Up Telephone Contact are not required for subjects who participate in EP0151 or 
EP0152. 
Subjects who complete the study and discontinue use of LCM (as determined by the investigator in 
consultation with the subject and/or legal representative) should taper LCM gradually. These subjects 
should complete Visit 13/Termination Visit and enter the Taper Period. 
Subjects who prematurely discontinue the study should complete an Early Termination Visit (ETV). 
At the time of withdrawal from 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 withdraw from the study prematurely, depending on the 
treatment option selected by the investigator in consultation with the subject and/or legal 
representative(s). These subjects should complete the Safety Follow-Up Telephone Contact 30 days (-
1/+3 days) after the last dose of LCM. 
Subjects who withdraw from the study prematurely and discontinue use of LCM (as determined by the 
investigator in consultation with the subject and/or legal representative) should taper LCM gradually. 
These subjects should enter the Taper Period. 
Taper Period 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects who 
complete the study or withdraw from treatment during the study if the following doses are achieved: 
LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking 
tablets; lower doses will not require a taper. Taper of LCM may not be required for some subjects who 
complete the study or withdraw from the study prematurely, depending on the treatment option 
selected by the investigator in consultation with the subject and/or legal representative(s) or for 
subjects who participate in EP0151 or EP0152.  
End of study and Safety Follow-up Period 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of 
LCM, should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the last dose of LCM. A 
Safety Follow-Up Telephone Contact is required for all subjects (those who complete the study as 
planned or have withdrawn prematurely from the study). This telephone contact will occur 30 days (-
1/+3 days) after the last dose of LCM. The Safety Follow-Up Visit and the Safety Follow-Up 
Telephone Contact are not required for subjects who participate in EP0151 or EP0152. 
Unscheduled visits may be conducted at the discretion of the investigator. 
The maximum duration of LCM administration during EP0034 will be approximately 2 years. 
Detailed tabular schedules of study procedures and a study schematic diagram are included in 
Sections 5.2 and 5.3 of the protocol, respectively. 
2.4 
Determination of sample size 
Approximately 500 subjects from the SP0967 and the SP0969 study will be eligible to enroll in this 
open-label extension study. No formal hypothesis testing will be conducted in this study; therefore, 
no formal sample size calculations have been performed. 
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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 9.1 or higher. All tables and listings will use Courier New font size 9. 
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 (n), mean, standard 
deviation (SD), median, minimum, and maximum. 
Decimal places for descriptive statistics will always apply the following rules: 
• 
“n” will be an integer 
• 
Mean, SD, and median will use 1 additional decimal place compared to the original data 
• 
Minimum and maximum will have the same number of decimal places as the original 
value 
All summaries, unless otherwise stated below, will be presented overall for all subjects and 
additionally based on the subject’s age at time of entry into study EP0034, using the following age 
groups: 
• 
≥1 month to <4 years 
• 
≥4 to <18 years 
Summaries for PedsQL will be presented overall for all applicable subjects and additionally based 
on the subject’s age at Baseline (using the Baseline definition in Section 3.3), using the following 
age groups: 
• 
≥1 month to ≤12 months 
• 
>12 months to ≤24 months 
• 
>2 years to ≤4 years 
• 
≥5 to ≤7 years 
• 
≥8 to ≤12 years 
• 
≥13 to ≤18 years 
• 
Total ≥5 years to ≤18 years 
Summaries for CBCL/1½-5 will be presented overall for all applicable subjects and additionally 
based on the subject’s age at time of entry into study EP0034, using the following age groups: 
• 
≥18 months to <2 years 
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• 
≥2 to <4 years 
• 
Total <4 years 
• 
≥4 to <6 years 
Summaries for CBCL 6-18 will be presented overall for all applicable subjects and additionally 
based on the subject’s age at time of entry into study EP0034, using the following age groups: 
• 
≥6 to <12 years 
• 
≥12 to <16 years 
• 
Total ≥6 to <16 years 
• 
≥16 years 
Summaries for BRIEF-P will be presented overall for all applicable subjects and additionally based 
on the subject’s age at time of entry into study EP0034, using the following age groups: 
• 
≥2 to <4 years 
• 
≥4 to <5 years 
Summaries for BRIEF will be presented overall for all applicable subjects and additionally based on the 
subject’s age at time of entry into study EP0034, using the following age groups: 
• 
≥5 to <12 years 
• 
≥12 to <16 years 
 
• 
Total ≥5 to <16 years 
• 
≥16 years 
Summaries for Bayley-III assessments will be presented overall for all applicable subjects and 
additionally based on the subject’s age at time of entry into study EP0034, using the following age 
groups: 
• 
≥1 to <6 months 
• 
≥6 months to <1 year 
• 
≥1 year to <18 months 
 All summaries will be descriptive; no statistical hypothesis testing is planned. 
A complete set of listings containing all documented data and all calculated data (eg, change from 
Baseline) will be generated, and will be sorted by site, subject number and visit (where applicable). 
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3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
First and last dose of LCM 
Unless otherwise noted, all references to the first dose of LCM in this SAP refer to the first dose of 
LCM during EP0034 (ie, not the first dose of LCM from the previous study in which subjects 
participated prior to EP0034). Unless otherwise noted, all references to the last dose of LCM in this 
SAP refer to the last dose of LCM in the study. 
3.2.1.2 
Relative day 
Relative day will be calculated as the current date minus the date of first dose of LCM plus 1 for days 
on or after the day of first dose of LCM and prior to or on the day of last LCM dose (eg, the day of 
first dose will be Day 1). For days prior to the first dose of LCM (the day prior to first dose will be 
Day -1), relative day will be calculated as the current date minus the date of first dose of LCM. For 
days after the last dose of LCM, relative day will be calculated as the current date minus the date of 
last dose of LCM 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 or missing dates. 
3.2.2 
Study periods 
This study consists of a Treatment Period and a Post-Treatment Period.  
Treatment Period 
This is defined as the period of time from the date of first dose of LCM in EP0034 to the latter of the 
last LCM dose date and the study Termination Visit date. 
Post-Treatment Period 
This is defined as the period of time from the day after the end date of the Treatment Period and 
extending through to the Final Clinic Visit or last contact with the subject. 
3.2.3 
Mapping of assessments performed at Early Termination Visit 
Safety and efficacy assessments at an ETV that correspond to a scheduled visit will be summarized 
at the scheduled visit corresponding to the ETV if the assessment was scheduled to occur at that 
visit. Such assessments will also be considered for Last Visit. 
Subjects who prematurely discontinue the study will be evaluated based on the data collected at 
each visit attended. For those subjects, the ETV will be mapped to the next scheduled visit, ie, the 
assessments documented at ETV will be assigned to the next scheduled visit, for which the 
corresponding assessment is scheduled following the last documented visit. 
In particular, assessments which are done at all visits during the Treatment Period (eg, vital signs, 
body weight and height) will have ETVs corresponding to a scheduled visit mapped to the 
corresponding scheduled visit. 
3.2.4 
Study visit labeling 
Visits will be labeled in table summaries (according to the schedule outlined in Section 5.2 of the 
protocol) as follows: 
• 
“Visit X, Week X” for scheduled visits during the Treatment Period 
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• 
“Taper Visit” 
• 
“Safety Follow-up Visit” 
• 
“Last Visit” (see below in Section 3.2.6 for further information)  
Listings will also include “Unscheduled Visit” as applicable. 
3.2.5 
Monthly time intervals 
A month is defined as 28 days and time intervals based on monthly durations are defined as 
multiples of 28 days (eg, 12 months is defined as 336 days). The definition of 3-month intervals is 
based on the example durations in Table 3‒1 which use 28-day months where the date of the first 
dose of LCM is Day 1: 
 
Table 3‒1: 
Definition of monthly interval durations during the first year 
 
Interval 
Duration Definition 
Months 1 to 3 
Days 1 to 84 
Months 4 to 6 
Days 85 to 168 
Months 7 to 9 
Days 169 to 252 
Months 10 to 12 
Days 253 to 336 
Subsequent 3-month intervals are defined in a similar manner. 
For the analysis of safety outcomes in the Treatment Period, a subject is included in the analysis for a 
3-month interval if they are exposed to LCM at any time during that interval. 
3.2.6 
Last Visit 
The Last Visit for all assessments in EP0034 is the last non-missing assessment during the Treatment 
Period. All scheduled and unscheduled assessments within this time period will be considered. Last Visit 
will be determined separately for each study procedure where Last Visit is mentioned within this 
document. 
 
3.2.7 
Exposure duration 
The overall duration of LCM exposure for each subject will be calculated as the date of the last dose 
of LCM minus the date of the first dose of LCM plus 1 day. Gaps in treatment or days with unknown 
dosing will not be subtracted from the duration of exposure. The duration of LCM exposure will be 
summarized, separately, as a continuous parameter (in days) and as a categorical parameter, where 
categories will be defined using the following cumulative 6-month intervals for the Treatment Period: 
>0 months, >6 months, >12 months, >18 months, and >24 months. 
Subject-years of LCM exposure in the study is calculated as the duration of exposure (days) divided by 
365.25. Subject-years of LCM exposure will be summarized using the following cumulative 6-month 
time intervals for the Treatment Period: >0 months, >6 months, >12 months, 
>18 months, and >24 months, where 1 month is defined as 28 days. 
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3.2.8 
Modal and maximum daily LCM dose 
The modal daily LCM dose (mg/kg/day) is defined as the daily LCM dose the subject received for the 
longest duration during the Treatment Period in EP0034. 
The maximum daily LCM dose (mg/kg/day) is defined as the highest total daily dose a subject 
received during the Treatment Period in EP0034. 
Maximum daily LCM dose will be summarized as a continuous parameter (in mg/kg/day). Modal 
daily LCM dose will be summarized as a continuous (mg/kg/day) and categorical parameter, 
using the following categories (mg/kg/day) for the Treatment Period: 0.0 to <4.0, 
≥4.0 to <6.0, ≥6.0 to <8.0, ≥8.0 to <10.0, ≥10.0 to <12.0, and ≥12.0. This will require that tablet doses 
in mg/day be converted to mg/kg/day. The following steps will be applied: 
1. For days for which a subject received oral solution, the total daily dose in mg/kg/day will be 
classified into 1 of the above categories on a daily basis. 
2. For days for which a subject received tablets, the total daily dose in mg/day will be 
converted to mg/kg/day by dividing the total daily dose in mg/day by the most recently 
available body weight; the derived dose in mg/kg/day is then classified into 1 of the above 
categories on a daily basis. 
3. Once all total daily doses are converted to mg/kg/day and classified into 1 of the above 
categories, the modal daily dose is the dose category which was most frequent. 
Should subjects 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 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. 
The modal and maximum daily dose calculations are 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 and 
maximum daily 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 daily dose), the modal daily dose will be set to the lower of the doses. 
For efficacy analyses related to seizure frequency, modal daily LCM dose will be presented as the 
most frequent dose during the interval of observation for seizure frequency parameters. 
In summary tables and listings, modal daily dose will be presented with the following column headers: 
<4mg/kg/day to represent doses from 0 to <4.0mg/kg/day, 4mg/kg/day to represent doses 4.0 to 
<6.0mg/kg/day, 6mg/kg/day to represent doses 6.0 to <8.0mg/kg/day, 8mg/kg/day to represent doses 
8.0 to <10.0mg/kg/day, 10mg/kg/day to represent doses 10.0 to <12.0mg/kg/day, and ≥12 mg/kg/day 
to represent doses greater than or equal to 12.0mg/kg/day. 
3.2.9 
Age at entry and age at first diagnosis 
Age at entry into EP0034 will be given in years. For subjects with complete date of birth available, age 
at entry in to EP0034 will use the SDTM derivation definition in the analysis dataset. 
For subjects without a complete date of birth available, age at entry into EP0034 will be 
calculated as: 
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Age at entry into the previous pediatric study + (number of calendar months between the 
informed consent dates of the previous pediatric study and EP0034)/12. 
The age at entry into the previous pediatric study and date of birth are migrated from the previous 
pediatric study into the EP0034 SDTM.  
The age at first diagnosis will be given in years and will be derived applying all rules for missing date 
imputation (see Section 4.2.6) with the following formula: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25 
3.2.10 
Weight band 
Subjects will be classified as belonging to one of the following weight bands based on their 
weight at time of entry into study EP0034: 
• 
<30kg 
• 
≥30 to <50kg 
• 
≥50kg 
3.2.11 
Body mass index (BMI) 
Body mass index (BMI) will be calculated using the formula:  
BMI = weight (kg) / (height [m])2 
3.2.12 
Enrollment groups 
Subjects will be classified as belonging to one of the following enrollment groups for the 
purpose of disposition, demographic, and efficacy subgroup analyses: 
• 
SP0967 
• 
SP0969 
3.2.13 
Seizure frequency 
Seizure frequency per 28 days (SF) will be based on the number of days (D) for which seizure 
information was provided: 
SF = (Number of seizures) x (28/D) 
If a seizure cluster is reported, it will be assigned to the correct seizure type and the highest recorded 
daily number of seizures of that seizure type during the 28 days prior to the cluster event will be used 
as the imputed number of seizures for the day on which the cluster occurred. If no other seizures are 
recorded for that seizure type for the subject in the 28 days prior to the cluster event, the frequency 
will be set to 1.  
If more than 1 cluster event occurred on the same day for Type II or Type III seizure, the seizure 
cluster will be assigned to the correct seizure type and the frequency for each cluster event will be set 
to the highest recorded daily number of seizures of that seizure type during the 28 days prior to the 
cluster event. If no other seizures are recorded for that seizure type for the subject in the 28 days 
prior to the cluster event, the frequency will be set to the number of cluster episodes reported. 
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If more than 1 cluster event occurred on the same day for Type I seizure, the seizure clusters will be 
assigned to the correct seizure type and overall frequency will be set to the maximum of: 
• 
The highest recorded daily number of seizures of that seizure type during the 28 days prior to the 
cluster event 
• 
The number of cluster episodes reported on that day 
 
3.2.14 
Percent change in seizure frequency 
The percent change in seizure frequency per 28 days (PCH) from the Baseline value (B) (using the 
Baseline definition in Section 3.3) to the Treatment Period interval (T) is defined as: 
PCH = [(SFT – SFB) / SFB] x 100 
where SFT corresponds to the seizure frequency during the Treatment Period for the relative interval 
in the open-label study and SFB corresponds to the Baseline seizure frequency. (SFT – SFB) is defined 
as the absolute reduction in seizure frequency. The frequency for both periods will be standardized to 
the number of seizures per 28 days. 
3.2.15 
Response to treatment 
Response to treatment is based on the percent change in seizure frequency relative to Baseline (using 
the Baseline definition in Section 3.3). Subjects who experience at least a 50% reduction from 
Baseline will be considered ≥50% responders. Subjects who experience at least a 75% reduction 
from Baseline will be considered ≥75% responders. 
3.2.16 
Seizure day 
A seizure day is defined as a day where any type of seizure was reported in the seizure diary and 
seizures were assessed. Days in the seizure diary which are marked as “not done” on the eCRF will 
not be counted as a seizure day. 
3.2.17 
Seizure-free day 
A seizure-free day is defined as a day where no seizures were reported in the seizure diary and seizures 
were assessed. Days in the seizure diary which are marked as “not done” on the eCRF will not be 
counted as a seizure-free day. 
3.2.18 
Seizure-free status 
Subjects will be considered seizure-free for a given period if the subject completes the period, reports 
zero seizures during the period, and has no more than 10% of days in the period for which seizure data 
is not available (ie, “not done” is noted on the Seizure Frequency eCRF module). Seizure diary days 
where “not done” has been reported for days when subjects were participating in a previous study will 
not be counted toward the 10% of days with missing seizure diary data (eg, missing seizure data due to 
a previous study will not count against a subject in the assessment of seizure-free status). If a subject 
enrolls in a short-term iv substudy, days of participation in the substudy will also not be considered in 
the assessment of seizure-free status. 
3.2.19 
Completer cohorts 
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. 
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Subjects will be classified as belonging to one of the following completer cohorts for the purpose of 
subgroup analyses: 
• 
6 months 
 
• 
12 months 
• 
18 months 
• 
24 months 
3.2.20 
Number and percentage of seizure-free days 
The number of seizure-free days will be the total number of days within an interval for which daily 
diary data was available and no seizures were reported. The percentage of seizure-free days will be 
computed as 100 times the number of seizure-free days in the interval divided by the number of days in 
the interval for which daily diary data was available. Days without the corresponding daily diary data 
will not be used in these computations (ie, days where “not done” is marked on the Seizure Frequency 
eCRF module). The change in percentage of seizure-free days will be calculated relative to Baseline 
(using the Baseline definition in Section 3.3). 
3.2.21 
Seizure time intervals 
Subjects will be classified as belonging to one of the following time intervals for the purpose of 
seizure efficacy analyses: 
• 
≤3 months 
• 
>3 to ≤6 months 
• 
>6 to ≤12 months 
• 
>12 to ≤18 months 
• 
>18 to ≤24 months 
• 
≥24 months 
3.2.22 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions. 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 ≥1 month to ≤4 years of age. The PedsQL 
Measurement Model consists of developmentally appropriate forms for pediatric study subjects ≥1 
month to ≤12 months, ≥13 months to ≤24 months, >2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 
years to ≤12 years, and ≥13 years to ≤18 years of age. For each subject, the same version that is used 
at Baseline should be used for 12 months and thereafter the age appropriate age versions should be 
used. 
For versions intended for subjects ≤24 months of age, PedsQL infant scale scores will be calculated 
for each of the following 5 PedsQL scales: 
• Physical Functioning 
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• Physical Symptoms 
• Emotional Functioning 
• Social Functioning 
• Cognitive Functioning 
For versions intended for subjects >2 years of age, PedsQL generic core scale scores will be 
calculated for each of the following 4 PedsQL scales: 
• Physical Functioning 
• Emotional Functioning 
• Social Functioning 
• School Functioning 
For versions intended for subjects >8 years of age, Physical Functioning refers to questions “About 
my health and activities”; Emotional Functioning refers to questions “About my feelings”; Social 
Functioning refers to questions “How I get along with others”; School Functioning refers to 
questions “About school”. 
The PedsQL assessment is retrospective to the prior one month, 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 following formula in order to 
generate scores of 0, 25, 50, 75, and 100 where a higher value represents a better health-related 
quality of life (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 cognitive functioning items), and the 
physical health summary score (a combination of the physical functioning and physical symptoms items) 
for each subject ≤24 months of age. Also, 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) will be calculated for each subject >2 years of 
age. These summary scores will be missing if any of the scale scores contributing to their calculation is 
missing.  
3.2.23 
Hospital stay duration 
The duration of each hospital stay will be calculated as the discharge date minus the admission date 
(Hospitalization/Emergency Room [ER] Visit Date on the eCRF module) plus 1 day for hospital 
stays with a discharge date. 
3.2.24 
Age at time of visit/assessment 
If date of birth is a complete date then age at the time of visit/assessment will be calculated as: 
(Date of visit – date of birth)/365.25 
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If date of birth is a partial date then age at the time of visit/assessment will be calculated as:  
(Enrollment age in years) + [(date of visit - informed consent date)/365.25] 
This is converted to months by multiplying by 12 if required. 
 
3.3 
Definition of Baseline values 
In general, Baseline will be defined as the last non-missing value collected prior to the first dose of 
LCM in the previous pediatric studies for efficacy and safety variables, unless otherwise noted for a 
specific type of data. 
The Baseline value for seizure counts (only applicable for subjects from SP0969) will be taken from 
the subject diary completed during the 8-week Baseline Period before receiving LCM in study 
SP0969. 
3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which could potentially have a 
meaningful impact on either the primary or secondary outcomes for an individual subject. The criteria 
for identifying important protocol deviations and the classification of important protocol deviations 
will be defined separately in an important protocol deviations document. To the extent feasible, rules 
for identifying protocol deviations will be pre-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 
• 
Prohibited concomitant medications 
• 
LCM dosing regimen 
• 
Procedural non-compliance 
Important protocol deviations will be reviewed as part of the Data Evaluation Meetings (DEMs) and 
Data Cleaning meetings prior to database lock. A list of subjects with important protocol deviations 
will be agreed upon during the DEMs and will be documented in the DEM minutes. 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus disease 
2019 (COVID-19) will be documented. 
3.5 
Analysis sets 
3.5.1 
Safety Set 
The Safety Set (SS) will consist of all enrolled subjects who took at least 1 dose of LCM in this long-
term study. All safety analyses will be performed on the SS. 
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3.5.2 
Full Analysis Set 
The Full Analysis Set (FAS) will be used for the analysis of seizure data and will consist of all 
subjects in the SS, who have at least 1 completed post-Baseline seizure diary. Subjects whose 
efficacy data could not be source verified will be excluded from the FAS. 
3.6 
Treatment assignment and treatment groups 
This is an open-label study; subjects will not be randomized. 
Where specified within this SAP, data will be summarized by age group (defined in Section 3.1). 
 
3.7 
Center pooling strategy 
No pooling of centers is planned for this study. 
3.8 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA® v16.1). Medications will be coded using the World Health Organization Drug 
Dictionary (WHODD SEP/2013). Medical procedures will not be coded. 
3.9 
Changes to protocol-defined analyses 
3.9.1 
Examination of subgroups 
A number of subgroups which were not protocol-defined have been included in Section 3.2. 
3.9.2 
Planned safety analyses 
For planned safety analyses, the protocol states that: 
Summary tables will be presented over the Treatment Period by 3-month periods and by 
categories of total duration of exposure. 
However, only select AE tables will be presented by 3-month time intervals; incidence of all TEAEs 
with onset during the Treatment Period, incidence of all serious TEAEs with onset during the 
Treatment Period, incidence of drug-related TEAEs, incidence of TEAEs by maximum intensity, 
incidence of all TEAEs leading to discontinuation with onset during the Treatment Period, and 
incidence of all other significant TEAEs with onset during the Treatment Period. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No statistical testing is planned; therefore, this section is not applicable for this study. 
4.2 
Handling of dropouts or missing data 
4.2.1 
Missing data 
No imputation of missing values for analysis parameters is planned unless otherwise noted. 
Imputations for missing or partial values for dates for AEs and concomitant medications will be 
applied to determine if an event is to be considered treatment-emergent or concomitant. Across safety 
and efficacy analysis, only reported data will be used in each analysis time interval. 
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With respect to AEs, events with missing intensity will be assumed to be severe. Events with missing 
relationship to LCM per the investigator will be assumed to be related. Incomplete or missing dates 
for events will be handled as described in Section 4.2.2. 
4.2.2 
Incomplete dates for adverse events and concomitant medications 
For analyses of AEs and concomitant medication usage, a complete date must be established in order 
to correctly identify the AE or medication as occurring during treatment or not. For purposes of 
imputing missing components of partially-reported start and stop dates for AEs and for medication 
use, the algorithms listed below will be followed. Start and stop dates of AEs or concomitant 
medication will be displayed as reported in the subject data listings (ie, no imputed values will be 
displayed in data listings). 
• 
Missing start day, but month and year present: 
If the start of LCM occurred in the same month and year as the occurrence of the 
AE/concomitant medication, the start day of the event/concomitant medication will be 
assigned to the day of first intake of LCM. Otherwise the start day will be set to the 1st day 
of the month. 
• 
Missing start day and month, but year present: 
If the start of LCM occurred in the same year as the occurrence of the AE/concomitant 
medication, the start day and month will be assigned to the date of first intake of LCM. 
Otherwise the start day and month will be set to January 1st. 
• 
Missing end day, but month and year present: 
The end day will be set to the last day of the month. 
• 
Missing end day and month, but year present: 
The end day and month will be set to the maximum of the date of study termination or the date 
equivalent to 30 days after last intake of LCM 
However, if the study termination year and year for the date which is 30 days after last intake of LCM 
are greater than the event/concomitant medication year, the day and month are to be set to December 
31st. 
4.2.3 
Definition of concomitant medication in case of missing dates 
With respect to definition of medication as concomitant, the following rule will be applied in case 
of completely missing stop and/or start date information: 
Medications with a missing start date whose stop date is either unknown or after the date of the first 
dose of LCM will be considered as concomitant medication. Medications with missing start date 
whose stop date is prior to first intake of LCM will not be considered concomitant. 
In subject data listings, dates will be displayed as reported. 
4.2.4 
Incomplete dates for the last administration of LCM 
For purposes of imputing missing components of partially reported dates for the last administration of 
LCM, the algorithms listed below will be followed. Stop dates of LCM will be displayed as reported 
in the subject data listings (ie, no imputed values will be displayed in data listing). 
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• 
Missing last administration day, but month and year present: 
The last administration day will be set to the last day of the month or the date of the final 
contact, whichever is earlier in the month. 
• 
Missing last administration day and month, but year present: 
The last administration day will be set to the last day of the year or the date of the final 
contact, whichever is earlier in the year. 
• 
Completely missing date of last administration: 
For calculating the duration of exposure, if the date of last administration is completely 
missing and no information could be obtained from data cleaning exercises, the date of last 
administration should be imputed as the date of last contact according to the Study 
Termination eCRF module. For all other purposes, no imputation will be done if the date of 
last administration is completely missing. 
However, if a subject died during the study, and the imputed last administration date according to the 
rules above is after the date of death, the last administration date will be assigned to the date of death. 
4.2.5 
Incomplete dates for seizure diary data 
Seizure frequency and seizure-free days will be calculated over non-missing diary days during each 
time interval; days for which seizure diary data were not obtained will not be considered in the 
calculation of seizure frequency or seizure-free days. As the evaluation of efficacy is not the primary 
objective of this study, and because this is an uncontrolled study in a variable setting, which allows 
individualized optimization of dosing of LCM and concomitant antiepileptic drugs (AEDs), no 
summaries assessing the impact of missing seizure diary days are planned. 
 
4.2.6 
General imputation rule for incomplete dates 
Where necessary for the calculation of derived variables, partial dates will be completed using the 
earliest calendar date based on the partial date provided. This rule is valid for all partial dates with the 
exception of the following: 
• 
Start and stop dates of AEs 
• 
Start and stop dates of concomitant medication 
• 
Start and stop dates of LCM 
• 
Start and stop dates of seizure diary data 
Completely missing dates will not be replaced and the corresponding derived variables will be set to 
missing. 
4.3 
Interim analyses and data monitoring 
No formal interim analysis is planned. However, data may be reported prior to the completion of this 
study to support annual reports, regulatory submissions, and publications. 
4.4 
Multicenter studies 
No multicenter analyses are planned; therefore, this section is not applicable for this study. 
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4.5 
Multiple comparisons/multiplicity 
No statistical testing is planned; therefore, this section is not applicable for this study. 
4.6 
Use of an efficacy subset of subjects 
The FAS, defined in Section 3.5.2, is the primary analysis set for efficacy analyses. No 
additional efficacy subsets are defined for this study. 
4.7 
Active-control studies intended to show equivalence 
This section is not applicable for this study. 
4.8 
Examination of subgroups 
Subgroups for this study are defined in the sub-sections of Section 3.2. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
An overall summary of disposition will be provided for all screened subjects. All screened 
subjects is defined as all subjects enrolled into EP0034. 
A summary of disposition of subjects will be provided for all screened subjects. The date of first 
subject in (date of earliest Visit 1 for this study), date of last subject out (date of final scheduled or 
unscheduled visit), number of screened subjects, and the number of subjects in each analysis set (SS 
and FAS), will be summarized overall and by investigator site. Subjects who transferred sites will be 
summarized according to their original site. 
A summary of disposition of analysis sets will be provided for all subjects. The following will 
be summarized: 
• 
The number and percentage of subjects in the SS 
• 
The number and percentage of subjects in the FAS 
Additionally, a summary of disposition and discontinuation reasons will present the following for all 
subjects in the SS (overall and repeated by weight band and enrollment group using the levels defined 
in Sections 3.2.10 and 3.2.12 respectively) and FAS: 
• 
The number and percentage of subjects starting the study 
• 
The number and percentage of subjects completing the study 
• 
The number and percentage of subjects completing <12 months, 12, and ≥24 months of the 
study, where 1 month is defined as 28 days 
• 
The overall number and percentage of subjects discontinuing and the number and percentage 
of subjects discontinuing by primary reason for discontinuation. If the subject discontinued 
the study and the Study Termination eCRF module is not available, the reason for 
discontinuation will be reported as “UNKNOWN”. 
A summary of discontinuations due to AEs for all screened subjects will present the number and 
percentage of subjects who discontinued this study due to AEs broken down by type of AE. 
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The number and percentage of subjects enrolled under each protocol amendment (estimated by date 
of informed consent) will be presented. This will also 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 each relationship to COVID-19 as well as any relationship, 
overall and by country, for all subjects in the SS. This will also be presented in the subject data 
listings. 
5.2 
Protocol deviations 
Important protocol deviations defined in the important protocol deviations document, and additionally 
identified at the DEMs, will be listed. In addition, the number and percentage of subjects with at least 
1 important protocol deviation will be summarized overall and by category of important protocol 
deviation (as defined in Section 3.4) for the SS. The number and percentage of subjects with no 
important protocol deviations will also be summarized for the SS. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics and other Baseline characteristics 
Demographic variables, unless otherwise specified, will be obtained from the demographics data 
collected at the time of entry into the previous pediatric study. 
Demographic variables will be presented by weight band (using the levels defined in 
Section 3.2.10), by enrollment group (using the levels defined in Section 3.2.12) and overall for the 
SS. The variables to be considered are: 
• 
Age at entry into previous pediatric study (years) (as defined in Section 3.2.9) 
• 
Age at entry into EP0034 (years) (as defined in Section 3.2.9) – continuous and categorized 
as (28 days - <24 months, 24 months - <12 years, 12 years - <18 years) 
 
• 
Gender 
• 
Weight (kg) 
• 
Weight (kg) at entry into EP0034 
• 
Weight band at entry into EP0034 (as defined in Section 3.2.10) 
• 
Height (cm) 
• 
BMI (kg/m2) (as defined in Section 3.2.11) 
• 
Head circumference (cm) 
• 
Racial group (American Indian/Alaskan Native, Asian, Black, Native Hawaiian or Other 
Pacific Islander, White, and Other/Mixed) 
• 
Ethnicity (Hispanic or Latino, and not Hispanic or Latino) 
• 
Vagus nerve stimulation (VNS) use (Active VNS, No VNS, and VNS not active) 
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A listing of reproductive potential and birth control measures will be provided. No summaries of these 
results are planned. 
6.2 
Medical history and concomitant diseases 
6.2.1 
Medical History 
The number and percentage of subjects with a medical history condition (except epilepsy), including 
both resolved and ongoing conditions, will be summarized overall and by MedDRA® primary system 
organ class (SOC) and preferred term (PT) for the SS. 
6.2.2 
Concomitant diseases and conditions 
The number and percentage of subjects with concomitant diseases and conditions (medical history 
conditions noted as ongoing at study entry for the EP0034 study), except epilepsy, will be summarized 
by SOC and PT for the SS. 
6.3 
History of epilepsy 
The history of epilepsy uses eCRF information collected at the time of entry into the previous pediatric 
LCM study. 
6.3.1 
History of seizure types 
The number and percentage of subjects experiencing partial-onset seizures (type I), simple 
partial (type IA), complex partial (type IB), and partial, secondary generalized seizures (type 
IC), in addition to each seizure category within such, at any time prior to study entry will be 
summarized based on the 1981 International League Against Epilepsy (ILAE) Seizure 
Classification History CRF/eCRF module. This will be summarized for the SS, by seizure 
classification subgroups.  
For POS subjects the following classifications will be used. A subject will be classified as 
having a history of partial-onset seizures (I) if the subject has a history of simple partial (IA), 
complex partial (IB), or partial, secondary generalized (IC) seizures. A subject will be classified 
as having a history of simple partial seizures if the subject has a history of motor signs (IA1), 
somatosensory or special sensory symptoms (IA2), autonomic symptoms or signs (IA3), or 
psychic symptoms (IA4). A subject will be classified as having a history of complex partial 
seizures if the subject has a history of simple partial onset followed by impairment of 
consciousness with simple partial features (IB1a) or automatism (IB1b), or if the subject has a 
history of impairment of consciousness at onset with no other features (IB2a) or automatism 
(IB2b). A subject will be classified as having a history of partial, secondary generalized 
seizures if the subject has a history of simple partial evolving to generalized (IC1), complex 
partial evolving to generalized (IC2), or simple partial evolving to complex partial evolving to 
generalized (IC3) seizures.  
For subjects with generalized seizures the following classifications will be used. A subject will 
be classified as having a history of partial-onset seizures (I) if the subject has a history of 
simple partial (IA), complex partial (IB), or partial, secondary generalized (IC) seizures. A 
subject will be classified as having a history of simple partial seizures if the subject has a 
history of motor signs (IA1), somatosensory or special sensory symptoms (IA2), autonomic 
symptoms or signs (IA3), or psychic symptoms (IA4). A subject will be classified as having a 
history of generalized seizures (II) if the subject has a history of absence (IIA), myoclonic 
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(IIB), clonic (IIC), tonic (IID), tonic-clonic (IIE), or atonic (IIF) seizures. A subject may also be 
classified as having a history of unclassified epileptic seizures (III).  
6.3.2 
History of seizure characteristics 
Quantitative summaries of epilepsy duration and age at diagnosis (as defined in Section 3.2.9) 
will be summarized for the SS. 
6.3.3 
Historical seizure counts 
The Historical Seizure Counts eCRF module records the number of seizures per pre-selected ILAE 
seizure code experienced by the subject during the 4 weeks prior to Baseline. These data will be 
provided in a subject data listing. 
6.4 
Prior and concomitant medications 
A listing of all medications taken during the study will be presented. Medications ongoing from the 
parent study will be migrated.  
6.4.1 
Concomitant AEDs taken at the start of the EP0034 Treatment Period 
Concomitant AEDs taken at the start of the EP0034 Treatment Period are defined as AEDs taken 
concomitantly with LCM at the time of first dose of LCM in EP0034. 
The number of concomitant AEDs taken at the start of the EP0034 Treatment Period will be 
summarized for the SS based on the following categorization: 0 AEDs, 1 AED, 2 AEDs, 3 AEDs, and 
4 AEDs. The number and percentage of subjects taking concomitant AEDs at the start of the EP0034 
Treatment Period will be summarized, separately, by WHODD chemical subgroup (level 4) and 
medication name, for the SS. 
6.4.2 
Concomitant AEDs taken during the EP0034 Treatment Period 
Concomitant AEDs taken during the EP0034 Treatment Period are defined as AEDs taken 
concomitantly for at least one day in common with LCM in EP0034. 
The number and percentage of subjects taking concomitant AEDs during the EP0034 Treatment 
Period will be summarized overall and, separately, by WHODD chemical subgroup (level 4) and 
medication name, for the SS. 
VNS is allowed and will not be counted as a concomitant AED. 
6.4.3 
Concomitant medications (excluding AEDs) 
The number and percentage of subjects taking concomitant non-AEDs during the EP0034 
Treatment Period will be summarized overall and, separately, by WHODD anatomical main 
group (level 1) and therapeutic subgroup (level 2), for the SS. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Information reported on the eCRF regarding LCM dispensed and returned will be reported in subject 
data listings. No summaries of these results are planned. LCM dosing compliance will be evaluated 
through the review of important protocol deviations classified under LCM Dosing Regimen (see 
Section 3.4). 
8 
SAFETY ANALYSES 
All safety variables will be analyzed by descriptive methods on the SS. 
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8.1 
Extent of exposure 
All the summaries described below will also be presented for the FAS. 
The duration of LCM exposure (days), as defined in Section 3.2.7, will be summarized as a continuous 
parameter (in days) overall, and repeated by weight band using the levels defined in Section 3.2.10. In 
addition, the duration of LCM exposure will be summarized using the cumulative 6-month time 
intervals for the Treatment Period, as defined in Section 3.2.7. 
Subject-years of LCM exposure will be summarized using the cumulative 6-month time intervals for the 
Treatment Period, as defined in Section 3.2.7. 
The maximum daily LCM dose (mg/kg/day), as defined in Section 3.2.8, will be summarized 
overall, and repeated by weight band using the levels defined in Section 3.2.10. 
The modal daily LCM dose (mg/kg/day), as defined in Section 3.2.8, will be summarized, overall, 
and repeated by weight band using the levels defined in Section 3.2.10. In addition, the number of 
subjects and subject-years exposed in each of the modal daily LCM dose categories (mg/kg/day) will 
be summarized for the Treatment Period, as defined in Section 3.2.8. 
8.2 
Adverse events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented by 
weight band and enrollment group using the levels defined in Sections 3.2.10 and 3.2.12 
respectively. In addition, select AE tables will also be presented by 3-month time intervals (as 
defined in Section 3.2.5). The number and percentage of subjects experiencing each event at least 
once will be summarized. All summaries will be sorted alphabetically by SOC and by frequency of 
events within PTs, starting with the most frequent event overall. 
AEs will be classified as pre-treatment, treatment-emergent, or post-treatment. Pre-treatment AEs are 
defined as AEs which had an onset date prior to the first EP0034 dose of LCM. Treatment-emergent 
AEs (TEAEs) are defined as those events which started on or after the date of first EP0034 dose of 
LCM, or whose intensity worsened on or after the date of first EP0034 dose of LCM. AEs occurring 
within 30 days after last dose of LCM will be considered treatment emergent. Post-treatment AEs are 
defined as AEs which had an onset date after 30 days after the last dose of LCM. 
For results disclosure on public registries (eg, ClinicalTrials.gov), treatment-emergent adverse 
events and treatment-emergent serious adverse events will be published. 
All AEs reported during the study including pre-treatment and post-treatment AEs will be 
provided in a subject data listing. 
An overview of the incidence of TEAEs will provide the overall summary of TEAEs and the numbers 
and percentages of subjects with at least 1 TEAE, with a serious TEAE, with a drug- related TEAE, 
with a severe TEAE, and with a drug-related serious TEAE. The number and percentage of subject 
discontinuations due to TEAEs, the number and percentage of all deaths (if applicable), and the 
number and percentage of subjects with AEs leading to death (if applicable) will also be summarized. 
This overall summary will be repeated by weight band and enrollment group using the levels defined 
in Sections 3.2.10 and 3.2.12, respectively. 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• 
Incidence of TEAEs 
• 
Incidence of serious AEs 
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• 
Incidence of serious TEAEs 
• 
Incidence of non-serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation from the study 
• 
Incidence of TEAEs by relationship to LCM 
 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of TEAEs related to Potentially Drug Induced Liver Injury (PDILI) (defined in 
Appendix Section 12.3)  
• 
Incidence of pediatric growth-, neurodevelopment-, behavior-, and endocrine-related TEAEs 
(defined by manual medical review) 
• 
Incidence of non-serious TEAEs by relationship to LCM 
• 
Incidence of fatal TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects by relationship to 
LCM 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
The following summaries of AEs will also be repeated by weight band and enrollment group 
using the levels defined in Sections 3.2.10 and 3.2.12 respectively. 
• 
Incidence of TEAEs 
• 
Incidence of serious AEs 
• 
Incidence of serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation from the study 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
The following summaries of AEs will be presented for the 3-month time intervals (as defined in 
Section 3.2.5) of: ≤3 months, >3 to ≤6 months, >6 to ≤9 months, >9 to ≤12 months, >12 to 
≤15 months, >15 to ≤18 months, >18 to ≤21 months, >21 to ≤24 months, and ≥24 months: 
• 
Incidence of all TEAEs with onset during the Treatment Period 
• 
Incidence of all serious AEs with onset during the Treatment Period 
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• 
Incidence of all serious TEAEs with onset during the Treatment Period 
• 
Incidence of all TEAEs leading to discontinuation from the study with onset during the 
Treatment Period 
• Incidence of other significant TEAEs with onset during the Treatment Period (defined 
in Appendix 12.2) 
In addition, summaries for the incidence of TEAEs overall, incidence of serious AEs, incidence of 
serious TEAEs, incidence of TEAEs leading to discontinuation, incidence of other significant TEAEs, 
TEAEs related to PDILI, and pediatric growth-, neurodevelopment-, behavior-, and endocrine-related 
TEAEs will be repeated presenting the site and subject number of all those subjects experiencing each 
TEAE as well as in subject data listings. 
8.3 
Clinical laboratory evaluations 
Hematology, blood chemistry (including liver function tests), urinalysis, and endocrinology 
parameters are assessed throughout the study, according to the tabular schedules of study 
procedures. Urinalysis will be performed for subjects ≥5 years of age only. 
All summaries of laboratory parameters will only summarize parameters planned based on the 
protocol. However, both planned and unplanned laboratory parameters will be provided in 
subject data listings. Summaries will include hematology, chemistry and endocrinology results; 
urinalysis results will be included in subject data listings only. 
Observed values of hematology, chemistry, and non-gender specific endocrinology parameters 
(ie, thyroid stimulating hormone, triiodothyronine [total and serum-free], and thyroxine [total 
and serum-free]) will be summarized for each visit and Last Visit. Change from Baseline for 
hematology, chemistry, and non-gender specific endocrinology parameters will be summarized 
for all post-Baseline visits, and Last Visit. Gender specific endocrinology parameters (ie, follicle 
stimulating hormone, luteinizing hormone, and testosterone) will be presented similarly, by 
gender. 
A shift table that cross-tabulates Baseline versus maximum result during the Treatment Period in 
categories of <1 x ULN (upper limit of normal), 1 to <2 x ULN, 2 to <3 x ULN, ≥3 x ULN, and 
missing will be presented for liver function tests (LFT) which include ALT, AST, GGT, Total 
Bilirubin, and ALP. 
Treatment-emergent markedly abnormal (TEMA) values are defined as those TEMA values during 
the defined Treatment Period at scheduled or unscheduled visits which occur on or after the first 
EP0034 LCM administration through to the end of the study but were normal at Baseline. The age at 
the time of assessment will be used for determining TEMA (as defined in Section 3.2.24). 
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high value 
will be summarized, at each post-Baseline visit and Last Visit. Percentages will be relative to the 
number of subjects with a value at each time point. Criteria for determining if a value is TEMA are 
detailed in Appendix 12.1. 
Serum and urine pregnancy testing will be performed on all females of childbearing potential, 
according to the tabular schedules of study procedures. 
Serum and urine pregnancy test results will be listed. No summaries of these results are planned. 
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Potential drug induced liver injury (PDILI) criteria as outlined in the protocol, will be checked 
at all laboratory assessments. The number and percentage of subjects meeting PDILI criteria 
(ie, ALT criteria and/or AST criteria and/or total bilirubin criteria, and/or presence of 
symptoms), will be presented by treatment group. Percentages will be based on the number of 
subjects with a non-missing measurement for the variable of interest at the relevant visit. 
8.4 
Vital signs, physical findings, and other observations related to 
safety 
8.4.1 
Vital signs, body weight, height, BMI, and head circumference 
Vital signs (systolic BP [SBP], diastolic BP [DBP], and pulse rate) will be assessed after at least 3 
minutes at rest in a supine position throughout the study, according to the tabular schedules of 
procedures. Body weight, height, and head circumference will also be assessed throughout the study, 
according to the tabular schedules of procedures. 
Assessment of orthostatic changes (only in ambulatory subjects) will also be performed as follows: 
after the 3 minute measurement in supine position, the subject is asked to stand up, and SBP, DBP 
and pulse rate are taken approximately 1 minute and approximately 3 minutes after the subject stands 
up, as feasible. 
Observed values of SBP, DBP, pulse rate, body weight, height, BMI, and head circumference will be 
summarized for each visit and Last Visit. Change from Baseline for SBP, DBP, pulse rate, body 
weight, height, BMI, and head circumference will be summarized for all post-Baseline visits, and Last 
Visit. 
Orthostatic changes of SBP, DBP, and pulse rate will be summarized for each visit and Last 
Visit. 
 
 
Markedly abnormal (MA) values are defined as those MA values during the defined Treatment 
Period at scheduled or unscheduled visits which occur on or after the first EP0034 LCM 
administration through to the end of the study. The age at the time of assessment will be used for 
determining MA (as defined in Section 3.2.24). 
The number and percentage of subjects with a MA value, MA low value, and MA high value, at 
each post-Baseline visit and Last Visit, for which SBP, DBP, pulse rate, and body weight are 
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 as follows: 
 
 
Table 8‒1: 
Vital signs abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
Pulse Rate (beats/minute) 
<6m 
<100 
>180
6m - <3y 
<90 
>150
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Table 8‒1: 
Vital signs abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
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) 
<6m 
<60 
>100
6m - <3y 
<70 
>120
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) 
<6m 
<40 
>65
6m - <3y 
<45 
>75
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
Temperature 
>1m 
>101 °F (38.3 °C) 
Body Weight 
1m - <17y 
<3% or 97% of the normal body weight 
growth curve rangesa based on gender and the 
age of subject on date of weight assessment 
≥17y 
≥10% change from Baseline (an increase or a 
decrease) 
Abbreviations: m=months, y=years. A month is defined as 28 days; a year is defined as 365.25 days. 
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a Source: http//www.cdc.gov/growthcharts/. 
A subject data listing of all vital signs for study subjects with an AE mapped to the PT 
bradycardia or sinus bradycardia will be presented. 
A subject data listing of all vital signs values including body weight, height, BMI, and head 
circumference for all subjects will be presented. A separate listing including MA vital signs 
values will also be presented. 
8.4.2 
Electrocardiograms (ECGs) 
Standard 12-lead ECGs (2 interpretable recordings [20 to 30 minutes apart]) will be performed 
throughout the study, according to the tabular schedules of procedures. 
For ECGs, Baseline will be defined as the average of all pre-dose interpretable readings. For all post-
Baseline visits, the average of all interpretable readings at the specified visit will be used for 
summaries. 
Observed values of ECG results will be summarized for each visit and Last Visit. Change from 
Baseline in ECG results will be summarized for all post-Baseline visits, and Last Visit. This will be 
summarized overall and repeated by weight band using the levels defined in Section 3.2.10. 
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding, will be summarized for all visits, and Last 
Visit. Percentages will be relative to the number of subjects with an ECG assessment at each visit. 
Subjects are counted at most once at each visit based on the worst observed outcome across all 
abnormalities reported at that visit. 
Summaries of shifts from Baseline to post-Baseline visits, and from Baseline to Last Visit will also 
be provided based on the categories normal, abnormal, not clinically significant, and abnormal, 
clinically significant. 
A listing of ECG data will be provided for all subjects with other significant TEAEs in the Cardiac 
and ECG Related Terms category defined in Appendix 12.2. A subject data listing of all ECG 
parameter values for all subjects will also be presented. Listings will include results from each 
recording and the average of all recordings. 
The number and percentage of subjects with treatment-emergent ECG abnormalities will be 
presented for each post-Baseline visit and Last Visit. Abnormalities reported at an unscheduled 
visit will be summarized under the scheduled visit preceding the unscheduled visit (if the 
abnormality was not present already at the preceding scheduled visit). 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. The age at the time of 
visit/assessment will be used for determining abnormality criteria (as defined in Section 3.2.24). 
All ECG parameter values will be listed for subjects meeting any abnormality criteria. 
Abnormality criteria to be used in the determination of ECG abnormalities are defined as 
follows, where increase and decrease are relative to Baseline values: 
Table 8‒2: 
ECG abnormality criteria 
 
Parameter 
Age Range 
Abnormality Criteria 
QT interval (ms) 
1m - <12y 
>500 
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Parameter 
Age Range 
Abnormality Criteria 
>12y 
>500 or ≥60ms increase from Baseline 
QTc(F) (ms) 
<6m 
>490, or >15% increase from Baseline 
6m - <3y 
>440, or >15% increase from Baseline 
3y - <12y 
>440, or >15% increase from Baseline 
>12y - <17y 
>440, or >15% increase from Baseline 
≥17y 
>500 or ≥60ms increase from Baseline 
QTc(B) (ms) 
<6m 
>490, or >15% increase from Baseline 
6m - <3y 
>450, or >15% increase from Baseline 
3y - <12y 
>450, or >15% increase from Baseline 
>12y - <17y 
>450, or >15% increase from Baseline 
≥17y 
>500 or ≥60ms increase from Baseline 
PR interval (ms) 
<6m 
>150, or >25% increase from Baseline 
6m - <3y 
>170, or >25% increase from Baseline 
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) 
<6m 
>90, or >25% increase from Baseline 
6m - <3y 
>90, or >25% increase from Baseline 
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) 
<6m 
<100, >180 
6m - <3y 
<90, >150 
3y - <12y 
<60, >130 
>12y 
<50, >120 
Abbreviations: bpm=beats per minute; m=months; ms=milliseconds; QTc=corrected QT interval; y=years. A 
month is defined as 28 days; a year is defined as 365.25 days. 
A subject data listing will be provided that identifies subjects with a clinically significant finding 
after the first dose of LCM for each type of ECG abnormality. 
8.4.3 
Physical examination 
8.4.3.1 
Complete physical examination 
A complete physical examination will be performed throughout the study, according to the 
tabular schedules of procedures. 
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The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature measurement, and review of all body systems. 
Clinically significant physical examination findings will be reported as AEs. 
8.4.3.2 
Brief physical examination 
A brief physical examination will be performed throughout the study, according to the tabular 
schedules of procedures. 
The brief physical examination will include a review of the following body systems: 
• 
Cardiovascular 
• 
Pulmonary 
• 
Abdominal (hepato-gastrointestinal) 
• 
Dermatologic 
Clinically significant physical examination findings will be reported as AEs. 
8.4.4 
Neurological examination 
8.4.4.1 
Complete neurological examination 
A complete neurological examination will be performed throughout the study, according to the 
tabular schedules of procedures. 
The complete neurological examination will include selected assessment of: general neurological 
status (level of consciousness, mental status, speech), cranial nerves, reflexes, motor system 
(general motor status, muscle strength, muscle tone), coordination/cerebellar function, and 
sensation. 
Clinically significant neurological findings will be reported as AEs. Summaries of shift from 
Baseline to Last Visit will be provided based on categories normal, abnormal, not clinically 
significant, and abnormal, clinically significant. A listing of neurological examination findings 
from the complete neurological examination will also be provided. 
8.4.4.2 
Brief neurological examination 
A brief neurological examination will be performed throughout the study, according to the 
tabular schedules of procedures. 
The brief neurological examination will include selected assessment of: general neurological 
status, reflexes, muscle strength, and coordination/cerebella function. 
Clinically significant neurological findings will be reported as AEs. 
A listing of neurological examination findings from the brief neurological examination will also be 
provided. No summaries of these results are planned. 
8.4.5 
Vagus nerve stimulation 
VNS status is recorded throughout the study, according to the tabular schedules of procedures, only 
for those subjects with an implanted VNS device. 
A listing of VNS status will be provided only for those subjects with an implanted VNS device. 
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8.4.6 
Tanner stage assessment 
Tanner stage will be assessed throughout the study, according to the tabular schedules of 
procedures. 
The investigator or qualified designee 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 [entry to study] or who will enter puberty during the course of the study). 
A shift table will be produced showing the change in overall Tanner stage (1-5) from Baseline to Last 
Visit, by gender. 
 
8.4.7 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This will be completed according to the tabular schedules of study 
procedures. 
For subjects ≥6 years of age, this scale will be used for screening as well as to assess suicidal 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 entry to the study 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 use the Since Last Visit version at subsequent visits. 
For subjects <6 years of age, the C-SSRS is not validated and will not be used. For those 
subjects, signs and symptoms of depression will be assessed at each visit. 
Subject data listings of the data for the C-SSRS will be provided. No summaries of these results are 
planned. 
8.4.8 
Achenbach Child Behavior Checklist 
The Achenbach CBCL will be completed according to the tabular schedule of study procedures, 
only in countries where a validated translated version is available. 
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and 
behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the 
Achenbach CBCL is used. The CBCL/1½-5 is intended for use in children 18 months to 5 years 
and 11 months of age. For study subjects ≥6 years to ≤18 years, the CBCL/6-18 will be used.  
The CBCL/1½-5 comprises 100 questions and the CBCL/6-18 comprises 120 questions. In both 
questionnaires, the occurrence of certain problems and behaviors (in the past 2 months for the 
CBCL/1½-5 version and in the past 6 months for the CBCL/6-18 version) 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 
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The CBCL/1½-5 items will be grouped according to syndrome scales in Table 8‒3 and the 
CBCL/6-18 items will be grouped according to empirically based syndrome scales in Table 8‒4. 
For each syndrome, a raw score will be calculated as the sum of the considered item scores.  
Table 8‒3: 
CBCL/1½-5 
Syndrome scale 
Items 
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 
 
Table 8‒4: 
CBCL/6-18 
Syndrome scale 
Items 
Aggressive behavior 
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 
94, 95, 97, 104 
Anxious/depressed 
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112 
Attention problems 
1, 4, 8, 10, 13, 17, 41, 61, 78, 80 
Rule-breaking behavior 
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 
101, 105, 106 
Social problems 
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79 
Somatic complaints 
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g 
Thought problems 
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 
100 
Withdrawn/depressed 
5, 42, 65, 69, 75, 102, 103, 111 
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. Standardized T-scores determined from each subject’s raw syndrome scale 
scores will be reproduced programmatically using the appropriate scoring spreadsheets. 
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Raw scores 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. 
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. 
The Calculated T-scores, raw scores, and change from Baseline in raw scores will be listed. 
A decrease from Baseline (change from Baseline <0) in the CBCL syndrome raw score will indicate 
improvement in behavior, while an increase (change from Baseline > 0) indicates worsening. 
In addition, for both the CBCL/1½-5 syndrome and /6-18 syndrome, subjects will be categorized 
according to the Calculated T-score as follows: 
• 
T-score is < 65 = “Normal” 
• 
T-score is ≥ 65 = “Borderline or Clinical range (BCR)” 
Summaries of shifts from Baseline to each post-Baseline visit, and from Baseline to Last Visit 
will also be provided based on the CBCL calculated T-score categories of Normal and BCR. The 
descriptive summaries of change from Baseline and shift summaries will be presented only when 
a corresponding Baseline value from the same questionnaire is available.  
 
8.4.9 
BRIEF-P and BRIEF assessment 
The BRIEF-P/BRIEF assessments will be completed according to the tabular schedules of study 
procedures, only in countries where a validated translated version is available. 
The BRIEF-P and BRIEF are validated tools that will be used for the evaluation of subjects ≥2 to <5 
years of age, and ≥5 to ≤18 years of age, respectively. 
8.4.9.1 
BRIEF-P scores 
The BRIEF-P form comprises 63 questions with entry options N (never: scored as 1 point), S 
(sometimes: scored as 2 points), and O (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 8‒5. 
 
Table 8‒5: 
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 
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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. Tables that map each raw score to the 
appropriate T-score are provided in the BRIEF-P Professional Manual. Standardized T-scores 
determined from each subject’s raw GEC score, subscale scores and 5 individual component 
scores will be produced programmatically using the appropriate scoring spreadsheets. 
Raw scores and change from Baseline for the three index scores, the GEC and the 5 individual 
component scores for the BRIEF-P questionnaire will be summarized for each visit, and Last 
Visit.  
The Calculated T-scores, raw scores, and changes from Baseline in raw scores will be listed. 
A decrease from Baseline (change from Baseline <0) in the BRIEF-P syndrome raw score will 
indicate improvement in behavior, while an increase (change from Baseline > 0) indicates 
worsening. 
In addition, for BRIEF-P, subjects will be categorized according to the Calculated T-score as 
follows: 
• T-score is < 65 = “Normal” 
• T-score is ≥ 65 = “Elevated” 
Summaries of shifts from Baseline to each post-Baseline visit, and from Baseline to Last Visit 
will also be provided based on BRIEF-P calculated T-score categories of Normal and Elevated. 
The descriptive summaries of change from Baseline and shift summaries will be presented only 
when a corresponding Baseline value is available. 
All BRIEF-P assessment data will be listed. 
8.4.9.2 
BRIEF scores 
The BRIEF form comprises 86 questions with entry options N (never: scored as 1 point), S 
(sometimes: scored as 2 points), and O (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 8‒6. 
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Table 8‒6: 
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 
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. 
Raw scores 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 for each visit, 
and Last Visit.  
Standardized T-scores determined from each subject’s raw GEC score, subscale scores, and 8 
individual component scores will be produced programmatically using the appropriate scoring 
spreadsheets. The Standardized T-scores, raw scores, and changes from Baseline in raw scores 
will be listed. 
A decrease from Baseline (change from Baseline <0) in the BRIEF scores will indicate 
improvement in behavior, while an increase (change from Baseline > 0) indicates worsening. 
In addition, for BRIEF, subjects will be categorized according to the Calculated T-score as 
follows: 
• T-score is < 65 = “Normal” 
• T-score is ≥ 65 = “Elevated” 
Summaries of shifts from Baseline to each post-Baseline visit, and from Baseline to Last Visit 
will also be provided based on BRIEF calculated T-score categories of Normal and Elevated. 
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The descriptive summaries of change from Baseline and shift summaries will be presented only 
when a corresponding Baseline value is available. 
All BRIEF assessment data will be listed. 
8.4.10 
Bayley-III assessment 
The Bayley-III assessments will be completed according to the tabular schedules of study 
procedures for subjects <18 months of age at study entry if enrolled in English-speaking 
countries. 
This scale is validated as a tool for assessment of neurological development in young children and is 
therefore considered appropriate for this study. 
The same scale should be completed for 1 year after the Baseline assessment of the previous 
study, even if the subject turns >18 months of age during that period. 
The Bayley-III scales are an individually administered adaptive assessment that presents children 
with situations and tasks designed to produce an observable set of behavioral responses. They consist 
of a cognitive scale, a language composite scale with receptive and expressive language subscales, 
and a motor composite scale with fine and gross motor subscales to be completed by the Investigator 
or designee, and of a social-emotional scale, comprising social emotional competence, and sensory 
processing, and an adaptive behavior scale, which assesses the attainment of skills necessary for the 
development of independence, to be completed by the child’s parent or caregiver. 
The sum of scale scores entered on the eCRF module, and the change from Baseline for the scales, 
as well as the general adaptive composite sum scale score, will be summarized for each visit, and 
Last Visit. 
All Bayley-III assessment data will be listed. 
8.4.11 
Medical procedures 
The number of concomitant medical procedures per subject will be summarized for the 
Treatment Period. The number of concomitant medical procedures per subject will be 
summarized using the categories 0, 1, 2, and 3 or more. 
Subjects who had any concomitant medical procedures during the course of the study based on the 
Concomitant Medical Procedures eCRF module will be listed. 
 
9 
EFFICACY ANALYSES 
The study efficacy variables include seizure counts (assessed using seizure diaries in order to 
evaluate preliminary evidence of efficacy during long-term exposure in this population), the Clinical 
Global Impression of Change, the Caregiver Global Impression of Change, and quality of life 
assessments (PedsQL and health care resource use). 
All study efficacy variables will be summarized for the FAS, overall and repeated by enrollment 
group (where applicable), using the levels defined in Section 3.2.12. All summaries of efficacy data 
are descriptive; no statistical testing will be performed. 
All efficacy variables will be listed. 
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9.1 
Efficacy variables based on seizures 
In general, efficacy variables based on seizures will be measured using data obtained from 
EP0034 subject diaries. 
Each seizure code in the clinical database will be mapped to exactly 1 of the ILAE seizure codes 
based on the 1981 ILAE classification (Seizure Count eCRF module). 
9.1.1 
Percentage of seizure-free days 
The percentage of seizure-free days (as defined in Section 3.2.20) will be summarized by seizure time 
intervals (as defined in Section 3.2.21) and also for the entire Treatment Period. This will also be 
grouped by enrollment group. This will be repeated, separately by seizure type (simple partial, complex 
partial, or partial, secondary generalized). 
9.1.2 
Seizure frequency per 28 days 
The following analyses will only be done for subjects who participated in SP0969. 
Seizure frequency per 28 days (as defined in Section 3.2.13) will be summarized descriptively and 
presented graphically. 
9.1.3 
≥50% reduction in 28-days partial-onset seizure frequency 
The following analyses will only be done for subjects who participated in SP0969. 
The number and percentage of subjects with ≥50% reduction in 28-day partial-onset seizure 
frequency (≥50% responders as defined in Section 3.2.15) will be summarized by seizure time 
intervals (as defined in Section 3.2.21) and also for the entire Treatment Period. This will be 
repeated, separately by seizure type (simple partial, complex partial, or partial, secondary 
generalized). Any subject with seizure data during the time interval will be included in the 
summary for that seizure time interval and by seizure type.  
9.1.4 
≥75% reduction in 28-days partial-onset seizure frequency 
The analyses described in Section 9.1.3 for percentage of subjects with ≥50% reduction in 28-days 
partial-onset seizure frequency will also be performed for study subjects with ≥75% reduction in 28-day 
partial-onset seizure frequency (≥75% responders) for subjects who participated in SP0969. 
9.1.5 
Absolute and percent reduction in total partial-onset seizures 
The following analyses will only be done for subjects who participated in SP0969. 
Absolute and percent reduction from Baseline (as defined in Section 3.2.14) in total partial-onset 
seizures will be summarized by seizure time intervals (as defined in Section 3.2.21) and also for the 
entire Treatment Period. This will be repeated, separately by seizure type (simple partial, complex 
partial, or partial, secondary generalized). 
9.1.6 
Seizure-free status 
The number and percentage of subjects who achieved seizure-free status (as defined in 
Section 3.2.18) will be summarized for the entire Treatment Period. This will be presented by 
completer cohorts (as defined in Section 3.2.19) and repeated by enrollment groups. 
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The number and percentage of study subjects seizure-free among completer cohorts (as defined in 
Section 3.2.19) will also be presented separately by seizure type (simple partial, complex partial, or 
partial, secondary generalized). 
Seizure-free status will also be presented by seizure time intervals (as defined in 
Section 3.2.21) and repeated by enrollment groups. The number and percentage of study 
subjects with seizure-free status at the end of each time interval during the treatment period will 
be presented separately by seizure type (simple partial, complex partial, partial, secondary 
generalized). 
9.2 
Analysis of other efficacy variables 
The following other efficacy variables will be computed for all subjects in this study and 
summarized for the FAS. 
9.2.1 
Clinical Global Impression of Change 
The Clinical Global Impression of Change is a 7-point categorical rating scale in which the 
investigator should provide his/her assessment of the subject’s clinical status, compared to Baseline, 
including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s 
functional status. This will be assessed at least once per year and will be completed according to the 
tabular schedule of study procedures. 
The number and percentage of subjects by Clinical Global Impression of Change value will be 
summarized by visit and Last Visit. This will be repeated by enrollment group. The denominator for 
the percentage calculation will be based on the number of subjects with non-missing values. In 
addition, the 3 improvement values (Very much improved, Much improved, and Minimally 
improved) grouped as “Improved” and the 3 worsening values (Minimally worse, Much worse, and 
Very much worse) grouped as “Worsened”, together with the “No change” group will be summarized 
by visit and Last Visit. The denominator for the percentage calculation will be based on the number 
of subjects with non- missing values. 
Clinical Global Impression of Change data will be listed. 
9.2.2 
Caregiver’s Global Impression of Change 
The Caregiver’s Global Impression of Change is a 7-point categorical rating scale in which the 
caregiver (including parent/legal guardian) should provide his/her assessment of the subject’s clinical 
status, compared to Baseline, including an evaluation of seizure frequency and intensity, the 
occurrence of AEs, and subject’s functional status. This will be assessed at least once per year and 
will be completed according to the tabular schedule of study procedures. 
 
The number and percentage of subjects by Caregiver’s Global Impression of Change value will be 
summarized by visit and Last Visit. This will be repeated by enrollment group. The denominator for 
the percentage calculation will be based on the number of subjects with non-missing values. In 
addition, the 3 improvement values (Very much improved, Much improved, and Minimally improved) 
grouped as “Improved” and the 3 worsening values (Minimally worse, Much worse, and Very much 
worse) grouped as “Worsened”, together with the “No change” group will be summarized by visit and 
Last Visit. The denominator for the percentage calculation will be based on the number of subjects 
with non- missing values. 
Caregiver’s Global Impression of Change data will be listed. 
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9.2.3 
Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions. The PedsQL will 
be completed up to two time per year and will be assessed according to the tabular schedule of 
study procedures. The Section 3.2.22 details how the scores for the core domains are 
calculated. 
9.2.3.1 
Pediatric Quality of Life Inventory Ages for ≤24 Months 
The multidimensional PedsQL ≤24 months generic core scales encompass the following core 
domains for pediatric HRQoL measurement: Physical Functioning, Physical Symptoms, 
Emotional Functioning, Social Functioning, and Cognitive Functioning. 
Calculated values and changes from Baseline for the total scale score (all items), the psychosocial 
health summary score, the physical health summary score and each of the 5 scale scores will be 
summarized for each visit and for Last Visit. This will be repeated by enrollment group. All changes 
from Baseline will only be calculated for visits when the subject uses the same form of the 
questionnaire as administered at baseline. 
All PedsQL ≤24 months data will be listed. 
9.2.3.2 
Pediatric Quality of Life Inventory Ages >2 years 
The multidimensional PedsQL >2 years generic core scales encompass the following core 
domains for pediatric HRQoL measurement: Physical Functioning, Emotional Functioning, 
Social Functioning, and School Functioning. 
Calculated values and changes from Baseline for the total scale score (all items), the 
psychosocial health summary score, the physical health summary score and each of the 4 scale 
scores will be summarized for each visit and for Last Visit. This will be repeated by enrollment 
group. For subjects 5 years and older at Baseline, changes from Baseline will be calculated for 
all visits, even when the questionnaire version used is different from the one at Baseline. For 
subjects less than 5 years at baseline, the change from Baseline will be calculated only when 
the same questionnaire version is used at Baseline and post-Baseline. All PedsQL >2 years data 
will be listed. 
9.2.4 
Health care resource use 
For health care resource use parameters, the following will be evaluated: concomitant 
medications (see Section 6.4), medical procedures, health care provider consultations not 
foreseen by the protocol, and hospitalization/ER visits. Health care resource use parameters 
will be collected according to the tabular schedules of study procedures. 
9.2.4.1 
Healthcare provider consultations 
The number of healthcare provider consultations per subject for the Treatment Period will be 
summarized. The number of healthcare provider consultations will be summarized using the 
categories 0, 1, 2, 3, 4, and 5 or more. 
The number of healthcare provider consultations during the Treatment Period will be summarized by 
type of provider (General Practitioner, Specialist Physician, Nurse, or Other). Percentages will be 
relative to the number of healthcare provider consultations during the Treatment Period. 
All healthcare provider consultations data will be listed. 
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9.2.4.2 
Hospital stays and ER visits 
The number of hospital stays per subject during the Treatment Period will be summarized. The 
number of hospital stays will be summarized using the categories 0, 1, 2, 3, 4, and 5 or more. The 
number and percentage of subjects with specific reasons for duration of hospital stays will be 
summarized for the duration of the Treatment Period. 
The durations of hospital stays for the Treatment Period will be summarized. Duration of hospital 
stays (as defined in Section 3.2.23) will be categorized as 0 days, 1-5 days, 6-10 days, 11-15 days, 
and >15 days, and summarized for the duration of the Treatment Period. 
An event logged on the Hospitalization/ER Visit eCRF module where ER 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. Descriptive 
statistics for the number of ER stays during the Treatment Period will be presented. The number of ER 
visits will be summarized using the categories 0, 1, 2, and 3 or more. The number and percentage of 
subjects with specific reasons for duration of ER visits will be summarized for the duration of the 
Treatment Period. 
Hospitalizations with either a partial admission or discharge date are ignored for the calculation of 
duration of hospital stay. However, such hospitalizations are counted for the number of hospital 
stays. Subjects with no hospital stays will have a duration of 0 days. Should distinct records for 
hospital stays overlap, then the days during the overlap will only be counted once. Similarly this also 
applies for ER visits. 
All hospitalization and ER data will be listed. 
10 
PHARMACOKINETICS AND PHARMACODYNAMICS 
This section is not applicable for this study. 
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11 
REFERENCES 
This section is not applicable for this study. 
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12 
APPENDICES 
12.1 
Marked abnormality criteria for laboratory data 
12.1.1 
Marked abnormality criteria for hematology data  
Table 12‒1: Hematology abnormality criteria  
Parameter 
Age Range 
Unit 
(conventional) 
Abnormality 
criteria 
(conventional 
unit) 
Unit 
(standard) 
Abnormality 
criteria 
(standard 
unit) 
Hematocrit 
<2y 
% 
≤27 
>45
% 
≤27 
>45
2y - <17y 
% 
≤29 
>47 
% 
≤29 
>47 
≥17y 
% 
≤85% of LLN 
≥115% of ULN 
% 
≤85% of LLN 
≥115% of ULN 
Hemoglobin 
<2y 
g/dL 
≤9.0 
 g/L 
≤90 
2y - <17y 
g/dL 
≤9.5 
g/L 
≤95 
≥17y 
g/dL 
≤85% of LLN 
g/L 
≤85% of LLN 
WBC/ 
Leukocytes
All 
109/L 
≤3.0 
≥16 0
G/L 
≤3.0 
≥16 0
Lymphocytes 
Absolute 
<2y 
109/L 
<1.0 
>9 8
G/L 
<1.0 
>9 8
2y - <6y 
109/L 
<0.7 
>6.9 
G/L 
<0.7 
>6.9 
≥6y 
109/L 
<0.6 
>5.0
G/L 
<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 
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Table 12‒1: Hematology abnormality criteria 
 
Parameter 
Age Range 
Unit 
(conventional) 
Abnormality 
criteria 
(conventional 
unit) 
Unit 
(standard) 
Abnormality 
criteria 
(standard 
unit) 
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 
<3.0 
T/L 
<3.0 
≥2y 
1012/L 
<3.5 
T/L 
<3.5 
Abbreviations: ANC=absolute neutrophil count; m=months, y= years. A month is defined as 28 days; a year is 
defined as 365.25 days. 
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12.1.2 
Marked abnormality criteria for chemistry data  
Table 12‒2: Chemistry abnormality criteria 
Parameter 
Age Range 
Unit 
(conventional) 
Abnormality 
criteria 
(conventional 
unit) 
Unit 
(standard) 
Abnormality 
criteria 
(standard 
unit) 
AST (SGOT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10 0
ULN
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10 0
ULN
ALT (SGPT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10 0
ULN
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10 0
ULN
Alkaline 
Phosphatase 
<4y 
U/L 
≥690 
U/L 
≥690 
4y - <10y 
U/L 
≥834 
U/L 
≥834 
10y - <17y 
U/L 
≥1761 
U/L 
≥1761 
≥17y 
U/L 
≥3.0 x ULN 
U/L 
≥3.0 x ULN 
GGT 
<6m 
U/L 
≥522 
U/L 
≥522 
6m - <1y 
U/L 
≥279 
U/L 
≥279 
1y - <13y 
U/L 
≥66 
U/L 
≥66 
13y - <17y 
U/L 
≥126 
U/L 
≥126 
≥17y 
U/L 
≥3.0 x ULN 
U/L 
≥3.0 x ULN 
Total Bilirubin 
>1m 
mg/dL 
≥2.0 
umol/L 
≥34.208 
Total Protein 
2m-<1y 
g/dL 
<3.0 
>11.9
g/L 
<30 
>119
1y - <17y 
g/dL 
<4.3 
>12.0
g/L 
<43 
>120
≥17y 
g/dL 
<4.3 
>13.0
g/L 
<43 
>130
Albumin 
<1y 
g/dL 
<1.6 
>7.2
g/L 
<16 
>72
≥1y - <17y 
g/dL 
<2.4 
>8.4
g/L 
<24 
>84
≥17y 
g/dL 
<2.6 
g/L 
<26 
BUN 
<1y 
mg/dL 
≥24 
mmol/L 
≥8.568 
1y - <17y 
mg/dL 
≥36 
mmol/L 
≥12.852 
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Parameter 
Age Range 
Unit 
(conventional) 
Abnormality 
criteria 
(conventional 
unit) 
Unit 
(standard) 
Abnormality 
criteria 
(standard 
unit) 
≥17y 
mg/dL 
≥40 
mmol/L 
≥14.28 
Urea 
<1y 
mg/dL 
>42 
mmol/L 
>7.014 
≥1y 
mg/dL 
>60 
mmol/L 
>10.02 
Creatinine 
1y - <10y 
mg/dL 
>1.2 
umol/L 
>106.8 
10y - <16y 
mg/dL 
>1.8 
umol/L 
>159.12 
≥16y 
mg/dL 
≥2.0 
umol/L 
≥176.8 
Creatinine 
Clearancea,b 
All 
mL/min 
<50 
mL/s 
<0.835 
Bicarbonate 
>1m - <17y 
mEq/L 
<15 
mmol/L 
<15 
>38 
>38 
≥17y 
mEq/L 
<18 
mmol/L 
<18 
>38 
>38 
Calcium 
<1y 
mg/dL 
<6.9 
mmol/L 
<1.725 
>12.2 
>3.05 
1y - <17y 
mg/dL 
<7.4 
mmol/L 
<1.85 
>11.7 
>2.925 
≥17y 
mg/dL 
≤7.6 
mmol/L 
≤1.9 
≥11.0 
≥2.75 
Chloride 
>1m 
mEq/L 
≤90 
mmol/L 
≤90 
≥112 
≥112 
Phosphorous 
<1y 
mg/dL 
<1.8 
mmol/L 
<0.5814 
>8.2 
>2.6486 
1y - <17y 
mg/dL 
<1.8 
mmol/L 
<0.5814 
>7.4 
>2.3902 
≥17y 
mg/dL 
≤2.0 
mmol/L 
≤0.646 
≥6.0 
≥1.938 
Potassium 
<1y 
mEq/L 
≤3.0 
mmol/L 
≤3.0 
≥6.5 
≥6.5 
≥1y 
mEq/L 
≤3.0 
mmol/L 
≤3.0 
≥6.0 
≥6.0 
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Parameter 
Age Range 
Unit 
(conventional) 
Abnormality 
criteria 
(conventional 
unit) 
Unit 
(standard) 
Abnormality 
criteria 
(standard 
unit) 
Sodium 
>1m 
mEq/L 
<127 
mmol/L 
<127 
>151 
>151 
Glucose 
>1m - <17y 
mg/dL 
<50 
mmol/L 
<2.775 
≥180 
≥9.99 
≥17y 
mg/dL 
<50 
mmol/L 
<2.775 
≥200 
≥11.1 
Total 
Cholesterol 
≥1y 
mg/dL 
>250 
mmol/L 
>6.475 
LDL 
(calculated) 
1y - <17y 
mg/dL 
>140 
mmol/L 
>3.626 
≥17y 
mg/dL 
>200 
mmol/L 
>5.18 
HDL 
≤2y 
mg/dL 
<10 
mmol/L 
<0.259 
>2y 
mg/dL 
<20 
mmol/L 
<0.518 
Triglycerides 
<1y 
mg/dL 
>750 
mmol/L 
>8.475 
≥1y 
mg/dL 
>300 
mmol/L 
>3.39 
Uric Acid 
<1y 
mg/dL 
>7.7 
umol/L 
>457.996 
1y - <13y 
mg/dL 
>6.5 
umol/L 
>386.62 
13y - <17y 
mg/dL 
>8.6 
umol/L 
>511.528 
≥17y 
mg/dL 
>9.5 
umol/L 
>565.06 
Thyroxine (T4) 
<1y 
ug/dL 
≤4.3 
nmol/L 
≤55.3453 
≥18.4 
≥236.8264 
≥1y 
ug/dL 
≤3.8 
nmol/L 
≤48.9098 
≥13.5 
≥173.7585 
Globulin 
<1y 
g/dL 
<1.0 
g/L 
<10 
>4.5 
>45 
≥1y 
g/dL 
<1.2 
g/L 
<12 
>5.3 
>53 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
dL=deciliter; GGT=gamma-glutamyl transferase; HDL=high density lipoprotein; LDL=low density lipoprotein; 
L=liter; m=months (a month is defined as 28 days) mg=milligram; mmol=millimoles; μg=microgram; U=unit; 
ULN=upper limit of normal; y=years (a year is defined as 365.25 days) 
a  Schwartz equation (subjects <12): Cr Cl ml/min=[Height (cm) * 0.55] / serum creatinine 
b 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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12.2 
Other Significant AEs 
 
The following MedDRA PTs are defined as other significant TEAEs. 
 
 
Table 12‒3: Other significant TEAEs 
MedDRA Preferred Term 
CARDIAC AND ECG RELATED TERMS 
Atrial conduction time prolongation 
Atrial fibrillation 
Atrial flutter 
Atrioventricular block second degree 
Atrioventricular block third degree  
Atrioventricular dissociation 
Bradyarrhythmia 
Bradycardia 
Brugada syndrome 
Cardiac arrest 
Cardiac fibrillation 
Cardiac flutter 
Cardiac pacemaker insertion 
Conduction disorder 
Defect conduction intraventricular 
Electrocardiogram QT prolonged 
Heart Rate decreased 
Implantable defibrillator insertion 
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Table 12‒3: Other significant TEAEs 
MedDRA Preferred Term 
Sick sinus syndrome 
Sinus arrest 
Sinus bradycardia 
Torsade de pointes 
Ventricular asystole 
Ventricular fibrillation 
Ventricular flutter 
Ventricular tachyarrhythmia 
Ventricular tachycardia 
SUICIDALITY RELATED TERMS 
Completed suicide 
Depression suicidal 
Intentional overdose 
Intentional self-injury 
Multiple drug overdose intentional 
Poisoning deliberate 
Self injurious behaviour 
Self-injurious ideation 
Suicidal behaviour 
Suicidal ideation 
Suicide attempt 
ADDITIONAL TERMS 
Abnormal behaviour 
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Table 12‒3: Other significant TEAEs 
MedDRA Preferred Term 
Appetite disorder 
Decreased appetite 
Diet refusal 
Food aversion 
Hypophagia 
Loss of consciousness 
Syncope 
 
 
 
12.3 
List of AEs for Potentially Drug Induced Liver Injury (PDILI) 
The following MedDRA PTs are defined as AEs for Potentially Drug Induced Liver Injury: 
Table 12‒4: AEs for PDILI 
MedDRA Preferred Term for PDILI 
Acute hepatic failure 
Alanine aminotransferase increased 
Allergic hepatitis 
Aspartate aminotransferase increased 
Asterixis 
Blood bilirubin abnormal 
Blood bilirubin increased 
Cholestasis 
Cholestatic liver injury 
Cholestatic pruritus 
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Chronic hepatitis 
Coma hepatic 
Cryptogenic cirrhosis 
Drug-induced liver injury 
Hepatic cirrhosis 
Hepatic encephalopathy 
Hepatic failure 
Hepatic infiltration eosinophilic 
Hepatic necrosis 
Hepatic steatosis 
Hepatitis 
Hepatitis acute 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis toxic 
Hepatobiliary disease 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatotoxicity 
Hyperbilirubinaemia 
Icterus index increased 
Jaundice 
Jaundice cholestatic 
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Jaundice hepatocellular 
Liver disorder 
Liver injury 
Mixed liver injury 
Non-alcoholic steatohepatitis 
Ocular icterus 
Subacute hepatic failure 
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13 
AMENDMENTS TO THE STATISTICAL ANALYSIS PLAN 
13.1 
Amendment 1 
Rationale for the amendment 
The primary purpose of this substantial amendment is for consistency with other SAPs and 
protocols in the LCM pediatric program. 
Specific changes 
Change #1 
SAP/Amendment Number and Date 
Final SAP 28 May 2015 
 
Has been changed to: 
SAP – Amendment 1 10 Feb 2016 
 
Change #2 
Section 2.3 Study design and conduct 
Investigators will be allowed to increase or decrease the dose of LCM to optimize tolerability and 
seizure reduction in each subject. LCM doses may be increased up to a maximum of LCM 600mg/day 
or 12mg/kg/day, whichever is lower based on body weight. 
 
Has been changed to: 
Investigators will be allowed to increase or decrease the dose of LCM to optimize tolerability and 
seizure reduction in each subject. LCM doses may be increased up to a maximum of LCM 600mg/day 
or 12mg/kg/day, whichever is lower based on body weight; LCM doses may be decreased to a 
minimum of LCM 100mg/day (tablet) or 2mg/kg/day (oral solution). 
 
Change #3 
Section 3.2.4 Study visit labeling 
Visits will be labeled in table summaries (according to the schedule outlined in Section 5.2 of the 
protocol) as follows: 
• 
“Visit X, Week X (Descriptor)” for scheduled visits during the Treatment Period 
• 
“Taper Visit” 
• 
“Safety Follow-up Visit” 
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• 
“Last Visit” (see below in Section 3.2.6 for further information) 
Listings will also include “Unscheduled Visit” as applicable. 
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Has been changed to: 
Visits will be labeled in table summaries (according to the schedule outlined in Section 5.2 of the 
protocol) as follows: 
• 
“Visit X, Week X” for scheduled visits during the Treatment Period 
• 
“Taper Visit” 
• 
“Safety Follow-up Visit” 
• 
“Last Visit” (see below in Section 3.2.6 for further information) 
Listings will also include “Unscheduled Visit” as applicable. 
 
Change #4 
Section 3.2.5 Monthly time intervals 
For the analysis of safety outcomes in the Treatment Period, a subject is included in the analysis for a 3-
month interval if they are exposed to LCM for the duration of that interval. 
 
Has been changed to: 
For the analysis of safety outcomes in the Treatment Period, a subject is included in the analysis for a 3-
month interval if they are exposed to LCM at any time during that interval. 
 
Change #5 
Section 3.2.18 Seizure-free status 
Subjects will be considered seizure-free for a given period if the subject completes the period, reports 
zero seizures during the period, and has no more than 10% of days in the period for which seizure data 
is not available (ie, “not done” is noted on the Seizure Frequency eCRF module). Seizure diary days 
where “not done” has been reported for days when subjects were participating in a previous study will 
not be counted toward the 10% of days with missing seizure diary data (eg, missing seizure data due 
to a previous study will not count against a subject in the assessment of seizure-free status). 
 
Has been changed to: 
Subjects will be considered seizure-free for a given period if the subject completes the period, reports 
zero seizures during the period, and has no more than 10% of days in the period for which seizure data is 
not available (ie, “not done” is noted on the Seizure Frequency eCRF module). Seizure diary days where 
“not done” has been reported for days when subjects were participating in a previous study will not be 
counted toward the 10% of days with missing seizure diary data (eg, missing seizure data due to a 
previous study will not count against a subject in the assessment of seizure-free status). If a subject 
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enrolls in a short-term iv substudy, days of participation in the substudy will also not be considered in the 
assessment of seizure-free status. 
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Change #6 
Section 3.8 Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA® v16.1). Medications will be coded using the World Health Organization Drug Dictionary 
(WHODD 3Q13). Medical procedures will not be coded. 
 
Has been changed to: 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA® v16.1). Medications will be coded using the World Health Organization Drug Dictionary 
(WHODD SEP/2013). Medical procedures will not be coded 
 
Change #7 
Added the following section: 
Section 3.9.5 Planned safety analyses 
For planned safety analyses, the protocol states that: 
Summary tables will be presented over the Treatment Period by 3-month periods and by 
categories of total duration of exposure. 
However, only select AE tables will be presented by 3-month time intervals; incidence of all TEAEs 
with onset during the Treatment Period, incidence of all serious TEAEs with onset during the Treatment 
Period, incidence of all TEAEs leading to discontinuation with onset during the Treatment Period, and 
incidence of all other significant TEAEs with onset during the Treatment Period. 
 
Change #8 
Section 5.1 Subject disposition 
Additionally, a summary of disposition and discontinuation reasons will present the following for all 
screened subjects, and those in the SS (overall and repeated by weight band and enrollment group 
using the levels defined in Sections 3.2.10 and 3.2.12 respectively) and FAS: 
• 
The number and percentage of subjects starting the study 
• 
The number and percentage of subjects completing the study 
• 
The number and percentage of subjects completing <12 months and ≥12 months of the study, 
where 1 month is defined as 28 days 
• 
The overall number and percentage of subjects discontinuing and the number and percentage of 
subjects discontinuing by primary reason for discontinuation. If the subject discontinued the 
study and the Study Termination eCRF module is not available, the reason for discontinuation 
will be reported as “UNKNOWN”. 
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Has been changed to: 
Additionally, a summary of disposition and discontinuation reasons will present the following for all 
subjects in the SS (overall and repeated by weight band and enrollment group using the levels defined 
in Sections 3.2.10 and 3.2.12 respectively) and FAS: 
• 
The number and percentage of subjects starting the study 
• 
The number and percentage of subjects completing the study 
• 
The number and percentage of subjects completing <12 months and ≥12 months of the study, 
where 1 month is defined as 28 days 
• 
The overall number and percentage of subjects discontinuing and the number and percentage of 
subjects discontinuing by primary reason for discontinuation. If the subject discontinued the 
study and the Study Termination eCRF module is not available, the reason for discontinuation 
will be reported as “UNKNOWN”. 
 
Change #9 
Section 6.3.1 History of seizure types 
The number and percentage of subjects experiencing partial-onset seizures (type I), simple partial (type 
IA), complex partial (type IB), and partial, secondary generalized seizures (type IC), in addition to each 
seizure category within such, at any time prior to entry into the previous study will be summarized for the 
SS based on the International League Against Epilepsy (ILAE) Seizure Classification History eCRF 
module. 
A subject will be classified as having a history of partial-onset seizures if the subject has a history of 
simple partial (IA), complex partial (IB), or partial, secondary generalized (IC) seizures. A subject will be 
classified as having a history of simple partial seizures if the subject has a history of motor signs (IA1), 
somatosensory or special sensory symptoms (IA2), autonomic symptoms or signs (IA3), or psychic 
symptoms (IA4). A subject will be classified as having a history of complex partial seizures if the subject 
has a history of simple partial onset followed by impairment of consciousness with simple partial features 
(IB1a) or automatism (IB1b), or if the subject has a history of impairment of consciousness at onset with 
no other features (IB2a) or automatism (IB2b). A subject will be classified as having a history of partial, 
secondary generalized seizures if the subject has a history of simple partial evolving to generalized (IC1), 
complex partial evolving to generalized (IC2), or simple partial evolving to complex partial evolving to 
generalized (IC3) seizures. 
 
Has been changed to: 
The number and percentage of subjects experiencing partial-onset seizures (type I), simple partial (type 
IA), complex partial (type IB), partial, secondary generalized seizures (type IC), generalized seizures 
(type II), absence (IIA1), atypical absence (IIA2), myoclonic (IIB), clonic (IIC), tonic (IID), tonic-
clonic (IIE), and atonic (IIF) seizures at any time prior to entry into the previous study will be 
summarized for the SS based on the International League Against Epilepsy (ILAE) Seizure 
Classification History eCRF module. 
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A subject will be classified as having a history of partial-onset seizures if the subject has a history of 
simple partial (IA), complex partial (IB), or partial, secondary generalized (IC) seizures. A subject will be 
classified as having a history of generalized seizures (II) if the subject has a history of absence (IIA1), 
atypical absence (IIA2), myoclonic (IIB), clonic (IIC), tonic (IID), tonic-clonic (IIE), or atonic (IIF) 
seizures. A subject may also be classified as having a history of unclassified epileptic seizures (III). 
 
Change #10 
Section 8.2 Adverse events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented by 
weight band and enrollment group using the levels defined in Sections 3.2.10 and 3.2.12 respectively. 
In addition, all AE summaries will be presented by 3-month time intervals (as defined in Section 
3.2.5). The number and percentage of subjects experiencing each event at least once will be 
summarized. All summaries will be sorted alphabetically by SOC and by frequency of events within 
PTs, starting with the most frequent event overall. 
 
Has been changed to: 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented by 
weight band and enrollment group using the levels defined in Sections 3.2.10 and 3.2.12 respectively. 
In addition, select AE tables will also be presented by 3-month time intervals (as defined in Section 
3.2.5). The number and percentage of subjects experiencing each event at least once will be 
summarized. All summaries will be sorted alphabetically by SOC and by frequency of events within 
PTs, starting with the most frequent event overall. 
 
And the following has been added: 
The following summaries of AEs will be presented for the 3-month time intervals (as defined in Section 
3.2.5) of: <=3 months, >3 to <=6 months, >6 to <=9 months, >9 to <=12 months, >12 to 
<=15 months, >15 to <=18 months, >18 to <=21 months, >21 to <=24 months, and >=24 
months: 
• 
Incidence of all TEAEs with onset during the Treatment Period 
• 
Incidence of all serious TEAEs with onset during the Treatment Period 
• 
Incidence of all TEAEs leading to discontinuation with onset during the Treatment Period 
• 
Incidence of all other significant TEAEs with onset during the Treatment Period (defined in 
Appendix 12.2) 
 
Change #11 
Section 8.3 Clinical laboratory evaluations 
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Observed values of hematology, chemistry, and endocrinology parameters will be summarized for each 
visit and Last Visit. Change from Baseline for hematology, chemistry, and endocrinology parameters 
will be summarized for all post-Baseline visits, and Last Visit. 
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Has been changed to: 
Observed values of hematology, chemistry, and non-gender specific endocrinology parameters (ie thyroid 
stimulating hormone, triiodothyronine [total and serum-free], and thyroxine [total and serum-free]) will 
be summarized for each visit and Last Visit. Change from Baseline for hematology, chemistry, and non-
gender specific endocrinology parameters will be summarized for all post-Baseline visits, and Last Visit. 
Gender specific endocrinology parameters (ie follicle stimulating hormone, luteinizing hormone, and 
testosterone) will be presented similarly, by gender. 
 
Change #12 
Section 8.4.2 Electrocardiograms (ECGs) 
The number and percentage of subjects with no abnormality, an abnormal but not clinically significant 
finding, and a clinically significant finding, will be summarized for all visits, and Last Visit. Percentages 
will be relative to the number of subjects with an ECG assessment at each time point. Subjects are 
counted at most once at each time point based on the worst observed outcome across all abnormalities 
reported at that time point. 
Has been changed to: 
The number and percentage of subjects with no abnormality, an abnormal but not clinically significant 
finding, and a clinically significant finding, will be summarized for all visits, and Last Visit. Percentages 
will be relative to the number of subjects with an ECG assessment at each visit. Subjects are counted at 
most once at each visit based on the worst observed outcome across all abnormalities reported at that 
visit. 
 
Change #13 
Section 8.4.9 BRIEF-P and BRIEF assessment 
The BRIEF-P form comprises 63 questions with entry options N (never: scored as 1 point), S (sometimes: 
scored as 2 points), and O (often: scored as 3 points). 
The 63 items are included in the raw Global Executive Composite (GEC) score which ranges from 63 
to 189, with higher scores reflecting poorer functioning. 
The 2 subscale scores and 5 individual component scores that make up these subscale scores are outlined 
in Table 8-5. 
 
Table 8-5: 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 
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Emotional Control 
1, 6, 11, 16, 21, 26, 31, 36, 41, 46 
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Scale/Index 
Questions 
BRI 
All from {Inhibit, Shift, and Emotional Control} 
Working Memory 
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 
59 61 63
Plan/Organize 
4, 9, 14, 19, 24, 29, 34, 39, 44, 49 
MI 
All from {Working Memory and Plan/Organize} 
GEC Score 
1-63 
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component scores. 
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 two indexed scores (BRI and MI) and 
GEC for the BRIEF-P questionnaire will be summarized for each visit, and Last Visit. 
All BRIEF-P assessment data will be listed. 
Has been changed to: 
The BRIEF-P form comprises 63 questions with entry options N (never: scored as 1 point), S 
(sometimes: scored as 2 points), and O (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 8-5. 
Table 8-5: 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 
Scale/Index 
Questions 
Emergent metacognition 
All from {Working Memory and Plan/Organize} 
GEC Score 
1-63 
GEC=Global Executive Composite 
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Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, 
flexibility, emergent metacognition, and component scores. 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 indexed scores and GEC for the 
BRIEF-P questionnaire will be summarized for each visit, and Last Visit. 
All BRIEF-P assessment data will be listed. 
 
 
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13.2 
Amendment 2 
Rationale for the amendment 
The primary purpose of this substantial amendment is for consistency with CTP amendment 2 
dated 24th March 2017. 
Specific changes 
Change #1 
SAP/Amendment Number and Date 
SAP – Amendment 1 10 Feb 2016 
  Has been changed to: 
  SAP – Amendment 2  21 Mar 2019 
 
 
Change #2 
 
Section 2.2.3.1 Other efficacy variables 
 
The following other efficacy variables will be computed for subjects from SP0969: 
• 
Percentage of 50% responders (subjects with at least a 50% reduction in total partial- onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period before 
receiving LCM in the previous pediatric study 
• 
Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure type 
(simple partial, complex partial, or secondarily generalized) compared to Baseline 
The following other efficacy variables will be computed for all subjects in EP0034: 
• 
Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• 
Clinical Global Impression of Change 
• 
Caregiver’s Global Impression of Change 
• 
Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) for subjects ≥2 years 
of age 
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• 
Health care resource use: concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and hospital stays 
 
Was changed to: 
 
The following other efficacy variables will be computed for subjects from SP0969: 
• 
Percentage of 50% responders (subjects with at least a 50% reduction in total partial- onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period before 
receiving LCM in the previous pediatric study 
• 
Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Percentage of 75% responders (subjects with at least a 75% reduction in total partial-
onset seizure frequency per 28 days compared to Baseline), with Baseline defined as the 
period before receiving study medication in the previous pediatric study 
• 
Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure type 
(simple partial, complex partial, or secondarily generalized) compared to Baseline 
• 
Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034: 
• 
Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure 
and per seizure type (simple partial, complex partial, or secondarily generalized) 
• 
Clinical Global Impression of Change 
• 
Caregiver’s Global Impression of Change 
• 
Change from Baseline in Pediatric Quality of Life Inventory (PedsQL)  
• 
Health care resource use: concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and hospital stays 
 
Change #3 
 
Section 2.3 Study design and conduct 
 
The Taper Period (up to 6 weeks, depending on dose level achieved) will be required for subjects who 
complete the study or withdraw from treatment during the study if the following doses are achieved: 
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LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking tablets; 
lower doses will not require a taper. A Taper Visit must be completed at the end of the Taper Period. 
 
Was changed to: 
 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects who 
complete the study or withdraw from treatment during the study if the following doses are achieved: 
LCM ≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking tablets; 
lower doses will not require a taper. A Taper Visit must be completed at the end of the Taper Period. 
 
Change #4 
 
Section 3.1 
 
Summaries for PedsQL will be presented overall for all applicable subjects and additionally based on 
the subject’s age at Baseline (using the Baseline definition in Section 3.3), using the following age 
groups: 
• 
>2 to ≤4 years 
• 
≥5 to ≤7 years 
• 
≥8 to ≤12 years 
• 
≥13 to ≤18 years 
 
 
Has been changed to: 
 
 
Summaries for PedsQL will be presented overall for all applicable subjects and additionally based on 
the subject’s age at Baseline (using the Baseline definition in Section 3.3), using the following age 
groups: 
• 
≥1 to ≤12 months 
• 
≥13 to ≤24 months 
• 
>2 to ≤4 years 
• 
≥5 to ≤7 years 
• 
≥8 to ≤12 years 
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• 
≥13 to ≤18 years 
 
 
 
Change #5 
 
Section 3.2.22 
 
The PedsQL assessment is retrospective to the prior one month, 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 health-related quality 
of life (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 for each subject. 
 
Was changed to: 
 
The PedsQL assessment is retrospective to the prior one month, 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 health-related quality 
of life (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), and the 
psychosocial health summary score (a combination of the emotional, social and school functioning 
questions) for each subject. 
 
Change #6 
 
The following paragraph was added to section 3.2.3 
Subjects who prematurely discontinue the study will be evaluated based on the data collected at each 
visit attended. For those subjects, the ETV will be mapped to the next scheduled visit ie, the 
assessments documented at ETV will be assigned to the next scheduled visit, for which the 
corresponding assessment is scheduled following the last documented visit. 
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Change #7 
Section 3.2.9 Age and age at first diagnosis 
 
Was changed to: 
Section 3.2.9 Age at entry and age at first diagnosis 
 
Change #8 
 
Section 3.2.13 Seizure frequency 
 
If a seizure cluster is reported, it will be assigned to the correct seizure type and the highest recorded daily 
number of seizures of that seizure type during the 28 days prior to the cluster event will be used as the 
imputed number of seizures for the day on which the cluster occurred. If no other seizures are recorded for 
that seizure type for the subject in the 28 days prior to the cluster event, the frequency will be set to 1 or the 
number of cluster episodes reported if more than 1 cluster event occurred on the same day. 
 
Was changed to: 
 
If a seizure cluster is reported, it will be assigned to the correct seizure type and the highest recorded 
daily number of seizures of that seizure type during the 28 days prior to the cluster event will be used as 
the imputed number of seizures for the day on which the cluster occurred. If no other seizures are 
recorded for that seizure type for the subject in the 28 days prior to the cluster event, the frequency will 
be set to 1.  
If more than 1 cluster event occurred on the same day for Type II or Type III seizure, the seizure cluster 
will be assigned to the correct seizure type and the frequency for each cluster event will be set to the 
highest recorded daily number of seizures of that seizure type during the 28 days prior to the cluster 
event. If no other seizures are recorded for that seizure type for the subject in the 28 days prior to the 
cluster event, the frequency will be set to the number of cluster episodes reported. 
If more than 1 cluster event occurred on the same day for Type I seizure, the seizure clusters will be 
assigned to the correct seizure type and overall frequency will be set to the maximum of: 
• 
The highest recorded daily number of seizures of that seizure type during the 28 days prior to the 
cluster event 
The number of cluster episodes reported on that day 
 
Change #9 
 
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The following paragraph was added to section 3.2.22 
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. The PedsQL Measurement Model 
consists of developmentally appropriate forms for pediatric subjects >=1 month to <=12 months, >=13 
months to <=24 months, >2 years to <=4 years, >=5 years to <=7 years, >=8 years to <=12 years, and 
>=13 years to <=18 years of age. For each subject, the same version that is used at Baseline should be 
used for 12 months and thereafter the age 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 
• 
School Functioning 
 
Change #10 
 
Section 3.4 Protocol deviations 
Important protocol deviations will be reviewed as part of the Data Evaluation Meetings (DEMs) prior to 
database lock. A list of subjects with important protocol deviations will be agreed upon during the 
DEMs and will be documented in the DEM minutes. 
 
Was changed to: 
Important protocol deviations will be reviewed as part of the Data Evaluation Meetings (DEMs) and 
Data Cleaning meetings prior to database lock. A list of subjects with important protocol deviations will 
be agreed upon during the DEMs and will be documented in the DEM minutes. 
 
Change #11 
 
Section 3.5.2 Full Analysis Set 
The FAS will be used for the analysis of seizure data and will consist of all subjects in the SS, who 
have at least 1 completed post-Baseline seizure diary. 
 
Was changed to: 
The FAS will be used for the analysis of seizure data and will consist of all subjects in the SS, who 
have at least 1 completed post-Baseline seizure diary. Subjects whose efficacy data could not be 
source verified will be excluded from the FAS. 
 
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Change #12 
 
Section 3.9.5 Planned safety analyses 
However, only select AE tables will be presented by 3-month time intervals; incidence of all TEAEs with 
onset during the Treatment Period, incidence of all TEAEs leading to discontinuation with onset during the 
Treatment Period, and incidence of all other significant TEAEs with onset during the Treatment Period. 
 
Was changed to: 
However, only select AE tables will be presented by 3-month time intervals; incidence of all TEAEs 
with onset during the Treatment Period, incidence of all serious TEAEs with onset during the Treatment 
Period, incidence of drug-related TEAEs, incidence of TEAEs by maximum intensity, incidence of all 
TEAEs leading to discontinuation with onset during the Treatment Period, and incidence of all other 
significant TEAEs with onset during the Treatment Period. 
 
Change #13 
Section 4.2.2 Incomplete dates for Adverse events 
For analyses of AEs and concomitant medication usage, a complete date must be established in order to 
correctly identify the AE or medication as occurring during treatment or not. For purposes of imputing 
missing components of partially-reported start and stop dates for AEs and for medication use, the 
algorithms listed below will be followed. Start and stop dates of AEs or concomitant medication will be 
displayed as reported in the subject data listings (ie, no imputed values will be displayed in data 
listings). 
• 
Missing start day, but month and year present: 
If the start of LCM occurred in the same month and year as the occurrence of the 
AE/concomitant medication, the start day of the event/concomitant medication will be 
assigned to the day of first intake of LCM. Otherwise the start day will be set to the 1st day of 
the month. 
• 
Missing start day and month, but year present: 
If the start of LCM occurred in the same year as the occurrence of the AE/concomitant 
medication, the start day and month will be assigned to the date of first intake of LCM. 
Otherwise the start day and month will be set to January 1st. 
• 
Missing end day, but month and year present: 
The end day will be set to the last day of the month. 
• 
Missing end day and month, but year present: 
The end day and month will be set to the maximum of the date of study termination or the date 
equivalent to 28 days after last intake of LCM. 
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However, if the study termination year and year for the date which is 28 days after last intake of LCM are 
greater than the event/concomitant medication year, the day and month are to be set to December 31st. 
 
Was changed to: 
For analyses of AEs and concomitant medication usage, a complete date must be established in order to 
correctly identify the AE or medication as occurring during treatment or not. For purposes of imputing 
missing components of partially-reported start and stop dates for AEs and for medication use, the 
algorithms listed below will be followed. Start and stop dates of AEs or concomitant medication will be 
displayed as reported in the subject data listings (ie, no imputed values will be displayed in data listings). 
• 
Missing start day, but month and year present: 
If the start of LCM occurred in the same month and year as the occurrence of the 
AE/concomitant medication, the start day of the event/concomitant medication will be assigned 
to the day of first intake of LCM. Otherwise the start day will be set to the 1st day of the month. 
• 
Missing start day and month, but year present: 
If the start of LCM occurred in the same year as the occurrence of the AE/concomitant medication, 
the start day and month will be assigned to the date of first intake of LCM. Otherwise the start day 
and month will be set to January 1st. 
• 
Missing end day, but month and year present: 
The end day will be set to the last day of the month. 
• 
Missing end day and month, but year present: 
The end day and month will be set to the maximum of the date of study termination or the date 
equivalent to 30 days after last intake of LCM. 
 
However, if the study termination year and year for the date which is 30 days after last intake of LCM are 
greater than the event/concomitant medication year, the day and month are to be set to December 31st. 
 
Change #14 
 
Section 5.1 Subject disposition 
 
A summary of disposition of analysis sets will be provided for all screened subjects. The following will be 
summarized: 
• 
The number of screened subjects 
• 
The number and percentage of subjects in the SS 
• 
The number and percentage of subjects in the FAS 
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Was changed to: 
 
A summary of disposition of analysis sets will be provided for all subjects. The following will be summarized: 
• 
The number and percentage of subjects in the SS 
• 
The number and percentage of subjects in the FAS 
 
Change #15 
 
Section 6.3.1 History of seizure types 
The number and percentage of subjects experiencing partial-onset seizures (type I), simple partial (type 
IA), complex partial (type IB), partial, secondary generalized seizures (type IC), generalized seizures 
(type II), absence (IIA1), atypical absence (IIA2), myoclonic (IIB), clonic (IIC), tonic (IID), tonic-clonic 
(IIE), and atonic (IIF) seizures at any time prior to entry into the previous study will be summarized for 
the SS based on the International League Against Epilepsy (ILAE) Seizure Classification History eCRF 
module. 
A subject will be classified as having a history of partial-onset seizures if the subject has a history of 
simple partial (IA), complex partial (IB), or partial, secondary generalized (IC) seizures. A subject will be 
classified as having a history of generalized seizures (II) if the subject has a history of absence (IIA1), 
atypical absence (IIA2), myoclonic (IIB), clonic (IIC), tonic (IID), tonic-clonic (IIE), or atonic (IIF) 
seizures. A subject may also be classified as having a history of unclassified epileptic seizures (III). 
 
Was changed to: 
The number and percentage of subjects experiencing partial-onset seizures (type I), simple partial 
(type IA), complex partial (type IB), and partial, secondary generalized seizures (type IC), in 
addition to each seizure category within such, at any time prior to study entry will be summarized 
based on the 1981 International League Against Epilepsy (ILAE) Seizure Classification History 
CRF/eCRF module. This will be summarized for the SS, by seizure classification subgroups.  
For POS subjects the following classifications will be used. A subject will be classified as having a 
history of partial-onset seizures (I) if the subject has a history of simple partial (IA), complex partial 
(IB), or partial, secondary generalized (IC) seizures. A subject will be classified as having a history 
of simple partial seizures if the subject has a history of motor signs (IA1), somatosensory or special 
sensory symptoms (IA2), autonomic symptoms or signs (IA3), or psychic symptoms (IA4). A 
subject will be classified as having a history of complex partial seizures if the subject has a history 
of simple partial onset followed by impairment of consciousness with simple partial features (IB1a) 
or automatism (IB1b), or if the subject has a history of impairment of consciousness at onset with no 
other features (IB2a) or automatism (IB2b). A subject will be classified as having a history of 
partial, secondary generalized seizures if the subject has a history of simple partial evolving to 
generalized (IC1), complex partial evolving to generalized (IC2), or simple partial evolving to 
complex partial evolving to generalized (IC3) seizures.  
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For subjects with generalized seizures the following classifications will be used. A subject will be 
classified as having a history of partial-onset seizures (I) if the subject has a history of simple partial 
(IA), complex partial (IB), or partial, secondary generalized (IC) seizures. A subject will be 
classified as having a history of simple partial seizures if the subject has a history of motor signs 
(IA1), somatosensory or special sensory symptoms (IA2), autonomic symptoms or signs (IA3), or 
psychic symptoms (IA4). A subject will be classified as having a history of generalized seizures (II) 
if the subject has a history of absence (IIA), myoclonic (IIB), clonic (IIC), tonic (IID), tonic-clonic 
(IIE), or atonic (IIF) seizures. A subject may also be classified as having a history of unclassified 
epileptic seizures (III). 
Change #16 
 
The following text was added to section 6.4 Prior and concomitant medications  
Medications ongoing from the parent study will be migrated.  
 
Change #17 
 
Section 6.4.1 Concomitant AEDs taken at the start of the EP0034 Treatment Period 
The number of concomitant AEDs taken at the start of the EP0034 Treatment Period will be summarized 
for the SS based on the following categorization: 1 AEDs, 2 AEDs and 3 AEDs. The number and 
percentage of subjects taking concomitant AEDs at the start of the EP0034 Treatment Period will be 
summarized, separately, by WHODD chemical subgroup (level 4) and preferred drug name, for the SS. 
 
Was changed to: 
The number of concomitant AEDs taken at the start of the EP0034 Treatment Period will be summarized 
for the SS based on the following categorization: 1 AEDs, 2 AEDs, 3 AEDs, and > 3 AEDs. The number 
and percentage of subjects taking concomitant AEDs at the start of the EP0034 Treatment Period will be 
summarized, separately, by WHODD chemical subgroup (level 4) and preferred drug name, for the SS. 
 
Change #18 
 
Section 8.2 
• 
Incidence of all other significant TEAEs with onset during the Treatment Period (defined in 
Appendix 12.2) 
In addition, summaries for the incidence of TEAEs overall, incidence of serious TEAEs, incidence of 
TEAEs leading to discontinuation, and incidence of other significant TEAEs will be repeated presenting the 
site and subject number of all those subjects experiencing each TEAE as well as in subject data listings.  
 
Has been changed to: 
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• 
Incidence of other significant TEAEs with onset during the Treatment Period (defined in Appendix 
12.2) 
In addition, summaries for the incidence of TEAEs overall, incidence of serious TEAEs, incidence of 
TEAEs leading to discontinuation, incidence of other significant TEAEs, and TEAES related to PDILI will 
be repeated presenting the site and subject number of all those subjects experiencing each TEAE as well as 
in subject data listings. 
 
Change #19 
 
Section 8.2 Adverse events 
 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• 
Incidence of TEAEs 
• 
Incidence of serious TEAEs 
• 
Incidence of non-serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation 
• 
Incidence of TEAEs by relationship to LCM 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of non-serious TEAEs by relationship to LCM 
• 
Incidence of fatal TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects by relationship to LCM 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
 
Was changed to: 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• 
Incidence of TEAEs 
• 
Incidence of serious TEAEs 
• 
Incidence of non-serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation 
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• 
Incidence of TEAEs by relationship to LCM 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of TEAEs related to Potentially Drug Induced Liver Injury (PDILI) 
• 
Incidence of non-serious TEAEs by relationship to LCM 
• 
Incidence of fatal TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects by relationship to LCM 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
 
Change #20 
 
The following paragraph was added to section 8.3 
 
Potential drug induced liver injury (PDILI) criteria as outlined in the protocol, will be checked at all laboratory 
assessments. The number and percentage of subjects meeting PDILI criteria (ie, ALT criteria and/or AST 
criteria and/or total bilirubin criteria, and/or presence of symptoms), will be presented by treatment group. 
Percentages will be based on the number of subjects with a non-missing measurement for the variable of 
interest at the relevant visit. 
 
Change #21 
 
Section 6.2 Medical History and concomitant diseases 
The number and percentage of subjects with a medical history condition (except epilepsy), at the time of 
entry into the previous pediatric study, including both resolved and ongoing conditions, will be summarized 
overall and by MedDRA® primary system organ class (SOC) and preferred term (PT) for the SS. 
 
Was changed to: 
6.2 Medical History and Concomitant Diseases 
6.2.1 Medical History 
The number and percentage of subjects with a medical history condition (except epilepsy), including both 
resolved and ongoing conditions, will be summarized overall and by MedDRA® primary system organ 
class (SOC) and preferred term (PT) for the SS. 
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6.2.2 Concomitant diseases and conditions 
The number and percentage of subjects with concomitant diseases and conditions (medical history 
conditions noted as ongoing at study entry for the EP0034 study), except epilepsy, will be summarized by 
SOC and PT for the SS. 
 
 
Change #22 
 
Section 8.4.7, Emotionally reactive domain for CBCL/1½-5  
 
Table 8‒3: 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, 28, 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, 
 
Was changed to: 
 
Table 8‒3: CBCL/1½-5 
 
Syndrome scale 
Questions 
Aggressive behavior 
8, 15, 16, 18, 20, 27, 29, 35, 40, 42, 44, 53, 58, 66, 
69 81 85 88 96
Anxious/depressed 
10, 33, 37, 43, 47, 68, 87, 90 
Attention problems 
5, 6, 56, 59, 95 
Emotionally reactive 
21, 46, 51, 79, 82, 83, 92, 97, 99 
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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, 
 
 
Change #23 
 
Section 8.49.2 
Table 8‒6: BRIEF questionnaire scoring 
 
Scale/Index 
Questions 
Working Memory 
2, 9, 17, 19, 24, 27, 32, 33, 37, 57 
Plan/Organize 
11, 15, 18, 22, 35, 36, 40, 46, 51, 53, 58 
Organization of Materials 
4, 29, 67, 68, 69, 72 
Monitor 
14, 21, 31, 34, 42, 52, 60, 63 
Metacognition Index (MI) 
All from {Initiate, Working Memory, 
Plan/Organize, Organization of Materials, and 
Monitor} 
GEC Score 
1-72 
 
Was changed to: 
Table 8‒6: BRIEF questionnaire scoring 
 
Scale/Index 
Questions 
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 
 
Change #24 
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Section 9.1.3 
 
Section 9.1.3 Percentage of 50% responders  
The number and percentage of ≥50% responders as defined in Section 3.2.15) will be summarized by 
seizure time intervals (as defined in Section 3.2.21) and also for the entire Treatment Period. Responder 
status will be assessed as described in Section 3.2.15 for a given seizure time interval based on the seizure 
data recorded during that interval. This will be grouped by modal daily LCM dose, using the levels defined 
in Section 3.2.8. This will be repeated, separately, by 6-month completer cohorts (as defined in Section 
3.2.19) and by seizure type (simple partial, complex partial, or secondarily generalized). 
 
Was changed to: 
 
Section 9.1.3 Percentage of subjects with ≥50% response to treatment 
The number and percentage of subjects with ≥50% reduction in 28-day partial-onset seizure frequency 
(≥50% responders as defined in Section 3.2.15) will be summarized by seizure time intervals (as defined in 
Section 3.2.21) and also for the entire Treatment Period. Responder status will be assessed as described in 
Section 3.2.15 for a given seizure time interval based on the seizure data recorded during that interval. This 
will be grouped by modal daily LCM dose, using the levels defined in Section 3.2.8. This will be repeated, 
separately, by 6-month completer cohorts (as defined in Section 3.2.19) and by seizure type (simple partial, 
complex partial, or secondarily generalized). 
 
Change #25 
 
Section 9.1.4 Percentage of 75% responders  
The analyses described in Section 9.1.3 for percentage ≥50% responders will also be performed for 
percentage of ≥75% responders for subjects who participated in SP0969. 
 
Was changed to: 
 
Section 9.1.4 Percentage of subjects with ≥75% response to treatment 
The analyses described in Section 9.1.3 for percentage of subjects with ≥50% response to treatment will also 
be performed for percentage of subjects with ≥75% reduction in 28-day partial-onset seizure frequency 
(≥75% responders) for subjects who participated in SP0969. 
 
Change #26 
 
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Section 9.1.6 Percentage of subjects who achieved “seizure-free” status 
 
Was changed to: 
 
Section 9.1.6 Percentage of subjects who achieved Seizure-free status 
 
Change #27 
 
Section 9.2.3 Pediatric Quality of Life Inventory (PedsQL) 
The multidimensional PedsQL generic core scales encompass the essential core domains for pediatric 
HRQoL measurement: Physical Functioning, Emotional Functioning, Social Functioning, and School 
Functioning. 
Calculated values and changes from Baseline for the total scale score and each of the 4 scale scores will be 
summarized for each visit and for Last Visit. This will be grouped by modal daily LCM dose, using the 
levels defined in Section 3.2.8.  
 
Was changed to: 
Calculated values and changes from Baseline for the total scale score and each of the 4 scale scores 
(defined in Section 3.2.22) will be summarized for each visit and for Last Visit. This will be grouped by 
modal daily LCM dose, using the levels defined in Section 3.2.8. All changes from Baseline will only be 
calculated for visits when the subject uses the same form of the questionnaire as administered at baseline. 
 
Change #28 
 
Section 12.2 Other significant AEs 
The following MedDRA PTs are defined as other significant TEAEs. 
 
MedDRA Preferred Term 
HEPATOTOXICITY RELATED TERMS 
Hepatitis toxic 
Hepatotoxicity 
CARDIAC AND ECG RELATED TERMS 
Atrioventricular block complete 
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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 
SUICIDALITY RELATED TERMS 
Completed suicide 
Depression suicidal 
Suicidal behaviour 
Suicidal ideation 
Suicide attempt 
Intentional self-injury 
Self injurious behaviour 
Self-injurious ideation 
Intentional overdose 
Poisoning deliberate 
ADDITIONAL TERMS 
Loss of consciousness 
Syncope 
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*All cases with reported reduced heart rate will be reviewed and only cases with marked bradycardia (marked 
reduction in heart rate) with HR <45 bpm will be listed as ‘Other Significant TEAEs’. 
 
 
Has been changed to: 
 
12.2 List of 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 
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Cardiac flutter 
Sinus arrest 
Torsade de pointes 
Ventricular asystole 
Ventricular flutter 
Ventricular tachyarrhythmia 
Implantable defibrillator insertion 
SUICIDALITY RELATED TERMS 
Completed suicide 
Depression suicidal 
Suicidal behaviour 
Suicidal ideation 
Suicide attempt 
Intentional self-injury 
Self injurious behaviour 
Self-injurious ideation 
Intentional overdose 
Multiple drug overdose intentional 
Poisoning deliberate 
ADDITIONAL TERMS 
Loss of consciousness 
Syncope 
Appetite disorder 
Decreased appetite 
Diet refusal 
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Change #29 
 
A new appendix 12.3 has been added 
 
 
 
Hypophagia 
Food aversion 
Abnormal behaviour 
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13.3 
Amendment 3 
 
Rationale for the amendment 
The primary purpose of this substantial amendment is to reflect the changes in Protocol amendment #3 
and for consistency with other SAPs in the LCM pediatric program. 
Specific changes 
Change #1 
SAP/Amendment Number 
Date 
SAP – Amendment 2 
21 Mar 2019 
 
Has been changed to: 
 
Final SAP 
28 May 2015 
SAP – Amendment 1 
10 Feb 2016 
SAP – Amendment 2 
21 Mar 2019 
SAP – Amendment 3 
03 Jun 2021 
 
Change #2 
List of abbreviations 
Added abbreviations for ALT, ALP, AST, BCR, COVID-19, GGT, and LFT. 
 
Change #3 
Section 2.2 Study variables 
Section 2.2.1 Safety variables 
The safety variables include the following: 
• 
Adverse event (AE) reporting 
• 
Safety laboratory tests (hematology; biochemistry including hepatic monitoring of alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, total bilirubin, 
and gamma-glutamyl transferase [GGT]; endocrinology for all subjects; and urinalysis for subjects 
≥5 years of age) 
• 
Electrocardiograms (ECGs) 
• 
Physical (Tanner Stage, if applicable depending on subject’s developmental status) and 
neurological examinations 
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• 
Vital signs (blood pressure and pulse rate) 
• 
Body weight and height 
Section 2.2.2 Other safety variables 
The other safety variables include the following: 
• 
Change from Baseline in the Achenbach Child Behavior Checklist (CBCL) score: the 
Achenbach CBCL/1½-5 for children from 1.5 to 5 years of age and the Achenbach CBCL/6-18 
for children ≥6 years of age 
• 
Change from Baseline in the Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) score for subjects ≥2 and <5 years of age 
• 
Change from Baseline in the Behavior Rating Inventory of Executive Function (BRIEF) score for 
subjects ≥5 years of age 
 
• 
Change from Baseline in the Bayley-III scales in subjects <18 months of age at study entry 
(applicable only to subjects enrolled in English-speaking countries) 
Section 2.2.3 Efficacy variables 
The efficacy variables planned for analysis will be based on seizure diary data from EP0034 and will 
include the following for all subjects: 
• 
Percentage of seizure-free days during the study 
Section 2.2.3.1 Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969: 
• 
Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset seizure 
frequency per 28 days compared to Baseline), with Baseline defined as the period before receiving 
LCM in the previous pediatric study 
• 
Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Percentage of 75% responders (subjects with at least a 75% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• 
Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure type 
(simple partial, complex partial, or secondarily generalized) compared to Baseline 
• 
Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034: 
• 
Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure and 
per seizure type (simple partial, complex partial, or secondarily generalized) 
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• 
Clinical Global Impression of Change 
• 
Caregiver’s Global Impression of Change 
• 
Change from Baseline in Pediatric Quality of Life Inventory (PedsQL)  
• 
Health care resource use: concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays 
 
Has been changed to: 
 
Section 2.2 Study variables 
Section 2.2.1 Primary Safety variables 
The primary safety variables include the following: 
• 
Incidence of TEAEs 
• 
Incidence of serious TEAEs 
• 
Incidence of TEAEs leading to study discontinuation 
Section 2.2.2 Other safety variables 
The other safety variables include the following: 
• 
Safety laboratory tests (hematology; biochemistry including hepatic monitoring of alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], total 
bilirubin, and gamma-glutamyl transferase [GGT]; endocrinology for all subjects; and urinalysis for 
subjects ≥5 years of age) 
• 
Electrocardiograms (ECGs) 
• 
Physical (Tanner Stage, if applicable depending on subject’s developmental status) and 
neurological examinations 
• 
Vital signs (blood pressure and pulse rate) 
• 
Body weight and height 
• 
Change from Baseline in the Achenbach Child Behavior Checklist (CBCL) score: the Achenbach 
CBCL/1½-5 for children from 1.5 to 5 years of age and the Achenbach CBCL/6-18 for children ≥6 
years of age 
• 
Change from Baseline in the Behavior Rating Inventory of Executive Function – 
Preschool Version (BRIEF-P) score for subjects ≥2 and <5 years of age 
• 
Change from Baseline in the Behavior Rating Inventory of Executive Function (BRIEF) score for 
subjects ≥5 years of age 
 
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• 
Change from Baseline in the Bayley-III scales in subjects <18 months of age at study entry 
(applicable only to subjects enrolled in English-speaking countries) 
Section 2.2.3 Efficacy variables 
Section 2.2.3.1 Primary efficacy variables 
No primary efficacy variables are defined for this study. 
Section 2.2.3.2 Secondary efficacy variables 
The secondary efficacy variable planned for analysis will be based on seizure diary data from EP0034 and 
will include the following for all subjects: 
• 
Percentage of seizure-free days during the study (presented for the overall Treatment Period only) 
Section 2.2.3.3 Other efficacy variables 
The following other efficacy variables will be computed for subjects from SP0969: 
• 
Percentage of 50% responders (subjects with at least a 50% reduction in total partial-onset seizure 
frequency per 28 days compared to Baseline), with Baseline defined as the period before receiving 
LCM in the previous pediatric study 
• 
Percentage of 50% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Percentage of 75% responders (subjects with at least a 75% reduction in total partial-onset 
seizure frequency per 28 days compared to Baseline), with Baseline defined as the period 
before receiving study medication in the previous pediatric study 
• 
Percentage of 75% responders per seizure type (simple partial, complex partial, or 
secondarily generalized) compared with Baseline 
• 
Absolute and percent reduction in total partial-onset seizures and per partial-onset seizure type 
(simple partial, complex partial, or secondarily generalized) compared to Baseline 
• 
Partial-onset seizure frequency per 28 days 
The following other efficacy variables will be computed for all subjects in EP0034: 
• 
Achievement of seizure-free status (no seizure) during the study for total partial-onset seizure and 
per seizure type (simple partial, complex partial, or secondarily generalized) 
• 
Clinical Global Impression of Change 
• 
Caregiver’s Global Impression of Change 
• 
Change from Baseline in Pediatric Quality of Life Inventory (PedsQL)  
• 
Health care resource use: concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays 
 
Change #4 
Section 2.3 Study design and conduct 
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The following text has been added in this section: 
The Safety Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required for subjects who 
participate in EP0151 or EP0152. 
 
Change #5 
Section 2.3 Study design and conduct 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects who 
complete the study or withdraw from treatment during the study if the following doses are achieved: LCM 
≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking tablets; lower 
doses will not require a taper. A Taper Visit must be completed at the end of the Taper Period. 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of 
LCM, should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the last dose of LCM. A Safety 
Follow-Up Telephone Contact is required for all subjects (those who complete the study as planned or have 
withdrawn prematurely from the study). This telephone contact will occur 30 days (-1/+3 days) after the last 
dose of LCM. 
Has been changed to: 
Taper Period 
The Taper Period (up to 4 weeks, depending on dose level achieved) will be required for subjects who 
complete the study or withdraw from treatment during the study if the following doses are achieved: LCM 
≥3mg/kg/day for subjects receiving oral solution, or LCM ≥150mg/day for subjects taking tablets; lower 
doses will not require a taper. Taper of LCM may not be required for some subjects who complete the study 
or withdraw from the study prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or legal representative(s) or for subjects who participate in EP0151 or 
EP0152.  
End of study and Safety Follow-up Period 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of 
LCM, should complete a Safety Follow-Up Visit 2 weeks (±2 days) after the last dose of LCM. A Safety 
Follow-Up Telephone Contact is required for all subjects (those who complete the study as planned or have 
withdrawn prematurely from the study). This telephone contact will occur 30 days (-1/+3 days) after the last 
dose of LCM. The Safety Follow-Up Visit and the Safety Follow-Up Telephone Contact are not required for 
subjects who participate in EP0151 or EP0152. 
 
Change #6 
Section 3.1 General presentation of summaries and analyses 
All summaries, unless otherwise stated below, will be presented overall for all subjects and additionally 
based on the subject’s age at time of entry into study EP0034, using the following age groups: 
• 
≥1 to <6 months 
• 
≥6 months to <1 year 
• 
≥1 to <2 years 
 
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• 
≥2 to <4 years 
• 
Total <4 years 
• 
≥4 to <12 years 
• 
≥12 to <16 years 
• 
Total ≥4 to <16 years 
• 
≥16 years 
Summaries for PedsQL will be presented overall for all applicable subjects and additionally based on 
the subject’s age at Baseline (using the Baseline definition in Section 3.3), using the following age 
groups: 
• 
≥1 to ≤12 months 
• 
≥13 to ≤24 months 
• 
>2 to ≤4 years 
• 
≥5 to ≤7 years 
• 
≥8 to ≤12 years 
• 
≥13 to ≤18 years 
 
Has been changed to: 
All summaries, unless otherwise stated below, will be presented overall for all subjects and additionally 
based on the subject’s age at time of entry into study EP0034, using the following age groups: 
• 
≥1 month to <4 years 
• 
≥4 to <18 years 
Summaries for PedsQL will be presented overall for all applicable subjects and additionally based on the 
subject’s age at Baseline (using the Baseline definition in Section 3.3), using the following age groups: 
• 
≥1 month to ≤12 months 
• 
>12 months to ≤24 months 
• 
>2 years to ≤4 years 
• 
≥5 to ≤7 years 
• 
≥8 to ≤12 years 
• 
≥13 to ≤18 years 
• 
Total ≥5 years to ≤18 years 
 
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Change #7 
Section 3.2.9 Age at entry and age at first diagnosis 
Age at entry into EP0034 will be given in years and will be derived applying all rules for missing date 
imputation (see Section 4.2.6) and the SDTM derivation definition, in the analysis dataset. 
The age at entry into the previous pediatric study and date of birth are migrated from the previous 
pediatric study into the EP0034 SDTM. 
The age at first diagnosis will be given in years and will be derived applying all rules for missing date 
imputation (see Section 4.2.6) with the following formula: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25 
 
Has been changed to: 
 
Section 3.2.9 Age at entry and age at first diagnosis 
Age at entry into EP0034 will be given in years. For subjects with complete date of birth available, age at 
entry in to EP0034 will use the SDTM derivation definition in the analysis dataset. 
For subjects without a complete date of birth available, age at entry into EP0034 will be calculated as: 
Age at entry into the previous pediatric study + (number of calendar months between the 
informed consent dates of the previous pediatric study and EP0034)/12. 
The age at entry into the previous pediatric study and date of birth are migrated from the previous pediatric 
study into the EP0034 SDTM.  
The age at first diagnosis will be given in years and will be derived applying all rules for missing date 
imputation (see Section 4.2.6) with the following formula: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25 
 
Change #8 
Section 3.2.22 Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with pediatric 
populations, including those with acute or chronic health conditions. The PedsQL Measurement Model 
consists of developmentally appropriate forms for pediatric subjects >=1 month to <=12 months, >=13 
months to <=24 months, >2 years to <=4 years, >=5 years to <=7 years, >=8 years to <=12 years, and 
>=13 years to <=18 years of age. For each subject, the same version that is used at Baseline should be 
used for 12 months and thereafter the age 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 
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• 
School Functioning 
The PedsQL assessment is retrospective to the prior one month, 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 health-related 
quality of life (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), and the 
psychosocial health summary score (a combination of the emotional, social and school functioning 
questions) for each subject. 
 
Has been changed to: 
 
Section 3.2.22 Pediatric Quality of Life Inventory (PedsQL) 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with pediatric 
populations, including those with acute or chronic health conditions. 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 ≥1 month to ≤4 years of age. The PedsQL Measurement 
Model consists of developmentally appropriate forms for pediatric study subjects ≥1 month to ≤12 
months, ≥13 months to ≤24 months, >2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and 
≥13 years to ≤18 years of age. For each subject, the same version that is used at Baseline should be used 
for 12 months and thereafter the age appropriate age versions should be used. 
For versions intended for subjects ≤24 months of age, PedsQL infant scale scores will be calculated for 
each of the following 5 PedsQL scales: 
• Physical Functioning 
• Physical Symptoms 
• Emotional Functioning 
• Social Functioning 
• Cognitive Functioning 
For versions intended for subjects >2 years of age, PedsQL generic core scale scores will be calculated for 
each of the following 4 PedsQL scales: 
• Physical Functioning 
• Emotional Functioning 
• Social Functioning 
• School Functioning 
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For versions intended for subjects >8 years of age, Physical Functioning refers to questions “About my 
health and activities”; Emotional Functioning refers to questions “About my feelings”; Social Functioning 
refers to questions “How I get along with others”; School Functioning refers to questions “About school”. 
The PedsQL assessment is retrospective to the prior one month, 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 following formula in order to generate scores of 
0, 25, 50, 75, and 100 where a higher value represents a better health-related quality of life (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 cognitive functioning items), and the physical 
health summary score (a combination of the physical functioning and physical symptoms items) for each 
subject ≤24 months of age. Also, 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) will be calculated for each subject >2 years of age. These summary scores 
will be missing if any of the scale scores contributing to their calculation is missing.  
 
Change #9 
New subsection added for 3.2.24 Age at time of visit/assessment 
 
Change #10 
Section 3.4 Protocol deviations 
The following text has been added in this section: 
In addition, protocol deviations related to the impact of the global pandemic of coronavirus disease 2019 
(COVID-19) will be documented. 
 
Change #11 
Section 3.6 Treatment assignment and treatment groups 
Summaries by modal daily dose have been deleted. 
 
Change #12 
Section 3.9 Changes to protocol-defined analyses 
The sections 3.9.1, 3.9.2, and 3.9.3 have been deleted, as the efficacy endpoints and handing of missing data 
was added in protocol amendment 2. The subsection numbering of 3.9.4 and 3.95 was updated to 3.9.1 and 
3.9.2. 
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Change #13 
Section 5.1 Subject disposition 
For the number and percentage of subject completing the study by interval, the ≥12 months category was 
changed to 12 and ≥24 months. 
 
Change #14 
Section 5.1 Subject disposition 
The following text has been added in this section: 
The number and percentages of subjects impacted by COVID-19 will be presented for each visit, overall 
and by impact category, for each relationship to COVID-19 as well as any relationship, overall and by 
country, for all subjects in the SS. This will also be presented in the subject data listings. 
 
Change #15 
Section 6.1 Demographics and other Baseline characteristics 
• 
Age at entry into previous pediatric study (years) (as defined in Section 3.2.9) – continuous and 
categorized as (28 days - <24 months, 24 months - <12 years, 12 years - 
<18 years) 
• 
Age at entry into EP0034 (years) (as defined in Section 3.2.9) 
• 
 
Has been changed to: 
• 
Age at entry into previous pediatric study (years) (as defined in Section 3.2.9)  
• 
Age at entry into EP0034 (years) (as defined in Section 3.2.9) – continuous and categorized as (28 
days - <24 months, 24 months - <12 years, 12 years -<18 years) 
 
Change #16 
Section 6.1 Demographics and other Baseline characteristics 
Weight at entry to EP0034 was added and weight band updated to use weight at entry to EP0034. 
 
Change #17 
Section 6.4.1 
Concomitant AEDs taken at the start of the EP0034 Treatment Period 
The additional categories for number of AEDs taken at the start of EP0034 were added in: 0 AEDs and 4 
AEDs. 
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Further, the wording preferred name was updated to medication name. 
 
Change #18 
Section 8.2 Adverse events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented by weight 
band and enrollment group using the levels defined in Sections 3.2.10 and 3.2.12 respectively. In 
addition, select AE tables will also be presented by 3-month time intervals (as defined in Section 3.2.5). 
The number and percentage of subjects experiencing each event at least once will be summarized. All 
summaries will be sorted alphabetically by SOC and by frequency of events within PTs, starting with the 
most frequent event overall. 
AEs will be classified as pre-treatment, treatment-emergent, or post-treatment. Pre-treatment AEs are 
defined as AEs which had an onset date prior to the first EP0034 dose of LCM. Treatment-emergent AEs 
(TEAEs) are defined as those events which started on or after the date of first EP0034 dose of LCM, or 
whose intensity worsened on or after the date of first EP0034 dose of LCM. AEs occurring within 30 days 
after last dose of LCM will be considered treatment emergent. Post-treatment AEs are defined as AEs 
which had an onset date after 30 days after the last dose of LCM. 
All AEs reported during the study including pre-treatment and post-treatment AEs will be provided 
in a subject data listing. 
An overview of the incidence of TEAEs will provide the overall summary of TEAEs and the numbers and 
percentages of subjects with at least 1 TEAE, with a serious TEAE, with a drug- related TEAE, with a 
severe TEAE, and with a drug-related serious TEAE. The number and percentage of subject 
discontinuations due to TEAEs, the number and percentage of all deaths (if applicable), and the number and 
percentage of subjects with AEs leading to death (if applicable) will also be summarized. This overall 
summary will be repeated by weight band and enrollment group using the levels defined in Sections 3.2.10 
and 3.2.12, respectively. 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• 
Incidence of TEAEs 
• 
Incidence of serious TEAEs 
• 
Incidence of non-serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation 
• 
Incidence of TEAEs by relationship to LCM 
 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of TEAEs related to Potentially Drug Induced Liver Injury (PDILI) 
• 
Incidence of non-serious TEAEs by relationship to LCM 
• 
Incidence of fatal TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects by relationship to LCM 
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• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
The following summaries of AEs will also be repeated by weight band and enrollment group using the 
levels defined in Sections 3.2.10 and 3.2.12 respectively. 
• 
Incidence of TEAEs 
• 
Incidence of serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
The following summaries of AEs will be presented for the 3-month time intervals (as defined in Section 
3.2.5) of: ≤3 months, >3 to ≤6 months, >6 to ≤9 months, >9 to ≤12 months, >12 to ≤15 months, >15 to ≤18 
months, >18 to ≤21 months, >21 to ≤24 months, and ≥24 months: 
• 
Incidence of all TEAEs with onset during the Treatment Period 
• 
Incidence of all serious TEAEs with onset during the Treatment Period 
• 
Incidence of all TEAEs leading to discontinuation with onset during the Treatment Period 
• 
Incidence of other significant TEAEs with onset during the Treatment Period (defined in Appendix 
12.2) 
In addition, summaries for the incidence of TEAEs overall, incidence of serious TEAEs, incidence of 
TEAEs leading to discontinuation, incidence of other significant TEAEs, and TEAEs related to PDILI will 
be repeated presenting the site and subject number of all those subjects experiencing each TEAE as well as 
in subject data listings. 
 
Has been changed to: 
 
Section 8.2 Adverse events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented by weight 
band and enrollment group using the levels defined in Sections 3.2.10 and 3.2.12 respectively. In 
addition, select AE tables will also be presented by 3-month time intervals (as defined in Section 3.2.5). 
The number and percentage of subjects experiencing each event at least once will be summarized. All 
summaries will be sorted alphabetically by SOC and by frequency of events within PTs, starting with the 
most frequent event overall. 
AEs will be classified as pre-treatment, treatment-emergent, or post-treatment. Pre-treatment AEs are 
defined as AEs which had an onset date prior to the first EP0034 dose of LCM. Treatment-emergent AEs 
(TEAEs) are defined as those events which started on or after the date of first EP0034 dose of LCM, or 
whose intensity worsened on or after the date of first EP0034 dose of LCM. AEs occurring within 30 days 
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after last dose of LCM will be considered treatment emergent. Post-treatment AEs are defined as AEs 
which had an onset date after 30 days after the last dose of LCM. 
For results disclosure on public registries (eg, ClinicalTrials.gov), treatment-emergent adverse 
events and treatment-emergent serious adverse events will be published. 
All AEs reported during the study including pre-treatment and post-treatment AEs will be provided 
in a subject data listing. 
An overview of the incidence of TEAEs will provide the overall summary of TEAEs and the numbers and 
percentages of subjects with at least 1 TEAE, with a serious TEAE, with a drug- related TEAE, with a 
severe TEAE, and with a drug-related serious TEAE. The number and percentage of subject 
discontinuations due to TEAEs, the number and percentage of all deaths (if applicable), and the number and 
percentage of subjects with AEs leading to death (if applicable) will also be summarized. This overall 
summary will be repeated by weight band and enrollment group using the levels defined in Sections 3.2.10 
and 3.2.12, respectively. 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• 
Incidence of TEAEs 
• 
Incidence of serious AEs 
• 
Incidence of serious TEAEs 
• 
Incidence of non-serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation from the study 
• 
Incidence of TEAEs by relationship to LCM 
 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of TEAEs related to Potentially Drug Induced Liver Injury (PDILI) (defined in Appendix 
Section 12.3  
• 
Incidence of pediatric growth-, neurodevelopment-, behavior-, and endocrine-related TEAEs (defined 
by manual medical review) 
• 
Incidence of non-serious TEAEs by relationship to LCM 
• 
Incidence of fatal TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects by relationship to LCM 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
The following summaries of AEs will also be repeated by weight band and enrollment group using the 
levels defined in Sections 3.2.10 and 3.2.12 respectively. 
• 
Incidence of TEAEs 
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• 
Incidence of serious AEs 
• 
Incidence of serious TEAEs 
• 
Incidence of TEAEs leading to discontinuation from the study 
• 
Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of other significant TEAEs (defined in Appendix 12.2) 
The following summaries of AEs will be presented for the 3-month time intervals (as defined in Section 
3.2.5) of: ≤3 months, >3 to ≤6 months, >6 to ≤9 months, >9 to ≤12 months, >12 to ≤15 months, >15 to ≤18 
months, >18 to ≤21 months, >21 to ≤24 months, and ≥24 months: 
• 
Incidence of all TEAEs with onset during the Treatment Period 
• 
Incidence of all serious AEs with onset during the Treatment Period 
• 
Incidence of all serious TEAEs with onset during the Treatment Period 
• 
Incidence of all TEAEs leading to discontinuation from the study with onset during the Treatment 
Period 
Incidence of other significant TEAEs with onset during the Treatment Period (defined in Appendix 12.2) 
In addition, summaries for the incidence of TEAEs overall, incidence of serious AEs, incidence of serious 
TEAEs, incidence of TEAEs leading to discontinuation, incidence of other significant TEAEs, TEAEs 
related to PDILI, and pediatric growth-, neurodevelopment-, behavior-, and endocrine-related TEAEs will 
be repeated presenting the site and subject number of all those subjects experiencing each TEAE as well as 
in subject data listings. 
 
Change #19 
Section 8.2 Clinical laboratory evaluations 
The following text has been added in this section: 
The age at the time of assessment will be used for determining TEMA (as defined in Section 3.2.24). 
 
Change #20 
Section 8.4.1 Vital signs, body weight, height, BMI, and head circumference 
The following text has been added in this section: 
The age at the time of assessment will be used for determining MA (as defined in Section 3.2.24). 
 
Change #21 
Section 8.4.1 Vital signs, body weight, height, BMI, and head circumference 
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MA criteria for temperature has been added. 
 
Change #22 
Section 8.4.1 Vital signs, body weight, height, BMI, and head circumference 
Additionally, a subject will be considered to have marked bradycardia if the pulse rate is <45bpm and an AE 
mapped to the PT bradycardia is reported for the subject. A listing of vital signs data will be provided for all 
subjects with marked bradycardia. Additionally, a subject data listing of all vital signs for subjects with an 
AE mapped to the PT bradycardia will be presented. 
 
Has been changed to: 
A subject data listing of all vital signs for study subjects with an AE mapped to the PT bradycardia or 
sinus bradycardia will be presented. 
 
Change #23 
Section 8.4.2 Electrocardiograms (ECGs) 
The following text has been added in this section: 
The age at the time of visit/assessment will be used for determining abnormality criteria (as defined in 
Section 3.2.24). 
 
Change #24 
Section 8.4.7 Achenbach Child Behavior Checklist 
The Achenbach CBCL will be completed according to the tabular schedules of study procedures, only in 
countries where a validated translated version is available. 
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and 
behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the Achenbach CBCL is 
used. The CBCL/1½-5 is intended for use in children 18 months to 5 years and 11 months of age. For 
subjects ≥6 years to ≤18 years, the CBCL/6-18 will be used. 
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 previous study, the 
CBCL/1½-5 should be completed for 1 year after the Baseline assessment of the previous study, and 
subsequently the CBCL/6-18 should be completed. 
The CBCL/1½-5 comprises 100 questions and the CBCL/6-18 comprises 120 questions. In both 
questionnaires, the occurrence of certain problems and behaviors in the past 6 months will be scored on the 
following scale: 
• 
0=not true (as far as known) 
• 
1=somewhat or sometimes true 
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• 
2=very true or often true 
The CBCL/1½-5 will be grouped according to syndrome scales in Table 8‒3 and the CBCL/6-18 will be 
grouped according to empirically based syndrome scales in Table 8‒4. 
 
Table 8‒3: 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 
 
Table 8‒4: CBCL/6-18 
 
Syndrome scale 
Questions 
Aggressive behavior 
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 
94, 95, 97, 104 
Anxious/depressed 
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112 
Attention problems 
1, 4, 8, 10, 13, 17, 41, 61, 78, 80 
Rule-breaking behavior 
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 
101, 105, 106 
Social problems 
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79 
Somatic complaints 
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g 
Thought problems 
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 
100 
Withdrawn/depressed 
5, 42, 65, 69, 75, 102, 103, 111 
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. 
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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. 
 
Has been changed to: 
 
Section 8.4.8 Achenbach Child Behavior Checklist 
The Achenbach CBCL will be completed according to the tabular schedule of study procedures, only 
in countries where a validated translated version is available. 
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and 
behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the Achenbach 
CBCL is used. The CBCL/1½-5 is intended for use in children 18 months to 5 years and 11 months of 
age. For study subjects ≥6 years to ≤18 years, the CBCL/6-18 will be used.  
The CBCL/1½-5 comprises 100 questions and the CBCL/6-18 comprises 120 questions. In both 
questionnaires, the occurrence of certain problems and behaviors (in the past 2 months for the 
CBCL/1½-5 version and in the past 6 months for the CBCL/6-18 version) 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 
The CBCL/1½-5 items will be grouped according to syndrome scales in Table 8‒3 and the CBCL/6-
18 items will be grouped according to empirically based syndrome scales in Table 8‒4. For each 
syndrome, a raw score will be calculated as the sum of the considered item scores.  
Table 8‒3: CBCL/1½-5 
Syndrome scale 
Items 
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 
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Table 8‒3: CBCL/1½-5 
Syndrome scale 
Items 
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 
 
Table 8‒4: CBCL/6-18 
Syndrome scale 
Items 
Aggressive behavior 
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 
94, 95, 97, 104 
Anxious/depressed 
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112 
Attention problems 
1, 4, 8, 10, 13, 17, 41, 61, 78, 80 
Rule-breaking behavior 
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 
101, 105, 106 
Social problems 
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79 
Somatic complaints 
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g 
Thought problems 
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 
100 
Withdrawn/depressed 
5, 42, 65, 69, 75, 102, 103, 111 
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. Standardized T-scores determined from each subject’s raw syndrome scale scores will be 
reproduced programmatically using the appropriate scoring spreadsheets. 
Raw scores 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. 
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. 
The Calculated T-scores, raw scores, and change from Baseline in raw scores will be listed. 
A decrease from Baseline (change from Baseline <0) in the CBCL syndrome raw score will indicate 
improvement in behavior, while an increase (change from Baseline > 0) indicates worsening. 
In addition, for both the CBCL/1½-5 syndrome and /6-18 syndrome, subjects will be categorized according to 
the Calculated T-score as follows: 
• 
T-score is < 65 = “Normal” 
• 
T-score is ≥ 65 = “Borderline or Clinical range (BCR)”   
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Summaries of shifts from Baseline to each post-Baseline visit, and from Baseline to Last Visit will also be 
provided based on the CBCL calculated T-score categories of Normal and BCR. The descriptive summaries of 
change from Baseline and shift summaries will be presented only when a corresponding Baseline value is 
available.  
 
Change #25 
Section 8.4.9.1 BRIEF-P scores 
Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, flexibility, 
emergent metacognition, and component scores. 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 indexed scores and GEC for the 
BRIEF-P questionnaire will be summarized for each visit, and Last Visit. 
 
Has been changed to: 
Section 8.4.9.1 BRIEF-P scores 
Standardized T-scores are determined from each subject’s raw GEC, inhibitory self-control, flexibility, 
emergent metacognition, and component scores. Tables that map each raw score to the appropriate T-
score are provided in the BRIEF-P Professional Manual. Standardized T-scores determined from each 
subject’s raw GEC score, subscale scores and 5 individual component scores will be produced 
programmatically using the appropriate scoring spreadsheets.  
Raw scores and change from Baseline for the three index scores, the GEC and the 5 individual 
component scores for the BRIEF-P questionnaire will be summarized for each visit, and Last Visit.  
The Calculated T-scores, raw scores, and changes from Baseline in raw scores will be listed. 
A decrease from Baseline (change from Baseline < 0) in the BRIEF-P syndrome raw score will indicate 
improvement in behavior, while an increase (change from Baseline > 0) indicates worsening. 
In addition, for BRIEF-P, subjects will be categorized according to the Calculated T-score as follows: 
• 
T-score is < 65 = “Normal” 
• 
T-score is ≥ 65 = “Elevated” 
Summaries of shifts from Baseline to each post-Baseline visit, and from Baseline to Last Visit will also be 
provided based on BRIEF-P calculated T-score categories of Normal and Elevated. 
The descriptive summaries of change from Baseline and shift summaries will be presented only when a 
corresponding Baseline value is available. 
 
Change #26 
Section 8.4.9.1 BRIEF scores 
Calculated T-score values and change from Baseline for the two indexed scores (BRI and MI) and GEC 
for the BRIEF questionnaire will be summarized for each visit, and Last Visit. 
 
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Has been changed to: 
 
Section 8.4.9.1 BRIEF scores 
Raw scores 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 for each visit, and Last 
Visit.  
Standardized T-scores determined from each subject’s raw GEC score, subscale scores, and 8 individual 
component scores will be produced programmatically using the appropriate scoring spreadsheets. The 
Standardized T-scores, raw scores, and changes from Baseline in raw scores will be listed. 
A decrease from Baseline (change from Baseline <0) in the BRIEF scores will indicate improvement in 
behavior, while an increase (change from Baseline > 0) indicates worsening. 
In addition, for BRIEF, subjects will be categorized according to the Calculated T-score as follows: 
• 
T-score is < 65 = “Normal” 
• 
T-score is ≥ 65 = “Elevated” 
Summaries of shifts from Baseline to each post-Baseline visit, and from Baseline to Last Visit will also be 
provided based on BRIEF calculated T-score categories of Normal and Elevated. The descriptive summaries 
of change from Baseline and shift summaries will be presented only when a corresponding Baseline value 
from the same questionnaire is available. 
 
Change #27 
The subsection 9.2.4.1 Medical procedures has been moved to be after the BRIEF-P and BRIEF assessment 
subsection and was renumbered to 8.4.11. 
 
Change #28 
Section 9.1.1 Percentage of seizure-free days 
The percentage of seizure-free days (as defined in Section 3.2.20) will be summarized by seizure time 
intervals (as defined in Section 3.2.21) and also for the entire Treatment Period. This will be grouped by 
modal daily LCM dose, using the levels defined in Section 3.2.8. This will be repeated, separately, by 6-
month completer cohorts (as defined in Section 3.2.19) and by seizure type (simple partial, complex partial, 
or secondarily generalized). 
 
Has been changed to: 
 
Section 9.1.1 Percentage of seizure-free days 
The percentage of seizure-free days (as defined in Section 3.2.20) will be summarized by seizure time 
intervals (as defined in Section 3.2.21) and also for the entire Treatment Period. This will also be grouped by 
enrollment group. This will be repeated, separately by seizure type (simple partial, complex partial, or 
partial, secondary generalized). 
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Change #29 
Section 9.1.2 Seizure frequency per 28 days 
The following analyses will only be done for subjects who participated in SP0969. 
Seizure frequency per 28 days (as defined in Section 3.2.13) will be summarized descriptively and 
presented graphically at each visit and grouped by modal daily LCM dose (as defined in Section 3.2.8). 
Observed values will be summarized by visit and change from Baseline will be summarized for all post-
Baseline visits, as appropriate. 
 
Has been changed to: 
 
Section 9.1.2 Seizure frequency per 28 days 
The following analyses will only be done for subjects who participated in SP0969. 
Seizure frequency per 28 days (as defined in Section 3.2.13) will be summarized descriptively and 
presented graphically. 
 
Change #30 
Section 9.1.3 Percentage of subjects with ≥50% response to treatment 
The following analyses will only be done for subjects who participated in SP0969. 
The number and percentage of subjects with ≥50% reduction in 28-day partial-onset seizure frequency 
(≥50% responders as defined in Section 3.2.15) will be summarized by seizure time intervals (as defined in 
Section 3.2.21) and also for the entire Treatment Period. Responder status will be assessed as described in 
Section 3.2.15 for a given seizure time interval based on the seizure data recorded during that interval. This 
will be grouped by modal daily LCM dose, using the levels defined in Section 3.2.8. This will be repeated, 
separately, by 6-month completer cohorts (as defined in Section 3.2.19) and by seizure type (simple partial, 
complex partial, or secondarily generalized). 
 
Has been changed to: 
 
Section 9.1.3 ≥50% reduction in 28-days partial-onset seizure frequency 
The following analyses will only be done for subjects who participated in SP0969. 
The number and percentage of subjects with ≥50% reduction in 28-day partial-onset seizure 
frequency (≥50% responders as defined in Section 3.2.15) will be summarized by seizure time 
intervals (as defined in Section 3.2.21) and also for the entire Treatment Period.. This will be 
repeated, separately by seizure type (simple partial, complex partial, or partial, secondary 
generalized). Any subject with seizure data during the time interval will be included in the summary 
for that seizure time interval and by seizure type.  
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Change #31 
Section 9.1.4 Percentage of subjects with ≥75% response to treatment 
The analyses described in Section 9.1.3 for percentage of subjects with ≥50% response to treatment will also 
be performed for percentage of subjects with ≥75% reduction in 28-day partial-onset seizure frequency (≥75% 
responders) for subjects who participated in SP0969. 
 
Has been changed to: 
 
Section 9.1.4 ≥75% reduction in 28-days partial-onset seizure frequency 
The analyses described in Section 9.1.3 for percentage of subjects with ≥50% reduction in 28-days partial-
onset seizure frequency will also be performed for study subjects with ≥75% reduction in 28-day partial-onset 
seizure frequency (≥75% responders) for subjects who participated in SP0969. 
 
Change #32 
Section 9.1.5 Absolute and percent reduction in total partial-onset seizures 
The following analyses will only be done for subjects who participated in SP0969. 
Absolute and percent reduction from Baseline (as defined in Section 3.2.14) in total partial-onset seizures 
will be summarized by seizure time intervals (as defined in Section 3.2.21) and also for the entire Treatment 
Period. This will be grouped by modal daily LCM dose, using the levels defined in Section 3.2.8. This will 
be repeated, separately, by 6-month completer cohorts (as defined in Section 3.2.19) and by seizure type 
(simple partial, complex partial, or secondarily generalized). 
 
Has been changed to: 
 
Section 9.1.5 Absolute and percent reduction in total partial-onset seizures 
The following analyses will only be done for subjects who participated in SP0969. 
Absolute and percent reduction from Baseline (as defined in Section 3.2.14) in total partial-onset seizures 
will be summarized by seizure time intervals (as defined in Section 3.2.21) and also for the entire Treatment 
Period. This will be repeated, separately by seizure type (simple partial, complex partial, or partial, secondary 
generalized). 
 
Change #33 
Section 9.1.6 Percentage of subjects who achieved Seizure-free status 
The number and percentage of subjects who achieved seizure-free status (as defined in 
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Section 3.2.18) will be summarized by seizure time intervals (as defined in Section 3.2.21) and also for the 
entire Treatment Period. This will be grouped by modal daily LCM dose, using the levels defined in Section 
3.2.8. This will be repeated, separately, by 6-month completer cohorts (as defined in Section 3.2.19) and by 
seizure type (simple partial, complex partial, or secondarily generalized). 
 
Has been changed to: 
 
Section 9.1.6 Seizure-free status 
The number and percentage of subjects who achieved seizure-free status (as defined in 
Section 3.2.18) will be summarized for the entire Treatment Period. This will be presented by completer 
cohorts (as defined in Section 3.2.19) and repeated by enrollment groups.  
The number and percentage of study subjects seizure-free among completer cohorts (as defined in 
Section 3.2.19) will also be presented separately by seizure type (simple partial, complex partial, or partial, 
secondary generalized). 
Seizure-free status will also be presented by seizure time intervals (as defined in Section 3.2.21) and 
repeated by enrollment groups. The number and percentage of study subjects with seizure-free status 
at the end of each time interval during the treatment period will be presented separately by seizure 
type (simple partial, complex partial, partial, secondary generalized). 
 
Change #34 
Section 9.2.1 Clinical Global Impression of Change 
The Clinical Global Impression of Change is a 7-point categorical rating scale in which the investigator 
should provide his/her assessment of the subject’s clinical status, compared to Baseline, including an 
evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional status. This 
will be assessed according to the tabular schedule of study procedures. 
 
The number and percentage of subjects by Clinical Global Impression of Change value will be summarized by 
visit and Last Visit and grouped by modal daily LCM dose, using the levels defined in Section 3.2.8. 
 
Has been changed to: 
 
Section 9.2.1 Clinical Global Impression of Change 
The Clinical Global Impression of Change is a 7-point categorical rating scale in which the investigator 
should provide his/her assessment of the subject’s clinical status, compared to Baseline, including an 
evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional status. This 
will be assessed at least once per year and will be completed according to the tabular schedule of study 
procedures. 
 
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The number and percentage of subjects by Clinical Global Impression of Change value will be summarized by 
visit and Last Visit . This will be repeated by enrollment group. 
 
Change #35 
Section 9.2.2 Caregiver’s Global Impression of Change 
The Caregiver Global Impression of Change is a 7-point categorical rating scale in which the caregiver 
(including parent/legal guardian) should provide his/her assessment of the subject’s clinical status, compared 
to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s 
functional status. This will be assessed according to the tabular schedule of study procedures. 
 
 
The number and percentage of subjects by Caregiver Global Impression of Change value will be summarized 
by visit and Last Visit and grouped by modal daily LCM dose, using the levels defined in Section 3.2.8.  
 
Has been changed to: 
 
Section 9.2.2 Caregiver’s Global Impression of Change 
The Caregiver’s Global Impression of Change is a 7-point categorical rating scale in which the caregiver 
(including parent/legal guardian) should provide his/her assessment of the subject’s clinical status, compared 
to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s 
functional status. This will be assessed at least once per year and will be completed according to the tabular 
schedule of study procedures. 
 
 
The number and percentage of subjects by Caregiver’s Global Impression of Change value will be summarized 
by visit and Last Visit. This will be repeated by enrollment group. 
 
Change #36 
Section 9.2.3 Pediatric Quality of Life Inventory (PedsQL) 
Calculated values and changes from Baseline for the total scale score and each of the 4 scale scores (defined 
in Section 3.2.22) will be summarized for each visit and for Last Visit. This will be grouped by modal daily 
LCM dose, using the levels defined in Section 3.2.8. All changes from Baseline will only be calculated for 
visits when the subject uses the same form of the questionnaire as administered at baseline. 
All PedsQL data will be listed. 
 
Has been changed to: 
 
Section 9.2.3 Pediatric Quality of Life Inventory (PedsQL) 
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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. The PedsQL will be completed up to two 
time per year and will be assessed according to the tabular schedule of study procedures. The Section 3.2.22 
details how the scores for the core domains are calculated. 
Section 9.2.3.1 Pediatric Quality of Life Inventory Ages for ≤24 Months 
The multidimensional PedsQL ≤24 months generic core scales encompass the following core domains for 
pediatric HRQoL measurement: Physical Functioning, Physical Symptoms, Emotional Functioning, Social 
Functioning, and Cognitive Functioning. 
Calculated values and changes from Baseline for the total scale score (all items), the psychosocial health 
summary score, the physical health summary score and each of the 5 scale scores will be summarized for 
each visit and for Last Visit. This will be repeated by enrollment group. All changes from Baseline will only 
be calculated for visits when the subject uses the same form of the questionnaire as administered at baseline. 
All PedsQL ≤24 months data will be listed. 
Section 9.2.3.2 Pediatric Quality of Life Inventory Ages >2 years 
The multidimensional PedsQL >2years generic core scales encompass the following core domains for pediatric 
HRQoL measurement: Physical Functioning, Emotional Functioning, Social Functioning, and School 
Functioning. 
Calculated values and changes from Baseline for the total scale score (all items), the psychosocial health 
summary score, the physical health summary score and each of the 4 scale scores will be summarized for each 
visit and for Last Visit. This will be repeated by enrollment group. For subjects 5 years and older at Baseline, 
changes from Baseline will be calculated for all visits, even when the questionnaire version used is different 
from the one at Baseline. For subjects less than 5 years at Baseline, the change from Baseline will be calculated 
only when the same questionnaire version is used at Baseline and post-Baseline. All PedsQL >2 years data will 
be listed. 
 
Change #37 
The subsections of 9.2.4 were renumbered as Medical procedures moved to subsection 8.4.11. 
 
Change #38 
Section 12.2 Other Significant AEs 
The following statement was added: The following MedDRA PTs are defined as other significant TEAEs. 
MedDRA preferred terms “Brugada syndrome”, “Cardiac arrest”, “Defect conduction intraventricular”, and 
“Electrocardiogram QT prolonged” were added. Preferred terms have been arranged in alphabetical order. 
 
Change #39 
Section 12.3 List of AEs for Potentially Drug Induced Liver Injury (PDILI) 
The following statement was added: The following MedDRA PTs are defined as AEs for Potentially Drug 
Induced Liver Injury. 
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MedDRA preferred terms “Alanine aminotransferase increased” and “Aspartate aminotransferase 
increased” were added. Preferred terms have been arranged in alphabetical order.
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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 below indicate that the final version of the SAP or amended 
SAP is released for execution. 
 
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Approval Signatures
Name:
ep0034-sap-amend-3
Version:
1. 0
Document Number:
CLIN-000173710
Title:
EP0034 SAP Amendment 3
Approved Date:
14 Jun 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 04-Jun-2021 15:03:51 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 14-Jun-2021 18:16:32 GMT+0000
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