Clinical trial NCT04627285
Conditions: Epilepsy
Keywords: Lacosamide Vimpat Epilepsy Pediatric
Sponsor: UCB Biopharma SRL
Start date: 2020-12-28; Completion date: 2025-02-12
Enrollment: 48 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess the long-term use of lacosamide oral solution dosed at 2 mg/kg/day to 12 mg/kg/day when administered to pediatric study participants with epilepsy who have completed NCT01964560 (EP0034) or NCT00938912 (SP848).

Detailed description:

Arms: arm 1: Subjects in this arm will receive various single doses of lacosamide
Interventions: intervention 1: Lacosamide
Intervention descriptions: intervention 1: * Pharmaceutical form: Oral-solution
* Route of administration: Oral use

Subjects will receive lacosamide in a pre-specified sequence during the Treatment Period.

Protocol documents:
Prot_000.pdf: 
UCB 
12 Oct 2023 
Clinical Study Protocol 
Lacosamide 
EP0151 
Confidential 
Page 1 of 57 
A MULTICENTER, OPEN-LABEL, FOLLOW-UP STUDY TO 
ASSESS THE LONG-TERM USE OF ORAL LACOSAMIDE IN 
STUDY PARTICIPANTS WHO COMPLETED EP0034 OR SP848 
AND RECEIVED LACOSAMIDE TREATMENT 
PROTOCOL EP0151 AMENDMENT 1 
PHASE 3B 
SHORT TITLE: 
Long-term use of oral lacosamide in pediatric study participants with epilepsy 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying numbers: 
Eudra CT Number: 
2020-001478-30 
EU CT Number: 
2022-502639-21-00 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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EP0151 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
Document History 
Document 
Date 
Type of amendment 
Amendment 1 
12 Oct 2023 
Nonsubstantial 
Original Protocol 
13 Apr 2020 
Not applicable 
 
Amendment 1 (12 Oct 2023) 
Overall Rationale for the Amendment 
The purpose of this nonsubstantial amendment is to add the European Union Clinical Trial 
number to the protocol.  
Section # and name 
Description of change 
Brief rationale 
Title page 
EU CT Number 
2022-502639-21-00 was added 
as a regulatory agency 
identifying number. 
Included for clarity under the 
new EU Clinical Trials 
Regulation. 
CT=Clinical Trial; EU=European Union 
 
 
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Clinical Study Protocol 
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EP0151 
 
 
 
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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 
Email 
Global: DS_ICT@ucb.com (for interventional clinical studies) 
 
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EP0151 
 
 
 
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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ................................................................................................. 7 
1.1 
Synopsis ......................................................................................................................... 7 
1.2 
Schema ......................................................................................................................... 10 
1.3 
Schedule of Activities .................................................................................................. 11 
2 
INTRODUCTION ........................................................................................................... 14 
2.1 
Study Rationale ............................................................................................................ 14 
2.2 
Background .................................................................................................................. 14 
2.2.1 
Lacosamide in pediatric studies ........................................................................... 15 
2.3 
Benefit/Risk Assessment ............................................................................................. 16 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 16 
4 
STUDY DESIGN ............................................................................................................. 16 
4.1 
Overall design .............................................................................................................. 16 
4.2 
Scientific rationale for study design ............................................................................ 18 
4.3 
Justification for dose .................................................................................................... 18 
4.4 
End of study definition................................................................................................. 18 
5 
STUDY POPULATION .................................................................................................. 18 
5.1 
Inclusion criteria .......................................................................................................... 19 
5.2 
Exclusion criteria ......................................................................................................... 19 
5.3 
Lifestyle restrictions..................................................................................................... 19 
5.4 
Screen failures .............................................................................................................. 20 
6 
STUDY TREATMENTS ................................................................................................. 20 
6.1 
Treatments administered .............................................................................................. 20 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 21 
6.2.1 
Drug accountability ............................................................................................. 22 
6.3 
Measures to minimize bias: randomization and blinding ............................................ 22 
6.4 
Treatment compliance .................................................................................................. 22 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 23 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 23 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 23 
6.5.3 
Rescue medication ............................................................................................... 23 
6.6 
Dose modification ........................................................................................................ 23 
6.7 
Criteria for study hold or dosing stoppage ................................................................... 23 
6.8 
Treatment after the end of the study ............................................................................ 24 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 24 
7.1 
Discontinuation of study medication ........................................................................... 24 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 24 
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7.1.2 
QTc stopping criteria ........................................................................................... 26 
7.2 
Participant discontinuation/withdrawal from the study ............................................... 26 
7.3 
Lost to follow-up.......................................................................................................... 27 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 27 
8.1 
Efficacy assessments .................................................................................................... 28 
8.2 
Safety assessments ....................................................................................................... 28 
8.2.1 
Vital signs ............................................................................................................ 28 
8.2.2 
Biometric parameters ........................................................................................... 28 
8.2.3 
Clinical safety laboratory assessments ................................................................ 28 
8.2.4 
Suicidal risk monitoring ...................................................................................... 29 
8.3 
Adverse events and serious adverse events ................................................................. 29 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 30 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 30 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 30 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 30 
8.3.5 
Adverse events of special interest ........................................................................ 31 
8.3.6 
Adverse events of special monitoring .................................................................. 32 
8.3.7 
Anticipated serious adverse events ...................................................................... 32 
8.4 
Safety signal detection ................................................................................................. 32 
8.5 
Treatment of overdose ................................................................................................. 33 
8.6 
Pharmacokinetics ......................................................................................................... 33 
8.7 
Genetics........................................................................................................................ 33 
8.8 
Pharmacodynamics ...................................................................................................... 33 
8.9 
Biomarkers ................................................................................................................... 33 
8.10 
Medical resource utilization and health economics ..................................................... 33 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 33 
9.1 
Definition of analysis sets ............................................................................................ 34 
9.2 
General statistical considerations ................................................................................. 34 
9.3 
Planned safety analyses................................................................................................ 34 
9.3.1 
Safety analyses ..................................................................................................... 34 
9.4 
Handling of protocol deviations................................................................................... 34 
9.5 
Handling of dropouts or missing data .......................................................................... 35 
9.6 
Planned interim analysis and data monitoring ............................................................. 35 
9.7 
Determination of sample size ....................................................................................... 35 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 35 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ......................... 35 
10.1.1 
Regulatory and ethical considerations ................................................................. 35 
10.1.2 
Financial disclosure ............................................................................................. 36 
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10.1.3 
Informed consent process .................................................................................... 36 
10.1.4 
Data protection ..................................................................................................... 37 
10.1.5 
Data quality assurance ......................................................................................... 37 
10.1.5.1 
Case Report Form completion ................................................................... 37 
10.1.5.2 
Apps ........................................................................................................... 38 
10.1.6 
Source documents ................................................................................................ 38 
10.1.7 
Study and site Closure ......................................................................................... 38 
10.1.8 
Publication policy ................................................................................................ 39 
10.2 
Appendix 2: Clinical laboratory tests .......................................................................... 40 
10.3 
Appendix 3: Adverse events – definitions and procedures for recording, evaluating, 
follow-up, and reporting .............................................................................................. 41 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ......... 46 
10.5 
Appendix 5: Genetics ................................................................................................... 47 
10.6 
Appendix 6: Liver safety – suggested actions and follow-up assessments ................. 48 
10.7 
Appendix 7: Medical device adverse events, adverse device effects, serious adverse 
events and device deficiencies: definition and procedures for recording, evaluating, 
follow-up, and reporting .............................................................................................. 51 
10.8 
Appendix 8: Rapid alert procedures ............................................................................ 52 
10.9 
Appendix 9: Country-specific requirements ................................................................ 53 
10.10 Appendix 10: Abbreviations and trademarks .............................................................. 54 
10.11 Appendix 11: Protocol amendment history ................................................................. 55 
11 REFERENCES ................................................................................................................ 56 
SPONSOR DECLARATION .................................................................................................. 57 
 
LIST OF TABLES 
Table 1-1: 
Schedule of study activities ............................................................................. 11 
Table 6-1: 
Summary of treatments administered .............................................................. 20 
Table 6-2: 
Lacosamide doses for Taper Period ................................................................. 21 
Table 8-1: 
Anticipated SAEs for the pediatric epilepsy population .................................. 32 
Table 10-1: 
Phase 3-4 liver chemistry stopping criteria and follow-up assessments .......... 48 
Table 10-2: 
Phase 3-4 liver chemistry increased monitoring criteria with continued 
study medication .............................................................................................. 50 
 
LIST OF FIGURES 
Figure 1-1: 
Study schematic ............................................................................................... 10 
Figure 7-1: 
Liver chemistry stopping criteria and increased monitoring algorithm ........... 24 
Figure 7-2: 
Liver chemistry increased monitoring algorithm with continued study 
intervention for participants with ALT 3xULN but <8xULN ....................... 25 
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Lacosamide 
EP0151 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: 
A multicenter, open-label, follow-up study to assess the long-term use of oral lacosamide in 
study participants who completed EP0034 or SP848 and received lacosamide treatment 
Short Title: 
Long-term use of oral lacosamide in pediatric study participants with epilepsy 
Rationale: 
Epilepsy is the second most prevalent neurological disorder in the world, with more than 
70 million people suffering from this disorder. 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. More than 30% of patients have inadequate seizure 
control on currently available antiepileptic drugs (AEDs) or experience significant adverse drug 
effects; therefore, there is a need for AEDs with improved effectiveness and tolerability. 
Lacosamide (LCM); (VIMPAT®; SPM 927 [or SPM 929 for neuropathic pain documents]; 
previously referred to as harkoseride; (R)-2-acetamido-N-benzyl-3-methoxypropionamide, 
Anticonvulsant Drug Development [ADD] 234037) belongs to a novel class of functionalized 
amino acids. Lacosamide has proven to be an effective and safe adjunctive treatment for 
partial-onset seizures (POS), with or without secondary generalization, based on 3 double-blind, 
placebo-controlled, multicenter studies (SP667, SP754, and SP755) in study participants with 
difficult-to-control POS. Lacosamide is being evaluated in pediatric study participants ≥1 month 
to <17 years of age with POS in completed and ongoing studies. 
EP0151 is an open-label extension study designed to assess the long-term use of LCM 
(2mg/kg/day to 12mg/kg/day) in pediatric study participants <6 years of age with epilepsy who 
have completed EP0034 or SP848. EP0151 will allow study participants treated with LCM in 
EP0034 or SP848 to continue treatment with LCM until either the participant reaches 6 years of 
age or until marketing application approval is achieved for pediatric patients <4 years of age in 
the region of participation and LCM oral solution is available (whichever is earliest). 
Objectives and Endpoints 
Objective 
Endpoints 
Primary 
• To assess the long-term use of LCM oral 
solution dosed at 2mg/kg/day to 
12mg/kg/day when administered to 
pediatric study participants with epilepsy 
who have completed EP0034 or SP848 
• TEAEs reported by the study participant 
or caregiver or observed by the 
Investigator 
• Withdrawals from study due to TEAEs 
• Withdrawals from study due to SAEs 
• Modal daily dose (mg/kg/day) 
• Maximum daily dose (mg/kg/day) 
LCM=lacosamide; SAE=serious adverse event; TEAE=treatment-emergent adverse event 
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Overall Design 
EP0151 is a multi-center, long-term, open-label, follow-up study to assess the long-term use of 
LCM oral solution (a formulation suitable for administration to children; also referred to as 
syrup) for pediatric study participants <6 years of age with epilepsy who have completed either 
EP0034 or SP848. 
Study participants who complete EP0034 or SP848 will be offered participation in EP0151 and 
will have access to open-label follow-up treatment with LCM. 
Lacosamide doses administered in EP0151 must be from 2mg/kg/day to 12mg/kg/day. During 
EP0151 study visits, Investigators will be allowed to increase or decrease the dose of LCM based 
on the Investigator’s clinical judgement to optimize tolerability and seizure control for each 
study participant. The Investigator may maintain the study participant’s LCM dose, decrease the 
dose in decrements of 2mg/kg/day per week to a minimum dose of LCM 2mg/kg/day, or increase 
the dose in increments of 2mg/kg/day per week up to a maximum dose of LCM 12mg/kg/day or 
600mg/day, whichever is lower. 
This study involves a Treatment Period of approximately up to 205 weeks, depending on the age 
of the study participant, and an End of Study Period of approximately 8 weeks (including a 
Taper Period and a Safety Follow-Up Period). Study participants who reach the end of the study 
and choose to continue treatment with LCM may be immediately prescribed LCM. The 
Termination Visit at the end of the Treatment Period will be the last study visit completed for 
study participants who continue treatment with prescribed LCM. Study participants who choose 
not to continue with LCM treatment and who are taking a dose of 3mg/kg/day or higher will 
enter an End of Study Period following completion of the Termination Visit or Early 
Termination Visit, and will gradually taper from LCM treatment during the Taper Period; a Final 
Visit will be conducted 30 days after the final dose of LCM. 
In situations where provision of LCM oral solution in certain participants >6 years of age 
(eg, developmental delay, need for more precise dosing as afforded by oral solution formulation, 
etc.) who may need a longer period of treatment with LCM oral solution, the situation will be 
assessed for approval by UCB on a case-by-case basis following discussions with the 
participant’s physician. 
The end of the study is defined as the date of the last visit of the last study participant in the 
study. 
Number of Participants 
Approximately 80 to 100 study participants are estimated to be eligible for enrollment. 
Treatment Groups and Duration 
The maximum total duration of the study per study participant will be approximately 213 weeks, 
and will include: 
• Treatment Period (up to approximately 205 weeks, depending upon the age of the study 
participant) 
• End of Study Period (up to 8 weeks, consisting of a 4-week Taper Period and 30-day Safety 
Follow-Up Period). 
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Visit 1 for EP0151 will be the same as Visit 13 in EP0034 or SP848. Clinic visits will be 
scheduled approximately every 26 weeks relative to the EP0151 Visit 1 date. Dose modifications 
required for optimization of seizure control or tolerability issues will be addressed in 
Unscheduled Visits or regularly scheduled visits. A visit window of ±7 days relative to Visit 1 is 
applicable for all regularly scheduled visits. 
All study participants in EP0151 will receive LCM. The Investigator may maintain the study 
participant’s LCM dose from previous studies EP0034 or SP848, decrease the dose in 
decrements of 2mg/kg/day per week to a minimum dose of LCM 2mg/kg/day, or increase the 
dose in increments of 2mg/kg/day per week up to a maximum dose of LCM 12mg/kg/day or 
600mg/day, whichever is lower, administered twice per day (BID). 
An interactive voice/web response system (IXRS) should be called any time there is a change in 
LCM dose. 
 
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1.2 
Schema 
A study schematic is presented in Figure 1-1. 
Figure 1-1: Study schematic 
 
FV=final visit; LCM=lacosamide; V=visit, W=week 
Note: During EP0151 study visits, Investigators will be allowed to increase or decrease the dose of LCM to optimize tolerability and seizure control. 
Note: A slower or faster taper is permitted, if medically necessary; however, the maximum duration of tapering should not exceed 6 weeks. 
Previous Study 
Dose              
(EP0034 or SP848)
V1
Termination / 
Early 
Termination 
Visit
FV
12mg/kg/day
12mg/kg/day
11mg/kg/day
11mg/kg/day
10mg/kg/day
10mg/kg/day
9mg/kg/day
9mg/kg/day
8mg/kg/day
8mg/kg/day
7mg/kg/day
7mg/kg/day
6mg/kg/day
6mg/kg/day
5mg/kg/day
5mg/kg/day
4mg/kg/day
4mg/kg/day
3mg/kg/day
3mg/kg/day
2mg/kg/day
2mg/kg/day
W1
WX
Taper W1
Taper W2
Taper W3
Taper W4
Treatment Period  (up to approximately 205 weeks)
End of Study Period
Taper Period
(up to 4 weeks)
Safety Follow Up 
Period (30 days after 
final LCM dose)
V2-VX (unscheduled visits included)
9mg/kg/day 6mg/kg/day 4mg/kg/day 2mg/kg/day
8mg/kg/day 6mg/kg/day 4mg/kg/day 2mg/kg/day
6mg/kg/day 4mg/kg/day 2mg/kg/day 2mg/kg/day
--
--
4mg/kg/day 2mg/kg/day 2mg/kg/day
--
2mg/kg/day 2mg/kg/day
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1.3 
Schedule of Activities 
A tabular scheme of study activities is presented in Table 1-1. 
Table 1-1: 
Schedule of study activities 
Procedure 
Treatment Perioda 
End of Study 
Period 
 
V1b 
V2, V3…VXc 
Termination 
Visit/Early 
Termination 
Visitd 
Final Visite 
Unscheduled 
Visitf 
W0 
W26, 
W52…WXg 
WXh 
Final dose + 
30 days 
NA 
Informed consent 
X 
 
 
 
 
Verification of inclusion/exclusion criteria 
X 
 
 
 
 
Demography 
Xi 
 
 
 
 
Medical history update 
X 
 
 
 
 
Concomitant AEDs 
X 
X 
X 
X 
X 
Concomitant non-AED medications 
X 
X 
X 
X 
X 
Concomitant medical procedures 
X 
X 
X 
X 
X 
Laboratory assessmentsj 
Xk 
X 
X 
X 
 
Call IXRS 
X 
X 
Xl 
Xl 
Xl 
Blood pressure and pulse ratem 
Xk 
X 
X 
X 
 
Body weight and height 
Xk 
X 
X 
X 
 
Dispense LCM  
X 
X 
Xn 
 
 
Review/return LCM 
 
X 
X 
X 
 
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Lacosamide 
 
EP0151 
 
 
 
 
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Table 1-1: 
Schedule of study activities 
Procedure 
Treatment Perioda 
End of Study 
Period 
 
V1b 
V2, V3…VXc 
Termination 
Visit/Early 
Termination 
Visitd 
Final Visite 
Unscheduled 
Visitf 
W0 
W26, 
W52…WXg 
WXh 
Final dose + 
30 days 
NA 
C-SSRSo 
  
 
X 
 
X 
Withdrawal criteria 
 
X 
 
 
 
Adverse event reviewp 
X 
X 
X 
X 
X 
AE=Adverse Event; AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; eCRF=electronic Case Report Form; 
IXRS=Interactive Voice Response System; LCM=lacosamide; NA=Not applicable; V=Visit; W=Week 
a A visit window of ±7 days relative to Visit 1 is applicable for all regularly scheduled visits except for the Final Visit. A clinic visit will occur approximately 
every 26 weeks relative to the EP0151 Visit 1. If necessary, doses may be adjusted during scheduled or unscheduled visits. 
b Visit 1 for EP0151 will be the same as Visit 13/Termination Visit of EP0034 or SP848. Prior to or at Visit 1 of EP0151, the study participant’s informed 
consent will be signed and eligibility assessed, concomitant medications including AEDs will be recorded, AEs will be assessed, and LCM dispensed (call to 
IXRS). 
c The total number of clinic visits will vary between individual study participants, as this study involves a Treatment Period of approximately up to 205 weeks 
depending upon the age of the study participant. Scheduled clinic visits will occur approximately every 26 weeks relative to EP0151 Visit 1 date. 
d The Termination Visit will be performed for participants who remain in the Treatment Period and either reach 6 years of age or who participate in a region 
where marketing application approval is achieved for pediatric patients <4 years of age and LCM oral solution is available (whichever is earliest). An Early 
Termination Visit must be completed for all participants who prematurely discontinue from the study. Study participants who require taper will complete the 
End of Study Period which is completed by a Final Visit. The Final Visit will be completed 30 days (-1/+3 days) after the final dose of LCM. 
e The End of Study Period starts after the Early Termination Visit or Termination Visit. In case of LCM withdrawal and taper, the Investigator may add any other 
AED during the End of Study Period, following the Investigator’s medical judgment. A Final Visit will be completed 30 days (-1/+3 days) after the final dose 
of LCM. 
f An Unscheduled Visit may be performed at the discretion of the Investigator. Such visits may be necessary if the dosage of LCM is to be adjusted in between 
scheduled visits. If an Unscheduled Visit is needed, then the assessments noted will be performed. Additional assessments may be performed at the 
Investigator’s discretion. Please refer to footnote “o” below regarding participants which meet the conditions for administration of the C-SSRS. Participants 
meeting these conditions will have the C-SSRS administered if the Unscheduled Visit is due to a safety or efficacy reason. 
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g The total number of weeks in the Treatment Period will vary between individual study participants, as this study involves a Treatment Period of approximately 
up to 205 weeks, depending upon the age of the study participant. Scheduled clinic visits will occur approximately every 26 weeks relative to EP0151 Visit 1 
date. 
h The week of the Termination Visit/Early Termination Visit will vary between individual study participants, depending on study participant age (for 
Termination Visit) or weeks in study when early termination occurs (for Early Termination Visit). 
i Demography information will be documented from the parent studies EP0034 or SP848. 
j Starting from Visit 2, blood specimens for routine assay of hematology and clinical chemistry testing will be analyzed by the local laboratory affiliated with the 
site. The individual laboratory parameter result data will not be collected in the eCRF; however, the Investigator will report out of range results judged to be 
clinically significant as an AE. 
k Designated procedures conducted at Visit 13/Termination Visit of EP0034 or SP848 will serve as the Baseline data for EP0151. 
l The IXRS should be called for any cases of dose adjustment. 
m Systolic and diastolic blood pressure and pulse rate will be measured in a semi-supine position after 5 minutes rest. 
n Dispensing of LCM will be done at the Termination Visit/Early Termination Visit only if tapering of LCM is required. 
o The “Already Enrolled” version of the C-SSRS should be completed at the Termination Visit or Early Termination Visit if the study participant reaches 6 years 
of age by the time that visit is conducted. Study participants who are ≥6 years of age who require additional treatment with LCM oral solution and are approved 
to continue will be administered the “Already Enrolled” version of the C-SSRS at the first visit (scheduled or unscheduled) which occurs upon the study 
participant reaching 6 years of age. The “Already Enrolled” C-SSRS version will continue to be administered at each subsequent visit (scheduled or 
unscheduled [see footnote “f” above]) up to and including the Termination Visit or Early Termination Visit. 
p If the participant reports an AE which could be due to a cardiac condition, an ECG should be performed. 
 
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2 
INTRODUCTION 
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 newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and pharmacokinetic (PK) characteristics (Herman and 
Pedley, 1998). However, more than 30% of patients have inadequate seizure control on currently 
available AEDs or experience significant adverse drug effects (Beghi and Sander, 2008). 
Therefore, a need remains for AEDs with improved effectiveness and tolerability 
(Shorvon, 2009). 
Lacosamide belongs to a novel class of functionalized amino acids. Lacosamide has proven to be 
an effective and safe adjunctive treatment for POS, with or without secondary generalization, 
based on 3 double-blind, placebo-controlled, multicenter studies (SP667, SP754, and SP755) in 
study participants with difficult-to-control POS. Lacosamide has also been shown to be an 
effective and safe adjunctive treatment over the long term (up to 9 years) for study participants 
with POS. Use of a loading dose for initiation of adjunctive LCM treatment (single loading dose 
of LCM 200mg, followed approximately 12 hours later by LCM 100mg twice daily [200mg/day] 
maintenance dose regimen) is approved in the EU, US, and other countries. 
In the US, oral tablets and oral solution (syrup) of LCM are indicated for the treatment of POS in 
patients ≥4 years of age. Additionally, LCM has been approved in the EU (oral tablets, oral 
solution, and solution for intravenous [iv] infusion), as monotherapy and adjunctive therapy in 
the treatment of POS with or without secondary generalization in patients ≥4 years of age. 
Lacosamide is being evaluated in pediatric study participants ≥1 month to <17 years of age with 
POS in completed and ongoing studies; see Section 2.2.1 for further detail. 
2.1 
Study Rationale 
This open-label extension study was designed to assess the long-term use of LCM (2mg/kg/day 
to 12mg/kg/day) in pediatric study participants <6 years of age with epilepsy, and allow study 
participants treated with LCM in EP0034 or SP848 to continue treatment with LCM until either 
the participant is at least 6 years of age or until LCM oral solution is approved in the 
participating country. 
2.2 
Background 
Lacosamide is a member of a series of functionalized amino acids that were specifically 
synthesized as anticonvulsive drug candidates. Lacosamide’s mode of action is proposed to be 
mediated by a selective enhancement of slow inactivation of voltage-gated sodium channels 
which may explain the anticonvulsant effects of LCM (Rogawski et al, 2015; 
Niespodziany et al, 2012; Errington et al, 2007). 
As of 31 Aug 2019, LCM has been approved in over 70 countries. Lacosamide has been 
approved as monotherapy and adjunctive treatment in patients with POS in the US (4 years and 
older for film-coated tablets and oral solution; 17 years of age and older for intravenous 
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[iv] infusion), Canada (18 years and older for film-coated tablets and iv infusion), EU (4 years 
and older for film-coated tablets, oral solution, and iv infusion), and Japan (4 years and older for 
film-coated tablets, dry syrup, and iv infusion). Currently, LCM is still under development for 
use as monotherapy in other regions and also as iv administration in patients with POS, for 
monotherapy and adjunctive therapy in pediatric patients ≥1 month to <4 years of age with 
epilepsy, and as adjunctive therapy for primary generalized tonic-clonic seizures in adult and 
pediatric patients ≥4 years of age with idiopathic generalized epilepsy. 
In the clinical development program for LCM, safety and tolerability of multiple doses of up to 
LCM 400mg given twice daily (LCM 800mg/day) were evaluated in approximately 700 study 
participants who received LCM in Phase 1 studies. Lacosamide is rapidly and completely 
absorbed after oral administration and has minimal protein-binding properties, thus a low risk of 
displacement drug-drug interactions. Lacosamide is neither a strong inhibitor nor a known 
inducer of the CYP450 enzymes and hence has a low potential for drug-drug interactions. Food 
does not affect the rate and extent of absorption. Peak plasma concentrations occur between 0.5 
and 4 hours after dosing. The PK properties of LCM are proportional to dose, with low 
intraparticipant and interparticipant variability. The terminal half-life of the unchanged drug in 
plasma is approximately 13 hours allowing for a twice-daily dose regimen. The O-desmethyl 
metabolite (referred to as SPM 12809) is excreted in the urine, represents about 30% of the dose, 
and has no known pharmacological activity. After single-dose administration in healthy study 
participants, bioequivalence has been shown between the tablet and solution for iv infusion as 
well as between the tablet and oral solution formulations. 
Further information on LCM preclinical results, as well as the PK, efficacy, and safety profiles, 
can be obtained from the current version of the LCM Investigator’s Brochure. 
2.2.1 
Lacosamide in pediatric studies 
Pellock et al (2012) conducted a systematic review of AEDs used in the treatment of POS. The 
AEDs that were shown to be superior to placebo for the adjunctive treatment of POS in adult 
clinical studies were also shown to be superior to placebo for adjunctive treatment of POS in the 
pediatric clinical studies (study participants >2 years of age) in which they were investigated. 
The efficacy and safety of LCM observed in clinical studies in adults and preclinical data, as 
well as many additional attributes of LCM, render the drug appropriate to investigate in pediatric 
study participants. These attributes include predictable and linear PK, lack of drug-drug 
interactions, easy twice daily dosing, and the availability of 3 different types of formulations in 
multiple strengths (allowing for flexibility in dose range and individualizing treatment). 
Given the demonstrated efficacy and safety of LCM as adjunctive treatment in study participants 
aged ≥16 years with POS, and the experience with other AEDs in pediatric study participants, 
the US Food and Drug Administration (FDA) and European Medicines Authority (EMA) 
determined that it is acceptable to extrapolate the effectiveness of drugs approved for the 
treatment of POS in adults to pediatrics. UCB chose to utilize extrapolation of efficacy from 
adults to the pediatric population (≥4 years of age) for the indication of POS in the US and the 
EU. Based on this extrapolation, the EMA approved this indication on 14 Sep 2017, and the US 
FDA approved this indication (tablets and oral solution only) on 03 Nov 2017. 
Lacosamide is being evaluated in pediatric study participants ≥1 month to ≤17 years of age with 
seizures in completed and ongoing studies. The completed pediatric studies include SP847 
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(open-label, safety, tolerability, and PK study) and SP1047 (PK study for study participants 
prescribed LCM); ongoing pediatric studies include SP848 and EP0034 (open-label, long-term 
safety studies). In SP847, SP848, and EP0034, study participants with POS have received LCM 
oral solution at doses up to 12mg/kg/day based on tolerability. In SP1047, study participants with 
epilepsy received LCM oral tablets (50mg, 100mg, 150mg, or 200mg), or LCM oral solution 
(LCM 10mg/mL) that they had been prescribed for epilepsy and brought with them to the clinic 
for dosing. Preliminary data have not demonstrated any clinically relevant changes in vital signs, 
electrocardiograms (ECGs), or clinical laboratory values; or evidence of cardiac-related 
treatment-emergent adverse events (TEAEs) or body weight changes. SP0967 is an ongoing 
Phase 3, multicenter, double-blind, randomized, PBO-controlled, parallel-group study to evaluate 
the efficacy and safety of LCM oral solution (LCM 8mg/kg/day to 12mg/kg/day, or matching 
PBO) as adjunctive therapy in study participants ≥1 month to <4 years of age with POS. SP0967 
has completed enrollment, and no safety issues have been identified by safety monitoring and an 
external Data Monitoring Committee. EP0060 is a completed study that evaluated the safety and 
tolerability of the LCM iv formulation (infusion duration 15 minutes to 60 minutes) in children 
with epilepsy ≥1 month to <17 years of age. Lacosamide was well tolerated in that study and no 
safety issues were identified. 
2.3 
Benefit/Risk Assessment 
Epilepsy is a condition for which an improved benefit/risk ratio for medicinal products remains a 
challenge; this is especially true for pediatric patients. 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events (AEs) of LCM may be found in the Investigator’s Brochure. 
3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To assess the long-term use of LCM oral 
solution dosed at 2mg/kg/day to 
12mg/kg/day when administered to 
pediatric study participants with epilepsy 
who have completed EP0034 or SP848 
• TEAEs reported by the study participant 
or caregiver or observed by the 
Investigator 
• Withdrawals from study due to TEAEs 
• Withdrawals from study due to SAEs 
• Modal daily dose (mg/kg/day) 
• Maximum daily dose (mg/kg/day) 
LCM=lacosamide; SAE=serious adverse event; TEAE=treatment-emergent adverse event 
4 
STUDY DESIGN 
4.1 
Overall design 
EP0151 is a long-term, open-label, follow-up study for pediatric study participants <6 years of 
age with epilepsy who have previously received LCM in either EP0034 or SP848. Study 
participants who completed EP0034 or SP848 will be offered participation in EP0151 and will 
have access to open-label follow-up treatment with LCM oral solution. 
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Treatment Period 
Visit 1 for EP0151 will be the same as Visit 13 in EP0034 or SP848. Clinic visits are scheduled 
approximately every 26 weeks relative to the EP0151 Visit 1 date. Dose modifications required 
for optimization of seizure control or tolerability issues will be addressed in unscheduled visits or 
regularly scheduled visits. A visit window of ±7 days relative to Visit 1 is applicable for all 
regularly scheduled visits. 
In EP0034 and SP848, study participants received flexible dosing based on the Investigator’s 
clinical judgement, which ranged from a minimum dose of LCM 2mg/kg/day to a maximum 
dose of 12mg/kg/day or 600mg/day, whichever was lower. During EP0151 study visits, 
Investigators will be allowed to increase or decrease the dose of LCM to optimize tolerability 
and seizure control for each study participant. The Investigator may maintain the study 
participant’s LCM dose, decrease the dose in decrements of 2mg/kg/day per week to a minimum 
dose of LCM 2mg/kg/day, or increase the dose in increments of 2mg/kg/day per week up to a 
maximum dose of LCM 12mg/kg/day or 600mg/day, whichever is lower. Lacosamide doses 
administered in this study must be from 2mg/kg/day to 12mg/kg/day. An IXRS will be used and 
should be called any time there is a dose increase or dose reduction (Figure 1-1). 
Early Termination Visit with tapering of LCM 
Study participants who discontinue prematurely from EP0151 and who will not continue further 
treatment with LCM should gradually taper LCM. These study participants will perform an Early 
Termination Visit followed by the visits required for the End of Study Period. Study participants 
should be tapered off LCM at the recommended decrements (Table 6-2). The Taper Period is up 
to 4 weeks; a slower taper or faster taper is permitted, if medically necessary; however, the 
maximum duration of tapering should not exceed 6 weeks. All study participants who taper off 
LCM will attend a Final Visit 30 days after the final dose of LCM. In the case of LCM 
withdrawal and taper, the Investigator is allowed to add any other antiepileptic drugs (AEDs) 
during the End of Study Period, following the Investigator’s medical judgment. 
Termination Visit 
Study participants who remain in the Treatment Period and either reach 6 years of age or who 
participate in a region where marketing application approval is achieved for pediatric patients 
<4 years of age and LCM oral solution is available (whichever is earliest) will have met the 
conditions for completing the study. A Termination Visit will be performed for these study 
participants at the time of the next scheduled visit. Study participants who reach the end of the 
study and choose to continue treatment with LCM may be immediately prescribed LCM. The 
Termination Visit will be the last study visit completed for study participants who continue 
treatment with prescribed LCM. Study participants who choose not to continue with LCM 
treatment and who are taking a dose of LCM 3mg/kg/day or higher will enter an End of Study 
Period following completion of the Termination Visit, and will gradually taper from LCM 
treatment during the Taper Period; a Final Visit will be conducted 30 days after the final dose of 
LCM. 
In situations where provision of LCM oral solution in certain participants >6 years of age 
(eg, developmental delay, need for more precise dosing as afforded by oral solution formulation, 
etc.) who may need a longer period of treatment with LCM oral solution, the situation will be 
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assessed for approval by UCB on a case-by-case basis following discussions with the 
participant’s physician. 
The maximum total duration of the study will be approximately 213 weeks, including an 
approximate 205-week Treatment Period and up to an 8 week End of Study Period (4-week 
Taper Period and 30-day Safety Follow-up Period). The end of the study is defined as the date of 
the last visit of the last study participant in the study. 
4.2 
Scientific rationale for study design 
EP0151 is an open-label extension study designed to assess the long-term use of LCM (ranging 
in dose between LCM 2mg/kg/day to 12mg/kg/day) in pediatric study participants <6 years of 
age with epilepsy who have previously completed EP0034 or SP848. 
EP0151 will allow study participants treated with LCM in EP0034 or SP848 to continue 
treatment with LCM until either the study participant reaches 6 years of age or until marketing 
application approval is achieved for pediatric patients <4 years of age in the region of 
participation and LCM oral solution is available (whichever is earliest). Cases where provision of 
LCM oral solution that do not meet these set criteria (eg, developmental delay, need for more 
precise dosing as afforded by LCM oral solution formulation, etc.) will be assessed on a 
case-by-case basis. 
4.3 
Justification for dose 
Dose selection in EP0151 is based on the doses offered in the previous studies, EP0034 or 
SP848. During EP0151, Investigators will be allowed to increase or decrease the dose of LCM to 
optimize tolerability and seizure reduction for each study participant (Section 6.6). Lacosamide 
doses may be adjusted from a minimum dose of LCM 2mg/kg/day up to a maximum of 
12mg/kg/day or 600mg/day, whichever is lower. This dose range is anticipated to be clinically 
safe and effective for monotherapy. 
4.4 
End of study definition 
Study participants who remain in the Treatment Period and either reach 6 years of age or who 
participate in a region where marketing application approval is achieved for pediatric patients 
<4 years of age and LCM oral solution is available (whichever is earliest) will have met the 
conditions for completing the study. 
The end of the study is defined as the date of the last visit of the last study participant in the 
study. 
5 
STUDY POPULATION 
Approximately 80 to100 participants from SP848 and EP0034 may be eligible to enroll in this 
open-label study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
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5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant is male or female, aged <6 years at the time of signing the Informed Consent 
Form (ICF). 
Type of participant and disease characteristics 
2. Participant has completed participation in EP0034 or SP848. 
3. Participant is expected to benefit from participation, in the opinion of the Investigator. 
Informed consent 
4. An Independent Ethics Committee (IEC) approved written ICF is signed and dated by the 
participant or by the parent(s) or legal representative. The ICF or a specific Assent form, 
where required, will be signed and dated by minors (see Section 10.1.3). 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study. 
2. Participant has a known hypersensitivity to any components of the study medication or 
comparative drugs as stated in this protocol. 
Prior/Concomitant therapy 
3. Participant is receiving any investigational drugs or using any experimental devices in 
addition to LCM. 
Prior/Concurrent clinical study experience 
4. Participant meets a mandatory withdrawal criterion (ie, MUST withdraw criterion) for 
EP0034 or SP848, or is experiencing an ongoing serious AE (SAE). 
Other exclusions 
5. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy 
that, in the opinion of the Investigator or Medical Monitor, contraindicates participation in 
the study. 
5.3 
Lifestyle restrictions 
No restrictions are required. 
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5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), or placebo 
intended to be administered to a study participant according to the study protocol. 
6.1 
Treatments administered 
A summary of treatments administered is provided in Table 6-1. 
Table 6-1: 
Summary of treatments administered 
ARM Name 
 
Intervention name 
Lacosamide 
Type 
Drug 
Dose formulation 
Oral solution 
Unit dose strength(s) 
LCM 10mg/mL 
Dosage level(s) 
Minimum dose of 2mg/kg/day to maximum 
dose of 12mg/kg/day or 600mg/day, 
whichever is lower, administered BID in the 
morning and evening. 
Route of administration 
Oral use 
Use 
Active open-label 
IMP and NIMP 
IMP 
Sourcing 
Provided by UCB 
Packaging and labeling 
Clinical drug supplies will be labeled in 
accordance with the current ICH guidelines 
on GCP and GMP and will include any 
locally required statements. If necessary, 
labels will be translated into the local 
language. 
Primary packaging: bottles with 
child-resistant closure 
Current/former name(s) or alias(es) 
Not applicable 
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BID=twice per day; GCP=Good Clinical Practice; GMP=Good Manufacturing Practice; ICH=International 
Council for Harmonisation; IMP=investigational medicinal product; LCM=lacosamide; NIMP=non-IMP 
Study participants will receive LCM oral solution administered BID from a minimum dose of 
2mg/kg/day to a maximum dose of 12mg/kg/day or 600mg/day, whichever is lower, based on 
optimization of seizure control and tolerability in the judgement of the Investigator. 
The Investigator may maintain the LCM dose administered to the study participant in the 
previous study, decrease the dose to a minimum dose of LCM 2mg/kg/day, or increase the dose 
to a maximum dose of LCM 12mg/kg/day or 600mg/day, whichever is lower. An IXRS will be 
used and should be called any time there is a dose increase or dose reduction. 
Study participants who are taking a dose of 3mg/kg/day or higher and who either withdraw 
during the study or complete the study and do not continue treatment with LCM should taper off 
LCM. 
It is recommended that the dose be tapered gradually in weekly decrements according to  
Table 6-2. A slower taper is permitted, if medically necessary, but should not exceed 6 weeks. In 
case of an emergency, a faster taper is permitted, after discussion with the Medical Monitor 
whenever possible. 
Table 6-2: 
Lacosamide doses for Taper Period 
LCM dose achieved 
LCM doses for Taper Period 
Week 1 
Week 2 
Week 3 
Week 4 
11-12mg/kg/day 
9mg/kg/day 
6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
9-10mg/kg/day 
8mg/kg/day 
6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
7-8mg/kg/day 
6mg/kg/day 
4mg/kd/day 
2mg/kg/day 
2mg/kg/day 
5-6mg/kg/day 
4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
---- 
3-4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
---- 
---- 
LCM=lacosamide 
6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator (or designee) must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions, with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the investigational medicinal product (IMP) Handling Manual. 
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The Investigator (or designee) will instruct the participant to store the study medication 
following the instructions on the label. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the IMP Handling Manual. 
6.2.1 
Drug accountability 
The Drug Accountability form will be used to record study medication dispensing and return 
information on a by-participant basis and will serve as source documentation during the course 
of the study. Details of any study medication 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 study medication until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the study medication is used only in accordance with this 
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 study medication must be 
reconciled and either destroyed at the site according to local laws, regulations, and UCB standard 
operating procedures 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. 
6.3 
Measures to minimize bias: randomization and blinding 
This is an open-label study. Therefore, randomization is not applicable and no blinding is 
required. 
Study participant numbers that were utilized in SP848 and EP0034 will continue to be used in 
EP0151. The study participant number must be incorporated into the electronic Case Report 
Form (eCRF). 
The IXRS will generate individual assignments for kits of study medication, as appropriate, 
according to the visit schedule and assigned dose. Participant numbers and kit numbers will be 
tracked via the IXRS. The IXRS will allocate kit numbers to the participant based on the 
participant number during the course of the study. 
The participant number will be required in all communication between the Investigator or 
designee and the IXRS regarding a particular participant. 
6.4 
Treatment compliance 
At each visit after study medication is dispensed, participants must return all unused study 
medication and empty study medication containers. Drug accountability must be done in the 
participant’s presence in order to obtain explanations regarding discrepancies in compliance with 
the dosing regimen. Drug accountability must be recorded on the Drug Accountability form. 
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If a participant is found to be persistently noncompliant (defined as less than 75% or more than 
125% compliant with the dosage schedule), the Sponsor, in conjunction with the Investigator, 
will make a decision as to whether the participant should be withdrawn from the study. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are permitted during the study: 
• If needed to optimize tolerability and seizure reduction in selected 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 participant lives. New concomitant 
AEDs should be added only when the participant has not optimally or adequately responded 
to a maximum tolerated dose of LCM. 
• Implantation of and/or changes in vagal nerve stimulation settings are permitted. 
• The Investigator must contact the Medical Monitor if surgery is planned for any participant. 
In general, it is not necessary to discontinue LCM for participants undergoing surgery, 
although each case must be discussed on a case-by-case basis. The Investigator must contact 
the Medical Monitor before re-starting LCM after a surgery. 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications are prohibited during the study: 
• Clozapine 
• Monoamine oxidase-A inhibitors 
• Cannabidiols (when not approved or indicated for epilepsy by local health authority) 
6.5.3 
Rescue medication 
Therapy that becomes necessary, in the Investigator’s opinion, during the course of the study 
must not be refused to a participant, even if described above as a therapy that is expressly not 
permitted in the frame of this study. The study participant's participation in this study may be 
discontinued in such a case. 
Any rescue medication is allowed. The date and time of rescue medication administration, as 
well as the name and dosage regimen of the rescue medication, must be recorded in the eCRF. 
6.6 
Dose modification 
In case a dose modification is necessary, the study treatment will be administered as described in 
Section 6.1. The IXRS should be called any time there is a dose increase or dose reduction. 
6.7 
Criteria for study hold or dosing stoppage 
Selected data, including SAEs and AEs, from this study will be reviewed periodically to detect 
as early as possible any safety concern(s) related to the study medication and will make 
recommendations on the continuation or modification of the study as appropriate. 
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6.8 
Treatment after the end of the study 
There is no treatment planned after the end of the study. 
Study participants who reach the end of the study and choose to continue treatment with LCM 
may be immediately prescribed LCM following the Termination Visit. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study treatment for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Figure 7-1 or Figure 7-2 
or if the Investigator believes that it is in best interest of the participant. 
Study medication will be discontinued immediately and permanently for a study participant if 
liver chemistry stopping criteria are met. 
Figure 7-1: Liver chemistry stopping criteria and increased monitoring algorithm 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal 
Note: Algorithm for continued therapy with increased liver chemistry monitoring can be found in Figure 7-2. 
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Figure 7-2: Liver chemistry increased monitoring algorithm with continued study 
intervention for participants with ALT 3xULN but <8xULN 
 
ALT=alanine aminotransferase; AST= aspartate aminotransferase; bili=bilirubin; INR=international normalized 
ratio; SAE=serious adverse event; ULN=upper limit of normal 
Specific assessments and follow up actions for potential drug-induced liver injury are provided 
in Appendix 6 (Section 10.6). 
Study participants with potential drug-induced liver injury (PDILI) must be assessed to 
determine if study medication 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 study medication: 
• Participants with either of the following: 
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5x upper limit of 
normal (ULN) 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of study medication: 
• Participants with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
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upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below allows for participants to continue on study medication at the 
discretion of the Investigator: 
• Participants 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). 
7.1.2 
QTc stopping criteria 
If the participant reports an AE which could be due to a cardiac condition, an ECG should be 
performed. 
A participant with corrected QT interval (QTc)>500 msec OR Uncorrected QT>600 msec based 
on the average of triplicate ECG readings will be withdrawn from study medication. 
Any new clinically relevant finding should be reported as an AE. 
7.2 
Participant discontinuation/withdrawal from the study 
Participants or the participant’s legal representatives are free to withdraw the participant from the 
study at any time, without prejudice to their continued care. 
A participant may withdraw from the study at any time at his/her own request or at the study 
participant’s legal representative’s request, or may be withdrawn at any time at the discretion of 
the Investigator for safety, behavioral, compliance, or administrative reasons. 
If a participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
See the Schedule of Activities (Table 1-1) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Participants must be withdrawn from this study if any of the following events occur: 
1. Participant experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the Investigator, preclude further participation in the study. 
2. The Sponsor or a regulatory agency requests withdrawal of the participant. 
3. Participant is unwilling or unable to continue or legal representative is unwilling or unable to 
allow the participant to continue in the study. 
4. Investigator decides that withdrawal from further participation would be in the participant’s 
best interest. 
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Participants should be withdrawn from the study if any of the following events occur: 
1. Participant develops an illness that would interfere with his/her continued participation 
2. Participant and/or legal representative is noncompliant with study procedures or medication, 
in the opinion of the Investigator 
3. Participant takes prohibited concomitant medications as defined in this protocol 
(Section 6.5.2) 
4. Participant withdraws his/her consent 
5. Any clinically relevant change in medical or psychiatric condition (if, in the opinion of the 
Investigator, the condition warrants discontinuation from the study) 
Study Participants discontinuing LCM for any reason should taper off medication as described in 
Section 4.1. Whenever possible, these cases should be discussed with the Medical Monitor prior 
to withdrawing the participant from the study 
7.3 
Lost to follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (at least 1 phone call and 1 written message 
to the participant), and document his/her effort (date and summary of the phone call and copy 
of the written message in the source documents), to complete the final evaluation. All results 
of these evaluations and observations, together with a narrative description of the reason(s) 
for removing the participant, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up documented in the eCRF. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Table 1-1). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Table 1-1), is essential and required for study conduct. 
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All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Blood collected from each participant over the duration of the study, including any extra 
assessments, will be done respecting the requirements for collection and volume endorsed for use 
by the local laboratory. Blood will be collected for laboratory assessments during scheduled 
visits, which will occur infrequently (approximately every 26 weeks). Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples. 
8.1 
Efficacy assessments 
Not applicable. 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Table 1-1). 
8.2.1 
Vital signs 
Pulse rate and blood pressure will be assessed according to the Schedule of Activities 
(Table 1-1). 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
systolic and diastolic blood pressure, and pulse rate. 
8.2.2 
Biometric parameters 
Biometric parameters of height and weight will be measured according to the Schedule of 
Activities Table 1-1). 
8.2.3 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency. Starting from Visit 2, blood specimens for 
routine assay of hematology and clinical chemistry testing will be analyzed by the local 
laboratory affiliated with the site. The individual laboratory parameter result data will not be 
collected in the eCRF; however, the Investigator will report any out of range results judged to be 
clinically significant as an AE. 
The Investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study medication should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
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If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the Schedule of Activities (Table 1-1). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
8.2.4 
Suicidal risk monitoring 
Lacosamide is considered to be an antiepileptic. There has been some concern that antiepileptics 
may be associated with an increased risk of suicidal ideation or behavior when given to some 
participants with epilepsy. Although this study treatment or other similar drugs in this class have 
not been shown to be associated with an increased risk of suicidal thinking or behavior when 
given to pediatric participants with epilepsy, UCB considers it important to monitor for such 
events before and during this clinical study. 
Study participants being treated with LCM should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing LCM in study participants who experience signs 
of suicidal ideation or behavior. 
Where appropriate, suicidality will be assessed by trained study personnel using the 
Columbia-Suicide Severity Rating Scale (C-SSRS; Columbia University Medical Center, 2008). 
The C-SSRS will be completed at the scheduled timepoints as described in the Schedule of 
Activities (Table 1-1). The C-SSRS is not validated for study participants <6 years of age and 
will not be used for this population. Study participants 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. Parents and caregivers 
should be advised accordingly and effort should be made at clinic visits to specifically assess 
potential depression. Families and caregivers of study participants being treated with LCM 
should be instructed to monitor participants for the emergence of unusual changes in behavior, as 
well as the emergence of suicidal ideation and behavior, and to report such symptoms 
immediately to the study Investigator. 
The “Already Enrolled” version of the C-SSRS should be completed at the Termination Visit or 
Early Termination Visit if the participant reaches 6 years of age by the time that visit is 
conducted. Participants who are ≥6 years of age who require additional treatment with LCM oral 
solution (Section 4.1 ) and are approved to continue will be administered the “Already Enrolled” 
version of the C-SSRS at the first visit (scheduled or unscheduled) which occurs upon reaching 6 
years of age. The “Already Enrolled” C-SSRS version will continue to be administered at each 
subsequent visit (scheduled or unscheduled) up to and including the Termination or Early 
Termination Visit. 
8.3 
Adverse events and serious adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
participant to discontinue the study medication (see Section 7). 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF until the end of the study at the 
time points specified in the Schedule of Activities (Table 1-1). 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no study medication was taken but specific study 
procedures were conducted. This includes all AEs not present prior to the Visit 1 and all AEs that 
recurred or worsened after Visit 1. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the study 
medication), up to 30 days from the end of the study for each study participant, and to also 
inform study participants of the need to inform the Investigator of any SAE within this period. 
Serious AEs that the Investigator thinks may be associated with the study medication must be 
reported to UCB regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports is provided in Appendix 3. 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the study participant or caregiver is the preferred method to 
inquire about AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest and 
AEs of special monitoring (as defined in Section 8.3.5 and Section 8.3.6, respectively), will be 
followed until resolution, stabilization, the Investigator determines that it is no longer clinically 
significant, the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authorities, IECs, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IEC, if appropriate according to local 
requirements. 
8.3.5 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound.For LCM, the following events require immediate 
reporting (within 24 hours regardless of seriousness) to UCB: 
• Hy’s Law 
−  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 (ie, without waiting for any additional etiologic investigations 
to have been concluded). Follow-up information should be reported if an alternative 
etiology is identified during investigation and monitoring of the participant. 
• The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (2nd degree Type I and II and 3rd degree), and marked bradycardia (<45 beats/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 United States 
Food and Drug Administration: 
An AE or laboratory value (as defined below) suggestive of internal organ involvement 
(including, but not limited to, hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, 
pancreatitis, myositis, arthritis, or hematologic system involvement) combined with at least 1 
of the following: fever, rash, lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
− Eosinophils % ≥10% 
− Eosinophils absolute ≥0.5G/L 
− Neutrophils absolute <1.5G/L 
− Platelets ≤100G/L 
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− ALT ≥2xULN 
− AST ≥2xULN 
8.3.6 
Adverse events of special monitoring 
An AE of special monitoring is a product-specific AE, adverse reaction, or safety topic requiring 
special monitoring by UCB. 
For LCM, events of epileptic spasms require immediate reporting (within 24 hours regardless of 
seriousness) to UCB.Anticipated serious adverse events 
The following SAEs (Table 8-1) are anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure. 
This list does not change the Investigator’s obligation to report all SAEs (including anticipated 
SAEs) as detailed in Section 8.3.1 and Section 10.3. 
Table 8-1: 
Anticipated SAEs for the pediatric epilepsy population 
MedDRA SOC 
MedDRA PT 
Congenital, familial and genetic disorders 
Teratogenicity 
General disorders and administration site conditions 
Sudden unexplained death in epilepsy 
Nervous system disorders 
Convulsion 
 
Incontinence 
 
Status epilepticus 
Psychiatric disorders 
Psychotic behavior 
 
Abnormal behavior 
 
Anxiety 
 
Sleep disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SOC=system organ class; 
SAE=serious adverse event 
8.4 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that Investigators, clinical study participants, 
regulatory authorities, and 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 
representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, ECG results) for which data will be periodically reviewed during the course 
of the study. 
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8.5 
Treatment of overdose 
Overdose events are only considered AEs or SAEs if there are associated clinical signs and 
symptoms or if the act of taking the excess study medication itself is an AE or SAE (eg, suicide 
attempt). 
Excessive dosing (beyond that prescribed in the protocol and including overdose 
[≥14mg/kg/day]) should be recorded in the eCRF. Any SAE or non-serious AE associated with 
excessive dosing must be followed as any other SAE or non-serious AE. These events are only 
considered AEs or SAEs if there are associated clinical signs and symptoms. 
UCB does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the study participant for any AE/SAE and laboratory abnormalities until 
return to normal and for at least 3 days. 
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.6 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.10 
Medical resource utilization and health economics 
Medical resource utilization and health economics are not evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan. 
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9.1 
Definition of analysis sets 
The primary analysis set will be the Safety Set, which is defined as all participants who sign an 
ICF, and take at least 1 dose of study medication. This analysis set will be used for summaries of 
all variables. 
9.2 
General statistical considerations 
Descriptive statistics will be used to provide an overview of the primary variables. For 
categorical parameters, the number and percentage of study participants in each category will be 
presented. The denominator for percentages will be based on the number of study participants 
appropriate for the purpose of analysis. For continuous variables, descriptive statistics will 
include number of study participants, mean, standard deviation, median, minimum, and 
maximum. No statistical hypothesis testing will be performed. Baseline values for primary 
variables will be determined from Baseline values of the EP0034 or SP848 study, unless 
otherwise noted. 
All computations for the analyses will be performed using SAS® version 9.4 or later (SAS 
Institute, NC, USA). 
9.3 
Planned safety analyses 
9.3.1 
Safety analyses 
Treatment-emergent AEs will be defined as those events which started on or after the date of first 
dose of LCM in EP0151, or events for which severity worsened on or after the date of first dose 
of LCM in EP0151. Adverse events which occur within 30 days after final dose of LCM in 
EP0151 will be considered treatment-emergent. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities® 
(MedDRA). Pretreatment AEs, TEAEs, non-serious TEAEs, withdrawals due to TEAEs, 
withdrawals due to SAEs, and SAEs will be tabulated by system organ class and preferred term. 
The incidence of TEAEs will also be summarized by intensity and by relationship to LCM. In 
addition, all AEs will be listed. 
Long-term use of LCM will be assessed by modal daily dose (mg/kg/day) and maximum daily 
dose (mg/kg/day). These doses will be summarized using descriptive statistics, along with 
duration of exposure (days). 
Actual measurements and changes from Baseline in vital signs, body weight, height, and 
calculated BMI will be summarized descriptively by visit. In addition, shift tables may be used to 
evaluate the number and percent of study participants having a different post-Baseline status 
when compared with their Baseline status. 
The endpoints for assessment of long-term use include TEAEs, study participant withdrawals 
due to TEAEs and SAEs, modal daily dose, and maximum daily dose. Available data related to 
these measurements will be presented in participant data listings. 
Responses to the C-SSRS will be presented in participant data listings. 
9.4 
Handling of protocol deviations 
All data will be used to the maximum possible extent, but without any imputations for missing 
data for any parameter. Important protocol deviations are deviations from the protocol that could 
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potentially have a meaningful impact on study conduct or on the key safety outcomes for an 
individual study participant. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the appropriate 
protocol-specific document (eg, the Specification of Important Protocol Deviations). To the 
extent feasible, rules for identifying protocol deviations will be defined without review of the 
data and without consideration of the frequency of occurrence of such deviations. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock. 
9.5 
Handling of dropouts or missing data 
For evaluation of safety variables, study participants who prematurely discontinue the study will 
be evaluated based on the data collected at each visit attended. 
9.6 
Planned interim analysis and data monitoring 
No formal interim analysis or Data Monitoring Committee is planned. However, data may be 
reported prior to the completion of this study to support annual reports, regulatory submissions, 
and publications. 
9.7 
Determination of sample size 
No formal sample size calculations have been performed for this study, as there are no statistical 
hypotheses being tested. The sample size will be determined by the number of participants in 
EP0034 or SP848 who have been treated with LCM that are eligible to enter this open-label 
follow-up study. It is anticipated that approximately 80 to100 participants who completed 
EP0034 or SP848 will participate in this follow-up study. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IEC, as defined in local regulations, 
International Council for Harmonisation (ICH)-Good Clinical Practice (GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IEC that complies with the 
requirements of the current ICH-GCP version or applicable country-specific regulations will be 
responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, 
Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), advertisement (if 
applicable), and all other participant-related documents to be used for the study to the IEC for its 
review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IEC for the protocol. 
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The Investigator will also promptly report to the IEC all changes in the study, all unanticipated 
problems involving risks to participants or others, and any protocol deviations, to eliminate 
immediate hazards to participants. 
The Investigator will not make any changes in the study or study conduct without IEC approval, 
except where necessary to eliminate apparent immediate hazards to the participants. 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 IEC as allowed. 
As part of the IEC requirements for continuing review of approved studies, the Investigator will 
be responsible for submitting periodic progress reports to the IEC (based on IEC requirements), 
at intervals appropriate to the degree of participant risk involved, but no less than once per year. 
The Investigator should provide a final report to the IEC following study completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IEC will also be informed by the Investigator or the Sponsor, as specified by the 
applicable regulatory requirements in each concerned country. Where applicable, Investigators 
are to provide the Sponsor (or its representative) with evidence of such IEC notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the Investigator and/or CRO agreements, as applicable. 
10.1.3 
Informed consent process 
Participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. When possible or as required according to local IEC, 
assent also will be obtained from the study participant. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee). Each participant will have the opportunity to discuss the study and its alternatives 
with the Investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The participant or his/her legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, each participant must 
consent to direct access to his/her medical records for study-related monitoring, auditing, IEC 
review, and regulatory inspection. 
If the ICF is amended during the study, the Investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IEC and use of the amended form. 
The participant may withdraw his/her consent to participate in the study at any time. A 
participant is considered as enrolled in the study when he/she has signed the ICF. An eCRF must 
not be started, nor may any study specific procedure be performed for a given participant, 
without having obtained his/her written consent to participate in the study. 
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10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the participant number. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
participant’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 participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Data quality assurance 
All participant data relating to the study will be recorded on a printed or eCRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the Investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. 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. 
10.1.5.1 
Case Report Form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
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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. 
10.1.5.2 
Apps 
No Apps will be used in this study. 
10.1.6 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, or video, 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 study participant’s source documents. 
The Investigator will facilitate the process for enabling the Monitor to compare the content of 
printouts and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.7 
Study and site Closure 
The Sponsor (or designee) reserves the right to close a study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IEC or local 
health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
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• Discontinuation of further study medication development 
10.1.8 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.4 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information 
Not applicable. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver safety – suggested actions and follow-up 
assessments 
Participants with potential drug-induced liver injury must be assessed to determine if study 
medication must be discontinued. In addition, all concomitant medications and herbal 
supplements that are not medically necessary should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury 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 study medication discontinuation and/or participant 
withdrawal (if applicable), must be recorded in the source documents. The eCRF must document 
the primary reason for discontinuation of study medication and withdrawal from the study. 
A specific monitoring plan must be agreed between the UCB Study Physician and the 
Investigator for study participants who have ALT>5ULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values)(see Table 10-1 
and Table 10-2). 
Phase 3-4 liver chemistry stopping criteria are designed to assure participant safety and to 
evaluate liver event etiology. 
Table 10-1: Phase 3-4 liver chemistry stopping criteria and follow-up 
assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT8xULN 
ALT increase 
ALT5xULN but <8xULN persists for 2 weeks 
ALT3xULN but <5xULN persists for 4 weeks 
Bilirubina,b 
ALT3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR b 
ALT3xULN and INR>1.5, if INR measured 
Cannot 
monitor 
ALT5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomaticc 
ALT3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity 
Suggested Actions and Follow up Assessments 
Actions 
Follow-up Assessments 
• 
Immediately discontinue study medication 
• 
Report the event to UCB within 24 hours 
• 
Complete the Liver Event eCRF, and complete 
an SAE data collection tool if the event also 
met the criteria for an SAE b 
• 
Viral hepatitis serologyd 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward trend 
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Table 10-1: Phase 3-4 liver chemistry stopping criteria and follow-up 
assessments 
Liver Chemistry Stopping Criteria 
• 
Perform liver chemistry follow-up assessments 
• 
Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to 
baseline (see MONITORING) 
• 
Do not restart/rechallenge participant with 
study medication unless allowed per protocol 
and UCB approval is granted 
• 
If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
medication and continue participant in the study 
for any protocol specified follow up 
assessmentsConsider the need for a toxicology 
screening 
 
MONITORING: 
For bilirubin or INR criteria 
• 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow-up assessments 
within 24 hours 
• 
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline 
• 
A specialist or hepatology consultation is 
recommended 
For all other criteria  
• 
Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver chemistry follow-up assessments 
within 24 to 72 hours 
• 
Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline 
• 
Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen), 
quantitative hepatitis B DNA and hepatitis 
delta antibodye 
• 
Obtain blood sample for PK analysisf 
• 
Serum CPK and LDH 
• 
Fractionate bilirubin, if total bilirubin 
 2xULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury (eg, 
fatigue, nausea, vomiting, right upper 
quadrant pain), or hypersensitivity, on the 
AE report form 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the Concomitant Medications eCRF. 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total IgG or gamma globulins 
• 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week [James, 2009]) 
NOTE: Not required in China. 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver 
Biopsy eCRFs 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; 
DNA=deoxyribonucleic acid; eCRF=electronic Case Report Form; HBcAb=hepatitis B core antibody; 
HBsAg=hepatitis B surface antigen; HPLC=high performance liquid chromatography; IgG=immunoglobulin G; 
IgM= immunoglobulin M; INR=internal normalized ratio; LDH=lactate dehydrogenase; PCR=polymerase chain 
reaction; PK=pharmacokinetic; RNA=ribonucleic acid; ULN=upper limit of normal; SAE=serious adverse event 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study medication if ALT ≥3xULN and bilirubin ≥2xULN. Additionally, if 
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serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
b All events of ALT≥3xULN and bilirubin≥2xULN (>35% direct bilirubin) or ALT≥3xULN and INR>1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not 
apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 
d Includes: Hepatitis A IgM antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM antibody; 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and 
hepatitis E IgM antibody. 
e If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) (Le Gal, 2005). 
f PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study medication prior to 
the PK blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the participant’s 
best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected 
in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the Study Reference Manual. 
Table 10-2: Phase 3-4 liver chemistry increased monitoring criteria with 
continued study medication 
Liver Chemistry Increased Monitoring Criteria 
Criteria 
Actions 
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and can be monitored 
weekly for 2 weeks 
OR 
ALT3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and can be monitored 
weekly for 4 weeks 
• 
Notify the UCB Medical Monitor within 24 hours of 
learning of the abnormality to discuss study 
participant safety 
• 
Participant can continue study medication 
• 
Participant must return weekly for repeat liver 
chemistry tests (ALT, AST, alkaline phosphatase, 
bilirubin) until the abnormalities resolve, stabilize, or 
return to baseline 
• 
If at any time, the participant meets liver chemistry 
stopping criteria, proceed as described in Table 10-1 
• 
If ALT decreases from ALT5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly 
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistry tests resolve, stabilize, or return 
to baseline 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal 
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10.7 
Appendix 7: Medical device adverse events, adverse device 
effects, serious adverse events and device deficiencies: 
definition and procedures for recording, evaluating, follow-up, 
and reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid alert procedures 
Not applicable. 
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10.9 
Appendix 9: Country-specific requirements 
Not applicable. 
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10.10 
Appendix 10: Abbreviations and trademarks 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice per day 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IXRS 
interactive voice/web response system 
LCM 
lacosamide 
MedDRA 
Medical Dictionary for Regulatory Activities® 
PK 
pharmacokinetic 
POS 
partial-onset seizures 
QTc 
corrected QT interval 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
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10.11 
Appendix 11: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
 
 
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11 
REFERENCES 
Beghi E, Sander JW. The natural history and prognosis of epilepsy. In: Engel J Jr, Pedley TA, 
editors. Epilepsy: A Comprehensive Textbook. 2nd ed. Philadelphia: Lippincott William and 
Wilkins; 2008. p. 65-70. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed 18 Mar 2020. 
Dichek B. Epilepsy: an ancient ailment that still eludes a cure. Scrip Magazine. 1999;76:9-11. 
Errington AC, Stöhr T, Heers C, Lees G. The investigational anticonvulsant lacosamide 
selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol. 
2008 Jan;73(1):157-69. Epub 2007 Oct 16. 
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280(8):693-4. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and 
Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns 
of Virological Response to Interferon Therapy in Chronically Infected Patients. J Clin Microbiol. 
2005;43(5):2363–2369. 
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. 
Niespodziany I, Leclere N, Foerch P, Wolff C. Comparative study of lacosamide and classic 
sodium channel blocking antiepileptic drugs on sodium channel slow inactivation. J Neurosci 
Res. 2012;9:436–443. 
Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of 
antiepileptic drugs in adults predicts efficacy in children: A systematic review. Neurology. 
2012;79;1482-9. 
Perucca E. Established antiepileptic drugs. Baillieres Clin Neurol. 1996;5(4):693-722. 
Rogawski MA, Tofighy A, White HS, Matagne A, Wolff C. Current understanding of the 
mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res. 2015 Feb;110:189-205. 
Epub 2014 Dec 03. 
Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: The second 50 years, 
1959-2009. Epilepsia. 2009;50 Suppl 3:93-130. 
 
 
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SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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SAP_001.pdf: 
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08 Dec 2020 
Statistical Analysis Plan 
Lacosamide 
EP0151 
Confidential 
Page 1 of 25 
STATISTICAL ANALYSIS PLAN 
Study: EP0151 
Product: Lacosamide 
A MULTICENTER, OPEN-LABEL, FOLLOW-UP STUDY TO 
ASSESS THE LONG-TERM USE OF ORAL LACOSAMIDE IN 
STUDY PARTICIPANTS WHO COMPLETED EP0034 OR SP848 
AND RECEIVED LACOSAMIDE TREATMENT  
LONG-TERM USE OF ORAL LACOSAMIDE IN PEDIATRIC 
STUDY PARTICIPANTS WITH EPILEPSY 
Sponsor Name: UCB Biopharma SRL 
Legal Registered Address: Allée de la Recherche 60, 1070 Brussels, Belgium 
Regulatory Agency Identifier Number(s): 
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. 
Registry 
ID 
Eudra CT Number 
2020-001478-30 
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TABLE OF CONTENTS 
VERSION HISTORY ................................................................................................................ 4 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1 
INTRODUCTION ............................................................................................................. 6 
1.1 
Objectives and Estimands/Endpoints ............................................................................. 6 
1.2 
Study design ................................................................................................................... 6 
2 
STATISTICAL HYPOTHESES ........................................................................................ 7 
3 
SAMPLE SIZE DETERMINATION ................................................................................ 7 
4 
POPULATIONS FOR ANALYSIS ................................................................................... 7 
5 
STATISTICAL ANALYSES ............................................................................................ 7 
5.1 
General Considerations .................................................................................................. 7 
5.1.1 
Handling of missing data ....................................................................................... 8 
5.1.1.1 
Missing data ................................................................................................ 8 
5.1.1.2 
Incomplete dates for adverse events and concomitant medications ............ 8 
5.1.1.3 
Definition of concomitant medication in case of missing dates .................. 9 
5.1.1.4 
Incomplete dates for the last administration of LCM .................................. 9 
5.1.1.5 
General imputation rule for incomplete dates ............................................ 10 
5.1.2 
General study level definitions ............................................................................ 10 
5.1.2.1 
Analysis Time Points ................................................................................. 10 
5.1.2.2 
Body mass index (BMI) ............................................................................ 12 
5.1.2.3 
Exposure duration ...................................................................................... 12 
5.1.2.4 
Modal and maximum daily LCM dose ...................................................... 12 
5.1.2.5 
Completer cohorts ..................................................................................... 13 
5.1.2.6 
Protocol Deviations ................................................................................... 13 
5.1.2.7 
Treatment assignment and treatment groups ............................................. 13 
5.1.2.8 
Center pooling strategy ............................................................................. 14 
5.1.2.9 
Coding dictionaries .................................................................................... 14 
5.1.2.10 
Hospital stay duration ................................................................................ 14 
5.2 
Participant Disposition ................................................................................................. 14 
5.3 
Primary Endpoint(s) Analysis ...................................................................................... 15 
5.3.1 
Definition of endpoints ........................................................................................ 15 
5.4 
Secondary Endpoint(s) Analysis .................................................................................. 15 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis.................................................................. 15 
5.6 
(Other) Safety Analyses ............................................................................................... 15 
5.6.1 
Extent of Exposure .............................................................................................. 15 
5.6.2 
Adverse Events .................................................................................................... 16 
5.6.3 
Additional Safety Assessments ............................................................................ 17 
5.6.3.1 
Clinical laboratory evaluations .................................................................. 17 
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5.6.3.2 
Vital Signs ................................................................................................. 17 
5.6.3.3 
Other safety endpoint(s) ............................................................................ 19 
5.7 
Other Analyses ............................................................................................................. 19 
5.8 
Subgroup analyses ....................................................................................................... 19 
5.9 
Interim Analyses .......................................................................................................... 19 
5.10 
Data Monitoring Committee (DMC) or Other Review Board ..................................... 19 
6 
SUPPORTING DOCUMENTATION ............................................................................. 19 
6.1 
Appendix 1 Non-key analysis specifications ............................................................... 19 
6.1.1 
Baseline characteristics and demographics ......................................................... 19 
6.1.2 
Protocol deviations .............................................................................................. 19 
6.1.3 
Medical history .................................................................................................... 20 
6.1.4 
Concomitant diseases and conditions .................................................................. 20 
6.1.5 
Concomitant medications .................................................................................... 20 
6.1.6 
Other significant AEs .......................................................................................... 20 
6.1.7 
AEs for PDILI ...................................................................................................... 22 
6.1.8 
Health care resource use ...................................................................................... 24 
6.1.8.1 
Medical procedures ................................................................................... 24 
6.1.8.2 
Healthcare provider consultations ............................................................. 24 
6.1.8.3 
Hospital stays and ER visits ...................................................................... 24 
6.2 
Appendix 3: Changes to Protocol-Planned Analyses .................................................. 25 
7 
REFERENCES ................................................................................................................ 25 
 
LIST OF TABLES 
Table 1‒1: 
Objectives and Estimands/Endpoints ................................................................. 6 
Table 5‒1: 
Vital signs abnormality criteria ........................................................................ 18 
Table 6‒1: 
Other significant AEs ....................................................................................... 20 
Table 6‒2: 
AEs for PDILI .................................................................................................. 22 
 
 
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Statistical Analysis Plan 
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EP0151 
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study EP0151 is based on the protocol dated 13 Apr 
2020.  
SAP Version 
Approval Date 
Change 
Rationale 
1 
<DD Mmm YYYY> 
Not Applicable 
Original version 
LIST OF ABBREVIATIONS 
List of Abbreviations 
AE 
Adverse Event 
AED 
Antiepileptic Drug 
BMI 
Body Mass Index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ETV 
Early Termination Visit 
LCM 
Lacosamide 
MA 
Markedly Abnormal 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDILI 
Potential Drug-Induced Liver Injury 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
VNS 
Vagus Nerve Stimulation 
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List of Abbreviations 
WHODD 
World Health Organization Drug Dictionary 
 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report for EP0151. 
 
1.1 
Objectives and Estimands/Endpoints 
 
Table 1‒1: 
Objectives and Estimands/Endpoints 
Objectives 
Endpoints 
Primary 
Primary Objective:  
To assess the long-term use of 
Lacosamide (LCM) oral 
solution dosed at 2mg/kg/day to 
12mg/kg/day when 
administered to pediatric study 
participants with epilepsy who 
have completed EP0034 or 
SP848 
Primary Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) reported by the 
study participant or caregiver or observed by the Investigator 
• 
Withdrawals from study due to TEAEs 
• 
Withdrawals from study due to Serious adverse events (SAEs) 
• 
Modal daily dose (mg/kg/day) 
• 
Maximum daily dose (mg/kg/day) 
 
 
1.2 
Study design 
EP0151 is a multi-center, long-term, open-label, follow-up study to assess the long-term use of 
LCM oral solution (a formulation suitable for administration to children; also referred to as 
syrup) for pediatric study participants <6 years of age with epilepsy who have completed either 
EP0034 or SP848. 
Study participants who complete EP0034 or SP848 will be offered participation in EP0151 and 
will have access to open-label follow-up treatment with LCM. Approximately 80 to 100 study 
participants are estimated to be eligible for enrollment. 
Visit 1 for EP0151 will be the same as Visit 13 in EP0034 or SP848. Clinic visits will be 
scheduled approximately every 26 weeks relative to the EP0151 Visit 1 date. A visit window of 
±7 days relative to Visit 1 is applicable for all regularly scheduled visits. 
All study participants in EP0151 will receive LCM. The Investigator may maintain the study 
participant’s LCM dose from previous studies EP0034 or SP848, decrease the dose in 
decrements of 2mg/kg/day per week to a minimum dose of LCM 2mg/kg/day, or increase the 
dose in increments of 2mg/kg/day per week up to a maximum dose of LCM 12mg/kg/day or 
600mg/day, whichever is lower, administered twice per day (BID). 
This study involves a Treatment Period of approximately up to 205 weeks, depending on the age 
of the study participant, and an End of Study Period of approximately 8 weeks (including a 
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Taper Period and a Safety Follow-Up Period). Study participants who reach the end of the study 
and choose to continue treatment with LCM may be immediately prescribed LCM. The 
Termination Visit at the end of the Treatment Period will be the last study visit completed for 
study participants who continue treatment with prescribed LCM. Study participants who choose 
not to continue with LCM treatment and who are taking a dose of 3mg/kg/day or higher will 
enter an End of Study Period following completion of the Termination Visit or Early 
Termination Visit, and will gradually taper from LCM treatment during the Taper Period; a Final 
Visit will be conducted 30 days after the final dose of LCM. 
In situations where provision of LCM oral solution in certain participants >6 years of age 
(eg, developmental delay, need for more precise dosing as afforded by oral solution formulation, 
etc.) who may need a longer period of treatment with LCM oral solution, the situation will be 
assessed for approval by UCB on a case-by-case basis following discussions with the 
participant’s physician. 
The end of the study is defined as the date of the last visit of the last study participant in the 
study. 
 
2 
STATISTICAL HYPOTHESES 
No statistical hypotheses testing will be conducted in this study.   
 
3 
SAMPLE SIZE DETERMINATION 
No formal sample size calculations have been performed for this study, as there are no statistical 
hypotheses being tested. The sample size will be determined by the number of participants in 
EP0034 or SP848 who have been treated with LCM that are eligible to enter this open-label 
follow-up study. Approximately 80 to 100 study participants are estimated to be eligible for 
enrollment. 
 
4 
POPULATIONS FOR ANALYSIS 
The Safety Set (SS) will consist of all study participants who sign an informed consent form 
(ICF), and take at least 1 dose of study medication in this study. This analysis set will be used for 
all safety analyses. 
 
5 
STATISTICAL ANALYSES 
 
5.1 
General Considerations 
Statistical analysis and generation of tables, figures, participant data listings, and statistical 
output will be performed using SAS Version 9.4 or higher. All tables and listings will use 
Courier New font size 9. 
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Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical parameters, the number and percentage of participants in each category will be 
presented. The denominator for percentages will be based on the number of 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 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 
• 
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 participants and 
additionally based on the participant’s age at time of entry into study EP0151, using the 
following age groups: 
• 
≥2 to <4 years 
• 
≥4 to <6 years 
All summaries will be descriptive; no statistical hypothesis testing is planned.  
Only scheduled visits will be included in summaries. A complete set of listings containing all 
documented data including scheduled and unscheduled and all calculated data (eg, change from 
Baseline) will be generated, and will be sorted by site, participant number and visit (where 
applicable). Study participant numbers that were utilized in SP848 and EP0034 will continue to 
be used in EP0151.  
5.1.1 
Handling of missing data 
5.1.1.1 
Missing data 
No imputation of missing values for analysis parameters is planned unless otherwise noted. 
Imputations for missing or partial values for dates for adverse events (AEs) and medications will 
be applied to determine if they are to be considered treatment-emergent or concomitant, 
respectively.  
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 5.1.1.2. 
5.1.1.2 
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 
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will be displayed as reported in the participant data listings (ie, no imputed values will be displayed in 
data listings). 
• 
Missing start day, but month and year present: 
If the start of LCM occurred in the same month and year as the occurrence of the 
AE/concomitant medication, the start day of the event/concomitant medication will be 
assigned to the day of first intake of LCM. Otherwise the start day will be set to the 1st day 
of the month. 
• 
Missing start day and month, but year present: 
If the start of LCM occurred in the same year as the occurrence of the AE/concomitant 
medication, the start day and month will be assigned to the date of first intake of LCM. 
Otherwise the start day and month will be set to January 1st. 
• 
Missing end day, but month and year present: 
The end day will be set to the last day of the month. 
• 
Missing end day and month, but year present: 
The end day and month will be set to the latest of the date of Final Visit or the date equivalent 
to 30 days after last intake of LCM. 
However, if the Final Visit 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. 
5.1.1.3 
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 participant data listings, dates will be displayed as reported. 
5.1.1.4 
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 participant 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. 
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• 
Completely missing date of last administration: 
For calculating the duration of exposure, if the date of last administration is completely 
missing and no information could be obtained from data cleaning exercises, the date of last 
administration should be imputed as the date of last contact according to the Study 
Termination eCRF module. For all other purposes, no imputation will be done if the date of 
last administration is completely missing. 
If a participant 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. 
5.1.1.5 
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 
Completely missing dates will not be replaced and the corresponding derived variables will be 
set to missing. 
5.1.2 
General study level definitions 
5.1.2.1 
Analysis Time Points 
5.1.2.1.1 
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 EP0151 (ie, not the first dose of LCM from the previous study in which 
participants participated prior to EP0151). Unless otherwise noted, all references to the last dose 
of LCM in this SAP refer to the last dose of LCM in EP0151. 
5.1.2.1.2 
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.) Relative day will be calculated as date of first dose of LCM 
minus the current date for days prior to the first dose of LCM (the day prior to first dose will be 
Day -1). 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 posttreatment days (e.g., the day 
after the last dose will be Day +1). Relative day will not be calculated for partial dates or 
completely missing dates. 
 
 
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5.1.2.1.3 
Study periods 
This study consists of a Treatment Period and an End of Study Period. 
Treatment Period 
This is defined as the period of time from the date of first dose of LCM (Visit 1) to the 
Termination Visit for participants who complete the study or to the ETV for those who 
discontinued.  
End of Study Period (Taper Period  + Safety Follow-up 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 Visit or last contact with the subject. No scheduled visits are 
planned in the Taper Period. Final Visit is the only scheduled visit in Safety Follow-up Period.  
The maximum total duration of the study will be approximately 213 weeks, including an 
approximate 205-week Treatment Period and up to an 8 week Post-Treatment Period (4-week 
Taper Period and a Final Visit 30 days after the last dose). The end of the study is defined as the 
date of the last visit of the last study participant in the study. 
5.1.2.1.4 
End date of the Treatment Period 
The end date of the Treatment Period will be either the date of Termination Visit for participants 
completing the Treatment Period, or the date of the Early Termination Visit (ETV) for 
participants who discontinued during the Treatment Period.  
5.1.2.1.5 
Mapping of assessments performed at Early Termination Visit 
Safety assessments at an ETV that correspond to a scheduled visit will be summarized at the 
scheduled visit corresponding to the ETV if the assessment was scheduled to occur at that visit. 
If the ETV doesn’t correspond to a scheduled visit, the assessment will be summarized at the 
next scheduled visit.  
5.1.2.1.6 
Definition of Baseline values 
Baseline is defined as the last non-missing value collected prior to the first dose of LCM in the 
first LCM study. The Baseline values in EP0034 and SP0848 will be used as Baseline for safety 
variables in EP0151, if not stated otherwise. Visit 13/Termination Visit of EP0034 or SP848 will 
be Visit 1, Week 0 for EP0151. The vital signs measured after the 3 minute measurement in 
supine position of EP0034 at Visit 13/Termination Visit will be used as vital signs at Visit 1, 
Week 0 for EP0151.  
5.1.2.1.7 
Study visit labeling 
Visits will be labelled in table summaries (according to the schedule outlined in Section 1.3 of 
the protocol) as follows: 
• 
“Baseline”   
• 
“Visit X, Week X” for scheduled visits during the Treatment Period  
• 
“Termination Visit”  
• 
“Last Visit”, which is the last non-missing assessment during the Treatment Period. All 
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scheduled and unscheduled assessments within this time period will be considered during the 
Treatment Period  
• 
“Final Visit” 
Listings will also include “Unscheduled Visit” and "Early Termination Visit" as applicable. 
5.1.2.2 
Body mass index (BMI) 
BMI will be calculated using the formula:  
BMI = weight (kg) / (height [m])2 
5.1.2.3 
Exposure duration 
The overall duration of LCM exposure for each participant 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 descriptively, 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, where 1 month is defined 
as 28 days. 
Participant-years of LCM exposure in the study is calculated as the duration of exposure (days) 
divided by 365.25. 
Participant-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. 
Participant-months of exposure will be calculated as the sum of days of exposure divided by 28.  
5.1.2.4 
Modal and maximum daily LCM dose 
The modal daily LCM dose (mg/kg/day) is defined as the daily LCM dose the participant 
received for the longest duration during the Treatment Period in EP0151.  
The maximum daily LCM dose (mg/kg/day) is defined as the highest total daily dose a 
participant received during the Treatment Period in EP0151.  
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. 
The modal and maximum daily dose calculations are based on the number of days a participant 
was on a given daily dose. Gaps in LCM dosing will be excluded from the determination of 
modal and maximum daily dose (i.e., no imputation for days with missing dosing log 
information will be performed). If a participant was on two different LCM doses for the same 
duration of time (i.e., a tie when calculating modal daily dose), the modal daily dose will be set 
to the lower of the doses. 
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 
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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. 
5.1.2.5 
Completer cohorts 
A completer cohort will be defined as the subset of participants in the SS that were enrolled and 
treated with LCM for a specified duration of time. For example, a 12-month completer cohort 
consists of participants enrolled and treated with LCM for at least 12 months where a month is 
defined as 28 days. 
Participants will be classified as belonging to one of the following completer cohorts for the 
purpose of subgroup analyses: 
• 
12 months 
• 
24 months 
• 
36 months 
• 
48 months 
5.1.2.6 
Protocol Deviations 
Important protocol deviations are deviations from the protocol that could potentially have a 
meaningful impact on study conduct or on the key safety outcomes for an individual study 
participant. The criteria for identifying important protocol deviations and the classification of 
important protocol deviations will be defined within the appropriate protocol-specific document. 
To the extent feasible, rules for identifying protocol deviations will be defined without review of 
the data and without consideration of the frequency of occurrence of such deviations. 
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 ongoing data cleaning process prior 
to database lock. A list of participants with important protocol deviations will be agreed upon 
during the Data Evaluation Meetings (DEMs) and will be documented in the DEM minutes. 
5.1.2.7 
Treatment assignment and treatment groups 
This is an open-label 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 dose (Section 5.1.2.4).   
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5.1.2.8 
Center pooling strategy 
No pooling of centers is planned for this study.  
5.1.2.9 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA® v16.1). Medications will be coded using the World Health Organization Drug 
Dictionary (WHODD SEP/2013). Medical procedures will not be coded. 
5.1.2.10 
Hospital stay duration 
The duration of each hospital stay will be calculated as the discharge date minus the admission 
date (Hospitalization/Emergency Room [ER] Visit Date on the eCRF module) plus 1 day for 
hospital stays with a discharge date. 
5.2 
Participant Disposition 
The number of participants screened, and number and percentage of participants who were 
screen failures, broken down by primary reason for screen failure, will be presented for all 
screened participants.  
The date of first participant in (date of earliest Visit 1 for this study), date of last participant out 
(date of final scheduled or unscheduled visit), number of screened participants, and the number 
of participants in SS, will be summarized overall and by investigator site. Participants who 
transfer sites will be summarized according to their original site. 
A summary of disposition of analysis sets will be provided for all screened participants. The 
following will be summarized: 
• 
The number and percentage of participants in the SS 
Additionally, a summary of disposition and discontinuation reasons will present the following 
for all participants in the SS: 
• 
The number and percentage of participants starting the study 
• 
The number and percentage of participants completing the study 
• 
The number and percentage of participants completing <12 months, ≥12 to <24 months, 
≥24 to <36 months,  ≥36 to <48 months, and ≥48 months where 1 month is defined as 28 
days 
• 
The overall number and percentage of participants discontinuing and the number and 
percentage of participants discontinuing by primary reason for discontinuation. 
A summary of discontinuations due to AEs for SS will present the number and percentage of 
participants who discontinued from this study due to AEs broken down by type of AE. 
The number and percentages of participants 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 participants in the SS. This will also be presented in 
the participant data listings. Relationship categories include confirmed COVID-19, suspected 
COVID-19, general circumstances around COVID-19 without infection, and Other. The table of 
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impact of COVID-19 for any reason includes only the events within the first three relationship 
categories.  
5.3 
Primary Endpoint(s) Analysis 
In this open-label extension study, no statistical modelling will be used for analysis of the 
primary endpoints. The primary endpoints will be presented in descriptive statistics in the 
respective sections.  
5.3.1 
Definition of endpoints 
TEAEs reported by the study participant or caregiver or observed by the Investigator 
TEAEs will be defined as those events which started on or after the date of first dose of LCM in 
EP0151, or events for which severity worsened on or after the date of first dose of LCM in 
EP0151. AEs which occur within 30 days after final dose of LCM in EP0151 will be considered 
treatment-emergent. 
Withdrawals from study due to TEAEs 
Primary reason for premature study termination is collected in eCRF, one of which is AE. 
Together with the AE information for such participants collected in eCRF, early termination due 
to TEAE will be derived based on the definition of TEAE.  
Withdrawals from study due to SAEs 
The premature study termination due to AE collected in eCRF will be further considered for AEs 
indicated as serious in the eCRF.  
Modal daily dose (mg/kg/day) 
Definition of modal daily dose is in Section 5.1.2.4.  
Maximum daily dose (mg/kg/day) 
Definition of maximum daily dose is in Section 5.1.2.4.  
5.4 
Secondary Endpoint(s) Analysis 
Not applicable. 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis 
Not applicable.  
5.6 
(Other) Safety Analyses 
All safety variables will be analyzed by descriptive methods for the SS. 
5.6.1 
Extent of Exposure 
The duration of LCM exposure (days), as defined in Section 5.1.2.3, will be summarized as a 
continuous parameter (in days). 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 5.1.2.3. 
Participant-years of LCM exposure will be summarized using the cumulative 6-month time 
intervals for the Treatment Period, as defined in Section 5.1.2.3. 
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The maximum daily LCM dose (mg/kg/day), as defined in Section 5.1.2.4, will be summarized 
descriptively.  
The modal daily LCM dose (mg/kg/day), as defined in Section 5.1.2.4, will be summarized 
descriptively. In addition, the number of participants and participant-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 5.1.2.4. 
Most recent study medication for PDILI will be listed for subjects in cases when PDILI occurred.  
5.6.2 
Adverse Events 
AEs will be tabulated by MedDRA system organ class (SOC) and MedDRA preferred term (PT). 
The number and percentage of 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 ongoing at entry, treatment-emergent and post-treatment. Ongoing AEs 
at entry are defined as AEs which had an onset date prior to the first EP0151 dose of LCM. 
TEAEs  will be defined as those events which started on or after the date of first dose of LCM in 
EP0151, or events for which severity worsened on or after the date of first dose of LCM in 
EP0151. AEs which occur within 30 days after final dose of LCM in EP0151 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 ongoing AE at entry and post-treatment AEs will be 
provided in a participant data listing. Ongoing AEs from EP0034 and SP848 will be followed up 
and reported in this study.  
An overview of the incidence of TEAEs will provide the overall summary of TEAEs and the 
numbers and percentages of participants with at least 1 TEAE, with a serious TEAE, with a drug- 
related TEAE, with a severe TEAE. The number and percentage of participant discontinuations 
due to TEAEs, the number and percentage of all deaths (if applicable), and the number and 
percentage of participants with TEAEs leading to death (if applicable) will also be summarized.  
The number and percentage of participants who discontinued due to SAE (regardless of 
treatment emergent) will also be summarized.  
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 ongoing AEs at EP0151 study entry 
• 
Incidence of TEAEs leading to discontinuation 
• 
Incidence of SAEs leading to discontinuation 
• 
Incidence of TEAEs related to potential drug-induced liver injury (PDILI) (defined in 
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Appendix 6.1.7) 
• 
Incidence of TEAEs by relationship to LCM 
• 
Incidence of fatal TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs by relationship to LCM 
• 
Incidence of non-serious TEAEs occurring in at least 5% of participants  
• 
 Incidence of TEAEs by maximum intensity 
• 
Incidence of other significant TEAEs (defined in Appendix 6.1.6) 
• 
Incidence of drug-related TEAEs by seriousness 
• 
Incidence of TEAEs by 100 participant-months of exposure. The event rates are derived using 
the total number of TEAEs, including unique and non-unique TEAEs, divided by the 
participant-months exposed, and multiplied by 100.   
In addition, summaries for the incidence of TEAEs overall, incidence of serious TEAEs, 
incidence of TEAEs leading to discontinuation, incidence of SAEs leading to discontinuation, 
TEAEs related to PDILI, other significant TEAEs, and pediatric growth-, neurodevelopment-, 
behavior-, and endocrine-related TEAEs will be repeated presenting the site and participant 
number of all those participants experiencing each TEAE as well as in participant data listings. 
Pediatric growth-, neurodevelopment-, behavior-, and endocrine-related TEAEs will determined 
by manual medical review of reported MedDRA PTs.  
5.6.3 
Additional Safety Assessments  
5.6.3.1 
Clinical laboratory evaluations 
Starting from Visit 2, blood specimens for routine assay of hematology and clinical chemistry 
testing will be analyzed by the local laboratory affiliated with the site. The individual laboratory 
parameter result data will not be collected in the eCRF; however, the Investigator will report any 
out of range results judged to be clinically significant as an AE.  
No laboratory data will be summarized in tables. Laboratory test for PDILI will be listed if it 
occurred. Blood sample collection for pharmacokinetics for PDILI and suspected hepatic event 
for PDILI will be listed if it occurred.  
5.6.3.2 
Vital Signs 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse rate) will be 
assessed in a semi-supine position after 5 minutes rest throughout the study, according to the 
tabular schedules of procedures in Section 1.3 of protocol. Body weight and height will also be 
assessed throughout the study, according to the tabular schedules of procedures. BMI will be 
derived as defined in Section 5.1.2.2.   
5.6.3.2.1 
Vital Sign Values Over Time 
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 participant data listings. 
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Observed values of SBP, DBP, pulse rate, body weight, height and BMI will be summarized for 
each scheduled visit. Change from Baseline for SBP, DBP, pulse rate, body weight, height, and 
BMI will be summarized for all scheduled post-baseline visits. 
5.6.3.2.2 
Individual Participant Changes of Vital Sign Values 
Markedly abnormal (MA) values are defined as those MA values at scheduled or unscheduled 
visits which occur on or after the first EP0151 LCM administration through to the end of the 
study. While referring to the MA criteria, age at time of assessment should be considered by 
adding time between informed consent and the visit date. 
The number and percentage of participants with a MA value, MA low value, and MA high value, 
at each post-Baseline visit and Final Visit, for which SBP, DBP, pulse rate, and body weight are 
scheduled to be assessed, will be presented. Percentages will be relative to the number of 
participants with a value at each time point.  
The abnormal vital sign criteria are defined as follows: 
Table 5‒1: 
Vital signs abnormality criteria 
Parameter 
Age Range 
Abnormality Criteria 
Pulse Rate (beats/minute) 
6m - <3y 
<90 
>150 
3y - <12y 
<60 
>130 
SBP (mmHg) 
6m - <3y 
<70 
>120 
3y - <12y 
<80 
>140 
DBP (mmHg) 
6m - <3y 
<45 
>75 
3y - <12y 
<50 
>80 
Body Weight 
1m - <17y 
<3% or 97% of the normal 
body weight growth curve 
rangesa based on gender and the 
age of participant on date of 
weight assessment 
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 participant data listing of all vital signs for participants with an AE mapped to the PT 
bradycardia will be presented. 
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A participant data listing of all vital signs values including body weight, height, and BMI for all 
participants will be presented. A separate listing including MA vital signs values will also be 
presented. Vital signs for PDILI will be listed if it occurred. 
5.6.3.3 
Other safety endpoint(s) 
Where appropriate, suicidality will be assessed by trained study personnel using the 
Columbia-Suicide Severity Rating Scale (C-SSRS; Columbia University Medical Center, 2008).  
The “Already Enrolled” version of the C-SSRS should be completed at the Termination Visit or 
Early Termination Visit if the participant reaches 6 years of age by the time that visit is 
conducted. Participants who are ≥6 years of age who require additional treatment with LCM oral 
solution and are approved to continue will be administered the “Already Enrolled” version of the 
C-SSRS at the first visit (scheduled or unscheduled) which occurs upon reaching 6 years of age. 
The “Already Enrolled” C-SSRS version will continue to be administered at each subsequent 
visit (scheduled or unscheduled) up to and including the Termination or Early Termination Visit. 
Participant data listings of the data for the C-SSRS will be provided. No summaries of these 
results are planned. 
5.7 
Other Analyses 
Not applicable. 
5.8 
Subgroup analyses 
No other subgroup analyses are planned.  
5.9 
Interim Analyses 
Not applicable.  
5.10 
Data Monitoring Committee (DMC) or Other Review Board 
Not applicable.  
6 
SUPPORTING DOCUMENTATION 
6.1 
Appendix 1 Non-key analysis specifications 
6.1.1 
Baseline characteristics and demographics 
Demographics and baseline characteristics will be summarized descriptively for the SS. The 
summary comprises age (years) at entry into EP0151, age (years) at entry into first pediatric 
study,  and age at entry into EP0151 categorized as (24 months - <12 years), 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), weight 
(kg), height (cm) and BMI (kg/m2). The number of participants and percentage for age groups, 
gender and countries will also be presented for the SS.  
Demographic data will also be listed for the SS.  
6.1.2 
Protocol deviations 
Important protocol deviations defined in the important protocol deviations document, and 
additionally identified at the DEMs, will be listed. In addition, the number and percentage of 
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participants with at least 1 important protocol deviation will be summarized overall and by 
category of important protocol deviation (as defined in Section 5.1.2.6) for the SS.  
6.1.3 
Medical history 
The number and percentage of participants with a medical history condition (except epilepsy), 
including both resolved and ongoing conditions that were not reported in the parent studies, will 
be summarized overall and by MedDRA® primary SOC and PT for the SS. 
Lifestyle and family medical history for PDILI participants will be listed if it occurred.  
6.1.4 
Concomitant diseases and conditions 
The number and percentage of participants with concomitant diseases and conditions (medical 
history conditions noted as ongoing at study entry for the EP0151 study), except epilepsy, will be 
summarized by SOC and PT for the SS. 
6.1.5 
Concomitant medications 
Concomitant AEDs taken at the start of the EP0151 Treatment Period are defined as AEDs taken 
concomitantly with LCM at the time of first dose of LCM in EP0151. Ongoing concomitant 
medications from EP0034 and SP848 will be followed up and reported in this study.  
The number of concomitant AEDs taken at the start of the EP0151 Treatment Period will be 
summarized for the SS based on the following categorization: 0 AEDs, 1 AEDs, 2 AEDs, 3 
AEDs, and >3 AEDs. The number and percentage of participants taking concomitant AEDs at 
the start of the EP0151 Treatment Period will be summarized, separately, by WHODD chemical 
subgroup (level 4) and medication name, for the SS. AEDs taken as rescue medication will be 
excluded from the summary. 
Concomitant AEDs taken during the EP0151 Treatment Period are defined as AEDs taken 
concomitantly for at least one day in common with LCM in EP0151. 
The number and percentage of participants taking concomitant AEDs during the EP0151 
Treatment Period will be summarized overall and, separately, by WHODD chemical subgroup 
(level 4) and medication name, for the SS. AEDs taken as rescue medication will be excluded 
from the summary. 
VNS is allowed and will not be counted as a concomitant AED. 
The number and percentage of participants taking concomitant non-AEDs during the EP0151 
Treatment Period will be summarized overall and, separately, by WHODD anatomical main 
group (level 1) and therapeutic subgroup (level 2), for the SS. 
Potential hepato-toxic medications inquiries and physical examination for PDILI will be listed if 
it occurred. 
6.1.6 
Other significant AEs  
Table 6‒1: 
Other significant AEs 
MedDRA Preferred Term 
CARDIAC AND ECG RELATED TERMS 
                             Atrioventricular block third degree 
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MedDRA Preferred Term 
                             Atrioventricular block second degree 
                             Bradyarrhythmia 
                             Bradycardia 
                             Cardiac pacemaker insertion 
                             Atrial fibrillation 
                             Atrial flutter 
                             Sinus bradycardia 
                             Ventricular tachycardia 
                             Ventricular fibrillation 
                             Heart Rate decreased 
                             Sick sinus syndrome 
                             Atrial conduction time prolongation 
                             Atrioventricular dissociation 
                             Conduction disorder 
                             Cardiac arrest 
                             Cardiac fibrillation 
                             Cardiac flutter 
                             Sinus arrest 
                            Torsade de pointes 
                            Ventricular asystole 
                            Ventricular flutter 
                            Ventricular tachyarrhythmia 
                            Implantable defibrillator insertion 
SUICIDALITY RELATED TERMS 
                           Completed suicide 
                           Depression suicidal 
                           Suicidal behaviour 
                           Suicidal ideation 
                           Suicide attempt 
                           Intentional self-injury 
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MedDRA Preferred Term 
                           Self injurious behaviour 
                           Self-injurious ideation 
                           Intentional overdose 
                           Multiple drug overdose intentional 
                           Poisoning deliberate 
ADDITIONAL TERMS 
                           Loss of consciousness 
                           Syncope 
                           Appetite disorder 
                           Decreased appetite 
                           Diet refusal 
                           Hypophagia 
                           Food aversion 
                          Abnormal behaviour 
 
6.1.7 
AEs for PDILI 
The following MedDRA PTs are defined as AEs for PDILI: 
Table 6‒2: 
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 
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MedDRA Preferred Term for PDILI 
Coma hepatic 
Cryptogenic cirrhosis 
Drug-induced liver injury 
Hepatic cirrhosis 
Hepatic encephalopathy 
Hepatic failure 
Hepatic infiltration eosinophilic 
Hepatic necrosis 
Hepatic steatosis 
Hepatitis 
Hepatitis acute 
Hepatitis cholestatic 
Hepatitis chronic active 
Hepatitis chronic persistent 
Hepatitis fulminant 
Hepatitis toxic 
Hepatobiliary disease 
Hepatocellular foamy cell syndrome 
Hepatocellular injury 
Hepatotoxicity 
Hyperbilirubinaemia 
Icterus index increased 
Jaundice 
Jaundice cholestatic 
Jaundice hepatocellular 
Liver disorder 
Liver injury 
Mixed liver injury 
Non-alcoholic steatohepatitis 
Ocular icterus 
Subacute hepatic failure 
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6.1.8 
Health care resource use 
For health care resource use parameters, the following will be evaluated: concomitant 
medications (see Section 6.1.5), medical procedures, health care provider consultations not 
foreseen by the protocol, and hospitalization/ER visits.  
6.1.8.1 
Medical procedures 
The number of concomitant medical procedures per participant will be summarized for the 
Treatment Period. The number of concomitant medical procedures per participant will be 
summarized using the categories 0, 1, 2, and 3 or more. 
Participants who had any concomitant medical procedures during the course of the study based 
on the Concomitant Medical Procedures eCRF module will be listed. 
6.1.8.2 
Healthcare provider consultations 
The number of healthcare provider consultations per participant 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. 
All healthcare provider consultations data will be listed. 
6.1.8.3 
Hospital stays and ER visits 
The number of hospital stays per participant 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 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 5.1.2.10) will be categorized as 0 days, 1-5 days, 6-10 days, 
11-15 days, and >15 days, and summarized for the duration of the Treatment Period. 
An event logged on the Hospitalization/ER Visit eCRF module where ER is marked as initial 
entry point will be defined as an ER visit. An ER visit with a participant transfer to an inpatient 
general ward will also be counted as a hospitalization. However, all other instances of ER visits 
(where participant 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 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. 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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6.2 
Appendix 3: Changes to Protocol-Planned Analyses 
No changes to protocol planned analyses.  
7 
REFERENCES 
This section is not applicable for this study.  
 
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Approval Signatures
Name:
ep0151-sap
Version:
1. 0
Document Number:
CLIN-000159707
Title:
EP0151 Statistical Analysis Plan
Approved Date:
14 Dec 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 09-Dec-2020 19:36:48 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 14-Dec-2020 17:47:22 GMT+0000
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