Clinical trial NCT00938912
Conditions: Epilepsy
Keywords: Lacosamide (VIMPAT)
Sponsor: UCB BIOSCIENCES, Inc.
Start date: 2009-12-09; Completion date: 2021-05-18
Enrollment: 366 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
SP848 is an open-label study to evaluate long-term safety, tolerability, and efficacy in children with epilepsy treated with Lacosamide (LCM) oral solution (syrup) or LCM tablets as adjunctive therapy.

Detailed description:
SP848 is an open-label study to evaluate long-term safety, tolerability, and efficacy in children with epilepsy treated with Lacosamide (LCM) oral solution (syrup) or LCM tablets as adjunctive therapy. In addition, the study is designed to provide continued availability of LCM to subjects who have completed the SP847 (NCT00938431) study and to subjects who have discontinued from SP847 (NCT00938431) and who, in the investigator's opinion, would benefit from long-term administration of LCM.

SP848 will be open to subjects who have participated in other LCM pediatric clinical studies in epilepsy and will also be open to up to 100 subjects enrolling directly into SP848. Permissible LCM doses in SP848 are between 2-12 mg/kg/day (oral solution \[syrup\]) or the corresponding tablet dose up to a maximum dose of 600 mg/day.

Subjects enrolled in SP848 have the option of remaining on the oral solution formulation of LCM or switching to the commercial tablet formulation, if feasible.

Arms: arm 1: Subjects and their caregivers may chose to receive Lacosamide oral solution (syrup) or Lacosamide tablets. The maximum duration of LCM administration will be approximately 2 years.
Interventions: intervention 1: Lacosamide intervention 2: Lacosamide
Intervention descriptions: intervention 1: Lacosamide oral solution (syrup): Total daily dose between 2 mg/kg/day (1 mg/kg bid) to 12 mg/kg/day (6 mg/kg bid) intervention 2: Lacosamide tablets: Total daily dose between 100 mg (50mg bid) - 600mg (300 mg bid).

The maximum permissible dose of LCM will be 12 mg/kg/day or 600 mg/day.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
STUDY NUMBER: SP848 
PHASE OF STUDY: 2 
AN OPEN-LABEL STUDY TO DETERMINE SAFETY, TOLERABILITY, 
AND EFFICACY OF LONG-TERM ORAL LACOSAMIDE (LCM) AS 
ADJUNCTIVE THERAPY IN CHILDREN WITH EPILEPSY 
EudraCT Number: 2011-001559-35 
Sponsor: 
UCB BIOSCIENCES, Inc 
8010 Arco Corporate Drive 
Raleigh, NC 27617 
United States 
Confidential Material 
All information supplied by Sponsor or the Sponsor’s affiliates to the Investigators or the Institution 
including, but not limited to, information contained in the Protocol, shall be deemed confidential and 
proprietary information of Sponsor (“Confidential Information”). Confidential Information shall not be 
used for any purpose other than that of the Study, shall be maintained in strict confidence and shall not be 
transferred or disclosed to any third party other than the Institution’s staff members involved in the Study. 
 
 
Protocol version: Final 
Date of protocol: 02 Mar 2009 
Date of protocol amendment 1: 12 Nov 2009 
Date of protocol amendment 2: 13 Dec 2010 
Date of protocol amendment 3: 29 Jul 2011 
Date of protocol amendment 4: 09 Apr 2012 
Date of protocol amendment 5: 22 Jan 2013 
Date of protocol amendment 5.1 (Italy): 15 May 2014 
Date of protocol amendment 5.2 (Japan): 17 Jul 2014 
Date of protocol amendment 5.3 (Japan): 07 Aug 2014 
Date of protocol amendment 5.3.1 (Japan): 30 Oct 2017 
Date of protocol amendment 5.4 (China): 15 Dec 2015 
Date of protocol amendment 5.5 (China): 30 Nov 2016 
Date of protocol amendment 5.6 (China): 21 Dec 2016 
Date of protocol amendment 5.7 (China): 01 Feb 2017 
Date of protocol amendment 6: 16 Nov 2016 
Date of protocol amendment 7: 06 Feb 2017 
Date of protocol amendment 8: 20 Oct 2020 
 
 
 
 
 
 
 
 
 
 
 
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Principal or Coordinating Investigator(s): 
Will be listed separately. 
Sponsor: 
Name: 
UCB BIOSCIENCES, Inc. 
Address: 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
+1-866-724-2467 / +1-919-767-2570 
Clinical Program Director:  
Name: 
  
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Project Manager:  
Name: 
 
Address: 
UCB BIOSCIENCES, Inc 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone: 
  
E-mail: 
 
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Clinical Trial Biostatistician: 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Medical Director (Medical Therapeutics):  
Name: 
 
Address: 
UCB BIOSCIENCES, GmbH 
Alfred-Nobel- Straße 10 
40789 Monheim am Rhein 
GERMANY  
Phone: 
  
E-mail: 
 
Safety Representative (Patient Safety): 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
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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 
Japan: + 81 3 6864 7400 
Email 
Europe and Rest of the World: DS_ICT@ucb.com or 
DSICT.-@ucb.com  
Japan: JDSO@ucb.com 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
BACKGROUND INFORMATION ................................................................................ 13 
3 
STUDY OBJECTIVES .................................................................................................... 15 
4 
STUDY DESIGN ............................................................................................................. 16 
4.1 
Study description ......................................................................................................... 16 
4.1.1 
Subjects enrolling from SP847 or other LCM pediatric clinical studies in 
epilepsy ................................................................................................................ 16 
4.1.2 
Subjects enrolling directly into SP848 ................................................................ 16 
4.2 
Variables to be assessed ............................................................................................... 17 
4.2.1 
Safety variables .................................................................................................... 17 
4.2.1.1 
Primary safety variables ............................................................................ 17 
4.2.1.2 
Other safety variables ................................................................................ 17 
4.2.2 
PK variables ......................................................................................................... 18 
4.2.2.1 
Primary PK variables ................................................................................. 18 
4.2.2.2 
Other PK variables .................................................................................... 18 
4.2.3 
Efficacy variables ................................................................................................ 18 
4.2.3.1 
Primary efficacy variables ......................................................................... 18 
4.2.3.2 
Secondary efficacy variables ..................................................................... 18 
4.2.3.3 
Other efficacy variables ............................................................................. 18 
4.3 
Selection and withdrawal of subjects ........................................................................... 18 
4.3.1 
Inclusion criteria .................................................................................................. 18 
4.3.2 
Exclusion criteria ................................................................................................. 19 
4.3.3 
Criteria for withdrawal ........................................................................................ 21 
4.3.3.1 
Potential drug-induced liver injury IMP discontinuation criteria.............. 23 
4.4 
Study treatments........................................................................................................... 24 
4.4.1 
Treatments to be administered ............................................................................. 24 
4.4.1.1 
Subjects enrolling from SP847 or other LCM pediatric clinical studies in 
epilepsy ...................................................................................................... 24 
4.4.1.2 
Subjects enrolling directly into SP848 ...................................................... 24 
4.4.1.3 
All subjects ................................................................................................ 25 
4.4.1.4 
Study completion ....................................................................................... 27 
4.4.2 
Description of investigational medicinal product ................................................ 27 
4.4.3 
Randomization ..................................................................................................... 27 
4.5 
Expected duration of the study .................................................................................... 27 
4.6 
Concomitant medication(s)/treatment(s) ..................................................................... 28 
4.7 
Procedures for monitoring subject compliance ............................................................ 28 
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5 
TREATMENT PROCEDURES BY VISIT ..................................................................... 28 
5.1 
Screening Visit ............................................................................................................. 29 
5.2 
Titration Visit(s) (TV1, TV2, TV3, TV4, TV5, TV6) ................................................. 30 
5.3 
Visit 1 (Week 0) ........................................................................................................... 31 
5.4 
Telephone contacts (Weeks 2, 6, 10, 16, 24, 32, 40, 48, 66, and 78) .......................... 33 
5.5 
Visit 2 (Week 4) ........................................................................................................... 33 
5.6 
Visit 3 (Week 8) ........................................................................................................... 35 
5.7 
Visit 4 (Week 12) ......................................................................................................... 35 
5.8 
Visit 5 (Week 20) ......................................................................................................... 36 
5.9 
Visit 6 (Week 28) ......................................................................................................... 37 
5.10 
Visit 7 (Week 36) ......................................................................................................... 37 
5.11 
Visit 8 (Week 44) ......................................................................................................... 37 
5.12 
Visit 9 (Week 52) ......................................................................................................... 37 
5.13 
Visit 10 (Week 60) ....................................................................................................... 37 
5.14 
Visit 11 (Week 72) ....................................................................................................... 37 
5.15 
Visit 12 (Week 84) ....................................................................................................... 38 
5.16 
Visit 13/Termination Visit (Week 96) ......................................................................... 38 
5.17 
Early Termination Visit ............................................................................................... 39 
5.18 
Unscheduled Visit(s) .................................................................................................... 40 
5.19 
Final Visit..................................................................................................................... 41 
5.20 
Safety Follow-Up telephone contact ............................................................................ 42 
5.21 
Study conduct due to coronavirus disease 2019 pandemic .......................................... 42 
6 
ASSESSMENT OF EFFICACY ...................................................................................... 43 
6.1 
Seizure counts .............................................................................................................. 43 
6.2 
Global Impression of Change ...................................................................................... 43 
6.2.1 
Clinical Global Impression of Change ................................................................ 43 
6.2.2 
Caregiver Global Impression of Change ............................................................. 44 
6.3 
Pediatric Quality of Life Inventory .............................................................................. 44 
6.4 
Health care resource use .............................................................................................. 45 
7 
ASSESSMENT OF PHARMACOKINETICS ................................................................ 45 
8 
ASSESSMENT OF SAFETY .......................................................................................... 45 
8.1 
Adverse events ............................................................................................................. 45 
8.1.1 
Definition of AE .................................................................................................. 45 
8.1.2 
Procedures for reporting and recording AEs ....................................................... 46 
8.1.3 
Description of AEs .............................................................................................. 46 
8.1.4 
Follow up on adverse events ................................................................................ 46 
8.1.5 
Rule for repetition of an adverse event ................................................................ 46 
8.1.6 
Pregnancy ............................................................................................................ 46 
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8.1.7 
Suspected transmission of an infectious agent via a medicinal product .............. 47 
8.1.8 
Overdose of investigational medicinal product ................................................... 47 
8.1.9 
Safety signal detection in ongoing clinical studies and Data Monitoring 
Committees .......................................................................................................... 47 
8.1.10 
Occurrence of COVID-19 .................................................................................... 48 
8.2 
Serious adverse events ................................................................................................. 48 
8.2.1 
Definition of serious adverse event ..................................................................... 48 
8.2.2 
AEs of special interest ......................................................................................... 49 
8.2.3 
Immediate reporting of AEs ................................................................................ 50 
8.2.4 
Procedures for reporting serious adverse events ................................................. 50 
8.2.5 
Follow up of serious adverse events .................................................................... 50 
8.2.6 
Anticipated serious adverse events ...................................................................... 50 
8.3 
Laboratory measurements ............................................................................................ 51 
8.3.1 
Pregnancy testing ................................................................................................. 52 
8.3.2 
Liver function tests and evaluation of PDILI ...................................................... 52 
8.3.2.1 
Consultation with Medical Monitor and local hepatologist ...................... 56 
8.3.2.2 
Immediate action: determination of IMP discontinuation ......................... 56 
8.3.2.3 
Testing: identification/exclusion of alternative etiology ........................... 56 
8.3.2.4 
Follow-up evaluation ................................................................................. 58 
8.4 
Other measurements..................................................................................................... 59 
8.4.1 
Physical examination ........................................................................................... 59 
8.4.1.1 
Complete physical examination ................................................................ 59 
8.4.1.2 
Brief physical examination ........................................................................ 59 
8.4.2 
Neurological examination .................................................................................... 59 
8.4.2.1 
Complete neurological examination .......................................................... 59 
8.4.2.2 
Brief neurological examination ................................................................. 59 
8.4.3 
Vital signs and body weight ................................................................................ 59 
8.4.4 
12-lead ECG ........................................................................................................ 59 
8.4.4.1 
Overall ECG interpretation ....................................................................... 60 
8.4.4.2 
Specific QTcB criteria ............................................................................... 60 
8.4.5 
Tanner Stage ........................................................................................................ 60 
8.4.6 
Assessment of suicidality .................................................................................... 60 
8.4.7 
Achenbach CBCL ................................................................................................ 61 
8.4.8 
Bayley Scales of Infant and Toddler Development, Third Edition ..................... 61 
8.4.9 
Palatability and ease of use questionnaire for LCM ............................................ 62 
8.4.10 
Behavior Rating Inventory of Executive Function .............................................. 62 
9 
MANUFACTURING, HANDLING, AND ACCOUNTABILITY OF STUDY 
MEDICATION ................................................................................................................ 63 
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9.1 
Manufacturing, packaging, and labeling ...................................................................... 63 
9.2 
Supply, handling, and storage ...................................................................................... 64 
9.3 
Drug accountability procedures ................................................................................... 64 
9.4 
Retrieval/recall of study medication ............................................................................ 65 
9.5 
Alternative study treatment supply due to COVID-19 pandemic ................................ 65 
10 DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................... 65 
10.1 
Site qualification .......................................................................................................... 65 
10.2 
Monitoring ................................................................................................................... 65 
10.2.1 
Definition of source data ..................................................................................... 65 
10.2.2 
Source data verification ....................................................................................... 66 
10.3 
Auditing ....................................................................................................................... 66 
11 DATA HANDLING AND RECORD KEEPING ........................................................... 66 
11.1 
Case Report form completion ...................................................................................... 66 
11.2 
Database entry and reconciliation ................................................................................ 67 
11.3 
Subject Screening and Enrollment log/Subject Identification Code list ...................... 67 
11.4 
Archiving and data retention ........................................................................................ 67 
11.5 
Data management......................................................................................................... 67 
12 STATISTICS ................................................................................................................... 67 
12.1 
Description of statistical methods ................................................................................ 67 
12.1.1 
Definition of analysis sets .................................................................................... 68 
12.1.2 
Statistical analysis of safety variables ................................................................. 68 
12.1.2.1 
Primary safety variables ............................................................................ 68 
12.1.2.2 
Other safety variables ................................................................................ 68 
12.1.3 
Statistical analysis of PK variables ...................................................................... 69 
12.1.3.1 
Descriptive statistics .................................................................................. 69 
12.1.3.2 
Population PK analysis .............................................................................. 69 
12.1.4 
Statistical analysis of efficacy variables .............................................................. 69 
12.1.4.1 
Secondary efficacy variables ..................................................................... 69 
12.1.4.2 
Other efficacy variables ............................................................................. 70 
12.1.5 
Handling of protocol violators, drop-outs, and missing values ........................... 70 
12.1.6 
Interim analysis .................................................................................................... 70 
12.2 
Determination of sample size ....................................................................................... 71 
13 ETHICS AND REGULATORY ...................................................................................... 71 
13.1 
Informed consent ......................................................................................................... 71 
13.2 
Notification/submission to relevant regulatory authority(ies) ..................................... 72 
13.3 
Institutional Review Board/Independent Ethics Committee........................................ 72 
13.3.1 
Reporting to ethics committee ............................................................................. 72 
13.4 
Basic principles and appropriate national guidelines................................................... 73 
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13.5 
Subject privacy............................................................................................................. 73 
13.6 
Protocol amendments and emergency deviations ........................................................ 73 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 73 
15 REFERENCES ................................................................................................................ 73 
16 SUPPLEMENTS .............................................................................................................. 76 
16.1 
Tabular schedule of study procedures.......................................................................... 76 
16.2 
International Classification of Epileptic Seizures (1981) ............................................ 85 
17 APPENDICES ................................................................................................................. 86 
17.1 
PROTOCOL AMENDMENT 1 .................................................................................. 86 
17.2 
PROTOCOL AMENDMENT 2 ................................................................................ 112 
17.3 
PROTOCOL AMENDMENT 3 ................................................................................ 144 
17.4 
PROTOCOL AMENDMENT 4 ................................................................................ 171 
17.5 
PROTOCOL AMENDMENT 5 ................................................................................ 226 
17.6 
PROTOCOL AMENDMENT 6 ................................................................................ 247 
17.7 
PROTOCOL AMENDMENT 7 ................................................................................ 292 
17.8 
PROTOCOL AMENDMENT 8 ................................................................................ 294 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 323 
19 SPONSOR DECLARATION ........................................................................................ 324 
 
LIST OF TABLES 
Table 8‒1: 
Required investigations and follow up of PDILI ............................................. 54 
Table 8‒2: 
PDILI laboratory measurements ...................................................................... 57 
Table 8‒3: 
PDILI information to be collected ................................................................... 58 
Table 16‒1: 
Schedule of study procedures for SP848 (Year 1) ........................................... 77 
Table 16‒2: 
Schedule of study procedures for SP848 (Year 2) ........................................... 80 
Table 16‒3: 
Schedule of study procedures for SP848 (Screening Visit and Titration 
Visits, subjects enrolling directly into SP848) ................................................. 83 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
Bid 
twice daily 
BMI 
body mass index 
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 
COVID-19 
coronavirus disease 2019 
Cmax 
maximum plasma concentration 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EEG 
electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethic Committee 
IRB 
Institutional Review Board 
iv 
intravenous 
LCM 
lacosamide 
LFT 
liver function test 
MAOI 
monoamine oxidase inhibitor 
MedDRA® 
Medical Dictionary for Regulatory Activities 
n 
number of subjects 
PDILI 
potential drug-induced liver injury 
PedsQL™ 
Pediatric Quality of Life Inventory 
PET 
polyethylene terephthalate 
PK 
pharmacokinetic(s) 
PKS 
Pharmacokinetic Set 
PS 
Patient Safety 
PT 
preferred term 
QTc 
corrected QT interval 
QTcB 
corrected QT interval using the Bazett method 
RDC 
remote data capture 
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SAE 
serious adverse event 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SPM 12809 
O-desmethyl-LCM 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
TV 
Titration Visit 
ULN 
upper limit of normal 
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1 
SUMMARY 
SP848 is an open-label study to obtain long-term safety, tolerability, and pharmacokinetic (PK) 
data in children with epilepsy (partial-onset seizures and other pediatric epilepsy syndromes) 
treated with lacosamide (LCM) oral solution (syrup) or LCM tablets as adjunctive therapy. In 
addition, the study is designed to obtain preliminary efficacy data on seizure frequency during 
long-term exposure. The study will also provide continued availability of LCM to subjects who 
have completed the SP847 epilepsy study and to subjects who have discontinued from SP847 
due to a dose reduction or status epilepticus, and who, in the investigator’s opinion, would 
benefit from long-term administration of LCM. 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes. SP848 includes subjects ≥1 month to ≤18 years of age since subjects who complete 
SP847 or another applicable LCM pediatric epilepsy study in subjects <18 years of age may have 
aged to 18 years old by the time they complete that study and enroll in SP848. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. Beginning with local Protocol 
Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years to 
≤17 years of age with partial-onset seizures who have not previously received LCM will directly 
enroll at approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 for sites 
in China, approximately 60 additional eligible pediatric subjects with partial-onset seizures aged 
≥4 years to ≤17 years, who have not previously participated in a LCM clinical study, will enroll 
directly into SP848. The purpose of enrolling these subjects directly into SP848 is to obtain 
sufficient long-term safety exposures in the age range of ≥4 years to ≤17 years of age; the 
long-term safety data will be included in planned regulatory submissions for LCM as adjunctive 
therapy for partial-onset seizures in pediatric subjects ≥4 years to ≤17 years of age with epilepsy.  
Protocol Amendment 6 allows up to approximately 75 additional eligible pediatric subjects with 
epilepsy who participated in EP0060 to enroll into SP848. Protocol Amendment 8 allows an 
enrollment increase from 75 to 100 eligible pediatric subjects ≥1 month to ≤17 years of age with 
epilepsy who participated in EP0060 to enroll in SP848 in order to reflect EP0060’s inclusion of 
subjects down to 1 month of age. In addition, subjects already enrolled in SP848 may participate 
in EP0060, if eligible, and then resume participation in SP848. These subjects may either 
voluntarily choose to have an iv LCM infusion even though they are capable of taking oral LCM 
or require iv LCM infusion due to a medical reason or procedure (ie, unable to take oral LCM). 
Approximately 200 subjects who may participate in other LCM pediatric clinical studies in 
epilepsy will be eligible to participate in SP848. In total, up to approximately 400 subjects may 
be eligible to participate in SP848. 
Subjects who complete SP847 or another applicable LCM pediatric epilepsy study and choose to 
enter this open-label study will begin on the LCM dose they achieved in SP847 or their previous 
pediatric LCM study. Subjects who discontinued from SP847 due to a dose reduction or status 
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epilepticus, but for whom it is determined medically appropriate to enter this open-label study, 
will also begin on the LCM dose they achieved in SP847. Subjects who enroll from EP0060 will 
begin SP848 with an equivalent LCM dose as they last received in EP0060; however, the LCM 
dose may be further titrated/adjusted to a level to optimize tolerability and seizure control (up to 
a maximum level as described below). Subjects who meet eligibility requirements and enroll 
directly into SP848 without previous participation in a LCM clinical study will initiate treatment 
with LCM, and the LCM dose will be titrated to a level to optimize tolerability and seizure 
control (up to a maximum level as described below). 
Subjects will be able to receive LCM oral solution (syrup) or LCM tablets. During the study, 
investigators will be allowed to increase or decrease the dose of LCM and/or concomitant 
antiepileptic drugs (AEDs) to optimize tolerability and seizure reduction for each subject. The 
investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the corresponding 
dose levels for the tablet formulation) not to exceed 600mg/day based on body weight, even if 
the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in SP848 is 
12mg/kg/day or 600mg/day, whichever is lower. An increase in the LCM dose must occur only 
during office visits. 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. When subjects withdraw from the study, it is recommended that LCM be 
tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day 
(tablets) for subjects who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or 
≥300mg/day (tablet). A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the medical monitor, whenever possible. 
The study variables to be assessed are defined in Section 4.2.  
2 
BACKGROUND INFORMATION 
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated that 
almost 70 million people suffer from epilepsy (Ngugi et al, 2011). Although some forms of 
epilepsy may respond to surgical treatment and others may not require any treatment at all, most 
patients with epilepsy require appropriate pharmacological therapy (Perucca, 1996). In the past 
decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
The classification of epilepsies in children was described in 1989 by the Commission on 
Classification and Terminology of the International League Against Epilepsy (1989; Aicardi, 
1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
according to a number of criteria including seizure type, cause, anatomy, precipitating factors, 
age of onset, and sometimes prognosis. 
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and PK characteristics (Herman and Pedley, 1998). However, more 
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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; 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 (LCM, Vimpat®, SPM 927, [R]-2-acetamido-N-benzyl-3-methoxypropionamide) 
belongs to a novel class of functionalized amino acids. It has minimal protein binding and effect 
on cytochrome P450 enzyme system function (reducing the risk of drug-drug interactions), high 
oral bioavailability, and a half-life of approximately 13 hours (in adults), which allows a twice 
daily (bid) dose regimen. It also displays dose-proportional PK following administration over a 
range of doses up to 800mg in adults. 
Lacosamide (200mg/day to 400mg/day) is approved and indicated as adjunctive therapy in the 
treatment of partial-onset seizures with or without secondary generalization in adult and 
adolescent (16 to 18 years of age) patients with epilepsy and was first approved in Aug 2008 by 
the European Commission. Lacosamide is available in tablet (50mg, 100mg, 150mg, and 200mg) 
and syrup (10mg/mL) oral formulations as well as solution for infusion (10mg/mL) formulation 
for use as temporary iv replacement when oral administration is not feasible. Lacosamide 
(200mg/day to 400mg/day) was approved in the US in Oct 2008 as adjunctive therapy and in 
Aug 2014 as monotherapy in the treatment of partial-onset seizures in patients 17 years of age 
and older. Initiation of adjunctive LCM treatment with a single loading dose of LCM 200mg 
(oral tablets, syrup, or iv infusion) followed 12 hours later by a LCM 100mg twice daily 
(200mg/day) maintenance dose regimen was also approved by the European Commission in Nov 
2012. Use of a LCM 200mg loading dose for initiation of initial LCM monotherapy, conversion 
to LCM monotherapy, or adjunctive therapy was approved in the US in Aug 2014.  
The oral solution (syrup) is a formulation suitable for administration to children. Bioequivalence 
has been shown between the tablet and oral solution (syrup) formulations, comparing 2 tablets of 
LCM 100mg and the oral solution (syrup) containing LCM 200mg, after single-dose 
administration in healthy subjects. The PK of LCM and its major metabolite, SPM 12809 
(O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after single oral 
doses of LCM 200mg administered as tablets or as oral solution (syrup). 
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 
randomized dose (200mg/day, 400mg/day, or 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 adverse events (TEAEs) were central nervous 
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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 adverse events (AEs) were comparable to adjunctive therapy with other marketed 
AEDs. Safety evaluations support the further development of LCM as an AED. 
SP847 was an open-label, dose-titration, safety, tolerability, and PK study to evaluate LCM as 
adjunctive therapy in children with uncontrolled partial-onset seizures. The study completed on 
26 Aug 2014. Forty-seven subjects (aged 1 month to 17 years) with uncontrolled partial-onset 
seizures on a stable dose regimen of at least 1 but no more than 3 AEDs were enrolled and 
treated during the study. The study consisted of a Screening Phase, a Treatment Phase, and an 
End-of-Study Phase. The duration of treatment for an individual subject was up to approximately 
13 weeks.  
SP848 is an open-label study to obtain long-term safety, tolerability, and pharmacokinetic (PK) 
data in children with epilepsy (partial-onset seizures and other pediatric epilepsy syndromes) 
treated with LCM oral solution (syrup) or LCM tablets as adjunctive therapy. In addition, the 
study is designed to obtain preliminary efficacy data on seizure frequency during long-term 
exposure. The study will also provide continued availability of LCM to subjects who have 
completed the SP847 epilepsy study and to subjects who have discontinued from SP847 due to a 
dose reduction or status epilepticus, and who, in the investigator’s opinion, would benefit from 
long-term administration of LCM. 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes. In addition, at selected sites, beginning with Protocol Amendment 4, up to 
approximately 100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset 
seizures (deemed appropriate for treatment with adjunctive LCM) who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. Beginning 
with local Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric 
subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not previously 
received LCM will directly enroll at approximately 9 sites in Japan. Beginning with local 
Protocol Amendment 5.4 for sites in China, approximately 60 additional eligible pediatric 
subjects with partial-onset seizures aged ≥4 years to ≤17 years, who have not previously 
participated in a LCM clinical study, will enroll directly into SP848. The purpose of enrolling 
these subjects directly into SP848 is to obtain additional long-term safety exposures in the age 
range of ≥4 years to ≤17 years of age; the additional long-term safety data will be included in 
planned regulatory submissions for LCM as adjunctive therapy for partial-onset seizures. 
3 
STUDY OBJECTIVES 
The objectives of this study are: 
• To obtain information about the safety, tolerability, and PK of LCM during long-term 
exposure 
• To obtain preliminary efficacy data on seizure frequency during long-term exposure 
• To allow subjects who have participated in SP847 (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
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• To allow subjects who have participated in other LCM pediatric clinical studies in epilepsy to 
continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously received 
LCM to begin receiving LCM 
4 
STUDY DESIGN 
4.1 
Study description 
4.1.1 
Subjects enrolling from SP847 or other LCM pediatric clinical studies 
in epilepsy 
Subjects who complete SP847 (including discontinuation from SP847 due to a dose reduction or 
status epilepticus) or subjects from another applicable LCM pediatric clinical study in epilepsy 
and who choose to enter the open-label study, will begin with an equivalent LCM dose as they 
last received in the primary study. Subjects will be able to continue on LCM oral solution (syrup) 
or switch to LCM tablets. During the study, investigators will be allowed to increase or decrease 
the dose of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for 
each subject. The investigator may titrate/adjust the LCM dose to a minimum of 2mg/kg/day 
(oral solution [syrup]) or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution 
[syrup]) or the corresponding dose levels for the tablet formulation), not to exceed 600mg/day 
based on body weight, even if the subject’s body weight exceeds 50kg. The maximum permitted 
LCM dose in SP848 is 12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM 
dose must occur only during office visits. 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. When subjects withdraw from the study, it is 
recommended that the study medication be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have achieved a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly 
decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if 
medically necessary. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible.  
4.1.2 
Subjects enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously participated in a LCM clinical 
study will be permitted to enroll directly into SP848. Beginning with local Protocol Amendment 
5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years to ≤17 years of age 
with partial-onset seizures who have not previously received LCM will directly enroll at 
approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 for sites in China, 
approximately 60 additional eligible pediatric subjects with partial-onset seizures aged ≥4 years 
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to ≤17 years, who have not previously participated in a LCM clinical study, will enroll directly 
into SP848. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control (see Section 4.4.1). Subjects 
will be able to receive LCM oral solution or LCM tablets for up to 2 years as determined 
appropriate by the investigator. 
SP848 includes subjects ≥1 month to ≤18 years of age since subjects who complete SP847 or 
another applicable LCM pediatric epilepsy study in subjects <18 years of age may have aged to 
18 years old by the time they complete that study and enroll in SP848. 
The same study conditions described in Section 4.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and study medication taper) also 
apply.  
4.2 
Variables to be assessed 
4.2.1 
Safety variables 
4.2.1.1 
Primary safety variables 
The primary safety variables are: 
• Incidence of TEAEs 
• Incidence of serious AEs (SAEs) 
• Subject withdrawal from the study due to TEAEs 
4.2.1.2 
Other safety variables 
The other safety variables are: 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner Stage (if applicable) 
• Achenbach Child Behavior Checklist (CBCL) at Baseline for children 18 months and older 
(CBCL/1½-5 and CBCL/6-18) assessing behavior 
• Bayley-III scales at Baseline for children <18 months of age at time of enrollment 
(applicable only to subjects enrolled in English-speaking countries) 
• Cognitive function assessments (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/BRIEF®-Preschool Version [BRIEF®-P]) (if applicable) 
• LCM palatability and ease of use questionnaire 
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4.2.2 
PK variables 
4.2.2.1 
Primary PK variables 
No primary PK variables are defined for this study. 
4.2.2.2 
Other PK variables 
The other PK variables are: 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
4.2.3 
Efficacy variables 
4.2.3.1 
Primary efficacy variables 
No primary efficacy variables are defined for this study. 
4.2.3.2 
Secondary efficacy variables 
The secondary efficacy variables, based on daily seizure diaries, are: 
• Percent change from Baseline in 28-day partial-onset seizure frequency  
• ≥50% reduction in 28-day partial-onset seizure frequency 
• ≥75% reduction in 28-day partial-onset seizure frequency 
• Seizure days per 28 days (subjects with generalized seizures only) 
• Seizure-free status 
4.2.3.3 
Other efficacy variables 
The other efficacy variables are: 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• Quality of life assessments (Pediatric Quality of Life Inventory [PedsQL™]) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study)  
• All seizure frequency analyses as described in the secondary efficacy variables (presented for 
the overall Treatment Period only) may be additionally presented by modal daily dose group, 
by seizure type, by seizure classification subgroup, by time interval, by visit or time period, 
or by completer cohort 
4.3 
Selection and withdrawal of subjects 
4.3.1 
Inclusion criteria 
All subjects in SP848 must fulfill the following inclusion criteria: 
1. A signed informed consent form has been obtained from the parent/legal guardian and assent 
has been obtained from the subject (when possible or as required according to local 
Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]). 
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4. Subject and caregiver (which may be a parent, legal guardian, or other delegated caregiver) 
are willing and able to comply with all study requirements, including maintaining a daily 
seizure diary. 
Subjects who have participated in SP847 or other LCM pediatric clinical studies in 
epilepsy must fulfill the following inclusion criteria: 
2. Subject has completed SP847 (or the subject discontinued SP847 due to a dose reduction or 
status epilepticus) for the treatment of uncontrolled partial-onset seizures, or subject has 
participated in other LCM pediatric clinical studies in epilepsy.  
3. Subject is expected to benefit from participation, in the opinion of the investigator. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical 
study must fulfill the following inclusion criteria: 
5. Subject is male or female and ≥4 years to ≤17 years of age.  
6. Subject has a diagnosis of epilepsy with partial-onset seizures.  
• The results of at least 1 prior electroencephalogram (EEG) AND 1 prior magnetic 
resonance imaging/computerized tomography scan should be consistent with the above 
diagnosis. 
7. Subject has been observed to have uncontrolled partial-onset seizures after an adequate 
course of treatment (in the opinion of the investigator) with at least 2 AEDs (concurrently or 
sequentially). 
8. Subject has been observed to have at least 2 countable seizures in the 4-week period prior to 
Screening. 
• In the case of simple partial seizures, only those with motor signs will be counted 
towards meeting the inclusion criteria (only partial seizures with a recognizable and 
countable manifestation). 
9. Subject is on a stable dosage regimen of 1 to 3 AEDs. The daily dosage regimen of 
concomitant AED therapy must be kept constant for a period of at least 1 week prior to 
Screening. Vagal nerve stimulation is not counted as medical therapy; however, VNS settings 
must be kept constant for a period of at least 1 week prior to Screening. 
10. Subject is an acceptable candidate for venipuncture. 
4.3.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria are met: 
1. Subject is receiving any investigational drugs or using any experimental devices in addition 
to LCM. 
3.  Subject ≥6 years of age has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening. 
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Subjects who have participated in SP847 or other LCM pediatric clinical studies in 
epilepsy are not permitted to enroll in the study if any of the following criteria are met: 
2. Subject meets either of the following: 
a. Withdrawal criteria for the primary study (with the exception of subjects who discontinued 
due to a dose reduction or status epilepticus). For subjects entering from EP0060, if the 
subject (or legal guardian) withdraws consent solely due to route of LCM administration (iv) 
or if the subject requires more than 10 iv LCM infusions, the subject may be allowed to 
participant in SP848 after discussion with and agreement from the Medical Monitor. 
b. Ongoing serious AE (SAE).  
Subjects who enroll directly into SP848 without previous participation in a LCM clinical 
study are not permitted to enroll in the study if any of the following criteria are met: 
4. Subject has ever received LCM. 
5. Subject has any medical or psychiatric condition that, in the opinion of the investigator, could 
jeopardize or would compromise the subject’s ability to participate in this study. 
6. Subject has a medical condition that could reasonably be expected to interfere with drug 
absorption, distribution, metabolism, or excretion. 
7. Subject has a known hypersensitivity to any component of the investigational medicinal 
product. 
8. Subject is a female of childbearing potential and does not practice an acceptable method of 
contraception for the duration of the study. 
• Medically acceptable contraceptive method includes oral or depot contraceptive 
treatment with at least 30μg ethinylestradiol per intake (or 50μg if associated with 
carbamazepine [or other strong enzyme inducers, eg, phenobarbital, primidone, 
oxcarbazepine]) which must be used in conjunction with a barrier method. Sexual 
abstinence is also an acceptable method of contraception.  
• The subject must understand the consequences and potential risks of inadequately 
protected sexual activity, be educated about and understand the proper use of 
contraceptive methods, and undertake to inform the investigator of any potential change 
in status. Females of childbearing potential must have a negative pregnancy test at the 
Screening Visit.  
9. Subject has a creatinine clearance less than 30mL/min. 
10. Subject has a clinically relevant ECG abnormality, in the opinion of the principal investigator 
(ie, second or third degree heart block at rest or a QT prolongation greater than 450ms). 
11. Subject has hemodynamically significant heart disease (eg, heart failure). 
12. Subject has an arrhythmic heart condition requiring medical therapy. 
13. Subject has a known history of severe anaphylactic reaction or serious blood dyscrasias. 
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14. Subject has nonepileptic events, including psychogenic seizures, that could be confused with 
seizures. If both epileptic and nonepileptic events are present, epileptic events must be 
distinguished from nonepileptic phenomena. 
15. Subject has a history of primary generalized epilepsy. 
17. Subject is taking monoamine oxidase inhibitors-A (MAOI-A) or narcotic analgesics. 
18. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively 
neurodegenerative disease, such as Rasmussen syndrome. 
19. Subject has a known sodium channelopathy, such as Brugada syndrome. 
20. Subject has >2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a Baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
Subjects who were directly enrolled in EP0060 for iv LCM replacement therapy or to 
initiate LCM treatment are not permitted to enroll in the study if any of the following 
criteria are met: 
21. Subjects have previously participated in a long-term, open-label LCM study. 
 
4.3.3 
Criteria for withdrawal 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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 following criteria for subject withdrawal from SP848 are outlined 
below. Additional discontinuation criteria for potential drug-induced liver injury (PDILI) are 
presented in Section 4.3.3.1. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
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3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is unwilling 
or unable to allow the subject to continue in the study. 
8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
9.    Subject experiences convulsive status epilepticus (if none had occurred prior to study entry) 
and is compliant with study treatment 
11.   For subject who did not complete a C-SSRS at Screening, subject has a lifetime history 
(prior to study entry or since study start) of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt) of the screening version of the C-SSRS. The 
investigator must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
12. For all subjects ≥6 years of age, regardless of whether or not a C-SSRS was completed at 
Screening, subject has actual suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “since last visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study. 
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
5.   For subject who did not complete a C-SSRS at Screening, subject had actual suicidal ideation 
in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the screening version of the C-SSRS. The investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the patient from the study. 
If a subject from SP848 enrolls in EP0060 and either withdraws consent solely due to route of 
LCM administration (iv) or if the subject requires more than 10 iv LCM infusions, the subject 
may be allowed to return to SP848 after discussion with and agreement from the Medical 
Monitor. If a subject from SP848 is advised to withdraw from the SP848 after participation in 
EP0060, the subject will be required to return to the SP848 to complete the required ETV and 
Safety Follow-up assessments. 
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Investigators should attempt to obtain information on subjects in the case of withdrawal. For 
subjects considered as lost to follow up, the investigator should make efforts (at least 1 phone 
call and 1 written message to the subject), and document his/her efforts (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The eCRF 
must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
4.3.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be 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  
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below requires discussion with the Medical Monitor to decide whether the 
subject is allowed to continue on IMP. 
• 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 8.3.2. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
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4.4 
Study treatments 
4.4.1 
Treatments to be administered 
4.4.1.1 
Subjects enrolling from SP847 or other LCM pediatric clinical studies 
in epilepsy 
Subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), 
who are eligible to participate in the open-label study SP848, and who choose to enter SP848, 
will begin SP848 on the LCM dose they achieved in the primary study. 
Subjects who enroll from EP0060 will begin SP848 with an equivalent dose to the last dose they 
received in EP0060; however, the LCM dose may be further titrated/adjusted to a level to 
optimize tolerability and seizure control (up to a maximum level as described in Section 4.4.1.3). 
For those subjects who initiated adjunctive LCM treatment in EP0060, the recommended LCM 
dose titration approach is outlined in Section 4.4.1.2. 
4.4.1.2 
Subjects enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. Beginning with local Protocol 
Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years to 
≤17 years of age with partial-onset seizures who have not previously received LCM will directly 
enroll at approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 for sites 
in China, approximately 60 additional eligible pediatric subjects with partial-onset seizures aged 
≥4 years to ≤17 years, who have not previously participated in a LCM clinical study, will enroll 
directly into SP848. After Screening, eligible subjects will initiate treatment with LCM (oral 
solution or tablet, as chosen by the investigator and subject/caregiver), and the LCM dose will be 
titrated to a level to optimize tolerability and seizure control. 
At the first Titration Visit (TV) (see Section 5.2), subjects who have enrolled directly into SP848 
will receive a single dose of LCM (1mg/kg [oral solution] or 50mg [tablet]) during the clinic 
visit. Over the following days, subjects will be administered LCM 1mg/kg bid (oral solution) or 
LCM 50mg bid (tablet), and will begin titrating in weekly increments of 2mg/kg/day (oral 
solution) or 100mg/day (tablet) up to a level to optimize tolerability and seizure control (not to 
exceed 12mg/kg/day [or 600mg/day based on body weight, whichever is lower]). Subjects must 
be on each LCM dose for at least 5 days before titrating up to the next dose. 
A total of up to 6 Titration Visits may be required (eg, for a subject whose dose is titrated to the 
maximum permitted dose of LCM 12mg/kg/day). However, based on tolerability and seizure 
control, a subject’s LCM dose may be titrated to a lower dose level; in such a case, fewer than 
6 Titration Visits would be required. 
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The following table summarizes the recommended titration steps for the oral solution and tablet 
formulations: 
Recommended LCM dose titration for subjects enrolling directly into SP848 
Formulation 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Oral solution 
(syrup) 
2mg/kg/day 
(1mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
6mg/kg/day 
(3mg/kg bid) 
8mg/kg/day 
(4mg/kg bid) 
10mg/kg/day 
(5mg/kg bid) 
12mg/kg/day 
(6mg/kg bid) 
Tablet 
100mg/day 
(50mg bid) 
200mg/day 
(100mg bid) 
300mg/day 
(150mg bid) 
400mg/day 
(200mg bid) 
500mg/day 
(250mg bid) 
600mg/day 
(300mg bid) 
bid=twice daily; LCM=lacosamide 
4.4.1.3 
All subjects 
The investigator, together with the subject/caregiver (including parent/legal guardian), will be 
able to choose either the oral solution (syrup) formulation or the tablet formulation of LCM in 
this study. The study medication will be orally administered bid (at 12-hour intervals, once in the 
morning and once in the evening) in equally divided doses. The oral solution (syrup) formulation 
will be measured and orally administered via a dosing syringe. The selection of doses, titration 
scheme, and rate of taper in SP847 were based on adult studies and were adjusted to a mg/kg 
basis plus 40% (ie, 600mg/day adult dose of LCM corresponds to [600mg/70kg] x 1.4 = 
approximately 12mg/kg/day for a child). The selection of doses in this trial is based on the 
maximum recommended dose in SP847. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. 
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. The investigator may decrease the 
dose of LCM to a minimum of 2mg/kg/day (oral solution [syrup] or the corresponding dose level 
for the tablet formulation). Increases in the LCM dose must occur only during office visits. It 
should be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the syrup), 
missed doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
Subjects enrolling from SP847 will have the option of remaining on the oral solution formulation 
of LCM or switching to the commercial tablet formulation, if feasible. Consideration of the 
current LCM milligram dose in the oral solution (syrup) should occur if/when transitioning to the 
tablet formulation. In cases where the LCM dose received with the oral solution (syrup) is not 
supported by the tablet strengths available in SP848 (50mg and 100mg), a clinical decision must 
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be made by the investigator or other study physician to either increase or decrease the LCM dose 
to the next multiple of 100mg with a maximum permitted dose of 600mg/day. 
Subjects achieving a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet) 
who withdraw during the study should taper off study medication. It is recommended that the 
dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (see tables below). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Recommended LCM dose reduction (taper) for oral solution (syrup) formulation 
Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
12mg/kg/day 
(6mg/kg bid) 
8mg/kg/day 
(4mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
0 
10mg/kg/day 
(5mg/kg bid) 
6mg/kg/day 
(3mg/kg bid) 
2mg/kg/day 
(1mg/kg bid) 
0 
8mg/kg/day 
(4mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
0 
– 
6mg/kg/day 
(3mg/kg bid) 
2mg/kg/day 
(1mg/kg bid) 
0 
– 
4mg/kg/day 
(2mg/kg bid) 
0 
– 
– 
bid=twice daily; LCM=lacosamide 
a     Maximum LCM dose achieved is based upon the maximum recommended dose in SP847. 
Recommended LCM dose reduction (taper) for tablet formulation 
Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
600mg/day 
(300mg bid) 
400mg/day 
(200mg bid) 
200mg/day 
(100mg bid) 
0 
500mg/day 
(250mg bid) 
300mg/day 
(150mg bid) 
100mg/day 
(50mg bid) 
0 
400mg/day 
(200mg bid) 
200mg/day 
(100mg bid) 
0 
– 
300mg/day 
(150mg bid) 
100mg/day 
(50mg bid) 
0 
– 
200mg/day 
(100mg bid) 
0 
– 
– 
bid=twice daily; LCM=lacosamide 
a     Maximum LCM dose achieved is based upon the maximum recommended dose in SP847. 
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4.4.1.4 
Study completion 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final 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 parent/legal guardian) should taper LCM gradually as 
described in Section 4.4.1.3. These subjects should complete Visit 13/Termination Visit, 
followed by the Final Visit which occurs 2 weeks after the final dose of study medication, and 
then the Safety Follow-Up telephone contact which occurs 28 to 35 days after the last dose of 
LCM. 
4.4.2 
Description of investigational medicinal product 
Beginning with protocol Amendment 3, the oral solution formulation contains 10mg/mL of drug 
substance (formerly containing 15mg/mL of drug substance) and is colorless to pale yellow in 
appearance. The oral solution (syrup) will be packaged in amber polyethylene terephthalate 
(PET) bottles with a white, child-proof, polypropylene screw cap.  
The tablet formulation will be supplied in doses of 50mg and 100mg. The 50mg tablets are light 
pink, oval, film-coated tablets debossed with “SP” on 1 side and “50” on the other. The 100mg 
tablets are dark yellow, oval, film-coated tablets debossed with “SP” on one side and “100” on 
the other. The tablets will be packaged in high-density polyethylene bottles with a child-proof, 
polypropylene screw cap. 
4.4.3 
Randomization 
This is an open-label study; subjects will not be randomized. Subjects who participated in SP847 
or other LCM pediatric clinical studies in epilepsy will keep the unique number assigned in the 
primary study. 
Subjects enrolling directly into SP848 without participation in a previous LCM clinical study 
will be assigned unique numbers for the purpose of study and subject identification, as well as 
for subject confidentiality. At the Screening Visit, each subject will be assigned the unique 
identifying number for this study. 
4.5 
Expected duration of the study 
The maximum duration of LCM administration for an individual subject will be approximately 
2 years or until approval of the marketing application (for Japan only), whichever comes first. 
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 visit of the last subject in the study. 
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4.6 
Concomitant medication(s)/treatment(s) 
The following medications/therapies are prohibited during the course of this study: 
• Monoamine oxidase inhibitor-A compounds 
• Narcotic analgesics 
• Cannabidiols not approved or indicated for epilepsy by a local health authority 
All concomitant medications and treatments must be recorded in the appropriate study 
documents (eCRF and source document). 
Stable use of amphetamines and sedative antihistamines is allowed during the study. Also, 
stable, low doses of anxiolytics or hypnotics (ie, diazepam 5mg/day) are allowed for nonepilepsy 
indications only. 
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. The subject's participation in this study may be discontinued in such a case. 
4.7 
Procedures for monitoring subject compliance 
Subjects’ caregivers (including parent/legal guardian) will be instructed to return unused 
medication at each study visit. Returned medication will be reconciled by the investigator (or 
designee) in order to monitor the subject’s compliance with the medication schedule. Drug 
accountability must be done in the subject’s/caregiver’s presence in order to obtain explanations 
regarding discrepancies in compliance with the dosing regimen. 
All findings will be documented on forms provided by UCB BIOSCIENCES. Subject’s 
noncompliance with regards to intake of LCM is defined as being less than 75% or more than 
125% compliant with the dosage schedule.  
If a subject is found to be noncompliant, a decision will be made by the investigator, in 
conjunction with UCB BIOSCIENCES, as to whether the subject should be withdrawn from the 
study. 
5 
TREATMENT PROCEDURES BY VISIT 
For all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact), a visit window of ±7 days relative to Visit 1 is applicable. The Safety 
Follow-Up telephone contact will be performed 28-35 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.  
Assessments will be done during monthly visits for the first 3 months, every 2 months for the 
remainder of Year 1, and every 3 months for Year 2. A detailed tabular schedule of study 
procedures is provided in Section 16.1. For further details of the assessments and the required 
procedures and methods, please refer to Section 6, Section 7, and Section 8. 
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5.1 
Screening Visit 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. 
At the Screening Visit, subjects entering directly into SP848 (ie, subjects who have not 
participated in SP847 or another applicable LCM pediatric clinical study in epilepsy) will be 
evaluated for their suitability for enrollment in SP848. The Screening Visit is not applicable for 
subjects who have participated in SP847 or another applicable LCM pediatric clinical study in 
epilepsy; the first visit in SP848 for these subjects is Visit 1 (see Section 5.3). 
The Screening assessments will be conducted up to 14 days prior to the first administration of 
LCM. It is acceptable for the Screening assessments to be conducted on more than 1 day, 
although it should not be done over longer than 1 week. Prior to the conduct of any study-related 
procedures, a complete explanation (both verbally 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 parent/legal guardian by the investigator (or designee). The subject’s 
parent/legal guardian will be requested to sign and date the IRB/IEC-approved Informed Consent 
Form. When possible, or as required by the local IRB/IEC, the subject will be requested to give 
assent to participate in the study. Each subject’s eligibility for the study will be determined on 
the basis of the inclusion/exclusion criteria and the results of the following pretreatment 
assessments (for further details of the assessments and the required procedures and methods, 
please refer to Section 6, Section 7, and Section 8 of this protocol). 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Medical history assessment 
• Seizure history over the past 4 weeks (historical Baseline) 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse)  
• Body weight assessment 
• Height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• C-SSRS 
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• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary 
The subject will be scheduled to return for a clinic visit (TV) less than 14 days from the last 
Screening Visit assessment(s). 
5.2 
Titration Visit(s) (TV1, TV2, TV3, TV4, TV5, TV6) 
Eligible subjects who enter directly into SP848 (without prior participation in SP847 or another 
applicable LCM primary study) will initiate treatment with LCM at TV1, and the LCM dose will 
be titrated over the following week(s). Titration Visits are not applicable for subjects who have 
participated in SP847 or another LCM primary study; the first visit in SP848 for these subjects is 
Visit 1 (see Section 5.3). 
At TV1, subjects who have enrolled directly into SP848 will receive a single dose of LCM 
(1mg/kg [oral solution] or 50mg [tablet]) during the clinic visit. Over the following days, 
subjects will be administered LCM 1mg/kg bid (oral solution) or LCM 50mg bid (tablet), and 
will begin titrating in weekly increments of 2mg/kg/day (oral solution) or 100mg/day (tablet) up 
to a level to optimize tolerability and seizure control (not to exceed 12mg/kg/day [or 600mg/day 
based on body weight, whichever is lower]). Subjects must be on each LCM dose for at least 
5 days before titrating up to the next dose. It should be noted, in cases of incomplete doses (eg, 
subject spits out all or a portion of the syrup), missed doses, or administration of an erroneous 
volume of syrup, study medication should not be readministered and these cases would not be 
considered dose reductions. The LCM dose titration steps are summarized in Section 4.4.1.2. 
A total of up to 6 Titration Visits may be required (eg, for a subject whose dose is titrated to the 
maximum permitted dose of LCM 12mg/kg/day). However, based on tolerability and seizure 
control, a subject’s LCM dose may be titrated to a lower dose level; in such a case, fewer than 
6 Titration Visits would be required. 
The following assessments are required for each TV: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
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• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• Blood sample for clinical chemistry, hematology, and endocrinology (TV4 only) 
• Urine sample for urinalysis (TV4 only) 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary 
• Dispense LCM (as applicable) 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM 
maximum plasma concentration (Cmax) 1 week after an initial LCM dose increase to a LCM dose 
level that is ≥8mg/kg/day or a new concomitant AED is introduced. Subjects 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). 
5.3 
Visit 1 (Week 0) 
For subjects who completed SP847, Visit 1 for SP848 was the same as Day 2 of the second PK 
collection time period (which may include an overnight stay at a hospital or medical facility) in 
SP847 (Day 28 for Cohorts 1, 2, 3, and 5 with maximum recommended dose of 8mg/kg/day; 
Day 35 for Cohorts 2 to 5 with maximum recommended dose of 10mg/kg/day; and Day 42 for 
Cohorts 2 to 5 with maximum recommended dose of 12mg/kg/day). For subjects who 
discontinued SP847 due to a dose reduction or status epilepticus, Visit 1 was the Early 
Termination Visit in SP847. For subjects in SP847 who were titrated up to the maximum 
permitted dose of 600mg/day sooner than the study schedule would ordinarily indicate (based on 
body weight) and who enroll in SP848, the Early Termination Visit of SP847 also served as 
Visit 1 for SP848. 
For subjects who enroll in SP848 after participation in other LCM pediatric clinical studies 
besides SP847 (ie, SP0966 and EP0060) in epilepsy, SP848 Visit 1 will be specified in the 
respective primary study protocol. 
For subjects who enter directly into SP848 (without prior participation in SP847 or other LCM 
pediatric clinic studies in epilepsy), the LCM dose will be titrated at weekly intervals as 
described in Section 4.4.1.2 and Section 5.2. These subjects will reach Visit 1 either (1) when the 
LCM dose is titrated to a level that, in the opinion of the investigator, optimizes tolerability and 
seizure control, or (2) when the maximum permitted LCM dose is reached (12mg/kg/day [or 
600mg/day based on body weight, whichever is lower]). In the case of a subject who requires a 
dose reduction during the Titration Visits, the subject’s LCM dose will be returned to the 
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previous dose level and the next clinic visit will be Visit 1 at the reduced level. Visit 1 should 
occur at least 5 days after the final TV. At Visit 1, the progress in SP848 for subjects who 
entered directly into SP848 and for subjects who have enrolled from SP847 or other LCM 
pediatric clinical studies in epilepsy will be aligned; subsequent regularly scheduled clinic visits 
for all subjects will be at 4-week intervals as outlined in the following sections. 
The informed consent process for SP848 will be conducted at Visit 1 for subjects who have not 
previously been through the informed consent process at the Screening Visit (ie, subjects 
enrolling from SP847 or other LCM pediatric clinical studies in epilepsy for whom Visit 1 is the 
first study visit in SP848). Prior to the conduct of any study-related procedures, a complete 
explanation (both verbally 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 
parent/legal guardian by the investigator (or designee). The subject’s parent/legal guardian will 
be requested to sign and date the IRB/IEC-approved Informed Consent Form. When possible, or 
as required by local IRB/IEC, the subject will be requested to give assent to participate in the 
study. 
Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments (applicable only for subjects for whom Visit 1 is the first 
clinic visit for SP848), and a complete medical history update will be obtained. If available, the 
data for the following assessments will be taken from the last assessment during SP847 (or other 
primary study, as applicable): 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment but 30 minutes to 1 hour after the administration of LCM) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• C-SSRS 
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• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) (subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
(subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
5.4 
Telephone contacts (Weeks 2, 6, 10, 16, 24, 32, 40, 48, 66, 
and 78) 
Between scheduled clinic visits, the investigator (or designee) should contact the subject’s 
caregiver (including parent/legal guardian) by telephone. The investigator (or designee) should 
remind the subject’s caregiver (including parent/legal guardian) to ensure the diary is completed 
and to bring unused LCM to the next clinic visit. The following should be performed via 
telephone: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Adverse event reporting 
If an AE necessitates the subject’s withdrawal from the study, the subject should return for an 
Early Termination Visit (Section 5.17) as soon as possible. 
Lacosamide is supplied so that the subject or caregiver (including parent/legal guardian) 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. 
5.5 
Visit 2 (Week 4) 
During Visit 2 (Week 4), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Brief physical examination 
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• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry and hematology 
• Blood samples for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine pregnancy test for female subjects of childbearing potential 
• LCM return/compliance. Subject’s caregivers will be instructed to return unused LCM at 
each study visit. Returned medication will be reconciled by the investigator (or designee) in 
order to monitor the subject’s compliance with the medication schedule. If a subject is found 
to be noncompliant, a decision will be made by the investigator, in conjunction with UCB 
BIOSCIENCES, as to whether the subject should be withdrawn from the study. 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased to a LCM dose level that is ≥8mg/kg/day or a new concomitant AED is introduced. 
The ECG should be performed after the increased dose of LCM or the new AED has reached 
steady-state. This ECG can be done at the next scheduled visit. When the ECG assessment is 
done, 2 interpretable recordings will be performed approximately 20 to 30 minutes apart 
prior to vital sign assessment and collection of blood samples (if applicable), but 30 minutes 
to 1 hour after the administration of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day. This ECG 
can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
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5.6 
Visit 3 (Week 8) 
During Visit 3 (Week 8), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Urine pregnancy test for female subjects of childbearing potential 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parents/legal guardians) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased to a LCM level dose that is ≥8mg/kg/day or a new concomitant AED is introduced. 
The ECG should be performed after the increased dose of LCM or the new AED has reached 
steady-state. This ECG can be done at the next scheduled visit. When the ECG assessment is 
done, 2 interpretable recordings will be performed approximately 20 to 30 minutes apart 
prior to vital sign assessment and collection of blood samples (if applicable), but 30 minutes 
to 1 hour after the administration of LCM (if applicable). 
• All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM 
Cmax 1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day. 
This ECG can be conducted at an Unscheduled Visit if necessary. These subjects 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). 
5.7 
Visit 4 (Week 12) 
Assessments for Visit 4 (Week 12) are the same as those described for Visit 3 (Week 8), in 
Section 5.6. 
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5.8 
Visit 5 (Week 20) 
During Visit 5 (Week 20), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine sample for urinalysis 
• Urine pregnancy test for female subjects of childbearing potential 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) (subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
(subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parents/legal guardians) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
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A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is increased 
to a LCM dose level that is ≥8mg/kg/day or a new concomitant AED is introduced. The ECG 
should be performed after the increased dose of LCM or the new AED has reached steady-state. 
This ECG can be done at the next scheduled visit. When the ECG assessment is done, 2 
interpretable recordings will be performed approximately 20 to 30 minutes apart prior to vital 
sign assessment and collection of blood samples (if applicable), but 30 minutes to 1 hour after 
the administration of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day. This ECG 
can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
5.9 
Visit 6 (Week 28) 
Assessments for Visit 6 (Week 28) are the same as those described for Visit 3 (Week 8) in 
Section 5.6, with the following exception: completion of the palatability and ease of use 
questionnaire and a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart prior to vital signs assessment and collection of blood sample) are conducted at Visit 6. 
5.10 
Visit 7 (Week 36) 
Assessments for Visit 7 (Week 36) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exception: a 12-lead ECG is not conducted at Visit 7. 
5.11 
Visit 8 (Week 44) 
Assessments for Visit 8 (Week 44) are the same as those described for Visit 3 (Week 8), in 
Section 5.6, with the following exception: a Tanner Stage assessment is conducted at Visit 8 (if 
applicable). 
5.12 
Visit 9 (Week 52) 
Assessments for Visit 9 (Week 52) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exception: completion of the palatability and ease of use 
questionnaire and a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart prior to vital signs assessment and collection of blood sample) are conducted at Visit 9. 
5.13 
Visit 10 (Week 60) 
Assessments for Visit 10 (Week 60) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exceptions: a 12-lead ECG is not conducted at Visit 10 (all sites) 
and a PK sample is routinely drawn at sites in Japan (removed for all other sites). 
5.14 
Visit 11 (Week 72) 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions for all sites: brief physical and neurological exams are 
conducted (instead of complete physical and neurological exams as indicated for Visit 5), the 
laboratory blood sample is collected only for clinical chemistry and hematology (ie, no 
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endocrinology), the palatability and ease of use questionnaire is completed, and a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted. In addition to the noted differences, a PK sample is 
routinely drawn at sites in Japan (removed for all other sites). 
5.15 
Visit 12 (Week 84) 
Assessments for Visit 12 (Week 84) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exceptions for all sites: the laboratory blood sample is collected 
for endocrinology as well as clinical chemistry and hematology and a 12-lead ECG is not 
conducted. In addition to the noted differences, a PK sample is routinely drawn at sites in Japan 
(removed for all other sites). 
5.16 
Visit 13/Termination Visit (Week 96)  
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final 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 parent/legal guardian) should taper LCM gradually as 
described in Section 4.4.1.3. These subjects should complete Visit 13/Termination Visit, 
followed by the Final Visit which occurs 2 weeks after the final dose of study medication, and 
then the Safety Follow-Up telephone contact which occurs 28 to 35 days after the last dose of 
LCM. 
Assessments for Visit 13/Termination Visit (Week 96) are the same as those described for 
Visit 5 (Week 20), in Section 5.8, with the following exceptions for all sites: the laboratory blood 
sample is collected only for clinical chemistry and hematology (ie, no endocrinology), a 12-lead 
ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of blood sample) is conducted, a Tanner Stage assessment is 
conducted (if applicable), an Achenbach CBCL is conducted, Bayley-III scales are conducted, 
BRIEF-P/BRIEF and PedsQL scores are obtained, and the palatability and ease of use 
questionnaire is completed. In addition to the noted differences, a PK sample is routinely drawn 
at sites in Japan (removed for all other sites). 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of 
LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) 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 
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be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. 
5.17 
Early Termination Visit 
Subjects who withdraw from the study prematurely must complete an Early Termination Visit. 
At the time of withdrawal from the study, investigators should discuss treatment options with the 
subject and/or their parent/legal guardian 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 
parent/legal guardian. These subjects should complete the Early Termination Visit and then 
complete the Safety Follow-Up telephone contact 28 to 35 days after the Early Termination 
Visit. The Final Visit is not required for subjects who withdraw from the study prematurely and 
who do not undergo taper 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 parent/legal guardian) should taper 
LCM gradually as described in Section 4.4.1.3. These subjects should complete the Early 
Termination Visit, followed by the Final Visit which occurs 2 weeks after the final dose of study 
medication, and then the Safety Follow-Up telephone contact. 
The following will be performed at the Early Termination Visit: 
• Concomitant medication assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM)  
− Under any circumstance for an ETV during Year 1 
− If possible, if the early termination during Year 2 is due to a SAE and the event is 
ongoing 
• Urine sample for urinalysis 
• Serum pregnancy test for females of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Clinical Global Impression of Change 
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• Caregiver Global Impression of Change 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Palatability and ease of use questionnaire 
• Adverse event reporting 
• Health care resource use 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs) 
• Dispense LCM. Lacosamide for taper will be dispensed only for subjects who achieve a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that 
the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution 
[syrup]) or 200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) 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 parent/legal guardian. 
5.18 
Unscheduled Visit(s) 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, if an LCM dose increase is required at 
any time, or if a new concomitant AED is introduced, the subject must return for an Unscheduled 
Visit. If an AE prompts a dose reduction, the reduction can be implemented immediately at the 
investigator’s discretion. However, the subject should return to the clinic as soon as possible for 
an Unscheduled Visit. 
The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
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• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• C-SSRS (only if Unscheduled Visit is conducted due to an AE) 
• Adverse event reporting 
• Health care resource use 
• Dispense LCM (as applicable) 
• If possible, a blood sample for LCM and concomitant AED plasma concentrations (at any 
time post-dosing with LCM) if the unscheduled visit is due to a SAE  
Additional assessments can be performed at the investigator’s discretion. 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day or after 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 vital signs assessment) can be performed 
30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
5.19 
Final Visit 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. The Final Visit is not required for subjects who participate in EP0151 or EP0152.  
During the Final Visit, the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
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• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Health care resource use 
5.20 
Safety Follow-Up telephone contact 
The Safety Follow-Up telephone contact is required for all subjects (those who complete the 
study as planned or have withdrawn prematurely from the study) who do not participate in 
EP0151 or EP0152. For subjects who complete the study, this telephone contact will occur 28 to 
35 days after Visit 13/Termination Visit (subjects who do not undergo taper of LCM) or 28 to 
35 days after the last dose of LCM (subjects who discontinue use of LCM [ie, taper]). For 
subjects who withdraw prematurely from the study, this telephone contact will occur 28 to 
35 days after the Early Termination Visit (subjects who do not undergo taper of LCM) or 28 to 
35 days after the last dose of LCM (subjects who discontinue use of LCM [ie, taper]). 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 a definite outcome is achieved (Section 8.1.2). 
5.21 
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 participant 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 study participant 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 
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telephone contact, investigators will confirm whether the subject could continue the current 
study treatment based upon the outcome of the safety assessment. 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 9.5.  
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). 
6 
ASSESSMENT OF EFFICACY 
6.1 
Seizure counts 
At Screening of SP847 (or other primary study as applicable) or at the Screening Visit of SP848 
(for subjects who entered directly into SP848) subjects/caregivers (including parents/legal 
guardians) will be asked how many seizures the subject has had in the previous 4 weeks; this will 
serve as a historical Baseline. After the subject is enrolled in the SP848 study, seizure data will 
be collected in diaries provided to subjects/caregivers (including parents/legal guardians). Each 
subject/caregiver (including parent/legal guardian) will keep a diary to note daily seizure activity 
throughout the current study. The subject/caregiver (including parent/legal guardian) should be 
reminded to bring the diary with them at each clinic visit. The following information will be 
recorded: 
• Seizure type 
• Seizure frequency 
6.2 
Global Impression of Change 
6.2.1 
Clinical Global Impression of Change 
The Clinical Global Impression of Change will be assessed at least once per year and be 
completed according to the tabular schedule of study procedures, Section 16.1. 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 
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of SP847 (or other primary study as applicable) will serve as Baseline; the Screening Visit of 
SP848 will serve as Baseline for those subjects entering directly into SP848. 
The investigator will be asked to check the number that best describes the subject’s condition 
over the past 4 weeks compared to Baseline: 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No Change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
6.2.2 
Caregiver Global Impression of Change 
The Caregiver Global Impression of Change will be assessed at least once per year and be 
completed according to the tabular schedule of study procedures, Section 16.1. 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 of SP847 (or other primary study as applicable) 
will serve as Baseline; the Screening Visit of SP848 will serve as Baseline for those subjects 
entering directly into SP848. 
The caregiver will be asked to check the number that best describes the subject’s condition over 
the past 4 weeks compared to Baseline: 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No Change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
6.3 
Pediatric Quality of Life Inventory 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions (Varni et al, 2001; 
Varni et al, 2011). The PedsQL will be completed up to two times per year and will be 
administered according to the tabular schedule of study procedures, Section 16.1. 
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 
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≤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 ≥1 month to ≤18 years of age.  
The multidimensional PedsQL scale encompasses the essential core domains for pediatric 
HRQoL measurement: 1) Physical Functioning/Symptoms, 2) Emotional Functioning, 3) Social 
Functioning, and 4) Cognitive/School Functioning. The PedsQL assessment is retrospective to 
the prior month, and individual items are scored using a 5-point Likert scale (never, almost 
never, sometimes, often, or always). A total health summary score is calculated from the sum of 
the raw scores of the individual items, with higher scores indicating higher HRQoL. 
6.4 
Health care resource use 
For health care resource use parameters, the following will be evaluated: concomitant AEDs, 
medical procedures, health care provider consultations not related to study, and hospitalizations 
not related to study. Health care resource use parameters will be collected according to the 
tabular schedule of study procedures, Section 16.1. 
7 
ASSESSMENT OF PHARMACOKINETICS 
Blood samples will be collected at selected visits for the assessment of LCM and concomitant 
AED plasma concentrations (for population PK analysis). These blood samples will be collected 
along with the clinical chemistry/hematology samples at any time after intake of study 
medication according to the tabular schedule of study procedures, Section 16.1. In each case, the 
exact time and dose (in mg) when the subject took the most recent doses of LCM and 
concomitant AED(s), and the exact time of blood sampling must be recorded.  
Each blood sample drawn will be split into 2 duplicate samples. The samples will be centrifuged 
and stored at ≤-20ºC until shipped to a central laboratory. The central laboratory will store the 
plasma samples at -20ºC until analysis. Details of plasma sample collection and processing, 
sample labeling, and shipment will be provided in the laboratory manual. 
8 
ASSESSMENT OF SAFETY 
8.1 
Adverse events 
8.1.1 
Definition of AE 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product which 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 
signature of the Informed Consent), 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. These include all AEs not present prior to 
the initial visit and all AEs which recurred or worsened after the initial visit.  
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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. 
8.1.2 
Procedures for reporting and recording AEs 
The study participant will be given the opportunity to report AEs spontaneously. A general 
prompt will also be given 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. 
8.1.3 
Description of AEs 
When recording an AE, the investigator should use overall diagnosis or syndrome using standard 
medical terminology, rather than recording individual symptoms or signs. The eCRF and source 
documents should be consistent. Any discrepancies between the subject’s own words on his/her 
own records (eg, diary card) and the corresponding medical terminology should be clarified in 
the source documentation. 
Details for completion of the AE eCRF page (including judgment of relationship to trial 
medication) are described in the AE Completion Guideline in the eCRF. 
8.1.4 
Follow up on adverse events 
If an AE is still ongoing at the end of the study for a subject, a follow-up report should be 
provided until resolution/stable level of sequelae, the investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow-up. If no follow-up report is provided, 
the investigator must provide a justification. The follow-up will be usually continued for 30 days 
after the subject has completed the study.  
UCB BIOSCIENCES may request that the investigator perform or arrange for the conduct of 
supplementary measurements and/or evaluations. 
8.1.5 
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. 
8.1.6 
Pregnancy  
Should a subject become pregnant after the first intake of any investigational medicinal product, 
UCB BIOSCIENCES 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 discontinuation visit 
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• The subject should immediately stop the intake of the investigational medicinal product or be 
down-titrated as instructed at the early discontinuation visit 
• A Safety Follow-up visit should be scheduled 28 to 35 days after the subject has discontinued 
the investigational medicinal product. 
The investigator must inform the subject of information currently known about potential risks 
and about the available alternatives, eg, voluntary termination with medication (to be proposed 
on a study-specific basis).   
In cases where the partner of a male subject enrolled in a clinical trial becomes pregnant, UCB 
BIOSCIENCES 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. The 
progression of the pregnancy and the eventual birth (if applicable) must be followed-up using the 
Pregnancy Report and Outcome form in which the investigator has to report on the health of the 
mother and of the child. The health of the child must be followed for 30 days after birth for any 
significant medical issues.  
In certain circumstances, UCB BIOSCIENCES 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 serious events must be additionally reported using the 
Investigator SAE Report Form. 
8.1.7 
Suspected transmission of an infectious agent via a medicinal 
product 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
8.1.8 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed per the protocol and including overdose) should be 
recorded in the source documents and eCRF module. Any SAE or non-serious AE associated 
with excessive dosing must be followed as any other serious or non-serious AE. These events 
may be symptomatic, in that the excessive dosing results in clinical signs and symptoms, or the 
excessive intake may itself be a symptom. 
8.1.9 
Safety signal detection in ongoing clinical studies and Data 
Monitoring Committees 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the investigational medicinal product so that investigators, clinical 
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study subjects, regulatory authorities, and IRBs/IECs will be informed appropriately and as early 
as possible.  
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Patient Safety (PS) 
representative. 
As appropriate for the stage of development and accumulated experience with the investigational 
medicinal product, medically qualified personnel at UCB may identify additional safety 
measures (examples: AEs, vital signs, laboratory or ECG results) for which data will be 
periodically reviewed during the course of the study.  
8.1.10 
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. 
8.2 
Serious adverse events 
8.2.1 
Definition of serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. A SAE must meet 1 or more of the following criteria: 
• Death 
• Life-threatening   
Life-threatening does not include a reaction that might have caused death had it occurred in a 
more severe form. 
• Significant or persistent disability/incapacity 
• Congenital anomaly/birth defect (including that occurring in a fetus) 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition of serious 
(Important medical events include, but are not limited to, potential Hy’s Law [see 
Section 8.2.2], allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse.) 
• Initial inpatient hospitalization or prolongation of hospitalization 
A patient admitted to a hospital, even if released on the same day, meets the criteria for the 
initial inpatient hospitalization. An emergency room visit that results in admission to the 
hospital would also qualify for the initial inpatient hospitalization criteria. However, 
emergency room visits that do not result in admission to the hospital would not qualify for 
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this criteria and, instead, should be evaluated for one 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 criterion. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need 
to be determined. 
8.2.2 
AEs of special interest  
An AE of special interest is any AE that a regulatory authority has mandated to 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 the LCM 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 
Food and Drug Administration: 
An AE or laboratory value (as defined below) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system 
involvement) combined with at least one of the following: fever, rash, 
lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
• Eosinophils % ≥10% 
• Eosinophils absolute ≥0.5G/L 
• Neutrophils absolute <1.5G/L 
• Platelets ≤100G/L 
• ALT ≥2x ULN 
• AST ≥2x ULN 
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• 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. 
8.2.3 
Immediate reporting of AEs 
The following AEs must be reported immediately: 
• SAE: AEs that the investigator classifies as serious by the above definitions, regardless of 
causality. 
• Suspected transmission of an infectious agent via a medicinal product. 
• AEs of special interest (as defined in Section 8.2.2). 
8.2.4 
Procedures for reporting serious adverse events 
If an SAE is reported, UCB BIOSCIENCES must be informed within 24 hours of receipt of this 
information by the site (see contact details for SAE reporting listed in the Study Contact 
Information section). The investigator must forward to UCB BIOSCIENCES (or its 
representative) a duly completed Investigator SAE Report form provided by UCB 
BIOSCIENCES, 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. 
A copy of the Investigator SAE Report form will be provided to the investigator. The 
Investigator SAE Report form must be completed in English. 
Additional information (eg, autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE Report form. 
The reference document for the assessment of the expectedness of the SAEs is the Investigator 
Brochure. 
8.2.5 
Follow up of serious adverse events 
A SAE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events are provided in Section 8.3.2.4. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety database without limitation of time. 
8.2.6 
Anticipated serious adverse events 
The following list of anticipated SAEs is anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure. This list does not change the 
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investigator’s obligation to report all SAEs (including anticipated SAEs) as detailed in 
Section 8.2.4. 
Anticipated SAEs for the pediatric epilepsy population 
MedDRA SOC 
MedDRA PT 
Congenital, familial and genetic disorders 
Teratogenicity 
General disorders and administrative site 
conditions 
Sudden unexplained death in epilepsy 
Nervous system disorders 
Convulsion 
Incontinence 
Status epilepticus 
Pregnancy, puerperium and perinatal disorders Abortion spontaneous 
Psychiatric disorders 
Psychotic behavior 
Abnormal behavior 
Anxiety 
Sleep disorder 
Reproductive system and breast disorders 
Menstrual disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SAE=serious adverse event; SOC=system organ 
class 
8.3 
Laboratory measurements 
Blood and urine specimens (approximately 5 to 15mL each) for routine assay of hematology, 
clinical chemistry, endocrinology, and urinalysis testing will be collected according to the tabular 
schedule of study procedures, Section 16.1. For subjects aged 5 to 17 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 samples. 
The procedures for handling and shipping these specimens will be provided to the sites. 
The following laboratory tests will be performed: 
Urinalysis 
Hematology 
Clinical chemistry 
Endocrinology 
Specific gravity 
RBC 
Total serum 
protein 
Cholesterol 
FSH 
pH 
WBC 
Albumin 
Triglycerides 
LH 
Protein 
Differential count 
Calcium 
Total bilirubin 
Testosterone 
Glucose 
Platelet count 
Phosphorus 
Alkaline 
phosphatase 
TSH 
Ketone 
Hemoglobin 
Glucose 
Creatinine 
T3 (total and 
serum-free) 
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Urinalysis 
Hematology 
Clinical chemistry 
Endocrinology 
Microscopic exam 
for blood cells for 
casts/hpf 
Hematocrit 
Serum electrolytes 
(sodium, 
potassium, 
chloride, 
bicarbonate) 
AST 
ALT 
GGT 
T4 (total and 
serum-free) 
 
 
Uric acid 
BUN 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle stimulating hormone; 
GGT=gamma glutamyl transferase; hpf=high power field; LH=luteinizing hormone; RBC=red blood cells; T3=triiodothyronine; 
T4=thyroxine; TSH=thyroid stimulating hormone; WBC=white blood cells 
8.3.1 
Pregnancy testing 
Females of childbearing potential will have serum and urine pregnancy tests performed during 
the study according to the tabular schedule of study procedures, Section 16.1. 
8.3.2 
Liver function tests and evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 4.3.3.1 with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 8.2.2), and, if applicable, also reported as an 
SAE (see Section 8.2.1).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 8‒1 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 8.3.2.1). 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 8.3.2.4).  
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. 
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When IMP is stopped due to PDILI (as described in Section 4.3.3.1), IMP must be permanently 
discontinued. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
The table below summarizes the approach to investigate PDILI.  
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Table 8‒1: 
Required investigations and follow up of 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 8.3.2.3); 
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 
≥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 8.3.2.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
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Table 8‒1: 
Required investigations and follow up of 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 8.3.2.3) 
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 8.3.2.1. 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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8.3.2.1 
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 8.3.2.3) and SAE report (if applicable). 
8.3.2.2 
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 4.3.3.1 and Table 8‒1 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. 
8.3.2.3 
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 8‒2 (laboratory measurements) and Table 8‒3 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
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Table 8‒2: 
PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
WBC count 
WBC differential 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 
ALT 
AST 
ALP 
GGT 
Albumin 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
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ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine 
phosphokinase; GGT=gamma-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: 
Table 8‒3: 
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 
 
8.3.2.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in  
Table 8‒1. Monitoring should continue until liver chemistry values normalize, stabilize, or return 
to Baseline. Determination of stabilization is at the discretion of the investigator in consultation 
with the hepatologist (as applicable) and UCB responsible physician, as needed. 
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8.4 
Other measurements 
8.4.1 
Physical examination 
Physical examinations will be performed by medically qualified clinicians licensed to perform 
the examination according to the tabular schedule of study procedures, Section 16.1. Height will 
be measured without shoes according to the tabular schedule of study procedures, Section 16.1. 
8.4.1.1 
Complete physical examination 
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems.  
8.4.1.2 
Brief physical examination 
The brief physical examination will includes a review of the following body systems: 
• Cardiovascular 
• Pulmonary 
• Abdominal (hepato-gastrointestinal) 
• Dermatologic 
8.4.2 
Neurological examination 
The neurological examination will be performed according to the tabular schedule of study 
procedures, Section 16.1. The neurological examination should be conducted 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 or other epilepsy syndrome. 
8.4.2.1 
Complete neurological examination 
The complete neurological examination will include selected assessment of mental status, 
sensory systems, motor functions, cranial nerves, reflexes, and coordination/cerebellar function. 
8.4.2.2 
Brief neurological examination 
The brief neurological examination will include selected assessment of mental status, cranial 
nerves, and coordination/cerebellar function. 
8.4.3 
Vital signs and body weight 
Noninvasive blood pressure (systolic and diastolic) and pulse rate will be measured at all visits in 
a sitting position after at least 3 minutes at rest. Body weight will be determined without shoes 
and wearing light clothing, according to the tabular schedule of study procedures, Section 16.1. 
8.4.4 
12-lead ECG 
Standard 12-lead ECGs will be performed according to the tabular schedule of study procedures, 
Section 16.1, and as described in Section 5. 
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 an initial LCM dose increase to a 
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LCM dose level that is ≥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 vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM 
steady state Cmax). 
Care should be taken to assure proper lead placement and quality of ECG recording. Subjects 
should rest in a supine position at least 5 minutes prior to each recording and should be 
motionless during the recording. 
8.4.4.1 
Overall ECG interpretation 
An immediate initial review of the ECGs will be conducted locally by the investigator, 
subinvestigator, or qualified designated reader. If this reading identifies abnormal ECG findings 
that are assessed by the investigator or subinvestigator to be clinically significant, then the ECG 
should be repeated in 1 hour, unless circumstances require a more rapid assessment. If the 
clinically significant abnormality is confirmed by the repeat ECG or if the investigator feels it is 
medically necessary, then the subject must be withdrawn from the study (see Section 4.3.3). 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. 
8.4.4.2 
Specific QTcB criteria 
The ECG recorder provides a corrected QT interval using the Bazett method (QTcB) for each 
QT interval measurement. The value of the QTcB is used to determine subject eligibility to enter 
and to continue in the study (as noted in Section 4.3.2 and Section 4.3.3). 
8.4.5 
Tanner Stage 
At selected visits for applicable subjects, the investigator or qualified designee will evaluate the 
subject’s sexual development using the 3-item scale. The investigator should use clinical 
judgment in deciding which subjects are selected for evaluation of Tanner Stage (ie, those 
subjects who are pubescent at screening or those subjects who become pubescent during the 
course of the study). 
The evaluation of Tanner Stage for applicable subjects will be completed according to the tabular 
schedule of study procedures, Section 16.1. 
8.4.6 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). 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. The C-SSRS will be 
completed according to the tabular schedule of study procedures, Section 16.1. 
Subjects enrolling directly who are ≥6 years of age will complete the “Baseline/Screening” 
version of the C-SSRS at Visit 1 and will complete the “Since Last Visit” version at subsequent 
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visits. If a subject becomes 6 years of age during the study, the “Already Enrolled” version of the 
C-SSRS should be used at the first visit at which the subject is 6 years of age and the “Since Last 
Visit” version used at subsequent visits. 
The C-SSRS is not validated and will not be used for subjects <6 years of age. 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. 
8.4.7 
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 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. For subjects ≥6 years to ≤17 years of age, the CBCL/6-18 version will be 
used. 
The Achenbach CBCL will be completed according to the tabular schedule of study procedures, 
Section 16.1. 
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 
Syndrome scores will be calculated from these questions, which will in turn be summarized by 
2 composite scores. Additionally, for each syndrome and composite scores, categorizations based 
on a normative sample will be used to evaluate normal, borderline, or clinically relevant 
behavior. 
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests. 
8.4.8 
Bayley Scales of Infant and Toddler Development, Third Edition 
The Bayley-III scales are recognized internationally as one of the most comprehensive 
developmental assessment instruments (Sattler and Hoge, 2006) used to examine the major 
facets of a young child’s development (Bayley, 2006). The Bayley Scales of Infant and Toddler 
Development, Third Edition (Bayley-III) are a standardized individually administered adaptive 
assessment that measures the developmental functioning of infants and young children 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 (BSID-II) (Bayley, 1993). The Bayley-III 
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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 children 
and is therefore considered appropriate for SP848. 
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 completion of the Bayley-III scales will require approximately 50 minutes for children who 
are 12 months old or younger and 90 minutes for children aged 13 months and older. 
The Bayley-III scales will be completed according to the tabular schedule of study procedures, 
Section 16.1. 
8.4.9 
Palatability and ease of use questionnaire for LCM 
UCB BIOSCIENCES has created a palatability and ease of use questionnaire to collect data from 
the subject or caregiver regarding different aspects of LCM and its administration. The 
questionnaire will assess the subject or caregiver’s response regarding the formulation of LCM 
the subject is receiving for palatability items (eg, taste, smell, ability to swallow, aftertaste), 
mode of administration, and administration device as applicable. 
The questionnaire will be completed according to the tabular schedule of study procedures, 
Section 16.1. 
8.4.10 
Behavior Rating Inventory of Executive Function 
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of subjects 
≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P/BRIEF will be 
administered according to the tabular schedule of study procedures, Section 16.1. 
The BRIEF-P and BRIEF include rating forms used by parents to assess subjects’ executive 
functioning. Executive functions broadly encompass a set of cognitive skills that are responsible 
for the planning, initiation, sequencing, and monitoring of complex goal-directed behavior. 
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. The 
clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and Emergent 
Metacognition) and 1 composite score (Global Executive Composite). 
The BRIEF rating form consists of items that measure various aspects of executive functioning: 
Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, Organization of 
materials, and Monitor. These clinical scales form 2 broader Indexes: Behavioral Regulation 
(3 scales) and Metacognition (5 scales), as well as a Global Executive Composite score. 
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Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses. 
9 
MANUFACTURING, HANDLING, AND ACCOUNTABILITY OF 
STUDY MEDICATION 
9.1 
Manufacturing, packaging, and labeling 
Lacosamide is manufactured, packaged, and labeled according to Good Manufacturing Practice 
guidelines and applicable laws and regulations. It is suitably packaged, in such a way as to 
protect the product from deterioration during transport and storage. 
Description of packaging: 
Lacosamide oral solution (syrup) will be packaged in 200mL amber PET bottles with a white, 
child-proof, polypropylene screw cap. Different volumes of LCM syrup will be taken to obtain 
the appropriate dose.  
Lacosamide tablets will be packaged in high-density polyethylene bottles with a child-proof, 
polypropylene screw cap.  
Contents of the labels: 
The labels for LCM will include the following information (not all information will appear on all 
labels): 
• Sponsor name, address, and telephone number 
• Statement “Caution: New drug – Limited by federal law to investigational use” 
• Statement “For clinical trial use only” 
• Study number 
• Kit number 
• Pharmaceutical dosage form 
• Name of drug 
• Route of administration 
• Directions for use 
• Date bottle opened 
• Do not use after (date) 
• Strength per unit 
• Quantity of dosage units 
• Batch number 
• Statement “Keep out of reach of children” 
• Storage conditions 
• Expiry date  
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• Subject number 
• Visit number 
• Date dispensed 
• Name of investigator and telephone number 
• Statement “Return all empty, partially used, and unused product” 
• Statement “Class scheduling as a controlled substance” 
9.2 
Supply, handling, and storage 
Lacosamide (oral solution [syrup] and tablet) is stable at room temperature and is to be stored at 
temperatures not exceeding 25.4°C (77.7°F) or below 14.5°C (58.1°F). Lacosamide should not 
be frozen or refrigerated. 
The investigator (or designee) is responsible for safe and proper storage of LCM at the site. 
Lacosamide stored by the investigator is to be kept in a secured area with limited access 
according to the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlling the temperature and by 
completion of a temperature log in accordance with local requirements on a regular basis, 
showing minimum and maximum temperatures reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label. 
9.3 
Drug accountability procedures 
A Drug Accountability form will be used to record LCM dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any LCM lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review. 
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of LCM until returned or destroyed by a UCB representative. 
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 LCM is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired LCM must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol. 
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9.4 
Retrieval/recall of study medication 
Lacosamide being returned following study completion or due to product expiration or defect 
should be returned to UCB BIOSCIENCES or designee for final inventory using the provided 
forms. UCB BIOSCIENCES or designee will oversee destruction of returned drug after the 
clinical study report is completed. 
9.5 
Alternative study treatment supply due to COVID-19 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. 
10 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Site qualification 
A site visit will be performed by UCB BIOSCIENCES or designee to discuss the protocol, to 
ensure the availability of appropriate study personnel, adequate resources, and to assess their 
ability to properly conduct the study according to International Council for Harmonisation-Good 
Clinical Practice (ICH-GCP) guidelines and local requirements. These procedures do not need to 
be repeated for this extension study (if a site needs to be added to SP848 that did not participate 
in SP847, an assessment will be made to determine whether a site visit is required). 
10.2 
Monitoring 
UCB BIOSCIENCES 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 BIOSCIENCES to a CRO or a contract monitor. 
The investigator and his/her staff will be expected to cooperate with UCB BIOSCIENCES 
personnel or agents of UCB BIOSCIENCES 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 inspections. 
10.2.1 
Definition of source data 
All source documents must be accurate, legible, 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 correcting fluid or have temporary 
attachments (such as removable self-stick notes). Photocopies of CRF forms are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/physician records, charts, diaries, x-rays, laboratory results, printouts, pharmacy 
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records, care records, ECG or other printouts, completed scales, or Quality of Life 
Questionnaires, for example. Source documents should be kept in a secure, limited access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the subject’s source documents. The 
investigator will authorize 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 EEG records, must be saved and 
stored as instructed by UCB BIOSCIENCES (or designee). 
10.2.2 
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. 
10.3 
Auditing 
The investigator will permit study-related audits mandated by UCB, 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). 
11 
DATA HANDLING AND RECORD KEEPING 
The parent/legal guardian’s consent, subject’s assent, and enrollment in the study must be 
recorded in the subject’s medical record. These data should identify the study and document the 
dates of the subject’s participation. 
11.1 
Case Report form completion 
This study is performed using remote data capture (RDC); the investigator is responsible for 
prompt reporting of accurate, complete, and legible data in the eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. The investigator should 
maintain a list of personnel authorized to enter data into the eCRF. Detailed instructions will be 
provided in the eCRF Completion Guidelines. 
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11.2 
Database entry and reconciliation 
Electronic 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 
eCRFs once and are subsequently verified. An electronic audit trail system will be maintained 
within the CDMS to track all data changes in the database once the data have been saved initially 
into the system or electronically loaded. Regular backups of the electronic data will be 
performed. 
11.3 
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. 
11.4 
Archiving and data retention 
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The investigator will contact 
UCB for authorization prior to the destruction of any study records or in the event of accidental 
loss or destruction of any study records. The investigator will also notify UCB should he/she 
relocate or move the study-related files to a location other than that specified in the sponsor’s 
trial master file. 
11.5 
Data management 
Details regarding data management will be elaborated in the study-specific Data Management 
Manual. 
12 
STATISTICS 
This study has an explorative, descriptive aim and does not intend to prove or disprove any 
statistical hypotheses. Hence, inferential statistical tests are not planned for the primary and 
secondary variables described below. 
12.1 
Description of statistical methods 
Descriptive statistics will be used to provide an overview of the study results. For categorical 
parameters, these will consist of the number and percentage of subjects in each category. The 
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denominator for percentages will be based on the number of subjects appropriate for the purpose 
of analysis. For continuous parameters, descriptive statistics will include the number of subjects 
(n), mean, standard deviation (SD), median, minimum, and maximum. 
Visit 1 of SP847 (or other primary study as applicable) or the Screening Visit of SP848 (for 
subjects who enter directly into SP848) will serve as Baseline values for safety and efficacy 
variables unless otherwise noted. 
Further statistical methods are presented below, and will be described in more detail in the 
Statistical Analysis Plan. 
12.1.1 
Definition of analysis sets 
The Safety Set (SS), which is defined as all enrolled subjects who take at least 1 dose of LCM in 
this study. All safety analyses will be performed on the SS. 
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects from the SS having 
provided at least 1 measurable post-dose plasma sample (with recorded sampling time) on at 
least 1 visit with documented LCM intake times.  
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. 
12.1.2 
Statistical analysis of safety variables 
12.1.2.1 
Primary safety variables 
The primary variables, for assessment of safety and tolerability, are the incidence of TEAEs and 
the incidence of SAEs.  
12.1.2.1.1 
AEs 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), and tabulated by system organ class and preferred term. 
Treatment-emergent AEs will be defined as those events which started on or after the date of first 
SP848 LCM administration, or whose severity worsened on or after the date of first SP848 LCM 
administration. Adverse events occurring within 30 days after last dose of LCM will be 
considered treatment-emergent. The incidence of TEAEs will be presented by system organ class 
and preferred term. Serious AEs will also be tabulated and listed. 
12.1.2.2 
Other safety variables 
The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, endocrinology, and urinalysis), 12-lead ECG measurements, vital sign measurements 
(blood pressure and pulse rate), physical and neurological exam findings, body weight, height, 
calculated BMI, and Tanner Stage (if applicable). The actual measurement and its change from 
Baseline (SP847 [or other primary study as applicable] Visit 1) or the Screening Visit (for 
subjects who entered directly into SP848) will be analyzed descriptively and presented by visit. 
In addition, shift tables may be used to evaluate the number and percentage of subjects having a 
different post-Baseline status when compared with their Baseline status. 
The shift from Baseline to the subject’s last visit at which a physical and/or neurological 
examination was performed post-Baseline will be summarized by category. 
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Laboratory, ECG, and vital signs data outside of the respective reference ranges will be listed 
and highlighted. 
Changes in behavior and development from Baseline as measured using the Achenbach CBCL 
for children 18 months and older (CBCL/1½-5 and CBCL/6-18) and Bayley-III scales for 
children <18 months of age will be summarized descriptively and presented by visit. Changes in 
cognitive function as measured using the BRIEF-P/BRIEF will be summarized by descriptive 
statistics at each visit. Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy 
studies. Baseline values for subjects who enroll directly into SP848 will be taken from the 
Screening Visit. 
12.1.2.2.1 
Palatability and ease of use questionnaire 
Data from the palatability and ease of use questionnaire will be summarized descriptively at each 
visit where it is assessed. 
12.1.3 
Statistical analysis of PK variables 
12.1.3.1 
Descriptive statistics 
Descriptive summaries (n, mean, SD, coefficient of variation (CV), median, minimum, and 
maximum) for the LCM plasma concentration and the plasma concentrations for selected 
concomitant AEDs will be presented by visit and actual dose.  
12.1.3.2 
Population PK analysis 
The plasma concentration data of SP848 will be included in a population PK model of LCM, 
using the LCM plasma concentrations and dosing records, as well as demographic covariates and 
the presence of concomitant AEDs. 
Further details will be described in the Statistical Analysis Plan or in a separate Population PK 
analysis plan. 
12.1.4 
Statistical analysis of efficacy variables 
12.1.4.1 
Secondary efficacy variables 
12.1.4.1.1 
Percent change from Baseline in 28-day partial-onset seizure 
frequency  
Seizure frequency will be assessed using seizure diaries in order to evaluate the preliminary 
efficacy of LCM in this population. Seizure frequency per 28 days will be calculated as ([number 
of seizures over the specified time interval]) divided by [number of days in the interval]) 
multiplied by 28 and summarized descriptively for the overall Treatment Period. 
12.1.4.1.2 
≥50% reduction in 28-day partial-onset seizure frequency 
For subjects with POS, the number and percentage with ≥50% reduction in 28-day partial-onset 
seizure frequency (≥50% responders) will be summarized for the overall Treatment Period.  
12.1.4.1.3 
≥75% reduction in 28-day partial-onset seizure frequency 
For subjects with POS, the number and percentage with ≥75% reduction in 28-day partial-onset 
seizure frequency (≥75% responders) will be summarized for the overall Treatment Period.  
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12.1.4.1.4 
Seizure days per 28 days (subjects with generalized seizures only) 
For subjects with generalized seizures, the number of seizure days per 28 days will be 
summarized descriptively for the overall Treatment Period. 
12.1.4.1.5 
Seizure-free status 
The number and percentage of subjects achieving a seizure-free status for the overall Treatment 
Period will be presented. 
12.1.4.2 
Other efficacy variables 
12.1.4.2.1 
Clinical Global Impression of Change and Caregiver Global 
Impression of Change 
The number and percentage of subjects with each Clinical Global Impression of Change and 
Caregiver Global Impression of Change value will be summarized at each visit in which they are 
assessed and grouped by dose. 
12.1.4.2.2 
PedsQL 
The PedsQL score and change from Baseline scores will be analyzed in a descriptive manner. 
Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy studies. Baseline values 
for subjects who enroll directly into SP848 will be taken from the Screening Visit. 
12.1.4.2.3 
Health care resource use 
Descriptive statistics will be presented for the number of medical resources used (medications, 
consultations, procedures, hospitalizations, and length of hospital stays). 
12.1.4.2.4 
Seizure frequency analyses 
All seizure frequency analyses as described in the secondary efficacy variables (Section 12.1.4.1) 
may be additionally presented by modal daily dose group, by seizure type, by seizure 
classification subgroup, by time interval, by visit or time period, or by completer cohort. 
Additional details will be provided in the Statistical Analysis Plan. 
12.1.5 
Handling of protocol violators, drop-outs, and missing values 
All data will be used to their maximum possible extent, but without any imputations for missing 
data for any parameter. Important protocol deviations will be reviewed as part of the ongoing 
data cleaning process and data evaluation. All important deviations will be identified and 
documented prior to database lock to confirm exclusion from analysis sets. 
Subjects who discontinue from the study prematurely will be evaluated based on the data 
collected at each visit attended. 
Protocol deviations (eg, missing assessments or visits) related to COVID-19 will be documented. 
12.1.6 
Interim analysis 
No formal interim analysis is planned. However, data will be reported prior to the completion of 
this study to support annual reports, regulatory submissions, and publications. 
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12.2 
Determination of sample size 
Approximately 42 subjects from the SP847 study will be eligible to enroll in this open-label 
study. Other subjects will be eligible to enroll as other LCM pediatric clinical studies in epilepsy 
are undertaken.  
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated 
in a LCM clinical study will be permitted to enroll directly into SP848. Beginning with local 
Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years 
to ≤17 years of age with partial-onset seizures who have not previously received LCM will 
directly enroll at approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 
for sites in China, approximately 60 additional eligible pediatric subjects with partial-onset 
seizures aged ≥4 years to ≤17 years, who have not previously participated in a LCM clinical 
study, will enroll directly into SP848. The purpose of enrolling these subjects directly into SP848 
is to obtain additional long-term safety exposures in the age range from which adequate PK data 
have already been obtained in SP847; the additional long-term safety data will be included in 
planned LCM marketing applications for subjects ≥4 years of age. 
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. Protocol 
Amendment 8 allows an enrollment increase from 75 to 100 eligible pediatric subjects ≥1 month 
to ≤17 years of age with epilepsy who participated in EP0060 to enroll in SP848 in order to 
reflect EP0060’s inclusion of subjects down to 1 month of age. 
In total, up to approximately 400 subjects may be eligible to participate in SP848. 
13 
ETHICS AND REGULATORY 
13.1 
Informed consent 
Informed consent has to be obtained from the subject’s parent/legal guardian 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 and/or the subject’s parent/legal guardian in both oral 
and written form by the investigator (or designee). Each subject and/or subject’s parent/legal 
guardian will have the opportunity to discuss the study and its alternatives with the investigator. 
Prior to participation in the study, the written informed consent form should be signed and 
personally dated by the subject’s parent/legal guardian and by the person who conducted the 
informed consent discussion (investigator or designee). The subject’s parent/legal guardian must 
receive a copy of the signed and dated informed consent form. As part of the consent process, 
each subject’s parent/legal guardian must consent to direct access to the subject’s medical 
records for study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
The informed consent form should be updated or amended whenever new information becomes 
available that may be relevant to the subject. The subject’s parent/legal guardian should then sign 
the revised informed consent form. 
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13.2 
Notification/submission to relevant regulatory authority(ies) 
UCB BIOSCIENCES in conjunction with the CRO is responsible for fulfilling all regulatory 
aspects of the study with regard to regulatory submissions/filings. 
13.3 
Institutional Review Board/Independent Ethics Committee 
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 BIOSCIENCES 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 BIOSCIENCES will forward copies 
of the protocol, informed consent form, investigator’s brochure, investigator’s curriculum vitae, 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the investigator will have written, signed, 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. 
The investigator is specifically requested to collect and report to UCB BIOSCIENCES (or its 
representative) any SAEs (even if the investigator is certain that they are in no way associated 
with the investigational product), up to 30 days from the end of the study for each subject, and to 
also inform participating subjects of the need to inform the investigator of any AE within this 
period. Adverse events that the investigator thinks may be associated with the investigational 
product must be reported to UCB BIOSCIENCES regardless of the time between the event and 
the end of the study. 
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 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. 
13.3.1 
Reporting to ethics committee 
The investigator is responsible for reporting to the IRB/IEC (eg, reporting of SAEs) in 
accordance with national or local requirements. 
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13.4 
Basic principles and appropriate national guidelines 
This protocol will be conducted under the current ICH E6 guideline commonly known as GCP, 
the applicable national requirements, and ethical principles that have their origins in the 
Declaration of Helsinki. 
13.5 
Subject privacy 
UCB BIOSCIENCES staff or any designees affirm and uphold the subject’s confidentiality. 
Throughout this study, all data forwarded to UCB BIOSCIENCES will be identified only by an 
identification number. 
The investigator agrees that representatives of UCB BIOSCIENCES, 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). 
13.6 
Protocol amendments and emergency deviations 
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. 
Other than in an emergency, all items in the protocol and amendment(s) are to be followed 
exactly. If an amendment is required, this must be made in written form and receive approval 
according to the appropriate SOP. Protocol amendment(s) will be distributed to investigator(s) 
with instructions. All protocol amendments, except those with only logistical/administrative 
implications will be submitted to the IRB/IEC for review and approval prior to implementation 
and to regulatory authorities for approval/notification, as applicable. 
In the event that an emergency or other medical event occurs that requires a protocol deviation, 
the investigator (or designee) must contact UCB BIOSCIENCES as soon as possible to decide 
whether the subject should continue with the study. The protocol deviation will be documented. 
14 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in separate agreements as appropriate. 
15 
REFERENCES 
Aicardi J. Syndromic classification in the management of childhood epilepsy. J Child Neurol. 
1994;9(Suppl 2):2S14-18. 
Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as 
add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, 
placebo-controlled study: Gabapentin Pediatric Study Group. Epilepsia. 1999;40:1147-54. 
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: The Psychological 
Corporation; 1993. 
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Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed 19 Jun 2011. 
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. 
CHMP/EWP/566/98 Guideline on clinical investigation of medicinal products in the treatment of 
epileptic disorders (EMA) Rev 2, 20 Jan 2010. 
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 S-C, Pledger G, et al. A double-blind, 
randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children: 
Topiramate YP Study Group. Neurology. 1999;52:1338-44. 
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing 
clinical evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, 07/2009.  
Food and Drug Administration. Guidance for Industry. Suicidality: Prospective assessment of 
occurrence in clinical trials. US Dept of Health and Human Services, Center for Drug Evaluation 
and Research, 09/2010. Available upon request. 
Food and Drug Administration. Guidance for Industry and Investigators. Safety reporting 
requirements for INDs and BE/BA studies. US Dept of Health and Human Services, Center for 
Drug Evaluation and Research, 09/2010. Available upon request. 
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 BFD. Antiepileptic drug treatment in children. Expert Rev 
Neurother. 2007;7:179-193. 
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4. 
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of 
epilepsy: A systematic review and meta-analysis. Neurology. 2011; 77(10): 1005–12. 
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. 
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Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. 5th 
ed. La Mesa: Jerome M Sattler; 2006. 
Varni JW, Limbers CA, Neighbors K, Schulz K, Lieu JE, Heffer RW, et al. The PedsQL™ 
Infant Scales: feasibility, internal consistency reliability, and validity in healthy and ill infants. 
Qual Life Res. 2011;20:45-55. 
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 
2001;39:800-12. 
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16 
SUPPLEMENTS 
16.1 
Tabular schedule of study procedures 
 
 
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Table 16‒1: Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh, j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKk 
Xh, j 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Blood sample for concomitant AEDsk 
Xh, j 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 17 years) 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testl 
Xh, j, S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagem 
Xh, j 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xo 
 
 
LCM return/compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
X 
 
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Table 16‒1: Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSp 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
X 
 
Achenbach CBCL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Bayley-III scales 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
PedsQL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
AE reportingr 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; TC=telephone contact; S=serum; SAE= serious adverse event; U=urine; 
Unsch=Unscheduled; V=Visit 
Note: All subjects who directly enrolled into SP848 should follow the titration schedule in Table 16‒3.  
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
For subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), Visit 1 is also the last visit of the primary study. At Visit 1, 
the informed consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be updated, body weight and height and 
concomitant medications including AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject 
must return for an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
f 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. The Final Visit is not required for subjects who participate in EP0151 or EP0152. 
g 
This TC occurs 28 to 35 days after the last dose of LCM. The Safety Follow-Up TC is not required for subjects who participate in EP0151 or EP0152. 
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h 
For subjects enrolling from SP847 or other LCM pediatric clinical studies in epilepsy, assessments may have been done as part of the last visit of the primary 
study. For subjects enrolling directly into SP848, these assessments should be completed at Visit 1. 
i 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM 
dose level that is ≥8mg/kg/day or 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 vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
j 
For subjects enrolling from EP0060, these assessments should be completed at Visit 1. 
k 
Blood samples may be drawn at any time post-dosing with LCM. 
l 
For female subjects of childbearing potential, serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and the Final Visit. Urine 
pregnancy tests will be performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
m The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
n 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
o 
As applicable.  
p 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version 
should be completed thereafter. 
q 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
r 
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 16‒2: Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-
Up 
Visita 
V10 
TCb 
V11 
V12 
V13/ 
TermV  
ETVc 
Unsch 
Visitd 
Final 
Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PK 
Xh 
 
Xh 
Xh 
Xh 
Xi 
Xi 
 
 
Blood sample for concomitant 
AEDs 
 
 
 
 
 
Xi 
Xi 
 
 
Urinalysis (subjects aged 5 to 
17 years) 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testj 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagek 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xl 
Xl 
Xm 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xm 
X 
 
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Table 16‒2: Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-
Up 
Visita 
V10 
TCb 
V11 
V12 
V13/ 
TermV  
ETVc 
Unsch 
Visitd 
Final 
Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
C-SSRSn 
X 
 
X 
X 
X 
X 
Xo 
X 
 
Achenbach CBCL 
 
 
X 
 
X 
X 
 
 
 
Bayley-III scales 
 
 
X 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
 
 
X 
 
X 
X 
 
 
 
PedsQL 
 
 
X 
 
X 
X 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; S=serum; TC=telephone contact; TermV=Termination Visit; U=urine; 
Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject 
must return for an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. The Final Visit is not required for subjects who participate in EP0151 or EP0152. 
f 
This TC occurs 28-35 days after the last dose of LCM. The Safety Follow-Up TC is not required for subjects who participate in EP0151 or EP0152. 
g 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM 
dose level that is ≥8mg/kg/day or 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 
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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). 
h 
Blood sample for LCM PK will be routinely collected for subjects enrolled at sites in Japan. Blood samples may be drawn at any time post-dosing with LCM. 
i 
Blood samples for LCM and concomitant other AEDs may be collected at an Unscheduled Visit or Early Termination Visit if the visit is related to an ongoing 
SAE. 
j 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Early Termination Visit and at the Final Visit. Urine pregnancy 
tests will be performed at Visits 10, 11, 12, and 13. 
k 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
l 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
m As applicable. 
n 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version 
should be completed thereafter. 
o 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
 
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Table 16‒3: Schedule of study procedures for SP848 (Screening Visit and Titration Visits, subjects enrolling 
directly into SP848) 
Study SP848 
Screening 
Titration Visits 
Visit 
Screening Visit 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Seizure history 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
X 
 
 
 
 
 
 
Physical exam (brief) 
 
X 
X 
X 
X 
X 
X 
Neurological exam (complete) 
X 
 
 
 
 
 
 
Neurological exam (brief) 
 
X 
X 
X 
X 
X 
X 
12-lead ECGa 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Clinical chemistry and hematology blood 
sample 
X 
 
 
 
X 
 
 
Endocrinology blood sample 
X 
 
 
 
X 
 
 
Urinalysis (subjects aged 5 to 17 years) 
X 
 
 
 
X 
 
 
Pregnancy testb 
X 
 
 
 
 
 
 
Tanner Stage 
X 
 
 
 
 
 
 
Clinical GIC 
 
 
 
 
 
 
 
Caregiver GIC 
 
 
 
 
 
 
 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
LCM return/compliance 
 
X 
X 
X 
X 
X 
X 
Dispense diary 
X 
X 
X 
X 
X 
X 
X 
Diary assessment 
 
X 
X 
X 
X 
X 
X 
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Table 16‒3: Schedule of study procedures for SP848 (Screening Visit and Titration Visits, subjects enrolling 
directly into SP848) 
Study SP848 
Screening 
Titration Visits 
Visit 
Screening Visit 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
C-SSRSc 
X 
X 
X 
X 
X 
X 
X 
Achenbach CBCL 
X 
 
 
 
 
 
 
Bayley-III scales 
X 
 
 
 
 
 
 
BRIEF-P/BRIEF 
X 
 
 
 
 
 
 
PedsQL 
X 
 
 
 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AEDs=antiepileptic drugs; Cmax=maximum plasma concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; GIC=Global Impression of Change; LCM=lacosamide 
a 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
b 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Screening Visit.  
c 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
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16.2 
International Classification of Epileptic Seizures (1981) 
Adapted from the International Classification of Epileptic Seizures (1981) 
I. Partial seizures (focal, local) 
A. Simple partial seizures (consciousness not impaired) 
1. With motor signs 
2. With somatosensory or special sensory symptoms (simple hallucinations, 
eg, tingling, light flashes, buzzing) 
3. With autonomic symptoms or signs (including epigastric sensation, pallor, sweating, 
flushing, piloerection, and pupillary dilatation) 
4. With psychic symptoms (disturbance of higher cerebral function). These symptoms 
rarely occur without impairment of consciousness and are much more commonly 
experienced as complex partial seizures. 
B. Complex partial seizures (with impairment of consciousness: may sometimes begin 
with simple symptomatology) 
C. Partial seizures evolving to secondarily generalized seizures (this may be generalized 
tonic-clonic, tonic, or clonic) 
II. Generalized seizures (convulsive or non-convulsive) 
A. Absence seizures 
B. Myoclonic seizures - Myoclonic jerks (single or multiple) 
C. Clonic seizures 
D. Tonic seizures 
E. Tonic-clonic seizures 
F. Atonic seizures - (Astatic) 
Unclassified epileptic seizures 
Includes all seizures that cannot be classified because of inadequate or incomplete data and some 
that defy classification in hitherto described categories. This includes some neonatal seizures, 
eg, rhythmic eye movements, chewing, and swimming movements. 
Status epilepticus (prolonged partial or generalized seizures without recovery between attacks) 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. 
Epilepsia. 1981; 22:489-501. 
 
 
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17 
APPENDICES 
17.1 
PROTOCOL AMENDMENT 1 
Rationale for the Amendment 
The AEs of special interest were revised to reflect the Sponsor’s current understanding of the 
potential risks of LCM based on a comprehensive review of the data from clinical trials and 
commitments to regulatory agencies. 
The LFT withdrawal criteria were revised to reflect the Sponsor’s current understanding of the 
safety profile of LCM based on a comprehensive review of the data from clinical trials. 
The remainder of the changes in this amendment are administrative and are described in detail 
below. 
MODIFICATIONS/CHANGES 
• The title and contact information of the Medical Director (Medical Therapeutics) and 
Associate Medical Director (Drug Safety) were updated. 
• For clarification, updated dose reduction wording as follows: the investigator may decrease 
the dose of LCM to a minimum of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet). 
• For clarification, text was added indicating that incomplete doses should not be 
readministered (Section 4.4.1 Treatments to be administered). 
• For Unscheduled Visits (Section 5.16) added text to discuss LCM dose increase between 
scheduled visits. 
• For Unscheduled Visits (Section 5.16 Unscheduled Visit(s) and Section 16.1 [Tables 1 to 2]) 
in regards to dispensing LCM and LCM return/compliance, “as applicable” was added. 
• Revised text regarding safety signal detection (Section 8.1.8 Safety signal detection in 
ongoing clinical studies and Data Monitoring Committees).  
• Revised text regarding AEs of special interest (Section 8.2.2 AEs of Special Interest) and 
immediate reporting of AEs (Section 8.2.3 Immediate reporting of AEs). 
• Revised text on ability to collect and provide urine samples (Section 8.3 Laboratory 
measurements). 
• Revised text regarding liver function tests (Section 8.3.1 Liver function tests). 
• Text was revised to indicate that Tanner staging is performed for applicable subjects at 
scheduled visits (Section 8.4.5 Tanner Stage). 
• The tabular schedules of trial procedures were updated to reflect the changes to the protocol. 
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REFERENCE 
Clinical Trial Protocol, Contact information for the Senior Medical Director (Medical 
Therapeutics) and Associate Medical Director (Drug Safety). Page 3. Original text: 
Senior Medical Director (Medical Therapeutics): 
Name: 
 MD, PhD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Associate Medical Director (Drug Safety): 
Name: 
 MD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
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Was revised as follows: 
Medical Director (Medical Therapeutics): 
Name: 
, MD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Associate Medical Director (Drug Safety): 
Name: 
, MD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
Clinical Trial Protocol, Section 1 (Summary). Page 10; paragraph 1 (third sentence) and 
paragraph 2 (second sentence). Original text: 
Paragraph 1: 
The study will also provide continued availability of LCM to subjects who have completed the 
SP847 epilepsy study and to subjects who have discontinued from SP847 due to a second dose 
reduction or status epilepticus, and who, in the investigator’s opinion, would benefit from 
long-term administration of LCM. 
Paragraph 2: 
Subjects who discontinued from SP847 due to a second dose reduction or status epilepticus, but 
for whom it is determined medically appropriate to enter this open-label extension study, will 
also begin on the LCM dose they achieved in SP847. 
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Was revised as follows: 
Paragraph 1: 
The study will also provide continued availability of LCM to subjects who have completed the 
SP847 epilepsy study and to subjects who have discontinued from SP847 due to a dose reduction 
or status epilepticus, and who, in the investigator’s opinion, would benefit from long-term 
administration of LCM. 
Paragraph 2: 
Subjects who discontinued from SP847 due to a dose reduction or status epilepticus, but for 
whom it is determined medically appropriate to enter this open-label extension study, will also 
begin on the LCM dose they achieved in SP847. 
Clinical Trial Protocol, Section 2 (Background Information). Page 12; paragraph 5 (second 
sentence) and paragraph 6 (last  sentence). Original text: 
Paragraph 5: 
A total of 30 children (aged 2 to 17 years) with uncontrolled partial-onset seizures after an 
adequate course of treatment with at least 2 AEDs (concurrently or sequentially) will be enrolled. 
Paragraph 6: 
The study will also provide continued availability of LCM to subjects who have completed the 
SP847 epilepsy study (or discontinued SP847 due to a second dose reduction or status 
epilepticus), and who, in the investigator’s opinion, would benefit from long-term administration 
of LCM. 
Was revised as follows: 
Paragraph 5: 
Approximately 30 children (aged 2 to 17 years) with uncontrolled partial-onset seizures on a 
stable dose regimen of at least 1 but no more than 3 AEDs will be enrolled.  
Paragraph 6: 
The study will also provide continued availability of LCM to subjects who have completed the 
SP847 epilepsy study (or discontinued SP847 due to a dose reduction or status epilepticus), and 
who, in the investigator’s opinion, would benefit from long-term administration of LCM. 
Clinical Trial Protocol, Section 3 (Study Objectives). Page 13; last bullet point. Original text: 
• To allow subjects who have completed the SP847 study (or discontinued SP847 due to a 
second dose reduction or status epilepticus) to continue receiving LCM 
Was revised as follows: 
• To allow subjects who have completed the SP847 study (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
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Clinical Trial Protocol, Section 4.1 (Study description). Page 13; paragraph 1 (first sentence) 
Original text: 
Subjects who complete the SP847 study (or discontinue SP847 due to a second dose reduction or 
status epilepticus) and who choose to enter the open-label extension study, will begin on the 
LCM dose they achieved in SP847. 
Was revised as follows: 
Subjects who complete the SP847 study (or discontinue SP847 due to a dose reduction or status 
epilepticus) and who choose to enter the open-label extension study, will begin on the LCM dose 
they achieved in SP847. 
Clinical Trial Protocol, Section 4.3.1 (Inclusion criteria). Page 14; second bullet point.  
Original text: 
2.  Subject has completed SP847 (or the subject discontinued SP847 due to a second dose 
reduction or status epilepticus) for the treatment of uncontrolled partial-onset seizures. 
Was revised as follows: 
2.  Subject has completed SP847 (or the subject discontinued SP847 due to a dose reduction or 
status epilepticus) for the treatment of uncontrolled partial-onset seizures. 
Clinical Trial Protocol, Section 4.3.2 (Exclusion criteria). Page 14; second bullet point.  
Original text: 
2.  Subject meets the withdrawal criteria for the primary study (SP847) (with the exception of 
subjects who discontinued due to a second dose reduction or status epilepticus), or is 
experiencing an ongoing serious AE (SAE). 
Was revised as follows: 
2.  Subject meets the withdrawal criteria for the primary study (SP847) (with the exception of 
subjects who discontinued due to a dose reduction or status epilepticus), or is experiencing an 
ongoing serious AE (SAE). 
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Clinical Trial Protocol, Section 4.3.3 (Criteria for withdrawal). Page 15; 10th bullet point.  
Original text: 
10th bullet point:  
10.  Liver function test (LFT) results are above the upper limit of normal (ULN), to the extent 
specified in the table below. Subjects with abnormal LFTs are to be followed as specified below. 
Abnormal liver function test results requiring discontinuation from the 
study 
Liver function test result 
Action 
Transaminases (AST and/or ALT): 
≥3x to <5x ULN 
And 
Total bilirubin ≥2x ULN 
Lacosamide to be discontinued immediately 
 
Liver function tests to be repeated as soon as possible (within 7 days) and 
thereafter as clinically indicated. 
Transaminases (AST and/or ALT): 
≥5x ULN 
Lacosamide to be discontinued immediately. 
 
Liver function tests to be repeated as soon as possible (within 7 days). 
Liver function test monitoring should continue until resolved. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal 
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. 
3.  Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
4.  Liver function test results are above the ULN, to the extent specified in the table below. 
Subjects with abnormal LFTs are to be followed as specified below. 
Abnormal liver function test results that may require discontinuation from 
the study 
Liver function test result 
Action 
Transaminases (AST and/or ALT): 
≥3x to <5x ULN 
And 
Total bilirubin within normal range 
Lacosamide discontinuation at investigator discretion. 
 
Confirm results within a few days. If the repeat test confirms the 
abnormality, twice weekly LFT monitoring should continue until resolved. 
Transaminases (AST and/or ALT): 
≥3x ULN 
Test subject for hepatitis A, B, and C. 
ALT=alanine aminostransferase; AST=aspartate aminotransferase; LFT=liver function test; ULN=upper limit of 
normal 
Was revised as follows: 
10th bullet point: 
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10.  In the case of liver function test (LFT) results of transaminases (AST and/or ALT) ≥3x ULN 
to <5x ULN and total bilirubin ≥2x ULN or transaminases (AST and/or ALT) ≥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.  
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
Clinical Trial Protocol, Section 4.4.1 (Treatments to be administered). Pages 16; paragraph 1 
(first sentence) and paragraph 2. Original text: 
Paragraph 1: 
Subjects who complete the SP847 study (or discontinue SP847 due to a second dose reduction or 
status epilepticus) and choose to enter the open-label extension study will begin on the LCM 
dose they achieved in SP847. 
Paragraph 2:  
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 8, 10, or 12mg/kg/day (oral solution [syrup]) or 
400, 500, or 600mg/day (tablet), depending on the maximum recommended dose in SP847. The 
investigator may decrease the dose of LCM by 2mg/kg/day (oral solution [syrup]) or 100mg/day 
(tablet) per week to a minimum of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet). 
Increases in the LCM dose must occur only during office visits. 
Was revised as follows: 
Paragraph 1: 
Subjects who complete the SP847 study (or discontinue SP847 due to a dose reduction or status 
epilepticus) and choose to enter the open-label extension study will begin on the LCM dose they 
achieved in SP847. 
Paragraph 2: 
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 8, 10, or 12mg/kg/day (oral solution [syrup]) or 
400, 500, or 600mg/day (tablet), depending on the maximum recommended dose in SP847. The 
investigator may decrease the dose of LCM to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet). Increases in the LCM dose must occur only during office visits. It should 
be noted, in cases of incomplete doses (eg subject spits out all or a portion of the syrup), missed 
doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
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Clinical Trial Protocol, Section 4.5 (Expected duration of study). Page 18; paragraph 1. 
Original text: 
The maximum duration of LCM administration will be approximately 2 years. The trial can be 
terminated by the Sponsor once LCM is commercially available. If LCM is not commercially 
available in a subject’s country at the time the Sponsor closes the trial, access to LCM will be 
provided according to local laws. 
Was revised as follows: 
The maximum duration of LCM administration will be approximately 2 years.  
Clinical Trial Protocol, Section 4.7 (Procedures for monitoring subject compliance). Page 19; 
paragraph 2 (removal of last sentence). Original text: 
All findings will be documented on forms provided by SCHWARZ BIOSCIENCES. Subject’s 
noncompliance with regards to intake of LCM is defined as being less than 75% or more than 
125% compliant with the dosage schedule. Compliance will be determined by assessment of the 
remaining volume of LCM using a graduated cylinder (oral solution [syrup]) or pill count 
(tablet). 
Was revised as follows: 
All findings will be documented on forms provided by SCHWARZ BIOSCIENCES. Subject’s 
noncompliance with regards to intake of LCM is defined as being less than 75% or more than 
125% compliant with the dosage schedule. 
Clinical Trial Protocol, Section 5.1 (Visit 1[Week 0]). Page 19; paragraph 1. Original text: 
For subjects who complete the SP847 study, Visit 1 is the second day of the second inpatient 
hospitalization in SP847 (Day 28 for Cohorts 1 to 3 with maximum recommended dose of 
8mg/kg/day; Day 35 for Cohorts 2 to 4 with maximum recommended dose of 10mg/kg/day; and 
Day 42 for Cohorts 2 to 4 with maximum recommended dose of 12mg/kg/day). For subjects who 
discontinue the SP847 study due to a second dose reduction or status epilepticus, Visit 1 is the 
Early Termination Visit in SP847. 
Was revised as follows: 
For subjects who complete the SP847 study, Visit 1 is Day 2 of the second overnight stay at a 
hospital or medical facility in SP847 (Day 28 for Cohorts 1 to 3 with maximum recommended 
dose of 8mg/kg/day; Day 35 for Cohorts 2 to 4 with maximum recommended dose of 
10mg/kg/day; and Day 42 for Cohorts 2 to 4 with maximum recommended dose of 
12mg/kg/day). For subjects who discontinue the SP847 study due to a dose reduction or status 
epilepticus, Visit 1 is the Early Termination Visit in SP847. 
Clinical Trial Protocol, Section 5.2 (Telephone contacts [Week 2, 6, 10, 16, 24, 32, 40, 48, 66, 
and 78]); Page 20; last paragraph. Original text: 
Lacosamide is supplied so that the subject or caregiver (including parent/legal guardian) can 
immediately decrease their dose by a step of 2mg/kg/day (oral solution [syrup]) or 100mg/day 
(tablet), 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. 
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Was revised as follows: 
Lacosamide is supplied so that the subject or caregiver (including parent/legal guardian) 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. 
Clinical Trial Protocol, Section 5.16 (Unscheduled visit[s]); Page 25; first sentence and added 
bullet points 7 and 10. Original text: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, the subject must return for an 
Unscheduled Visit. The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Subject diary assessment 
• Adverse event reporting 
Additional assessments can be performed at the investigator’s discretion. 
Was revised as follows: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required 
between scheduled clinic visits, the subject must return for an Unscheduled Visit. The following 
assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
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• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
Clinical Trial Protocol, Section 8.1.7 (Overdose of investigational medicinal product); Page 30; 
first sentence. Original text: 
Excessive dosing (beyond that prescribed per the protocol and including overdose) should be 
recorded in the Drug Accountability or Drug Dosing module. 
Was revised as follows: 
Excessive dosing (beyond that prescribed per the protocol and including overdose) should be 
recorded in the source documents and Drug Accountability or Drug Dosing Log CRF module. 
Clinical Trial Protocol, Section 8.1.8 (Safety Signal detection in ongoing clinical studies and 
Data Monitoring Committees)); Page 30; replaced entire text. Original text: 
A regular monitoring of safety data collected during clinical studies will be performed as 
described in the Safety Signal Detection in Ongoing Clinical Trials Charter for lacosamide. 
This ongoing monitoring of safety data will be performed at the product level, possibly by an 
independent Data Monitoring Committee in some studies.  
Safety data, including SAEs, AEs, vital signs, laboratory results and ECG data (as applicable) 
will be periodically reviewed by SCHWARZ BIOSCIENCES. 
The data from all studies with the same investigational medicinal product will be scrutinized to 
detect as early as possible any safety concern related to the investigational medicinal product so 
that the investigators, the clinical study subjects, the regulatory authorities, and the ethics 
committees will be informed in the most appropriate manner. 
Was replaced as follows: 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the investigational medicinal product 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 GCSP 
representative. 
As appropriate for the stage of development and accumulated experience with the investigational 
medicinal product, medically qualified personnel at UCB may identify additional safety 
measures (examples: AEs, vital signs, laboratory or electrocardiogram results) for which data 
will be periodically reviewed during the course of the study.  
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Clinical Trial Protocol, Section 8.2.2 (AEs of Special Interest); Page 31; replaced entire text. 
Original text: 
The following are AEs of special interest:   
• Any case of torsade de points 
• Any ECG abnormality accompanied by related clinical symptoms 
• Any case of discontinuation due to any ECG abnormality or QTc prolongation 
Was replaced as follows: 
The following are AEs of special interest:  
• The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (2nd degree Type I and II and 3rd 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 
Food and Drug Administration: 
An AE or laboratory value (as defined below) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system 
involvement) combined with at least one of the following: fever, rash, 
lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
• Eosinophils % ≥10% 
• Eosinophils absolute ≥0.5G/L 
• Neutrophils absolute <1.5G/L 
• Platelets ≤100G/L 
• ALT ≥2x ULN 
• AST ≥2x ULN 
Clinical Trial Protocol, Section 8.2.3 (Immediate reporting of AEs); Page 31; replaced entire 
text. Original text: 
The following AEs must be reported immediately: 
• SAE: AEs that the investigator classifies as serious by the above definitions regardless of 
causality. 
• Suspected transmission via a medicinal product of an infectious agent. 
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• AEs of special interest:   
• 
Any case of torsade de points 
• 
Any ECG abnormality accompanied by related clinical symptoms 
• 
Any case of discontinuation due to any ECG abnormality or QTc prolongation 
Was replaced as follows: 
The following AEs must be reported immediately: 
• SAE: AEs that the investigator classifies as serious by the above definitions, regardless of 
causality. 
• Suspected transmission of an infectious agent via a medicinal product. 
• AEs of special interest (as defined in Section 8.2.2). 
Clinical Trial Protocol, Section 8.3 (Laboratory measurement); Page 32; first paragraph. 
Original text: 
Blood and urine specimens (approximately 5 to 15mL each) for routine assay of hematology, 
clinical chemistry, endocrinology, and urinalysis testing will be collected according to the tabular 
schedule of study procedures, Section 16.1. A central laboratory will perform the routine analysis 
of blood and urine samples. The procedures for handling and shipping these specimens will be 
provided to the sites. 
Was revised as follows: 
Blood and urine specimens (approximately 5 to 15mL each) for routine assay of hematology, 
clinical chemistry, endocrinology, and urinalysis testing will be collected according to the tabular 
schedule of study procedures, Section 16.1. For subjects aged 5 to 17 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 samples. 
The procedures for handling and shipping these specimens will be provided to the sites. 
Clinical Trial Protocol, Section 8.3.1 (Liver function tests); Page 32, 33; replaced entire text. 
Original text: 
Transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or both) 
greater than or equal to 3 times but less than 5 times the ULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat test confirms the abnormality 
(ie, transaminases are greater than or equal to 3 times but less than 5 times the ULN with normal 
bilirubin) twice weekly monitoring of LFTs should continue until resolved. The investigator is to 
decide whether or not to stop the study medication. 
Transaminases (AST, ALT, or both) greater than or equal to 3 times but less than 5 times the 
ULN, in the presence of total bilirubin greater than or equal to 2 times the ULN, will result in 
immediate discontinuation of the 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 7 days later and 
thereafter as clinically indicated. 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 98 of 324 
Transaminases (AST, ALT, or both) greater than or equal to 5 times the ULN will result in 
immediate discontinuation of the study medication and withdrawal of the subject from the study, 
regardless of the total bilirubin level. The LFTs will be repeated as soon as possible, and in no 
case more than 7 days later. Liver function test monitoring should continue until resolved. 
In all cases of transaminases (AST, ALT, or both) greater than or equal to 3 times the ULN, 
testing for hepatitis A, B, and C will be done. 
All LFTs that meet the criteria above will be followed until resolution (ie, Baseline or stable 
condition). 
Referral to a specialist (ie, hepatologist or gastroenterologist) is at the discretion of the 
investigator. This is recommended especially if the transaminase abnormalities greater than 
3 times the ULN persist after discontinuation of the study medication. 
Was replaced as follows: 
Transaminases (AST, ALT, or both) ≥3x ULN but <5x ULN, in the presence of total bilirubin 
≥2x ULN, or transaminases (AST, ALT, or both) ≥5x ULN will result in immediate 
discontinuation of LCM 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 (see Section 4.3.3). 
Clinical Trial Protocol, Section 8.4.5 (Tanner Stage); Page 35; first paragraph (first sentence). 
Original text: 
At each scheduled visit for selected patients, the investigator will evaluate the subject’s sexual 
development using the 3-item scale. 
Was replaced as follows: 
At selected visits for applicable subjects, the investigator or qualified designee will evaluate the 
subject’s sexual development using the 3-item scale. 
Clinical Trial Protocol, Section 12.1.2.2 (Other safety variables); Page 40; first paragraph 
(second sentence). Original text: 
The actual measurement and its change from Baseline (SP847 Visit 1) will be analyzed 
descriptively and presented by visit and day of collection. 
Was revised as follows: 
The actual measurement and its change from Baseline (SP847 Visit 1) will be analyzed 
descriptively and presented by visit. 
Clinical Trial Protocol, Section 16.1 (Table 1 and 2); Pages 46 to 51). Original table: 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 99 of 324 
Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-
Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
(complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam 
(brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam 
(brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and 
pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 100 of 324 
Study SP848 
Year 1 
Safety 
Follow-
Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Body weight and 
height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical chemistry 
and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology 
blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for 
LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Blood sample for 
concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Urinalysis 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Clinical GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
 
 
 
LCM return/ 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 101 of 324 
Study SP848 
Year 1 
Safety 
Follow-
Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE reportingn 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; LCM=lacosamide; 
PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Visit 1 is also the last visit of the primary study (SP847). At Visit 1, the informed consent will be signed (and assent, if applicable) and eligibility assessed, 
the medical history will be updated, body weight and height and concomitant medications including AEDs will be recorded, AEs will be assessed, and the 
subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between visits due to an AE, the subject must return for an Unscheduled Visit. 
f 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM. 
g 
This TC occurs 28-35 days after the last dose of LCM. 
h 
Assessments should have been done as part of the last visit of the previous SP847 study. 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 102 of 324 
I 
An ECG is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the increased dose 
of LCM or the new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 ECGs will be 
performed approximately 20 to 30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), and prior to administration of 
LCM (if applicable). 
j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential (ie, females who have begun menstruating), serum pregnancy tests will be performed at Visit 1, the Early 
Termination Visit, and the Final Visit. Urine pregnancy tests will be performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
n 
Ongoing aEs from the primary study (SP847) will be followed, as well as recording of new aEs during the current study. 
REDACTED COPY 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 103 of 324 
Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13 
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam 
(brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and 
pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and 
height 
X 
 
X 
X 
X 
X 
 
X 
 
Clinical chemistry and 
hematology blood 
sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood 
sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM 
PKh 
X 
 
X 
X 
X 
X 
 
X 
 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 104 of 324 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13 
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
X 
 
Urinalysis 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
 
 
 
LCM 
return/compliance 
X 
 
X 
X 
X 
X 
 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; LCM=lacosamide; 
PK=pharmacokinetics; S=serum; TC=telephone contact; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between visits due to an AE, the subject must return for an Unscheduled Visit. 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 105 of 324 
e 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
An ECG is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the increased dose 
of LCM or the new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 ECGs will be 
performed approximately 20 to 30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), and prior to administration of 
LCM (if applicable). 
h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential (ie, females who have begun menstruating), serum pregnancy tests will be performed at the Early Termination 
Visit and at the Final Visit. Urine pregnancy tests will be performed at Visits 10, 11, 12, and 13. 
j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 106 of 324 
Was revised as follows: 
Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Blood sample for concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Urinalysis 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xn 
 
 
LCM return/ compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 107 of 324 
Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE reportingo 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; LCM=lacosamide; 
PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone contact). 
b 
Visit 1 is also the last visit of the primary study (SP847). At Visit 1, the informed consent will be signed (and assent, if applicable) and eligibility assessed, the medical history 
will be updated, body weight and height and concomitant medications including AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an Unscheduled Visit. 
f 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM 
g 
This TC occurs 28-35 days after the last dose of LCM. 
h 
Assessments should have been done as part of the last visit of the previous SP847 study. 
i 
An ECG is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the increased dose of LCM or the 
new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 ECGs will be performed approximately 20 to 
30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), and prior to administration of LCM (if applicable). 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 108 of 324 
j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential (ie, females who have begun menstruating), serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and 
the Final Visit. Urine pregnancy tests will be performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical monitor, whenever possible. 
n 
As applicable  
o 
Ongoing AEs from the primary study (SP847) will be followed, as well as recording of new AEs during the current study. 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 109 of 324 
 
Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13  
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PKh 
X 
 
X 
X 
X 
X 
 
X 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
X 
 
Urinalysis 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
Xl 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xl 
X 
 
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CONFIDENTIAL 
 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
Page 110 of 324 
Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13  
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; LCM=lacosamide; 
PK=pharmacokinetics; S=serum; TC=telephone contact; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone 
contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM 
dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an 
Unscheduled Visit. 
e 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
An ECG is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the increased dose of 
LCM or the new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 ECGs will be performed 
approximately 20 to 30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), and prior to administration of LCM (if applicable). 
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h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential (ie, females who have begun menstruating), serum pregnancy tests will be performed at the Early Termination Visit and 
at the Final Visit. Urine pregnancy tests will be performed at Visits 10, 11, 12, and 13. 
j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended 
that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral 
solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical 
monitor, whenever possible. 
l 
As applicable. 
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Clinical Trial Protocol, Section 17.1. (Declarations and signatures of persons responsible for 
the study) Page 53. Original text: 
Senior Medical Director  
(Medical Therapeutics) 
, MD, PhD 
Was revised as follows: 
Medical Director  
(Medical Therapeutics) 
, MD 
17.2 
PROTOCOL AMENDMENT 2 
RATIONALE FOR THE AMENDMENT 
The primary purposes of this protocol amendment are to define an absolute maximum dose of 
LCM 600mg/day to be received by subjects in the study, to revise withdrawal criteria and 
follow-up recommendations for abnormal LFTs, and to specify that subjects who participate in 
future studies (in addition to SP847) may participate in SP848. The rationales for these changes 
are described below. 
Based on the analysis of SP847 Cohort 1 (subjects aged 5 to 11 years) safety and PK data, the 
maximum permitted LCM dose in SP848 is 12mg/kg/day (for subjects weighing up to 50kg), or 
600mg/day (for subjects weighing >50kg). 
The decision to re-insert additional withdrawal criteria and follow-up recommendations for 
abnormal LFTs is based on the following: 
1) Newly adopted FDA Guidance on Drug-Induced Liver Injury (July 2009) and a 
recommendation from the FDA to re-insert previously included wording regarding additional 
withdrawal criteria and follow-up recommendations for abnormal LFTs in LCM protocols. 
2) Although no new liver-related safety issues with LCM have been identified, LFT 
abnormal has been added as a postmarketing adverse drug reaction in the LCM Company 
Core Data Sheet, and the EU Summary of Product Characteristics. Therefore, LCM protocols 
are being amended to reflect this addition. 
With these revisions, liver-related safety signals will continue to be detected via protocol 
directed monitoring and additional follow-up in ongoing and future LCM clinical studies. 
In order to allow subjects who participate in other future LCM pediatric clinical studies in 
epilepsy (ie, in addition to SP847) to continue receiving LCM treatment, these subjects will be 
provided the opportunity to participate in SP848. 
The remainder of the changes in this amendment were administrative in nature and are described 
in detail below. 
MODIFICATIONS/CHANGES 
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• The contact information of the Clinical Project Manager, Clinical Pharmacokineticist, and 
Associate Medical Director (Global Clinical Safety and Pharmacovigilance) were updated. 
• Information was added to Section 1 (Summary) and throughout the protocol to specify that 
subjects who participate in future studies (in addition to SP847) may participate in SP848. 
• Information was added to Section 1 (Summary) and throughout the protocol to indicate that 
the maximum permitted LCM dose in SP848 is 12mg/kg/day (for subjects weighing up to 
50kg), or 600mg/day (for subjects weighing >50kg). 
• The withdrawal criteria (Section 4.3.3) and follow-up recommendations for abnormal LFTs 
throughout the protocol were revised. 
• Information was added to Section 4.4.1 (Treatments to be administered) to clarify dosing for 
subjects who switch to the LCM tablet formulation. 
• The tabular schedules of trial procedures were updated to reflect the changes to the protocol. 
REFERENCE 
Clinical Study Protocol, Contact information for the Clinical Project Manager, Clinical Trial 
Biostatistician, Clinical Pharmacokineticist, and Associate Medical Director (Global Clinical 
Safety and Pharmacovigilance), pages 2 and 3. Original text: 
Clinical Project Manager: 
Name: 
, BS 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
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Clinical Trial Biostatistician: 
Name: 
, MPH 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Pharmacokineticist: 
Name: 
 
Address: 
UCB S.A. 
Chemin du Foriest 
B-1420 Braine-l'Alleud 
Phone/Fax: 
 
E-mail: 
 
Associate Medical Director (Drug Safety): 
Name: 
, MD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
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Was revised as follows: 
Clinical Project Manager: 
Name: 
 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Trial Biostatistician: 
Name: 
 MPH 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Pharmacokineticist: 
Name: 
 
Address: 
UCB Celltech 
UCB Pharma Ltd 
208 Bath Road 
Slough, Berkshire SL1 3WE, UK 
Phone/Fax: 
  
E-mail: 
 
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Associate Medical Director (Global Clinical Safety and Pharmacovigilance): 
Name: 
 MD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
Clinical Study Protocol, List of Abbreviations, page 9. The following abbreviation was deleted: 
IRAE 
immediately reportable adverse event 
 
Clinical Study Protocol, Section 1 (Summary), paragraphs 1 and 2. Original text: 
SP848 is an open-label extension study to obtain long-term safety, tolerability, and 
pharmacokinetic (PK) data in children with partial-onset seizures treated with lacosamide (LCM) 
oral solution (syrup) or LCM tablets as adjunctive therapy. In addition, the study is designed to 
obtain preliminary efficacy data on seizure frequency during long-term exposure. The study will 
also provide continued availability of LCM to subjects who have completed the SP847 epilepsy 
study and to subjects who have discontinued from SP847 due to a dose reduction or status 
epilepticus, and who, in the investigator’s opinion, would benefit from long-term administration 
of LCM. 
Subjects who complete the SP847 study and choose to enter this open-label extension study will 
begin on the LCM dose they achieved in SP847. Subjects who discontinued from SP847 due to a 
dose reduction or status epilepticus, but for whom it is determined medically appropriate to enter 
this open-label extension study, will also begin on the LCM dose they achieved in SP847. 
Subjects will be able to continue on LCM oral solution (syrup) or switch to LCM tablets. During 
the study, investigators will be allowed to increase or decrease the dose of LCM and/or 
concomitant antiepileptic drugs (AEDs) to optimize tolerability and seizure reduction for each 
subject. The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) and a maximum of 8, 10, or 12mg/kg/day (oral solution [syrup]) 
or 400, 500, or 600mg/day (tablet), depending on the maximum recommended dose in SP847. 
An increase in the LCM dose must occur only during office visits. 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 
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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. When 
subjects withdraw from the study, it is recommended that LCM be tapered gradually in weekly 
decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have 
achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower 
taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is 
permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
Was revised as follows: 
SP848 is an open-label extension study to obtain long-term safety, tolerability, and 
pharmacokinetic (PK) data in children with partial-onset seizures treated with lacosamide (LCM) 
oral solution (syrup) or LCM tablets as adjunctive therapy. In addition, the study is designed to 
obtain preliminary efficacy data on seizure frequency during long-term exposure. The study will 
also provide continued availability of LCM to subjects who have completed the SP847 epilepsy 
study and to subjects who have discontinued from SP847 due to a dose reduction or status 
epilepticus, and who, in the investigator’s opinion, would benefit from long-term administration 
of LCM. SP848 will also be open to subjects who participate in other future LCM pediatric 
clinical studies in epilepsy. 
Subjects who complete SP847 and choose to enter this open-label extension study will begin on 
the LCM dose they achieved in SP847. Subjects who discontinued from SP847 due to a dose 
reduction or status epilepticus, but for whom it is determined medically appropriate to enter this 
open-label extension study, will also begin on the LCM dose they achieved in SP847. Subjects 
will be able to receive LCM oral solution (syrup) or LCM tablets. During the study, investigators 
will be allowed to increase or decrease the dose of LCM and/or concomitant antiepileptic drugs 
(AEDs) to optimize tolerability and seizure reduction for each subject. The investigator may 
adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) 
and a maximum of 12mg/kg/day (oral solution [syrup] or the corresponding dose levels for the 
tablet formulation) not to exceed 600mg/day based on body weight, even if the subject’s body 
weight exceeds 50kg. An increase in the LCM dose must occur only during office visits. 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. When subjects withdraw from the study, it is recommended that LCM be tapered 
gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for 
subjects who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day 
(tablet). A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
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Clinical Study Protocol, Section 2 (Background information). Original text: 
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). 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). In 
the past decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
The classification of epilepsies in children was described in 1989 by the Commission on 
Classification and Terminology of the International League Against Epilepsy (1989; Aicardi, 
1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
according to a number of criteria including seizure type, cause, anatomy, precipitating factors, 
age of onset, and sometimes prognosis. 
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and PK characteristics (Herman and Pedley, 1998). However, more 
than 30% of patients have inadequate seizure control on currently-available AEDs or experience 
significant adverse drug effects (CPMP/EWP/566/98, 2000). Therefore, a need remains for 
AEDs with improved effectiveness and tolerability (Sander, 1998). 
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 (Appleton et al, 1999; Duchowny et al, 1999; 
Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006). 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). Therefore, a need remains for AEDs with improved effectiveness and tolerability.  
Lacosamide (LCM, Vimpat®, SPM 927, [R]-2-acetamido-N-benzyl-3-methoxypropionamide) 
belongs to a novel class of functionalized amino acids. It has minimal protein binding and effect 
on cytochrome P450 enzyme system function (reducing the risk of drug-drug interactions), high 
oral bioavailability, and a half-life of approximately 13 hours (in adults), which allows a twice 
daily (bid) dose regimen. It also displays dose-proportional PK following administration over a 
range of doses up to 800mg in adults. 
Lacosamide has been approved 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 (oral tablets, oral solution [syrup], and solution for intravenous [iv] infusion) and in 
patients 17 years of age and older in the United States (oral tablets and solution for iv infusion). 
The oral solution (syrup) is a formulation suitable for administration to children. Bioequivalence 
has been shown between the tablet and oral solution (syrup) formulations, comparing 2 tablets of 
LCM 100mg and the oral solution (syrup) containing LCM 200mg, after single-dose 
administration in healthy subjects. The PK of LCM and its major metabolite, SPM 12809 
(O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after single oral 
doses of LCM 200mg administered as tablets or as oral solution (syrup). 
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In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
400mg bid (800mg/day) were evaluated in approximately 700 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 2200 adult subjects in other indications (eg, neuropathic pain, 
osteoarthritis, fibromyalgia). In addition, LCM solution for infusion was evaluated as short-term 
replacement therapy in a subset of subjects with partial-onset seizures (199 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 
randomized dose (200mg/day, 400mg/day, or 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, headache, 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. 
SP847, the primary study, is an open-label, dose-titration, safety, tolerability, and PK study to 
evaluate LCM as adjunctive therapy in children with uncontrolled partial-onset seizures. 
Approximately 30 children (aged 2 to 17 years) with uncontrolled partial-onset seizures on a 
stable dose regimen of at least 1 but no more than 3 AEDs will be enrolled. The study consists of 
a Screening Phase, a Treatment Phase, and an End-of-Study Phase. The duration of treatment for 
an individual subject may be up to approximately 13 weeks. 
SP848 is an open-label extension study to obtain long-term safety, tolerability, and PK data in 
children with partial-onset seizures treated with LCM oral solution (syrup) or LCM tablets as 
adjunctive therapy. In addition, the study is designed to obtain preliminary efficacy data on 
seizure frequency during long-term exposure. The study will also provide continued availability 
of LCM to subjects who have completed the SP847 epilepsy study (or discontinued SP847 due to 
a dose reduction or status epilepticus), and who, in the investigator’s opinion, would benefit from 
long-term administration of LCM. 
Was revised as follows: 
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). 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). In 
the past decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
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, 
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1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
according to a number of criteria including seizure type, cause, anatomy, precipitating factors, 
age of onset, and sometimes prognosis. 
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and PK characteristics (Herman and Pedley, 1998). However, more 
than 30% of patients have inadequate seizure control on currently-available AEDs or experience 
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 5 (gabapentin, lamotrigine, oxcarbazepine, topiramate, and 
levetiracetam) have successfully demonstrated efficacy as adjunctive therapy in children with 
difficult to treat partial-onset seizures (Appleton et al, 1999; Duchowny et al, 1999; 
Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006). 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 (LCM, Vimpat®, SPM 927, [R]-2-acetamido-N-benzyl-3-methoxypropionamide) 
belongs to a novel class of functionalized amino acids. It has minimal protein binding and effect 
on cytochrome P450 enzyme system function (reducing the risk of drug-drug interactions), high 
oral bioavailability, and a half-life of approximately 13 hours (in adults), which allows a twice 
daily (bid) dose regimen. It also displays dose-proportional PK following administration over a 
range of doses up to 800mg in adults. 
Lacosamide has been approved 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 (oral tablets, oral solution [syrup], and solution for intravenous [iv] infusion) and in 
patients 17 years of age and older in the United States (oral tablets, oral solution, and solution for 
iv infusion). The oral solution (syrup) is a formulation suitable for administration to children. 
Bioequivalence has been shown between the tablet and oral solution (syrup) formulations, 
comparing 2 tablets of LCM 100mg and the oral solution (syrup) containing LCM 200mg, after 
single-dose administration in healthy subjects. The PK of LCM and its major metabolite, 
SPM 12809 (O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after 
single oral doses of LCM 200mg administered as tablets or as oral solution (syrup). 
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
400mg bid (800mg/day) were evaluated in approximately 700 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 2200 adult subjects in other indications (eg, 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 (199 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 
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therapy (1 to 3 concomitant AEDs) in subjects with difficult to control partial-onset seizures. In 
these studies, LCM was initiated at a dose of 100mg/day (in 2 divided doses) and escalated to the 
randomized dose (200mg/day, 400mg/day, or 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, headache, 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. 
SP847, the current primary study, is an open-label, dose-titration, safety, tolerability, and PK 
study to evaluate LCM as adjunctive therapy in children with uncontrolled partial-onset seizures. 
Approximately 42 children (aged 1 month to 17 years) with uncontrolled partial-onset seizures 
on a stable dose regimen of at least 1 but no more than 3 AEDs will be enrolled. The study 
consists of a Screening Phase, a Treatment Phase, and an End-of-Study Phase. The duration of 
treatment for an individual subject may be up to approximately 13 weeks. Approximately 
300 additional subjects who may participate in other future LCM primary pediatric clinical 
studies in epilepsy will also be eligible to participate in SP848. 
SP848 is an open-label extension study to obtain long-term safety, tolerability, and PK data in 
children with partial-onset seizures treated with LCM oral solution (syrup) or LCM tablets as 
adjunctive therapy. In addition, the study is designed to obtain preliminary efficacy data on 
seizure frequency during long-term exposure. The study will also provide continued availability 
of LCM to subjects who have completed the SP847 epilepsy study (or discontinued SP847 due to 
a dose reduction or status epilepticus), and who, in the investigator’s opinion, would benefit from 
long-term administration of LCM. SP848 will also be open to subjects who participate in other 
future LCM pediatric clinical studies in epilepsy. 
Clinical Study Protocol, Section 3 (Objectives), third and objectives. Original text: 
• To allow subjects who have completed the SP847 study (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
Was revised as follows, and a fourth objective was added: 
• To allow subjects who have participated in SP847 (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
• To allow subjects who have participated in other future LCM pediatric clinical studies in 
epilepsy to continue receiving LCM 
Clinical Study Protocol, Section 4 (Study description). Original text: 
Subjects who complete the SP847 study (or discontinue SP847 due to a dose reduction or status 
epilepticus) and who choose to enter the open-label extension study, will begin on the LCM dose 
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they achieved in SP847. Subjects will be able to continue on LCM oral solution (syrup) or switch 
to LCM tablets. During the study, investigators will be allowed to increase or decrease the dose 
of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for each 
subject. The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) and a maximum of 8, 10, or 12mg/kg/day (oral solution [syrup]) 
or 400, 500, or 600mg/day (tablet), depending on the maximum recommended dose in SP847. 
Increases in the LCM dose must occur only during office visits. 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. When subjects 
withdraw from the study, it is recommended that the study medication be tapered gradually in 
weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects 
who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). 
A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day 
(tablets) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted 
after discussion with the medical monitor, whenever possible.  
Was revised as follows: 
Subjects who complete SP847 (or discontinue SP847 due to a dose reduction or status 
epilepticus) and who choose to enter the open-label extension study, will begin on the LCM dose 
they achieved in SP847. Subjects will be able to continue on LCM oral solution (syrup) or switch 
to LCM tablets. During the study, investigators will be allowed to increase or decrease the dose 
of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for each 
subject. The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the 
corresponding dose levels for the tablet formulation), not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. Increases in the LCM dose must occur 
only during office visits. 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. When subjects withdraw from the study, it is 
recommended that the study medication be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have achieved a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly 
decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if 
medically necessary. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible. 
Clinical Study Protocol, Section 4.3.1 (Inclusion criteria), criterion 2. Original text: 
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1. Subject has completed SP847 (or the subject discontinued SP847 due to a dose reduction or 
status epilepticus) for the treatment of uncontrolled partial-onset seizures. 
Was revised as follows: 
1. Subject has completed SP847 (or the subject discontinued SP847 due to a dose reduction or 
status epilepticus) for the treatment of uncontrolled partial-onset seizures, or subject has 
participated in other LCM pediatric clinical studies in epilepsy.  
Clinical Study Protocol, Section 4.3.2 (Exclusion criteria), criterion 2. Original text: 
1. Subject meets the withdrawal criteria for the primary study (SP847) (with the exception of 
subjects who discontinued due to a dose reduction or status epilepticus), or is experiencing 
an ongoing serious AE (SAE). 
Was revised as follows: 
1. Subject meets the withdrawal criteria for the primary study (with the exception of subjects 
who discontinued due to a dose reduction or status epilepticus), or is experiencing an 
ongoing serious AE (SAE). 
Clinical Study Protocol, Section 4.3.3 (Criteria for withdrawal). Original text: 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is 
unwilling or unable to allow the subject to continue in the study. 
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8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
9.    Subject experiences status epilepticus 
10.  In the case of liver function test (LFT) results of transaminases (AST and/or ALT) ≥3x ULN 
to <5x ULN and total bilirubin ≥2x ULN or transaminases (AST and/or ALT) ≥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.  
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
Was revised as follows: 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is 
unwilling or unable to allow the subject to continue in the study. 
8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
9.    Subject experiences status epilepticus 
10.  In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x ULN to <5x ULN and total bilirubin ≥2x ULN or transaminases (AST, ALT, or both) 
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≥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.  
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
4.   Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3xULN or stable condition). The investigator is 
to decide whether or not to stop the study medication. 
Clinical Study Protocol, Section 4.4.1 (Treatments to be administered). Original text: 
Subjects who complete the SP847 study (or discontinue SP847 due to a dose reduction or status 
epilepticus) and choose to enter the open-label extension study will begin on the LCM dose they 
achieved in SP847. The investigator, together with the subject/caregiver (including parent/legal 
guardian), will be able to choose either the oral solution (syrup) formulation or the tablet 
formulation of LCM in this study. The study medication will be orally administered bid (at 
12-hour intervals, once in the morning and once in the evening) in equally divided doses. The 
oral solution (syrup) formulation will be measured and orally administered via a dosing syringe. 
The selection of doses, titration scheme, and rate of taper in SP847 were based on adult studies 
and were adjusted to a mg/kg basis plus 40% (ie, 600mg/day adult dose of LCM corresponds to 
[600mg/70kg] x 1.4 = approximately 12mg/kg/day for a child). The selection of doses in this 
trial is based on the maximum recommended dose in SP847. 
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 8, 10, or 12mg/kg/day (oral solution [syrup]) 
or 400, 500, or 600mg/day (tablet), depending on the maximum recommended dose in SP847. 
The investigator may decrease the dose of LCM to a minimum of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet). Increases in the LCM dose must occur only during office visits. 
It should be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the 
syrup), missed doses, or administration of an erroneous volume of syrup, study medication 
should not be readministered and these subjects would remain at their assigned dose. 
Subjects achieving a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet) 
who withdraw during the study should taper off study medication. It is recommended that the 
dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (see tables below). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
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100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Was revised as follows: 
Subjects who have participated in SP847 (or other future LCM pediatric clinical studies in 
epilepsy), who are eligible to participate in the open-label extension study SP848, and who 
choose to enter SP848, will begin SP848 on the LCM dose they achieved in the primary study. 
The investigator, together with the subject/caregiver (including parent/legal guardian), will be 
able to choose either the oral solution (syrup) formulation or the tablet formulation of LCM in 
this study. The study medication will be orally administered bid (at 12-hour intervals, once in the 
morning and once in the evening) in equally divided doses. The oral solution (syrup) formulation 
will be measured and orally administered via a dosing syringe. The selection of doses, titration 
scheme, and rate of taper in SP847 were based on adult studies and were adjusted to a mg/kg 
basis plus 40% (ie, 600mg/day adult dose of LCM corresponds to [600mg/70kg] x 1.4 = 
approximately 12mg/kg/day for a child). The selection of doses in this trial is based on the 
maximum recommended dose in SP847. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg  
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The investigator may decrease the dose 
of LCM to a minimum of 2mg/kg/day (oral solution [syrup] or the corresponding dose level for 
the tablet formulation). Increases in the LCM dose must occur only during office visits. It should 
be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the syrup), missed 
doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
Subjects enrolled in SP848 have the option of remaining on the oral solution formulation of 
LCM or switching to the commercial tablet formulation, if feasible. Consideration of the current 
LCM milligram dose in the oral solution (syrup) should occur if/when transitioning to the tablet 
formulation. In cases where the LCM dose received with the oral solution (syrup) is not 
supported by the tablet strengths available in SP848 (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 100mg with a maximum permitted dose of 600mg/day. 
Subjects achieving a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet) 
who withdraw during the study should taper off study medication. It is recommended that the 
dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (see tables below). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
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Clinical Study Protocol, Section 4.4.3 (Randomization). Original text: 
This is an open-label extension study; subjects will not be randomized. Subjects will keep the 
unique number assigned in the SP847 study. 
Was revised as follows: 
This is an open-label extension study; subjects will not be randomized. Subjects will keep the 
unique number assigned in the primary study. 
Clinical Study Protocol, Section 5.1 (Visit 1 [Week 0]). Original text: 
For subjects who complete the SP847 study, Visit 1 is Day 2 of the second overnight stay at a 
hospital or medical facility in SP847 (Day 28 for Cohorts 1 to 3 with maximum recommended 
dose of 8mg/kg/day; Day 35 for Cohorts 2 to 4 with maximum recommended dose of 
10mg/kg/day; and Day 42 for Cohorts 2 to 4 with maximum recommended dose of 
12mg/kg/day). For subjects who discontinue the SP847 study due to a dose reduction or status 
epilepticus, Visit 1 is the Early Termination Visit in SP847. 
Prior to the conduct of any study-related procedures, a complete explanation (both verbally 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 parent/legal guardian by the 
investigator (or designee). The subject’s parent/legal guardian will be requested to sign and date 
the IRB/IEC-approved Informed Consent Form. When possible, or as required by local IRB/IEC, 
the subject will be requested to give assent to participate in the study. 
Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments, and a complete medical history update will be obtained. 
The data for the following assessments will be taken from the last assessment during the SP847 
study: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
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• Tanner Stage assessment (if applicable) 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
Was revised as follows: 
For subjects who complete SP847, Visit 1 is Day 2 of the second PK collection time period 
(which may include an overnight stay at a hospital or medical facility) in SP847 (Day 28 for 
Cohorts 1, 2, 3, and 5 with maximum recommended dose of 8mg/kg/day; Day 35 for Cohorts 2 
to 5 with maximum recommended dose of 10mg/kg/day; and Day 42 for Cohorts 2 to 5 with 
maximum recommended dose of 12mg/kg/day). For subjects who discontinue SP847 due to a 
dose reduction or status epilepticus, Visit 1 is the Early Termination Visit in SP847. For subjects 
in SP847 who are titrated up to the maximum permitted dose of 600mg/day sooner than the 
study schedule would ordinarily indicate (based on body weight) and who enroll in SP848, the 
Early Termination Visit of SP847 will also serve as Visit 1 for SP848. 
For subjects who enroll in SP848 after participation in future LCM pediatric clinical studies in 
epilepsy, SP848 Visit 1 will be specified in the respective primary study protocol. 
Prior to the conduct of any study-related procedures, a complete explanation (both verbally 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 parent/legal guardian by the 
investigator (or designee). The subject’s parent/legal guardian will be requested to sign and date 
the IRB/IEC-approved Informed Consent Form. When possible, or as required by local IRB/IEC, 
the subject will be requested to give assent to participate in the study. 
Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments, and a complete medical history update will be obtained. 
The data for the following assessments will be taken from the last assessment during SP847 (or 
other primary study as applicable): 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
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• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
Clinical Study Protocol, Section 5.3 (Visit 2 [Week 4]), bullet 5. Original text: 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of blood sample) 
Was revised as follows: 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
Clinical Study Protocol, Section 5.4 (Visit 3 [Week 8), final paragraph. Original text: 
• A 12-lead ECG is also required when the dose of LCM is increased or a new concomitant 
AED is introduced. The ECG should be performed after the increased dose of LCM or the 
new AED has reached steady-state. This ECG can be done at the next scheduled visit. When 
the ECG assessment is done, 2 ECGs will be performed approximately 20 to 30 minutes 
apart prior to vital sign assessment, collection of blood samples (if applicable), and prior to 
administration of LCM (if applicable). 
Was revised as follows: 
• A 12-lead ECG is also required when the dose of LCM is increased or a new concomitant 
AED is introduced. The ECG should be performed after the increased dose of LCM or the 
new AED has reached steady-state. This ECG can be done at the next scheduled visit. When 
the ECG assessment is done, 2 interpretable ECGs will be performed approximately 20 to 30 
minutes apart prior to vital sign assessment, collection of blood samples (if applicable), and 
prior to administration of LCM (if applicable). 
Clinical Study Protocol, Section 5.6 (Visit 5 [Week 20]), final paragraph. Original text: 
A 12-lead ECG is also required when the dose of LCM is increased or a new concomitant AED 
is introduced. The ECG should be performed after the increased dose of LCM or the new AED 
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has reached steady-state. This ECG can be done at the next scheduled visit. When the ECG 
assessment is done, 2 ECGs will be performed approximately 20 to 30 minutes apart prior to 
vital sign assessment, collection of blood samples (if applicable), and prior to administration of 
LCM (if applicable). 
Was revised as follows: 
A 12-lead ECG is also required when the dose of LCM is increased or a new concomitant AED 
is introduced. The ECG should be performed after the increased dose of LCM or the new AED 
has reached steady-state. This ECG can be done at the next scheduled visit. When the ECG 
assessment is done, 2 interpretable ECGs will be performed approximately 20 to 30 minutes 
apart prior to vital sign assessment, collection of blood samples (if applicable), and prior to 
administration of LCM (if applicable). 
Clinical Study Protocol, Section 5.7 (Visit 6 [Week 28]). Original text: 
Assessments for Visit 6 (Week 28) are the same as those described for Visit 3 (Week 8) in 
Section 5.6, with the following exception: a 12-lead ECG (2 recordings approximately 20 to 
30 minutes apart prior to vital signs assessment and collection of blood sample) is conducted at 
Visit 6. 
Was revised as follows: 
Assessments for Visit 6 (Week 28) are the same as those described for Visit 3 (Week 8) in 
Section 5.6, with the following exception: a 12-lead ECG (2 interpretable recordings 
approximately 20 to 30 minutes apart prior to vital signs assessment and collection of blood 
sample) is conducted at Visit 6. 
Clinical Study Protocol, Section 5.10 (Visit 9 [Week 52]). Original text: 
Assessments for Visit 9 (Week 52) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exception: a 12-lead ECG (2 recordings approximately 20 to 
30 minutes apart prior to vital signs assessment and collection of blood sample) is conducted at 
Visit 9. 
Was revised as follows: 
Assessments for Visit 9 (Week 52) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exception: a 12-lead ECG (2 interpretable recordings 
approximately 20 to 30 minutes apart prior to vital signs assessment and collection of blood 
sample) is conducted at Visit 9. 
Clinical Study Protocol, Section 5.12 (Visit 11 [Week 72]). Original text: 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: brief physical and neurological exams are conducted 
(instead of complete physical and neurological exams as indicated for Visit 5), the laboratory 
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blood sample is collected only for clinical chemistry and hematology (ie, no endocrinology), and 
a 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted. 
Was revised as follows: 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: brief physical and neurological exams are conducted 
(instead of complete physical and neurological exams as indicated for Visit 5), the laboratory 
blood sample is collected only for clinical chemistry and hematology (ie, no endocrinology), and 
a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) is conducted. 
Clinical Study Protocol, Section 5.14 (Visit 13 [Week 96]). Original text: 
Assessments for Visit 13 (Week 96) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: the laboratory blood sample is collected only for 
clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG (2 recordings 
approximately 20 to 30 minutes apart prior to vital signs assessment and collection of blood 
sample) is conducted, and a Tanner Stage assessment is conducted (if applicable). 
Was revised as follows: 
Assessments for Visit 13 (Week 96) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: the laboratory blood sample is collected only for 
clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG (2 interpretable 
recordings approximately 20 to 30 minutes apart prior to vital signs assessment and collection of 
blood sample) is conducted, and a Tanner Stage assessment is conducted (if applicable). 
Clinical Study Protocol, Section  5.15 (Early Termination Visit), bullet 5. Original text: 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of blood samples) 
Was revised as follows: 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
Clinical Study Protocol, Section 5.16 (Unscheduled Visit[s]). Original text: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required 
between scheduled clinic visits, the subject must return for an Unscheduled Visit. The following 
assessments are required: 
• Concomitant medications assessment  
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• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
Was revised as follows: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if an LCM dose increase is required 
between scheduled clinic visits, the subject must return for an Unscheduled Visit. If an AE 
prompts a dose reduction, the reduction can be implemented immediately at the investigator’s 
discretion. However, the subject should return to the clinic as soon as possible for an 
Unscheduled Visit. 
The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
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Clinical Study Protocol, Section 5.17 (Final Visit [2 weeks after the last LCM dose]), bullet 5. 
Original text: 
• 12-lead ECG (2 recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of blood samples) 
Was revised as follows: 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
Clinical Study Protocol, Section 6.1 (Seizure counts). Original text: 
At Screening of the primary study, SP847, subjects/caregivers (including parents/legal 
guardians) will be asked how many seizures the subject has had in the previous 4 weeks; this will 
serve as a historical Baseline. After the subject is enrolled in the SP848 study, seizure data will 
be collected in diaries provided to subjects/caregivers (including parents/legal guardians). Each 
subject/caregiver (including parent/legal guardian) will keep a diary to note daily seizure activity 
throughout the current study. The subject/caregiver (including parent/legal guardian) should be 
reminded to bring the diary with them at each clinic visit. The following information will be 
recorded: 
• Seizure type 
• Seizure frequency 
Was revised as follows: 
At Screening of SP847 (or other primary study as applicable) subjects/caregivers (including 
parents/legal guardians) will be asked how many seizures the subject has had in the previous 
4 weeks; this will serve as a historical Baseline. After the subject is enrolled in the SP848 study, 
seizure data will be collected in diaries provided to subjects/caregivers (including parents/legal 
guardians). Each subject/caregiver (including parent/legal guardian) will keep a diary to note 
daily seizure activity throughout the current study. The subject/caregiver (including parent/legal 
guardian) should be reminded to bring the diary with them at each clinic visit. The following 
information will be recorded: 
• Seizure type 
• Seizure frequency 
Clinical Study Protocol, Section 6.2.1 (Clinical Global Impression of Change), paragraph 2. 
Original text: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 
of SP847 (primary study) will serve as Baseline. 
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Was revised as follows: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 
of SP847 (or other primary study as applicable) will serve as Baseline. 
Clinical Study Protocol, Section 6.2.2 (Caregiver Global Impression of Change), paragraph 2. 
Original text: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 of SP847 (primary study) will serve as Baseline. 
Was revised as follows: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 of SP847 (or other primary study as applicable) 
will serve as Baseline. 
Clinical Study Protocol, Section 7 (Assessment of pharmacokinetics), paragraph 2. Original 
text: 
Each blood sample drawn will be split into 2 duplicate samples. The samples will be centrifuged 
and stored at -20ºC until shipped to a central laboratory. The central laboratory will store the 
plasma samples at -70ºC until analysis. Details of plasma sample collection and processing, 
sample labeling, and shipment will be provided in the laboratory manual. 
Was revised as follows: 
Each blood sample drawn will be split into 2 duplicate samples. The samples will be centrifuged 
and stored at ≤-20ºC until shipped to a central laboratory. The central laboratory will store the 
plasma samples at -20ºC until analysis. Details of plasma sample collection and processing, 
sample labeling, and shipment will be provided in the laboratory manual. 
Clinical Study Protocol, Section 8.2.2 (AEs of special interest), bullet 1. Original text: 
• The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (2nd degree Type I and II and 3rd degree), and marked bradycardia (<45beats/min) 
Was revised as follows: 
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• 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) 
Clinical Study Protocol, Section 8.3 (Laboratory measurements). The laboratory parameter: 
Acetone 
Was replaced with: 
Ketone 
Clinical Study Protocol, Section 8.3.1 (Liver function tests). Original text: 
Transaminases (AST, ALT, or both) ≥3x ULN but <5x ULN, in the presence of total bilirubin 
≥2x ULN, or transaminases (AST, ALT, or both) ≥5x ULN will result in immediate 
discontinuation of LCM 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 (see Section 4.3.3). 
Was revised as follows: 
Transaminases (AST, ALT, or both) ≥3x ULN but <5x ULN, in the presence of total bilirubin 
≥2x ULN, or transaminases (AST, ALT, or both) ≥5x ULN will result in immediate 
discontinuation of LCM 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 (see Section 4.3.3). 
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. 
Clinical Study Protocol, Section 9.1 (Manufacturing, packaging, and labeling). The following 
bullets were added: 
• Date bottle opened 
• Do not use after (date) 
Clinical Study Protocol, Section 10.2 (Monitoring), paragraph 1. Original text: 
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SCHWARZ BIOSCIENCES 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. 
Was revised as follows: 
SCHWARZ BIOSCIENCES 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 SCHWARZ BIOSCIENCES to a CRO or a 
contract monitor. 
Clinical Study Protocol, Section 12.1 (Description of statistical methods), paragraph 2. Original 
text: 
Visit 1 of SP847 (primary study) will serve as Baseline values for safety and efficacy variables 
unless otherwise noted. 
Was revised as follows: 
Visit 1 of SP847 (or other primary study as applicable) will serve as Baseline values for safety 
and efficacy variables unless otherwise noted. 
Clinical Study Protocol, Section 12.1.2.2 (Other safety variables), paragraph 1. Original text: 
The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, and urinalysis), ECG measurements, vital sign measurements (blood pressure and 
pulse rate), body weight, height, calculated BMI, and Tanner Stage (if applicable). The actual 
measurement and its change from Baseline (SP847 Visit 1) will be analyzed descriptively and 
presented by visit. In addition, shift tables may be used to evaluate the number and percentage of 
subjects having a different postBaseline status when compared with their Baseline status. 
Was revised as follows: 
The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, and urinalysis), ECG measurements, vital sign measurements (blood pressure and 
pulse rate), body weight, height, calculated BMI, and Tanner Stage (if applicable). The actual 
measurement and its change from Baseline (SP847 [or other primary study as applicable] Visit 
1) will be analyzed descriptively and presented by visit. In addition, shift tables may be used to 
evaluate the number and percentage of subjects having a different post-Baseline status when 
compared with their Baseline status. 
Clinical Study Protocol, Section 12.1.4.1 (Seizure frequency). Original text: 
Seizure frequency will be assessed using seizure diaries in order to evaluate the preliminary 
efficacy of LCM in this population. Seizure frequency per 7 days will be calculated as ([number 
of seizures over the specified time interval]) divided by [number of days in the interval]) 
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multiplied by 7 and summarized descriptively and presented graphically at each visit and 
grouped by dose.  
Was revised as follows: 
Seizure frequency will be assessed using seizure diaries in order to evaluate the preliminary 
efficacy of LCM in this population. Seizure frequency per 28 days will be calculated as ([number 
of seizures over the specified time interval]) divided by [number of days in the interval]) 
multiplied by 28 and summarized descriptively and presented graphically at each visit and 
grouped by dose.  
Clinical Study Protocol, Section 12.1.5 (Handling of protocol violators, drop-outs, and missing 
values), paragraph 1. Original text: 
All data will be used to their maximum possible extent, but without any imputations for missing 
data for any parameter. Protocol deviations will be assessed during data review by a panel 
consisting of the study manager, the trial biostatistician, a representative of the monitoring team, 
and other appropriate study team members. 
Was revised as follows: 
All data will be used to their maximum possible extent, but without any imputations for missing 
data for any parameter. Protocol deviations will be assessed during data review by a panel 
consisting of the study manager, the study biostatistician, a representative of the monitoring 
team, and other appropriate study team members. 
Clinical Study Protocol, Section 12.2 (Determination of sample size). Original text: 
Up to 30 subjects from the SP847 study will enroll in this open-label extension study. 
Was revised as follows: 
Approximately 42 subjects from the SP847 study will be eligible to enroll in this open-label 
extension study. Other subjects will be eligible to enroll as future LCM pediatric clinical studies 
in epilepsy are undertaken. 
Clinical Study Protocol, Section 15 (References). The following reference was updated: 
CHMP/EWP/566/98 Guideline on clinical investigation of medicinal products in the treatment of 
epileptic disorders (EMA) Rev 2, 20 Jan 2010. 
Clinical Study Protocol, Section 16.1 (Tabular schedule of study procedures) was updated to the 
following: 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Blood sample for concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Urinalysis 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xn 
 
 
LCM return/ compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE reportingo 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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AE=adverse event; AED=antiepileptic drug; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; LCM=lacosamide; 
PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone contact). 
b 
Visit 1 is also the last visit of the primary study. At Visit 1, the informed consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be 
updated, body weight and height and concomitant medications including AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an Unscheduled Visit. 
Height will not be recorded at an Unscheduled Visit. 
f 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM  
g 
This TC occurs 28 to 35 days after the last dose of LCM. 
h 
Assessments should have been done as part of the last visit of the primary study. 
i 
An ECG is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the increased dose of LCM or the 
new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 interpretable ECGs will be performed 
approximately 20 to 30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), and prior to administration of LCM (if applicable). 
j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential (ie, females who have begun menstruating), serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and 
the Final Visit. Urine pregnancy tests will be performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical monitor, whenever possible. 
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n 
As applicable  
o 
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 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13  
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PKh 
X 
 
X 
X 
X 
X 
 
X 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
X 
 
Urinalysis 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
Xl 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xl 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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AE=adverse event; AED=antiepileptic drug; ECG=electrocardiogram; ETV=Early Termination Visit; GIC=Global Impression of Change; LCM=lacosamide; 
PK=pharmacokinetics; S=serum; TC=telephone contact; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject 
must return for an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
An ECG is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the increased dose 
of LCM or the new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 interpretable 
ECGs will be performed approximately 20 to 30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), and prior to 
administration of LCM (if applicable). 
h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential (ie, females who have begun menstruating), serum pregnancy tests will be performed at the Early Termination 
Visit and at the Final Visit. Urine pregnancy tests will be performed at Visits 10, 11, 12, and 13. 
j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
l 
As applicable. 
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Clinical Study Protocol, Section 16.3 (Declarations and signatures of persons responsible for 
the study). Original text: 
Clinical Project Manager 
, BS 
 
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
Clinical Trial Biostatistician 
 MPH  
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
Medical Director (Medical Therapeutics) 
, MD  
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
Associate Clinical Program Director 
, BS 
 
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
Was revised as follows: 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
Clinical Project Manager 
 
 
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
Clinical Trial Biostatistician 
, MPH  
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
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Medical Director (Medical Therapeutics) 
, MD  
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
Associate Clinical Program Director 
  
 
 
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
17.3 
PROTOCOL AMENDMENT 3 
RATIONALE FOR THE AMENDMENT 
The sponsor’s name has been changed to UCB BIOSCIENCES, INC. Specific sponsor contact 
information has been updated. 
As recommended by the FDA, text has been added or modified to make it clear that the 
maximum permitted LCM dose in SP848 is 12mg/kg/day or 600mg/day, whichever is lower. 
As recommended by the FDA, the C-SSRS has been added to evaluate and identify subjects at 
risk for suicide while participating in a clinical study of a drug with CNS activity (FDA, 
Guidance for Industry, 2010). 
Beginning with protocol Amendment 3, the oral solution (syrup) formulation of LCM to be used 
in this study contains 10mg/mL of drug substance (formerly containing 15mg/mL of drug 
substance). 
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 an initial LCM dose increase. This 
ECG can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
A list of anticipated SAEs has been included in this amendment in compliance with the recent 
US FDA guidance on safety reporting requirements for studies conducted under an open IND 
(effective 28 Mar 2011; FDA, Guidance for Industry and Investigators, 2010). 
Other changes made in this amendment are administrative in nature and are included in the 
specific changes below. 
MODIFICATIONS/CHANGES 
• The name of the sponsor was changed from SCHWARZ BIOSCIENCES to UCB 
BIOSCIENCES throughout the text; each occurrence of this change is not included in 
Section REFERENCE. 
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• The EudraCT number has been added to the cover page. 
• The name and contact information for the Safety Physician (Global Clinical Safety and 
Pharmacovigilance) were updated. 
• Information was added to Section 1 (Summary) and throughout the protocol to indicate 
that the maximum permitted LCM dose in SP848 is 12mg/kg/day or 600mg/day, 
whichever is lower. 
• In Section 4.3.2 (Exclusion criteria), Section 4.3.3 (Criteria for withdrawal), and 
Section 8.4.6 (Assessment of suicidality), language was added to address the 
recommendations from the FDA to evaluate and identify subjects at risk for suicide while 
participating in a clinical study of a drug with CNS activity. 
• In Section 8.2.6 (Anticipated serious adverse events), a list of anticipated SAEs was 
added to follow the recent FDA guidance on safety reporting requirements for studies 
conducted under an open IND (effective 28 Mar 2011; FDA, Guidance for Industry and 
Investigators, 2010). 
• The tabular schedules of study procedures were updated to reflect the changes to the 
protocol. 
REFERENCE 
Clinical Study Protocol, cover page. The EudraCT number was added as follows: 
EudraCT Number: 2011-001559-35 
Clinical Study Protocol, Contact information for the Safety Physician (Global Clinical Safety 
and Pharmacovigilance). Original text: 
Associate Medical Director (Global Clinical Safety and Pharmacovigilance): 
Name: 
, MD 
Address: 
SCHWARZ BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
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Was revised as follows: 
Safety Physician (Global Clinical Safety and Pharmacovigilance ): 
Name: 
, MB BCh BAO, MRCGP 
Address: 
UCB Pharma S.A. Belgium 
Chemin du Foriest 
B-1420 Braine-L’Alleud, Belgium 
Phone/Fax: 
 
E-mail: 
 
Clinical Study Protocol, List of Abbreviations. The following abbreviations were added: 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
FDA 
Food and Drug Administration 
PT 
preferred term 
SOC 
system organ class 
 
Clinical Study Protocol, Section 1 (Summary), paragraph 2. Original text: 
Subjects who complete SP847 and choose to enter this open-label extension study will begin on 
the LCM dose they achieved in SP847. Subjects who discontinued from SP847 due to a dose 
reduction or status epilepticus, but for whom it is determined medically appropriate to enter this 
open-label extension study, will also begin on the LCM dose they achieved in SP847. Subjects 
will be able to receive LCM oral solution (syrup) or LCM tablets. During the study, investigators 
will be allowed to increase or decrease the dose of LCM and/or concomitant antiepileptic drugs 
(AEDs) to optimize tolerability and seizure reduction for each subject. The investigator may 
adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) 
and a maximum of 12mg/kg/day (oral solution [syrup] or the corresponding dose levels for the 
tablet formulation) not to exceed 600mg/day based on body weight, even if the subject’s body 
weight exceeds 50kg. An increase in the LCM dose must occur only during office visits. 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. When subjects withdraw from the study, it is recommended that LCM be tapered 
gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for 
subjects who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day 
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(tablet). A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Was revised as follows: 
Subjects who complete SP847 and choose to enter this open-label extension study will begin on 
the LCM dose they achieved in SP847. Subjects who discontinued from SP847 due to a dose 
reduction or status epilepticus, but for whom it is determined medically appropriate to enter this 
open-label extension study, will also begin on the LCM dose they achieved in SP847. Subjects 
will be able to receive LCM oral solution (syrup) or LCM tablets. During the study, investigators 
will be allowed to increase or decrease the dose of LCM and/or concomitant antiepileptic drugs 
(AEDs) to optimize tolerability and seizure reduction for each subject. The investigator may 
adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) 
and a maximum of 12mg/kg/day (oral solution [syrup] or the corresponding dose levels for the 
tablet formulation) not to exceed 600mg/day based on body weight, even if the subject’s body 
weight exceeds 50kg. The maximum permitted LCM dose in SP848 is 12mg/kg/day or 
600mg/day, whichever is lower. An increase in the LCM dose must occur only during office 
visits. 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. When subjects withdraw from the study, it is recommended that LCM be 
tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day 
(tablets) for subjects who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or 
≥300mg/day (tablet). A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the medical monitor, whenever possible. 
Clinical Study Protocol, Section 2 (Background information), paragraph 9. Original text: 
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, headache, 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. 
Was revised as follows: 
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 
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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. 
Clinical Study Protocol, Section 4.1 (Study description). Original text: 
Subjects who complete SP847 (or discontinue SP847 due to a dose reduction or status 
epilepticus) and who choose to enter the open-label extension study, will begin on the LCM dose 
they achieved in SP847. Subjects will be able to continue on LCM oral solution (syrup) or switch 
to LCM tablets. During the study, investigators will be allowed to increase or decrease the dose 
of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for each subject. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the 
corresponding dose levels for the tablet formulation), not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. Increases in the LCM dose must occur 
only during office visits. 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. When subjects withdraw from the study, it is 
recommended that the study medication be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have achieved a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly 
decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if 
medically necessary. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible.  
Was revised as follows: 
Subjects who complete SP847 (or discontinue SP847 due to a dose reduction or status 
epilepticus) and who choose to enter the open-label extension study, will begin on the LCM dose 
they achieved in SP847. Subjects will be able to continue on LCM oral solution (syrup) or switch 
to LCM tablets. During the study, investigators will be allowed to increase or decrease the dose 
of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for each subject. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the 
corresponding dose levels for the tablet formulation), not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM dose must occur 
only during office visits. 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 
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responded to a maximum tolerated dose of LCM. When subjects withdraw from the study, it is 
recommended that the study medication be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have achieved a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly 
decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if 
medically necessary. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible.  
Clinical Study Protocol, Section 4.3.2 (Exclusion criteria). Exclusion criterion 3 was newly 
added as follows: 
1. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Screening. 
Clinical Study Protocol, Section 4.3.3 (Criteria for withdrawal). Original text: 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is unwilling 
or unable to allow the subject to continue in the study. 
8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
9.    Subject experiences status epilepticus 
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10.  In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x 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.  
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
4.   Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3xULN or stable condition). The investigator is 
to decide whether or not to stop the study medication. 
Was revised as follows: 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is unwilling 
or unable to allow the subject to continue in the study. 
8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
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9.    Subject experiences status epilepticus 
10.  In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x 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.  
11. For subject who did not complete a C-SSRS at Screening, subject has a lifetime history 
(prior to study entry or since study start) of suicide attempt (including an active attempt, 
interrupted attempt, or aborted attempt) of the screening version of the C-SSRS. The 
investigator must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
12. For all subjects, regardless of whether or not a C-SSRS was completed at Screening, subject 
has active suicidal ideation as indicated by a positive response (“Yes”) to either Question 4 
or Question 5 of the “since last visit” version of the C-SSRS. The subject should be referred 
immediately to a Mental Healthcare Professional and must be withdrawn from the study. 
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
4.   Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3xULN or stable condition). The investigator is 
to decide whether or not to stop the study medication. 
5.   For subject who did not complete a C-SSRS at Screening, subject had active suicidal ideation 
in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the screening version of the C-SSRS. The investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the patient from the study. 
Clinical Study Protocol, Section 4.4.1 (Treatments to be administered), paragraph 2 and 
paragraph 3. Original text: 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg  
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The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The investigator may decrease the dose 
of LCM to a minimum of 2mg/kg/day (oral solution [syrup] or the corresponding dose level for 
the tablet formulation). Increases in the LCM dose must occur only during office visits. It should 
be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the syrup), missed 
doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
Was revised as follows: 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. 
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. The investigator may decrease the 
dose of LCM to a minimum of 2mg/kg/day (oral solution [syrup] or the corresponding dose level 
for the tablet formulation). Increases in the LCM dose must occur only during office visits. It 
should be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the syrup), 
missed doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
Clinical Study Protocol, Section 4.4.2 (Description of investigational product), paragraph 1. 
Original text: 
The oral solution (syrup) formulation contains 15mg/mL of drug substance and is colorless to 
pale yellow in appearance. The oral solution (syrup) will be packaged in amber polyethylene 
terephthalate (PET) bottles with a white, child-proof, polypropylene screw cap.  
Was revised as follows: 
Beginning with protocol Amendment 3, the oral solution formulation contains 10mg/mL of drug 
substance (formerly containing 15mg/mL of drug substance) and is colorless to pale yellow in 
appearance. The oral solution (syrup) will be packaged in amber polyethylene terephthalate 
(PET) bottles with a white, child-proof, polypropylene screw cap.  
Clinical Study Protocol, Section 5.1 (Visit 1 [Week 0]), list of assessments. Original text: 
• Concomitant medications assessment  
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• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
Was revised as follows: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment but 30 minutes to 1 hour after the administration of LCM) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
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• C-SSRS 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
Clinical Study Protocol, Section 5.3 (Visit 2 [Week 4]). Original text: 
During Visit 2 (Week 4), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry and hematology 
• Blood samples for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine pregnancy test for female subjects of childbearing potential 
• LCM return/compliance. Subject’s caregivers will be instructed to return unused LCM at 
each study visit. Returned medication will be reconciled by the investigator (or designee) in 
order to monitor the subject’s compliance with the medication schedule. If a subject is found 
to be noncompliant, a decision will be made by the investigator, in conjunction with 
SCHWARZ BIOSCIENCES, as to whether the subject should be withdrawn from the study. 
• Subject diary assessment 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
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Was revised as follows: 
During Visit 2 (Week 4), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry and hematology 
• Blood samples for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine pregnancy test for female subjects of childbearing potential 
• LCM return/compliance. Subject’s caregivers will be instructed to return unused LCM at 
each study visit. Returned medication will be reconciled by the investigator (or designee) in 
order to monitor the subject’s compliance with the medication schedule. If a subject is found 
to be noncompliant, a decision will be made by the investigator, in conjunction with UCB 
BIOSCIENCES, as to whether the subject should be withdrawn from the study. 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased or a new concomitant AED is introduced. The ECG should be performed after the 
increased dose of LCM or the new AED has reached steady-state. This ECG can be done at 
the next scheduled visit. When the ECG assessment is done, 2 interpretable recordings will 
be performed approximately 20 to 30 minutes apart prior to vital sign assessment and 
collection of blood samples (if applicable), but 30 minutes to 1 hour after the administration 
of LCM (if applicable). 
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• All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM 
Cmax 1 week after an initial LCM dose increase. This ECG can be conducted at an 
Unscheduled Visit, if necessary. These subjects 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). 
Clinical Study Protocol, Section 5.4 (Visit 3 [Week 8]). Original text: 
During Visit 3 (Week 8), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Urine pregnancy test for female subjects of childbearing potential 
• LCM return/compliance 
• Subject diary assessment 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parents/legal guardians) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening. 
• A 12-lead ECG is also required when the dose of LCM is increased or a new concomitant 
AED is introduced. The ECG should be performed after the increased dose of LCM or the 
new AED has reached steady-state. This ECG can be done at the next scheduled visit. When 
the ECG assessment is done, 2 interpretable ECGs will be performed approximately 20 to 30 
minutes apart prior to vital sign assessment, collection of blood samples (if applicable), and 
prior to administration of LCM (if applicable). 
Was revised as follows: 
During Visit 3 (Week 8), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
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• Brief physical examination 
• Brief neurological examination 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Urine pregnancy test for female subjects of childbearing potential 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parents/legal guardians) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased or a new concomitant AED is introduced. The ECG should be performed after the 
increased dose of LCM or the new AED has reached steady-state. This ECG can be done at 
the next scheduled visit. When the ECG assessment is done, 2 interpretable recordings will 
be performed approximately 20 to 30 minutes apart prior to vital sign assessment and 
collection of blood samples (if applicable), but 30 minutes to 1 hour after the administration 
of LCM (if applicable). 
• All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM 
Cmax 1 week after an initial LCM dose increase. This ECG can be conducted at an 
Unscheduled Visit if necessary. These subjects 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). 
Clinical Study Protocol, Section 5.6 (Visit 5 [Week 20]). Original text: 
During Visit 5 (Week 20), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
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• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine sample for urinalysis 
• Urine pregnancy test for female subjects of childbearing potential 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• LCM return/compliance 
• Subject diary assessment 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parents/legal guardians) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
A 12-lead ECG is also required when the dose of LCM is increased or a new concomitant AED 
is introduced. The ECG should be performed after the increased dose of LCM or the new AED 
has reached steady-state. This ECG can be done at the next scheduled visit. When the ECG 
assessment is done, 2 interpretable ECGs will be performed approximately 20 to 30 minutes 
apart prior to vital sign assessment, collection of blood samples (if applicable), and prior to 
administration of LCM (if applicable). 
Was revised as follows: 
During Visit 5 (Week 20), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
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• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine sample for urinalysis 
• Urine pregnancy test for female subjects of childbearing potential 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs until the next clinic visit) 
• Dispense LCM. Subjects and caregivers (including parents/legal guardians) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is increased 
or a new concomitant AED is introduced. The ECG should be performed after the increased dose 
of LCM or the new AED has reached steady-state. This ECG can be done at the next scheduled 
visit. When the ECG assessment is done, 2 interpretable recordings will be performed 
approximately 20 to 30 minutes apart prior to vital sign assessment and collection of blood 
samples (if applicable), but 30 minutes to 1 hour after the administration of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
Clinical Study Protocol, Section 5.14 (Visit 13 [Week 96]). Original text: 
Assessments for Visit 13 (Week 96) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: the laboratory blood sample is collected only for 
clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG (2 interpretable 
recordings approximately 20 to 30 minutes apart prior to vital signs assessment and collection of 
blood sample) is conducted, and a Tanner Stage assessment is conducted (if applicable). 
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Was revised as follows: 
Assessments for Visit 13 (Week 96) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: the laboratory blood sample is collected only for 
clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG (2 interpretable 
recordings approximately 20 to 30 minutes apart prior to vital signs assessment and collection of 
blood sample) is conducted, and a Tanner Stage assessment is conducted (if applicable). 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of 
LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Clinical Study Protocol, Section 5.15 (Early Termination Visit). The following assessment was 
added: 
• C-SSRS 
Clinical Study Protocol, Section 5.16 (Unscheduled Visit[s]). Original text: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if an LCM dose increase is required 
between scheduled clinic visits, the subject must return for an Unscheduled Visit. If an AE 
prompts a dose reduction, the reduction can be implemented immediately at the investigator’s 
discretion. However, the subject should return to the clinic as soon as possible for an 
Unscheduled Visit. 
The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
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• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
Was revised as follows: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if an LCM dose increase is required 
between scheduled clinic visits, the subject must return for an Unscheduled Visit. If an AE 
prompts a dose reduction, the reduction can be implemented immediately at the investigator’s 
discretion. However, the subject should return to the clinic as soon as possible for an 
Unscheduled Visit. 
The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
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Clinical Study Protocol, Section 5.17 (Final Visit [2 weeks after the last LCM dose]). The 
following assessment was added: 
• C-SSRS 
Clinical Study Protocol, Section 8.2.6 (Anticipated serious adverse events), was newly added as 
follows: 
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 8.2.4. 
Anticipated SAEs for the pediatric epilepsy population 
MedDRA SOC 
MedDRA PT 
Congenital, familial and genetic disorders 
Teratogenicity 
General disorders and administrative site 
conditions 
Sudden unexplained death in epilepsy 
Nervous system disorders 
Convulsion 
Incontinence 
Status epilepticus 
Pregnancy, puerperium and perinatal disorders Abortion spontaneous 
Psychiatric disorders 
Psychotic behavior 
Abnormal behavior 
Anxiety 
Sleep disorder 
Reproductive system and breast disorders 
Menstrual disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SAE=serious adverse event; SOC=system organ 
class 
Clinical Study Protocol, Section 8.3.2 (Pregnancy testing). Original text: 
Females of childbearing potential (ie, female subjects who have begun menstruating) will have 
serum and urine pregnancy tests performed during the study according to the tabular schedule of 
study procedures, Section 16.1. 
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Was revised as follows: 
Females of childbearing potential will have serum and urine pregnancy tests performed during 
the study according to the tabular schedule of study procedures, Section 16.1. 
Clinical Study Protocol, Section 8.4.4 (12-lead ECG). Original text: 
Standard 12-lead ECGs will be performed according to the tabular schedule of study procedures, 
Section 16.1, and as described in Section 5. 
Care should be taken to assure proper lead placement and quality of ECG recording. Subjects 
should rest in a supine position at least 5 minutes prior to each recording and should be 
motionless during the recording. 
Was revised as follows: 
Standard 12-lead ECGs will be performed according to the tabular schedule of study procedures, 
Section 16.1, and as described in Section 5. 
Beginning with Protocol Amendment 3, 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 an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
Care should be taken to assure proper lead placement and quality of ECG recording. Subjects 
should rest in a supine position at least 5 minutes prior to each recording and should be 
motionless during the recording. 
Clinical Study Protocol, Section 8.4.6 (Assessment of suicidality) was newly added as follows: 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). 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. The C-SSRS will be 
completed according to the tabular schedule of study procedures, Section 16.1. 
Clinical Study Protocol, Section 15 (References). The following references were added: 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed 19 Jun 2011. 
Food and Drug Administration. Guidance for Industry. Suicidality: Prospective assessment of 
occurrence in clinical trials. US Dept of Health and Human Services, Center for Drug Evaluation 
and Research, 09/2010. Available upon request. 
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Food and Drug Administration. Guidance for Industry and Investigators. Safety reporting 
requirements for INDs and BE/BA studies. US Dept of Health and Human Services, Center for 
Drug Evaluation and Research, 09/2010. Available upon request. 
Clinical Study Protocol, Section 16.1 (Tabular schedule of study procedures) was updated to the 
following: 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Blood sample for concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Urinalysis 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xn 
 
 
LCM return/compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSo 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
AE reportingp 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone contact). 
b 
Visit 1 is also the last visit of the primary study. At Visit 1, the informed consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be 
updated, body weight and height and concomitant medications including AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an Unscheduled Visit. 
Height will not be recorded at an Unscheduled Visit. 
f 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM  
g 
This TC occurs 28 to 35 days after the last dose of LCM. 
h 
Assessments should have been done as part of the last visit of the primary study. 
i 
An ECG (2 interpretable recordings) is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be performed after the 
increased dose of LCM or the new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG assessment is performed, 2 interpretable 
recordings will be performed approximately 20 to 30 minutes apart prior to vital signs assessment, collection of blood samples (if applicable), but 30 minutes to 1 hour after 
the administration of LCM (if applicable). 
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Beginning with Protocol Amendment 3, all subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM 
dose increase. This ECG can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential, serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and the Final Visit. Urine pregnancy tests will be 
performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical monitor, whenever possible. 
n 
As applicable  
o 
For all subjects ≥6 years of age already enrolled, the screening version should be completed at the next clinic visit, and the “since last visit” version should be completed 
thereafter. 
p 
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 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13  
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PKh 
X 
 
X 
X 
X 
X 
 
X 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
X 
 
Urinalysis 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
Xl 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xl 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
C-SSRSm 
X 
 
X 
X 
X 
X 
X 
X 
 
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Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13  
ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; S=serum; TC=telephone contact; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject 
must return for an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
A Final Visit should be performed 2 weeks after a subject has tapered off LCM. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
An ECG (2 interpretable recordings) is also required when the dose of LCM is increased or a new concomitant AED is introduced. The ECG should be 
performed after the increased dose of LCM or the new AED has reached steady state. This ECG can be done at the next scheduled visit. When the ECG 
assessment is performed, 2 interpretable recordings will be performed approximately 20 to 30 minutes apart prior to vital signs assessment, collection of 
blood samples (if applicable), but 30 minutes to 1 hour after the administration of LCM (if applicable). 
 
Beginning with Protocol Amendment 3, all subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after 
an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, if necessary. These subjects 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 
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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). 
h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Early Termination Visit and at the Final Visit. Urine pregnancy 
tests will be performed at Visits 10, 11, 12, and 13. 
j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
l 
As applicable. 
m For all subjects ≥6 years of age already enrolled, the screening version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
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17.4 
PROTOCOL AMENDMENT 4 
RATIONALE FOR THE AMENDMENT 
The primary purpose of this protocol amendment is to permit (at selected sites) up to 
approximately 100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset 
seizures (deemed appropriate for treatment with adjunctive LCM) who have not previously 
participated in a LCM clinical study to enroll directly into SP848. The purpose of enrolling these 
subjects directly into SP848 is to obtain sufficient long-term safety exposures in the age range of 
≥4 years to ≤17 years of age; the additional long-term safety data will be included in planned 
regulatory submissions for LCM as adjunctive therapy for partial-onset seizures in pediatric 
subjects ≥4 years to ≤17 years of age with epilepsy. 
In addition, based on regulatory agency recommendations, the Achenbach CBCL, Bayley-III 
scales, and a LCM palatability and ease of use questionnaire have been added as assessments in 
SP848. 
Other changes made in this amendment are administrative in nature and are included in the 
specific changes below. 
MODIFICATIONS/CHANGES 
• With this protocol amendment, approximately 100 eligible pediatric subjects ≥4 years to 
≤17 years of age with partial-onset seizures (deemed appropriate for treatment with 
adjunctive LCM) who have not previously participated in a LCM clinical study will be 
permitted to enroll directly into SP848. Therefore, the study title has been updated to reflect 
that SP848 is no longer exclusively an “extension study.” 
• Study contact information has been updated (eg, Clinical Program Director, Safety Physician, 
and SAE reporting). 
• Information was added to Section 1 (Summary) and throughout the protocol to indicate that 
approximately 100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset 
seizures (deemed appropriate for treatment with adjunctive LCM) who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. A 
Screening and Titration Visits have been added for subjects enrolling directly into SP848. 
• Information was added to Section 1 (Summary) and throughout the protocol to reflect the 
addition of the Achenbach CBCL, Bayley-III scales, and a LCM palatability and ease of use 
questionnaire as assessments in SP848. 
• Modifications were made to Section 4.3.1 (Inclusion criteria) and Section 4.3.2 (Exclusion 
criteria) in order to address subjects who have participated in SP847 or other LCM pediatric 
clinical studies in epilepsy or who have enrolled directly into SP848 without previous 
participation in a LCM clinical study. 
• Information was added to Section 8.4.4 (12-lead ECG) and throughout the protocol to clarify 
that 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 an initial LCM 
dose increase to a LCM dose that is ≥8mg/kg/day or when a new concomitant AED is 
introduced. 
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REFERENCE 
Clinical Study Protocol, cover page, study title. Original text: 
AN OPEN-LABEL EXTENSION STUDY TO DETERMINE SAFETY, 
TOLERABILITY, AND EFFICACY OF LONG-TERM ORAL 
LACOSAMIDE (LCM) AS ADJUNCTIVE THERAPY IN CHILDREN 
WITH PARTIAL-ONSET SEIZURES 
Was revised as follows: 
AN OPEN-LABEL STUDY TO DETERMINE SAFETY, TOLERABILITY, 
AND EFFICACY OF LONG-TERM ORAL LACOSAMIDE (LCM) AS 
ADJUNCTIVE THERAPY IN CHILDREN WITH EPILEPSY 
Clinical Study Protocol, cover page, sponsor information. The following text was deleted: 
A member of the UCB Group 
Clinical Study Protocol, Contact information for the Clinical Program Director and Safety 
Physician. Original text: 
Associate Clinical Program Director: 
Name: 
, BS 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
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Safety Physician (Global Clinical Safety and Pharmacovigilance): 
Name: 
, MB BCh BAO, MRCGP 
Address: 
UCB Pharma S.A. Belgium 
Chemin du Foriest 
B-1420 Braine-L’Alleud, Belgium 
Phone/Fax: 
 
E-mail: 
 
 
Was revised as follows: 
Clinical Program Director: 
Name: 
, BS 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
Safety Physician (Drug Safety): 
Name: 
 MD 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
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Clinical Study Protocol, Serious Adverse Event reporting contact information was added as 
follows: 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h), safety related issues,  
and emergency unblinding 
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 5283 1869 
Email 
Europe and Rest of the World (except Japan): GCSP@ucb.com 
Japan: JDSO@ucb.com 
 
Clinical Study Protocol, List of Abbreviations. The following abbreviations were added: 
Cmax 
maximum plasma concentration 
DS 
Drug Safety (formerly known as Global Clinical 
Safety and Pharmacovigilance) 
EEG 
electroencephalogram 
GCSP 
Global Clinical Safety and Pharmacovigilance 
MAO 
monoamine oxidase 
TV 
Titration Visit 
 
Clinical Study Protocol, Section 1 (Summary). Original text: 
SP848 is an open-label extension study to obtain long-term safety, tolerability, and 
pharmacokinetic (PK) data in children with partial-onset seizures treated with lacosamide (LCM) 
oral solution (syrup) or LCM tablets as adjunctive therapy. In addition, the study is designed to 
obtain preliminary efficacy data on seizure frequency during long-term exposure. The study will 
also provide continued availability of LCM to subjects who have completed the SP847 epilepsy 
study and to subjects who have discontinued from SP847 due to a dose reduction or status 
epilepticus, and who, in the investigator’s opinion, would benefit from long-term administration 
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of LCM. SP848 will also be open to subjects who participate in other future LCM pediatric 
clinical studies in epilepsy. 
Subjects who complete SP847 and choose to enter this open-label extension study will begin on 
the LCM dose they achieved in SP847. Subjects who discontinued from SP847 due to a dose 
reduction or status epilepticus, but for whom it is determined medically appropriate to enter this 
open-label extension study, will also begin on the LCM dose they achieved in SP847. Subjects 
will be able to receive LCM oral solution (syrup) or LCM tablets. During the study, investigators 
will be allowed to increase or decrease the dose of LCM and/or concomitant antiepileptic drugs 
(AEDs) to optimize tolerability and seizure reduction for each subject. The investigator may 
adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) 
and a maximum of 12mg/kg/day (oral solution [syrup] or the corresponding dose levels for the 
tablet formulation) not to exceed 600mg/day based on body weight, even if the subject’s body 
weight exceeds 50kg. The maximum permitted LCM dose in SP848 is 12mg/kg/day or 
600mg/day, whichever is lower. An increase in the LCM dose must occur only during office 
visits. 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. When subjects withdraw from the study, it is recommended that LCM be 
tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day 
(tablets) for subjects who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or 
≥300mg/day (tablet). A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the medical monitor, whenever possible. 
The primary variables for assessment of safety and tolerability are: 
• Adverse events (AEs) reported spontaneously by the subject and/or caregiver or observed by 
the investigator 
• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
The secondary 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, and the Caregiver Global Impression of Change. 
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Was revised as follows: 
SP848 is an open-label study to obtain long-term safety, tolerability, and pharmacokinetic (PK) 
data in children with epilepsy (partial-onset seizures and other pediatric epilepsy syndromes) 
treated with lacosamide (LCM) oral solution (syrup) or LCM tablets as adjunctive therapy. In 
addition, the study is designed to obtain preliminary efficacy data on seizure frequency during 
long-term exposure. The study will also provide continued availability of LCM to subjects who 
have completed the SP847 epilepsy study and to subjects who have discontinued from SP847 
due to a dose reduction or status epilepticus, and who, in the investigator’s opinion, would 
benefit from long-term administration of LCM. 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies in other epilepsy syndromes. In addition, at selected sites, 
beginning with Protocol Amendment 4, up to approximately 100 eligible pediatric subjects 
≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate for treatment with 
adjunctive LCM) who have not previously participated in a LCM clinical study will be permitted 
to enroll directly into SP848. The purpose of enrolling these subjects directly into SP848 is to 
obtain sufficient long-term safety exposures in the age range of ≥4 years to ≤17 years of age; the 
long-term safety data will be included in planned regulatory submissions for LCM as adjunctive 
therapy for partial-onset seizures in pediatric subjects ≥4 years to ≤17 years of age with epilepsy. 
At selected sites, subjects may also be able to participate in a substudy without withdrawing from 
SP848. 
Subjects who complete SP847 or another applicable LCM pediatric epilepsy study and choose to 
enter this open-label study will begin on the LCM dose they achieved in SP847 or their previous 
pediatric LCM study. Subjects who discontinued from SP847 due to a dose reduction or status 
epilepticus, but for whom it is determined medically appropriate to enter this open-label study, 
will also begin on the LCM dose they achieved in SP847. Subjects who meet eligibility 
requirements and enroll directly into SP848 without previous participation in a LCM clinical 
study will initiate treatment with LCM, and the LCM dose will be titrated to a level to optimize 
tolerability and seizure control (up to a maximum level as described below). 
Subjects will be able to receive LCM oral solution (syrup) or LCM tablets. During the study, 
investigators will be allowed to increase or decrease the dose of LCM and/or concomitant 
antiepileptic drugs (AEDs) to optimize tolerability and seizure reduction for each subject. The 
investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the corresponding 
dose levels for the tablet formulation) not to exceed 600mg/day based on body weight, even if 
the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in SP848 is 
12mg/kg/day or 600mg/day, whichever is lower. An increase in the LCM dose must occur only 
during office visits. 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. When subjects withdraw from the study, it is recommended that LCM be 
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CONFIDENTIAL 
20 Oct 2020
 
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tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day 
(tablets) for subjects who have achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or 
≥300mg/day (tablet). A slower taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster 
taper is permitted after discussion with the medical monitor, whenever possible. 
The primary variables for assessment of safety and tolerability are: 
• Adverse events (AEs) reported spontaneously by the subject and/or caregiver or observed by 
the investigator 
• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
• Achenbach CBCL for children 18 months and older (CBCL/1½-5 and CBCL/6-18) assessing 
behavior 
• Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
subjects enrolled in English-speaking countries) 
The secondary 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 a LCM 
palatability and ease of use questionnaire. 
Clinical Study Protocol, Section 2 (Background information). Original text: 
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). 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). In 
the past decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
The classification of epilepsies in children was described in 1989 by the Commission on 
Classification and Terminology of the International League Against Epilepsy (1989; Aicardi, 
1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
according to a number of criteria including seizure type, cause, anatomy, precipitating factors, 
age of onset, and sometimes prognosis. 
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The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and PK characteristics (Herman and Pedley, 1998). However, more 
than 30% of patients have inadequate seizure control on currently-available AEDs or experience 
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 5 (gabapentin, lamotrigine, oxcarbazepine, topiramate, and 
levetiracetam) have successfully demonstrated efficacy as adjunctive therapy in children with 
difficult to treat partial-onset seizures (Appleton et al, 1999; Duchowny et al, 1999; 
Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006). 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 (LCM, Vimpat®, SPM 927, [R]-2-acetamido-N-benzyl-3-methoxypropionamide) 
belongs to a novel class of functionalized amino acids. It has minimal protein binding and effect 
on cytochrome P450 enzyme system function (reducing the risk of drug-drug interactions), high 
oral bioavailability, and a half-life of approximately 13 hours (in adults), which allows a twice 
daily (bid) dose regimen. It also displays dose-proportional PK following administration over a 
range of doses up to 800mg in adults. 
Lacosamide has been approved 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 (oral tablets, oral solution [syrup], and solution for intravenous [iv] infusion) and in 
patients 17 years of age and older in the United States (oral tablets, oral solution, and solution for 
iv infusion). The oral solution (syrup) is a formulation suitable for administration to children. 
Bioequivalence has been shown between the tablet and oral solution (syrup) formulations, 
comparing 2 tablets of LCM 100mg and the oral solution (syrup) containing LCM 200mg, after 
single-dose administration in healthy subjects. The PK of LCM and its major metabolite, 
SPM 12809 (O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after 
single oral doses of LCM 200mg administered as tablets or as oral solution (syrup). 
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
400mg bid (800mg/day) were evaluated in approximately 700 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 2200 adult subjects in other indications (eg, 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 (199 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 
randomized dose (200mg/day, 400mg/day, or 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 
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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. 
SP847, the current primary study, is an open-label, dose-titration, safety, tolerability, and PK 
study to evaluate LCM as adjunctive therapy in children with uncontrolled partial-onset seizures. 
Approximately 42 children (aged 1 month to 17 years) with uncontrolled partial-onset seizures 
on a stable dose regimen of at least 1 but no more than 3 AEDs will be enrolled. The study 
consists of a Screening Phase, a Treatment Phase, and an End-of-Study Phase. The duration of 
treatment for an individual subject may be up to approximately 13 weeks. Approximately 
300 additional subjects who may participate in other future LCM primary pediatric clinical 
studies in epilepsy will also be eligible to participate in SP848. 
SP848 is an open-label extension study to obtain long-term safety, tolerability, and PK data in 
children with partial-onset seizures treated with LCM oral solution (syrup) or LCM tablets as 
adjunctive therapy. In addition, the study is designed to obtain preliminary efficacy data on 
seizure frequency during long-term exposure. The study will also provide continued availability 
of LCM to subjects who have completed the SP847 epilepsy study (or discontinued SP847 due to 
a dose reduction or status epilepticus), and who, in the investigator’s opinion, would benefit from 
long-term administration of LCM. SP848 will also be open to subjects who participate in other 
future LCM pediatric clinical studies in epilepsy. 
Was revised as follows: 
Epilepsy is the second most prevalent neurological disorder in the world. More than 40 million 
people have epilepsy–about 1% of the world’s population (Dichek, 1999). 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). In the 
past decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
The classification of epilepsies in children was described in 1989 by the Commission on 
Classification and Terminology of the International League Against Epilepsy (1989; Aicardi, 
1994). Seizures are categorized based on whether the onset is focal or generalized and whether 
the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are further classified 
according to a number of criteria including seizure type, cause, anatomy, precipitating factors, 
age of onset, and sometimes prognosis. 
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and PK characteristics (Herman and Pedley, 1998). However, more 
than 30% of patients have inadequate seizure control on currently-available AEDs or experience 
significant adverse drug effects (CHMP/EWP/566/98, 2010). Therefore, a need remains for 
AEDs with improved effectiveness and tolerability (Sander, 1998). 
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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 (Appleton et al, 1999; Duchowny et al, 1999; 
Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006). 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 (LCM, Vimpat®, SPM 927, [R]-2-acetamido-N-benzyl-3-methoxypropionamide) 
belongs to a novel class of functionalized amino acids. It has minimal protein binding and effect 
on cytochrome P450 enzyme system function (reducing the risk of drug-drug interactions), high 
oral bioavailability, and a half-life of approximately 13 hours (in adults), which allows a twice 
daily (bid) dose regimen. It also displays dose-proportional PK following administration over a 
range of doses up to 800mg in adults. 
Lacosamide has been approved 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 (oral tablets, oral solution [syrup], and solution for intravenous [iv] infusion) and in 
patients 17 years of age and older in the United States (oral tablets, oral solution, and solution for 
iv infusion). The oral solution (syrup) is a formulation suitable for administration to children. 
Bioequivalence has been shown between the tablet and oral solution (syrup) formulations, 
comparing 2 tablets of LCM 100mg and the oral solution (syrup) containing LCM 200mg, after 
single-dose administration in healthy subjects. The PK of LCM and its major metabolite, 
SPM 12809 (O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after 
single oral doses of LCM 200mg administered as tablets or as oral solution (syrup). 
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
400mg bid (800mg/day) were evaluated in approximately 700 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 2200 adult subjects in other indications (eg, 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 (199 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 
randomized dose (200mg/day, 400mg/day, or 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. 
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SP847 is an open-label, dose-titration, safety, tolerability, and PK study to evaluate LCM as 
adjunctive therapy in children with uncontrolled partial-onset seizures. Approximately 
42 children (aged 1 month to 17 years) with uncontrolled partial-onset seizures on a stable dose 
regimen of at least 1 but no more than 3 AEDs will be enrolled. The study consists of a 
Screening Phase, a Treatment Phase, and an End-of-Study Phase. The duration of treatment for 
an individual subject may be up to approximately 13 weeks. Approximately 200 additional 
subjects who may participate in other LCM pediatric clinical studies in epilepsy will also be 
eligible to participate in SP848. 
SP848 is an open-label study to obtain long-term safety, tolerability, and pharmacokinetic (PK) 
data in children with epilepsy (partial-onset seizures and other pediatric epilepsy syndromes) 
treated with lacosamide (LCM) oral solution (syrup) or LCM tablets as adjunctive therapy. In 
addition, the study is designed to obtain preliminary efficacy data on seizure frequency during 
long-term exposure. The study will also provide continued availability of LCM to subjects who 
have completed the SP847 epilepsy study and to subjects who have discontinued from SP847 
due to a dose reduction or status epilepticus, and who, in the investigator’s opinion, would 
benefit from long-term administration of LCM. 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies in other epilepsy syndromes. In addition, at selected sites, 
beginning with Protocol Amendment 4, up to approximately 100 eligible pediatric subjects 
≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate for treatment with 
adjunctive LCM) who have not previously participated in a LCM clinical study will be permitted 
to enroll directly into SP848. The purpose of enrolling these subjects directly into SP848 is to 
obtain additional long-term safety exposures in the age range of ≥4 years to ≤17 years of age; the 
additional long-term safety data will be included in planned regulatory submissions for LCM as 
adjunctive therapy for partial-onset seizures. 
Clinical Study Protocol, Section 3 (Study objectives). Original text: 
The objectives of this study are: 
• To obtain information about the safety, tolerability, and PK of LCM during long-term 
exposure 
• To obtain preliminary efficacy data on seizure frequency during long-term exposure 
• To allow subjects who have participated in SP847 (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
• To allow subjects who have participated in other future LCM pediatric clinical studies in 
epilepsy to continue receiving LCM 
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Was revised as follows: 
The objectives of this study are: 
• To obtain information about the safety, tolerability, and PK of LCM during long-term 
exposure 
• To obtain preliminary efficacy data on seizure frequency during long-term exposure 
• To allow subjects who have participated in SP847 (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
• To allow subjects who have participated in other LCM pediatric clinical studies in epilepsy to 
continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously received 
LCM to begin receiving LCM 
Clinical Study Protocol, Section 4.1 (Study description). Original text: 
Subjects who complete SP847 (or discontinue SP847 due to a dose reduction or status 
epilepticus) and who choose to enter the open-label extension study, will begin on the LCM dose 
they achieved in SP847. Subjects will be able to continue on LCM oral solution (syrup) or switch 
to LCM tablets. During the study, investigators will be allowed to increase or decrease the dose 
of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for each subject. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the 
corresponding dose levels for the tablet formulation), not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM dose must occur 
only during office visits. 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. When subjects withdraw from the study, it is 
recommended that the study medication be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have achieved a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly 
decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if 
medically necessary. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible.  
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Was revised as follows (including additions of subsection headings 4.1.1 [Subjects enrolling 
from SP847 or other LCM pediatric clinical studies in epilepsy] and 4.1.2 [Subjects enrolling 
directly in SP848]): 
Subjects who complete SP847 (including discontinuation from SP847 due to a dose reduction or 
status epilepticus) or subjects from another applicable LCM pediatric clinical study in epilepsy 
and who choose to enter the open-label study, will begin on the LCM dose they achieved in the 
primary study. Subjects will be able to continue on LCM oral solution (syrup) or switch to LCM 
tablets. During the study, investigators will be allowed to increase or decrease the dose of LCM 
and/or concomitant AEDs to optimize tolerability and seizure reduction for each subject. The 
investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the corresponding 
dose levels for the tablet formulation), not to exceed 600mg/day based on body weight, even if 
the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in SP848 is 
12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM dose must occur only 
during office visits. 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. When subjects withdraw from the study, it is recommended that the 
study medication be tapered gradually in weekly decrements of 4mg/kg/day (oral solution 
[syrup]) or 200mg/day (tablets) for subjects who have achieved a dose of LCM ≥6mg/kg/day 
(oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly decrements of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if medically necessary. In 
case of an emergency, a faster taper is permitted after discussion with the medical monitor, 
whenever possible.  
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously participated in a LCM clinical 
study will be permitted to enroll directly into SP848. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control (see Section 4.4.1). Subjects 
will be able to receive LCM oral solution or LCM tablets for up to 2 years as determined 
appropriate by the investigator. 
The same study conditions described in Section 4.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and study medication taper) also 
apply. 
Clinical Study Protocol, Section 4.2.1 (Primary variables). The following variables were added: 
• Achenbach CBCL at Baseline for children 18 months and older (CBCL/1½-5 and 
CBCL/6-18) assessing behavior 
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• Bayley-III scales at Baseline for children <18 months of age at time of enrollment 
(applicable only to subjects enrolled in English-speaking countries) 
Clinical Study Protocol, Section 4.2.2 (Secondary variables). Original text: 
Secondary efficacy variables include: 
• Seizure counts, which will be assessed using seizure diaries in order to evaluate preliminary 
evidence of efficacy during long-term exposure in this population 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
Was revised as follows: 
Secondary variables include: 
• Seizure counts, which will be assessed using seizure diaries in order to evaluate preliminary 
evidence of efficacy during long-term exposure in this population 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• LCM palatability and ease of use questionnaire 
Clinical Study Protocol, Section 4.3.1 (Inclusion criteria). Original text: 
Subjects must fulfill the following inclusion criteria: 
1. A signed informed consent form has been obtained from the parent/legal guardian and assent 
has been obtained from the subject (when possible or as required according to local 
Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]). 
2. Subject has completed SP847 (or the subject discontinued SP847 due to a dose reduction or 
status epilepticus) for the treatment of uncontrolled partial-onset seizures, or subject has 
participated in other LCM pediatric clinical studies in epilepsy.  
3. Subject is expected to benefit from participation, in the opinion of the investigator. 
4. Subject and caregiver (which may be a parent, legal guardian, or other delegated caregiver) 
are willing and able to comply with all study requirements, including maintaining a daily 
seizure diary. 
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Was revised as follows: 
All subjects in SP848 must fulfill the following inclusion criteria: 
1. A signed informed consent form has been obtained from the parent/legal guardian and assent 
has been obtained from the subject (when possible or as required according to local 
Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]). 
4. Subject and caregiver (which may be a parent, legal guardian, or other delegated caregiver) 
are willing and able to comply with all study requirements, including maintaining a daily 
seizure diary. 
Subjects who have participated in SP847 or other LCM pediatric clinical studies in epilepsy must 
fulfill the following inclusion criteria: 
2. Subject has completed SP847 (or the subject discontinued SP847 due to a dose reduction or 
status epilepticus) for the treatment of uncontrolled partial-onset seizures, or subject has 
participated in other LCM pediatric clinical studies in epilepsy.  
3. Subject is expected to benefit from participation, in the opinion of the investigator. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
must fulfill the following inclusion criteria: 
5. Subject is male or female and ≥4 years to ≤17 years of age. 
6. Subject has a diagnosis of epilepsy with partial-onset seizures.  
a. The results of at least 1 prior electroencephalogram (EEG) AND 1 prior magnetic 
resonance imaging/computerized tomography scan should be consistent with the above 
diagnosis. 
7. Subject has been observed to have uncontrolled partial-onset seizures after an adequate 
course of treatment (in the opinion of the investigator) with at least 1 AED (concurrently or 
sequentially). 
8. Subject has been observed to have at least 2 countable seizures in the 4-week period prior to 
Screening. 
a. In the case of simple partial seizures, only those with motor signs will be counted 
towards meeting the inclusion criteria (only partial seizures with a recognizable and 
countable manifestation). 
9. Subject is on a stable dosage regimen of 1 to 3 AEDs. The daily dosage regimen of 
concomitant AED therapy must be kept constant for a period of at least 1 week prior to 
Screening. Vagal nerve stimulation is not counted as medical therapy; however, VNS settings 
must be kept constant for a period of at least 1 week prior to Screening. 
10. Subject is an acceptable candidate for venipuncture. 
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Clinical Study Protocol, Section 4.3.2 (Exclusion criteria). Original text: 
Subjects are not permitted to enroll in the study if any of the following criteria are met: 
1. Subject is receiving any investigational drugs or using any experimental devices in addition 
to LCM. 
2. Subject meets the withdrawal criteria for the primary study (with the exception of subjects 
who discontinued due to a dose reduction or status epilepticus), or is experiencing an 
ongoing serious AE (SAE). 
3. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Screening. 
Was revised as follows: 
Subjects are not permitted to enroll in the study if any of the following criteria are met: 
1. Subject is receiving any investigational drugs or using any experimental devices in addition 
to LCM. 
3. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Screening. 
Subjects who have participated in SP847 or other LCM pediatric clinical studies in epilepsy are 
not permitted to enroll in the study if any of the following criteria are met: 
2. Subject meets the withdrawal criteria for the primary study (with the exception of subjects 
who discontinued due to a dose reduction or status epilepticus), or is experiencing an 
ongoing serious AE (SAE). 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
are not permitted to enroll in the study if any of the following criteria are met: 
4. Subject has ever received LCM. 
5. Subject has any medical or psychiatric condition that, in the opinion of the investigator, could 
jeopardize or would compromise the subject’s ability to participate in this study. 
6. Subject has a medical condition that could reasonably be expected to interfere with drug 
absorption, distribution, metabolism, or excretion. 
7. Subject has a known hypersensitivity to any component of the investigational medicinal 
product. 
8. Subject is a female of childbearing potential and does not practice an acceptable method of 
contraception for the duration of the study. 
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• Medically acceptable contraceptive method includes oral or depot contraceptive 
treatment with at least 30μg ethinylestradiol per intake (or 50μg if associated with 
carbamazepine [or other strong enzyme inducers, eg, phenobarbital, primidone, 
oxcarbazepine]) which must be used in conjunction with a barrier method. Sexual 
abstinence is also an acceptable method of contraception. 
• The subject must understand the consequences and potential risks of inadequately 
protected sexual activity, be educated about and understand the proper use of 
contraceptive methods, and undertake to inform the investigator of any potential change 
in status. Females of childbearing potential must have a negative pregnancy test at the 
Screening Visit. 
9. Subject has an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin level greater than or equal to 2 times the upper limit of normal (ULN), or creatinine 
clearance less than 50mL/min. 
10. Subject has a clinically relevant ECG abnormality, in the opinion of the principal investigator 
(ie, second or third degree heart block at rest or a QT prolongation greater than 450ms). 
11. Subject has hemodynamically significant heart disease (eg, heart failure). 
12. Subject has an arrhythmic heart condition requiring medical therapy. 
13. Subject has a known history of severe anaphylactic reaction or serious blood dyscrasias. 
14. Subject has nonepileptic events, including psychogenic seizures, that could be confused with 
seizures. If both epileptic and nonepileptic events are present, epileptic events must be 
distinguished from nonepileptic phenomena. 
15. Subject has a history of primary generalized epilepsy. 
16. Subject has been treated with vigabatrin or felbamate for at least 12 months prior to entering 
the study and has experienced any toxicity issues with these treatments. Note: Any subject 
who is currently treated with vigabatrin or felbamate, and has received vigabatrin for a period 
of less than 12 months, is excluded from the study. Subjects who have received vigabatrin in 
the past must have documentation of an assessment for visual field defects after completion 
of vigabatrin therapy. 
17. Subject is taking monoamine oxidase (MAO) inhibitors or narcotic analgesics. 
18. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively 
neurodegenerative disease, such as Rasmussen syndrome. 
19. Subject has a known sodium channelopathy, such as Brugada syndrome. 
Clinical Study Protocol, Section 4.3.3 (Criteria for withdrawal), criterion 9. Original text: 
9.    Subject experiences status epilepticus 
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Was revised as follows: 
9.    Subject experiences convulsive status epilepticus (if none had occurred prior to study entry) 
and is compliant with study treatment 
Clinical Study Protocol, Section 4.4.1 (Treatments to be administered). Original text: 
Subjects who have participated in SP847 (or other future LCM pediatric clinical studies in 
epilepsy), who are eligible to participate in the open-label extension study SP848, and who 
choose to enter SP848, will begin SP848 on the LCM dose they achieved in the primary study. 
The investigator, together with the subject/caregiver (including parent/legal guardian), will be 
able to choose either the oral solution (syrup) formulation or the tablet formulation of LCM in 
this study. The study medication will be orally administered bid (at 12-hour intervals, once in the 
morning and once in the evening) in equally divided doses. The oral solution (syrup) formulation 
will be measured and orally administered via a dosing syringe. The selection of doses, titration 
scheme, and rate of taper in SP847 were based on adult studies and were adjusted to a mg/kg 
basis plus 40% (ie, 600mg/day adult dose of LCM corresponds to [600mg/70kg] x 1.4 = 
approximately 12mg/kg/day for a child). The selection of doses in this trial is based on the 
maximum recommended dose in SP847. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. 
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. The investigator may decrease the 
dose of LCM to a minimum of 2mg/kg/day (oral solution [syrup] or the corresponding dose level 
for the tablet formulation). Increases in the LCM dose must occur only during office visits. It 
should be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the syrup), 
missed doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
Subjects enrolled in SP848 have the option of remaining on the oral solution formulation of 
LCM or switching to the commercial tablet formulation, if feasible. Consideration of the current 
LCM milligram dose in the oral solution (syrup) should occur if/when transitioning to the tablet 
formulation. In cases where the LCM dose received with the oral solution (syrup) is not 
supported by the tablet strengths available in SP848 (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 100mg with a maximum permitted dose of 600mg/day. 
Subjects achieving a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet) 
who withdraw during the study should taper off study medication. It is recommended that the 
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dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (see tables below). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Recommended LCM dose reduction (taper) for oral solution (syrup) 
formulation 
Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
12mg/kg/day 
(6mg/kg bid) 
8mg/kg/day 
(4mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
0 
10mg/kg/day 
(5mg/kg bid) 
6mg/kg/day 
(3mg/kg bid) 
2mg/kg/day 
(1mg/kg bid) 
0 
8mg/kg/day 
(4mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
0 
– 
6mg/kg/day 
(3mg/kg bid) 
2mg/kg/day 
(1mg/kg bid) 
0 
– 
4mg/kg/day 
(2mg/kg bid) 
0 
– 
– 
bid=twice daily; LCM=lacosamide 
a     Maximum LCM dose achieved is based upon the maximum recommended dose in SP847. 
Recommended LCM dose reduction (taper) for tablet formulation 
Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
600mg/day 
(300mg bid) 
400mg/day 
(200mg bid) 
200mg/day 
(100mg bid) 
0 
500mg/day 
(250mg bid) 
300mg/day 
(150mg bid) 
100mg/day 
(50mg bid) 
0 
400mg/day 
(200mg bid) 
200mg/day 
(100mg bid) 
0 
– 
300mg/day 
(150mg bid) 
100mg/day 
(50mg bid) 
0 
– 
200mg/day 
(100mg bid) 
0 
– 
– 
bid=twice daily; LCM=lacosamide 
a     Maximum LCM dose achieved is based upon the maximum recommended dose in SP847. 
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Was revised as follows (including additions of subsection headings 4.4.1.1 [Subjects enrolling 
from SP847 or other LCM pediatric clinical studies in epilepsy], 4.4.1.2 [Subjects enrolling 
directly in SP848], 4.4.1.3 [All subjects], and 4.4.1.4 [Study completion]): 
Subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), 
who are eligible to participate in the open-label study SP848, and who choose to enter SP848, 
will begin SP848 on the LCM dose they achieved in the primary study. 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. After Screening, eligible subjects 
will initiate treatment with LCM (oral solution or tablet, as chosen by the investigator and 
subject/caregiver), and the LCM dose will be titrated to a level to optimize tolerability and 
seizure control. 
At the first Titration Visit (TV) (see Section 5.2), subjects who have enrolled directly into SP848 
will receive a single dose of LCM (1mg/kg [oral solution] or 50mg [tablet]) during the clinic 
visit. Over the following days, subjects will be administered LCM 1mg/kg bid (oral solution) or 
LCM 50mg bid (tablet), and will begin titrating in weekly increments of 2mg/kg/day (oral 
solution) or 100mg/day (tablet) up to a level to optimize tolerability and seizure control (not to 
exceed 12mg/kg/day [or 600mg/day based on body weight, whichever is lower]). Subjects must 
be on each LCM dose for at least 5 days before titrating up to the next dose. 
A total of up to 6 Titration Visits may be required (eg, for a subject whose dose is titrated to the 
maximum permitted dose of LCM 12mg/kg/day). However, based on tolerability and seizure 
control, a subject’s LCM dose may be titrated to a lower dose level; in such a case, fewer than 
6 Titration Visits would be required. 
The following table summarizes the recommended titration steps for the oral solution and tablet 
formulations: 
Recommended LCM dose titration for subjects enrolling directly into SP848 
Formulation 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Oral solution 
(syrup) 
2mg/kg/day 
(1mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
6mg/kg/day 
(3mg/kg bid) 
8mg/kg/day 
(4mg/kg bid) 
10mg/kg/day 
(5mg/kg bid) 
12mg/kg/day 
(6mg/kg bid) 
Tablet 
100mg/day 
(50mg bid) 
200mg/day 
(100mg bid) 
300mg/day 
(150mg bid) 
400mg/day 
(200mg bid) 
500mg/day 
(250mg bid) 
600mg/day 
(300mg bid) 
bid=twice daily; LCM=lacosamide 
The investigator, together with the subject/caregiver (including parent/legal guardian), will be 
able to choose either the oral solution (syrup) formulation or the tablet formulation of LCM in 
this study. The study medication will be orally administered bid (at 12-hour intervals, once in the 
morning and once in the evening) in equally divided doses. The oral solution (syrup) formulation 
will be measured and orally administered via a dosing syringe. The selection of doses, titration 
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scheme, and rate of taper in SP847 were based on adult studies and were adjusted to a mg/kg 
basis plus 40% (ie, 600mg/day adult dose of LCM corresponds to [600mg/70kg] x 1.4 = 
approximately 12mg/kg/day for a child). The selection of doses in this trial is based on the 
maximum recommended dose in SP847. 
The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. 
The investigator may increase the dose of LCM no faster than 2mg/kg/day (oral solution [syrup]) 
or 100mg/day (tablet) per week to a maximum of 12mg/kg/day (oral solution [syrup] or the 
corresponding dose levels for the tablet formulation) not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. The investigator may decrease the 
dose of LCM to a minimum of 2mg/kg/day (oral solution [syrup] or the corresponding dose level 
for the tablet formulation). Increases in the LCM dose must occur only during office visits. It 
should be noted, in cases of incomplete doses (eg, subject spits out all or a portion of the syrup), 
missed doses, or administration of an erroneous volume of syrup, study medication should not be 
readministered and these subjects would remain at their assigned dose. 
Subjects enrolling from SP847 will have the option of remaining on the oral solution formulation 
of LCM or switching to the commercial tablet formulation, if feasible. Consideration of the 
current LCM milligram dose in the oral solution (syrup) should occur if/when transitioning to the 
tablet formulation. In cases where the LCM dose received with the oral solution (syrup) is not 
supported by the tablet strengths available in SP848 (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 100mg with a maximum permitted dose of 600mg/day. 
Subjects achieving a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet) 
who withdraw during the study should taper off study medication. It is recommended that the 
dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (see tables below). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Recommended LCM dose reduction (taper) for oral solution (syrup) 
formulation 
Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
12mg/kg/day 
(6mg/kg bid) 
8mg/kg/day 
(4mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
0 
10mg/kg/day 
(5mg/kg bid) 
6mg/kg/day 
(3mg/kg bid) 
2mg/kg/day 
(1mg/kg bid) 
0 
8mg/kg/day 
(4mg/kg bid) 
4mg/kg/day 
(2mg/kg bid) 
0 
– 
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Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
6mg/kg/day 
(3mg/kg bid) 
2mg/kg/day 
(1mg/kg bid) 
0 
– 
4mg/kg/day 
(2mg/kg bid) 
0 
– 
– 
bid=twice daily; LCM=lacosamide 
a     Maximum LCM dose achieved is based upon the maximum recommended dose in SP847. 
Recommended LCM dose reduction (taper) for tablet formulation 
Maximum LCM dose 
achieveda 
Taper schedule 
Week 1 
Week 2 
Week 3 
600mg/day 
(300mg bid) 
400mg/day 
(200mg bid) 
200mg/day 
(100mg bid) 
0 
500mg/day 
(250mg bid) 
300mg/day 
(150mg bid) 
100mg/day 
(50mg bid) 
0 
400mg/day 
(200mg bid) 
200mg/day 
(100mg bid) 
0 
– 
300mg/day 
(150mg bid) 
100mg/day 
(50mg bid) 
0 
– 
200mg/day 
(100mg bid) 
0 
– 
– 
bid=twice daily; LCM=lacosamide 
a     Maximum LCM dose achieved is based upon the maximum recommended dose in SP847. 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final Visit is not required for subjects 
who complete the study and who do not undergo taper of LCM. 
Subjects who complete the study and discontinue use of LCM (as determined by the investigator 
in consultation with the subject and/or parent/legal guardian) should taper LCM gradually as 
described in Section 4.4.1.3. These subjects should complete Visit 13/Termination Visit, 
followed by the Final Visit which occurs 2 weeks after the final dose of study medication, and 
then the Safety Follow-Up telephone contact which occurs 28 to 35 days after the last dose of 
LCM. 
Clinical Study Protocol, Section 4.4.3. Original text: 
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This is an open-label extension study; subjects will not be randomized. Subjects will keep the 
unique number assigned in the primary study. 
Was revised as follows: 
This is an open-label study; subjects will not be randomized. Subjects who participated in SP847 
or other LCM pediatric clinical studies in epilepsy will keep the unique number assigned in the 
primary study. 
Subjects enrolling directly into SP848 without participation in a previous LCM clinical study 
will be assigned unique numbers for the purpose of study and subject identification, as well as 
for subject confidentiality. At the Screening Visit, each subject will be assigned the unique 
identifying number for this study. 
Clinical Study Protocol, Section 4.5 (Expected duration of the study), first sentence. Original 
text: 
The maximum duration of LCM administration will be approximately 2 years. 
Was revised as follows: 
The maximum duration of LCM administration for an individual subject will be approximately 
2 years. 
Clinical Study Protocol, Section 5.1 (Screening Visit) was newly added as follows and 
subsequent section numbers were adjusted accordingly: 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. 
At the Screening Visit, subjects entering directly into SP848 (ie, subjects who have not 
participated in SP847 or another applicable LCM pediatric clinical study in epilepsy) will be 
evaluated for their suitability for enrollment in SP848. The Screening Visit is not applicable for 
subjects who have participated in SP847 or another applicable LCM pediatric clinical study in 
epilepsy; the first visit in SP848 for these subjects is Visit 1 (see Section 5.3). 
The Screening assessments will be conducted up to 14 days prior to the first administration of 
LCM. It is acceptable for the Screening assessments to be conducted on more than 1 day, 
although it should not be done over longer than 1 week. Prior to the conduct of any study-related 
procedures, a complete explanation (both verbally 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 parent/legal guardian by the investigator (or designee). The subject’s 
parent/legal guardian will be requested to sign and date the IRB/IEC-approved Informed Consent 
Form. When possible, or as required by the local IRB/IEC, the subject will be requested to give 
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assent to participate in the study. Each subject’s eligibility for the study will be determined on 
the basis of the inclusion/exclusion criteria and the results of the following pretreatment 
assessments (for further details of the assessments and the required procedures and methods, 
please refer to Section 6, Section 7, and Section 8 of this protocol). 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Medical history assessment 
• Seizure history over the past 4 weeks (historical Baseline) 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) 
• Vital signs assessment (blood pressure and pulse)  
• Body weight assessment 
• Height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• C-SSRS 
• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
• Adverse event reporting 
• Dispense subject diary 
The subject will be scheduled to return for a clinic visit (TV) less than 14 days from the last 
Screening Visit assessment(s). 
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Clinical Study Protocol, Section 5.2 (Titration Visit[s] [TV1, TV2, TV3, TV4, TV5, TV6]) was 
newly added as follows and subsequent section numbers were adjusted accordingly: 
Eligible subjects who enter directly into SP848 (without prior participation in SP847 or another 
applicable LCM primary study) will initiate treatment with LCM at TV1, and the LCM dose will 
be titrated over the following week(s). Titration Visits are not applicable for subjects who have 
participated in SP847 or another LCM primary study; the first visit in SP848 for these subjects is 
Visit 1 (see Section 5.3). 
At TV1, subjects who have enrolled directly into SP848 will receive a single dose of LCM 
(1mg/kg [oral solution] or 50mg [tablet]) during the clinic visit. Over the following days, 
subjects will be administered LCM 1mg/kg bid (oral solution) or LCM 50mg bid (tablet), and 
will begin titrating in weekly increments of 2mg/kg/day (oral solution) or 100mg/day (tablet) up 
to a level to optimize tolerability and seizure control (not to exceed 12mg/kg/day [or 600mg/day 
based on body weight, whichever is lower]). Subjects must be on each LCM dose for at least 
5 days before titrating up to the next dose. It should be noted, in cases of incomplete doses (eg, 
subject spits out all or a portion of the syrup), missed doses, or administration of an erroneous 
volume of syrup, study medication should not be readministered and these cases would not be 
considered dose reductions. The LCM dose titration steps are summarized in Section 4.4.1.2. 
A total of up to 6 Titration Visits may be required (eg, for a subject whose dose is titrated to the 
maximum permitted dose of LCM 12mg/kg/day). However, based on tolerability and seizure 
control, a subject’s LCM dose may be titrated to a lower dose level; in such a case, fewer than 
6 Titration Visits would be required. 
The following assessments are required for each TV: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• Blood sample for clinical chemistry, hematology, and endocrinology (TV2 and TV4 only) 
• Urine sample for urinalysis (TV2 and TV4 only) 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense subject diary 
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• Dispense LCM (as applicable) 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM 
maximum plasma concentration (Cmax) 1 week after an initial LCM dose increase to a LCM dose 
level that is ≥8mg/day or a new concomitant AED is introduced. Subjects 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). 
Clinical Study Protocol, Section 5.3 (Visit 1 [Week 0]). Original text: 
For subjects who complete SP847, Visit 1 is Day 2 of the second PK collection time period 
(which may include an overnight stay at a hospital or medical facility) in SP847 (Day 28 for 
Cohorts 1, 2, 3, and 5 with maximum recommended dose of 8mg/kg/day; Day 35 for Cohorts 2 
to 5 with maximum recommended dose of 10mg/kg/day; and Day 42 for Cohorts 2 to 5 with 
maximum recommended dose of 12mg/kg/day). For subjects who discontinue SP847 due to a 
dose reduction or status epilepticus, Visit 1 is the Early Termination Visit in SP847. For subjects 
in SP847 who are titrated up to the maximum permitted dose of 600mg/day sooner than the 
study schedule would ordinarily indicate (based on body weight) and who enroll in SP848, the 
Early Termination Visit of SP847 will also serve as Visit 1 for SP848. 
For subjects who enroll in SP848 after participation in future LCM pediatric clinical studies in 
epilepsy, SP848 Visit 1 will be specified in the respective primary study protocol. 
Prior to the conduct of any study-related procedures, a complete explanation (both verbally 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 parent/legal guardian by the 
investigator (or designee). The subject’s parent/legal guardian will be requested to sign and date 
the IRB/IEC-approved Informed Consent Form. When possible, or as required by local IRB/IEC, 
the subject will be requested to give assent to participate in the study. 
Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments, and a complete medical history update will be obtained. 
The data for the following assessments will be taken from the last assessment during SP847 (or 
other primary study as applicable): 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment but 30 minutes to 1 hour after the administration of LCM) 
• Vital signs assessment (blood pressure and pulse) 
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• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• C-SSRS 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
Was revised as follows: 
For subjects who complete SP847, Visit 1 for SP848 is the same as Day 2 of the second PK 
collection time period (which may include an overnight stay at a hospital or medical facility) in 
SP847 (Day 28 for Cohorts 1, 2, 3, and 5 with maximum recommended dose of 8mg/kg/day; 
Day 35 for Cohorts 2 to 5 with maximum recommended dose of 10mg/kg/day; and Day 42 for 
Cohorts 2 to 5 with maximum recommended dose of 12mg/kg/day). For subjects who 
discontinue SP847 due to a dose reduction or status epilepticus, Visit 1 is the Early Termination 
Visit in SP847. For subjects in SP847 who are titrated up to the maximum permitted dose of 
600mg/day sooner than the study schedule would ordinarily indicate (based on body weight) and 
who enroll in SP848, the Early Termination Visit of SP847 will also serve as Visit 1 for SP848. 
For subjects who enroll in SP848 after participation in other LCM pediatric clinical studies in 
epilepsy, SP848 Visit 1 will be specified in the respective primary study protocol. 
For subjects who enter directly into SP848 (without prior participation in SP847 or other LCM 
pediatric clinic studies in epilepsy), the LCM dose will be titrated at weekly intervals as 
described in Section 4.4.1.2 and Section 5.2. These subjects will reach Visit 1 either (1) when the 
LCM dose is titrated to a level that, in the opinion of the investigator, optimizes tolerability and 
seizure control, or (2) when the maximum permitted LCM dose is reached (12mg/kg/day [or 
600mg/day based on body weight, whichever is lower]). In the case of a subject who requires a 
dose reduction during the Titration Visits, the subject’s LCM dose will be returned to the 
previous dose level and the next clinic visit will be Visit 1 at the reduced level. Visit 1 should 
occur at least 5 days after the final TV. At Visit 1, the progress in SP848 for subjects who 
entered directly into SP848 and for subjects who have enrolled from SP847 or other LCM 
pediatric clinical studies in epilepsy will be aligned; subsequent regularly scheduled clinic visits 
for all subjects will be at 4-week intervals as outlined in the following sections. 
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The informed consent process for SP848 will be conducted at Visit 1 for subjects who have not 
previously been through the informed consent process at the Screening Visit (ie, subjects 
enrolling from SP847 or other LCM pediatric clinical studies in epilepsy for whom Visit 1 is the 
first study visit in SP848). Prior to the conduct of any study-related procedures, a complete 
explanation (both verbally 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 
parent/legal guardian by the investigator (or designee). The subject’s parent/legal guardian will 
be requested to sign and date the IRB/IEC-approved Informed Consent Form. When possible, or 
as required by local IRB/IEC, the subject will be requested to give assent to participate in the 
study. 
Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments (applicable only for subjects for whom Visit 1 is the first 
clinic visit for SP848), and a complete medical history update will be obtained. The data for the 
following assessments will be taken from the last assessment during SP847 (or other primary 
study as applicable): 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment but 30 minutes to 1 hour after the administration of LCM) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• Tanner Stage assessment (if applicable) 
• C-SSRS 
• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) (subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
(subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• Adverse event reporting 
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• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs for the following 4 weeks) 
• Dispense LCM. Subjects and caregivers (including parent/legal guardian) will be instructed 
to administer LCM at approximately 12-hour intervals (once in the morning and once in the 
evening). 
Clinical Study Protocol, Section 5.5 (Visit 2 [Week 4]), final 2 paragraphs. Original text: 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased or a new concomitant AED is introduced. The ECG should be performed after the 
increased dose of LCM or the new AED has reached steady-state. This ECG can be done at 
the next scheduled visit. When the ECG assessment is done, 2 interpretable recordings will 
be performed approximately 20 to 30 minutes apart prior to vital sign assessment and 
collection of blood samples (if applicable), but 30 minutes to 1 hour after the administration 
of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
Was revised as follows: 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased to a LCM dose level that is ≥8mg/kg/day or a new concomitant AED is introduced. 
The ECG should be performed after the increased dose of LCM or the new AED has reached 
steady-state. This ECG can be done at the next scheduled visit. When the ECG assessment is 
done, 2 interpretable recordings will be performed approximately 20 to 30 minutes apart 
prior to vital sign assessment and collection of blood samples (if applicable), but 30 minutes 
to 1 hour after the administration of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day. This ECG 
can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
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Clinical Study Protocol, Section 5.6 (Visit 3 [Week 8]), final 2 paragraphs. Original text: 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased or a new concomitant AED is introduced. The ECG should be performed after the 
increased dose of LCM or the new AED has reached steady-state. This ECG can be done at 
the next scheduled visit. When the ECG assessment is done, 2 interpretable recordings will 
be performed approximately 20 to 30 minutes apart prior to vital sign assessment and 
collection of blood samples (if applicable), but 30 minutes to 1 hour after the administration 
of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
Was revised as follows: 
• A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is 
increased to a LCM dose level that is ≥8mg/kg/day or a new concomitant AED is introduced. 
The ECG should be performed after the increased dose of LCM or the new AED has reached 
steady-state. This ECG can be done at the next scheduled visit. When the ECG assessment is 
done, 2 interpretable recordings will be performed approximately 20 to 30 minutes apart 
prior to vital sign assessment and collection of blood samples (if applicable), but 30 minutes 
to 1 hour after the administration of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day. This ECG 
can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
Clinical Study Protocol, Section 5.8 (Visit 5 [Week 20]), final 2 paragraphs. Original text: 
A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is increased 
or a new concomitant AED is introduced. The ECG should be performed after the increased dose 
of LCM or the new AED has reached steady-state. This ECG can be done at the next scheduled 
visit. When the ECG assessment is done, 2 interpretable recordings will be performed 
approximately 20 to 30 minutes apart prior to vital sign assessment and collection of blood 
samples (if applicable), but 30 minutes to 1 hour after the administration of LCM (if applicable). 
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All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
Was revised as follows: 
A 12-lead ECG (2 interpretable recordings) is also required when the dose of LCM is increased 
to a LCM dose level that is ≥8mg/kg/day or a new concomitant AED is introduced. The ECG 
should be performed after the increased dose of LCM or the new AED has reached steady-state. 
This ECG can be done at the next scheduled visit. When the ECG assessment is done, 2 
interpretable recordings will be performed approximately 20 to 30 minutes apart prior to vital 
sign assessment and collection of blood samples (if applicable), but 30 minutes to 1 hour after 
the administration of LCM (if applicable). 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day. This ECG 
can be conducted at an Unscheduled Visit, if necessary. These subjects 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). 
Clinical Study Protocol, Section 5.9 (Visit 6 [Week 28]). Original text: 
Assessments for Visit 6 (Week 28) are the same as those described for Visit 3 (Week 8) in 
Section 5.6, with the following exception: a 12-lead ECG (2 interpretable recordings 
approximately 20 to 30 minutes apart prior to vital signs assessment and collection of blood 
sample) is conducted at Visit 6. 
Was revised as follows: 
Assessments for Visit 6 (Week 28) are the same as those described for Visit 3 (Week 8) in 
Section 5.6, with the following exception: completion of the palatability and ease of use 
questionnaire and a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart prior to vital signs assessment and collection of blood sample) are conducted at Visit 6. 
Clinical Study Protocol, Section 5.2 (Visit 9 [Week 52]). Original text: 
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Assessments for Visit 9 (Week 52) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exception: a 12-lead ECG (2 interpretable recordings 
approximately 20 to 30 minutes apart prior to vital signs assessment and collection of blood 
sample) is conducted at Visit 9. 
Was revised as follows: 
Assessments for Visit 9 (Week 52) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exception: completion of the palatability and ease of use 
questionnaire and a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes 
apart prior to vital signs assessment and collection of blood sample) are conducted at Visit 9. 
Clinical Study Protocol, Section 5.14 (Visit 11 [Week 72]). Original text: 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: brief physical and neurological exams are conducted 
(instead of complete physical and neurological exams as indicated for Visit 5), the laboratory 
blood sample is collected only for clinical chemistry and hematology (ie, no endocrinology), and 
a 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood sample) is conducted. 
Was revised as follows: 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: brief physical and neurological exams are conducted 
(instead of complete physical and neurological exams as indicated for Visit 5), the laboratory 
blood sample is collected only for clinical chemistry and hematology (ie, no endocrinology), the 
palatability and ease of use questionnaire is completed, and a 12-lead ECG (2 interpretable 
recordings approximately 20 to 30 minutes apart prior to vital signs assessment and collection of 
blood sample) is conducted. 
Clinical Study Protocol, Section 5.16 (Visit 13/Termination Visit [Week 96]). Original text: 
Assessments for Visit 13 (Week 96) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: the laboratory blood sample is collected only for 
clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG (2 interpretable 
recordings approximately 20 to 30 minutes apart prior to vital signs assessment and collection of 
blood sample) is conducted, and a Tanner Stage assessment is conducted (if applicable). 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of 
LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
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100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is 
permitted after discussion with the medical monitor, whenever possible. 
Was revised as follows: 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final Visit is not required for subjects 
who complete the study and who do not undergo taper of LCM. 
Subjects who complete the study and discontinue use of LCM (as determined by the investigator 
in consultation with the subject and/or parent/legal guardian) should taper LCM gradually as 
described in Section 4.4.1.3. These subjects should complete Visit 13/Termination Visit, 
followed by the Final Visit which occurs 2 weeks after the final dose of study medication, and 
then the Safety Follow-Up telephone contact which occurs 28 to 35 days after the last dose of 
LCM. 
Assessments for Visit 13/Termination Visit (Week 96) are the same as those described for 
Visit 5 (Week 20), in Section 5.8, with the following exceptions: the laboratory blood sample is 
collected only for clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted, a Tanner Stage assessment is conducted (if 
applicable), an Achenbach CBCL is conducted, Bayley-III scales are conducted, and the 
palatability and ease of use questionnaire is completed. 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of 
LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 
200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) 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 complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. 
Clinical Study Protocol, Section 5.17 (Early Termination Visit). Original text: 
Subjects who withdraw from the study prematurely must complete an Early Termination Visit.  
The following will be performed: 
• Concomitant medication assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
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• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine sample for urinalysis 
• Serum pregnancy test for females of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs) 
• Dispense LCM. Lacosamide for taper will be dispensed only for subjects who achieve a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that 
the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution 
[syrup]) or 200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, 
a faster taper is permitted after discussion with the medical monitor, whenever possible. 
Was revised as follows: 
Subjects who withdraw from the study prematurely must complete an Early Termination Visit. 
At the time of withdrawal from the study, investigators should discuss treatment options with the 
subject and/or their parent/legal guardian 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 
parent/legal guardian. These subjects should complete the Early Termination Visit and then 
complete the Safety Follow-Up telephone contact 28 to 35 days after the Early Termination 
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Visit. The Final Visit is not required for subjects who withdraw from the study prematurely and 
who do not undergo taper 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 parent/legal guardian) should taper 
LCM gradually as described in Section 4.4.1.3. These subjects should complete the Early 
Termination Visit, followed by the Final Visit which occurs 2 weeks after the final dose of study 
medication, and then the Safety Follow-Up telephone contact. 
The following will be performed at the Early Termination Visit: 
• Concomitant medication assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine sample for urinalysis 
• Serum pregnancy test for females of childbearing potential 
• Tanner Stage assessment (if applicable) 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
• Palatability and ease of use questionnaire 
• Adverse event reporting 
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• Dispense subject diary (to assess seizure frequency, document the intake of concomitant 
AEDs, and record AEs) 
• Dispense LCM. Lacosamide for taper will be dispensed only for subjects who achieve a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that 
the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution 
[syrup]) or 200mg/day (tablet) (Section 4.4.1). A slower taper of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) 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 parent/legal guardian. 
Clinical Study Protocol, Section 5.18 (Unscheduled Visit[s]). Original text: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if an LCM dose increase is required 
between scheduled clinic visits, the subject must return for an Unscheduled Visit. If an AE 
prompts a dose reduction, the reduction can be implemented immediately at the investigator’s 
discretion. However, the subject should return to the clinic as soon as possible for an 
Unscheduled Visit. 
The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
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if necessary. These subjects 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). 
Was revised as follows: 
An Unscheduled Visit may be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, if an LCM dose increase is required at 
any time, or if a new concomitant AED is introduced, the subject must return for an Unscheduled 
Visit. If an AE prompts a dose reduction, the reduction can be implemented immediately at the 
investigator’s discretion. However, the subject should return to the clinic as soon as possible for 
an Unscheduled Visit. 
The following assessments are required: 
• Concomitant medications assessment  
• Concomitant AEDs assessment 
• Brief physical examination 
• Brief neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of any blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight 
• LCM return/compliance (as applicable) 
• Subject diary assessment 
• C-SSRS (only if Unscheduled Visit is conducted due to an AE) 
• Adverse event reporting 
• Dispense LCM (as applicable) 
Additional assessments can be performed at the investigator’s discretion. 
All subjects will be required to have an ECG (2 interpretable recordings) conducted at LCM Cmax 
1 week after an initial LCM dose increase to a LCM dose level that is ≥8mg/kg/day or after 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 vital signs assessment) can be performed 
30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
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Clinical Study Protocol, Section 5.19 (Final Visit). Original text: 
During the Final Visit (2 weeks after the last LCM dose), the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
• Vital signs assessment (blood pressure and pulse) 
• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM) 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
Was revised as follows: 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. 
During the Final Visit, the following will be performed: 
• Concomitant medications assessment 
• Concomitant AEDs assessment 
• Complete physical examination 
• Complete neurological examination 
• 12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital 
signs assessment and collection of blood samples) 
• Vital signs assessment (blood pressure and pulse) 
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• Body weight and height assessment 
• Blood sample for clinical chemistry, hematology, and endocrinology 
• Urine sample for urinalysis 
• Serum pregnancy test for female subjects of childbearing potential 
• LCM return/compliance 
• Subject diary assessment 
• C-SSRS 
• Adverse event reporting 
Clinical Study Protocol, Section 5.20 (Safety Follow-up telephone contact). Original text: 
The Safety Follow-Up telephone contact is required for all subjects (those who have withdrawn 
prematurely from the study or completed the study as planned). This telephone contact will occur 
28 to 35 days after the last dose of LCM. 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 a definite outcome is achieved (Section 8.1.2). 
Was revised as follows: 
The Safety Follow-Up telephone contact is required for all subjects (those who complete the 
study as planned or have withdrawn prematurely from the study). For subjects who complete the 
study, this telephone contact will occur 28 to 35 days after Visit 13/Termination Visit (subjects 
who do not undergo taper of LCM) or 28 to 35 days after the last dose of LCM (subjects who 
discontinue use of LCM [ie, taper]). For subjects who withdraw prematurely from the study, this 
telephone contact will occur 28 to 35 days after the Early Termination Visit (subjects who do not 
undergo taper of LCM) or 28 to 35 days after the last dose of LCM (subjects who discontinue 
use of LCM [ie, taper]). 
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 a definite outcome is achieved (Section 8.1.2). 
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Clinical Study Protocol, Section 6.1 (Seizure counts), first sentence. Original text: 
At Screening of SP847 (or other primary study as applicable) subjects/caregivers (including 
parents/legal guardians) will be asked how many seizures the subject has had in the previous 
4 weeks; this will serve as a historical Baseline. 
Was revised as follows: 
At Screening of SP847 (or other primary study as applicable) or at the Screening Visit of SP848 
(for subjects who entered directly into SP848) subjects/caregivers (including parents/legal 
guardians) will be asked how many seizures the subject has had in the previous 4 weeks; this will 
serve as a historical Baseline. 
Clinical Study Protocol, Section 6.2.1 (Clinical Global Impression of Change), second 
paragraph. Original text: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 
of SP847 (or other primary study as applicable) will serve as Baseline. 
Was revised as follows: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 
of SP847 (or other primary study as applicable) will serve as Baseline; the Screening Visit of 
SP848 will serve as Baseline for those subjects entering directly into SP848. 
Clinical Study Protocol, Section 6.2.2 (Caregiver Global Impression of Change), second 
paragraph. Original text: 
For the assessment of the Clinical Global Impression of Change, 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. Visit 1 of SP847 (or other primary study as applicable) 
will serve as Baseline. 
Was revised as follows: 
For the assessment of the Clinical Global Impression of Change, 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 
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of AEs, and subject’s functional status. Visit 1 of SP847 (or other primary study as applicable) 
will serve as Baseline; the Screening Visit of SP848 will serve as Baseline for those subjects 
entering directly into SP848. 
Clinical Study Protocol, Section 8.1.8 (Safety signal detection in ongoing clinical studies and 
Data Monitoring Committees), second and third paragraphs. Original text: 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the GCSP 
representative. 
As appropriate for the stage of development and accumulated experience with the investigational 
medicinal product, medically qualified personnel at UCB may identify additional safety 
measures (examples: AEs, vital signs, laboratory or electrocardiogram results) for which data 
will be periodically reviewed during the course of the study. 
Was revised as follows: 
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 (DS) 
representative. 
As appropriate for the stage of development and accumulated experience with the investigational 
medicinal product, medically qualified personnel at UCB may identify additional safety 
measures (examples: AEs, vital signs, laboratory or ECG results) for which data will be 
periodically reviewed during the course of the study. 
Clinical Study Protocol, Section 8.2.4 (Procedures for reporting serious adverse events), first 
sentence. Original text: 
If an SAE is reported, UCB BIOSCIENCES must be informed within 24 hours of receipt of this 
information by the site (see contact numbers for SAE reporting listed in the Study Contact 
Information section). 
Was revised as follows: 
If an SAE is reported, UCB BIOSCIENCES must be informed within 24 hours of receipt of this 
information by the site (see contact details for SAE reporting listed in the Study Contact 
Information section). 
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Clinical Study Protocol, Section 8.2.5 (Follow-up of serious adverse events), final sentence. 
Original text: 
Information on SAEs obtained after clinical database lock will be captured through the Global 
Clinical Safety & Pharmacovigilance database without limitation of time. 
Was revised as follows: 
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time. 
Clinical Study Protocol, Section 8.4.4 (12-lead ECG), second paragraph. Original text: 
Beginning with Protocol Amendment 3, 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 an initial LCM dose increase. This ECG can be conducted at an Unscheduled Visit, 
if necessary. These subjects 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). 
Was revised as follows: 
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 an initial LCM dose increase 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 vital signs assessment) can be performed 
30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
Clinical Study Protocol, Section 8.4.7 (Achenbach CBCL) was newly added as follows and 
subsequent section numbers were adjusted accordingly: 
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 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. For subjects ≥6 years to ≤17 years of age, the CBCL/6-18 version will be 
used. 
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The same scale will be completed at the Screening Visit (subjects enrolling directly into SP848), 
Visit 1 (subjects enrolling from SP847 or other pediatric clinical studies in epilepsy), and 
Visit 13/Termination Visit (or Early Termination Visit) (all subjects) by the parent(s)/legal 
representative(s). The completion of the Achenbach CBCL will require approximately 
45 minutes.  
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
• 0=not true (as far as known) 
• 1=somewhat or sometimes true 
• 2=very true or often true 
Eight syndrome scores will be calculated from these 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 Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests. 
Clinical Study Protocol, Section 8.4.8 (Bayley Scales of Infant and Toddler Development, Third 
Edition) was newly added as follows and subsequent section numbers were adjusted 
accordingly: 
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 Scales of Infant and Toddler 
Development, Third Edition (Bayley-III) are a standardized individually administered adaptive 
assessment that measures the developmental functioning of infants and young children 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 (BSID-II) (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 children 
and is therefore considered appropriate for SP848. 
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.  
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The completion of the Bayley-III scales will require approximately 50 minutes for children who 
are 12 months old or younger and 90 minutes for children aged 13 months and older. 
The same scale will be completed at the Screening Visit (subjects enrolling directly into SP848), 
Visit 1 (subjects enrolling from SP847 or other pediatric clinical studies in epilepsy), and 
Visit 13/Termination Visit (or Early Termination Visit) (all subjects) for children from 1 month 
to <18 months of age enrolled in English-speaking countries. 
Clinical Study Protocol, Section 8.4.9 (Palatability and ease of use questionnaire) was newly 
added as follows: 
UCB BIOSCIENCES has created a palatability and ease of use questionnaire to collect data from 
the subject or caregiver regarding different aspects of LCM and its administration. The 
questionnaire will assess the subject or caregiver’s response regarding the formulation of LCM 
the subject is receiving for palatability items (eg taste, smell, ability to swallow, aftertaste), mode 
of administration, and administration device as applicable. 
Clinical Study Protocol, Section 10.1 (Site qualification), first sentence. Original text: 
A site visit will be performed by UCB BIOSCIENCES or designee prior to the start of the 
primary study (SP847) to discuss the protocol, to ensure the availability of appropriate study 
personnel, adequate resources, and to assess their ability to properly conduct the study according 
to International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines and 
local requirements. 
Was revised as follows: 
A site visit will be performed by UCB BIOSCIENCES or designee to discuss the protocol, to 
ensure the availability of appropriate study personnel, adequate resources, and to assess their 
ability to properly conduct the study according to International Conference on Harmonisation-
Good Clinical Practice (ICH-GCP) guidelines and local requirements. 
Clinical Study Protocol, Section 10.2.1 (Definition of source data), final sentence. Original text: 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB BIOSCIENCES (or designee). 
Was revised as follows: 
Electronic data records, such as Holter monitor records or EEG records, must be saved and 
stored as instructed by UCB BIOSCIENCES (or designee). 
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Clinical Study Protocol, Section 12.1 (Description of statistical methods), second paragraph. 
Original text: 
Visit 1 of SP847 (or other primary study as applicable) will serve as Baseline values for safety 
and efficacy variables unless otherwise noted. 
Was revised as follows: 
Visit 1 of SP847 (or other primary study as applicable) or the Screening Visit of SP848 (for 
subjects who enter directly into SP848) will serve as Baseline values for safety and efficacy 
variables unless otherwise noted. 
Clinical Study Protocol, Section 12.1.1 (Definition of analysis sets), second sentence. Original 
text: 
All subjects from the SS with valid concentration data and the absence of major protocol 
deviations that may have an influence on the concentration data will be included in the PK Set 
(PKS). 
Was revised as follows: 
All subjects from the SS with valid concentration data and the absence of major protocol 
deviations that may have an influence on the concentration data will be included in the 
Pharmacokinetic Per-Protocol Set (PK-PPS). 
Clinical Study Protocol, Section 12.1.2.2 (Other safety variables). Original text: 
The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, and urinalysis), ECG measurements, vital sign measurements (blood pressure and 
pulse rate), body weight, height, calculated BMI, and Tanner Stage (if applicable). The actual 
measurement and its change from Baseline (SP847 [or other primary study as applicable] Visit 1) 
will be analyzed descriptively and presented by visit. In addition, shift tables may be used to 
evaluate the number and percentage of subjects having a different post-Baseline status when 
compared with their Baseline status. 
The shift from Baseline to the subject’s last visit at which a physical and/or neurological 
examination was performed post-Baseline will be summarized by category. 
Laboratory, ECG, and vital signs data outside of the respective reference ranges will be listed 
and highlighted. 
Was revised as follows: 
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The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, and urinalysis), ECG measurements, vital sign measurements (blood pressure and 
pulse rate), body weight, height, calculated BMI, and Tanner Stage (if applicable). The actual 
measurement and its change from Baseline (SP847 [or other primary study as applicable] Visit 1) 
or the Screening Visit (for subjects who entered directly into SP848) will be analyzed 
descriptively and presented by visit. In addition, shift tables may be used to evaluate the number 
and percentage of subjects having a different post-Baseline status when compared with their 
Baseline status. 
The shift from Baseline to the subject’s last visit at which a physical and/or neurological 
examination was performed post-Baseline will be summarized by category. 
Laboratory, ECG, and vital signs data outside of the respective reference ranges will be listed 
and highlighted. 
Changes in behavior and development from Baseline as measured using the Achenbach CBCL 
for children 18 months and older (CBCL/1½-5 and CBCL/6-18) and Bayley-III scales for 
children <18 months of age will be summarized descriptively and presented by visit. Baseline is 
defined as Visit 1 for subjects from SP847 or other epilepsy studies. Baseline values for subjects 
who enroll directly into SP848 will be taken from the Screening Visit. 
Clinical Study Protocol, Section 12.1.4.3 (Palatability and ease of use questionnaire) was newly 
added as follows: 
Data from the palatability and ease of use questionnaire will be summarized descriptively at each 
visit where it is assessed. 
Clinical Study Protocol, Section 12.2 (Determination of sample size). Original text: 
Approximately 42 subjects from the SP847 study will be eligible to enroll in this open-label 
extension study. Other subjects will be eligible to enroll as future LCM pediatric clinical studies 
in epilepsy are undertaken. 
Was revised as follows: 
Approximately 42 subjects from the SP847 study will be eligible to enroll in this open-label 
study. Other subjects will be eligible to enroll as other LCM pediatric clinical studies in epilepsy 
are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated 
in a LCM clinical study will be permitted to enroll directly into SP848. The purpose of enrolling 
these subjects directly into SP848 is to obtain additional long-term safety exposures in the age 
range from which adequate PK data have already been obtained in SP847; the additional 
long-term safety data will be included in planned LCM marketing applications for subjects 
≥4 years of age. 
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Clinical Study Protocol, Section 15 (References). The following references were added: 
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. 5th 
ed. La Mesa: Jerome M Sattler; 2006. 
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: The Psychological 
Corporation; 1993. 
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006. 
Clinical Study Protocol, Section 16.1 (Tabular schedule of study procedures) was updated to the 
following (including the addition of Table 3). 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Blood sample for concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 17 years) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xn 
 
 
LCM return/compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSo 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X 
 
Achenbach CBCL 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Bayley-III scales 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
AE reportingq 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone contact). 
b 
For subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), Visit 1 is also the last visit of the primary study. At Visit 1, the informed 
consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be updated, body weight and height and concomitant medications including 
AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an Unscheduled Visit. 
Height will not be recorded at an Unscheduled Visit. 
f 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final 
dose of study medication. 
g 
This TC occurs 28 to 35 days after the last dose of LCM. 
h 
Assessments should have been done as part of the last visit of the primary study. 
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i 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential, serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and the Final Visit. Urine pregnancy tests will be 
performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical monitor, whenever possible. 
n 
As applicable  
o 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
p 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
q 
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 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13/TermV  ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PKh 
X 
 
X 
X 
X 
X 
 
 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 
17 years) 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
Xl 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xl 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
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Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13/TermV  ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
C-SSRSm 
X 
 
X 
X 
X 
X 
Xn 
X 
 
Achenbach CBCL 
 
 
 
 
X 
X 
 
 
 
Bayley-III scales 
 
 
 
 
X 
X 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; S=serum; TC=telephone contact; TermV=Termination Visit; U=urine; 
Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for 
an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 
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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). 
h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Early Termination Visit and at the Final Visit. Urine pregnancy 
tests will be performed at Visits 10, 11, 12, and 13. 
j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
l 
As applicable. 
m 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
n 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
 
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Table 3.  Schedule of study procedures for SP848 (Screening Visit and Titration Visits, subjects enrolling directly into SP848) 
Study SP848 
Screening 
Titration Visits 
Visit 
Screening Visit 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Seizure history 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
X 
 
 
 
 
 
 
Physical exam (brief) 
 
X 
X 
X 
X 
X 
X 
Neurological exam (complete) 
X 
 
 
 
 
 
 
Neurological exam (brief) 
 
X 
X 
X 
X 
X 
X 
12-lead ECGa 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Clinical chemistry and hematology blood 
sample 
X 
 
X 
 
X 
 
 
Endocrinology blood sample 
X 
 
X 
 
X 
 
 
Urinalysis (subjects aged 5 to 17 years) 
X 
 
X 
 
X 
 
 
Pregnancy testb 
X 
 
 
 
 
 
 
Tanner Stage 
X 
 
 
 
 
 
 
Clinical GIC 
X 
 
 
 
 
 
 
Caregiver GIC 
X 
 
 
 
 
 
 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
LCM return/compliance 
 
X 
X 
X 
X 
X 
X 
Dispense diary 
X 
X 
X 
X 
X 
X 
X 
Diary assessment 
 
X 
X 
X 
X 
X 
X 
C-SSRSc 
X 
X 
X 
X 
X 
X 
X 
Achenbach CBCL 
X 
 
 
 
 
 
 
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Table 3.  Schedule of study procedures for SP848 (Screening Visit and Titration Visits, subjects enrolling directly into SP848) 
Study SP848 
Screening 
Titration Visits 
Visit 
Screening Visit 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Bayley-III scales 
X 
 
 
 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AEDs=antiepileptic drugs; Cmax=maximum plasma concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; GIC=Global Impression of Change; LCM=lacosamide 
a 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
b 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Screening Visit.  
c 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
 
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17.5 
PROTOCOL AMENDMENT 5 
RATIONALE FOR THE AMENDMENT 
In the FDA Division of Neurology Products’ 06 Aug 2012 Request for Information regarding 
SP847 protocol Amendment 5, the Agency recommended that UCB revise an inclusion criterion 
to require the use of more than 1 AED as monotherapy before initiating adjunctive LCM therapy 
in SP847. UCB has made this recommended change in the SP847 protocol (Amendment 6). In 
alignment with SP847, the primary purpose of this protocol amendment for SP848 is to modify 
inclusion criterion 7 to require that each subject in SP848 has been observed to have 
uncontrolled partial-onset seizures after an adequate course of treatment (in the opinion of the 
investigator) with at least 2 AEDs (concurrently or sequentially). Inclusion criterion 7 applies 
only to subjects who enroll directly into SP848 without previous participation in a LCM clinical 
study. 
In addition, the BRIEF/BRIEF-P, PedsQL, and health care resource use have been added as 
assessments in SP848. 
Other changes made in this amendment are included in the specific changes below. 
MODIFICATIONS/CHANGES 
• Study contact information has been updated (eg, Clinical Project Manager, Safety Physician, 
and SAE reporting). 
• The List of Abbreviations was updated. 
• Information was added to Section 1 (Summary) and throughout the protocol as appropriate to 
reflect the addition of the BRIEF/BRIEF-P, the PedsQL, and assessment of health care 
resource use. 
• Inclusion criterion 7 (Section 4.3.1) was modified to require that each subject in SP848 has 
been observed to have uncontrolled partial-onset seizures after an adequate course of 
treatment (in the opinion of the investigator) with at least 2 AEDs (concurrently or 
sequentially). Inclusion criterion 7 applies only to subjects who enroll directly into SP848 
without previous participation in a LCM clinical study. 
• Information was added to Section 8.4.6 (Assessment of suicidality) to provide for monitoring 
for any changes in mood, ideas, or behavior for warning signs of depression in subjects 
<6 years of age for whom the C-SSRS is not used. 
REFERENCE 
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Clinical Study Protocol, Contact information for the Clinical Project Manager and Safety 
Physician. Original text: 
Clinical Project Manager: 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Safety Physician (Drug Safety): 
Name: 
, MD 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
Was revised as follows: 
Clinical Project Manager: 
Name: 
, RN, MSN 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
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Safety Physician (Drug Safety): 
Name: 
, MD 
Address: 
UCB Pharma S.A. Belgium 
Chemin du Foriest 
B-1420 Braine-L’Alleud, Belgium 
 
Phone/Fax: 
 
E-mail: 
 
 
Clinical Study Protocol, Serious Adverse Event reporting contact information. Original text: 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h), safety related issues,  
and emergency unblinding 
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 5283 1869 
Email 
Europe and Rest of the World (except Japan): GCSP@ucb.com 
Japan: JDSO@ucb.com 
 
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Was revised as follows: 
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 5283 1869 
Email 
Global (except Japan): DS_ICT@ucb.com 
Japan: JDSO@ucb.com 
 
List of Abbreviations. The following abbreviations were added: 
BRIEF® 
Behavior Rating Inventory of Executive 
Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive 
Function®-Preschool Version 
CBCL 
Child Behavior Checklist 
HRQoL 
health-related quality of life 
PedsQL™ 
Pediatric Quality of Life Inventory 
 
Clinical Study Protocol, Section 1 (Summary). Original text: 
The primary variables for assessment of safety and tolerability are: 
• Adverse events (AEs) reported spontaneously by the subject and/or caregiver or observed by 
the investigator 
• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
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• Achenbach CBCL for children 18 months and older (CBCL/1½-5 and CBCL/6-18) assessing 
behavior 
Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
subjects enrolled in English-speaking countries)The secondary 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 a LCM palatability and ease of use questionnaire. 
 
Was revised as follows: 
The primary variables for assessment of safety and tolerability are: 
• Adverse events (AEs) reported spontaneously by the subject and/or caregiver or observed by 
the investigator 
• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner stage (if applicable) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
• Achenbach Child Behavior Checklist (CBCL) for children 18 months and older (CBCL/1½-5 
and CBCL/6-18) assessing behavior 
• Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
subjects enrolled in English-speaking countries) 
• Cognitive function assessments (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/BRIEF®-Preschool Version [BRIEF®-P]) (if applicable) 
The secondary 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, quality of 
life assessments (Pediatric Quality of Life Inventory [PedsQL™]), health care resource use, and 
a LCM palatability and ease of use questionnaire. 
 
Clinical Study Protocol, Section 4.2.1 (Primary variables). The following variable was added: 
• Cognitive function assessments (BRIEF-P/BRIEF) (if applicable) 
 
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Clinical Study Protocol, Section 4.2.2 (Secondary variables). The following variables were 
added: 
• Quality of life assessments (PedsQL) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study) 
 
Clinical Study Protocol, Section 4.3.1 (Inclusion criteria). The following criterion: 
7. Subject has been observed to have uncontrolled partial-onset seizures after an adequate 
course of treatment (in the opinion of the investigator) with at least 1 AED (concurrently or 
sequentially). 
 
Was revised as follows: 
7. Subject has been observed to have uncontrolled partial-onset seizures after an adequate 
course of treatment (in the opinion of the investigator) with at least 2 AEDs (concurrently or 
sequentially). 
 
Clinical Study Protocol, Section 4.3.2 (Exclusion criteria). The following criterion: 
3. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Screening. 
 
Was revised as follows: 
3. Subject ≥6 years of age has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening. 
 
Clinical Study Protocol, Section 4.3.3 (Criteria for withdrawal). The following criteria: 
11. For subject who did not complete a C-SSRS at Screening, subject has a lifetime history 
(prior to study entry or since study start) of suicide attempt (including an active attempt, 
interrupted attempt, or aborted attempt) of the screening version of the C-SSRS. The 
investigator must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
12. For all subjects, regardless of whether or not a C-SSRS was completed at Screening, subject 
has active suicidal ideation as indicated by a positive response (“Yes”) to either Question 4 
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or Question 5 of the “since last visit” version of the C-SSRS. The subject should be referred 
immediately to a Mental Healthcare Professional and must be withdrawn from the study. 
5.   For subject who did not complete a C-SSRS at Screening, subject had active suicidal ideation 
in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the screening version of the C-SSRS. The investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the patient from the study. 
 
Were revised as follows: 
11. For subject who did not complete a C-SSRS at Screening, subject has a lifetime history 
(prior to study entry or since study start) of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt) of the screening version of the C-SSRS. The 
investigator must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
12. For all subjects ≥6 years of age, regardless of whether or not a C-SSRS was completed at 
Screening, subject has actual suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “since last visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study. 
5.   For subject who did not complete a C-SSRS at Screening, subject had actual suicidal ideation 
in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the screening version of the C-SSRS. The investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the patient from the study. 
 
Clinical Study Protocol, Section 5.1 (Screening Visit). The following assessments were added: 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Health care resource use 
 
Clinical Study Protocol, Section 5.2 (Titration Visit[s] [TV1, TV2, TV3, TV4, TV5, TV6]). The 
following assessments: 
• Blood sample for clinical chemistry, hematology, and endocrinology (TV2 and TV4 only) 
• Urine sample for urinalysis (TV2 and TV4 only) 
 
Were revised as follows: 
• Blood sample for clinical chemistry, hematology, and endocrinology (TV4 only) 
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• Urine sample for urinalysis (TV4 only) 
 
Clinical Study Protocol, Section 5.2 (Titration Visit[s] [TV1, TV2, TV3, TV4, TV5, TV6]). The 
following assessment was added: 
• Health care resource use 
 
Clinical Study Protocol, Section 5.3 (Visit 1 [Week 0]). The following assessments were added: 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Health care resource use 
 
Clinical Study Protocol, Section 5.5 (Visit 2 [Week 4]). The following assessment was added: 
• Health care resource use 
 
Clinical Study Protocol, Section 5.6 (Visit 3 [Week 8]). The following assessment was added: 
• Health care resource use 
 
Clinical Study Protocol, Section 5.8 (Visit 5 [Week 20]). The following assessments were added: 
• Achenbach CBCL to be completed by the parent(s)/legal representative(s) (CBCL/1½-5 for 
children from 18 months to 5 years 11 months and CBCL/6-18 for children 6 years and 
older) (subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• Bayley-III scales for children <18 months of age enrolled in English-speaking countries 
(subjects enrolling from SP847 or another applicable LCM pediatric clinical study in 
epilepsy) 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Health care resource use 
 
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Clinical Study Protocol, Section 5.16 (Visit 13/Termination Visit [Week 96]), third paragraph. 
Original text: 
Assessments for Visit 13/Termination Visit (Week 96) are the same as those described for 
Visit 5 (Week 20), in Section 5.8, with the following exceptions: the laboratory blood sample is 
collected only for clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted, a Tanner Stage assessment is conducted (if 
applicable), an Achenbach CBCL is conducted, Bayley-III scales are conducted, and the 
palatability and ease of use questionnaire is completed. 
 
Was revised as follows: 
Assessments for Visit 13/Termination Visit (Week 96) are the same as those described for 
Visit 5 (Week 20), in Section 5.8, with the following exceptions: the laboratory blood sample is 
collected only for clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted, a Tanner Stage assessment is conducted (if 
applicable), an Achenbach CBCL is conducted, Bayley-III scales are conducted, 
BRIEF-P/BRIEF and PedsQL scores are obtained, and the palatability and ease of use 
questionnaire is completed. 
 
Clinical Study Protocol, Section 5.17 (Early Termination Visit). The following assessments were 
added: 
• BRIEF-P/BRIEF score (if applicable) 
• PedsQL score (if applicable) 
• Health care resource use 
 
Clinical Study Protocol, Section 5.18 (Unscheduled Visit[s]). The following assessment was 
added: 
• Health care resource use 
 
Clinical Study Protocol, Section 5.19 (Final Visit). The following assessment was added: 
• Health care resource use 
 
Clinical Study Protocol, Section 6.3 (Pediatric Quality of Life Inventory) was newly added as 
follows: 
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; 
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Varni et al, 2011). The PedsQL will be administered according to the tabular schedule of study 
procedures, Section 16.1. 
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 ≥1 month to ≤18 years of age.  
The multidimensional PedsQL scale encompasses the essential core domains for pediatric 
HRQoL measurement: 1) Physical Functioning/Symptoms, 2) Emotional Functioning, 3) Social 
Functioning, and 4) Cognitive/School Functioning. The PedsQL assessment is retrospective to 
the prior month, and individual items are scored using a 5-point Likert scale (never, almost 
never, sometimes, often, or always). A total health summary score is calculated from the sum of 
the raw scores of the individual items, with higher scores indicating higher HRQoL. 
 
Clinical Study Protocol, Section 6.4 (Health care resource use) was newly added as follows: 
For health care resource use parameters, the following will be evaluated: concomitant AEDs, 
medical procedures, health care provider consultations not related to study, and hospitalizations 
not related to study. Health care resource use parameters will be collected according to the 
tabular schedule of study procedures, Section 16.1. 
 
Clinical Study Protocol, Section 8.4 section heading. Original text: 
Other safety measurements 
 
Was revised as follows: 
Other measurements 
 
Clinical Study Protocol, Section 8.4.2 (Neurological examination), final sentence. Original text: 
The investigator or subinvestigator is responsible for confirming the diagnosis of partial-onset 
seizures. 
 
Was revised as follows: 
The investigator or subinvestigator is responsible for confirming the diagnosis of partial-onset 
seizures or other epilepsy syndrome. 
 
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Clinical Study Protocol, Section 8.4.6 (Assessment of suicidality), the following paragraph was 
added: 
The C-SSRS is not validated and will not be used for subjects <6 years of age. 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. 
 
Clinical Study Protocol, Section 8.4.10 (Behavior Rating Inventory of Executive Function) was 
newly added as follows: 
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of subjects 
≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P/BRIEF will be 
administered according to the tabular schedule of study procedures, Section 16.1. 
The BRIEF-P and BRIEF include rating forms used by parents to assess subjects’ executive 
functioning. Executive functions broadly encompass a set of cognitive skills that are responsible 
for the planning, initiation, sequencing, and monitoring of complex goal-directed behavior. 
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. The 
clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and Emergent 
Metacognition) and 1 composite score (Global Executive Composite). 
The BRIEF rating form contains items in nonoverlapping clinical scales. These theoretically and 
statistically derived scales form 2 broader Indexes: Behavioral Regulation (3 scales) and 
Metacognition (5 scales), as well as a Global Executive Composite score. 
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses. 
 
Clinical Study Protocol, Section 12.1.2.2 (Other safety variables), final paragraph. Original 
text: 
Changes in behavior and development from Baseline as measured using the Achenbach CBCL 
for children 18 months and older (CBCL/1½-5 and CBCL/6-18) and Bayley-III scales for 
children <18 months of age will be summarized descriptively and presented by visit. Baseline is 
defined as Visit 1 for subjects from SP847 or other epilepsy studies. Baseline values for subjects 
who enroll directly into SP848 will be taken from the Screening Visit. 
 
Was revised as follows: 
Changes in behavior and development from Baseline as measured using the Achenbach CBCL 
for children 18 months and older (CBCL/1½-5 and CBCL/6-18) and Bayley-III scales for 
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children <18 months of age will be summarized descriptively and presented by visit. Changes in 
cognitive function as measured using the BRIEF-P/BRIEF will be summarized by descriptive 
statistics at each visit. Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy 
studies. Baseline values for subjects who enroll directly into SP848 will be taken from the 
Screening Visit. 
 
Clinical Study Protocol, Section 12.1.4.4 (PedsQL) was newly added as follows: 
The PedsQL score and change from Baseline scores will be analyzed in a descriptive manner. 
Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy studies. Baseline values 
for subjects who enroll directly into SP848 will be taken from the Screening Visit. 
 
Clinical Study Protocol, Section 12.1.4.5 (Health care resource use) was newly added as 
follows: 
Descriptive statistics will be presented for the number of medical resources used (medications, 
consultations, procedures, hospitalizations, and length of hospital stays). 
 
Clinical Study Protocol, Section 15 (References). The following references were added: 
Varni JW, Limbers CA, Neighbors K, Schulz K, Lieu JE, Heffer RW, et al. The PedsQL™ 
Infant Scales: feasibility, internal consistency reliability, and validity in healthy and ill infants. 
Qual Life Res. 2011;20:45-55. 
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 
2001;39:800-12. 
 
Clinical Study Protocol, Section 16.1 (Tabular schedule of study procedures) was updated to the 
following: 
 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Blood sample for concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 17 years) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xn 
 
 
LCM return/compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSo 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X 
 
Achenbach CBCL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Bayley-III scales 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
PedsQL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
AE reportingq 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone contact). 
b 
For subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), Visit 1 is also the last visit of the primary study. At Visit 1, the informed 
consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be updated, body weight and height and concomitant medications including 
AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an Unscheduled Visit. 
Height will not be recorded at an Unscheduled Visit. 
f 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final 
dose of study medication. 
g 
This TC occurs 28 to 35 days after the last dose of LCM. 
h 
For subjects enrolling from SP847 or other LCM pediatric clinical studies in epilepsy, assessments should have been done as part of the last visit of the primary study. For 
subjects enrolling directly into SP848, these asssessments should be completed at Visit 1. 
i 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
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j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential, serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and the Final Visit. Urine pregnancy tests will be 
performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical monitor, whenever possible. 
n 
As applicable  
o 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
p 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
q 
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 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13/TermV  ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PKh 
X 
 
X 
X 
X 
X 
 
 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 
17 years) 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
Xl 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xl 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
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Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13/TermV  ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
C-SSRSm 
X 
 
X 
X 
X 
X 
Xn 
X 
 
Achenbach CBCL 
 
 
X 
 
X 
X 
 
 
 
Bayley-III scales 
 
 
X 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
 
 
X 
 
X 
X 
 
 
 
PedsQL 
 
 
X 
 
X 
X 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; S=serum; TC=telephone contact; TermV=Termination Visit; U=urine; 
Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for 
an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Early Termination Visit and at the Final Visit. Urine pregnancy 
tests will be performed at Visits 10, 11, 12, and 13. 
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j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
l 
As applicable. 
m 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
n 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
 
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Table 3.  Schedule of study procedures for SP848 (Screening Visit and Titration Visits, subjects enrolling directly into SP848) 
Study SP848 
Screening 
Titration Visits 
Visit 
Screening Visit 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Seizure history 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
X 
 
 
 
 
 
 
Physical exam (brief) 
 
X 
X 
X 
X 
X 
X 
Neurological exam (complete) 
X 
 
 
 
 
 
 
Neurological exam (brief) 
 
X 
X 
X 
X 
X 
X 
12-lead ECGa 
X 
X 
X 
X 
X 
X 
X 
Blood pressure and pulse 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Clinical chemistry and hematology blood 
sample 
X 
 
 
 
X 
 
 
Endocrinology blood sample 
X 
 
 
 
X 
 
 
Urinalysis (subjects aged 5 to 17 years) 
X 
 
 
 
X 
 
 
Pregnancy testb 
X 
 
 
 
 
 
 
Tanner Stage 
X 
 
 
 
 
 
 
Clinical GIC 
 
 
 
 
 
 
 
Caregiver GIC 
 
 
 
 
 
 
 
Dispense LCM 
 
X 
X 
X 
X 
X 
X 
LCM return/compliance 
 
X 
X 
X 
X 
X 
X 
Dispense diary 
X 
X 
X 
X 
X 
X 
X 
Diary assessment 
 
X 
X 
X 
X 
X 
X 
C-SSRSc 
X 
X 
X 
X 
X 
X 
X 
Achenbach CBCL 
X 
 
 
 
 
 
 
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Table 3.  Schedule of study procedures for SP848 (Screening Visit and Titration Visits, subjects enrolling directly into SP848) 
Study SP848 
Screening 
Titration Visits 
Visit 
Screening Visit 
Titration 
Visit 1 
Titration 
Visit 2 
Titration 
Visit 3 
Titration 
Visit 4 
Titration 
Visit 5 
Titration 
Visit 6 
Bayley-III scales 
X 
 
 
 
 
 
 
BRIEF-P/BRIEF 
X 
 
 
 
 
 
 
PedsQL 
X 
 
 
 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; AEDs=antiepileptic drugs; Cmax=maximum plasma concentration; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; GIC=Global Impression of Change; LCM=lacosamide 
a 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
b 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Screening Visit.  
c 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
 
 
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Clinical Study Protocol, Section 16.3 (Declaration and signatures of person responsible for the 
study). The signature block for the Clinical Project Manager was updated as follows: 
 
Clinical Project Manager 
, RN, MSN  
 
_________________________________________ 
 
 
 
 
 
 
Date / Signature 
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17.6 
PROTOCOL AMENDMENT 6 
RATIONALE FOR THE AMENDMENT 
The primary purpose of this protocol amendment is to permit enrollment of up to approximately 
75 eligible pediatric subjects ≥4 years to <17 years of age with partial-onset seizures (deemed 
appropriate for treatment with LCM) who previously participated in the iv LCM clinical study, 
EP0060. The purpose of enrolling these subjects is to obtain additional long-term safety 
exposures in the age range of ≥4 years to <17 years of age; the additional long-term safety data 
will be included in planned regulatory submissions for LCM as adjunctive therapy for 
partial-onset seizures in pediatric subjects ≥4 years to ≤17 years of age with epilepsy. 
In addition, Sponsor language for monitoring of PDILI events was added to increase clarity for 
the sites and to align across programs. Addition of this language is to align with FDA guidance 
regarding monitoring of PDILI events and does not reflect a change in the liver safety signal for 
LCM. 
Furthermore, administrative changes, including the update of the study team and minor 
corrections (ie, CRF to eCRF and Drug Safety to Patient Safety), incorporation of updated 
protocol template language, and update of the Sponsor Declaration for electronic signature, have 
been made. 
MODIFICATIONS/CHANGES 
• The name and contact information for the Clinical Project Manager, Medical Director 
(Medical Therapeutics), and Safety Representative (Patient Safety) were updated. Update to 
Sponsor site fax number to other contacts is not detailed below. 
• Serious AE reporting number was updated for Canada and was removed for Japan (falls 
under global number) 
• Clarifications were added that SP847 is a completed study and that new subjects enrolling 
into SP848 either enroll directly or from other pediatric studies of LCM.  
• Text added to clarify that up to 75 subjects may enroll in SP848 from EP0060. 
• Background information was updated for current status of LCM clinical development 
program 
• Exclusion Criterion 2 was revised to potentially allow subjects from EP0060 who either 
withdrew consent for the sole reason of route of LCM administration or who required more 
than 10 infusions to participate in SP848 pending discussion with and agreement from the 
Medical Monitor. 
• Exclusion Criterion 9 was modified to update creatinine clearance exclusion to <30mL/min 
to align with the rest of the LCM program. The liver function requirements from Exclusion 
Criterion 9 were moved to a new exclusion criterion (19). 
• Exclusion Criterion 16, which excluded use of vigabatrin or felbamate, was removed. 
• Exclusion Criterion 17 and the list of prohibited medications were updated to exclude use of 
MAOI-A inhibitors and cannabidiols. 
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• Exclusion Criterion 20 was added such that subjects who initiated treatment in EP0060 could 
not enter SP848 if they had previously participated in a long-term open-label study. 
• Clarification was added to withdrawal criteria for subjects transitioning to SP848 from 
EP0060. 
• Sponsor language for monitoring of PDILI events was added to increase clarity for the sites 
and to align across programs . 
• Clarification was added for prohibited concomitant medications. 
• Routine blood samples for LCM PK analysis during Year 2 will be collected for subjects 
enrolled at sites in Japan. Across all sites, a blood sample for LCM PK analysis may be 
collected if the subject has an Unscheduled Visit due to a SAE. 
• Blood samples for concomitant AED PK analysis were removed from Year 2 visits; however, 
a sample may be collected if the subject has an Unscheduled Visit due to a SAE. 
• Updates to the CRF language were incorporated to accommodate use of an eCRF. Minor 
edits to change CRF to eCRF in Section 8 are not itemized below. 
• Updated protocol template language was incorporated regarding suspected transmission of 
infectious agent, AEs of special interest, drug supply, drug accountability, auditing, and data 
handling and record keeping. 
• Schedules of Assessments were updated to reflect changes above and to indicate which 
Visit 1 assessments would need to be performed for subjects enrolling from EP0060. 
• The Sponsor Declaration has been updated for electronic signature. 
REFERENCE 
Clinical Study Protocol, Contact information for the Clinical Project Manager, Medical 
Director (Medical Therapeutics), and Safety Representative (Patient Safety) were updated. 
Original text: 
Clinical Project Manager: 
Name: 
, RN, MSN 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
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Medical Director (Medical Therapeutics): 
Name: 
 MD 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Safety Physician (Drug Safety): 
Name: 
, MD 
Address: 
UCB Pharma S.A. Belgium 
Chemin du Foriest 
B-1420 Braine-L’Alleud, Belgium 
Phone/Fax: 
 
E-mail: 
 
Were revised as follows: 
Clinical Project Manager: 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Medical Director (Medical Therapeutics): 
Name: 
, MD 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
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Safety Representative (Patient Safety): 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
 
Clinical Study Protocol, Serious Adverse Event Reporting details were updated. Original text: 
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 5283 1869 
Email 
Global (except Japan): DS_ICT@ucb.com 
Japan: JDSO@ucb.com  
Was revised as follows: 
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 
 
List of Abbreviations: 
The abbreviations of ALP, CDMS, PDILI, and RDC were added. The abbreviation eCRF and PS 
replaced the terms CRF and DS, respectively. The term MAO was clarified to MAOI, and the 
definition of ICH was updated to reflect the recent name change. 
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Clinical Study Protocol, Section 1 (Summary, Original text, second and third paragraphs:  
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies in other epilepsy syndromes. In addition, at selected sites, 
beginning with Protocol Amendment 4, up to approximately 100 eligible pediatric subjects 
≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate for treatment with 
adjunctive LCM) who have not previously participated in a LCM clinical study will be permitted 
to enroll directly into SP848. The purpose of enrolling these subjects directly into SP848 is to 
obtain sufficient long-term safety exposures in the age range of ≥4 years to ≤17 years of age; the 
long-term safety data will be included in planned regulatory submissions for LCM as adjunctive 
therapy for partial-onset seizures in pediatric subjects ≥4 years to ≤17 years of age with epilepsy. 
At selected sites, subjects may also be able to participate in a substudy without withdrawing from 
SP848. 
Subjects who complete SP847 or another applicable LCM pediatric epilepsy study and choose to 
enter this open-label study will begin on the LCM dose they achieved in SP847 or their previous 
pediatric LCM study. Subjects who discontinued from SP847 due to a dose reduction or status 
epilepticus, but for whom it is determined medically appropriate to enter this open-label study, 
will also begin on the LCM dose they achieved in SP847. Subjects who meet eligibility 
requirements and enroll directly into SP848 without previous participation in a LCM clinical 
study will initiate treatment with LCM, and the LCM dose will be titrated to a level to optimize 
tolerability and seizure control (up to a maximum level as described below). 
Was revised as follows:  
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes.  
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. The purpose of enrolling these 
subjects directly into SP848 is to obtain sufficient long-term safety exposures in the age range of 
≥4 years to ≤17 years of age; the long-term safety data will be included in planned regulatory 
submissions for LCM as adjunctive therapy for partial-onset seizures in pediatric subjects 
≥4 years to ≤17 years of age with epilepsy.  
Protocol Amendment 6 allows up to approximately 75 additional eligible pediatric subjects with 
epilepsy who participated in EP0060 to enroll into SP848. In addition, subjects already enrolled 
in SP848 may participate in EP0060, if eligible, and then resume participation in SP848. These 
subjects may either voluntarily choose to have an iv LCM infusion even though they are capable 
of taking oral LCM or require iv LCM infusion due to a medical reason or procedure (ie, unable 
to take oral LCM). 
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Subjects who complete SP847 or another applicable LCM pediatric epilepsy study and choose to 
enter this open-label study will begin on the LCM dose they achieved in SP847 or their previous 
pediatric LCM study. Subjects who discontinued from SP847 due to a dose reduction or status 
epilepticus, but for whom it is determined medically appropriate to enter this open-label study, 
will also begin on the LCM dose they achieved in SP847. Subjects who enroll from EP0060 will 
begin SP848 with an equivalent LCM dose as they last received in EP0060; however, the LCM 
dose may be further titrated/adjusted to a level to optimize tolerability and seizure control (up to 
a maximum level as described below). Subjects who meet eligibility requirements and enroll 
directly into SP848 without previous participation in a LCM clinical study will initiate treatment 
with LCM, and the LCM dose will be titrated to a level to optimize tolerability and seizure 
control (up to a maximum level as described below). 
 
Clinical Study Protocol, Section 2 (Background information). Original text, first paragraph: 
Epilepsy is the second most prevalent neurological disorder in the world. More than 40 million 
people have epilepsy–about 1% of the world’s population (Dichek, 1999). 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). In the 
past decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
Was revised as follows: 
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated that 
almost 70 million people suffer from epilepsy (Ngugi et al, 2011). Although some forms of 
epilepsy may respond to surgical treatment and others may not require any treatment at all, most 
patients with epilepsy require appropriate pharmacological therapy (Perucca, 1996). In the past 
decade, several new options for the medical treatment of epilepsy have been introduced, 
including novel AEDs and vagus nerve stimulation. 
 
Clinical Study Protocol, Section 2 (Background information). Original text, fourth paragraph: 
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 (Appleton et al, 1999; Duchowny et al, 1999; 
Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006). 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). 
Was revised as follows: 
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; 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 
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available AEDs, or experience significant adverse drug effects (Hadjiloizou and Bourgeois, 
2007). 
 
Clinical Study Protocol, Section 2 (Background information). Original text, sixth and seventh 
paragraphs: 
Lacosamide has been approved 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 (oral tablets, oral solution [syrup], and solution for intravenous [iv] infusion) and in 
patients 17 years of age and older in the United States (oral tablets, oral solution, and solution for 
iv infusion). The oral solution (syrup) is a formulation suitable for administration to children. 
Bioequivalence has been shown between the tablet and oral solution (syrup) formulations, 
comparing 2 tablets of LCM 100mg and the oral solution (syrup) containing LCM 200mg, after 
single-dose administration in healthy subjects. The PK of LCM and its major metabolite, SPM 
12809 (O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after 
single oral doses of LCM 200mg administered as tablets or as oral solution (syrup). 
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
400mg bid (800mg/day) were evaluated in approximately 700 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 2200 adult subjects in other indications (eg, 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 (199 patients) who were receiving adjunctive LCM tablets. 
Were revised as follows: 
Lacosamide (200mg/day to 400mg/day) is approved and indicated as adjunctive therapy in the 
treatment of partial-onset seizures with or without secondary generalization in adult and 
adolescent (16 to 18 years of age) patients with epilepsy and was first approved in Aug 2008 by 
the European Commission. Lacosamide is available in tablet (50mg, 100mg, 150mg, and 200mg) 
and syrup (10mg/mL) oral formulations as well as solution for infusion (10mg/mL) formulation 
for use as temporary iv replacement when oral administration is not feasible. Lacosamide 
(200mg/day to 400mg/day) was approved in the US in Oct 2008 as adjunctive therapy and in 
Aug 2014 as monotherapy in the treatment of partial-onset seizures in patients 17 years of age 
and older. Initiation of adjunctive LCM treatment with a single loading dose of LCM 200mg 
(oral tablets, syrup, or iv infusion) followed 12 hours later by a LCM 100mg twice daily 
(200mg/day) maintenance dose regimen was also approved by the European Commission in Nov 
2012. Use of a LCM 200mg loading dose for initiation of initial LCM monotherapy, conversion 
to LCM monotherapy, or adjunctive therapy was approved in the US in Aug 2014.  
The oral solution (syrup) is a formulation suitable for administration to children. Bioequivalence 
has been shown between the tablet and oral solution (syrup) formulations, comparing 2 tablets of 
LCM 100mg and the oral solution (syrup) containing LCM 200mg, after single-dose 
administration in healthy subjects. The PK of LCM and its major metabolite, SPM 12809 
(O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after single oral 
doses of LCM 200mg administered as tablets or as oral solution (syrup). 
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Clinical Study Protocol, Section 2 (Background information). Original text, tenth paragraph: 
SP847 is an open-label, dose-titration, safety, tolerability, and PK study to evaluate LCM as 
adjunctive therapy in children with uncontrolled partial-onset seizures. Approximately 
42 children (aged 1 month to 17 years) with uncontrolled partial-onset seizures on a stable dose 
regimen of at least 1 but no more than 3 AEDs will be enrolled. The study consists of a 
Screening Phase, a Treatment Phase, and an End-of-Study Phase. The duration of treatment for 
an individual subject may be up to approximately 13 weeks. Approximately 200 additional 
subjects who may participate in other LCM pediatric clinical studies in epilepsy will also be 
eligible to participate in SP848. 
Was revised as follows: 
SP847 was an open-label, dose-titration, safety, tolerability, and PK study to evaluate LCM as 
adjunctive therapy in children with uncontrolled partial-onset seizures. The study completed on 
26 Aug 2014. Forty-seven subjects (aged 1 month to 17 years) with uncontrolled partial-onset 
seizures on a stable dose regimen of at least 1 but no more than 3 AEDs were enrolled and 
treated during the study. The study consisted of a Screening Phase, a Treatment Phase, and an 
End-of-Study Phase. The duration of treatment for an individual subject was up to approximately 
13 weeks.  
 
Clinical Study Protocol, Section 2 (Background information). Original text, last paragraph: 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies in other epilepsy syndromes. In addition, at selected sites, 
beginning with Protocol Amendment 4, up to approximately 100 eligible pediatric subjects 
≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate for treatment with 
adjunctive LCM) who have not previously participated in a LCM clinical study will be permitted 
to enroll directly into SP848. The purpose of enrolling these subjects directly into SP848 is to 
obtain additional long-term safety exposures in the age range of ≥4 years to ≤17 years of age; the 
additional long-term safety data will be included in planned regulatory submissions for LCM as 
adjunctive therapy for partial-onset seizures. 
Was revised as follows: 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes. In addition, at selected sites, beginning with Protocol Amendment 4, up to 
approximately 100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset 
seizures (deemed appropriate for treatment with adjunctive LCM) who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. The purpose 
of enrolling these subjects directly into SP848 is to obtain additional long-term safety exposures 
in the age range of ≥4 years to ≤17 years of age; the additional long-term safety data will be 
included in planned regulatory submissions for LCM as adjunctive therapy for partial-onset 
seizures. 
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Clinical Study Protocol, Section 4.1.1 (Subjects enrolling from SP847 or other LCM pediatric 
clinical studies in epilepsy). Original text: 
Subjects who complete SP847 (including discontinuation from SP847 due to a dose reduction or 
status epilepticus) or subjects from another applicable LCM pediatric clinical study in epilepsy 
and who choose to enter the open-label study, will begin on the LCM dose they achieved in the 
primary study. Subjects will be able to continue on LCM oral solution (syrup) or switch to LCM 
tablets. During the study, investigators will be allowed to increase or decrease the dose of LCM 
and/or concomitant AEDs to optimize tolerability and seizure reduction for each subject. The 
investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the corresponding 
dose levels for the tablet formulation), not to exceed 600mg/day based on body weight, even if 
the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in SP848 is 
12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM dose must occur only 
during office visits. 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. When subjects withdraw from the study, it is recommended that the 
study medication be tapered gradually in weekly decrements of 4mg/kg/day (oral solution 
[syrup]) or 200mg/day (tablets) for subjects who have achieved a dose of LCM ≥6mg/kg/day 
(oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly decrements of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if medically necessary. In 
case of an emergency, a faster taper is permitted after discussion with the medical monitor, 
whenever possible. 
Was revised as follows: 
Subjects who complete SP847 (including discontinuation from SP847 due to a dose reduction or 
status epilepticus) or subjects from another applicable LCM pediatric clinical study in epilepsy 
and who choose to enter the open-label study, will begin with an equivalent LCM dose as they 
last received in the primary study. Subjects will be able to continue on LCM oral solution (syrup) 
or switch to LCM tablets. During the study, investigators will be allowed to increase or decrease 
the dose of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for 
each subject. The investigator may titrate/adjust the LCM dose to a minimum of 2mg/kg/day 
(oral solution [syrup]) or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution 
[syrup]) or the corresponding dose levels for the tablet formulation), not to exceed 600mg/day 
based on body weight, even if the subject’s body weight exceeds 50kg. The maximum permitted 
LCM dose in SP848 is 12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM 
dose must occur only during office visits. 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. When subjects withdraw from the study, it is 
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recommended that the study medication be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for subjects who have achieved a dose 
of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower taper in weekly 
decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is permitted, if 
medically necessary. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible. 
 
Clinical Study Protocol, Section 4.3.2 (Exclusion criteria). Original text: 
2. Subject meets the withdrawal criteria for the primary study (with the exception of subjects 
who discontinued due to a dose reduction or status epilepticus), or is experiencing an 
ongoing serious AE (SAE). 
9. Subject has an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin level greater than or equal to 2 times the upper limit of normal (ULN), or creatinine 
clearance less than 50mL/min. 
16. Subject has been treated with vigabatrin or felbamate for at least 12 months prior to entering 
the study and has experienced any toxicity issues with these treatments. Note: Any subject 
who is currently treated with vigabatrin or felbamate, and has received vigabatrin for a period 
of less than 12 months, is excluded from the study. Subjects who have received vigabatrin in 
the past must have documentation of an assessment for visual field defects after completion 
of vigabatrin therapy. 
17. Subject is taking monoamine oxidase (MAO) inhibitors or narcotic analgesics. 
Were revised as follows: 
2. Subject meets either of the following: 
b. Withdrawal criteria for the primary study (with the exception of subjects who discontinued 
due to a dose reduction or status epilepticus).  For subjects entering from EP0060, if the 
subject (or legal guardian) withdraws consent solely due to route of LCM administration (iv) 
or if the subject requires more than 10 iv LCM infusions, the subject may be allowed to 
participant in SP848 after discussion with and agreement from the Medical Monitor. 
c. Ongoing serious AE (SAE).  
9. Subject has a creatinine clearance less than 30mL/min. 
16. Subject is taking monoamine oxidase inhibitors-A (MAOI-A) or narcotic analgesics. 
19. Subject has >2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a Baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
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If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
Subjects who were directly enrolled in EP0060 for iv LCM replacement therapy or to 
initiate LCM treatment are not permitted to enroll in the study if any of the following 
criteria are met: 
20. Subjects have previously participated in a long-term, open-label LCM study. 
 
Clinical Study Protocol, Section 4.3.3 (Criteria for withdrawal). Original text: 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is unwilling 
or unable to allow the subject to continue in the study. 
8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
9.    Subject experiences convulsive status epilepticus (if none had occurred prior to study entry) 
and is compliant with study treatment 
10.  In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x 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 
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withdrawn from the study. The LFTs will be repeated as soon as possible, and in no case 
more than 1 week later.  
11. For subject who did not complete a C-SSRS at Screening, subject has a lifetime history 
(prior to study entry or since study start) of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt) of the screening version of the C-SSRS. The 
investigator must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
12. For all subjects ≥6 years of age, regardless of whether or not a C-SSRS was completed at 
Screening, subject has actual suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “since last visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study. 
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
4.   Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3xULN or stable condition). The investigator is 
to decide whether or not to stop the study medication. 
5.   For subject who did not complete a C-SSRS at Screening, subject had actual suicidal ideation 
in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the screening version of the C-SSRS. The investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the patient from the study. 
Was revised as follows: 
All subjects discontinuing treatment with study medication for any reason should taper off 
medication as described in Section 4.4.1. Whenever possible, these cases should be discussed 
with the medical monitor prior to withdrawing the subject from the study. 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 following criteria for subject withdrawal from SP848 are outlined 
below. Additional discontinuation criteria for potential drug-induced liver injury are presented in 
Section 4.3.3.1. 
Participation in this study must be discontinued for any of the following reasons: 
1.   Intolerable AEs, including clinically relevant abnormal laboratory findings that, in the 
opinion of the investigator, preclude further participation in the study 
2.   The request of the Sponsor or a Regulatory Agency 
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3.    Subject achieves menarche during the study and does not practice an acceptable method of 
contraception for the duration of the study (unless sexually abstinent). 
4.    Subject becomes pregnant, as evidenced by a positive pregnancy test. 
5.    Subject has a corrected QT interval (QTc) of greater than or equal to 500ms as confirmed by 
a cardiologist overread on any ECG. 
6.    Subject develops a second-degree atrioventricular (AV) block while awake or develops a 
third-degree AV block at any time. 
7.    Subject is unwilling or unable to continue, or the caregiver/parent/legal guardian is unwilling 
or unable to allow the subject to continue in the study. 
8.    Investigator’s decision that withdrawal from further participation would be in the subject’s 
best interest. 
9.    Subject experiences convulsive status epilepticus (if none had occurred prior to study entry) 
and is compliant with study treatment 
11.   For subject who did not complete a C-SSRS at Screening, subject has a lifetime history 
(prior to study entry or since study start) of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt) of the screening version of the C-SSRS. The 
investigator must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
12. For all subjects ≥6 years of age, regardless of whether or not a C-SSRS was completed at 
Screening, subject has actual suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “since last visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be withdrawn 
from the study. 
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. 
3.   Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator. 
5.   For subject who did not complete a C-SSRS at Screening, subject had actual suicidal ideation 
in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the screening version of the C-SSRS. The investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the patient from the study. 
If a subject from SP848 enrolls in EP0060 and either withdraws consent solely due to route of 
LCM administration (iv) or if the subject requires more than 10 iv LCM infusions, the subject 
may be allowed to return to SP848 after discussion with and agreement from the Medical 
Monitor. If a subject from SP848 is advised to withdraw from the SP848 after participation in 
EP0060, the subject will be required to return to the SP848 to complete the required ETV and 
Safety Follow-up assessments. 
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Investigators should attempt to obtain information on subjects in the case of withdrawal. For 
subjects considered as lost to follow up, the investigator should make efforts (at least 1 phone 
call and 1 written message to the subject), and document his/her efforts (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The eCRF 
must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
4.3.3.1 Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
• Subjects with either of the following: 
− ALT or AST ≥5xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP: 
• 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 8.3.2. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
 
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Clinical Study Protocol, Section 4.4.1.1 (Subjects enrolling from SP847 or other LCM pediatric 
clinical studies in epilepsy).  
The following text was added as a last paragraph:  
Subjects who enroll from EP0060 will begin SP848 with an equivalent dose to the last dose they 
received in EP0060; however, the LCM dose may be further titrated/adjusted to a level to 
optimize tolerability and seizure control (up to a maximum level as described in Section 4.4.1.3). 
For those subjects who initiated adjunctive LCM treatment in EP0060, the recommended LCM 
dose titration approach is outlined in Section 4.4.1.2. 
 
Clinical Study Protocol, Section 4.6 (Concomitant medication[s]/treatment[s]). Original text, 
through second paragraph: 
The following medications/therapies are prohibited during the course of this study: 
• Monoamine oxidase inhibitors 
• Narcotic analgesics 
All concomitant medications and treatments must be recorded in the appropriate study 
documents (case report form [CRF] and source document). 
Was revised as follows: 
The following medications/therapies are prohibited during the course of this study: 
• Monoamine oxidase inhibitor-A compounds 
• Narcotic analgesics 
• Cannabidiols not approved or indicated for epilepsy by a local health authority 
All concomitant medications and treatments must be recorded in the appropriate study 
documents (eCRF and source document). 
 
Clinical Study Protocol, Section 5.3 (Visit 1[Week 0]). Original text, first, second, and fifth 
paragraphs: 
For subjects who complete SP847, Visit 1 for SP848 is the same as Day 2 of the second PK 
collection time period (which may include an overnight stay at a hospital or medical facility) in 
SP847 (Day 28 for Cohorts 1, 2, 3, and 5 with maximum recommended dose of 8mg/kg/day; 
Day 35 for Cohorts 2 to 5 with maximum recommended dose of 10mg/kg/day; and Day 42 for 
Cohorts 2 to 5 with maximum recommended dose of 12mg/kg/day). For subjects who 
discontinue SP847 due to a dose reduction or status epilepticus, Visit 1 is the Early Termination 
Visit in SP847. For subjects in SP847 who are titrated up to the maximum permitted dose of 
600mg/day sooner than the study schedule would ordinarily indicate (based on body weight) and 
who enroll in SP848, the Early Termination Visit of SP847 will also serve as Visit 1 for SP848. 
For subjects who enroll in SP848 after participation in other LCM pediatric clinical studies in 
epilepsy, SP848 Visit 1 will be specified in the respective primary study protocol. 
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Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments (applicable only for subjects for whom Visit 1 is the first 
clinic visit for SP848), and a complete medical history update will be obtained. The data for the 
following assessments will be taken from the last assessment during SP847 (or other primary 
study as applicable): 
Were revised as follows: 
For subjects who completed SP847, Visit 1 for SP848 was the same as Day 2 of the second PK 
collection time period (which may include an overnight stay at a hospital or medical facility) in 
SP847 (Day 28 for Cohorts 1, 2, 3, and 5 with maximum recommended dose of 8mg/kg/day; 
Day 35 for Cohorts 2 to 5 with maximum recommended dose of 10mg/kg/day; and Day 42 for 
Cohorts 2 to 5 with maximum recommended dose of 12mg/kg/day). For subjects who 
discontinued SP847 due to a dose reduction or status epilepticus, Visit 1 was the Early 
Termination Visit in SP847. For subjects in SP847 who were titrated up to the maximum 
permitted dose of 600mg/day sooner than the study schedule would ordinarily indicate (based on 
body weight) and who enroll in SP848, the Early Termination Visit of SP847 also served as 
Visit 1 for SP848. 
For subjects who enroll in SP848 after participation in other LCM pediatric clinical studies 
besides SP847 (ie, SP0966 and EP0060) in epilepsy, SP848 Visit 1 will be specified in the 
respective primary study protocol. 
Each subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria and 
the results of the following assessments (applicable only for subjects for whom Visit 1 is the first 
clinic visit for SP848), and a complete medical history update will be obtained. If available, the 
data for the following assessments will be taken from the last assessment during SP847 (or other 
primary study, as applicable): 
 
Clinical Study Protocol, Section 5.13 (Visit 10 [Week 60]). Original text: 
Assessments for Visit 10 (Week 60) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exception: a 12-lead ECG is not conducted at Visit 10. 
Was revised as follows: 
Assessments for Visit 10 (Week 60) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exceptions: a 12-lead ECG is not conducted at Visit 10 (all sites) 
and a PK sample is routinely drawn at sites in Japan (removed for all other sites). 
 
Clinical Study Protocol, Section 5.14 (Visit 11 [Week 72]). Original text: 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions: brief physical and neurological exams are conducted 
(instead of complete physical and neurological exams as indicated for Visit 5), the laboratory 
blood sample is collected only for clinical chemistry and hematology (ie, no endocrinology), the 
palatability and ease of use questionnaire is completed, and a 12-lead ECG (2 interpretable 
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recordings approximately 20 to 30 minutes apart prior to vital signs assessment and collection of 
blood sample) is conducted. 
Was revised as follows: 
Assessments for Visit 11 (Week 72) are the same as those described for Visit 5 (Week 20), in 
Section 5.8, with the following exceptions for all sites: brief physical and neurological exams are 
conducted (instead of complete physical and neurological exams as indicated for Visit 5), the 
laboratory blood sample is collected only for clinical chemistry and hematology (ie, no 
endocrinology), the palatability and ease of use questionnaire is completed, and a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted. In addition to the noted differences, a PK sample is 
routinely drawn at sites in Japan (removed for all other sites). 
 
Clinical Study Protocol, Section 5.15 (Visit 12 [Week 84]). Original text: 
Assessments for Visit 12 (Week 84) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exceptions: the laboratory blood sample is collected for 
endocrinology as well as clinical chemistry and hematology and a 12-lead ECG is not conducted. 
Was revised as follows: 
Assessments for Visit 12 (Week 84) are the same as those described for Visit 2 (Week 4), in 
Section 5.5, with the following exceptions for all sites: the laboratory blood sample is collected 
for endocrinology as well as clinical chemistry and hematology and a 12-lead ECG is not 
conducted. In addition to the noted differences, a PK sample is routinely drawn at sites in Japan 
(removed for all other sites). 
 
Clinical Study Protocol, Section 5.16 (Visit 13/Termination Visit [Week 96]). Original text, third 
paragraph: 
Assessments for Visit 13/Termination Visit (Week 96) are the same as those described for 
Visit 5 (Week 20), in Section 5.8, with the following exceptions: the laboratory blood sample is 
collected only for clinical chemistry and hematology (ie, no endocrinology), a 12-lead ECG 
(2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment 
and collection of blood sample) is conducted, a Tanner Stage assessment is conducted (if 
applicable), an Achenbach CBCL is conducted, Bayley-III scales are conducted, 
BRIEF-P/BRIEF and PedsQL scores are obtained, and the palatability and ease of use 
questionnaire is completed. 
Was revised as follows: 
Assessments for Visit 13/Termination Visit (Week 96) are the same as those described for 
Visit 5 (Week 20), in Section 5.8, with the following exceptions for all sites: the laboratory blood 
sample is collected only for clinical chemistry and hematology (ie, no endocrinology), a 12-lead 
ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs 
assessment and collection of blood sample) is conducted, a Tanner Stage assessment is 
conducted (if applicable), an Achenbach CBCL is conducted, Bayley-III scales are conducted, 
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BRIEF-P/BRIEF and PedsQL scores are obtained, and the palatability and ease of use 
questionnaire is completed. In addition to the noted differences, a PK sample is routinely drawn 
at sites in Japan (removed for all other sites). 
 
Clinical Study Protocol, Section 5.17 (Early Termination Visit). Original text, ninth bullet: 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM)  
Was revised as follows: 
• Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM)  
− Under any circumstance for an ETV during Year 1 
− If possible, if the early termination during Year 2 is due to a SAE and the event is 
ongoing 
 
Clinical Study Protocol, Section 5.18 (Unscheduled Visit[s]). The final bullet point was added: 
• If possible, a blood sample for LCM and concomitant AED plasma concentrations (at any 
time post-dosing with LCM) if the unscheduled visit is due to a SAE  
 
Clinical Study Protocol, Section 8.1.7 (Suspected transmission of an infectious agent via a 
medicinal product). Was added to align with new protocol template and subsequent sections 
were renumbered as a result: 
8.1.7  Suspected transmission of an infectious agent via a medicinal product 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
 
Clinical Study Protocol, Section 8.2.1 (Definition of serious adverse event). Original text, fifth 
bullet point: 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition of serious 
Important medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home or blood dyscrasias that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
Was revised as follows:  
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• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition of serious 
(Important medical events include, but are not limited to, potential Hy’s Law [see 
Section 8.2.2], 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.) 
 
Clinical Study Protocol, Section 8.2.2 (AEs of special interest). Original text: 
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 
Food and Drug Administration: 
An AE or laboratory value (as defined below) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system 
involvement) combined with at least one of the following: fever, rash, 
lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
• Eosinophils % ≥10% 
• Eosinophils absolute ≥0.5G/L 
• Neutrophils absolute <1.5G/L 
• Platelets ≤100G/L 
• ALT ≥2x ULN 
• AST ≥2x ULN 
Was revised as follows:  
An AE of special interest is any AE that a regulatory authority has mandated to 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 the LCM AEs of special interest:  
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• 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 
Food and Drug Administration: 
An AE or laboratory value (as defined below) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, 
colitis, encephalitis, pancreatitis, myositis, arthritis, or hematologic system 
involvement) combined with at least one of the following: fever, rash, 
lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
• Eosinophils % ≥10% 
• Eosinophils absolute ≥0.5G/L 
• Neutrophils absolute <1.5G/L 
• Platelets ≤100G/L 
• ALT ≥2x ULN 
• AST ≥2x 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. 
 
Clinical Study Protocol, Section 8.2.5 (Follow up of serious adverse events). Original text: 
A 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. 
Was revised as follows:  
A SAE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. This 
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follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events are provided in Section 8.3.2.4. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety database without limitation of time. 
 
Clinical Study Protocol, Section 8.2.6 (Anticipated serious adverse events). Original text, first 
paragraph: 
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 8.2.4. 
Was revised as follows:  
The following list of anticipated SAEs is anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure. This list does not change the 
investigator’s obligation to report all SAEs (including anticipated SAEs) as detailed in 
Section 8.2.4. 
 
Clinical Study Protocol, Section 8.3.1 (Liver function tests). Original text: 
8.3.1  Liver function tests 
Transaminases (AST, ALT, or both) ≥3x ULN but <5x ULN, in the presence of total bilirubin 
≥2x ULN, or transaminases (AST, ALT, or both) ≥5x ULN will result in immediate 
discontinuation of LCM 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 (see Section 4.3.3). 
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. 
Was revised as follows:  
8.3.2  Liver function tests and evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 4.3.3.1 with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
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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 8.2.2), and, if applicable, also reported as an 
SAE (see Section 8.2.1).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 8‒1 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 8.3.2.1). 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 8.3.2.4).  
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 4.3.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
The table below summarizes the approach to investigate PDILI.   
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Table 8-1: 
Required investigations and follow up of 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 8.3.2.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within Baseline 
values.d 
 
≥5xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥3xULN 
(and ≥2x 
Baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met. 
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 8.3.2.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
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Table 8-1: 
Required investigations and follow up of 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 8.3.2.3) 
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 8.3.2.1. 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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8.3.2.1 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 8.3.2.3) and SAE report (if applicable). 
8.3.2.2 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 4.3.3.1 and Table 8‒1 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. 
8.3.2.3 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 8‒2 (laboratory measurements) and Table 8‒3 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
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Table 8-2: 
PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; 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: 
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Table 8-3: 
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 
 
8.3.2.4 Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in  
Table 8‒1. 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. 
 
Clinical Study Protocol, Section 8.3.2 (Pregnancy testing). Number revised to Section 8.3.1. 
 
Clinical Study Protocol, Section 9.1 (Manufacturing, packaging, and labeling). Original text, 
first paragraph: 
Lacosamide oral solution (syrup) and tablets are manufactured and supplied by UCB 
BIOSCIENCES GmbH, Monheim am Rhein, Germany. Lacosamide is manufactured, packaged, 
and labeled according to Good Manufacturing Practice guidelines and applicable laws and 
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regulations. It is suitably packaged, in such a way as to protect the product from deterioration 
during transport and storage. 
Was revised as follows:  
Lacosamide is manufactured, packaged, and labeled according to Good Manufacturing Practice 
guidelines and applicable laws and regulations. It is suitably packaged, in such a way as to 
protect the product from deterioration during transport and storage. 
 
Clinical Study Protocol, Section 9.2 (Supply, handling, and storage). Original text: 
Lacosamide (oral solution [syrup] and tablet) is stable at room temperature and is to be stored at 
temperatures not exceeding 25°C (77°F). Lacosamide should not be frozen. 
The investigator (or designee) is responsible for safe and proper storage of LCM at the site. 
Lacosamide stored by the investigator is to be kept in a secured area with limited access. 
Was revised as follows:  
Lacosamide (oral solution [syrup] and tablet) is stable at room temperature and is to be stored at 
temperatures not exceeding 25°C (77°F). Lacosamide should not be frozen. 
The investigator (or designee) is responsible for safe and proper storage of LCM at the site. 
Lacosamide stored by the investigator is to be kept in a secured area with limited access 
according to the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlling the temperature and by 
completion of a temperature log in accordance with local requirements on a regular basis, 
showing minimum and maximum temperatures reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label. 
 
Clinical Study Protocol, Section 9.3 (Drug accountability procedures). Original text: 
Responsibility for drug accountability at the study site rests with the investigator. 
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 LCM is used only in accordance with the protocol. 
The investigator (or designee) is expected to collect and retain all used, unused, and partially 
used containers of LCM until collection. 
The investigator should maintain records that document the drug’s delivery to the study site, the 
inventory at the site, the use by each subject, and return to UCB BIOSCIENCES or alternative. 
These records include dates, quantities, batch numbers, expiry dates, and the unique code 
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numbers assigned to the LCM and study subjects. The investigator (or designee) should maintain 
records that document adequately that the subjects were provided the doses specified by the 
protocol and reconcile all LCM received from UCB BIOSCIENCES. 
Completed accountability records and all used/unused dosing containers will be returned to UCB 
BIOSCIENCES or Contract Research Organization (CRO) at completion of the study. 
Was revised as follows:  
A Drug Accountability form will be used to record LCM dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any LCM lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review. 
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of LCM until returned or destroyed by a UCB representative. 
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 LCM is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired LCM must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol. 
 
Clinical Study Protocol, Section 10.3 (Auditing). Original text: 
As a quality assurance measure, UCB BIOSCIENCES or regulatory authorities may undertake 
audits before, during, and after the study. 
Regulatory authorities and representatives of the relevant IRB/IEC must be allowed to conduct 
inspections at the site. 
The investigator should notify UCB BIOSCIENCES if regulatory authorities contact them to 
schedule an inspection. 
Was revised as follows:  
The investigator will permit study-related audits mandated by UCB, 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 
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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). 
 
Clinical Study Protocol, Section 11.1 (Data handling) and Section 11.2 (Record keeping). 
Original text: 
11.1 
Data handling 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
CRFs and in all required reports. 
Any change or correction to the CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry. Use of correction fluid is not permitted. 
Corrections made after the investigator’s review and signature of the completed CRF will be 
re-signed and dated by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the CRF. 
The investigator will keep a list containing all subjects enrolled into the study. This list remains 
with the investigator and is used for unambiguous identification of each subject. The list contains 
the subject identification number, full name, date of birth, date of enrollment in the study, and 
the hospital number or National Health Security number, if applicable. 
The parent/legal guardian’s consent, subject’s assent, and enrollment in the study must be 
recorded in the subject’s medical record. These data should identify the study and document the 
dates of the subject’s participation. 
11.2 
Record keeping 
To comply with international regulations, the investigator will arrange for the retention of 
essential study documents as described in the ICH-GCP guideline. The guideline requires that 
the documents be retained at least 2 years after the last approval of a marketing application in an 
ICH region when there are no pending or contemplated marketing applications in an ICH region 
or at least 2 years after the formal discontinuation of clinical development of LCM. However, 
UCB BIOSCIENCES requires the documents be retained at least 15 years after completion of the 
study. The documents should be retained for a longer period if required by the applicable 
regulatory authorities. UCB BIOSCIENCES will inform the investigator/institution when 
records no longer need to be retained. 
The investigator should take measures to prevent accidental or premature destruction of records. 
If archiving can no longer be maintained at the site, the investigator will notify the Sponsor. 
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Were revised as follows:  
The parent/legal guardian’s consent, subject’s assent, and enrollment in the study must be 
recorded in the subject’s medical record. These data should identify the study and document the 
dates of the subject’s participation. 
11.1 Case Report form completion 
This study is performed using remote data capture (RDC); the investigator is responsible for 
prompt reporting of accurate, complete, and legible data in the eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. The investigator should 
maintain a list of personnel authorized to enter data into the eCRF. Detailed instructions will be 
provided in the eCRF Completion Guidelines. 
11.2 Database entry and reconciliation 
Electronic 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 
eCRFs once and are subsequently verified. An electronic audit trail system will be maintained 
within the CDMS to track all data changes in the database once the data have been saved initially 
into the system or electronically loaded. Regular backups of the electronic data will be 
performed. 
11.3 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. 
11.4 Archiving and data retention 
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The investigator will contact 
UCB for authorization prior to the destruction of any study records or in the event of accidental 
loss or destruction of any study records. The investigator will also notify UCB should he/she 
relocate or move the study-related files to a location other than that specified in the sponsor’s 
trial master file. 
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Clinical Study Protocol, Section 11.3 (Data Management) is now numbered Section 11.5. 
 
Clinical Study Protocol, Section 12.1.1 (Definition of analysis sets). Original text: 
The primary analysis set will be the Safety Set (SS), which is defined as all subjects who meet 
the inclusion/exclusion criteria, sign an informed consent form, and take at least 1 dose of LCM. 
All subjects from the SS with valid concentration data and the absence of major protocol 
deviations that may have an influence on the concentration data will be included in the 
Pharmacokinetic Per-Protocol Set (PK-PPS). The validity of concentration data will be 
determined by the responsible UCB BIOSCIENCES study team including the responsible 
clinical pharmacokineticist and bioanalytic personnel. 
Was revised as follows:  
The Safety Set (SS), which is defined as all enrolled subjects who take at least 1 dose of LCM in 
this study. All safety analyses will be performed on the SS. 
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects from the SS having 
provided at least 1 measurable post-dose plasma sample (with recorded sampling time) on at 
least 1 visit with documented LCM intake times.  
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. 
 
Clinical Study Protocol, Section 12.1.5 (Handling of protocol violators, drop-outs, and missing 
values). Original text, first paragraph: 
All data will be used to their maximum possible extent, but without any imputations for missing 
data for any parameter. Protocol deviations will be assessed during data review by a panel 
consisting of the study manager, the study biostatistician, a representative of the monitoring 
team, and other appropriate study team members. 
Was revised as follows:  
All data will be used to their maximum possible extent, but without any imputations for missing 
data for any parameter. Important protocol deviations will be reviewed as part of the ongoing 
data cleaning process and data evaluation. All important deviations will be identified and 
documented prior to database lock to confirm exclusion from analysis sets. 
 
Clinical Study Protocol, Section 12.2 (Determination of sample size). The following final 
paragraph was added: 
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. 
 
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Clinical Study Protocol, Section 15 (References). The following references were added: 
Clinical Global Impression of Change, the Caregiver Global Impression of Change, quality of 
life assessments (Pediatric Quality of Life Inventory [PedsQL™]). 
http://www.pedsql.org/PedsQL-CostStructure.pdf and http://plaza.umin.ac.jp/qol-research/. 
Accessed on 10 July 2014.  
Cognitive function assessments (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/BRIEF® Preschool Version [BRIEF® P]. 
http://www4.parinc.com/Products/PermsLicensing.aspx?id=6 and 
http://www4.parinc.com/products/PermsLicensing.aspx?id=8. Accessed 10 July 2014.  
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing 
clinical evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, 07/2009.  
Kyoto International; Social Welfare Exchange Centre (KISWEC). Achenbach Child Behavior 
Checklist (CBCL) for children 18 months and older. 
http://www.kiswec.com/aseba%20-%20order.html. Accessed 10 July 2014. 
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of 
epilepsy: A systematic review and meta-analysis. Neurology. 2011; 77(10): 1005–12. 
Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial onset 
seizures. Neuropsychiatr Dis Treat. 2013;9:629-37. 
 
And the following reference was deleted: 
Dichek B. Epilepsy: an ancient ailment that still eludes a cure. Scrip Magazine. 1999;Feb:9-11. 
 
Clinical Study Protocol, Section 16.1(Table 1 Schedule of study procedures for SP848 [Year 1]). 
Original table: 
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Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Blood sample for concomitant AEDsj 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 17 years) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testk 
Xh,S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagel 
Xh 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xn 
 
 
LCM return/compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 281 of 324 
Table 1.  Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSo 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X 
 
Achenbach CBCL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Bayley-III scales 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
PedsQL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
AE reportingq 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; TC=telephone contact; S=serum; U=urine; Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up telephone contact). 
b 
For subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), Visit 1 is also the last visit of the primary study. At Visit 1, the informed 
consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be updated, body weight and height and concomitant medications including 
AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If the LCM dose is 
decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for an Unscheduled Visit. 
Height will not be recorded at an Unscheduled Visit. 
f 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final 
dose of study medication. 
g 
This TC occurs 28 to 35 days after the last dose of LCM. 
h 
For subjects enrolling from SP847 or other LCM pediatric clinical studies in epilepsy, assessments should have been done as part of the last visit of the primary study. For 
subjects enrolling directly into SP848, these asssessments should be completed at Visit 1. 
i 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 282 of 324 
j 
Blood samples may be drawn at any time post-dosing with LCM. 
k 
For female subjects of childbearing potential, serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and the Final Visit. Urine pregnancy tests will be 
performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
l 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
m 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is recommended that the 
LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 2mg/kg/day (oral solution [syrup]) or 
100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after discussion with the medical monitor, whenever possible. 
n 
As applicable  
o 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
p 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
q 
Ongoing AEs from the primary study will be followed, as well as recording of new AEs during the current study. 
 
Was revised to: 
Table 16-1: 
Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
Xh 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
12-lead ECGi 
Xh 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
Xh, j 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 283 of 324 
Table 16-1: 
Schedule of study procedures for SP848 (Year 1) 
Study SP848 
Year 1 
Safety 
Follow-Up 
Visita 
V1b 
TCc 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
ETVd 
Unsch 
Visite 
Final 
Visitf 
TCg 
Weeks in study 
0 
 
4 
8 
12 
20 
28 
36 
44 
52 
 
 
 
 
Clinical chemistry and hematology 
blood sample 
Xh 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
 
Endocrinology blood sample 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Blood sample for LCM PKk 
Xh, j 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Blood sample for concomitant AEDsk 
Xh, j 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 17 years) 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Pregnancy testl 
Xh, j, S 
 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagem 
Xh, j 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Clinical GIC 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Caregiver GIC 
Xh, j 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xn 
Xo 
 
 
LCM return/compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diary assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSp 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
X 
 
Achenbach CBCL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Bayley-III scales 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
PedsQL 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
AE reportingr 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; TC=telephone contact; S=serum; SAE= serious adverse event; U=urine; 
Unsch=Unscheduled; V=Visit 
Note: All subjects who directly enrolled into SP848 should follow the titration schedule in Table 16‒3.  
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 284 of 324 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
For subjects who have participated in SP847 (or other LCM pediatric clinical studies in epilepsy), Visit 1 is also the last visit of the primary study. At Visit 1, 
the informed consent will be signed (and assent, if applicable) and eligibility assessed, the medical history will be updated, body weight and height and 
concomitant medications including AEDs will be recorded, AEs will be assessed, and the subject diary and LCM dispensed. 
c 
Telephone contacts are scheduled during the following weeks during Year 1: Weeks 2, 6, 10, 16, 24, 32, 40, and 48. 
d 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
e 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject 
must return for an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
f 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. 
g 
This TC occurs 28 to 35 days after the last dose of LCM. 
h 
For subjects enrolling from SP847 or other LCM pediatric clinical studies in epilepsy, assessments may have been done as part of the last visit of the primary 
study. For subjects enrolling directly into SP848, these assessments should be completed at Visit 1. 
i 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM 
dose level that is ≥8mg/kg/day or 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 vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
j 
For subjects enrolling from EP0060, these assessments should be completed at Visit 1. 
k 
Blood samples may be drawn at any time post-dosing with LCM. 
l 
For female subjects of childbearing potential, serum pregnancy tests will be performed at Visit 1, the Early Termination Visit, and the Final Visit. Urine 
pregnancy tests will be performed at Visits 2, 3, 4, 5, 6, 7, 8, and 9. 
m The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
n 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of  LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
o 
As applicable  
p 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version 
should be completed thereafter. 
q 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
r 
Ongoing AEs from the primary study will be followed, as well as recording of new AEs during the current study. 
 
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020 
 
 
Clinical Study Protocol 
                              SPM 927 
SP848 
 
 
 
Page 285 of 324 
Clinical Study Protocol, Section 16.1 (Table 2 Schedule of study procedures for SP848 
[Year 2]). Original table: 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 286 of 324 
 
Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13/TermV  ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam 
(complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
Blood sample for LCM PKh 
X 
 
X 
X 
X 
X 
 
 
 
Blood sample for 
concomitant AEDsh 
X 
 
X 
X 
X 
X 
 
 
 
Urinalysis (subjects aged 5 to 
17 years) 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testi 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagej 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xk 
Xk 
Xl 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xl 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 287 of 324 
Table 2.  Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-Up 
Visita 
V10 
TCb 
V11 
V12 
V13/TermV  ETVc 
Unsch Visitd 
Final Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
C-SSRSm 
X 
 
X 
X 
X 
X 
Xn 
X 
 
Achenbach CBCL 
 
 
X 
 
X 
X 
 
 
 
Bayley-III scales 
 
 
X 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
 
 
X 
 
X 
X 
 
 
 
PedsQL 
 
 
X 
 
X 
X 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; S=serum; TC=telephone contact; TermV=Termination Visit; U=urine; 
Unsch=Unscheduled; V=Visit 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject must return for 
an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM dose level that is 
≥8mg/kg/day or 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 vital signs assessment) can be performed 30 minutes to 1 hour after the 
administration of LCM (ie, at LCM steady state Cmax). 
h 
Blood samples may be drawn at any time post-dosing with LCM. 
i 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Early Termination Visit and at the Final Visit. Urine pregnancy 
tests will be performed at Visits 10, 11, 12, and 13. 
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 288 of 324 
j 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
k 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
l 
As applicable. 
m 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version should be 
completed thereafter. 
n 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
 
Was revised to: 
Table 16-2: 
Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-
Up 
Visita 
V10 
TCb 
V11 
V12 
V13/ 
TermV  
ETVc 
Unsch 
Visitd 
Final 
Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Physical exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
Neurological exam (complete) 
 
 
 
 
X 
X 
 
X 
 
Neurological exam (brief) 
X 
 
X 
X 
 
 
X 
 
 
12-lead ECGg 
 
 
X 
 
X 
X 
X 
X 
 
Blood pressure and pulse 
X 
 
X 
X 
X 
X 
X 
X 
 
Body weight and height 
X 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry and 
hematology blood sample 
X 
 
X 
X 
X 
X 
 
X 
 
Endocrinology blood sample 
 
 
 
X 
 
X 
 
X 
 
REDACTED COPY 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 289 of 324 
Table 16-2: 
Schedule of study procedures for SP848 (Year 2) 
Study SP848 
Year 2 
Safety 
Follow-
Up 
Visita 
V10 
TCb 
V11 
V12 
V13/ 
TermV  
ETVc 
Unsch 
Visitd 
Final 
Visite 
TCf 
Weeks in study 
60 
 
72 
84 
96 
 
 
 
 
Blood sample for LCM PK 
Xh 
 
Xh 
Xh 
Xh 
Xi 
Xi 
 
 
Blood sample for concomitant 
AEDs 
 
 
 
 
 
Xi 
Xi 
 
 
Urinalysis (subjects aged 5 to 
17 years) 
 
 
X 
 
X 
X 
 
X 
 
Pregnancy testj 
XU 
 
XU 
XU 
XU 
XS 
 
XS 
 
Tanner Stagek 
 
 
 
 
X 
X 
 
 
 
Clinical GIC 
 
 
X 
 
X 
X 
 
 
 
Caregiver GIC 
 
 
X 
 
X 
X 
 
 
 
Palatability and ease of use 
questionnaire 
 
 
X 
 
X 
X 
 
 
 
Dispense LCM 
X 
 
X 
X 
Xl 
Xl 
Xm 
 
 
LCM return/compliance 
X 
 
X 
X 
X 
X 
Xm 
X 
 
Dispense diary 
X 
 
X 
X 
X 
X 
 
 
 
Diary assessment 
X 
 
X 
X 
X 
X 
X 
X 
 
C-SSRSn 
X 
 
X 
X 
X 
X 
Xo 
X 
 
Achenbach CBCL 
 
 
X 
 
X 
X 
 
 
 
Bayley-III scales 
 
 
X 
 
X 
X 
 
 
 
BRIEF-P/BRIEF 
 
 
X 
 
X 
X 
 
 
 
PedsQL 
 
 
X 
 
X 
X 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health care resource use 
X 
 
X 
X 
X 
X 
X 
X 
 
AE=adverse event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; ETV=Early Termination Visit; 
GIC=Global Impression of Change; LCM=lacosamide; PK=pharmacokinetics; S=serum; TC=telephone contact; TermV=Termination Visit; U=urine; 
Unsch=Unscheduled; V=Visit 
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CONFIDENTIAL 
20 Oct 2020
 
Clinical Study Protocol 
SPM 927 
SP848
 
 
Page 290 of 324 
a 
A time window of ±7 days relative to Visit 1 is applicable for all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact). 
b 
Telephone contacts are scheduled during the following weeks during Year 2: Weeks 66 and 78. 
c 
An Early Termination Visit must be completed for all subjects who prematurely discontinue from the study. 
d 
If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments can be performed at the investigator’s discretion. If 
the LCM dose is decreased between scheduled clinic visits due to an AE, or if a LCM dose increase is required between scheduled clinic visits, the subject 
must return for an Unscheduled Visit. Height will not be recorded at an Unscheduled Visit. 
e 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue use of LCM (ie, taper), should complete the Final Visit 
2 weeks after the final dose of study medication. 
f 
This TC occurs 28-35 days after the last dose of LCM. 
g 
All subjects will be required to have a 12-lead ECG (2 interpretable recordings) conducted at LCM Cmax 1 week after an initial LCM dose increase to a LCM 
dose level that is ≥8mg/kg/day or 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 vital signs 
assessment) can be performed 30 minutes to 1 hour after the administration of LCM (ie, at LCM steady state Cmax). 
h 
Blood sample for LCM PK will be routinely collected for subjects enrolled at sites in Japan. Blood samples may be drawn at any time post-dosing with LCM. 
i 
Blood samples for LCM and concomitant other AEDs may be collected at an Unscheduled Visit or Early Termination Visit if the visit is related to an ongoing 
SAE. 
j 
For female subjects of childbearing potential, serum pregnancy tests will be performed at the Early Termination Visit and at the Final Visit. Urine pregnancy 
tests will be performed at Visits 10, 11, 12, and 13. 
k 
The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study. 
l 
Lacosamide for taper will be dispensed only for subjects who achieve a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). It is 
recommended that the LCM dose be tapered gradually in weekly decrements of 4mg/kg/day (oral solution [syrup]) or 200mg/day (tablet). A slower taper of 
2mg/kg/day (oral solution [syrup]) or 100mg/day (tablet) is permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible. 
m As applicable. 
n 
For all subjects ≥6 years of age already enrolled, the “already enrolled” version should be completed at the next clinic visit, and the “since last visit” version 
should be completed thereafter. 
o 
The C-SSRS assessment should be completed if the Unscheduled Visit is due to an AE. 
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Clinical Study Protocol, Section 16.3 (Declarations and signatures of persons responsible for 
study) and Section 16.4 (Declaration and signature of investigator) were moved to new 
Section 18 (Declaration and signature of investigator) and new Section 19 (Sponsor 
declaration), respectively. 
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17.7 
PROTOCOL AMENDMENT 7 
RATIONALE FOR THE AMENDMENT 
This administrative amendment is to fix the numbering of exclusion criteria. During Protocol 
Amendment 6, Exclusion Criterion 16 was deleted. The remaining criteria should have been 
numbered 17 through 21, inclusive, to align with the CRF. 
The rationale for removal of Exclusion Criterion 16 during Protocol Amendment 6 was to allow 
physicians to have these medications as options for treatment during the open-label study. 
MODIFICATIONS/CHANGES 
• Exclusion Criteria 16 through 20, inclusive, were mistakenly misnumbered. 
. 
REFERENCE 
Clinical Study Protocol, Section 4.3.2 (Exclusion criteria). Original text: 
16. Subject is taking monoamine oxidase inhibitors-A (MAOI-A) or narcotic analgesics. 
17. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively 
neurodegenerative disease, such as Rasmussen syndrome. 
18. Subject has a known sodium channelopathy, such as Brugada syndrome. 
19. Subject has >2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a Baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
Subjects who were directly enrolled in EP0060 for iv LCM replacement therapy or to 
initiate LCM treatment are not permitted to enroll in the study if any of the following 
criteria are met: 
20. Subjects have previously participated in a long-term, open-label LCM study. 
 
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Were revised as follows: 
17. Subject is taking monoamine oxidase inhibitors-A (MAOI-A) or narcotic analgesics. 
18. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively 
neurodegenerative disease, such as Rasmussen syndrome. 
19. Subject has a known sodium channelopathy, such as Brugada syndrome. 
20. Subject has >2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a Baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
Subjects who were directly enrolled in EP0060 for iv LCM replacement therapy or to 
initiate LCM treatment are not permitted to enroll in the study if any of the following 
criteria are met: 
21. Subjects have previously participated in a long-term, open-label LCM study. 
 
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17.8 
PROTOCOL AMENDMENT 8 
RATIONALE FOR THE AMENDMENT 
The primary purpose of this protocol amendment is to align with modifications made to the 
Paediatric Investigation Plan. The primary changes include:  
• A new categorization for main primary and secondary endpoints key binding element was 
proposed in order to ensure reporting compliance with registries (EudraCT, 
clinicaltrials.gov). This categorization does not affect the type or processing of data collected 
and reported in the study report as they will be assessed as initially planned. 
• UCB also took the occasion to provide further clarification to the study duration as well as 
the primary, secondary, and other variables wording and categorization. 
In addition, language specifying applicable study conduct modifications due to the COVID-19 
pandemic has been added.  
Furthermore, minor administrative changes have been done, including the update of the study 
team and minor editorial corrections to correct typographical errors and to update document 
abbreviations.  
MODIFICATIONS/CHANGES 
• The name and contact information for the Clinical Program Director, Clinical Project 
Manager, Clinical Trial Biostatistician, and Medical Director (Medical Therapeutics) were 
updated.  
• Reorganization and clarification of the study variables and corresponding statistical analyses 
sections was completed. 
• Text added to allow 100 subjects to enroll in SP848 from EP0060. 
• Text added to identify the subjects directly enrolling from sites in Japan and China.  
• Text added to clarify study conduct due the COVID-19 pandemic. 
• Text updated to clarify the study duration. 
• Text updated to clarify that the Safety Follow-Up Visit or the Safety Follow-Up telephone 
contact is not required for subjects who participate in EP0151 or EP0152. 
REFERENCE 
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Contact information for the Clinical Program Director, Clinical Project Manager, Clinical Trial 
Biostatistician, and Medical Director (Medical Therapeutics) were updated. Original text: 
Clinical Program Director: 
Name: 
, BS 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Project Manager: 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Trial Biostatistician: 
Name: 
 MPH 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
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Medical Director (Medical Therapeutics): 
Name: 
, MD 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Were revised as follows: 
Clinical Program Director:  
Name: 
  
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Clinical Project Manager:  
Name: 
 
Address: 
UCB BIOSCIENCES, Inc 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone: 
  
E-mail: 
 
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Clinical Trial Biostatistician:  
Name: 
 
Address: 
UCB BIOSCIENCES, Inc. 
8010 Arco Corporate Drive, Suite 100 (courier) 
Raleigh, NC 27617, USA 
PO Box 110167 (mail) 
Research Triangle Park, NC 27709, USA 
Phone/Fax: 
 
E-mail: 
 
Medical Director (Medical Therapeutics):  
Name: 
 MD 
Address: 
UCB BIOSCIENCES, GmbH 
Alfred-Nobel- Straße 10 
40789 Monheim am Rhein 
GERMANY  
Phone: 
  
E-mail: 
 
Serious Adverse Event Reporting phone numbers and emails were updated. Original text: 
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 
 
Were revised as follows: 
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 
Japan: + 81 3 6864 7400 
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Email 
Europe and Rest of the World: DS_ICT@ucb.com or 
DSICT.-@ucb.com  
Japan: JDSO@ucb.com 
 
Clinical Study Protocol, Section 1 (Summary). Original text, second, third, and fourth 
paragraphs: 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes.  
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. The purpose of enrolling these 
subjects directly into SP848 is to obtain sufficient long-term safety exposures in the age range of 
≥4 years to ≤17 years of age; the long-term safety data will be included in planned regulatory 
submissions for LCM as adjunctive therapy for partial-onset seizures in pediatric subjects 
≥4 years to ≤17 years of age with epilepsy.  
Protocol Amendment 6 allows up to approximately 75 additional eligible pediatric subjects with 
epilepsy who participated in EP0060 to enroll into SP848. In addition, subjects already enrolled 
in SP848 may participate in EP0060, if eligible, and then resume participation in SP848. These 
subjects may either voluntarily choose to have an iv LCM infusion even though they are capable 
of taking oral LCM or require iv LCM infusion due to a medical reason or procedure (ie, unable 
to take oral LCM). 
Were revised as follows:  
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes. SP848 includes subjects ≥1 month to ≤18 years of age since subjects who complete 
SP847 or another applicable LCM pediatric epilepsy study in subjects <18 years of age may have 
aged to 18 years old by the time they complete that study and enroll in SP848. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. Beginning with local Protocol 
Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years to 
≤17 years of age with partial-onset seizures who have not previously received LCM will directly 
enroll at approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 for sites 
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in China, approximately 60 additional eligible pediatric subjects with partial-onset seizures aged 
≥4 years to ≤17 years, who have not previously participated in a LCM clinical study, will enroll 
directly into SP848. The purpose of enrolling these subjects directly into SP848 is to obtain 
sufficient long-term safety exposures in the age range of ≥4 years to ≤17 years of age; the 
long-term safety data will be included in planned regulatory submissions for LCM as adjunctive 
therapy for partial-onset seizures in pediatric subjects ≥4 years to ≤17 years of age with epilepsy.  
Protocol Amendment 6 allows up to approximately 75 additional eligible pediatric subjects with 
epilepsy who participated in EP0060 to enroll into SP848. Protocol Amendment 8 allows an 
enrollment increase from 75 to 100 eligible pediatric subjects ≥1 month to ≤17 years of age with 
epilepsy who participated in EP0060 to enroll in SP848 in order to reflect EP0060’s inclusion of 
subjects down to 1 month of age. In addition, subjects already enrolled in SP848 may participate 
in EP0060, if eligible, and then resume participation in SP848. These subjects may either 
voluntarily choose to have an iv LCM infusion even though they are capable of taking oral LCM 
or require iv LCM infusion due to a medical reason or procedure (ie, unable to take oral LCM).  
Approximately 200 subjects who may participate in other LCM pediatric clinical studies in 
epilepsy will be eligible to participate in SP848. In total, up to approximately 400 subjects may 
be eligible to participate in SP848. 
 
Clinical Study Protocol, Section 1 (Summary). Original text, seventh and eighth paragraphs: 
The primary variables for assessment of safety and tolerability are: 
• Adverse events (AEs) reported spontaneously by the subject and/or caregiver or observed by 
the investigator 
• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner stage (if applicable) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
• Achenbach Child Behavior Checklist (CBCL) for children 18 months and older (CBCL/1½-5 
and CBCL/6-18) assessing behavior 
• Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
subjects enrolled in English-speaking countries) 
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• Cognitive function assessments (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/BRIEF®-Preschool Version [BRIEF®-P]) (if applicable) 
The secondary 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, quality of 
life assessments (Pediatric Quality of Life Inventory [PedsQL™]), health care resource use, and 
a LCM palatability and ease of use questionnaire. 
Were revised as follows:  
The study variables to be assessed are defined in Section 4.2.  
 
Clinical Study Protocol, Section 2 (Background Information). Original text, final paragraph: 
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes. In addition, at selected sites, beginning with Protocol Amendment 4, up to 
approximately 100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset 
seizures (deemed appropriate for treatment with adjunctive LCM) who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. The purpose 
of enrolling these subjects directly into SP848 is to obtain additional long-term safety exposures 
in the age range of ≥4 years to ≤17 years of age; the additional long-term safety data will be 
included in planned regulatory submissions for LCM as adjunctive therapy for partial-onset 
seizures. 
Was revised as follows:  
SP848 was originally designed as an open-label extension study for pediatric subjects in SP847 
with partial-onset seizures. SP848 is now amended to be open to subjects who participate in 
other LCM pediatric clinical studies, including partial-onset seizures and other epilepsy 
syndromes. In addition, at selected sites, beginning with Protocol Amendment 4, up to 
approximately 100 eligible pediatric subjects ≥4 years to ≤17 years of age with partial-onset 
seizures (deemed appropriate for treatment with adjunctive LCM) who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. Beginning 
with local Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric 
subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not previously 
received LCM will directly enroll at approximately 9 sites in Japan. Beginning with local 
Protocol Amendment 5.4 for sites in China, approximately 60 additional eligible pediatric 
subjects with partial-onset seizures aged ≥4 years to ≤17 years, who have not previously 
participated in a LCM clinical study, will enroll directly into SP848. The purpose of enrolling 
these subjects directly into SP848 is to obtain additional long-term safety exposures in the age 
range of ≥4 years to ≤17 years of age; the additional long-term safety data will be included in 
planned regulatory submissions for LCM as adjunctive therapy for partial-onset seizures. 
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Clinical Study Protocol, Section 4.1.2 (Subjects enrolling directly into SP848). Original text, 
first and second paragraph, new third paragraph: 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously participated in a LCM clinical 
study will be permitted to enroll directly into SP848. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control (see Section 4.4.1). Subjects 
will be able to receive LCM oral solution or LCM tablets for up to 2 years as determined 
appropriate by the investigator. 
Was revised as follows:  
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously participated in a LCM clinical 
study will be permitted to enroll directly into SP848. Beginning with local Protocol Amendment 
5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years to ≤17 years of age 
with partial-onset seizures who have not previously received LCM will directly enroll at 
approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 for sites in China, 
approximately 60 additional eligible pediatric subjects with partial-onset seizures aged ≥4 years 
to ≤17 years, who have not previously participated in a LCM clinical study, will enroll directly 
into SP848. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control (see Section 4.4.1). Subjects 
will be able to receive LCM oral solution or LCM tablets for up to 2 years as determined 
appropriate by the investigator. 
SP848 includes subjects ≥1 month to ≤18 years of age since subjects who complete SP847 or 
another applicable LCM pediatric epilepsy study in subjects <18 years of age may have aged to 
18 years old by the time they complete that study and enroll in SP848. 
 
Clinical Study Protocol, Section 4.2 (Variables to be assessed). Original text, Section 4.2.1 and 
Section 4.2.2: 
4.2 Variables to be assessed 
4.2.1 Primary variables 
Safety and tolerability will be assessed using the following variables: 
• Adverse events reported spontaneously by the subject and/or caregiver, or observed by the 
investigator 
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• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead ECGs 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated BMI 
• Tanner Stage (if applicable) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
• Achenbach CBCL at Baseline for children 18 months and older (CBCL/1½-5 and 
CBCL/6-18) assessing behavior 
• Bayley-III scales at Baseline for children <18 months of age at time of enrollment 
(applicable only to subjects enrolled in English-speaking countries) 
• Cognitive function assessments (BRIEF-P/BRIEF) (if applicable) 
4.2.2 Secondary variables 
Secondary variables include: 
• Seizure counts, which will be assessed using seizure diaries in order to evaluate preliminary 
evidence of efficacy during long-term exposure in this population 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• Quality of life assessments (PedsQL) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study) 
• LCM palatability and ease of use questionnaire 
Was revised as follows:  
4.2 Variables to be assessed 
4.2.1 Safety variables 
4.2.1.1 Primary safety variables 
The primary safety variables are: 
• Incidence of TEAEs 
• Incidence of serious AEs (SAEs) 
• Subject withdrawal from the study due to TEAEs 
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4.2.1.2 Other safety variables 
The other safety variables are: 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner Stage (if applicable) 
• Achenbach Child Behavior Checklist (CBCL) at Baseline for children 18 months and older 
(CBCL/1½-5 and CBCL/6-18) assessing behavior 
• Bayley-III scales at Baseline for children <18 months of age at time of enrollment 
(applicable only to subjects enrolled in English-speaking countries) 
• Cognitive function assessments (Behavior Rating Inventory of Executive Function® 
[BRIEF®]/BRIEF®-Preschool Version [BRIEF®-P]) (if applicable) 
• LCM palatability and ease of use questionnaire 
4.2.2 PK variables 
4.2.2.1 Primary PK variables 
No primary PK variables are defined for this study. 
4.2.2.2 Other PK variables 
The other PK variables are: 
• Plasma concentrations of LCM (for population PK analysis) and concomitant AEDs 
4.2.3 Efficacy variables 
4.2.3.1 Primary efficacy variables 
No primary efficacy variables are defined for this study. 
4.2.3.2 Secondary efficacy variables 
The secondary efficacy variables, based on daily seizure diaries, are: 
• Percent change from Baseline in 28-day partial-onset seizure frequency  
• ≥50% reduction in 28-day partial-onset seizure frequency 
• ≥75% reduction in 28-day partial-onset seizure frequency 
• Seizure days per 28 days (subjects with generalized seizures only) 
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• Seizure-free status 
4.2.3.3 Other efficacy variables 
The other efficacy variables are: 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• Quality of life assessments (Pediatric Quality of Life Inventory [PedsQL™]) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study) 
• All seizure frequency analyses as described in the secondary efficacy variables (presented for 
the overall Treatment Period only) may be additionally presented by modal daily dose group, 
by seizure type, by seizure classification subgroup, by time interval, by visit or time period, 
or by completer cohort 
 
Clinical Study Protocol, Section 4.3.3.1 (Potential drug-induced liver injury IMP 
discontinuation criteria). Original text, first, second, third, and fourth paragraphs: 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
• Subjects with either of the following: 
− ALT or AST ≥5xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP: 
• 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). 
Was revised as follows:  
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Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be immediately and permanently discontinued. In addition, all concomitant medications 
and herbal supplements that are not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
• Subjects with either of the following: 
− ALT or AST ≥5xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below requires discussion with the Medical Monitor to decide whether the 
subject is allowed to continue on IMP. 
• 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). 
 
Clinical Study Protocol, Section 4.4.1.2 (Subjects enrolling directly into SP848). Original text, 
first paragraph: 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. After Screening, eligible subjects 
will initiate treatment with LCM (oral solution or tablet, as chosen by the investigator and 
subject/caregiver), and the LCM dose will be titrated to a level to optimize tolerability and 
seizure control. 
Was revised as follows:  
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a LCM 
clinical study will be permitted to enroll directly into SP848. Beginning with local Protocol 
Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years to 
≤17 years of age with partial-onset seizures who have not previously received LCM will directly 
enroll at approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 for sites 
in China, approximately 60 additional eligible pediatric subjects with partial-onset seizures aged 
≥4 years to ≤17 years, who have not previously participated in a LCM clinical study, will enroll 
directly into SP848. After Screening, eligible subjects will initiate treatment with LCM (oral 
solution or tablet, as chosen by the investigator and subject/caregiver), and the LCM dose will be 
titrated to a level to optimize tolerability and seizure control. 
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Clinical Study Protocol, Section 4.4.1.4 (Study completion). Original text, first paragraph: 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final Visit is not required for subjects 
who complete the study and who do not undergo taper of LCM. 
Was revised as follows:  
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final 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. 
 
Clinical Study Protocol, Section 4.5 (Expected duration of the study). Original text, first 
paragraph: 
The maximum duration of LCM administration for an individual subject will be approximately 
2 years. 
Was revised as follows:  
The maximum duration of LCM administration for an individual subject will be approximately 
2 years or until approval of the marketing application (for Japan only), whichever comes first. 
 
Clinical Study Protocol, Section 5 (Treatment Procedures By Visit). Original text, first and 
second paragraphs: 
For all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact), a visit window of ±7 days relative to Visit 1 is applicable. The Safety 
Follow-Up telephone contact will be performed 28-35 days after the last dose of LCM. A 
detailed tabular schedule of study procedures is provided in Section 16.1. For further details of 
the assessments and the required procedures and methods, please refer to Section 6, Section 7, 
and Section 8. 
Were revised as follows:  
For all scheduled visits and telephone contacts (with the exception of the Safety Follow-Up 
telephone contact), a visit window of ±7 days relative to Visit 1 is applicable. The Safety 
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Follow-Up telephone contact will be performed 28-35 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.  
Assessments will be done during monthly visits for the first 3 months, every 2 months for the 
remainder of Year 1, and every 3 months for Year 2. A detailed tabular schedule of study 
procedures is provided in Section 16.1. For further details of the assessments and the required 
procedures and methods, please refer to Section 6, Section 7, and Section 8. 
 
Clinical Study Protocol, Section 5.16 (Visit 13/Termination Visit [Week 96]). Original text, first 
paragraph: 
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final Visit is not required for subjects 
who complete the study and who do not undergo taper of LCM. 
Was revised as follows:  
At the completion of the study, investigators should discuss treatment options with the subject 
and/or their parent/legal guardian to best manage the subject’s epilepsy. Taper of LCM may not 
be required for some subjects who complete the study depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal guardian. These subjects 
should complete Visit 13/Termination Visit and then complete the Safety Follow-Up telephone 
contact 28 to 35 days after Visit 13/Termination Visit. The Final 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. 
 
Clinical Study Protocol, Section 5.19 (Final Visit). Original text, first paragraph: 
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. 
Was revised as follows:  
Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. The Final Visit is not required for subjects who participate in EP0151 or EP0152.  
 
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Clinical Study Protocol, Section 5.20 (Safety Follow-Up telephone contact). Original text, first 
paragraph: 
The Safety Follow-Up telephone contact is required for all subjects (those who complete the 
study as planned or have withdrawn prematurely from the study). For subjects who complete the 
study, this telephone contact will occur 28 to 35 days after Visit 13/Termination Visit (subjects 
who do not undergo taper of LCM) or 28 to 35 days after the last dose of LCM (subjects who 
discontinue use of LCM [ie, taper]). For subjects who withdraw prematurely from the study, this 
telephone contact will occur 28 to 35 days after the Early Termination Visit (subjects who do not 
undergo taper of LCM) or 28 to 35 days after the last dose of LCM (subjects who discontinue 
use of LCM [ie, taper]). 
Was revised as follows:  
The Safety Follow-Up telephone contact is required for all subjects (those who complete the 
study as planned or have withdrawn prematurely from the study) who do not participate in 
EP0151 or EP0152. For subjects who complete the study, this telephone contact will occur 28 to 
35 days after Visit 13/Termination Visit (subjects who do not undergo taper of LCM) or 28 to 
35 days after the last dose of LCM (subjects who discontinue use of LCM [ie, taper]). For 
subjects who withdraw prematurely from the study, this telephone contact will occur 28 to 
35 days after the Early Termination Visit (subjects who do not undergo taper of LCM) or 28 to 
35 days after the last dose of LCM (subjects who discontinue use of LCM [ie, taper]). The Safety 
Follow-Up telephone contact is not required for subjects who participate in EP0151 or EP0152. 
 
Clinical Study Protocol, Section 5.21(Study conduct due to coronavirus disease 2019 pandemic) 
was newly added as follows: 
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 participant 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 study participant 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 
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study treatment based upon the outcome of the safety assessment. 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 9.5.  
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). 
 
Clinical Study Protocol, Section 6.2.1 (Clinical Global Impression of Change). Original text, 
first paragraph: 
The Clinical Global Impression of Change will be completed according to the tabular schedule of 
study procedures, Section 16.1. 
Was revised as follows:  
The Clinical Global Impression of Change will be assessed at least once per year and be 
completed according to the tabular schedule of study procedures, Section 16.1. 
 
Clinical Study Protocol, Section 6.2.2 (Caregiver Global Impression of Change). Original text, 
first paragraph: 
The Caregiver Global Impression of Change will be completed according to the tabular schedule 
of study procedures, Section 16.1. 
Was revised as follows:  
The Caregiver Global Impression of Change will be assessed at least once per year and be 
completed according to the tabular schedule of study procedures, Section 16.1. 
 
Clinical Study Protocol, Section 6.3 (Pediatric Quality of Life Inventory). Original text, first 
paragraph: 
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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 (Varni et al, 2001; 
Varni et al, 2011). The PedsQL will be administered according to the tabular schedule of study 
procedures, Section 16.1. 
Was revised as follows:  
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; 
Varni et al, 2011). The PedsQL will be completed up to two times per year and will be 
administered according to the tabular schedule of study procedures, Section 16.1. 
 
Clinical Study Protocol, Section 8.1.10 (Occurrence of COVID-19) was newly added as follows: 
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. 
 
Clinical Study Protocol, Section 8.3 (Laboratory measurements). Original text, laboratory test 
table: 
Urinalysis 
Hematology 
Clinical chemistry 
Endocrinology 
Specific gravity 
RBC 
Total serum 
protein 
Cholesterol 
FSH 
pH 
WBC 
Albumin 
Triglycerides 
LH 
Albumin 
Differential count 
Calcium 
Total bilirubin 
Testosterone 
Glucose 
Platelet count 
Phosphorus 
Alkaline 
phosphatase 
TSH 
Ketone 
Hemoglobin 
Glucose 
Creatinine 
T3 (total and 
serum-free) 
Microscopic exam 
for blood cells for 
casts/hpf 
Hematocrit 
Serum electrolytes 
(sodium, 
potassium, 
chloride, 
bicarbonate) 
AST 
ALT 
GGT 
T4 (total and 
serum-free) 
 
 
Uric acid 
BUN 
 
Was revised as follows:  
Urinalysis 
Hematology 
Clinical chemistry 
Endocrinology 
Specific gravity 
RBC 
Total serum 
protein 
Cholesterol 
FSH 
pH 
WBC 
Albumin 
Triglycerides 
LH 
Protein 
Differential count 
Calcium 
Total bilirubin 
Testosterone 
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Urinalysis 
Hematology 
Clinical chemistry 
Endocrinology 
Glucose 
Platelet count 
Phosphorus 
Alkaline 
phosphatase 
TSH 
Ketone 
Hemoglobin 
Glucose 
Creatinine 
T3 (total and 
serum-free) 
Microscopic exam 
for blood cells for 
casts/hpf 
Hematocrit 
Serum electrolytes 
(sodium, 
potassium, 
chloride, 
bicarbonate) 
AST 
ALT 
GGT 
T4 (total and 
serum-free) 
 
 
Uric acid 
BUN 
 
 
Clinical Study Protocol, Section 8.3.2 (Liver function tests and evaluation of PDILI). Original 
text, seventh paragraph: 
When IMP is stopped due to PDILI (as described in Section 4.3.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. 
Was revised as follows:  
When IMP is stopped due to PDILI (as described in Section 4.3.3.1), IMP must be permanently 
discontinued. 
 
Clinical Study Protocol, Section 8.3.2.3 (Testing: identification/exclusion of alternative 
etiology). Original text, Table 8-2: 
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Table 8‒2: 
PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; 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). 
Was revised as follows:  
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Table 8‒2: 
PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
WBC count 
WBC differential 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 
ALT 
AST 
ALP 
GGT 
Albumin 
Additional 
Prothrombin time/INRa 
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Serum pregnancy test 
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). 
 
Clinical Study Protocol, Section 8.4.5 (Tanner Stage). New final paragraph added as follows: 
The evaluation of Tanner Stage for applicable subjects will be completed according to the tabular 
schedule of study procedures, Section 16.1. 
 
Clinical Study Protocol, Section 8.4.6 (Assessment of suicidality). New second paragraph added 
as follows: 
Subjects enrolling directly who are ≥6 years of age will complete the “Baseline/Screening” 
version of the C-SSRS at Visit 1 and will complete the “Since Last Visit” version at subsequent 
visits. If a subject becomes 6 years of age during the study, the “Already Enrolled” version of the 
C-SSRS should be used at the first visit at which the subject is 6 years of age and the “Since Last 
Visit” version used at subsequent visits. 
 
Clinical Study Protocol, Section 8.4.7 (Achenbach CBCL). Original text, second, third, and 
fourth paragraphs: 
The same scale will be completed at the Screening Visit (subjects enrolling directly into SP848), 
Visit 1 (subjects enrolling from SP847 or other pediatric clinical studies in epilepsy), and 
Visit 13/Termination Visit (or Early Termination Visit) (all subjects) by the parent(s)/legal 
representative(s). The completion of the Achenbach CBCL will require approximately 
45 minutes.  
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
• 0=not true (as far as known) 
• 1=somewhat or sometimes true 
• 2=very true or often true 
Eight syndrome scores will be calculated from these questions, which will in turn be summarized 
by 2 composite scores. Additionally, for each score on the question, syndrome, and total level, 
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categorizations based on a normative sample will be used to evaluate normal, borderline, or 
clinically relevant behavior. 
Was revised as follows:  
The Achenbach CBCL will be completed according to the tabular schedule of study procedures, 
Section 16.1. 
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 
Syndrome scores will be calculated from these questions, which will in turn be summarized by 
2 composite scores. Additionally, for each syndrome and composite scores, categorizations based 
on a normative sample will be used to evaluate normal, borderline, or clinically relevant 
behavior. 
 
Clinical Study Protocol, Section 8.4.8 (Bayley Scales of Infant and Toddler Development, Third 
Edition). Original text, final paragraph: 
The same scale will be completed at the Screening Visit (subjects enrolling directly into SP848), 
Visit 1 (subjects enrolling from SP847 or other pediatric clinical studies in epilepsy), and 
Visit 13/Termination Visit (or Early Termination Visit) (all subjects) for children from 1 month 
to <18 months of age enrolled in English-speaking countries. 
Was revised as follows:  
The Bayley-III scales will be completed according to the tabular schedule of study procedures, 
Section 16.1. 
 
Clinical Study Protocol, Section 8.4.9 (Palatability and ease of use questionnaire for LCM). New 
final paragraph added as follows: 
The questionnaire will be completed according to the tabular schedule of study procedures, 
Section 16.1. 
 
Clinical Study Protocol, Section 8.4.10 (Behavior Rating Inventory of Executive Function). 
Original text, fourth paragraph: 
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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. 
Was revised as follows:  
The BRIEF rating form consists of items that measure various aspects of executive functioning: 
Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, Organization of 
materials, and Monitor. These clinical scales form 2 broader Indexes: Behavioral Regulation 
(3 scales) and Metacognition (5 scales), as well as a Global Executive Composite score. 
 
Clinical Study Protocol, Section 9.2 (Supply, handling, and storage). Original text, first 
paragraph: 
Lacosamide (oral solution [syrup] and tablet) is stable at room temperature and is to be stored at 
temperatures not exceeding 25°C (77°F). Lacosamide should not be frozen. 
Was revised as follows:  
Lacosamide (oral solution [syrup] and tablet) is stable at room temperature and is to be stored at 
temperatures not exceeding 25.4°C (77.7°F) or below 14.5°C (58.1°F). Lacosamide should not 
be frozen or refrigerated. 
 
Clinical Study Protocol, Section 9.5 (Alternative study treatment supply due to COVID-19 
pandemic) was newly added as follows: 
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. 
 
Clinical Study Protocol, Section 12.1.2 (Statistical analysis of safety variables). Original text, 
Section 12.1.2.1 and Section 12.1.2.2: 
12.1.2 Statistical analysis of primary variables 
The primary variables, for assessment of safety and tolerability, are AEs as well as subject 
withdrawals due to AEs; changes in vital signs, ECGs, clinical laboratory tests, body weight, 
height, and calculated BMI; and physical and neurological examination findings. 
12.1.2.1 AEs 
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Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), and tabulated by system organ class and preferred term. 
Treatment-emergent AEs will be defined as those events which started on or after the date of first 
SP848 LCM administration, or whose severity worsened on or after the date of first SP848 LCM 
administration. Adverse events occurring within 30 days after last dose of LCM will be 
considered treatment emergent. The incidence of TEAEs will be presented by system organ class 
and preferred term. Serious AEs will also be tabulated and listed. 
12.1.2.2 Other safety variables 
The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, and urinalysis), ECG measurements, vital sign measurements (blood pressure and 
pulse rate), body weight, height, calculated BMI, and Tanner Stage (if applicable). The actual 
measurement and its change from Baseline (SP847 [or other primary study as applicable] Visit 1) 
or the Screening Visit (for subjects who entered directly into SP848) will be analyzed 
descriptively and presented by visit. In addition, shift tables may be used to evaluate the number 
and percentage of subjects having a different post-Baseline status when compared with their 
Baseline status. 
The shift from Baseline to the subject’s last visit at which a physical and/or neurological 
examination was performed post-Baseline will be summarized by category. 
Laboratory, ECG, and vital signs data outside of the respective reference ranges will be listed 
and highlighted. 
Changes in behavior and development from Baseline as measured using the Achenbach CBCL 
for children 18 months and older (CBCL/1½-5 and CBCL/6-18) and Bayley-III scales for 
children <18 months of age will be summarized descriptively and presented by visit. Changes in 
cognitive function as measured using the BRIEF-P/BRIEF will be summarized by descriptive 
statistics at each visit. Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy 
studies. Baseline values for subjects who enroll directly into SP848 will be taken from the 
Screening Visit. 
Was revised as follows:  
12.1.2 Statistical analysis of safety variables 
12.1.2.1 Primary safety variables 
The primary variables, for assessment of safety and tolerability, are the incidence of TEAEs and 
the incidence of SAEs.  
12.1.2.1.1 AEs 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®), and tabulated by system organ class and preferred term. 
Treatment-emergent AEs will be defined as those events which started on or after the date of first 
SP848 LCM administration, or whose severity worsened on or after the date of first SP848 LCM 
administration. Adverse events occurring within 30 days after last dose of LCM will be 
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considered treatment-emergent. The incidence of TEAEs will be presented by system organ class 
and preferred term. Serious AEs will also be tabulated and listed. 
12.1.2.2 Other safety variables 
The other safety variables include changes in laboratory parameters (ie, hematology, clinical 
chemistry, endocrinology, and urinalysis), 12-lead ECG measurements, vital sign measurements 
(blood pressure and pulse rate), physical and neurological exam findings, body weight, height, 
calculated BMI, and Tanner Stage (if applicable). The actual measurement and its change from 
Baseline (SP847 [or other primary study as applicable] Visit 1) or the Screening Visit (for 
subjects who entered directly into SP848) will be analyzed descriptively and presented by visit. 
In addition, shift tables may be used to evaluate the number and percentage of subjects having a 
different post-Baseline status when compared with their Baseline status. 
The shift from Baseline to the subject’s last visit at which a physical and/or neurological 
examination was performed post-Baseline will be summarized by category. 
Laboratory, ECG, and vital signs data outside of the respective reference ranges will be listed 
and highlighted. 
Changes in behavior and development from Baseline as measured using the Achenbach CBCL 
for children 18 months and older (CBCL/1½-5 and CBCL/6-18) and Bayley-III scales for 
children <18 months of age will be summarized descriptively and presented by visit. Changes in 
cognitive function as measured using the BRIEF-P/BRIEF will be summarized by descriptive 
statistics at each visit. Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy 
studies. Baseline values for subjects who enroll directly into SP848 will be taken from the 
Screening Visit. 
12.1.2.2.1 Palatability and ease of use questionnaire 
Data from the palatability and ease of use questionnaire will be summarized descriptively at each 
visit where it is assessed. 
 
Clinical Study Protocol, Section 12.1.4 (Statistical analysis of secondary variables). Original 
text, Section 12.1.4.1 and Section 12.1.4.2: 
12.1.4 Statistical analysis of secondary variables 
12.1.4.1 Seizure frequency 
Seizure frequency will be assessed using seizure diaries in order to evaluate the preliminary 
efficacy of LCM in this population. Seizure frequency per 28 days will be calculated as ([number 
of seizures over the specified time interval]) divided by [number of days in the interval]) 
multiplied by 28 and summarized descriptively and presented graphically at each visit and 
grouped by dose. 
12.1.4.2 Clinical Global Impression of Change and Caregiver Global Impression of Change 
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The number and percentage of subjects with each Clinical Global Impression of Change and 
Caregiver Global Impression of Change value will be summarized at each visit in which they are 
assessed and grouped by dose. 
12.1.4.3 Palatability and ease of use questionnaire 
Data from the palatability and ease of use questionnaire will be summarized descriptively at each 
visit where it is assessed. 
12.1.4.4 PedsQL 
The PedsQL score and change from Baseline scores will be analyzed in a descriptive manner. 
Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy studies. Baseline values 
for subjects who enroll directly into SP848 will be taken from the Screening Visit. 
12.1.4.5 Health care resource use 
Descriptive statistics will be presented for the number of medical resources used (medications, 
consultations, procedures, hospitalizations, and length of hospital stays). 
Was revised as follows:  
12.1.4 Statistical analysis of efficacy variables 
12.1.4.1 Secondary efficacy variables 
12.1.4.1.1 Percent change from Baseline in 28-day partial-onset seizure frequency  
Seizure frequency will be assessed using seizure diaries in order to evaluate the preliminary 
efficacy of LCM in this population. Seizure frequency per 28 days will be calculated as ([number 
of seizures over the specified time interval]) divided by [number of days in the interval]) 
multiplied by 28 and summarized descriptively for the overall Treatment Period. 
12.1.4.1.2 ≥50% reduction in 28-day partial-onset seizure frequency 
For subjects with POS, the number and percentage with ≥50% reduction in 28-day partial-onset 
seizure frequency (≥50% responders) will be summarized for the overall Treatment Period.  
12.1.4.1.3 ≥75% reduction in 28-day partial-onset seizure frequency 
For subjects with POS, the number and percentage with ≥75% reduction in 28-day partial-onset 
seizure frequency (≥75% responders) will be summarized for the overall Treatment Period.  
12.1.4.1.4 Seizure days per 28 days (subjects with generalized seizures only) 
For subjects with generalized seizures, the number of seizure days per 28 days will be 
summarized descriptively for the overall Treatment Period. 
12.1.4.1.5 Seizure-free status 
The number and percentage of subjects achieving a seizure-free status for the overall Treatment 
Period will be presented. 
12.1.4.2 Other efficacy variables 
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12.1.4.2.1 Clinical Global Impression of Change and Caregiver Global Impression of 
Change 
The number and percentage of subjects with each Clinical Global Impression of Change and 
Caregiver Global Impression of Change value will be summarized at each visit in which they are 
assessed and grouped by dose. 
12.1.4.2.2 PedsQL 
The PedsQL score and change from Baseline scores will be analyzed in a descriptive manner. 
Baseline is defined as Visit 1 for subjects from SP847 or other epilepsy studies. Baseline values 
for subjects who enroll directly into SP848 will be taken from the Screening Visit. 
12.1.4.2.3 Health care resource use 
Descriptive statistics will be presented for the number of medical resources used (medications, 
consultations, procedures, hospitalizations, and length of hospital stays). 
12.1.4.2.2 Seizure frequency analyses 
All seizure frequency analyses as described in the secondary efficacy variables (Section 12.1.4.1) 
may be additionally presented by modal daily dose group, by seizure type, by seizure 
classification subgroup, by time interval, by visit or time period, or by completer cohort. 
Additional details will be provided in the Statistical Analysis Plan. 
 
Clinical Study Protocol, Section 12.1.5 (Handling of protocol violators, drop-outs, and missing 
values). New final paragraph added as follows: 
Protocol deviations (eg, missing assessments or visits) related to COVID-19 will be documented. 
 
Clinical Study Protocol, Section 12.2 (Determination of sample size). Original text, second and 
third paragraphs: 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated 
in a LCM clinical study will be permitted to enroll directly into SP848. The purpose of enrolling 
these subjects directly into SP848 is to obtain additional long-term safety exposures in the age 
range from which adequate PK data have already been obtained in SP847; the additional 
long-term safety data will be included in planned LCM marketing applications for subjects 
≥4 years of age. 
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. 
Was revised as follows:  
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated 
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in a LCM clinical study will be permitted to enroll directly into SP848. Beginning with local 
Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric subjects ≥4 years 
to ≤17 years of age with partial-onset seizures who have not previously received LCM will 
directly enroll at approximately 9 sites in Japan. Beginning with local Protocol Amendment 5.4 
for sites in China, approximately 60 additional eligible pediatric subjects with partial-onset 
seizures aged ≥4 years to ≤17 years, who have not previously participated in a LCM clinical 
study, will enroll directly into SP848. The purpose of enrolling these subjects directly into SP848 
is to obtain additional long-term safety exposures in the age range from which adequate PK data 
have already been obtained in SP847; the additional long-term safety data will be included in 
planned LCM marketing applications for subjects ≥4 years of age. 
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. Protocol 
Amendment 8 allows an enrollment increase from 75 to 100 eligible pediatric subjects ≥1 month 
to ≤17 years of age with epilepsy who participated in EP0060 to enroll in SP848 in order to 
reflect EP0060’s inclusion of subjects down to 1 month of age. 
In total, up to approximately 400 subjects may be eligible to participate in SP848. 
 
Clinical Study Protocol, Section 16.1 (Tabular schedule of study procedures). Original text, 
Table 16-1 (Schedule of study procedures for SP848 [Year 1]), footnotes f and g: 
f  Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. 
 
g  This TC occurs 28 to 35 days after the last dose of LCM.  
Were revised as follows:  
f  Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. The Final Visit is not required for subjects who participate in EP0151 or EP0152. 
 
g  This TC occurs 28 to 35 days after the last dose of LCM. The Safety Follow-Up TC is not 
required for subjects who participate in EP0151 or EP0152. 
 
Clinical Study Protocol, Section 16.1 (Tabular schedule of study procedures). Original text, 
Table 16-2 (Schedule of study procedures for SP848 [Year 2]), footnotes e and f: 
e  Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. 
f  This TC occurs 28 to 35 days after the last dose of LCM.  
Were revised as follows:  
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e  Subjects who complete the study or withdraw prematurely from the study, and who discontinue 
use of LCM (ie, taper), should complete the Final Visit 2 weeks after the final dose of study 
medication. The Final Visit is not required for subjects who participate in EP0151 or EP0152. 
 
f  This TC occurs 28 to 35 days after the last dose of LCM. The Safety Follow-Up TC is not 
required for subjects who participate in EP0151 or EP0152. 
 
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18 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I received and have 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 
BIOSCIENCES. 
All rights of publication of the results reside with UCB BIOSCIENCES, unless other agreements 
were made in a separate contract. 
Investigator: 
 
 
 
 
Printed name  
 
Date/Signature 
 
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19 
SPONSOR DECLARATION 
I confirm that I have carefully read and understood 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:
SP848-protocol-amend-8
Version:
2. 0
Document Number:
CLIN-000127983
Title:
SP848 Protocol Amendment Version 8
Approved Date:
26 Oct 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 23-Oct-2020 15:46:49 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Medical
Date of Signature: 26-Oct-2020 08:03:05 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 26-Oct-2020 13:36:05 GMT+0000
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SAP_001.pdf: 
UCB 
 
15 Jan 2021 
Statistical Analysis Plan 
Lacosamide 
SP848 
 
 
 
 
Confidential                                                              Page 1 of 147 
STATISTICAL ANALYSIS PLAN  
Study: SP848 
Product: Lacosamide 
 
 
 
AN OPEN-LABEL STUDY TO DETERMINE SAFETY, TOLERABILITY, AND 
EFFICACY OF LONG-TERM ORAL LACOSAMIDE (LCM) AS ADJUNCTIVE 
THERAPY IN CHILDREN WITH EPILEPSY 
 
 
 
 
 
 
 
 
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 
SAP – Amendment 1 
27 Apr 2015 
18 Dec 2015 
SAP – Amendment 2 
8 Mar 2019 
SAP – Amendment 3 
25 Nov 2019 
SAP – Amendment 4 
15 Jan 2021 
 
 
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Statistical Analysis Plan 
Lacosamide 
SP848 
 
 
 
 
Confidential                                                              Page 2 of 147 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 7 
1 
INTRODUCTION ............................................................................................................. 9 
2 
PROTOCOL SUMMARY ................................................................................................. 9 
2.1 
Study objectives ....................................................................................................... 9 
2.2 
Study variables ......................................................................................................... 9 
2.3 
Safety variables ........................................................................................................ 9 
2.3.1 
Primary safety variables ................................................................................. 9 
2.3.2 
Other safety variables .................................................................................... 9 
2.3.3 
Pharmacokinetic variables ........................................................................... 10 
2.3.3.1 
Primary Pharmacokinetic variables ................................................... 10 
2.3.3.2 
Other Pharmacokinetic variables ....................................................... 10 
2.3.4 
Efficacy variables ........................................................................................ 10 
2.3.4.1 
Primary efficacy variables ................................................................. 10 
2.3.4.2 
Secondary efficacy variables ............................................................. 10 
2.3.4.3 
Other efficacy variables ..................................................................... 10 
2.4 
Study design and conduct ...................................................................................... 11 
2.4.1 
Study description ......................................................................................... 11 
2.4.1.1 
Study participants enrolling from SP847 or other LCM pediatric 
clinical studies in epilepsy (rollover study participants) .................... 11 
2.4.1.2 
Study participants enrolling directly into SP848 ............................... 11 
2.4.2 
Tabular schedule of study procedures ......................................................... 12 
2.5 
Determination of sample size ................................................................................. 12 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 12 
3.1 
General presentation of summaries and analyses .................................................. 12 
3.2 
General study level definitions .............................................................................. 14 
3.2.1 
Analysis time points ..................................................................................... 14 
3.2.1.1 
First and last dose of LCM ................................................................. 14 
3.2.1.2 
Relative day ....................................................................................... 15 
3.2.2 
Study periods ............................................................................................... 15 
3.2.3 
Mapping of assessments performed at Early Termination Visit .................. 15 
3.2.4 
Study visit labeling ...................................................................................... 16 
3.2.5 
Monthly time intervals ................................................................................. 16 
3.2.6 
Last Visit ...................................................................................................... 16 
3.2.7 
Exposure duration ........................................................................................ 16 
3.2.8 
Modal and maximum daily LCM dose ........................................................ 16 
3.2.9 
Age and age at first diagnosis ...................................................................... 17 
3.2.10 
Weight band ................................................................................................. 18 
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3.2.11 
Body mass index .......................................................................................... 18 
3.2.12 
Seizure Classification Subgroups ................................................................ 18 
3.2.13 
Seizure frequency ........................................................................................ 18 
3.2.14 
Percent change in seizure frequency ............................................................ 19 
3.2.15 
Response to treatment .................................................................................. 19 
3.2.16 
Seizure day ................................................................................................... 19 
3.2.17 
Seizure-free day ........................................................................................... 19 
3.2.18 
Seizure-free status ........................................................................................ 20 
3.2.19 
Completer cohorts ........................................................................................ 20 
3.2.20 
Number and percentage of seizure-free days ............................................... 20 
3.2.21 
Seizure time intervals ................................................................................... 20 
3.2.22 
Pediatric Quality of Life Inventory (PedsQL) ............................................. 21 
3.2.23 
Hospital stay duration .................................................................................. 22 
3.3 
Definition of Baseline values ................................................................................. 22 
3.4 
Protocol deviations................................................................................................. 22 
3.5 
Analysis sets........................................................................................................... 23 
3.5.1 
Safety Set ..................................................................................................... 23 
3.5.2 
Pharmacokinetic Per-Protocol Set ............................................................... 23 
3.5.3 
Full Analysis Set .......................................................................................... 23 
3.6 
Treatment assignment and treatment groups ......................................................... 23 
3.7 
Center pooling strategy .......................................................................................... 23 
3.8 
Coding dictionaries ................................................................................................ 24 
3.9 
Changes to protocol-defined analyses ................................................................... 24 
3.9.1 
Handling of dropouts or missing data .......................................................... 24 
3.9.2 
Examination of subgroups ........................................................................... 24 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 24 
4.1 
Adjustments for covariates .................................................................................... 24 
4.2 
Handling of dropouts or missing data .................................................................... 24 
4.2.1 
Missing data ................................................................................................. 24 
4.2.2 
Incomplete dates for adverse events and concomitant medications ............ 24 
4.2.3 
Definition of concomitant medication in case of missing dates .................. 25 
4.2.4 
Incomplete dates for the last administration of LCM .................................. 25 
4.2.5 
Incomplete dates for seizure diary data ....................................................... 26 
4.2.6 
General imputation rule for incomplete dates .............................................. 26 
4.2.7 
Missing data due to participation in solution for infusion formulation trials26 
4.3 
Interim analyses and data monitoring .................................................................... 27 
4.4 
Multicenter studies ................................................................................................. 27 
4.5 
Multiple comparisons/multiplicity ......................................................................... 27 
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4.6 
Use of an efficacy subset of study participants ...................................................... 27 
4.7 
Active-control studies intended to show equivalence ............................................ 27 
4.8 
Examination of subgroups ..................................................................................... 27 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 27 
5.1 
Subject disposition ................................................................................................. 27 
5.2 
Protocol deviations................................................................................................. 28 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 29 
6.1 
Demographics and other Baseline characteristics .................................................. 29 
6.2 
Medical history and concomitant diseases ............................................................. 29 
6.2.1 
Medical history ............................................................................................ 29 
6.2.2 
Concomitant diseases and conditions .......................................................... 29 
6.3 
History of epilepsy ................................................................................................. 30 
6.3.1 
History of seizure types ............................................................................... 30 
6.3.2 
History of seizure characteristics ................................................................. 30 
6.3.3 
Historical seizure counts .............................................................................. 30 
6.4 
Prior and concomitant medications ........................................................................ 31 
6.4.1 
Number of previous AEDs .......................................................................... 31 
6.4.2 
Concomitant AEDs taken at the start of the SP848 Treatment Period ........ 31 
6.4.3 
Concomitant AEDs taken during the SP848 Treatment Period ................... 31 
6.4.4 
Concomitant medications (excluding AEDs) .............................................. 31 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 31 
8 
SAFETY ANALYSES ..................................................................................................... 32 
8.1 
Extent of exposure ................................................................................................. 32 
8.2 
Adverse events ....................................................................................................... 32 
8.3 
Clinical laboratory evaluations .............................................................................. 34 
8.4 
Vital signs, physical findings, and other observations related to safety ................ 35 
8.4.1 
Vital signs, body weight, height, and BMI .................................................. 35 
8.4.2 
Electrocardiograms (ECGs) ......................................................................... 37 
8.4.3 
Physical examination ................................................................................... 39 
8.4.3.1 
Complete physical examination ......................................................... 39 
8.4.3.2 
Brief physical examination ................................................................ 39 
8.4.4 
Neurological examination ............................................................................ 40 
8.4.4.1 
Complete neurological examination .................................................. 40 
8.4.4.2 
Brief neurological examination .......................................................... 40 
8.4.5 
Vagus nerve stimulation .............................................................................. 40 
8.4.6 
Tanner stage assessment .............................................................................. 40 
8.4.7 
Assessment of suicidality ............................................................................. 41 
8.4.8 
Achenbach Child Behavior Checklist (CBCL) ............................................ 41 
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Statistical Analysis Plan 
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8.4.9 
BRIEF-P and BRIEF assessment ................................................................. 43 
8.4.9.1 
BRIEF-P scores .................................................................................. 43 
8.4.9.2 
BRIEF scores ..................................................................................... 44 
8.4.10 
Bayley-III assessment .................................................................................. 46 
8.5 
Palatability and ease of use questionnaires ............................................................ 46 
9 
PHARMACOKINETICS ................................................................................................. 47 
9.1 
Descriptive statistics .............................................................................................. 47 
10 EFFICACY ANALYSES ................................................................................................ 47 
10.1 
Seizure counts ........................................................................................................ 47 
10.1.1 
Seizure frequency per 28 days ..................................................................... 48 
10.1.2 
Percent change from Baseline in 28-day partial-onset seizure frequency ... 48 
10.1.3 
≥50% reduction in 28-days partial-onset seizure frequency ........................ 48 
10.1.4 
≥75% reduction in 28-days partial-onset seizure frequency ........................ 48 
10.1.5 
Seizure days per 28 days (subjects with generalized seizures only) ............ 48 
10.1.6 
Seizure-free status ........................................................................................ 49 
10.2 
Global Impression of Change ................................................................................ 49 
10.2.1 
Clinical Global Impression of Change ......................................................... 49 
10.2.2 
Caregiver Global Impression of Change ..................................................... 49 
10.3 
Pediatric Quality of Life Inventory (PedsQL) ....................................................... 50 
10.3.1 
Pediatric Quality of Life Inventory Ages for ≤24 Months .......................... 50 
10.3.2 
Pediatric Quality of Life Inventory Ages >2 years ...................................... 50 
10.4 
Health care resource use ........................................................................................ 50 
10.4.1 
Healthcare provider consultations ............................................................... 50 
10.4.2 
Hospital stays and ER visits ......................................................................... 51 
11 REFERENCES ................................................................................................................ 52 
12 APPENDICES ................................................................................................................. 53 
12.1 
Marked abnormality criteria for laboratory data .................................................... 53 
12.1.1 
Marked abnormality criteria for hematology data ....................................... 53 
12.1.2 
Marked abnormality criteria for chemistry data .......................................... 55 
12.2 
Other Significant TEAEs ....................................................................................... 59 
12.3 
AEs for Potentially Drug Induced Liver Injury (PDILI) ....................................... 61 
13 AMENDMENTS TO THE STATISTICAL ANALYSIS PLAN .................................... 63 
13.1 
Amendment 1 ......................................................................................................... 63 
13.2 
Amendment 2 ......................................................................................................... 82 
13.3 
Amendment 3 ....................................................................................................... 112 
13.4 
Amendment 4 ....................................................................................................... 126 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 147 
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Statistical Analysis Plan 
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SP848 
 
 
 
 
Confidential                                                              Page 6 of 147 
List of Tables 
Table 8‒1: Vital signs abnormality criteria ............................................................................. 36 
Table 8‒2: ECG abnormality criteria ....................................................................................... 38 
Table 8‒3: CBCL/1½-5 ........................................................................................................... 41 
Table 8‒4: CBCL/6-18 ............................................................................................................ 42 
Table 8‒5: BRIEF-P questionnaire scoring ............................................................................. 43 
Table 8‒6: BRIEF questionnaire scoring ................................................................................. 44 
Table 12‒1: Hematology abnormality criteria ......................................................................... 53 
Table 12‒2: Chemistry abnormality criteria ............................................................................ 55 
Table 12‒3: Other significant TEAEs...................................................................................... 59 
Table 12‒4: AEs for PDILI ...................................................................................................... 61 
 
 
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SP848 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
BCR 
borderline or clinical range 
BMI 
body mass index 
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 
CRF 
Case Report Form 
CV 
coefficient of variance 
DBP 
diastolic blood pressure 
DRM 
Data Review Meeting 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ER 
emergency room 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
HRQoL 
health-related quality of life 
IIL 
Initiating intravenous lacosamide Group 
ILAE 
International League Against Epilepsy 
LCM 
Lacosamide 
MA 
markedly abnormal 
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Statistical Analysis Plan 
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SP848 
 
 
 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
OLL 
Open-label lacosamide Group 
PDILI 
Potential Drug Induced Liver Injury 
PedsQL 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PT 
preferred term 
RxL 
Prescription lacosamide (eg, VIMPAT) Group 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SPD 
Specification of Protocol Deviations 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
ULN 
upper limit of normal 
VNS 
vagus nerve stimulation 
WHODD 
World Health Organization Drug Dictionary 
 
 
 
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Statistical Analysis Plan 
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SP848 
 
 
 
 
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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 SP848.  
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
The objectives of this study are: 
• To obtain information about the safety, tolerability, and pharmacokinetic (PK) of 
Lacosamide (LCM) during long-term exposure 
• To obtain preliminary efficacy data on seizure frequency during long-term exposure  
• To allow study participants who have participated in SP847 (or discontinued SP847 due to a 
dose reduction or status epilepticus) to continue receiving LCM 
• To allow study participants who have participated in other LCM pediatric clinical studies in 
epilepsy to continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not 
previously received LCM to begin receiving LCM  
2.2 
Study variables 
2.3 
Safety variables 
2.3.1 
Primary safety variables 
The primary safety variables are as follows:  
• Incidence of Treatment Emergent Adverse events (TEAEs)  
• Incidence of Serious Adverse Events (SAEs) 
• Subject withdrawal from the study due to TEAEs 
2.3.2 
Other safety variables 
The other safety variables are: 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner Stage (if applicable) 
• Achenbach Child Behavior Checklist (CBCL) for children 18 months and older (CBCL/1½-5 
and CBCL/6-18) assessing behavior 
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• Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
study participants enrolled in English-speaking countries) 
• Cognitive function assessments (Behavior Rating Inventory of Executive Function – 
Preschool Version [BRIEF-P]/ Behavior Rating Inventory of Executive Function [BRIEF]) 
(if applicable) for children >=2 years of age 
LCM palatability and ease of use questionnaire. 
2.3.3 
Pharmacokinetic variables 
2.3.3.1 
Primary Pharmacokinetic variables 
No primary PK variables are defined for this study. 
2.3.3.2 
Other Pharmacokinetic variables 
The other PK variables are: 
• Plasma concentration of LCM (for population PK analysis) and concomitant antiepileptic 
drugs (AEDs)  
2.3.4 
Efficacy variables 
2.3.4.1 
Primary efficacy variables 
No primary efficacy variables are defined for this study. 
2.3.4.2 
Secondary efficacy variables 
The secondary efficacy variables, based on daily seizure diaries are: 
• Percent change from Baseline in 28-day partial-onset seizure frequency 
• ≥50% reduction in 28-day partial-onset seizure frequency 
• ≥75% reduction in 28-day partial-onset seizure frequency 
• Seizure days per 28 days (subjects with generalized seizures only) 
• Seizure-free status 
2.3.4.3 
Other efficacy variables 
The other efficacy variables are: 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• Quality of life assessments (Pediatric Quality of Life Inventory [PedsQL™]) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study) 
• All seizure frequency analyses as described in secondary efficacy variables (presented for the 
overall Treatment Period only) may be additionally presented by modal daily dose group, by 
seizure type, by seizure classification subgroup, by time interval, by visit or time period, or 
by completer cohort.   
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2.4 
Study design and conduct 
2.4.1 
Study description 
2.4.1.1 
Study participants enrolling from SP847 or other LCM pediatric 
clinical studies in epilepsy (rollover study participants) 
Study participants who complete SP847 (including discontinuation from SP847 due to a dose 
reduction or status epilepticus) or study participants from another applicable LCM pediatric 
clinical study in epilepsy and who choose to enter the open-label study (rollover study 
participants), will begin on the LCM dose that they were receiving at the end of the previous 
pediatric study. Study participants will be able to continue on LCM oral solution (syrup) or 
switch to LCM tablets. During the study, investigators will be allowed to increase or decrease the 
dose of LCM and/or concomitant AEDs to optimize tolerability and seizure reduction for each 
subject. The investigator may adjust the LCM dose to a minimum of 2mg/kg/day (oral solution 
[syrup]) or 100mg/day (tablet) and a maximum of 12mg/kg/day (oral solution [syrup]) or the 
corresponding dose levels for the tablet formulation), not to exceed 600mg/day based on body 
weight, even if the subject’s body weight exceeds 50kg. The maximum permitted LCM dose in 
SP848 is 12mg/kg/day or 600mg/day, whichever is lower. Increases in the LCM dose must occur 
only during office visits. If needed to optimize tolerability and seizure reduction in selected study 
participants, 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. When study participants are withdrawn from 
the study, it is recommended that LCM be tapered gradually in weekly decrements of 
4mg/kg/day (oral solution [syrup]) or 200mg/day (tablets) for study participants who have 
achieved a dose of LCM ≥6mg/kg/day (oral solution [syrup]) or ≥300mg/day (tablet). A slower 
taper in weekly decrements of 2mg/kg/day (oral solution [syrup]) or 100mg/day (tablets) is 
permitted, if medically necessary. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible.  
2.4.1.2 
Study participants enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric study participants ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously received LCM will be 
permitted to enroll directly into SP848.  
Beginning with local Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM will be permitted to directly enroll at approximately 9 sites in Japan. 
Beginning with Protocol Amendment 5.4 for sites in China, approximately 60 additional eligible 
pediatric subjects with partial-onset seizures aged ≥4 years to ≤17 years, who have not 
previously participated in a LCM clinical study, will  directly enroll into SP848. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control. Subjects will be able to 
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receive LCM oral solution or LCM tablets for up to 2 years as determined appropriate by the 
investigator. 
SP848 includes subjects ≥1 month to ≤18 years of age since subjects who complete SP847 or 
another applicable LCM pediatric epilepsy study in subjects <18 years of age may have aged to 
18 years old by the time they complete that study and enroll in SP848. 
The same study conditions described in Section 2.4.1.1 (e.g., minimum and maximum LCM 
dose, required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
2.4.2 
Tabular schedule of study procedures 
The schedule of the study procedures for SP848 are provided in Section 16.1 of the study 
protocol and country specific protocol amendments for Japan and China.  
2.5 
Determination of sample size 
Approximately 42 study participants from the SP847 study will be eligible to enroll in this 
open-label study. Other subjects will be eligible to enroll as other LCM pediatric clinical studies 
in epilepsy are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. Beginning 
with local Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric 
subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not previously 
received LCM will directly enroll at approximately 9 sites in Japan. Beginning with local 
Protocol Amendment 5.4 for sites in China, approximately 60 additional eligible pediatric 
subjects with partial-onset seizures aged ≥4 years to ≤17 years, who have not previously 
participated in a LCM clinical study, will enroll directly into SP848. The purpose of enrolling 
these subjects directly into SP848 is to obtain additional long-term safety exposures in the age 
range from which adequate PK data have already been obtained in SP847; the additional 
long-term safety data will be included in planned LCM marketing applications for study 
participants ≥4 years of age.  
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. Protocol 
Amendment 8 allows an enrollment increase from 75 to 100 eligible pediatric subjects ≥1 month 
to ≤17 years of age with epilepsy who participated in EP0060 to enroll in SP848 in order to 
reflect EP0060’s inclusion of subjects down to 1 month of age. 
In total, up to approximately 400 subjects may be eligible to participate in SP848. 
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 study participants in each category will be 
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presented. The denominator for percentages will be based on the number of study participants 
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 study participants (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 
• Coefficient of variance (CV[%]) will be presented with 1 decimal place 
• 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 study participants 
and additionally based on the subject’s age at time of entry into study SP848, using the following 
age groups: 
• ≥1 month to <4 years 
• ≥4 to <18 years 
• Total ≥1 month to <18 years 
• ≥18 years 
• All subjects 
Summaries for PedsQL will be presented overall for all applicable study participants 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 study participants and 
additionally based on the subject’s age at time of entry into study SP848, using the following age 
groups: 
• ≥18 months to <2 years 
• ≥2 to <4 years 
• Total <4 years 
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• ≥4 to <6 years 
Summaries for CBCL 6-18 will be presented overall for all applicable study participants and 
additionally based on the subject’s age at time of entry into study SP848, 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 study participants and 
additionally based on the subject’s age at time of entry into study SP848, using the following age 
groups: 
• ≥2 to <4 years 
• ≥4 to <5 years 
Summaries for BRIEF will be presented overall for all applicable study participants and 
additionally based on the subject’s age at time of entry into study SP848, 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 study 
participants and additionally based on the subject’s age at time of entry into study SP848, 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 (e.g., change 
from Baseline) will be generated, and will be sorted by site, subject number and visit (where 
applicable). 
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 SP848 (ie, not the first dose of LCM from the previous study in which study 
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participants participated prior to SP848 for long-term follow-up study participants). 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 
(e.g., 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 SP848 to the latter of 
the last LCM dose date and the study Termination Visit (ie, Early Termination Visit) date.  
The Treatment Period is further broken down into the Titration Period and the Post-Titration 
Period for direct enrollers: 
• Titration Period: defined as the date of the first dose of study medication to the day prior to 
date of Visit 1 or the date of Early Termination (ET) visit in the situation where a subject 
discontinues prior to the last visit in the Titration Period. 
• Post-Titration Period: defined as the date of Visit 1 to the end of the Treatment Period. 
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 Early Termination Visit (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. Study participants who prematurely discontinue the study will be evaluated based on 
the data collected at each visit attended. For those study participants the ETV will be mapped to 
the next scheduled visit, ie, the assessments documented at Visit 13/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. 
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For study participants enrolled from sites in Japan, they are allowed to stay in the study longer 
than 2 years. Such study participants will have a separate ETV if they are in the study after Visit 
13.  
3.2.4 
Study visit labeling 
Visits will be labeled in table summaries (according to the schedule outlined in Section 16.1 of 
the protocol) as follows: 
• “Screening Visit” for study participants who directly enrolled into SP848 
• “Titration Visit X” for scheduled visits during titration for study participants who directly 
enrolled into SP848 
• “Visit X, Week X” for other scheduled visits during the Treatment Period 
• “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). A subject is included in the analysis 
for a 3-month interval if they are exposed to LCM at any time during that time interval. 
3.2.6 
Last Visit 
The Last Visit for all assessments in SP848 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, >24 
months, >30 months, >36 months, >42 months, and >48 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, >24 months, >30 months, >36 months, >42 months, and >48 months, where 
1 month is defined as 28 days. 
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 SP848.  
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The maximum daily LCM dose (mg/kg/day) is defined as the highest total daily dose a subject 
received during the Treatment Period in SP848. 
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 (in 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 study participants 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 parameter.  
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 and age at first diagnosis 
Age at entry into SP848 will be given in years. For direct enrollers and subjects with a complete 
date of birth available, age at entry into SP848 will use the SDTM derivation in the analysis 
dataset. For rollover subjects without a complete date of birth available, age at entry into SP848 
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 SP848)/12. 
The age at entry into the previous pediatric study is migrated from the previous pediatric study 
into the SP848 SDTM. 
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Missing or partial epilepsy diagnosis date will be derived applying all rules for missing data 
imputation (see Section 4.2.6) and age at diagnosis will use the following formula, where 
applicable. The age at first diagnosis will be given in years. 
If date of birth is a complete date then age at diagnosis will be calculated as: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25  
If date of birth is a partial date then age at diagnosis will be calculated as: 
(Enrollment age in years) – [(Informed consent date – Epilepsy diagnosis date) / 365.25]  
If this produces a negative value then age at diagnosis will be set to zero. 
3.2.10 
Weight band 
Study participants will be classified as belonging to one of the following weight bands based on 
their weight at time of enrollment into study SP848: 
• <30kg 
• ≥30 to <50kg 
• ≥50kg 
3.2.11 
Body mass index  
Body mass index (BMI) will be calculated using the formula: 
BMI = weight (kg) / (height (m))2 
3.2.12 
Seizure Classification Subgroups 
Study participants will be classified as belonging to one of the following seizure classification 
subgroups based on their seizure classification history for the purpose of disposition, 
demographic, efficacy, and exposure subgroup analyses: 
• POS study participants  
− Study participants from SP0966 who reported only Type I seizures 
− Study participants who reported any Type I seizure 
• Generalized seizure study participants 
− Study participants from SP0966 unless they reported only Type I seizures 
− Study participants who reported only Type II seizures 
• Unclassified  
− Study participants who reported only Type III seizures 
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 in the analysis period) x (28/D) 
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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 a Type II or Type III seizure, the 
seizure clusters 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 a Type I seizure, the seizure clusters 
will be assigned to the correct seizure type and the 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. 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). Study participants who experience at least a 50% 
reduction from Baseline will be considered ≥50% responders. Study participants 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 
CRF/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 
CRF/eCRF will not be counted as a seizure-free day. 
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3.2.18 
Seizure-free status 
Study participants will be considered seizure-free for a given period if the subject completes the 
period, reports zero seizures during the period, and have 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 
CRF/eCRF module). Seizure diary days where “not done” has been reported for days when study 
participants 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 the EP0060 iv 
study, days of participation in EP0060 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 study participants 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 study participants enrolled and treated with LCM for at 
least 6 months where a month is defined as 28 days.  
Study participants 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 
• 30 months 
• 36 months 
• 42 months 
• 48 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 CRF/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 
Study participants 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 
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• >6 to ≤12 months 
• >12 to ≤18 months 
• >18 to ≤24 months 
• >24 to ≤30 months 
• >30 to ≤36 months 
• >36 to ≤42 months 
• >42 to ≤48 months 
• >48 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 ≤18 years 
of age. The PedsQL Measurement Model consists of developmentally appropriate forms for 
pediatric study participants ≥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 
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 
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”. 
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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 CRF/eCRF module) plus 1 day 
for hospital stays with a discharge date. 
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 original study for rollover subjects and in SP848 for direct enrollers for safety and 
efficacy variables unless otherwise noted for a specific type of data.  The Baseline value for 
seizure counts for directly enrolled study participants will be taken from the Historical Seizure 
Count CRF/eCRF module collected in SP848 in combination with the seizure diary data 
collected from the date of the Screening Visit to the day prior to the date of first dose of LCM. 
For participants enrolling from EP0060 the baselines for the questionnaires will consider each 
EP0060 enrollment group separately, those are: IIL (Initiating intravenous lacosamide Group: 
not currently receiving LCM, i.e. LCM naïve), OLL (Open-label lacosamide Group: currently 
receiving oral LCM in open-label long term study), and RxL (Prescription lacosamide Group: 
currently receiving prescribed oral LCM from commercial supply, VIMPAT).  For ILL group 
baseline will be Visit 1 from SP848, for OLL group baseline will come from SP848 using above 
baseline definition, and for RxL group there will be no baseline data as they were on oral LCM 
prior to EP0060.  
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 study 
participant. The criteria for identifying important protocol deviations and the classification of 
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important protocol deviations will be defined separately in the Specification of Protocol 
Deviations (SPD) 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 study participants. 
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 Review Meeting (DRM) prior 
to database lock. A list of study participants with important protocol deviations will be agreed 
upon during the DRM and will be documented in the DRM 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 study participants who took at least 1 dose of 
LCM in this study. All safety analyses will be performed on the SS. 
3.5.2 
Pharmacokinetic Per-Protocol Set  
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all study participants from the 
SS having provided at least 1 measurable post-dose plasma sample (with recorded sampling 
time) on at least 1 visit with documented LCM intake times. 
3.5.3 
Full Analysis Set  
The Full Analysis Set (FAS) will be used for the analysis of seizure data and will consist of all 
study participants in the SS, who have at least 1 completed post-Baseline seizure diary. 
3.6 
Treatment assignment and treatment groups 
This is an open-label study; study participants will not be randomized.  
Where specified within this SAP, data will either be summarized by age group overall across all 
LCM doses or by modal daily LCM dose (defined in Section 3.2.8). 
3.7 
Center pooling strategy 
No pooling of centers is planned for this study. 
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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. 
3.9 
Changes to protocol-defined analyses 
3.9.1 
Handling of dropouts or missing data 
The following protocol-defined method of analysis is no longer applicable for this study: 
• All data will be used to their maximum possible extent, but without any imputations for 
missing data for any parameter. Study participants who discontinue from the study 
prematurely will be evaluated based on the data collected at each visit attended. 
This will be replaced with the following method of analysis (see Section 4.2): 
• 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.  
3.9.2 
Examination of subgroups 
A subgroup for weight which was not protocol-defined has been included in Section 3.2.  
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.  
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). 
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• 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). 
• 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: 
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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 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. 
4.2.7 
Missing data due to participation in solution for infusion formulation 
trials 
Study participants who participated in the iv trial EP0060 while also enrolled in SP848 will have 
missing data for seizure frequency and drug dosing during the period of participation in the iv 
trial.  As the duration of the iv trial is short, approximately 1 to 5 days, no imputation for data 
missing due to participation in the iv trial will be performed. 
Study participants were assigned the same dose in EP0060 as that assigned in SP848 for the two 
weeks prior to the start of the iv trial.  As such, time during the iv trial will not be subtracted 
from the exposure calculation (ie, exposure will be from the start of LCM treatment in SP848 
trial until the date of last dose of LCM in SP848).  The duration of treatment during EP0060 is 
approximately 1 to 5 days. 
For the calculation of variables related to seizure frequency, the dates during participation in 
EP0060 will be considered as not done for the purpose of efficacy analyses for SP848 (ie, the 
dates will not be considered as days evaluated for seizure frequency).  Due to the short nature of 
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EP0060, only 1 to 5 days of seizure frequency data are expected to be missing due to 
participation in EP0060. 
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. 
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 study participants 
The FAS, defined in Section 3.5.3, 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 
The number of study participants screened (screened study participants include study participants 
who signed an ICF), in addition to the number and percentage of those study participants who 
were screen failures, broken down by primary reason for screening failure, will be presented. A 
summary of disposition of study participants will be provided for all screened study participants. 
The date of first subject in (date of earliest entry visit for the SP848 study), date of last subject 
out (date of final scheduled or unscheduled visit), number of study participants screened, number 
of study participants enrolled, and the number of study participants in each analysis set (SS, PK-
PPS, and FAS), will be summarized overall and by investigator site. Study participants who 
transferred sites will be summarized according to their original site.  
A summary of disposition of analysis sets will be provided for all screened study participants. 
The following will be summarized: 
• The number of screened study participants 
• The number and percentage of enrolled study participants  
• The number and percentage of study participants in the SS 
• The number and percentage of study participants in the PK-PPS 
• The number and percentage of study participants in the FAS 
• The number of study participants from each parent study 
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• The number of original direct enrollers (excluding Japanese and Chinese direct enrollers) 
• The number of Japanese direct enrollers 
• The number of Chinese direct enrollers  
Additionally, a summary of disposition and discontinuation reasons will present the following 
for all study participants in the SS (overall and repeated by weight band and seizure 
classification subgroup using the levels defined in Sections 3.2.10 and 3.2.12, respectively), PK-
PPS, and FAS: 
The number and percentage of study participants starting the study 
The number and percentage of study participants completing <12 months, 12, 24, 36, and ≥48 
months of the study. 
The number and percentage of study participants completing the study (defined as study 
participants who have ‘Completed subject’ selected as status at termination – see Study 
Termination eCRF module). 
The overall number and percentage of study participants discontinuing and the number and 
percentage of study participants 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 study participants will present the 
number and percentage of study participants who discontinued this study due to AEs broken 
down by type of AE.  
The number and percentage of study participants enrolled under each protocol amendment 
(estimated by date of informed consent) will be presented for all global protocols, and separately, 
for Chinese direct enrollers from version 5.4 and for Japanese direct enrollers from version 5.3. 
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 SPD, and additionally identified at the DRM, will be 
listed. In addition, the number and percentage of study participants 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. 
 
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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 LCM study for those study participants 
who enrolled from SP847 (or other LCM pediatric clinical studies in epilepsy). Demographic 
variables will be obtained from the Screening Visit for those study participants who directly 
enrolled into SP848. 
Demographic variables will be presented by weight band (using the levels defined in 
Section 3.2.10), by seizure classification subgroup  (using the levels defined in Section 3.2.12) 
and overall for the SS. The variables to be considered are: 
• Age at entry into SP848 (as defined in Section 3.2.9) – continuous and categorized as (28 
days - <24 months, 24 months - <12 years, 12 years - <18 years) and categorized as (≤18 
years and 19 - < 65 years) 
• Age at entry into previous pediatric study for study participants from SP847 or other studies 
and age at entry into SP848 for directly enrolled study participants (years) (as defined in 
Section 3.2.9) 
• Gender 
• Weight (kg) at entry into SP848 
• Weight band (as defined in Section 3.2.10)  
• Height (cm) 
• BMI (kg/m2) (as defined in Section 3.2.11) 
• 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) 
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 study participants 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 study participants with concomitant diseases and conditions 
(medical history conditions noted as ongoing at study entry for the SP848 study), except 
epilepsy, will be summarized by SOC and PT for the SS.  
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6.3 
History of epilepsy 
The history of epilepsy uses CRF/eCRF information collected at the time of entry into the 
previous pediatric LCM study for those study participants who enrolled from SP847 (or other 
LCM pediatric clinical studies in epilepsy). The history of epilepsy will be obtained from the 
Screening Visit for those study participants who directly enrolled into SP848. 
6.3.1 
History of seizure types 
The number and percentage of study participants 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 (into 
the previous study for rollover study participants or into SP848 for those direct enrollers) 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 study participants 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 study participants 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). 
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. This will be summarized for the SS, by seizure classification 
subgroups.  
6.3.3 
Historical seizure counts 
The Historical Seizure Counts CRF/eCRF module records the number of seizures per pre-
selected ILAE seizure code experienced by the subject during the 4 weeks prior to Baseline. 
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These data will be provided in a subject data listing. This will be summarized for the SS, by 
seizure classification subgroups.  
6.4 
Prior and concomitant medications 
All prior and concomitant medications will be presented by seizure classification subgroup, age 
group, weight band and overall. Antiepileptic drugs defined as medications documented on the 
“Concomitant Medications (AEDs only)” log form. A medical review will be performed to 
ensure that the medications are documented correctly. A listing of all medications taken during 
the study will be presented.  
6.4.1 
Number of previous AEDs  
The number of previous AEDs defined as AEDs taken and stopped >28 days prior to entry into 
the study, will be summarized for the SS based on the following categorization: 0 AED, 1-3 
AEDs, 4-6 AEDs, and ≥7 AEDs. This summary will be based on the History of Previous AED 
Treatment CRF/eCRF module for applicable studies which only includes AEDs stopped prior to 
study entry. For study participants who rolled over from the SP0966 study, previous AEDs are 
defined as AEDs taken 12 months prior to informed consent date and stopped>28 days prior to 
entry into SP0966. 
6.4.2 
Concomitant AEDs taken at the start of the SP848 Treatment Period 
Concomitant AEDs taken at the start of the SP848 Treatment Period are defined as AEDs taken 
concomitantly with LCM at the time of first dose of LCM in SP848. 
The number of concomitant AEDs taken at the start of the SP848 Treatment Period will be 
summarized for the SS based on the following categorization: 0 AED, 1 AED, 2 AEDs,  3 AEDs 
and ≥4 AEDs. The number and percentage of study participants taking concomitant AEDs at the 
start of the SP848 Treatment Period will be summarized overall and, separately, by WHODD 
chemical subgroup (level 4) and preferred drug name, for the SS. 
6.4.3 
Concomitant AEDs taken during the SP848 Treatment Period 
Concomitant AEDs taken during the SP848 Treatment Period are defined as AEDs taken 
concomitantly for at least one day in common with LCM in SP848.  
The number and percentage of study participants taking concomitant AEDs during the SP848 
Treatment Period will be summarized overall and, separately, by WHODD chemical subgroup 
(level 4) and preferred drug name, for the SS.  
VNS is allowed and will not be counted as a concomitant AED. 
6.4.4 
Concomitant medications (excluding AEDs) 
The number and percentage of study participants taking concomitant non-AEDs during the 
SP848 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 
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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 for the SS. 
8.1 
Extent of exposure 
All the summaries described below will also be presented by seizure classification subgroup, 
using the levels defined in Section 3.2.7, and 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 study participants 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. 
Summary statistics (n, mean, SD, minimum and maximum) for the duration of LCM exposure 
(days) and median daily LCM dose (mg/kg/day) during each of the following analysis periods 
for direct enrollers: Titration, Post-Titration and Treatment Period will be summarized for the 
SS.  Duration of LCM exposure (days) and median daily LCM dose (mg/kg/day) for the 
Treatment Period will be summaries for the rollover and all study participants in the SS 
separately. 
8.2 
Adverse events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented 
by weight band and seizure classification subgroup using the levels defined in Sections 3.2.10 
and 3.2.12, respectively. Additional tables will also be presented by time interval using the 
definition in Section 3.2.5. The number and percentage of study participants 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 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. 
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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 study participants 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 study participants with AEs leading to 
death (if applicable) will also be summarized. This overall summary will be repeated by weight 
band and seizure classification subgroup using the levels defined in Sections 3.2.10 and 3.2.12 
respectively. In addition, the overall summary will be presented for the Titration Period, Post-
Titration Period and Treatment Period for the direct enrollers and the Treatment Period for the 
rollover study participants. 
The following summaries of AEs will be provided by MedDRA primary SOC and PT:  
• Incidence of TEAEs 
• Incidence of TEAEs with onset during the Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Post-Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Treatment Period for direct enrollers 
• Incidence of TEAEs for direct enrollers 
• Incidence of TEAEs for rollover study participants 
• 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 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 study participants 
• Incidence of non-serious TEAEs occurring in at least 5% of study participants 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 seizure classification 
subgroup 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 study participants 
• 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 time intervals (using the definition 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 to 
≤ 30  months, >30 to ≤36 months, >36 to ≤42 months, >42 to ≤48 months, >48 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 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 AEs, incidence 
of serious TEAEs, incidence of TEAEs leading to discontinuation from study, 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 study participants 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 study participants ≥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. 
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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 Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (AST), Gamma-glutamyl Transferase (GGT), Total 
Bilirubin, and Alkaline Phosphatase. 
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 SP848 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. The age at the time of 
visit/assessment will be obtained using date of informed consent to date of visit. 
The number and percentage of study participants 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 study participants 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 schedule of study procedures. Serum and urine pregnancy test results 
will be listed. No summaries of these results are planned. 
PDILI IMP discontinuation criteria as outlined in the protocol, will be evaluated at all laboratory 
assessments. The number and percentage of study participants meeting PDILI criteria (ie, ALT 
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 study participants 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, and BMI 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate, and 
temperature), body weight, and height will be collected according to the tabular schedule of 
study procedures. In addition, BMI will be calculated (as defined in Section 3.2.11) for each visit 
where weight and height are collected. 
Noninvasive blood pressure (systolic and diastolic) and pulse rate will be measured at all visits in 
a sitting position after at least 3 minutes at rest. Body weight will be determined without shoes 
and wearing light clothing. Height will be measured without shoes. 
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All summaries of vital signs, body weight, height, and BMI will only summarize variables 
planned based on the protocol. However, both planned and unplanned variables will be provided 
in subject data listings.  
Observed values of SBP, DBP, pulse rate, temperature, body weight, height, and BMI will be 
summarized for each visit and Last Visit. Change from Baseline for SBP, DBP, pulse rate, 
temperature, body weight, height, and BMI will be summarized for all post-Baseline visits, 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 SP848 LCM 
administration through to the end of the study. 
The number and percentage of study participants 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, temperature, 
and body weight were scheduled to be assessed, and Last Visit, will be presented. Percentages 
will be relative to the number of study participants 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 
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 
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 Table 8‒1: Vital signs abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
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.  
a Source: http//www.cdc.gov/growthcharts/. 
A subject data listing of all vital signs for study participants with an AE mapped to the PT 
bradycardia or sinus bradycardia will be presented. 
A subject data listing of all vital sign values including body weight, height, and BMI for all study 
participants 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 schedule of study procedures.  
For ECGs, Baseline will be defined as the average of all pre-dose interpretable readings. 
Assessments with missing time on day of first dose will be assumed pre-dose. 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 study participants 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 study participants with an 
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ECG assessment at each visit. Study participants 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 study participants 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 study participants will also be presented. Listings will include 
results from each recording and the average of all recordings. 
The number and percentage of study participants 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. The age at the time of 
assessment will be obtained using date of informed consent to date of visit. All ECG parameter 
values will be listed for study participants 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 
>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 
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Table 8‒2: ECG abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
>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 study participants 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 schedule of study procedures.  
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 
schedule of study 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. 
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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 schedule of study procedures.  
The complete neurological examination will include selected assessment of mental status, 
sensory systems, motor functions, cranial nerves, reflexes, and coordination/cerebellar function.  
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 schedule of study procedures.  
The brief neurological examination will include selected assessment of: mental status, cranial 
nerves, and coordination/cerebellar 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 schedule of study 
procedures, only for those study participants with an implanted VNS device.  
A listing of VNS status will be provided only for those study participants with an implanted VNS 
device.  
8.4.6 
Tanner stage assessment 
Tanner stage will be assessed throughout the study, according to the tabular schedule of study 
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 study participants are selected for evaluation of Tanner Stage (ie, those study participants 
who are pubescent at screening or those study participants who become pubescent during the 
course of the study). The investigator will only report the overall score on the Tanner Stage 
CRF/eCRF module and this will be used for the associated summaries and listings. 
A shift table will be produced showing the change in overall Tanner stage (1-5) from Baseline to 
Last Visit, by gender.  
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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 schedule of study 
procedures. 
For study participants ≥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 study participants enrolling 
directly in SP848 and who are ≥6 years of age will complete the Baseline/Screening version of 
the C-SSRS at Visit 1 and will complete the Since Last Visit version at subsequent visits. If a 
subject becomes 6 years of age during the study, the Already Enrolled version of the C-SSRS 
should be used at the first visit at which the subject is 6 years of age and use the Since Last Visit 
version at subsequent visits.  
The C-SSRS is not validated and will not be used for study participants <6 years of age. For 
those study participants, 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 (CBCL) 
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 participants ≥6 years to ≤18 years, the CBCL/6-18 will be used.  
The same scale will be completed by the parent(s)/legal representative(s).  
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 
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Table 8‒3: CBCL/1½-5 
Syndrome scale 
Items 
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 spreadsheets 
“c15group2-probscales18moto5yrs” and “cbcgroup2-probscales6to18”. 
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. 
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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 is available. 
8.4.9 
BRIEF-P and BRIEF assessment 
The BRIEF-P/BRIEF assessments will be completed according to the tabular schedule 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 study 
participants ≥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 
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 
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Table 8‒5: BRIEF-P questionnaire scoring 
Scale/Index 
Questions 
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 spreadsheet “briefp-tscores”. 
T-score values 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. 
Table 8‒6: BRIEF questionnaire scoring 
Scale/Index 
Questions 
Inhibit 
38, 41, 43, 44, 49, 54, 55, 56, 59, 65 
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Table 8‒6: BRIEF questionnaire scoring 
Scale/Index 
Questions 
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. 
T-score values and change from Baseline for the two indexed scores (BRI and MI), the GEC and 
the 8 individual component scores for the BRIEF questionnaire will be summarized 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 scoring spreadsheet 
“brief-tscores”. 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  indicates 
improvement, 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 is available. 
All BRIEF assessment data will be listed. 
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8.4.10 
Bayley-III assessment 
The Bayley-III assessments will be completed according to the tabular schedule of study 
procedures for study participants <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 will be completed for children from 1 month to <18 months of age enrolled in 
English-speaking countries. 
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 scaled scored entered on the CRF/eCRF module, and the change from Baseline for 
the scales, as well as the general adaptive composite sum scaled score, will be summarized for 
each visit, and Last Visit. 
All Bayley-III assessment data will be listed. 
8.4.11 Medical procedures 
Subjects who had any concomitant medical procedures during the study based on the 
Concomitant Medical Procedures eCRF module will be listed. Additionally, subjects who had 
any procedures or surgeries prior to study entry based on the Procedure History CRF/eCRF 
module will also be listed. 
8.5 
Palatability and ease of use questionnaires 
UCB has created a palatability and ease of use questionnaire to collect data from the subject or 
caregiver regarding different aspects of LCM and its administration. The questionnaire will 
assess the subject or caregiver’s response regarding the formulation of LCM the subject is 
receiving for palatability items (eg, taste, smell, ability to swallow, aftertaste), mode of 
administration, and administration device as applicable. 
The number and percentage of study participants who respond to each of the categories presented 
for the following questionnaires will be summarized at each visit it is assessed: 
• Tablet palatability and ease of use 
• Oral solution palatability and ease of use 
Summaries will be performed overall and by seizure classification group (as defined in Section 
3.2.12), with percentages based on the number of study participants with non-missing responses 
for the specified visit. All palatability and ease of use questionnaire data will be listed. 
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9 
PHARMACOKINETICS  
All study PK outcomes will be summarized for the PK-PPS. 
Blood samples for LCM PK will be completed according to the tabular schedule of study 
procedures, for the assessment of LCM and concomitant AED plasma concentrations. These 
blood samples will be collected along with the clinical chemistry/hematology samples at any 
time after intake of LCM.  
9.1 
Descriptive statistics 
Descriptive summaries (n, mean, SD, geometric mean, CV, geometric CV, median, minimum, 
and maximum) for the LCM plasma concentration and the plasma concentrations for selected 
concomitant AEDs will be presented by visit, timepoint and actual dose.  
10 
EFFICACY ANALYSES 
The study efficacy variables include seizure counts (assessed using seizure diaries in order to 
evaluate the preliminary efficacy of LCM 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 efficacy 
seizure classification subgroup (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. 
10.1 
Seizure counts 
At Screening of SP847 (or other LCM pediatric clinical studies in epilepsy) or at the Screening 
Visit of SP848 (for study participants who directly enrolled into SP848) study 
participants/caregivers (including parents/legal guardians) will be asked how many seizures the 
subject has had in the previous 4 weeks; this will serve as a historical Baseline. After the subject 
is enrolled in the SP848 study, seizure data will be collected in diaries provided to study 
participants/caregivers (including parents/legal guardians). Each subject/caregiver (including 
parent/legal guardian) will keep a diary to note daily seizure activity throughout the current 
study. The subject/caregiver (including parent/legal guardian) should be reminded to bring the 
diary with them at each clinic visit. The following information will be recorded: 
• Seizure type 
• Seizure frequency 
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 CRF/eCRF module). 
Determination of Baseline Period seizures will be made utilizing both the historical Baseline and 
the seizure diary data collected from the date of the Screening Visit to the day prior to the date of 
first dose of LCM. 
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10.1.1 
Seizure frequency per 28 days 
For study participants with POS, seizure frequency per 28 days (as defined in Section 3.2.13) 
will be summarized descriptively and presented graphically.  
Observed values and change from Baseline during the Titration Period, Post-Titration Period and 
the overall Treatment Period for the direct enrollers, overall Treatment Period for rollover study 
and overall Treatment Period for all study participants will be presented.  
10.1.2 
Percent change from Baseline in 28-day partial-onset seizure 
frequency 
For study participants with POS, descriptive statistics for percent change from Baseline (as 
defined in Section 3.2.14) in 28-day seizure frequency will be presented. Any subject with 
seizure data during the time interval will be included in the summary for that seizure time 
interval.  
Descriptive statistics will also be presented for percent change from Baseline in 28-day seizure 
frequency during the Titration Period, Post-Titration Period and for the overall Treatment Period 
for direct enrollers, for the overall Treatment Period for the rollover study participants and for 
the overall Treatment Period for all study participants.  
Descriptive statistics for percent change from Baseline in 28-day seizure frequency during the 
Treatment Period will also be presented by seizure type (simple partial, complex partial, 
secondarily generalized) for POS. Only study participants who experienced a seizure type during 
the Baseline Period will be included in the analysis for that seizure type with only the seizure 
frequencies of that seizure type being used in the analysis.  
Descriptive statistics for percent change from Baseline to each time interval in 28-day seizure 
frequency during the Treatment Period will also be presented. Any subject with seizure data 
during the time interval will be included in the summary for that seizure time interval and by 
seizure type. 
The percent change from Baseline in 28-day seizure frequency among completer cohorts (as 
defined in Section 3.2.19) will also be presented. 
10.1.3 
≥50% reduction in 28-days partial-onset seizure frequency  
For study participants with POS, the number and percentage with ≥50% reduction in 28-day 
partial-onset seizure frequency (≥50% responders) will be summarized by seizure time intervals 
(as defined in Section 3.2.21) and by seizure type (simple partial, complex partial, secondarily 
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.  
10.1.4 
≥75% reduction in 28-days partial-onset seizure frequency  
The analyses described in Section 10.1.3 for ≥50% reduction in 28-days partial-onset seizure 
frequency will also be performed for study participants with ≥75% reduction in 28-day partial-
onset seizure frequency (≥75% responders). 
10.1.5 
Seizure days per 28 days (subjects with generalized seizures only)  
For study participants with generalized seizures, the number of seizure days per 28 days (as 
defined in Section 3.2.16) will be summarized descriptively during the treatment period. 
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10.1.6 
Seizure-free status 
The number and percentage of study participants achieving a seizure-free status (as defined in 
Section 3.2.18) will be presented for overall treatment period. This will be presented by 
completer cohorts (as defined in Section 3.2.19).  
The number and percentage of study participants seizure-free among completer cohorts (as 
defined in Section 3.2.19) will also be presented separately by seizure type (simple partial, 
complex partial, secondarily generalized) for subjects with POS.  
Seizure-free status will also be presented by seizure time intervals (as defined in Section 3.2.21). 
The number and percentage of study participants 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, secondarily generalized) for POS. 
10.2 
Global Impression of Change 
10.2.1 
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 study participants by Clinical Global Impression of Change value 
will be summarized by visit and Last Visit. The denominator for the percentage calculation will 
be based on the number of study participants 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 and grouped by modal daily LCM dose, using the levels defined in Section 
3.2.8. The denominator for the percentage calculation will be based on the number of study 
participants with non-missing values. 
Clinical Global Impression of Change data will be listed. 
10.2.2 
Caregiver 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 at least once per 
year and will be completed according to the tabular schedule of study procedures. 
The number and percentage of study participants by Caregiver Global Impression of Change 
value will be summarized by visit and Last Visit. The denominator for the percentage calculation 
will be based on the number of study participants 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 and grouped by modal daily LCM dose, using the levels defined in Section 
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3.2.8. The denominator for the percentage calculation will be based on the number of study 
participants with non-missing values. 
Caregiver Global Impression of Change data will be listed. 
10.3 
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. 
10.3.1 
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. 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. 
10.3.2 
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. 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 >2 years data will be listed. 
10.4 
Health care resource use 
For health care resource use parameters, the following will be evaluated: concomitant 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 schedule of study procedures. Summaries will be presented during the Treatment Period.  
10.4.1 
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). 
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Percentages will be relative to the number of healthcare provider consultations during the 
Treatment Period. 
All healthcare provider consultations data will be listed. 
10.4.2 
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 study participants 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 CRF/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 study participants 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. Study participants 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. 
 
 
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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 
>15.0 
g/L 
≤90 
>150 
2y - <17y 
g/dL 
 
≤9.5 
>16.0 
g/L 
≤95 
>160 
≥17y 
g/dL 
 
≤85% of LLN 
≥115% of ULN 
g/L 
≤85% of LLN 
≥115% of ULN 
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 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
ALT (SGPT) 
All 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
U/L 
≥3.0 x ULN 
≥5.0 x ULN 
≥10.0 x ULN 
Alkaline 
Phosphatase 
<4y 
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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Table 12‒2: Chemistry abnormality criteria 
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 
>38 
mmol/L 
<15 
>38 
≥17y 
mEq/L 
<18 
>38 
mmol/L 
<18 
>38 
Calcium 
<1y 
mg/dL 
<6.9 
>12.2 
mmol/L 
<1.725 
>3.05 
1y - <17y 
mg/dL 
<7.4 
>11.7 
mmol/L 
<1.85 
>2.925 
≥17y 
mg/dL 
≤7.6 
≥11.0 
mmol/L 
≤1.9 
≥2.75 
Chloride 
>1m 
mEq/L 
≤90 
≥112 
mmol/L 
≤90 
≥112 
Phosphorous 
<1y 
mg/dL 
<1.8 
>8.2 
mmol/L 
<0.5814 
>2.6486 
1y - <17y 
mg/dL 
<1.8 
>7.4 
mmol/L 
<0.5814 
>2.3902 
≥17y 
mg/dL 
≤2.0 
≥6.0 
mmol/L 
≤0.646 
≥1.938 
Potassium 
<1y 
mEq/L 
≤3.0 
≥6.5 
mmol/L 
≤3.0 
≥6.5 
≥1y 
mEq/L 
≤3.0 
≥6.0 
mmol/L 
≤3.0 
≥6.0 
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Table 12‒2: Chemistry abnormality criteria 
Parameter 
Age Range 
Unit 
(conventional) 
Abnormality  
criteria 
(conventional 
unit) 
Unit 
(standard) 
Abnormality 
criteria 
(standard 
unit) 
Sodium 
>1m 
mEq/L 
<127 
>151 
mmol/L 
<127 
>151 
Glucose 
>1m - <17y 
mg/dL 
<50 
≥180 
mmol/L 
<2.775 
≥9.99 
≥17y 
mg/dL 
<50 
≥200 
mmol/L 
<2.775 
≥11.1 
Total 
Cholesterol 
≥1y 
mg/dL 
>250 
mmol/L 
>6.475 
LDL 
(calculated) 
1y - <17y 
mg/dL 
>140 
mmol/L 
>3.626 
≥17y 
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 
≥18.4 
nmol/L 
≤55.3453 
≥236.8264 
≥1y 
ug/dL 
≤3.8 
≥13.5 
nmol/L 
≤48.9098 
≥173.7585 
Globulin 
<1y 
g/dL 
<1.0 
>4.5 
g/L 
<10 
>45 
≥1y 
g/dL 
<1.2 
>5.3 
g/L 
<12 
>53 
Abbreviations: ALT= alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
dL=deciliter; GGT: gamma-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) 
aSchwartz equation (study participants <12): Cr Cl ml/min=[Height (cm) * 0.55] / serum creatinine 
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b Cockroft equation (study participants >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 TEAEs 
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  
Cardiac arrest 
Cardiac pacemaker insertion 
Cardiac fibrillation 
Cardiac flutter 
Conduction disorder 
Heart Rate decreased 
Implantable defibrillator insertion 
Sick sinus syndrome 
Sinus arrest 
Sinus bradycardia 
Torsade de pointes 
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Table 12‒3: Other significant TEAEs 
MedDRA Preferred Term 
Ventricular asystole 
Ventricular fibrillation 
Ventricular flutter 
Ventricular tachycardia 
Ventricular tachyarrhythmia 
SUICIDALITY RELATED TERMS 
Completed suicide 
Depression suicidal 
Intentional overdose 
Intentional self-injury 
Multiple drug overdose intentional 
Poisoning deliberate 
Suicidal behaviour 
Suicidal ideation 
Suicide attempt 
Self injurious behaviour 
Self-injurious ideation 
ADDITIONAL TERMS 
Abnormal behaviour 
Appetite disorder 
Decreased appetite 
Diet refusal 
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Table 12‒3: Other significant TEAEs 
MedDRA Preferred Term 
Food aversion 
Hypophagia 
Loss of consciousness 
Syncope 
 
12.3 
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 
Chronic hepatitis 
Coma hepatic 
Cryptogenic cirrhosis 
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Table 12‒4: AEs for PDILI 
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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Table 12‒4: AEs for PDILI 
Jaundice hepatocellular 
Liver disorder 
Liver injury 
Mixed liver injury 
Non-alcoholic steatohepatitis 
Ocular icterus 
Subacute hepatic failure 
 
 
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 27 Apr 2015 
Has been changed to: 
SAP – Amendment 1 18 Dec 2015 
Change #2 
List of Abbreviations 
Cmax has been deleted. 
Change #3 
Section 3.2.4 Study visit labeling  
Visits will be labeled in table summaries (according to the schedule outlined in Section 16.1 of 
the protocol) as follows: 
• “Screening Visit” for subjects who directly enrolled into SP848 
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• “Titration Visit X” for scheduled visits during titration for subjects who directly enrolled into 
SP848 
• “Visit X, Week X (Descriptor)” for other scheduled visits during the Treatment Period 
Listings will also include “Unscheduled Visit” as applicable. 
Has been changed to: 
Visits will be labeled in table summaries (according to the schedule outlined in Section 16.1 of 
the protocol) as follows: 
• “Screening Visit” for subjects who directly enrolled into SP848 
• “Titration Visit X” for scheduled visits during titration for subjects who directly enrolled into 
SP848 
• “Visit X, Week X” for other scheduled visits during the Treatment Period 
• “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  
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).  
Has been changed to: 
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). A subject is included in the analysis 
for a 3-month interval if they are exposed to LCM at any time during that time 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 have 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 CRF/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 have 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 CRF/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 
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subject in the assessment of seizure-free status). If a subject enrolls in the EP0060 iv study, days 
of participation in EP0060 will also not be considered in the assessment of seizure-free status. 
Change #6 
Section 3.5.1 Safety Set 
The Safety Set (SS) will consist of all subjects who meet the inclusion/exclusion criteria, sign an 
informed consent form, and take at least 1 dose of LCM in SP848. This is the primary analysis 
set. 
Has been changed to: 
The Safety Set (SS) will consist of all enrolled subjects who took at least 1 dose of LCM in this 
study. All safety analyses will be performed on the SS. 
Change #7 
Section 3.5.1 Full Analysis Set 
The FAS will consist of all subjects from the SS who had a Baseline seizure frequency 
assessment and at least 1 post-Baseline assessment from SP848 of seizure frequency data. 
Has been 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. 
Change #8 
Section 3.9.4 Analysis sets 
The protocol-defined PK-PPS has been updated to the text shown in Section 3.5.2. 
The FAS (defined in Section 3.5.3) has been added to the list of analysis sets for this study. 
Has been changed to: 
The protocol-defined SS has been updated to the text shown in Section 3.5.1 to clarify that all 
enrolled subjects who take at least one dose of LCM will be included. 
The protocol-defined PK-PPS has been updated to the text shown in Section 3.5.2. 
The FAS (defined in Section 3.5.3) has been added to the list of analysis sets for this study. 
Change #9 
Section 5.1 Subject disposition 
The number of subjects screened, in addition to the number and percentage of those subjects who 
were screen failures, broken down by primary reason for screening failure, will be presented. 
A summary of disposition of subjects will be provided for all screened subjects. The date of first 
subject in (date of earliest entry visit for the SP848 study), date of last subject out (date of final 
scheduled or unscheduled visit), number of subjects screened, number of subjects enrolled, and 
the number of subjects in each analysis set (SS, PK-PPS, and FAS), will be summarized overall 
and by investigator site. Subjects who transferred sites will be summarized according to their 
original site.  
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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 enrolled subjects  
• The number and percentage of subjects in the SS 
• The number and percentage of subjects in the PK-PPS 
• The number and percentage of subjects in the FAS 
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 
disposition enrollment group using the levels defined in Section 3.2.10 and (previously described 
in Section 3.2.12.2) respectively), PK-PPS, and FAS: 
The number and percentage of subjects starting the study 
The number and percentage of subjects completing the study (defined as subjects who have 
‘Completed subject’ selected as status at termination – see Study Termination eCRF module) 
The number and percentage of subjects completing 12, 24, 36 and >36 months of the study 
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.  
The number and percentage of subjects enrolled under each protocol amendment (estimated by 
date of informed consent) will be presented, separately, for global protocols prior to version 5.1 
and for Japanese direct enrollers. This will also be presented in the subject data listings. 
Has been changed to: 
The number of subjects screened, in addition to the number and percentage of those subjects who 
were screen failures, broken down by primary reason for screening failure, will be presented. 
A summary of disposition of subjects will be provided for all screened subjects. The date of first 
subject in (date of earliest entry visit for the SP848 study), date of last subject out (date of final 
scheduled or unscheduled visit), number of subjects screened, number of subjects enrolled, and 
the number of subjects in each analysis set (SS, PK-PPS, 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 screened subjects. The 
following will be summarized: 
• The number of screened subjects 
• The number and percentage of enrolled subjects  
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• The number and percentage of subjects in the SS 
• The number and percentage of subjects in the PK-PPS 
• 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 disposition enrollment group 
using the levels defined in Section 3.2.10 and (previously described in Section 3.2.12.1) 
respectively, PK-PPS, and FAS: 
The number and percentage of subjects starting the study 
The number and percentage of subjects completing the study (defined as subjects who have 
‘Completed subject’ selected as status at termination – see Study Termination eCRF module) 
The number and percentage of subjects completing 12, 24, 36 and >36 months of the study 
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.  
The number and percentage of subjects enrolled under each protocol amendment (estimated by 
date of informed consent) will be presented, separately, for global protocols prior to version 5.1 
and for Japanese direct enrollers. This will also be presented in the subject data listings. 
Change #10 
Section 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 LCM study for those subjects who 
enrolled from SP847 (or other LCM pediatric clinical studies in epilepsy). Demographic 
variables will be obtained from the Screening Visit for those subjects who directly enrolled into 
SP848. 
Demographic variables will be presented by weight band (using the levels defined in Section 
3.2.10), by demographic enrollment group (using the levels previously defined in Section 
3.2.12.2) and overall for the SS. The variables to be considered are: 
• Age at entry into previous pediatric study (years) (as defined in 3.2.9) – continuous and 
categorized as (28 days - <24 months, 24 months - <12 years, 12 years - <18 years) 
• Age at entry into SP848 (years) (as defined in Section 3.2.9) 
• Gender 
• Weight (kg) 
• Weight band (as defined in Section 3.2.10) 
• Height (cm) 
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• BMI (kg/m2) (as defined in Section 3.2.11) 
• 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) 
A listing of reproductive potential and birth control measures will be provided. No summaries of 
these results are planned. 
Has been changed to: 
Demographic variables, unless otherwise specified, will be obtained from the demographics data 
collected at the time of entry into the previous pediatric LCM study for those subjects who 
enrolled from SP847 (or other LCM pediatric clinical studies in epilepsy). Demographic 
variables will be obtained from the Screening Visit for those subjects who directly enrolled into 
SP848. 
Demographic variables will be presented by weight band (using the levels defined in Section 
3.2.10), by demographic enrollment group (using the levels previously defined in Section 
3.2.12.2)) and overall for the SS. The variables to be considered are: 
Age at entry into previous pediatric study for subjects from SP847 and age at entry into SP848 
for directly enrolled subjects (years) (as defined in 3.2.9) – continuous and categorized as (28 
days - <24 months, 24 months - <12 years, 12 years - <18 years) 
• Age at entry into SP848 (years) (as defined in Section 3.2.9) 
• Gender 
• Weight (kg) 
• Weight band (as defined in Section 3.2.10) 
• Height (cm) 
• BMI (kg/m2) (as defined in Section 3.2.11) 
• 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) 
A listing of reproductive potential and birth control measures will be provided. No summaries of 
these results are planned. 
Change #11 
Section 6.4.1 Number of Previous AEDs  
Has been changed to: 
Section 6.4.1 Number of previous AEDs  
Change #12 
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Section 6.4.2 Number of concomitant AEDs taken at the start of the SP848 Treatment 
Period 
The number of concomitant AEDs taken at the start of the SP848 Treatment Period will be 
summarized for the SS based on the following categorization: 1 AED, 2 AEDs, and 3 AEDs. 
Section 6.4.3 Concomitant AEDs taken at the start of the SP848 Treatment Period 
The number and percentage of subjects taking concomitant AEDs at the start of the SP848 
Treatment Period will be summarized overall and, separately, by WHODD chemical subgroup 
(level 4) and preferred drug name, for the SS. 
Has been changed to: 
Section 6.4.2 Concomitant AEDs taken at the start of the SP848 Treatment Period 
Concomitant AEDs taken at the start of the SP848 Treatment Period are defined as AEDs taken 
concomitantly with LCM at the time of first dose of LCM in SP848.  
The number of concomitant AEDs taken at the start of the SP848 Treatment Period will be 
summarized for the SS based on the following categorization: 1 AED, 2 AEDs, and 3 AEDs. The 
number and percentage of subjects taking concomitant AEDs at the start of the SP848 Treatment 
Period will be summarized overall and, separately, by WHODD chemical subgroup (level 4) and 
preferred drug name, for the SS. 
Change #13 
Section 6.4.4 Concomitant AEDs 
The number and percentage of subjects taking concomitant AEDs during the Treatment Period 
will be summarized overall and, separately, by WHODD chemical subgroup (level 4) and 
preferred drug name, for the SS. 
Vagus nerve stimulation (VNS) is allowed and will not be counted as a concomitant AED. 
Has been changed to: 
Section 6.4.3 Concomitant AEDs taken during the SP848 Treatment Period 
Concomitant AEDs taken during the SP848 Treatment Period are defined as AEDs taken 
concomitantly for at least one day in common with LCM in SP848.  
The number and percentage of subjects taking concomitant AEDs during the SP848 Treatment 
Period will be summarized overall and, separately, by WHODD chemical subgroup (level 4) and 
preferred drug name, for the SS.  
VNS is allowed and will not be counted as a concomitant AED. 
Change #14 
Section 6.4.5 Concomitant medications (excluding AEDs) 
The number and percentage of subjects taking concomitant non-AEDs during the Treatment 
Period will be summarized overall and, separately, by WHODD anatomical main group (level 1) 
and therapeutic subgroup (level 2), for the SS.  
Has been changed to: 
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Section 6.4.4 Concomitant medications (excluding AEDs) 
The number and percentage of subjects taking concomitant non-AEDs during the SP848 
Treatment Period will be summarized overall and, separately, by WHODD anatomical main 
group (level 1) and therapeutic subgroup (level 2), for the SS.  
Change #15 
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 demographic enrollment group using the levels defined in Section 3.2.10 and 
previously described in Section 3.2.12.2, respectively. 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 dose 
of LCM. AEs occurring within 28 days after last dose of LCM will be considered treatment 
emergent. Post-treatment AEs are defined as AEs which had an onset date after 28 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 
demographic enrollment group using the levels defined in Sections 3.2.10 and previously 
described in Section 3.2.12.2, 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 non-serious TEAEs by relationship to LCM 
• Incidence of fatal TEAEs by relationship to LCM 
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• 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 demographic 
enrollment group using the levels defined in Sections 3.2.10 and previously described in Section 
3.2.12.2, 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)) 
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: 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented 
by weight band and demographic enrollment group using the levels defined in Sections 3.2.10 
and previously described in Section 3.2.12.2, respectively. Additional tables will also be 
presented by time interval using the definition 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 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 
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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 
demographic enrollment group using the levels defined in Section 3.2.10 and previously 
described in Section 3.2.12.2, 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 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 12.1) 
The following summaries of AEs will also be repeated by weight band and demographic 
enrollment group using the levels defined in Sections 3.2.10 and previously described in Section 
3.2.12.2, 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 12.1) 
The following summaries of AEs will be presented for the time intervals (using the definition 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) 
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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. 
Change #16 
Section 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 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.  
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 Alkaline Phosphatase. 
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 SP848 LCM administration through to the end of the study but were normal at Baseline. 
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 test will be performed on all females of childbearing potential, 
according to the tabular schedule of study procedures.  
A listing of serum and urine pregnancy test results will be provided. No summaries of these 
results are planned. 
Has been changed to: 
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. 
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Observed values of hematology, chemistry, and non-gender specific endocrinology parameters 
(i.e. 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 (i.e. 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 Alkaline Phosphatase. 
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 SP848 LCM administration through to the end of the study but were normal at Baseline. 
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 schedule of study procedures.  
Serum and urine pregnancy test results will be listed. No summaries of these results are planned. 
Change #17 
Section 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 schedule of study procedures.  
All 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. 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). 
ECGs will be reviewed locally and at a central ECG laboratory. If any abnormal finding 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. The Investigator will determine whether the results of 
the ECG are normal or abnormal and assess the clinical significance of any abnormalities.  
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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 
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.  
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. 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 
>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 
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Table 8-2: ECG abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
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. 
Has been changed to: 
Standard 12-lead ECGs (2 interpretable recordings [20 to 30 minutes apart]) will be performed 
throughout the study, according to the tabular schedule of study 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. 
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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. 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 
>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 
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Table 8-2: ECG abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
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. 
Change #18 
Section 8.4.2 Vagus nerve stimulation 
VNS status is recorded throughout the study, according to the tabular schedule of study 
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. 
No descriptive summaries of these results are planned. 
Has been changed to: 
VNS status is recorded throughout the study, according to the tabular schedule of study 
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.  
Change #19 
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Section 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 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 
Emotional Control 
1, 6, 11, 16, 21, 26, 31, 36, 41, 46 
BRI 
All from {Inhibit, Shift, and Emotional Control} 
Working Memory 
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 
59, 61, 63 
Plan/Organize 
4, 9, 14, 19, 24, 29, 34, 39, 44, 49 
MI 
All from {Working Memory and Plan/Organize} 
GEC Score 
1-63 
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores. 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. 
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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 
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 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.  
Change #20 
Section 10.3 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. 
(defined in Section 3.2.22) will be summarized for each visit and for Last Visit. 
All PedsQL data will be listed. 
Has been changed to: 
Section 10.2.3 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 (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. 
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All PedsQL data will be listed. 
Change #21 
Section 10.4 Health care resource use 
Section 10.4.1 Medical procedures 
Section 10.4.2 Healthcare provider consultations 
Section 10.4.3 Hospital stays and ER visits 
Section 10.4.4 Palatability and ease of use questionnaires 
Have been changed to: 
Section 10.2.4 Health care resource use 
Section 10.2.4.1 Medical procedures 
Section 10.2.4.2 Healthcare provider consultations 
Section 10.2.4.3 Hospital stays and ER visits 
Section 10.2.5 Palatability and ease of use questionnaires 
 
 
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13.2 
Amendment 2 
Rationale for the amendment 
The primary purpose of this substantial amendment is for consistency with other SAPs and 
protocols in the LCM pediatric program and to incorporate Japan and China specific protocols. 
Specific changes 
Change #1 
SAP/Amendment Number and Date 
Final SAP 27 Apr 2015 
SAP – Amendment 1 18 Dec 2015 
Has been changed to: 
Final SAP 27 Apr 2015 
SAP – Amendment 1 18 Dec 2015 
SAP – Amendment 2 8 Mar 2019 
Change #2  
General Change throughout the document: “enrollment groups” has been changed to “seizure 
categories subgroups”. 
Change #3 
List of Tables 
Has been changed to: 
Added Table 12-3 Other significant TEAEs and Table 12-4 AEs for PDILI 
Change #4 
List of Abbreviations 
Has been changed to: 
PDILI   Potential Drug Induced Liver Injury has been added 
Change #5 
Section 2.1.3 Other objectives 
• To allow subjects who have participated in SP847 (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
• To allow subjects who have participated in other LCM pediatric clinical studies in epilepsy to 
continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously received 
LCM to begin receiving LCM  
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• Protocol Amendment 5.3 (specific to Japan) allows approximately 46 additional eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM to directly enroll at approximately 9 sites in Japan 
Has been changed to: 
To allow subjects who have participated in SP847 (or discontinued SP847 due to a dose 
reduction or status epilepticus) to continue receiving LCM 
• To allow subjects who have participated in other LCM pediatric clinical studies in epilepsy to 
continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously received 
LCM to begin receiving LCM  
• Protocol Amendment 5.3 (specific to Japan) allows approximately 46 additional eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM to directly enroll at approximately 9 sites in Japan 
• Protocol Amendment 5.4 (specific to China) allows approximately 60 additional pediatric 
subjects with partial-onset seizures aged ≥4 years to ≤17 years who have not previously 
received LCM to directly enroll in China 
• Protocol Amendment 6 allows approximately 75 additional eligible pediatric subjects with 
epilepsy who participated in EP0060 to receive LCM 
Change #6 
Section 2.3.1.1 Subjects enrolling from SP847 or other LCM pediatric clinical studies in epilepsy 
Has been changed to: 
Section 2.3.1.1 Subjects enrolling from SP847 or other LCM pediatric clinical studies in epilepsy 
(rollover subjects) 
Change #7 
Section 2.3.1.2 Subjects enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously participated in a LCM clinical 
study will be permitted to enroll directly into SP848.  
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control. Subjects will be able to 
receive LCM oral solution or LCM tablets for up to 2 years as determined appropriate by the 
investigator with the exception of subjects in Japan. For sites in Japan, the study will continue 
until the date of market approval for the partial-onset seizure indication for LCM in children or 
until the sponsor decides to discontinue the development of LCM in children in Japan.  
The same study conditions described in Section 2.5.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
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Has been changed to 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously received LCM will be permitted to 
enroll directly into SP848.  
Beginning with Protocol Amendment 5.3 (specific to Japan), approximately 46 eligible pediatric 
subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not previously 
received LCM will be permitted to directly enroll at approximately 9 sites in Japan. Beginning 
with Protocol Amendment 5.4 (specific to China), approximately 60 eligible pediatric subjects 
≥4 years to ≤17 years of age with partial-onset seizures who have not previously received LCM 
will be permitted to directly enroll in China. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control. Subjects will be able to 
receive LCM oral solution or LCM tablets for up to 2 years as determined appropriate by the 
investigator with the exception of subjects in Japan. For sites in Japan, the study will continue 
until the date of market approval for the partial-onset seizure indication for LCM in children or 
until the sponsor decides to discontinue the development of LCM in children in Japan.  
The same study conditions described in Section 2.5.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
Change #8 
Section 2.3.2 Tabular schedule of study procedures 
The schedule of study procedures for SP848 (Year 1, Year 2, and Year 3) is provided in Section 
16.1 of the protocol. 
Has been changed to 
The schedule of the study procedures for SP848 are provided in Section 16.1 of the study 
protocol and country specific protocol amendments for Japan and China.  
Change #9 
Section 2.4 Determination of sample size 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 100 
eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated in a 
LCM clinical study will be permitted to enroll directly into SP848. For sites in Japan, 
approximately 46 additional eligible pediatric subjects ≥4 years to ≤17 years of age with partial-
onset seizures who have not previously received LCM will enroll directly into SP848. The 
purpose of enrolling these subjects directly into SP848 is to obtain additional long-term safety 
exposures in the age range from which adequate PK data have already been obtained in SP847; 
the additional long-term safety data will be included in planned LCM marketing applications for 
subjects ≥4 years of age. 
Has been changed to 
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In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated 
in a LCM clinical study will be permitted to enroll directly into SP848. For sites in Japan, 
approximately 46 additional eligible pediatric subjects ≥4 years to ≤17 years of age with 
partial-onset seizures who have not previously received LCM will enroll directly into SP848. For 
sites in China, approximately 60 additional eligible pediatric subjects ≥4 years to ≤17 years of 
age with partial-onset seizures who have not previously received LCM will enroll directly in to 
SP848. The purpose of enrolling these subjects directly into SP848 is to obtain additional 
long-term safety exposures in the age range from which adequate PK data have already been 
obtained in SP847; the additional long-term safety data will be included in planned LCM 
marketing applications for subjects ≥4 years of age. 
Change #10 
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 SP848, using the following age 
groups:  
• ≥1 to <6 months  
• ≥6 months to <1 year  
• ≥1 to <2 years  
• ≥2 to <4 years  
• Total <4 years  
• ≥4 to <12 years  
• 12 to <16 years 
• Total ≥4 to <16 years  
• ≥16 years 
Summaries for Japan direct enrollers only well be presented overall for all applicable subjects 
and additionally based on the subject’s age at time of entry into study SP848, using the following 
age groups: 
• ≥4 to <12 years  
• ≥12 to <16 years 
• Total ≥4 to <16 years  
• ≥16 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 SP848, using the following age 
groups: 
• ≥1 month to <4 years 
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• ≥4 to <12 years 
• ≥12 to <16 years 
• Total ≥4 to <16 years 
• ≥16 years 
Change #11 
Section 3.1 General presentation of summaries and analyses 
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 SP848, using the following age groups: 
• ≥2 to <4 years 
• ≥4 to <5 years 
Has been changed to 
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 SP848, using the following age groups: 
• ≥2 to <4 years 
• ≥4 to <6 years 
Change #12 
Section 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 SP848 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. 
Has been changed to: 
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 SP848 to the latter of 
the last LCM dose date and the study Termination Visit (ie, Early Termination Visit) date.  
The Treatment Period is further broken down into the Titration Period and the Post-Titration 
Period for direct enrollers: 
Titration Period: defined as the date of the first dose of study medication to the day prior to date 
of Visit 1 or the date of Early Termination (ET) visit in the situation where a subject discontinues 
prior to the last visit in the Titration Period. 
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Post-Titration Period: defined as the date of Visit 1 to the end of the Treatment Period. 
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. 
Change #13 
Section 3.2.3 Mapping of assessments performed at Early Termination Visit 
Safety and efficacy assessments at an Early Termination Visit (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.  
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. 
Has been changed to 
Safety and efficacy assessments at an Early Termination Visit (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 Visit 13/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. 
For subjects enrolled from sites in Japan, they are allowed to stay in the study longer than 2 
years. Such subjects will have a separate ETV if they are in the study after Visit 13.  
Change #14 
Section 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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Has been changed to 
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, >24 
months, >30 months, >36 months, >42 months, and >48 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, >24 months, >30 months, >36 months, >42 months, and >48 months, where 
1 month is defined as 28 days. 
Change #15 
Section 3.2.12 Enrollment groups 
Enrollment groups 
3.2.12.1 Disposition 
Subjects will be classified as belonging to one of the following enrollment groups for the 
purpose of disposition subgroup analyses: 
• SP847 
• SP0966 (subjects with generalized epilepsy) 
• Direct enrollers 
• Japan direct enrollers 
Demographics 
Subjects will be classified as belonging to one of the following enrollment groups for the 
purpose of demographic subgroup analyses: 
• POS subjects (combining subjects from SP847, direct enrollers into SP848 and Japan direct 
enrollers) 
• SP0966 (subjects with generalized epilepsy) 
• Direct enrollers 
• Japan direct enrollers 
3.2.12.2  Efficacy 
Subjects will be classified as belonging to one of the following enrollment groups for the 
purpose of efficacy subgroup analyses: 
• POS subjects (combining subjects from SP847, direct enrollers into SP848 and Japan direct 
enrollers) 
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• SP0966 (subjects with generalized epilepsy) 
• Direct enrollers 
• Japan direct enrollers 
Exposure 
Subjects will be classified as belonging to one of the following enrollment groups for the 
purpose of exposure subgroup analyses: 
• POS subjects (combining subjects from SP847, direct enrollers into SP848 and Japan direct 
enrollers) 
• SP0966 (subjects with generalized epilepsy) 
• Direct enrollers 
• Japan direct enrollers 
Has been changed to 
Seizure Classification Subgroups 
Subjects will be classified as belonging to one of the following seizure classification subgroups 
based on their seizure classification history for the purpose of disposition, demographic, efficacy, 
and exposure subgroup analyses: 
• POS subjects  
− Subjects from SP0966 who reported only Type I seizures 
− Subjects who reported any Type I seizure 
• Generalized seizure subjects 
− Subjects from SP0966 unless they reported only Type I seizures 
− Subjects who reported only Type II seizures 
• Unclassified  
− Subjects who reported only Type III seizures 
Change #16  
Section 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 
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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. 
Has been changed to: 
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 in the analysis period) 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 a Type II or Type III seizure, the 
seizure clusters 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 a Type I seizure, the seizure clusters 
will be assigned to the correct seizure type and the 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 #17 
Section 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. 
Has been changed to 
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. 
Change #18  
Section 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:  
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• ≤3 months  
• >3 to ≤6 months  
• >6 to ≤12 months  
• >12 to ≤18 months  
• >18 to ≤24 months  
• ≥24 months 
Has been changed to 
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 to ≤30 months 
• >30 to ≤36 months 
• >36 to ≤ 42 months 
• > 42 to ≤48 months 
• >48 months 
Change #19 
Section 3.2.22 Pediatric Quality of Life Inventory (PedsQL) 
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) for 
each subject. 
Has been changed to 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions. The PedQL 
Measurement Model consists of developmentally appropriate forms for pediatric subjects 
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≥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 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 
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 #20 
Section 3.7 Center Pooling Strategy 
Except for the subgrouping of sites in Japan (see Section 3.2.12) no pooling of centers is planned 
for this study. 
Has been changed to: 
No pooling of centers is planned for this study. 
Change #21 
Section 3.9.1 Study variables 
The following primary variables, which are defined as only being assessed at Baseline in the 
protocol, will be assessed at all visits: 
Achenbach CBCL for children 18 months and older (CBCL/1½-5 and CBCL/6-18) assessing 
behavior.  
Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
subjects enrolled in English-speaking countries) 
Has been changed to: 
Section deleted 
Change #22 
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Section 3.9.2 Clarification of efficacy variables for seizure counts 
The following efficacy variables, which are not been defined in the protocol, will be assessed:  
• Percent change from Baseline in 28-day seizure frequency (as defined in Section 10.1.2)  
• ≥50% reduction in 28-day partial-onset seizure frequency (≥50% responders as defined in 
Section 10.1.3)  
• ≥75% reduction in 28-day partial-onset seizure frequency (≥75% responders as defined in 
Section 10.1.4)  
• Seizure-free status (as defined in Section 10.1.5)  
• Seizure days per 28 days (as defined in Sections 10.1.6)  
Has been changed to: 
The following efficacy variables, which are not defined in the protocol, will be assessed: 
• Percent change from Baseline in 28-day seizure frequency (as defined in Section 10.1.2) 
• Proportion of subjects with ≥50% reduction in 28-day partial-onset seizure frequency (≥50% 
responders as defined in Section 10.1.3) 
• Proportion of subjects with ≥75% reduction in 28-day partial-onset seizure frequency (≥75% 
responders as defined in Section 10.1.4) 
• Seizure-free status (as defined in Section 10.1.5) 
• Seizure days per 28 days (as defined in Section 10.1.6) 
Change #23 
Section 3.9.4 Analysis Sets 
The protocol-defined SS has been updated to the text shown in Section 3.5.1 to clarify that all 
enrolled subjects who take at least one dose of LCM will be included. 
The protocol-defined PK-PPS has been updated to the text shown in Section 3.5.2. 
The FAS (defined in Section 3.5.3) has been added to the list of analysis sets for this study. 
Has been changed to: 
Section deleted 
Change #24 
As a result of changes #22 and #24 
Section 3.9.1 Study variables 
Section 3.9.2 Clarification of efficacy variables for seizure counts 
Section 3.9.3 Treatment assignment and treatment groups 
Section 3.9.4 Analysis sets 
Section 3.9.5 Handling of dropouts or missing data 
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Section 3.9.6 Examination of subgroups 
Have been changed to: 
Section 3.9.1 Clarification of efficacy variables for seizure counts 
Section 3.9.2 Treatment assignment and treatment groups 
Section 3.9.3 Handling of dropouts or missing data  
Section 3.9.4 Examination of subgroups  
Change #25 
Section 4.4 Multicenter studies 
Except for the subgroup analyses of sites in Japan (see Section 3.2.12), no multicenter analyses 
are planned; therefore, this section is not applicable for this study. 
Has been changed to: 
No multicenter analyses are planned; therefore, this section is not applicable for this study. 
Change #26 
Section 5.1 Subject disposition 
 The number of subjects screened, in addition to the number and percentage of those subjects 
who were screen failures, broken down by primary reason for screening failure, will be 
presented. 
A summary of disposition of subjects will be provided for all screened subjects. The date of first 
subject in (date of earliest entry visit for the SP848 study), date of last subject out (date of final 
scheduled or unscheduled visit), number of subjects screened, number of subjects enrolled, and 
the number of subjects in each analysis set (SS, PK-PPS, 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 screened subjects. The 
following will be summarized: 
• The number of screened subjects 
• The number and percentage of enrolled subjects 
• The number and percentage of subjects in the SS 
• The number and percentage of subjects in the PK-PPS 
• 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 disposition enrollment group 
using the levels defined in Sections 3.2.10 and 3.2.12.1 respectively), PK-PPS, and FAS: 
The number and percentage of subjects starting the study 
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The number and percentage of subjects completing the study (defined as subjects who have 
‘Completed subject’ selected as status at termination – see Study Termination eCRF module) 
The number and percentage of subjects completing 12, 24, 36 and >36 months of the study 
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. 
The number and percentage of subjects enrolled under each protocol amendment (estimated by 
date of informed consent) will be presented, separately, for global protocols prior to version 5.1 
and for Japanese direct enrollers. This will also be presented in the subject data listings. 
Has been changed to: 
The number of subjects screened (screened subjects include subjects who signed an ICF), in 
addition to the number and percentage of those subjects who were screen failures, broken down 
by primary reason for screening failure, will be presented. A summary of disposition of subjects 
will be provided for all screened subjects. The date of first subject in (date of earliest entry visit 
for the SP848 study), date of last subject out (date of final scheduled or unscheduled visit), 
number of subjects screened, number of subjects enrolled, and the number of subjects in each 
analysis set (SS, PK-PPS, 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 screened subjects. The 
following will be summarized: 
• The number of screened subjects 
• The number and percentage of enrolled subjects  
• The number and percentage of subjects in the SS 
• The number and percentage of subjects in the PK-PPS 
• The number and percentage of subjects in the FAS 
• The number of subjects from each parent study 
• The number of original direct enrollers 
• The number of Japanese direct enrollers 
• The number of Chinese direct enrollers  
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 seizure classification 
subgroups using the levels defined in Sections 3.2.10 and 3.2.12, respectively), PK-PPS, and 
FAS: 
The number and percentage of subjects starting the study 
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The number and percentage of subjects completing the study (defined as subjects who have 
‘Completed subject’ selected as status at termination – see Study Termination eCRF module) 
The number and percentage of subjects completing 12, 24, 36 and >36 months of the study 
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.  
The number and percentage of subjects enrolled under each protocol amendment (estimated by 
date of informed consent) will be presented for all global protocols, and separately, for Chinese 
direct enrollers from version 5.4 and for Japanese direct enrollers from version 5.3. This will also 
be presented in the subject data listings. 
Change #27 
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 study entry (into the 
previous study for those subjects who enrolled from SP847 [or other LCM pediatric clinical 
studies in epilepsy] or into SP848 for those directly enrolled) will be summarized based on the 
International League Against Epilepsy (ILAE) Seizure Classification History CRF/eCRF 
module. This will be summarized for the SS, separately, for POS subjects (combining subjects 
from SP847, direct enrollers into SP848 and Japan direct enrollers) and for subjects from SP0966 
with generalized seizures. 
For POS subjects (combining subjects from SP847, direct enrollers into SP848 and Japan direct 
enrollers) 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 from SP0966 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 
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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. subject may also be 
classified as having a history of unclassified epileptic seizures (III). 
Has been 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 (into the 
previous study for rollover subjects or into SP848 for those direct enrollers) 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 (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 #28 
Section 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. This will be summarized, separately, for POS subjects 
(combining subjects from SP847, direct enroller into SP848 and Japan direct enrollers) and for 
subjects from SP0966 with generalized seizures. 
Has been changed to 
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Quantitative summaries of epilepsy duration and age at diagnosis (as defined in Section 3.2.9) 
will be summarized for the SS. This will be summarized for the SS, by seizure classification 
subgroups.  
Change #29 
Section 6.3.3 History of seizure counts 
The Historical Seizure Counts CRF/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. This will be listed, separately, for POS 
subjects (combining subjects from SP847, direct enrollers into SP848 and Japan direct enrollers) 
and for subjects from SP0966 with generalized seizures. 
Has been changed to 
The Historical Seizure Counts CRF/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. This will be summarized for the SS, by 
seizure classification subgroups.  
Change #30 
Section 6.4  Prior and concomitant medications 
A listing of all medications taken during the study will be presented.  
Has been changed to 
All prior and concomitant medications will be presented by seizure classification subgroup, age 
group, weight band and overall. Antiepileptic drugs defined as medications documented on the 
“Concomitant Medications (AEDs only)” log form. A medical review will be performed to 
ensure that the medications are documented correctly. A listing of all medications taken during 
the study will be presented.  
Change #31 
Section 8.1 Extent of Exposure 
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. 
Has been changed to: 
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. 
Summary statistics (n, mean, standard deviation (SD), minimum and maximum) for the duration 
of LCM exposure (days) and median daily LCM dose (mg/kg/day) during each of the following 
analysis periods for direct enrollers: Titration, Post-Titration and Treatment Period will be 
summarized for the SS.  Duration of LCM exposure (days) and median daily LCM dose 
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(mg/kg/day) for the Treatment Period will be summaries for the rollover and all subjects in the 
SS separately. 
Change #32 
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 demographic enrollment group using the levels defined in Sections 3.2.10 
and 3.2.12.2 respectively. Additional tables will also be presented by time interval using the 
definition 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 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 
demographic enrollment group using the levels defined in Sections 3.2.10 and 3.2.1.2.2 
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 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 demographic 
enrollment group using the levels defined in Sections 3.2.10 and 3.2.12.2 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 time intervals (using the definition 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) 
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 
in subject data listings. 
Has been changed to: 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented 
by weight band and seizure classification subgroup using the levels defined in Sections 3.2.10 
and 3.2.12, respectively. Additional tables will also be presented by time interval using the 
definition 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 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. 
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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 seizure 
classification subgroup using the levels defined in Sections 3.2.10 and 3.2.12 respectively. In 
addition, the overall summary will be presented for the Titration Period, Post-Titration Period 
and Treatment Period for the direct enrollers and the Treatment Period for the rollover subjects. 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• Incidence of TEAEs 
• Incidence of TEAEs with onset during the Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Post-Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Treatment Period for direct enrollers 
• Incidence of TEAEs for direct enrollers 
• Incidence of TEAEs for rollover subjects 
• 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 
• 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 seizure classification 
subgroup 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 
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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 be presented for the time intervals (using the definition 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 to 
≤ 30  months, >30 to ≤36 months, >36 to ≤42 months, >42 to ≤48 months, >48 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) 
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 #33 
Section 8.3 Clinical Laboratory evaluations  
Serum and urine pregnancy testing will be performed on all females of childbearing potential, 
according to the tabular schedule of study procedures. 
Serum and urine pregnancy test results will be listed. No summaries of these results are planned. 
Has been changed to: 
Serum and urine pregnancy testing will be performed on all females of childbearing potential, 
according to the tabular schedule of study procedures.  
Serum and urine pregnancy test results will be listed. No summaries of these results are planned. 
Potential drug-induce liver injury (PDILI) IMP discontinuation criteria as outlined in the 
protocol, will be evaluated at all laboratory assessments. The number and percentage of subjects 
meeting PDILI criteria (ie, ALT 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 #34 
Section 8.4.7 Achenbach Child Behavior Checklist (CBCL) 
 
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 
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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 same scale will be completed at the Screening Visit (subjects directly enrolled into SP848), 
Visit 1 (subjects enrolled from SP847 or other pediatric clinical studies in epilepsy), and Visit 
13/Termination Visit (or ETV) (all subjects) by the parent(s)/legal representative(s).  
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 
• 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. 
Has been changed to 
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 subjects ≥6 years to ≤18 years, the CBCL/6-18 will be used.  
The same scale will be completed by the parent(s)/legal representative(s).  
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 
• 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. 
Change #35 
Section 8.5 Palatability and ease of use questionnaires 
UCB has created a palatability and ease of use questionnaire to collect data from the subject or 
caregiver regarding different aspects of LCM and its administration. The questionnaire will 
assess the subject or caregiver’s response regarding the formulation of LCM the subject is 
receiving for palatability items (eg, taste, smell, ability to swallow, aftertaste), mode of 
administration, and administration device as applicable. 
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The number and percentage of subjects who respond to each of the categories presented for the 
following questionnaires will be summarized at each visit it is assessed: 
• Tablet palatability and ease of use 
• Oral solution palatability and ease of use 
All palatability and ease of use questionnaire data will be listed. 
Has been changed to: 
UCB has created a palatability and ease of use questionnaire to collect data from the subject or 
caregiver regarding different aspects of LCM and its administration. The questionnaire will 
assess the subject or caregiver’s response regarding the formulation of LCM the subject is 
receiving for palatability items (eg, taste, smell, ability to swallow, aftertaste), mode of 
administration, and administration device as applicable. 
The number and percentage of subjects who respond to each of the categories presented for the 
following questionnaires will be summarized at each visit it is assessed: 
• Tablet palatability and ease of use 
• Oral solution palatability and ease of use 
Summaries will be performed overall and by seizure classification group (as defined in Section 
3.2.12). All palatability and ease of use questionnaire data will be listed. 
Change #36 
Section 8.4.10 Bayley-III assessment 
The Bayley-III assessments will be completed according to the tabular schedule 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 will be completed at the Screening Visit (subjects enrolled directly into SP848),  
Visit 1 (subjects enrolled from SP847 or other pediatric clinical studies in epilepsy), and Visit 
13/Termination Visit (or ETV) (all subjects) for children from 1 month to <18 months of age 
enrolled in English-speaking countries. 
Has been changed to 
The Bayley-III assessments will be completed according to the tabular schedule 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 will be completed for children from 1 month to <18 months of age enrolled in 
English-speaking countries. 
Change #37 
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Section 10 Efficacy Analysis 
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, health care resource use, and a LCM palatability and ease of use 
questionnaire).  
All study efficacy variables will be summarized for the FAS, overall and repeated by efficacy 
seizure classification subgroup (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. 
Has been changed to 
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 efficacy 
seizure classification subgroup (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. 
Change #38 
Section 10.1  Seizure Counts 
At Screening of SP847 (or other LCM pediatric clinical studies in epilepsy) or at the Screening 
Visit of SP848 (for subjects who directly enrolled into SP848) subjects/caregivers (including 
parents/legal guardians) will be asked how many seizures the subject has had in the previous 
4 weeks; this will serve as a historical Baseline. After the subject is enrolled in the SP848 study, 
seizure data will be collected in diaries provided to subjects/caregivers (including parents/legal 
guardians). Each subject/caregiver (including parent/legal guardian) will keep a diary to note 
daily seizure activity throughout the current study. The subject/caregiver (including parent/legal 
guardian) should be reminded to bring the diary with them at each clinic visit. The following 
information will be recorded: 
• Seizure type 
• Seizure frequency 
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 CRF/eCRF module). 
Has been changed to:  
At Screening of SP847 (or other LCM pediatric clinical studies in epilepsy) or at the Screening 
Visit of SP848 (for subjects who directly enrolled into SP848) subjects/caregivers (including 
parents/legal guardians) will be asked how many seizures the subject has had in the previous 
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4 weeks; this will serve as a historical Baseline. After the subject is enrolled in the SP848 study, 
seizure data will be collected in diaries provided to subjects/caregivers (including parents/legal 
guardians). Each subject/caregiver (including parent/legal guardian) will keep a diary to note 
daily seizure activity throughout the current study. The subject/caregiver (including parent/legal 
guardian) should be reminded to bring the diary with them at each clinic visit. The following 
information will be recorded: 
• Seizure type 
• Seizure frequency 
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 CRF/eCRF module). 
Determination of Baseline Period seizures will be made utilizing both the historical Baseline and 
the seizure diary data collected from the date of the Screening Visit to the day prior to the date of 
first dose of LCM. 
Change #39 
Section 10.1.1 Seizure frequency per 28 days: 
For subjects with POS, 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: 
For subjects with POS, 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. 
Descriptive statistics will also be presented for the change from Baseline by modal daily LCM 
dose (as defined in Section 3.2.8) during the Titration Period, Post-Titration Period and the 
overall Treatment Period for the direct enrollers and the overall Treatment Period for rollover 
subjects and all subjects. 
Change #40 
Section 10.1.2 Percent change from Baseline in 28-day seizure frequency 
For subjects with POS, descriptive statistics for percent change from Baseline (as defined in 
Section 3.2.14) in 28-day seizure frequency will be presented by seizure time intervals (as 
defined in Section 3.2.21) and modal daily LCM dose (as defined in Section 3.2.8). Any subject 
with seizure data during the time interval will be included in the summary for that seizure time 
interval.  
Descriptive statistics will also be presented for percent change from Baseline in 28-day seizure 
frequency during the entire Treatment Period. Descriptive statistics for percent change from 
Baseline in 28-day seizure frequency during the Treatment Period will also be presented by 
Baseline seizure type (simple partial, complex partial, secondarily generalized). Only subjects 
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who experienced a seizure type during the Baseline Period will be included in the analysis for 
that seizure type with only the seizure frequencies of that seizure type being used in the analysis.  
The percent change from Baseline in 28-day seizure frequency among completer cohorts (as 
defined in Section 3.2.19) will also be presented by modal daily LCM dose (as defined in Section 
3.2.8). 
Has been changed to 
For subjects with POS, descriptive statistics for percent change from Baseline (as defined in 
Section 3.2.14) in 28-day seizure frequency will be presented by seizure time intervals (as 
defined in Section 3.2.21) and modal daily LCM dose (as defined in Section 3.2.8). Any subject 
with seizure data during the time interval will be included in the summary for that seizure time 
interval.  
Descriptive statistics will also be presented for percent change from Baseline by modal daily 
LCM dose (as defined in Section 3.2.8) in 28-day seizure frequency during the Titration Period, 
Post-Titration Period and for the overall Treatment Period for direct enrollers and for the overall 
Treatment Period for the rollover subjects and all subjects. Descriptive statistics for percent 
change from Baseline in 28-day seizure frequency during the Treatment Period will also be 
presented by Baseline seizure type (simple partial, complex partial, secondarily generalized). 
Only subjects who experienced a seizure type during the Baseline Period will be included in the 
analysis for that seizure type with only the seizure frequencies of that seizure type being used in 
the analysis.  
The percent change from Baseline in 28-day seizure frequency among completer cohorts (as 
defined in Section 3.2.19) will also be presented by modal daily LCM dose (as defined in Section 
3.2.8). 
Change #41 
Section 10.1.3 ≥50% response to treatment 
For subjects with POS, the number and percentage of ≥50% responders will be summarized by 
seizure time intervals and modal daily LCM dose (as defined in Section 3.2.8). This will also be 
presented separately by completer cohorts (as defined in Section 3.2.19), 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. The number and percentage of ≥50% responders will also be 
presented for the entire Treatment Period. 
The number and percentage of ≥50% responders will be presented in the same manner as 
described above but presented separately by seizure type (simple partial, complex partial, 
secondarily generalized) and by seizure time intervals (as defined in Section 3.2.21). 
Has been changed to: 
For subjects with POS, the number and percentage with ≥50% reduction in 28-day partial-onset 
seizure frequency (≥50% responders) will be summarized by seizure time intervals and modal 
daily LCM dose (as defined in Section 3.2.8). This will also be presented separately by 
completer cohorts (as defined in Section 3.2.19), 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 
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interval. The number and percentage of ≥50% responders will also be presented for the entire 
Treatment Period.  
The number and percentage of ≥50% responders will be presented in the same manner as 
described above but presented separately by seizure type (simple partial, complex partial, 
secondarily generalized) and by seizure time intervals (as defined in Section 3.2.21). 
Change #42 
Section 10.1.4 ≥75% response to treatment 
The analyses described in Section 10.1.3 for ≥50% response to treatment will also be performed 
for ≥75% response to treatment for subjects with POS. 
Has been changed to: 
The analyses described in Section 10.1.3 for ≥50% response to treatment will also be performed 
for subjects with ≥75% reduction in 28-day partial-onset seizure frequency (≥75% responders). 
Change #43 
Section 10.1.5 Seizure-free status 
The number and percentage of subjects achieving a seizure-free status (as defined in Section 
3.2.18) will be presented by completer cohorts (as defined in Section 3.2.19) overall and by 
modal daily LCM dose (as defined in Section 3.2.8). 
The number and percentage of 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, 
secondarily generalized). Seizure-free status will also be presented by seizure time intervals (as 
defined in Section 3.2.21). 
Has been changed to 
The number and percentage of subjects achieving a seizure-free status (as defined in Section 
3.2.18) will be presented by completer cohorts (as defined in Section 3.2.19) overall and by 
modal daily LCM dose and seizure classification subgroup (as defined in Sections 3.2.8 and 
3.2.12). 
The number and percentage of 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, 
secondarily generalized). Seizure-free status will also be presented by seizure time intervals (as 
defined in Section 3.2.21). 
Change #44 
Section 10.1.6 Seizure days per 28 days 
For subjects from SP0966 with generalized seizures, the number of seizure days per 28 days (as 
defined in Section 3.2.16) 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. 
Has been changed to  
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For subjects with generalized seizures, the number of seizure days per 28 days (as defined in 
Section 3.2.16) 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. 
Change #45 
Section 10.2.1 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. 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 
and grouped by modal daily LCM dose, using the levels defined in Section 3.2.8. 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. 
Has been changed to 
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 and Seizure 
Classification subgroup, using the levels defined in Sections 3.2.8 and 3.2.12. 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 and grouped by modal daily LCM dose, using the levels 
defined in Section 3.2.8. 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. 
Change #46 
Section 10.2.2 Caregiver Global Impression of Change 
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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. 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 
and grouped by modal daily LCM dose, using the levels defined in Section 3.2.8. The 
denominator for the percentage calculation will be based on the number of subjects with non-
missing values. 
Caregiver Global Impression of Change data will be listed. 
Has been changed to 
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 and Seizure 
Classification subgroup, using the levels defined in Sections 3.2.8 and 3.2.12. 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 and grouped by modal daily LCM dose, using the levels 
defined in Section 3.2.8. The denominator for the percentage calculation will be based on the 
number of subjects with non-missing values. 
Caregiver Global Impression of Change data will be listed. 
Change #47 
10.2.3 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 (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. 
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All PedsQL data will be listed. 
Has been 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, and also by 
Seizure Classification subgroup, using the levels defined in Section 3.2.12. 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. 
Change #48 
Section 10.2.4 Health care resource use 
For health care resource use parameters, the following will be evaluated: concomitant AEDs (as 
defined in Section 6.4.3), 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 schedule of study procedures. 
Has been changed to 
For health care resource use parameters, the following will be evaluated: concomitant 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 schedule of study procedures. Summaries will be performed overall and by Seizure 
Classification subgroup, using the levels defined in section 3.2.12. 
Changes #49-53 
Section 10.2.3 Pediatric Quality of Life Inventory (PedsQL) 
Section 10.2.4 Health care resource use 
Section 10.2.4.1 Medical procedures 
Section 10.2.4.2 Healthcare provider consultations 
Section 10.2.4.3 Hospital stays and ER visits 
Has been changed to 
Section 10.3 Pediatric Quality of Life Inventory (PedsQL) 
Section 10.4 Health care resource use 
Section 10.4.1 Medical procedures 
Section 10.4.2 Healthcare provider consultations 
Section 10.4.3 Hospital stays and ER visits 
Change #54  
Section 10.2.5  Palatability and ease of use questions  
Has been changed to:   
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Section 8.5 Palatability and ease of use questions  
Change #55 
Added Table header Table 12-3 to Section 12.2 Other Significant TEAEs and removed (*) and 
footnote. 
Change #56 
Added section 12.3 AEs for PDILI 
 
13.3 
Amendment 3 
Rationale for the amendment 
The primary purpose of this amendment is for consistency with other SAPs and protocols in the 
LCM pediatric program and to incorporate comments from DRM2 review. 
Specific changes 
Change #1 
SAP/Amendment Number and Date 
Final SAP 27 Apr 2015 
SAP – Amendment 1  18 Dec 2015 
SAP – Amendment 2  8 Mar 2019 
Has been changed to: 
Final SAP 27 Apr 2015 
SAP – Amendment 1  18 Dec 2015 
SAP – Amendment 2  8 Mar 2019 
SAP – Amendment 3  25 Nov 2019 
Change #2 
The wording of ‘subjects’ has changed to ‘study participants’ throughout the amended SAP text 
and TFL shells, to reflect the new UCB standard. 
 
 
 
 
Change #3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
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AED 
antiepileptic drug 
BMI 
body mass index 
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 
CRF 
Case Report Form 
CV 
coefficient of variance 
DBP 
diastolic blood pressure 
DRM 
Data Review Meeting 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ER 
emergency room 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
HRQoL 
health-related quality of life 
ILAE 
International League Against Epilepsy 
LCM 
Lacosamide 
MA 
markedly abnormal 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDILI 
PedsQL 
Potential Drug Induced Liver Injury 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
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PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SPD 
Specification of Protocol Deviations 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
ULN 
upper limit of normal 
VNS 
vagus nerve stimulation 
WHODD 
World Health Organization Drug Dictionary 
Has been changed to:  
LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
BMI 
body mass index 
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 
CRF 
Case Report Form 
CV 
coefficient of variance 
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DBP 
diastolic blood pressure 
DRM 
Data Review Meeting 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ER 
emergency room 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
HRQoL 
health-related quality of life 
IIL 
Initiating intravenous lacosamide Group 
ILAE 
International League Against Epilepsy 
LCM 
Lacosamide 
MA 
markedly abnormal 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLL 
Open-label lacosamide Group 
PDILI 
PedsQL 
Potential Drug Induced Liver Injury 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PT 
preferred term 
RxL 
Prescription lacosamide (eg, VIMPAT) Group 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
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SPD 
Specification of Protocol Deviations 
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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Change #4 
Section 2.3.1.2 Subjects enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures (deemed appropriate 
for treatment with adjunctive LCM) who have not previously received LCM will be permitted to 
enroll directly into SP848.  
Beginning with Protocol Amendment 5.3 (specific to Japan), approximately 46 eligible pediatric 
subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not previously 
received LCM will be permitted to directly enroll at approximately 9 sites in Japan. Beginning 
with Protocol Amendment 5.4 (specific to China), approximately 60 eligible pediatric subjects 
≥4 years to ≤17 years of age with partial-onset seizures who have not previously received LCM 
will be permitted to directly enroll in China. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
will be titrated to a level to optimize tolerability and seizure control. Subjects will be able to 
receive LCM oral solution or LCM tablets for up to 2 years as determined appropriate by the 
investigator with the exception of subjects in Japan. For sites in Japan, the study will continue 
until the date of market approval for the partial-onset seizure indication for LCM in children or 
until the sponsor decides to discontinue the development of LCM in children in Japan.  
The same study conditions described in Section 2.5.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
Has been changed to: 
Section 2.3.1.2 Study participants enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric study participants ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously received LCM will be 
permitted to enroll directly into SP848.  
Beginning with Protocol Amendment 5.3 (specific to Japan), approximately 46 eligible pediatric 
study participants ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM will be permitted to directly enroll at approximately 9 sites in Japan. 
Beginning with Protocol Amendment 5.4 (specific to China), approximately 60 eligible pediatric 
study participants ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM will be permitted to directly enroll in China. 
Study participants who enroll directly into SP848 without previous participation in a LCM 
clinical study will undergo screening. Eligible study participants will initiate treatment with 
LCM, and the LCM dose will be titrated to a level to optimize tolerability and seizure control. 
Study participants will be able to receive LCM oral solution or LCM tablets for up to 2 years as 
determined appropriate by the investigator with the exception of study participants in Japan. For 
sites in Japan, the study will continue until the date of market approval for the partial-onset 
seizure indication for LCM in children or until the sponsor decides to discontinue the 
development of LCM in children in Japan. Original direct enrollers are study participants who 
directly enroll outside of Japan or China. 
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The same study conditions described in Section 2.5.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
Study participants may enroll in study EP0060 (intravenous therapy) of LCM without 
withdrawing from SP848.  Study participants will continue to receive their SP848 assigned LCM 
daily dose during the iv trial.  Ongoing adverse events and concomitant medications originating 
in the iv trials will be followed in SP848 until resolution.  
Change #5 
Section 2.4 Determination of sample size 
Approximately 42 study participants from the SP847 study will be eligible to enroll in this 
open-label study. Approximately 200 other subjects will be eligible to enroll as other LCM 
pediatric clinical studies in epilepsy are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. For sites in 
Japan, approximately 46 additional eligible pediatric study participants ≥4 years to ≤17 years of 
age with partial-onset seizures who have not previously received LCM will enroll directly into 
SP848. For sites in China, approximately 60 additional eligible pediatric study participants 
≥4 years to ≤17 years of age with partial-onset seizures who have not previously received LCM 
will enroll directly in to SP848. The purpose of enrolling these study participants directly into 
SP848 is to obtain additional long-term safety exposures in the age range from which adequate 
PK data have already been obtained in SP847; the additional long-term safety data will be 
included in planned LCM marketing applications for study participants ≥4 years of age.  
Has been changed to: 
Approximately 42 study participants from the SP847 study will be eligible to enroll in this 
open-label study. Approximately 200 other subjects will be eligible to enroll as other LCM 
pediatric clinical studies in epilepsy are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. For sites in 
Japan, approximately 46 additional eligible pediatric study participants ≥4 years to ≤17 years of 
age with partial-onset seizures who have not previously received LCM will enroll directly into 
SP848. For sites in China, approximately 60 additional eligible pediatric study participants 
≥4 years to ≤17 years of age with partial-onset seizures who have not previously received LCM 
will enroll directly in to SP848. The purpose of enrolling these study participants directly into 
SP848 is to obtain additional long-term safety exposures in the age range from which adequate 
PK data have already been obtained in SP847; the additional long-term safety data will be 
included in planned LCM marketing applications for study participants ≥4 years of age. 
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. 
Change #6 
Section 3.1 General presentation of summaries and analyses 
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Approximately 42 subjects from the SP847 study will be eligible to enroll in this open-label 
study. Other subjects will be eligible to enroll as other LCM pediatric clinical studies in epilepsy 
are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric subjects ≥4 years to ≤17 years of age who have not previously participated 
in a LCM clinical study will be permitted to enroll directly into SP848. For sites in Japan, 
approximately 46 additional eligible pediatric subjects ≥4 years to ≤17 years of age with 
partial-onset seizures who have not previously received LCM will enroll directly into SP848. For 
sites in China, approximately 60 additional eligible pediatric subjects ≥4 years to ≤17 years of 
age with partial-onset seizures who have not previously received LCM will enroll directly in to 
SP848. The purpose of enrolling these subjects directly into SP848 is to obtain additional 
long-term safety exposures in the age range from which adequate PK data have already been 
obtained in SP847; the additional long-term safety data will be included in planned LCM 
marketing applications for subjects ≥4 years of age. 
Has been changed to: 
Approximately 42 study participants from the SP847 study will be eligible to enroll in this 
open-label study. Approximately 200 other subjects will be eligible to enroll as other LCM 
pediatric clinical studies in epilepsy are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. For sites in 
Japan, approximately 46 additional eligible pediatric study participants ≥4 years to ≤17 years of 
age with partial-onset seizures who have not previously received LCM will enroll directly into 
SP848. For sites in China, approximately 60 additional eligible pediatric study participants 
≥4 years to ≤17 years of age with partial-onset seizures who have not previously received LCM 
will enroll directly in to SP848. The purpose of enrolling these study participants directly into 
SP848 is to obtain additional long-term safety exposures in the age range from which adequate 
PK data have already been obtained in SP847; the additional long-term safety data will be 
included in planned LCM marketing applications for study participants ≥4 years of age. 
Change #7 
Section 3.1 General presentation of summaries and analyses 
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 SP848, using the following age groups: 
• ≥2 to <4 years 
• ≥4 to <6 years 
Has been changed to: 
Summaries for BRIEF-P will be presented overall for all applicable study participants and 
additionally based on the subject’s age at time of entry into study SP848, using the following age 
groups: 
• ≥2 to <4 years 
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• ≥4 to <5 years 
Change #8 
Section 3.2.9 Age and age at first diagnosis 
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: 
Missing or partial epilepsy diagnosis date will be derived applying all rules for missing data 
imputation (see Section 4.2.6) and age at diagnosis will use the following formula, where 
applicable. The age at first diagnosis will be given in years: 
If date of birth is a complete date then age at diagnosis will be calculated as: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25  
If date of birth is a partial date then age at diagnosis will be calculated as: 
(Enrollment age in years) – [(Informed consent date – Epilepsy diagnosis date) / 365.25]  
If this produces a value negative then age at diagnosis will be set to zero. 
Change #9 
Section 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 for safety and efficacy variables unless otherwise noted for a specific type of data. The 
Baseline values from SP847 and other previous pediatric studies will be designated as Baseline 
values for SP848. The baseline value for seizure counts for directly enrolled subjects will be 
taken from the Historical Seizure Count CRF/eCRF module collected in SP848. 
Has been changed to: 
In general, Baseline will be defined as the last non-missing value collected prior to the first dose 
of LCM for safety and efficacy variables unless otherwise noted for a specific type of data.  The 
Baseline value for seizure counts for directly enrolled study participants will be taken from the 
Historical Seizure Count CRF/eCRF module collected in SP848 in combination with the seizure 
diary data collected from the date of the Screening Visit to the day prior to the date of first dose 
of LCM.  
For participants enrolling from EP0060 the baselines for the questionnaires will consider each 
EP0060 enrollment group separately, those are: IIL (not currently receiving LCM, i.e. LCM 
naïve), OLL (currently receiving oral LCM in open-label long term study), and RxL (currently 
receiving prescribed oral LCM from commercial supply, VIMPAT).  For ILL group baseline will 
be Visit 1 from SP848, for OLL group baseline will come from SP848 using above baseline 
definition, and for RxL group there will be no baseline data as they were on oral LCM prior to 
EP0060. 
Change #10 
Added section 4.2.7 Missing data due to participation in solution for infusion formulation trials 
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Study participants who participated in the iv trial EP0060 while also enrolled in SP848 will have 
missing data for seizure frequency and drug dosing during the period of participation in the iv 
trial.  As the duration of the iv trial is short, approximately 1 to 5 days, not imputation for data 
missing due to participation in the iv trial will be performed.  
Study participants were assigned the same dose in EP0060 as that assigned in SP848 for the two 
weeks prior to the start of the iv trial.  As such, time during the iv trial will not be subtracted 
from the exposure calculation (ie, exposure will be from the start of LCM treatment in SP848 
trial until the date of last dose of LCM in SP848).  The duration of treatment during EP0060 is 
approximately 1 to 5 days. 
For the calculation of variables related to seizure frequency, the dates during participation in 
EP0060 will be considered as not done for the purpose of efficacy analyses for SP848 (ie, the 
dates will not be considered as days evaluated for seizure frequency).  Due to the short nature of 
EP0060, only 1 to 5 days of seizure frequency data are expected to be missing due to 
participation in EP0060. 
Change #11 
Section 5.1 Subject disposition 
The number of subjects screened (screened subjects include subjects who signed an ICF), in 
addition to the number and percentage of those subjects who were screen failures, broken down 
by primary reason for screening failure, will be presented. A summary of disposition of subjects 
will be provided for all screened subjects. The date of first subject in (date of earliest entry visit 
for the SP848 study), date of last subject out (date of final scheduled or unscheduled visit), 
number of subjects screened, number of subjects enrolled, and the number of subjects in each 
analysis set (SS, PK-PPS, 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 screened subjects. The 
following will be summarized: 
• The number of screened subjects 
• The number and percentage of enrolled subjects  
• The number and percentage of subjects in the SS 
• The number and percentage of subjects in the PK-PPS 
• The number and percentage of subjects in the FAS 
• The number of subjects from each parent study 
• The number of original direct enrollers 
• The number of Japanese direct enrollers 
• The number of Chinese direct enrollers  
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 seizure classification 
subgroup using the levels defined in Sections 3.2.10 and 3.2.12, respectively), PK-PPS, and 
FAS: 
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• The number and percentage of subjects starting the study 
• The number and percentage of subjects completing the study (defined as subjects who have 
‘Completed subject’ selected as status at termination – see Study Termination eCRF module) 
• The number and percentage of subjects completing 12, 24, 36 and >36 months of the study 
• 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.  
The number and percentage of subjects enrolled under each protocol amendment (estimated by 
date of informed consent) will be presented for all global protocols, and separately, for Chinese 
direct enrollers from version 5.4 and for Japanese direct enrollers from version 5.3. This will also 
be presented in the subject data listings. 
Has been changed to: 
The number of study participants screened (screened study participants include study participants 
who signed an ICF), in addition to the number and percentage of those study participants who 
were screen failures, broken down by primary reason for screening failure, will be presented. A 
summary of disposition of study participants will be provided for all screened study participants. 
The date of first subject in (date of earliest entry visit for the SP848 study), date of last subject 
out (date of final scheduled or unscheduled visit), number of study participants screened, number 
of study participants enrolled, and the number of study participants in each analysis set (SS, PK-
PPS, and FAS), will be summarized overall and by investigator site. Study participants who 
transferred sites will be summarized according to their original site.  
A summary of disposition of analysis sets will be provided for all screened study participants. 
The following will be summarized: 
• The number of screened study participants 
• The number and percentage of enrolled study participants  
• The number and percentage of study participants in the SS 
• The number and percentage of study participants in the PK-PPS 
• The number and percentage of study participants in the FAS 
• The number of study participants from each parent study 
• The number of original direct enrollers (excluding Japanese and Chinese direct enrollers) 
• The number of Japanese direct enrollers 
• The number of Chinese direct enrollers  
Additionally, a summary of disposition and discontinuation reasons will present the following 
for all study participants in the SS (overall and repeated by weight band and seizure 
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classification subgroup using the levels defined in Sections 3.2.10 and 3.2.12, respectively), PK-
PPS, and FAS: 
• The number and percentage of study participants starting the study 
• The number and percentage of study participants completing the study (defined as study 
participants who have ‘Completed subject’ selected as status at termination – see Study 
Termination eCRF module) 
• The number and percentage of study participants completing 12, 24, 36 and >36 months of 
the study 
• The overall number and percentage of study participants discontinuing and the number and 
percentage of study participants 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 study participants will present the 
number and percentage of study participants who discontinued this study due to AEs broken 
down by type of AE.  
The number and percentage of study participants enrolled under each protocol amendment 
(estimated by date of informed consent) will be presented for all global protocols, and separately, 
for Chinese direct enrollers from version 5.4 and for Japanese direct enrollers from version 5.3. 
This will also be presented in the subject data listings. 
Change #12 
Section 6.4.1 Number of previous AEDs 
The number of previous AEDs defined as AEDs taken and stopped >28 days prior to entry into 
the study, will be summarized for the SS based on the following categorization: 1-3 AEDs, 4-6 
AEDs, and ≥7 AEDs. This summary will be based on the History of Previous AED Treatment 
CRF/eCRF module for applicable studies which only includes AEDs stopped prior to study 
entry. For subjects who rolled over from the SP0966 study, previous AEDs are defined as AEDs 
taken 12 months prior to informed consent date and stopped >28 days prior to entry into SP0966. 
Has been changed to: 
The number of previous AEDs defined as AEDs taken and stopped >28 days prior to entry into 
the study, will be summarized for the SS based on the following categorization: 0 AED, 1-3 
AEDs, 4-6 AEDs, and ≥7 AEDs. This summary will be based on the History of Previous AED 
Treatment CRF/eCRF module for applicable studies which only includes AEDs stopped prior to 
study entry. For study participants who rolled over from the SP0966 study, previous AEDs are 
defined as AEDs taken 12 months prior to informed consent date and stopped>28 days prior to 
entry into SP0966. 
Change #13 
Section 6.4.2 Concomitant AEDs taken at the start of the SP848 Treatment Period 
Concomitant AEDs taken at the start of the SP848 Treatment Period are defined as AEDs taken 
concomitantly with LCM at the time of first dose of LCM in SP848. 
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The number of concomitant AEDs taken at the start of the SP848 Treatment Period will be 
summarized for the SS based on the following categorization: 1 AED, 2 AEDs, and 3 AEDs. The 
number and percentage of subjects taking concomitant AEDs at the start of the SP848 Treatment 
Period will be summarized overall and, separately, by WHODD chemical subgroup (level 4) and 
preferred drug name, for the SS. 
Has been changed to: 
Concomitant AEDs taken at the start of the SP848 Treatment Period are defined as AEDs taken 
concomitantly with LCM at the time of first dose of LCM in SP848. 
The number of concomitant AEDs taken at the start of the SP848 Treatment Period will be 
summarized for the SS based on the following categorization: 0 AED, 1 AED, 2 AEDs,  3 AEDs 
and ≥4 AEDs. The number and percentage of study participants taking concomitant AEDs at the 
start of the SP848 Treatment Period will be summarized overall and, separately, by WHODD 
chemical subgroup (level 4) and preferred drug name, for the SS. 
Change #14 
Section 8.4.2 Electrocardiograms (ECGs) 
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. 
Has been changed to: 
For ECGs, Baseline will be defined as the average of all pre-dose interpretable readings. 
Assessments with missing time on day of first dose will be assumed pre-dose. For all post-
Baseline visits, the average of all interpretable readings at the specified visit will be used for 
summaries. 
Change #15 
Section 8.4.9 BRIEF-P and BRIEF assessment 
The BRIEF-P/BRIEF assessments will be completed according to the tabular schedule 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 
<6 years of age, and ≥5 to ≤18 years of age, respectively.  
Has been changed to: 
The BRIEF-P/BRIEF assessments will be completed according to the tabular schedule 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 study 
participants ≥2 to <5 years of age, and ≥5 to ≤18 years of age, respectively.  
Change #16 
Section 8.5 Palatability and ease of use questionnaires 
UCB has created a palatability and ease of use questionnaire to collect data from the subject or 
caregiver regarding different aspects of LCM and its administration. The questionnaire will 
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assess the subject or caregiver’s response regarding the formulation of LCM the subject is 
receiving for palatability items (eg, taste, smell, ability to swallow, aftertaste), mode of 
administration, and administration device as applicable. 
The number and percentage of subjects who respond to each of the categories presented for the 
following questionnaires will be summarized at each visit it is assessed: 
• Tablet palatability and ease of use 
• Oral solution palatability and ease of use 
Summaries will be performed overall and by seizure classification group (as defined in Section 
3.2.12). All palatability and ease of use questionnaire data will be listed. 
Has been changed to: 
UCB has created a palatability and ease of use questionnaire to collect data from the subject or 
caregiver regarding different aspects of LCM and its administration. The questionnaire will 
assess the subject or caregiver’s response regarding the formulation of LCM the subject is 
receiving for palatability items (eg, taste, smell, ability to swallow, aftertaste), mode of 
administration, and administration device as applicable. 
The number and percentage of study participants who respond to each of the categories presented 
for the following questionnaires will be summarized at each visit it is assessed: 
• Tablet palatability and ease of use 
• Oral solution palatability and ease of use 
Summaries will be performed overall and by seizure classification group (as defined in Section 
3.2.12), with percentages based on the number of study participants with non-missing responses 
for the specified visit. All palatability and ease of use questionnaire data will be listed. 
 
 
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13.4 
Amendment 4 
Rationale for the amendment 
This amendment was done to reflect the changes in Protocol Amendment #8.  
Specific changes 
Change #1 
SAP/Amendment Number and Date 
Final SAP 27 Apr 2015 
SAP – Amendment 1  18 Dec 2015 
SAP – Amendment 2  8 Mar 2019 
SAP – Amendment 3 25 Nov 2019 
Has been changed to: 
Final SAP 27 Apr 2015 
SAP – Amendment 1  18 Dec 2015 
SAP – Amendment 2  8 Mar 2019 
SAP – Amendment 3  25 Nov 2019 
SAP – Amendment 4 15 Jan 2020 
Change #2 
Added abbreviations for BCR and COVID-19. 
Change #3 
2.1 Study objectives 
2.1.1 Primary objective 
• To obtain information about the safety, tolerability, and pharmacokinetic (PK) of 
Lacosamide (LCM) during long-term exposure 
2.1.2 Secondary objective 
• To obtain preliminary efficacy data on seizure frequency during long-term exposure  
2.1.3 Other objectives 
• To allow study participants who have participated in SP847 (or discontinued SP847 due to a 
dose reduction or status epilepticus) to continue receiving LCM 
• To allow study participants who have participated in other LCM pediatric clinical studies in 
epilepsy to continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not 
previously received LCM to begin receiving LCM  
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• Protocol Amendment 5.3 (specific to Japan) allows approximately 46 additional eligible 
pediatric study participants ≥4 years to ≤17 years of age with partial-onset seizures who have 
not previously received LCM to directly enroll at approximately 9 sites in Japan 
• Protocol Amendment 5.4 (specific to China) allows approximately 60 additional pediatric 
study participants with partial-onset seizures aged ≥4 years to ≤17 years who have not 
previously received LCM to directly enroll in China 
• Protocol Amendment 6 allows approximately 75 additional eligible pediatric study 
participants with epilepsy who participated in EP0060 to continue to receive LCM 
Has been changed to: 
2.1 Study objectives 
The objectives of this study are: 
• To obtain information about the safety, tolerability, and pharmacokinetic (PK) of 
Lacosamide (LCM) during long-term exposure 
• To obtain preliminary efficacy data on seizure frequency during long-term exposure  
• To allow study participants who have participated in SP847 (or discontinued SP847 due to a 
dose reduction or status epilepticus) to continue receiving LCM 
• To allow study participants who have participated in other LCM pediatric clinical studies in 
epilepsy to continue receiving LCM 
• Beginning with Protocol Amendment 4, at selected sites, to allow up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not 
previously received LCM to begin receiving LCM  
Change #4 
2.2.1 Primary variables 
Safety, tolerability, and PK will be assessed using the following variables: 
• Adverse events (AEs) reported spontaneously by the subject and/or caregiver, or observed by 
the investigator 
• Subject withdrawal due to AEs 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner Stage (if applicable) 
• Plasma concentrations of LCM (for population PK analysis) and concomitant antiepileptic 
drugs (AEDs)  
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• Achenbach Child Behavior Checklist (CBCL) for children 18 months and older (CBCL/1½-5 
and CBCL/6-18) assessing behavior 
• Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
study participants enrolled in English-speaking countries) 
• Cognitive function assessments (Behavior Rating Inventory of Executive Function – 
Preschool Version [BRIEF-P]/ Behavior Rating Inventory of Executive Function [BRIEF]) 
(if applicable) 
2.2.2 Secondary variables 
Efficacy will be assessed using the following variables: 
• Seizure counts, which will be assessed using seizure diaries in order to evaluate preliminary 
evidence of efficacy during long-term exposure in this population 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• Quality of life assessments (Pediatric Quality of Life Inventory [PedsQL]) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study) 
• LCM palatability and ease of use questionnaire 
Has been changed to: 
2.3 Safety variables 
2.3.1 Primary safety variables 
The primary safety variables are as follows:  
• Incidence of Treatment Emergent Adverse events (TEAEs)  
• Incidence of Serious Adverse Events (SAEs) 
• Subject withdrawal from the study due to TEAEs 
2.3.2 Other safety variables 
The other safety variables are: 
• Hematology, blood chemistry, endocrinology, and urinalysis parameters 
• 12-lead electrocardiograms (ECGs) 
• Vital sign measurements (blood pressure and pulse) 
• Physical and neurological examination findings 
• Body weight, height, and calculated body mass index (BMI) 
• Tanner Stage (if applicable) 
• Achenbach Child Behavior Checklist (CBCL) for children 18 months and older (CBCL/1½-5 
and CBCL/6-18) assessing behavior 
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• Bayley-III scales for children <18 months of age at time of enrollment (applicable only to 
study participants enrolled in English-speaking countries) 
• Cognitive function assessments (Behavior Rating Inventory of Executive Function – 
Preschool Version [BRIEF-P]/ Behavior Rating Inventory of Executive Function [BRIEF]) 
(if applicable) 
• LCM palatability and ease of use questionnaire 
2.3.3 Pharmacokinetic variables 
2.3.3.1 Primary Pharmacokinetic variables 
No primary PK variables are defined for this study. 
2.3.3.2 Other Pharmacokinetic variables 
The other PK variables are: 
• Plasma concentration of LCM (for population PK analysis) and concomitant antiepileptic 
drugs (AEDs)  
2.3.4 Efficacy variables 
2.3.4.1 Primary efficacy variables 
No primary efficacy variables are defined for this study. 
2.3.4.2 Secondary efficacy variables 
The secondary efficacy variables, based on daily seizure diaries are: 
• Percent change from Baseline in 28-day partial-onset seizure frequency 
• ≥50% reduction in 28-day partial-onset seizure frequency 
• ≥75% reduction in 28-day partial-onset seizure frequency 
• Seizure days per 28 days (subjects with generalized seizures only) 
• Seizure-free status 
2.3.4.3 Other efficacy variables 
The other efficacy variables are: 
• Clinical Global Impression of Change 
• Caregiver Global Impression of Change 
• Quality of life assessments (Pediatric Quality of Life Inventory [PedsQLTM]) (if applicable) 
• Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study) 
• All seizure frequency analyses as described in secondary efficacy variables (presented for the 
overall Treatment Period only) may be additionally presented by modal daily dose group, by 
seizure type, by seizure classification subgroup, by time interval, by visit or time period, or 
by completer cohort.   
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Change #5 
2.4.1.1 Study participants enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric study participants ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously received LCM will be 
permitted to enroll directly into SP848.  
Beginning with Protocol Amendment 5.3 (specific to Japan), approximately 46 eligible pediatric 
study participants ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM will be permitted to directly enroll at approximately 9 sites in Japan. 
Beginning with Protocol Amendment 5.4 (specific to China), approximately 60 eligible pediatric 
study participants ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM will be permitted to directly enroll in China. 
Study participants who enroll directly into SP848 without previous participation in a LCM 
clinical study will undergo screening. Eligible study participants will initiate treatment with 
LCM, and the LCM dose will be titrated to a level to optimize tolerability and seizure control. 
Study participants will be able to receive LCM oral solution or LCM tablets for up to 2 years as 
determined appropriate by the investigator with the exception of study participants in Japan. For 
sites in Japan, the study will continue until the date of market approval for the partial-onset 
seizure indication for LCM in children or until the sponsor decides to discontinue the 
development of LCM in children in Japan. Original direct enrollers are study participants who 
directly enroll outside of Japan or China. 
The same study conditions described in Section 2.5.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
Study participants may enroll in study EP0060 (intravenous therapy) of LCM without 
withdrawing from SP848.  Study participants will continue to receive their SP848 assigned LCM 
daily dose during the iv trial.  Ongoing adverse events and concomitant medications originating 
in the iv trials will be followed in SP848 until resolution.  
Has been changed to: 
2.3.1.2 Study participants enrolling directly into SP848 
Beginning with Protocol Amendment 4, at selected sites, up to approximately 100 eligible 
pediatric study participants ≥4 years to ≤17 years of age with partial-onset seizures (deemed 
appropriate for treatment with adjunctive LCM) who have not previously received LCM will be 
permitted to enroll directly into SP848.  
Beginning with local Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible 
pediatric subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not 
previously received LCM will be permitted to directly enroll at approximately 9 sites in Japan. 
Beginning with Protocol Amendment 5.4 for sites in China, approximately 60 additional eligible 
pediatric subjects with partial-onset seizures aged ≥4 years to ≤17 years, who have not 
previously participated in a LCM clinical study, will enroll directly enroll into SP848. 
Subjects who enroll directly into SP848 without previous participation in a LCM clinical study 
will undergo screening. Eligible subjects will initiate treatment with LCM, and the LCM dose 
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will be titrated to a level to optimize tolerability and seizure control. Subjects will be able to 
receive LCM oral solution or LCM tablets for up to 2 years as determined appropriate by the 
investigator. 
SP848 includes subjects ≥1 month to ≤18 years of age since subjects who complete SP847 or 
another applicable LCM pediatric epilepsy study in subjects <18 years of age may have aged to 
18 years old by the time they complete that study and enroll in SP848. 
The same study conditions described in Section 2.5.1.1 (eg, minimum and maximum LCM dose, 
required office visits for dose increases, concomitant AEDs, and LCM taper) also apply. 
Change #6 
2.4 Determination of sample size 
Approximately 42 study participants from the SP847 study will be eligible to enroll in this 
open-label study. Approximately 200 other subjects will be eligible to enroll as other LCM 
pediatric clinical studies in epilepsy are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. For sites in 
Japan, approximately 46 additional eligible pediatric study participants ≥4 years to ≤17 years of 
age with partial-onset seizures who have not previously received LCM will enroll directly into 
SP848. For sites in China, approximately 60 additional eligible pediatric study participants 
≥4 years to ≤17 years of age with partial-onset seizures who have not previously received LCM 
will enroll directly in to SP848. The purpose of enrolling these study participants directly into 
SP848 is to obtain additional long-term safety exposures in the age range from which adequate 
PK data have already been obtained in SP847; the additional long-term safety data will be 
included in planned LCM marketing applications for study participants ≥4 years of age. 
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. 
Has been changed to: 
2.5 Determination of sample size 
Approximately 42 study participants from the SP847 study will be eligible to enroll in this 
open-label study. Other subjects will be eligible to enroll as other LCM pediatric clinical studies 
in epilepsy are undertaken. 
In addition, at selected sites, beginning with Protocol Amendment 4, up to approximately 
100 eligible pediatric study participants ≥4 years to ≤17 years of age who have not previously 
participated in a LCM clinical study will be permitted to enroll directly into SP848. Beginning 
with local Protocol Amendment 5.2 for sites in Japan, approximately 46 eligible pediatric 
subjects ≥4 years to ≤17 years of age with partial-onset seizures who have not previously 
received LCM will directly enroll at approximately 9 sites in Japan. Beginning with local 
Protocol Amendment 5.4 for sites in China, approximately 60 additional eligible pediatric 
subjects with partial-onset seizures aged ≥4 years to ≤17 years, who have not previously 
participated in a LCM clinical study, will enroll directly into SP848. The purpose of enrolling 
these subjects directly into SP848 is to obtain additional long-term safety exposures in the age 
range from which adequate PK data have already been obtained in SP847; the additional 
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long-term safety data will be included in planned LCM marketing applications for study 
participants ≥4 years of age.  
Beginning with Protocol Amendment 6, up to 75 eligible pediatric subjects ≥4 years to <17 years 
of age who have participated in EP0060 will be permitted to enroll into SP848. Protocol 
Amendment 8 allows an enrollment increase from 75 to 100 eligible pediatric subjects ≥1 month 
to ≤17 years of age with epilepsy who participated in EP0060 to enroll in SP848 in order to 
reflect EP0060’s inclusion of subjects down to 1 month of age. 
In total, up to approximately 400 subjects may be eligible to participate in SP848. 
Change #7 
3.1 General presentation of summaries and analyses 
The age group for the age at time of entry into study SP848 is updated to following: 
• ≥1 month to <4 years 
• ≥4 to <18 years 
• Total ≥1 month to <18 years 
• ≥18 years 
• All subjects 
Change #8 
3.1 General presentation of summaries and analyses 
For summaries of PedsQL, the age group of  ≥1 month to ≤12 months,  >12 months to ≤24 
months, and Total ≥5 years to ≤18 years was added in. 
Change #9 
3.2.9 Age and age at first diagnosis 
Age at entry into SP848 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 is migrated from the previous pediatric study 
into the SP848 SDTM. 
Missing or partial epilepsy diagnosis date will be derived applying all rules for missing data 
imputation (see Section 4.2.6) and age at diagnosis will use the following formula, where 
applicable. The age at first diagnosis will be given in years. 
If date of birth is a complete date then age at diagnosis will be calculated as: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25  
If date of birth is a partial date then age at diagnosis will be calculated as: 
 
(Enrollment age in years) – [(Informed consent date – Epilepsy diagnosis date) / 365.25]  
If this produces a value negative then age at diagnosis will be set to zero. 
Has been changed to: 
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3.2.9 Age and age at first diagnosis 
Age at entry into SP848 will be given in years. For direct enrollers and subjects with a complete 
date of birth available, age at entry into SP848 will use the SDTM derivation in the analysis 
dataset. For rollover subjects without a complete date of birth available, age at entry into SP848 
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 SP848)/12. 
The age at entry into the previous pediatric study is migrated from the previous pediatric study 
into the SP848 SDTM. 
Missing or partial epilepsy diagnosis date will be derived applying all rules for missing data 
imputation (see Section 4.2.6) and age at diagnosis will use the following formula, where 
applicable. The age at first diagnosis will be given in years. 
If date of birth is a complete date then age at diagnosis will be calculated as: 
(Date of first diagnosis of epilepsy – date of birth) / 365.25  
If date of birth is a partial date then age at diagnosis will be calculated as: 
(Enrollment age in years) – [(Informed consent date – Epilepsy diagnosis date) / 365.25]  
If this produces a value negative then age at diagnosis will be set to zero. 
Change #10 
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 PedQL 
Measurement Model consists of developmentally appropriate forms for pediatric study 
participants ≥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 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 
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). 
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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: 
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 ≤18 years 
of age. The PedsQL Measurement Model consists of developmentally appropriate forms for 
pediatric study participants ≥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 
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 
For versions intended for subjects >8 years of age, Physical Functioning refers to questions 
”; Emotional Functioning refers to questions 
 
; Social Functioning refers to questions 
; School 
Functioning refers to questions “
. 
The PedsQL assessment is retrospective to the prior 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 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): 
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Item transform 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 #11 
Section 3.3 Definition of Baseline values 
The first dose date for rollover subjects and direct enrollers is clarified. 
Change #12 
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 #13 
3.5.3 Full Analysis Set 
Abbreviation of FAS is added in. 
Change #14 
3.9 Changes to protocol-defined analysis 
The section of 3.9.1 and 3.9.2 is deleted, as the efficacy variables and summarization by various 
sub-groups were added in protocol amendment 8. Further, the sub-section numbering of Section 
3.9.3 was updated 3.9.1.  
Change #15 
5.1 Subject disposition 
The number and percentage of subject completing the study by interval, following categories 
were added in: <12 months,  ≥48 months. 
Change #16 
5.1 Subject disposition 
The following text has been added in this section: 
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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 #17 
5.2 Protocol deviations.  
The statement “The number and percentage of study participants with no important protocol 
deviations will also be summarized for the SS” is deleted. 
Change #18 
6.1 Demographics and other Baseline characteristics 
The clinicaltrail.gov categories of age (≤18 years and 19 - < 65 years) are added in.  
Change #19 
6.1 Demographics and other Baseline characteristics 
The summarization weight (in kg) at the entry of SP848 study is clarified.  
Change #20 
8.2 Adverse Events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented 
by weight band and seizure classification subgroup using the levels defined in Sections 3.2.10 
and 3.2.123.2.12, respectively. Additional tables will also be presented by time interval using the 
definition in Section 3.2.5. The number and percentage of study participants 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 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 study participants 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 study participants with AEs leading to 
death (if applicable) will also be summarized. This overall summary will be repeated by weight 
band and seizure classification subgroup using the levels defined in Sections 3.2.10 and 3.2.12 
respectively. In addition, the overall summary will be presented for the Titration Period, Post-
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Titration Period and Treatment Period for the direct enrollers and the Treatment Period for the 
rollover study participants. 
The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• Incidence of TEAEs 
• Incidence of TEAEs with onset during the Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Post-Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Treatment Period for direct enrollers 
• Incidence of TEAEs for direct enrollers 
• Incidence of TEAEs for rollover study participants 
• 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 study participants 
• Incidence of non-serious TEAEs occurring in at least 5% of study participants 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 seizure classification 
subgroup 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 study participants 
• 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 time intervals (using the definition in 
Section 3.2.5) of: ≤3 months, >3 to ≤6 months, >6 to ≤9 months, >9 to ≤12 months, >12 to 
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≤ 15 months, >15 to ≤18 months, >18 to ≤21 months, >21 to ≤24 months, and >24 to 
≤ 30  months, >30 to ≤36 months, >36 to ≤42 months, >42 to ≤48 months, >48 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) 
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 
study participants experiencing each TEAE as well as in subject data listings. 
Has been changed to: 
8.2 Adverse Events 
AEs will be tabulated by MedDRA SOC and MedDRA PT; select tables will also be presented 
by weight band and seizure classification subgroup using the levels defined in Sections 3.2.10 
and 3.2.12, respectively. Additional tables will also be presented by time interval using the 
definition in Section 3.2.5. The number and percentage of study participants 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 SP848 dose of LCM. 
Treatment-emergent AEs (TEAEs) are defined as those events which started on or after the date 
of first SP848 dose of LCM, or whose intensity worsened on or after the date of first SP848 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 study participants 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 study participants with AEs leading to 
death (if applicable) will also be summarized. This overall summary will be repeated by weight 
band and seizure classification subgroup using the levels defined in Sections 3.2.10 and 3.2.12 
respectively. In addition, the overall summary will be presented for the Titration Period, Post-
Titration Period and Treatment Period for the direct enrollers and the Treatment Period for the 
rollover study participants. 
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The following summaries of AEs will be provided by MedDRA primary SOC and PT: 
• Incidence of TEAEs 
• Incidence of TEAEs with onset during the Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Post-Titration Period for direct enrollers 
• Incidence of TEAEs with onset during the Treatment Period for direct enrollers 
• Incidence of TEAEs for direct enrollers 
• Incidence of TEAEs for rollover study participants 
• 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 12.3 ) 
• Incidence of pediatric growth-, neurodevelopment-, behavior-, and endocrine-related TEAEs 
(defined in Appendix 12.4) 
• 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 study participants 
• Incidence of non-serious TEAEs occurring in at least 5% of study participants 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 seizure classification 
subgroup 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 study participants 
• Incidence of drug-related TEAEs by seriousness 
• Incidence of other significant TEAEs (defined in Appendix 12.2). 
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The following summaries of AEs will be presented for the time intervals (using the definition 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 to 
≤ 30  months, >30 to ≤36 months, >36 to ≤42 months, >42 to ≤48 months, >48 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 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 AEs, incidence 
of serious TEAEs, incidence of TEAEs leading to discontinuation from study, 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 study participants experiencing each TEAE as well as in subject data listings. 
Change #21 
8.3 Clinical laboratory evaluations 
The abbreviations of AST, ALT and GGT were added in at first occurrence.  
To determine the correct abnormality using age range, the age that would be considered at each 
visit/assessment is updated.  
Change #22 
8.4.1 Vital signs, body weight, height and BMI 
The following statement is deleted: 
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 study participants with marked bradycardia. 
Change #23 
8.4.1 Vital signs, body weight, height and BMI 
A subject data listing of all vital signs for study participants 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 participants with an AE mapped to the PT 
bradycardia or sinus bradycardia will be presented. 
Change #24 
8.4.2 Electrocardiograms (ECG) 
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To determine the correct abnormality using age range, the age that would be considered at each 
visit/assessment is updated.  
Change #25 
Section 8.4.8 Assessment of suicidality is updated to Section 8.4.7 Assessment of suicidality. 
Change #26 
The Section 8.4.7 Achenbach Child Behavior Checklist (CBCL) is updated to Section 8.4.8 
Achenbach Child Behavior Checklist (CBCL). 
Change #27 
8.4.8 Achenbach Child Behavior Checklist (CBCL) 
The following statement is added in: 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. 
Change #28 
8.4.8 Achenbach Child Behavior Checklist (CBCL) 
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. 
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: 
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 spreadsheets 
“c15group2-probscales18moto5yrs” and “cbcgroup2-probscales6to18”. 
Raw score 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 score 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-score will be listed along raw-score and change from baseline of raw score. 
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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, subject 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 visits, and from Baseline to Last Visit 
will also be provided based on the CBCL calculated T-score categories of Normal and BCR. The 
descriptive summarizes of change from baseline and shift summaries will be presented only 
when corresponding baseline value is available. 
Change #30 
8.4.9.1 BRIEF-P Scores 
Calculated T-score values and change from Baseline for the three index 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. 
Has been changed to: 
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 spreadsheet “briefp-tscores”. 
Raw score values and change from Baseline for the three index scores and GEC for the BRIEF-P 
questionnaire will be summarized for each visit, and Last Visit.  
The Calculated T-score will be listed along raw score and change from baseline of raw score. 
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, subject 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 visits, and from Baseline to Last Visit 
will also be provided based on BRIEF-P calculated T-score categories of Normal and Elevated. 
The descriptive summarizes of change from baseline and shift summaries will be presented only 
when corresponding baseline value is available. 
All BRIEF-P assessment data will be listed. 
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Change #31 
8.4.9.2 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.  
All BRIEF assessment data will be listed. 
Has been changed to: 
Raw-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.  
Standardized T-scores determined from each subject’s raw GEC score, subscale scores and 5 
individual component scores will be produced programmatically using the spreadsheet 
“brief-t-scores”. The Standardized T-score will be listed along raw-score and change from 
baseline of raw score. 
A decrease from baseline (change from baseline <0) in the BRIEF questionnaire raw score will 
indicate improvement, while an increase (change from baseline > 0) indicates worsening. 
In addition, for BRIEF, subject 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 visits, and from Baseline to Last Visit 
will also be provided based on BRIEF calculated T-score categories of Normal and Elevated. 
The descriptive summarizes of change from baseline and shift summaries will be presented only 
when corresponding baseline value is available. 
All BRIEF assessment data will be listed. 
Change #32 
9.1 Pharmacokinetic 
The summary of plasma concentration was updated to include timepoint.  
Change #33 
10.4.1 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. 
Study participants who had any concomitant medical procedures during the course of the study 
based on the Concomitant Medical Procedures CRF/eCRF module will be listed. Additionally, 
study participants who had any procedures or surgeries prior to study entry based on the 
Procedure History CRF/eCRF module will also be listed. 
Has been changed to: 
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8.4.11 Medical procedures  
Subjects who had any concomitant medical procedures during the course of the study based on 
the Concomitant Medical Procedures eCRF module will be listed. Additionally, subjects who 
had any procedures or surgeries prior to study entry based on the Procedure History CRF/eCRF 
module will also be listed. 
Change #34 
The text “partial-onset” was added in heading of Section 10.1.2 
Change #35 
10.1.3 ≥50% response to treatment 
For study participants with POS, the number and percentage with ≥50% reduction in 28-day 
partial-onset seizure frequency (≥50% responders) will be summarized by seizure time intervals 
and modal daily LCM dose (as defined in Section 3.2.8). This will also be presented separately 
by completer cohorts (as defined in Section 3.2.19), 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. The number and percentage of ≥50% responders will also be presented for 
the entire Treatment Period.  
The number and percentage of ≥50% responders will be presented in the same manner as 
described above but presented separately by seizure type (simple partial, complex partial, 
secondarily generalized) and by seizure time intervals (as defined in Section 3.2.21). 
Has been changed to: 
10.1.3 ≥50% reduction in 28-days partial-onset seizure frequency  
For study participants with POS, the number and percentage with ≥50% reduction in 28-day 
partial-onset seizure frequency (≥50% responders) will be summarized by seizure time intervals 
(as defined in Section 3.2.21) and by seizure type (simple partial, complex partial, secondarily 
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.≥75% reduction in 28-days partial-
onset seizure frequency.). 
Change #36 
10.1.4 ≥75% response to treatment 
The analyses described in Section 10.1.3 for ≥50% response to treatment will also be performed 
for study participants with ≥75% reduction in 28-day partial-onset seizure frequency (≥75% 
responders). 
Has been changed to: 
10.1.4 ≥75% reduction in 28-days partial-onset seizure frequency 
The analyses described in Section 10.1.3 for ≥50% reduction in 28-days partial-onset seizure 
frequency will also be performed for study participants with ≥75% reduction in 28-day partial-
onset seizure frequency (≥75% responders). 
Change #37 
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10.1.5 Seizure-free status 
The number and percentage of study participants achieving a seizure-free status (as defined in 
Section 3.2.18) will be presented by completer cohorts (as defined in Section 3.2.19) overall and 
by modal daily LCM dose and seizure classification subgroup (as defined in Sections 3.2.8 and 
3.2.12). 
The number and percentage of study participants seizure-free among completer cohorts (as 
defined in Section 3.2.19) will also be presented separately by seizure type (simple partial, 
complex partial, secondarily generalized). Seizure-free status will also be presented by seizure 
time intervals (as defined in Section 3.2.21). 
Has been changed to: 
10.1.6 Seizure-free status 
The number and percentage of study participants achieving a seizure-free status (as defined in 
Section 3.2.18) will be presented for overall treatment period. This will be presented by 
completer cohorts (as defined in Section 3.2.19).  
The number and percentage of study participants seizure-free among completer cohorts (as 
defined in Section 3.2.19) will also be presented separately by seizure type (simple partial, 
complex partial, secondarily generalized) for subjects with POS.  
Seizure-free status will also be presented by seizure time intervals (as defined in Section 3.2.21). 
The number and percentage of study participants 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, secondarily generalized) for POS. 
Change #38 
10.1.6 Seizure days per 28 days  
For study participants with generalized seizures, the number of seizure days per 28 days (as 
defined in Section 3.2.16) 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. 
Has been changed to: 
10.1.5 Seizure days per 28 days (subjects with generalized seizures only)  
For study participants with generalized seizures, the number of seizure days per 28 days (as 
defined in Section 3.2.16) will be summarized descriptively during the overall treatment period 
and grouped by modal daily LCM dose (as defined in Section 3.2.8). 
Change #39 
Has been changed to: 
10.3 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. 
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10.3.1 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 scales), 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 grouped by modal daily 
LCM dose, using the levels defined in Section 3.2.8, and also by Seizure Classification 
subgroup, using the levels defined in Section 3.2.12. 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. 
10.3.2 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 scales), 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 grouped by modal daily 
LCM dose, using the levels defined in Section 3.2.8, and also by Seizure Classification 
subgroup, using the levels defined in Section 3.2.12. 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 >2 years data will be listed. 
Change #40 
Subsections of Section 10.4 were renumbers as Medical Procedures were moved to Section 
10.4.1. 
Change #41 
Section 12.3 Other Significant TEAEs 
The preferred terms are arranged alphabetically. 
The preferred term “Cardiac arrest” is added in Table 12-3. 
Change #42 
Section 12.3 List of AEs for Potentially Drug Induced Liver Injury (PDILI) 
MedDRA Preferred Terms “Alanine aminotransferase increased” and “Aspartate 
aminotransferase increased” have been added, duplicates have been removed, and Preferred 
Terms have been arranged in alphabetical order. 
 
 
 
 
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UCB 
 
15 Jan 2021 
Statistical Analysis Plan 
Lacosamide 
SP848 
 
 
 
 
Confidential                                                              Page 147 of 147 
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:
sp848-sap-amend-4
Version:
1. 0
Document Number:
CLIN-000164210
Title:
SP0848: Draft SAP dated 04-Nov-2020
Approved Date:
18 Jan 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Jan-2021 19:28:55 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Jan-2021 16:56:18 GMT+0000
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