Clinical trial NCT03340064
Conditions: Partial Seizures
Keywords: Epilepsy Partial Seizures Levetiracetam Monotherapy Adjunctive Treatment
Sponsor: UCB Japan Co. Ltd.
Start date: 2017-11-30; Completion date: 2023-07-28
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a study to confirm the efficacy of levetiracetam as adjunctive treatment or as monotherapy in pediatric epilepsy subjects aged 1 month to less than 4 years of age with partial seizures.

Detailed description:
The study will consist of 2 periods. The First Period (6 weeks drug treatment) is designed to confirm efficacy of levetiracetam (LEV), and the Second Period is designed to evaluate the long-term efficacy and safety of LEV.

Arms: arm 1: Subjects aged 1 month to \<6 months will be started on levetiracetam (LEV) 14 mg/kg/day at Visit 3. The dose may be increased by LEV 14 mg/kg/day for subjects aged 1 month to \<6 months at 2-week intervals to a maximum dose of 42 mg/kg/day. Subjects aged 6 months to \<4 years will be started on LEV 20 mg/kg/day at Visit 3. The dose may be increased by LEV 20 mg/kg/day at 2-week intervals to a maximum dose of 60 mg/kg/day.

At Visit 6, subjects may enter the Second Period or enter the Down-Titration Period followed by a Safety Follow-Up Period. Subjects who do not enter the Second Period will be down-titrated. The dose will be decreased by LEV 14 mg/kg/day for subjects aged 1 month to \<6 months or by LEV 20 mg/kg/day for subjects aged 6 months to \<4 years at 2-week intervals to 0 mg/kg/day.
Interventions: intervention 1: Levetiracetam
Intervention descriptions: intervention 1: levetiracetam dry syrup 50% for oral administration and levetiracetam solution for infusion (100 mg/mL)

Protocol documents:
Prot_000.pdf: 
UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 1 of 157 
PROTOCOL EP0100 AMENDMENT 4 
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY OF 
LEVETIRACETAM AS MONOTHERAPY OR ADJUNCTIVE 
TREATMENT OF PARTIAL SEIZURES IN PEDIATRIC 
EPILEPTIC SUBJECTS RANGING FROM 1 MONTH TO LESS 
THAN 4 YEARS OF AGE 
PHASE 3 
Sponsor: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
JAPAN 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
06 Feb 2017 
Not applicable 
Protocol Amendment 1 
16 Jun 2017 
Non-substantial 
Protocol Amendment 2 
28 Jun 2018 
Substantial 
Protocol Amendment 3 
29 Jan 2020 
Substantial 
Protocol Amendment 4 
22 Feb 2023 
Substantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Levetiracetam 
EP0100 
 
 
 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower 
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
JAPAN 
Medical Expert 
Name: 
 
Affiliation: 
National Epilepsy Center Shizuoka Institute of Epilepsy and 
Neurological Disorders 
Address: 
886 Urushiyama 
Aoi-ku 
Shizuoka-city 
Shizuoka 420-8688 
JAPAN 
Phone: 
 
Fax: 
 
 
 
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Levetiracetam 
EP0100 
 
 
 
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Sponsor Study Physician 
Name: 
 
Address: 
 
Raffles City Shanghai Office Tower 
268 Tibet Road Central 
Shanghai 200001 
People’s Republic of China 
Phone: 
 
Fax: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
Japan 
Phone: 
 
Fax: 
 
 
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Levetiracetam 
EP0100 
 
 
 
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Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
Japan 
Phone: 
 
Fax: 
 
Clinical Monitoring Contract Research Organization 
Name: 
PAREXEL International Limited 
Address: 
70 Sir John Rogerson’s Quay 
Dublin 2 
Ireland 
Phone: 
 
Fax: 
 
Additional study contact information is provided in separate documents. 
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Levetiracetam 
EP0100 
 
 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Japan: +81 3 6864 7400 
Email 
Japan: JDSO@ucb.com 
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Levetiracetam 
EP0100 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 11 
1 
SUMMARY ..................................................................................................................... 13 
2 
INTRODUCTION ........................................................................................................... 14 
3 
STUDY OBJECTIVES .................................................................................................... 15 
3.1 
Primary objective ......................................................................................................... 15 
3.2 
Secondary objectives ................................................................................................... 15 
4 
STUDY VARIABLES ..................................................................................................... 15 
4.1 
Efficacy variables......................................................................................................... 15 
4.1.1 
Efficacy variables for subjects on adjunctive therapy ......................................... 16 
4.1.1.1 
Primary efficacy variable .......................................................................... 16 
4.1.1.2 
Secondary efficacy variables ..................................................................... 16 
4.1.1.3 
Other efficacy variables ............................................................................. 16 
4.1.2 
Efficacy variables for subjects on monotherapy .................................................. 17 
4.1.2.1 
Primary efficacy variable for subjects on monotherapy ............................ 17 
4.1.2.2 
Secondary efficacy variables ..................................................................... 17 
4.1.2.3 
Other efficacy variables ............................................................................. 17 
4.2 
Pharmacokinetic and pharmacodynamic variables ...................................................... 17 
4.3 
Safety variables ............................................................................................................ 17 
4.3.1 
Primary safety variable ........................................................................................ 17 
4.3.2 
Secondary safety variables .................................................................................. 18 
4.3.2.1 
First Period ................................................................................................ 18 
4.3.2.2 
Combined First and Second Periods ......................................................... 18 
4.3.3 
Other safety variables .......................................................................................... 18 
5 
STUDY DESIGN ............................................................................................................. 18 
5.1 
Study description ......................................................................................................... 18 
5.1.1 
Overall ................................................................................................................. 18 
5.1.2 
First Period ........................................................................................................... 18 
5.1.3 
Second Period ...................................................................................................... 19 
5.1.4 
Study duration per subject ................................................................................... 19 
5.1.5 
Planned number of subjects and sites .................................................................. 20 
5.1.6 
Anticipated regions and countries ....................................................................... 20 
5.2 
Schedule of study assessments..................................................................................... 20 
5.3 
Schematic diagram ....................................................................................................... 26 
5.4 
Rationale for study design and selection of dose ......................................................... 27 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 27 
6.1 
Inclusion criteria .......................................................................................................... 27 
6.2 
Exclusion criteria ......................................................................................................... 28 
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EP0100 
 
 
 
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6.3 
Withdrawal criteria ...................................................................................................... 29 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 30 
7 
STUDY TREATMENT(S) .............................................................................................. 31 
7.1 
Description of investigational medicinal product ........................................................ 31 
7.2 
Treatments to be administered ..................................................................................... 31 
7.3 
Packaging ..................................................................................................................... 32 
7.4 
Labeling ....................................................................................................................... 33 
7.5 
Handling and storage requirements ............................................................................. 33 
7.6 
Drug accountability ...................................................................................................... 33 
7.7 
Procedures for monitoring subject compliance ............................................................ 33 
7.8 
Concomitant medications/treatments ........................................................................... 34 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 34 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 35 
7.9 
Blinding........................................................................................................................ 35 
7.10 
Randomization and numbering of subjects .................................................................. 35 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 35 
8.1 
First Period ................................................................................................................... 35 
8.1.1 
Selection Period ................................................................................................... 35 
8.1.1.1 
Visit 1/Day -9 to Day -2 (Screening) ........................................................ 35 
8.1.1.2 
Visit 2/Day -2 to Day 0 ............................................................................. 36 
8.1.2 
Evaluation Period ................................................................................................. 36 
8.1.2.1 
Visit 3 (Week 0) ........................................................................................ 36 
8.1.2.2 
Visit 4 (Week 2) ........................................................................................ 37 
8.1.2.3 
Visit 5 (Week 4) ........................................................................................ 37 
8.1.3 
Visit 6 (Week 6) ................................................................................................... 37 
8.2 
Second Period .............................................................................................................. 38 
8.2.1 
Visit 7 (Week 8) ................................................................................................... 38 
8.2.2 
Visit 8 (Week 10) ................................................................................................. 38 
8.2.3 
Visit 9 (Week 12) ................................................................................................. 38 
8.2.4 
Visit 10 (Week 14) ............................................................................................... 38 
8.2.5 
Visit 11 (Week 18) ............................................................................................... 39 
8.2.6 
Visit 12 (Week 22) ............................................................................................... 39 
8.2.7 
Visit 13 (Week 26) ............................................................................................... 39 
8.2.8 
Visit 14 (Week 32) ............................................................................................... 40 
8.2.9 
Visit 15 (Week 38) ............................................................................................... 40 
8.2.10 
Visit 16 (Week 50) ............................................................................................... 40 
8.3 
Direct Enrollment......................................................................................................... 41 
8.4 
Safety Follow-Up Visit (if applicable) ........................................................................ 41 
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EP0100 
 
 
 
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8.5 
Early Discontinuation Visit .......................................................................................... 41 
8.6 
Unscheduled Visit (if applicable) ................................................................................ 42 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 42 
10 ASSESSMENT OF PHARMACOKINETIC VARIABLE ............................................. 42 
11 ASSESSMENT OF SAFETY .......................................................................................... 43 
11.1 
Adverse events ............................................................................................................. 43 
11.1.1 
Definitions ........................................................................................................... 43 
11.1.1.1 
Adverse event ............................................................................................ 43 
11.1.1.2 
Serious adverse event ................................................................................ 43 
11.1.1.3 
Adverse events of special interest ............................................................. 44 
11.1.2 
Procedures for reporting and recording adverse events ....................................... 44 
11.1.2.1 
Description of adverse events .................................................................... 44 
11.1.2.2 
Rule for repetition of an adverse event...................................................... 45 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 45 
11.1.3 
Follow up of adverse events ................................................................................ 45 
11.1.4 
Suspected transmission of an infectious agent via a medicinal product .............. 46 
11.1.5 
Overdose of investigational medicinal product ................................................... 46 
11.1.6 
Safety signal detection ......................................................................................... 46 
11.2 
Laboratory measurements ............................................................................................ 46 
11.2.1 
Evaluation of PDILI ............................................................................................ 47 
11.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 51 
11.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 51 
11.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 51 
11.2.1.4 
Follow-up evaluation ................................................................................. 53 
11.3 
Other safety measurements .......................................................................................... 53 
11.3.1 
Physical examination ........................................................................................... 53 
11.3.2 
Neurological examination .................................................................................... 53 
11.3.3 
Vital signs and body weight ................................................................................ 54 
11.3.4 
12-lead ECG ........................................................................................................ 54 
11.3.5 
Assessment of suicidality .................................................................................... 54 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 54 
12.1 
Adherence to protocol .................................................................................................. 54 
12.2 
Monitoring ................................................................................................................... 54 
12.2.1 
Definition of source data ..................................................................................... 55 
12.2.2 
Source data verification ....................................................................................... 55 
12.3 
Data handling ............................................................................................................... 55 
12.3.1 
Case Report form completion .............................................................................. 55 
12.3.2 
Database entry and reconciliation ........................................................................ 56 
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EP0100 
 
 
 
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12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 56 
12.4 
Termination of the study .............................................................................................. 56 
12.5 
Archiving and data retention ........................................................................................ 56 
12.6 
Audit and inspection .................................................................................................... 57 
12.7 
Good Clinical Practice ................................................................................................. 57 
13 STATISTICS ................................................................................................................... 57 
13.1 
Definition of analysis sets ............................................................................................ 57 
13.1.1 
Enrolled Set ......................................................................................................... 58 
13.1.2 
Safety Set ............................................................................................................. 58 
13.1.3 
Full Analysis Set .................................................................................................. 58 
13.1.4 
Per Protocol Set ................................................................................................... 58 
13.1.5 
Other analysis sets ............................................................................................... 58 
13.2 
Handling of data for subjects who were enrolled prior to protocol amendment 3 ...... 58 
13.3 
General statistical considerations ................................................................................. 58 
13.4 
Planned efficacy analyses ............................................................................................ 59 
13.4.1 
Analysis of the primary efficacy variable for adjunctive treatment .................... 59 
13.4.2 
Other efficacy analyses ........................................................................................ 59 
13.5 
Planned safety and other analyses................................................................................ 59 
13.5.1 
Safety analyses ..................................................................................................... 59 
13.5.2 
Other analyses ...................................................................................................... 59 
13.6 
Handling of protocol deviations................................................................................... 60 
13.7 
Handling of dropouts or missing data .......................................................................... 60 
13.8 
Planned interim analysis and data monitoring ............................................................. 60 
13.9 
Determination of sample size ....................................................................................... 60 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 60 
14.1 
Informed consent ......................................................................................................... 60 
14.2 
Subject identification cards .......................................................................................... 61 
14.3 
Institutional Review Boards and Independent Ethics Committees .............................. 61 
14.4 
Subject privacy............................................................................................................. 62 
14.5 
Protocol amendments ................................................................................................... 62 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 62 
16 REFERENCES ................................................................................................................ 62 
17 APPENDICES ................................................................................................................. 64 
17.1 
Appendix 1 ................................................................................................................... 64 
17.2 
Appendix 2 ................................................................................................................... 67 
17.3 
Appendix 3 ................................................................................................................... 69 
17.4 
Protocol Amendment 1 ................................................................................................ 71 
17.5 
Protocol Amendment 2 ................................................................................................ 91 
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EP0100 
 
 
 
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17.6 
Protocol Amendment 3 .............................................................................................. 115 
17.7 
Protocol Amendment 4 .............................................................................................. 153 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 156 
19 SPONSOR DECLARATION ........................................................................................ 157 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of assessments .................................................................................. 21 
Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures .......... 24 
Table 5‒3: 
Schedule of assessments for Down-Titration and SFU Periods ...................... 25 
Table 11‒1: 
Laboratory measurements ................................................................................ 47 
Table 11‒2: 
Required investigations and follow up for PDILI............................................ 49 
Table 11‒3: 
PDILI laboratory measurements ...................................................................... 52 
Table 11‒4: 
PDILI information to be collected ................................................................... 53 
Table 13-1: 
Analysis visit mapping table .......................................................................... 111 
 
LIST OF FIGURES 
Figure 5‒1: 
Schematic for subjects in the First and Second Periods .................................. 26 
Figure 7‒1: 
Schematic for Down-Titration and Safety Follow-Up Periods........................ 32 
 
 
 
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EP0100 
 
 
 
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LIST OF ABBREVIATIONS 
ADF 
average daily frequency 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CDMS 
clinical data management system 
CI 
confidence interval 
CNS 
central nervous system 
CPM 
Clinical Project Manager 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
DRC 
daily record card 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EDC 
electronic data capture 
EDV 
Early Discontinuation Visit 
EEG 
electroencephalogram 
EMA/EMEA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPSP 
Good Postmarketing Study Practice 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
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Levetiracetam 
EP0100 
 
 
 
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IRB 
Institutional Review Board 
IRT 
interactive response technology 
IVRS 
interactive voice response system 
IWRX 
interactive web response system 
LEV 
levetiracetam 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NDA 
New Drug Application 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
Per-Protocol Set 
PS 
Patient Safety 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
ULN 
upper limit of normal 
VNS 
vagal nerve stimulation 
WBC 
white blood cell 
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EP0100 
 
 
 
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1 
SUMMARY 
EP0100 is an open-label, single-arm, multicenter study with levetiracetam (LEV) as 
monotherapy or adjunctive treatment to evaluate the efficacy and safety of LEV in Japanese 
subjects aged 1 month to <4 years with partial seizures. The study will consist of 2 periods. The 
First Period is designed to confirm efficacy of LEV, and the Second Period is designed to 
evaluate the long-term efficacy and safety of LEV. Subjects with uncontrolled partial seizures 
will be enrolled into the Selection Period of the First Period. 
Seizure counts during the 2 weeks prior to Visit 1 will be used as a Retrospective Baseline. All 
eligible subjects will enter a 6-week Evaluation Period. Subjects aged 1 month to <6 months will 
be started on LEV 14mg/kg/day at Visit 3 (Week 0). The dose may be increased by LEV 
14mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 
42mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20mg/kg/day at Visit 3 
(Week 0). The dose may be increased by LEV 20mg/kg/day at 2-week intervals to a maximum 
dose of 60mg/kg/day. 
At Visit 6 (Week 6), subjects may enter the Second Period or enter the Down-Titration Period 
followed by a Safety Follow-Up Period. Subjects who do not enter the Second Period will be 
down-titrated. The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to 
<6 months or by LEV 20mg/kg/day for subjects aged 6 months to <4 years at 2-week intervals to 
0mg/kg/day. Subjects who withdraw from the study at the minimum age-related dose do not 
need to down-titrate. In order to provide LEV to subjects who completed the First Period, the 
Second Period will be conducted until approval or the program is discontinued. 
All subjects who do not enter the Second Period will enter the Safety Follow-Up Period, 
regardless of whether they down-titrate LEV. 
After approval in Japan for the indication of LEV as monotherapy or adjunctive treatment in 
patients aged 1 month to <4 years with partial seizures, this clinical study (Phase 3) will be 
continued as a postmarketing clinical study (Phase 4). All subjects who are still in the study as of 
the date of approval will be considered to have completed the study. After the date of approval, 
subjects should visit the investigational site as soon as possible to complete the study by 
switching to commercial LEV or discontinuing LEV after the assessments specified in 
Section 8.5 “Early Discontinuation Visit” in the protocol. 
After the study is continued as a postmarketing clinical study (Phase 4), the LEV dry syrup 50% 
prescribed during the study period will continue to be used, and the labeling of the IMP will not 
be changed. There will also be no change in the handling and storage conditions of the IMP. 
After the date of approval, EP0100 shall be continued as a postmarketing clinical study 
(Phase 4), and the description of EP0100 in this protocol shall read as follows. The term "clinical 
study" should be replaced with "postmarketing clinical study," the term "clinical trial" should be 
replaced with "postmarketing clinical study", the term "this (clinical) study" should be replaced 
with "this postmarketing clinical study", the term "protocol" should be replaced with 
"postmarketing clinical study protocol", the term "investigator" should be replaced with 
"investigator for postmarketing clinical study", the term "subinvestigator" should be replaced 
with "subinvestigator for postmarketing clinical study", the term "IMP" should be replaced with 
"IMP for postmarketing clinical study ", the term "Investigator’s Brochure" should be replaced 
with "package insert or precautions information", the term "Phase 3" should be replaced with 
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"Phase 4", the term "subject’s ID card" should be replaced with "subject’s ID card for 
postmarketing clinical study participation", and the term "Good Clinical Practice (GCP)" should 
be replaced with "GCP and Good Postmarketing Study Practice (GPSP)". 
2 
INTRODUCTION 
Epilepsy is one of the most common and challenging neurological disorders. About 65 million 
people worldwide are estimated to have epilepsy (Thurman et al, 2011). In Japan, the number of 
patients with epilepsy is estimated to be approximately 216,000 (MHLW, 2011). In addition, 
epilepsy affects 0.5% to 1% of the Japanese population (Inoue, 2005). There is also a report that 
suggests the total number of patients with epilepsy in Japan is approximately 1 million (Ueda, 
2007). The incidence varies greatly with age, with high rates occurring in childhood, falling to 
low levels in early adult life, but with a second peak in those aged over 65 years. In many people, 
particularly children, the condition may remit, although a significant proportion will have 
epilepsy lifelong. The disease duration is often determined by the underlying cause. As 
appropriate treatment in the initial stages of epilepsy is said to have a major impact on prognosis 
and mental development (Berg et al, 2014; Kwan and Brodie, 2001), it is important to provide 
appropriate pharmacotherapy at an early stage and prescribe treatment with a high level of safety 
in order to maintain patients’ daily and social activities in their long lives ahead. 
Levetiracetam has been developed as adjunctive therapy in the treatment of partial seizures in 
children aged 1 month to <4 years with epilepsy in N01009 and the open-label extension study 
N01148. The European Medicines Agency (EMA) and US Food and Drug Administration 
(FDA) approved the indication of adjunctive treatment in children down to 1 month of age with 
partial seizures in Sep 2009 and Dec 2011, respectively. UCB also conducted a 
noninterventional, post authorization safety study (N01357, Jan 2011 through Nov 2013), as 
agreed with the EMA. The objective of the study was to collect safety and efficacy data on 
Keppra® in clinical practice in subjects aged 1 month to <12 months with epilepsy. The study 
was conducted as a part of a risk management plan after obtaining approval for the indication in 
the EU (Sep 2009). 
In Japan, an open-label, single-arm, multicenter study (N01223) demonstrated that long-term 
adjunctive treatment with LEV (20mg/kg/day or 1000mg/day to 60mg/kg/day or 3000mg/day) 
was effective in Japanese children aged 4 to <16 years with partial seizures. The Pharmaceuticals 
and Medical Devices Agency (PMDA) approved the indication of LEV as adjunctive therapy in 
Japanese children aged 4 to <16 years with uncontrolled partial seizures in May 2013. 
For the purpose of this study, the seizure type classification will follow the 1981 International 
League Against Epilepsy (ILAE) classification of epileptic seizures, which speaks of partial 
seizures, classified as simple partial seizures (no alteration of consciousness), complex partial 
seizures (with alteration of consciousness), and secondarily generalized seizures, and defines 
generalized seizure types, referred to as absence seizures (typical and atypical), myoclonic 
seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. Apart from 
myoclonic seizures, consciousness is almost invariably impaired from the onset of the seizure 
(ILAE, 1981, Appendix 1 [Section 17.1]). 
Likewise, the classification of epilepsy syndromes will be used according to the 1989 ILAE-
publication (ILAE, 1989, Appendix 2 [Section 17.2]). 
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This study is designed to confirm the dosage and administration for Japanese subjects aged 
1 month to <4 years. The First Period is designed to confirm efficacy of LEV, and the Second 
Period is designed to evaluate the long-term efficacy and safety of LEV. 
EP0100 was initially started with a design to evaluate the efficacy of LEV using the percent 
reduction from Baseline in partial seizure frequency based on the number of seizures recorded by 
video-electroencephalography (EEG) as the primary efficacy endpoint, but subject recruitment 
was extremely difficult. One of the major factors for the difficulty in recruitment was that the 
48h video-EEG measurement was to be performed 3 times at Baseline, Week 2, and Week 6, 
thus increasing the burden on the subject/guardian. As a result, consent to participate in the study 
was not obtained from the guardian, and many potential subjects could not be screened for entry 
into the study. After consultation with the PMDA, the method of recording seizures was changed 
to a conventional patient diary, and the primary endpoint was changed to percent reduction in 
partial seizure frequency based on the patient diary. The percent reduction in partial seizure 
frequency calculated from the 48h video-EEG is included as an “other” efficacy variable. 
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
The primary objective of this study is to confirm the efficacy of LEV in reducing seizure 
frequency in the First Period compared to historical control as adjunctive treatment in pediatric 
epilepsy subjects aged 1 month to <4 years with partial seizures. 
3.2 
Secondary objectives 
The secondary objectives are the following: 
• To evaluate the safety and tolerability of LEV in the First Period in pediatric epilepsy 
subjects aged 1 month to <4 years with partial seizures 
• To evaluate the efficacy of LEV in reducing seizure frequency in the First Period compared 
to historical control as monotherapy in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures 
• To evaluate long-term safety and tolerability of LEV in the combined First and Second 
Periods in pediatric epilepsy subjects aged 1 month to <4 years with partial seizures receiving 
long-term treatment with LEV at individualized doses 
• To evaluate the efficacy of LEV in the combined First and Second Periods as monotherapy 
or adjunctive treatment in pediatric epilepsy subjects aged 1 month to <4 years with partial 
seizures 
• To characterize pharmacokinetics (PK) of LEV in the First and Second Periods in epileptic 
pediatric subjects aged 1 month to <4 years 
4 
STUDY VARIABLES 
4.1 
Efficacy variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
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4.1.1 
Efficacy variables for subjects on adjunctive therapy 
4.1.1.1 
Primary efficacy variable 
4.1.1.1.1 
First Period 
The primary efficacy variable for subjects on adjunctive therapy is the percent reduction in 
partial seizure frequency per week from Baseline to Visit 6. 
4.1.1.1.2 
Combined First and Second Periods 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
4.1.1.2 
Secondary efficacy variables 
4.1.1.2.1 
First Period 
The secondary efficacy variable for the First Period is the following: 
• Percent reduction in partial seizure frequency per week from Baseline to Visit 4 and Visit 5 
4.1.1.2.2 
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in partial seizure frequency per week from Baseline 
• For each visit, percent reduction in partial seizure frequency per week from Baseline grouped 
into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% 
4.1.1.3 
Other efficacy variables 
4.1.1.3.1 
First Period 
The other efficacy variables for the First Period for the number of seizures based on the 48h 
video-EEG recorded  through Protocol Amendment 2 are the following: 
• Percent reduction in average daily frequency (ADF) of partial seizure frequency monitored 
by the 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
4.1.1.3.2 
Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% 
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4.1.2 
Efficacy variables for subjects on monotherapy 
4.1.2.1 
Primary efficacy variable for subjects on monotherapy 
There is no primary efficacy variable for subjects on monotherapy. 
4.1.2.2 
Secondary efficacy variables 
4.1.2.2.1 
First Period 
There is no secondary efficacy variable for the First Period. 
4.1.2.2.2 
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in partial seizure frequency per week from Baseline 
• For each visit, percent reduction in partial seizure frequency per week monitored by the 
patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% 
4.1.2.3 
Other efficacy variables 
4.1.2.3.1 
First Period 
The other efficacy variables for the First Period for the number of seizures based on the 48h 
video-EEG recorded through Protocol Amendment 2 are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG to 
Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
4.1.2.3.2 
Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all types of seizure frequency per week from Baseline 
• For each visit, percent reduction in all types of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% 
• Percentage of subjects who are continuously 6-month seizure-free monitored by the patient 
diary 
4.2 
Pharmacokinetic and pharmacodynamic variables 
Levetiracetam (parent compound only) plasma levels is defined as the other PK variable. 
4.3 
Safety variables 
4.3.1 
Primary safety variable 
There is no primary safety variable. 
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4.3.2 
Secondary safety variables 
4.3.2.1 
First Period 
The secondary safety variables for the First Period are the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of treatment-emergent serious adverse events (SAEs) 
• Incidence of TEAEs leading to discontinuation from study medication 
4.3.2.2 
Combined First and Second Periods 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of treatment-emergent SAEs 
• Incidence of TEAEs leading to discontinuation from study medication 
4.3.3 
Other safety variables 
The other safety variables are the following: 
• Adverse events (AEs) (variables other than secondary safety variables) 
• Laboratory tests (blood chemistry and hematology) 
• Vital signs 
• Body weight and height 
• Physical and neurological examination 
5 
STUDY DESIGN 
5.1 
Study description 
5.1.1 
Overall 
EP0100 is an open-label, single-arm, multicenter study with LEV as monotherapy or adjunctive 
treatment to evaluate the efficacy and safety of LEV (14mg/kg/day to 42mg/kg/day for subjects 
aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 6 months to 
<4 years) in the treatment of partial seizures over the First Period (6 weeks), followed by the 
long-term follow-up (Second Period) in pediatric subjects. 
5.1.2 
First Period 
Eligible subjects will enter the First Period (6 weeks). Subjects aged 1 month to <6 months will 
be started on LEV 14mg/kg/day at Visit 3 (Week 0). The dose may be increased by LEV 
14mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 
LEV 42mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20mg/kg/day at 
Visit 3 (Week 0). The dose may be increased by LEV 20mg/kg/day at 2-week intervals to a 
maximum dose of 60mg/kg/day. The dose will be increased if seizure freedom has not been 
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attained according to the patient diary. However, if there is a safety concern for the subject in the 
opinion of the investigator, the dose can be kept. 
For the subjects aged 1 month to <12 months who have cluster seizures several times a day and 
are being treated on an inpatient basis under a physician’s supervision, the dose can be increased 
without waiting for the 2-week interval. If the subject is hospitalized and under supervision of a 
physician, the following rapid titration procedure (dose and interval) will be performed as the 
most rapid case: dose increments of LEV 14mg/kg/day for subjects aged 1 to <6 months and 
LEV 20mg/kg/day for subjects aged 6 months to <4 years at 1-day intervals. 
If an intolerable AE occurs during the First Period, the dose can be decreased only once as a 
fallback option. The dose will be decreased by LEV 14 mg/kg/day for subjects aged 1 month to 
<6 months or LEV 20mg/kg/day for subjects aged 6 months to <4 years. After decreasing the 
dose, a re-increase will not be allowed during the First Period. 
At Visit 6 (Week 6), subjects may enter either the Second Period or the Down-Titration Period, 
followed by the Safety Follow-Up Period. Subjects who do not enter the Second Period will be 
down-titrated. The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to 
<6 months or by LEV 20mg/kg/day at 2-week intervals to 0mg/kg/day. Subjects who withdraw 
from the study at the minimum age-related dose do not need to down-titrate. 
All subjects who do not enter the Second Period will enter the Down-Titration Period, followed 
by the Safety Follow-Up Period. 
5.1.3 
Second Period 
Subjects who complete the First Period will have a visit every 4 weeks ±7 days relative to Visit 3 
for the first 6 months of administration and then every 12 weeks ±14 days thereafter. Subjects 
will continue to receive LEV 14 to 42mg/kg/day in subjects aged 1 month to <6 months or LEV 
20 to 60mg/kg/day for subjects aged ≥6 months <4 years at the discretion of the Investigator. 
When subjects aged <6 months at the time of study enrollment reach 6 months of age, they can 
take a maximum of LEV 60mg/kg/day. 
A final visit will be required 2 weeks ±7 days after the final dose of LEV, or sooner if the subject 
will continue LEV (prescribed by the primary care provider as commercial LEV) after study 
completion. 
5.1.4 
Study duration per subject 
The study duration is as follows: 
Retrospective Baseline Period 
Seizure counts during the 2 weeks prior to Visit 1 will be used as a Retrospective Baseline 
Period. 
First Period 
• Selection Period (maximum of 9 days) 
• Evaluation Period (6 weeks) 
• Down-Titration Period (up to 4 weeks) 
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• Safety Follow-Up Period (2 weeks) 
Second Period 
• Maintenance Period (until approval or the program is discontinued) 
• Down-Titration Period (up to 4 weeks) 
• Safety Follow-Up Period (2 weeks) 
The end of the study is defined as the date of the final visit of the final subject in the study. 
5.1.5 
Planned number of subjects and sites 
The planned number of evaluable subjects in the First Period will be a total of 38 subjects for the 
primary efficacy analysis. Subjects will be enrolled into 4 age groups (1 month to <6 months, 
6 months to <1 year, 1 year to <2 years, and 2 years to <4 years), with a minimum of 5 subjects 
in each age group. 
The planned number of monotherapy subjects will be a total of 10 subjects. 
It is planned to have those subjects recruited in approximately 20 sites. 
5.1.6 
Anticipated regions and countries 
The study will be conducted in Japan. 
5.2 
Schedule of study assessments 
For Visit 4 through Visit 6, planned clinic visits should be scheduled as indicated with a window 
of ±4 days relative to Visit 3. For Visit 8 through Visit 15, planned clinic visits should be 
scheduled as indicated with a window of ±7 days relative to Visit 3. From Visit 16 onward, 
planned clinic visits should be scheduled as indicated with a window of ±14 days relative to 
Visit 3. 
 
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Table 5‒1: 
Schedule of assessments 
 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
Written informed consent 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety  
assessmenth 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Concomitant AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-
AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 5‒1: 
Schedule of assessments 
 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
Concomitant medical 
procedures 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CT scan/MRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEGk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/collect DRC  
Xl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fallback optionm 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
C-SSRSn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
Xn 
 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; 
ECG=electrocardiogram; EDV=Early Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response 
system; IWRS=interactive web response system; LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have W6 evaluations and the EDV evaluations. 
b In the Maintenance Period, visits will occur every 4 weeks from V8 to V13, and every 12 weeks thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. 
 
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Table 5‒1: 
Schedule of assessments 
 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
g Recorded from end of V1 through V3. 
h If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results 
should be available prior to V3, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
I Dispense study drug at V3. 
j Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have 
changes on physical examination which would suggest a lesion has occurred since the last imaging procedure. 
k If the EEG exam was not performed prior to V1, the assessment needs to be completed, and results must be available prior to V3. 
l Dispense DRC. 
m Fallback option is permitted. See Section 5.1.2 for details. 
n C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
 
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Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Not applicable. 
 
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Table 5‒3: 
Schedule of assessments for Down-Titration and SFU Periods  
Visit 
  Study Week 
EDVa 
SFUb 
W0 
W2 
W4 
 
Vital signsc 
X 
X 
X 
X 
Seizure counts 
X 
X 
X 
X 
Laboratory safety assessments 
X 
 
 
X 
Body weight  
X 
X 
X 
X 
Height 
X 
 
 
X 
Concomitant AED(s) 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
X 
X 
X 
Concomitant medical procedures 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
Dispense/return study drug 
X 
X 
X 
 
Study drug compliance 
X 
X 
X 
 
ECG 
X 
 
 
Xd 
IVRS/IWRS 
X 
X 
X 
X 
Dispense/collect DRC  
X 
X 
X 
Xe 
C-SSRSf 
Xf 
Xf 
Xf 
Xf 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; 
ECG=electrocardiogram; EDV=Early Discontinuation Visit; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response 
system; LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
a The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to <6 months or by LEV 20mg/kg/day for subjects aged 6 months to <4 years at 
2-week intervals to 0mg/kg/day. 
b Two weeks after final dose of study drug. 
c Including temperature, blood pressure, and heart rate. 
d Performed only if abnormal at EDV. 
e Collect DRC. 
f C-SSRS to be performed at each visit for subjects aged ≥6 years. 
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5.3 
Schematic diagram 
Figure 5‒1: Schematic for subjects in the First and Second Periods 
 
6m admin=6 months of administration; DRC=daily record card; V=Visit; W=weeks 
Note: The value in parentheses for dose is for subjects 1 month to <6 months of age. 
 
60 (42) mg/kg/day
60 (42) mg/kg/day
40 (28) mg/kg/day
40 (28) mg/kg/day
6 month to <4 years (1month to < 6months)
20 (14) mg/kg/day
First period
Second period
Retrospective
Baseline
(Selection Period)
Evaluation Period
Maintenance Period
2W
FallBack option
20 (14) mg/kg/day
FallBack option
Subject’s DRC
DRC
(V2)
(V7)
(V9)
(V14)
V1
V3
V4
V5
V13
V15
Vx
Week 2
Week 4
Week 6
Week 10
V8
Week 14
V10
V11
V12
V6
Informed consent
Registration
6m admin
Every 12weeks
Week 18
Week 22
Week 26
Week 38
(V3  -9 to -2day)
Week 0
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5.4 
Rationale for study design and selection of dose 
Levetiracetam has been developed as adjunctive therapy in the treatment of partial seizures in 
children aged 1 month to <4 years with epilepsy. The EMA and FDA have approved the new 
indication as adjunctive treatment in children down to 1 month of age with partial seizures in 
Sep 2009 and Dec 2011, respectively. The approved dosage and administration for infants aged 
1 month to < 6 months is 14 to 42 mg/kg/day, and for young children aged 6 months to <4 years, 
the approved dose is 20 to 60 mg/kg/day. These dose ranges were determined based on the 
results of N01288, a population PK analysis. The results show that the recommended dose ranges 
are 14 to 42mg/kg/day for infants aged <6 months, approximately 70% of the dose for 
4-year-olds (20 to 60mg/kg/day, demonstrating equivalent exposure to 1000 to 3000mg/kg/day 
in adults) and 20 to 60mg/kg/day for children aged 6 months or older (the same dose range as for 
4-year-olds). At the PMDA consultation, they suggested that the final dosage and administration 
(including up-titration method) should be established based on a confirmatory study. Based on 
this suggestion, EP0100 is planned to evaluate the efficacy of LEV at the same dosage approved 
by FDA and EMA, and the dose will be increased at 2-week intervals during the 6-week 
Evaluation Period. 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects who complete the First Period can start the Second Period without re-confirmation of 
the inclusion/exclusion criteria. 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
1a. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the parent(s) or legal representative. 
Subject/legal representative/caregiver is considered reliable and capable of adhering to the 
protocol (eg, able to understand and complete diaries), visit schedule, or medication intake 
according to the judgment of the Investigator. 
2a. Subject must have a diagnosis of epilepsy with partial onset seizures (ie, seizures of focal 
onset), whether or not secondarily generalized. 
Subject has had an EEG and a brain computerized tomography (CT) scan or brain magnetic 
imaging (MRI) consistent with a diagnosis of localized epilepsy according to the 
International Classification of Epilepsies and Epileptic Syndromes (1989) (see  Section 17.2) 
and consistent with partial onset seizures according to the Classification of Epileptic Seizures 
(1981) (see Section 17.1). If the EEG and brain CT scan and brain MRI were not performed 
prior to the Screening Visit (Visit 1), the assessment needs to be completed and results must 
be available prior to Visit 3. 
3. Subject must be male or female from 1 month to <4 years of age. Pre-term infants aged 
<1 year are to be stratified into an appropriate age category using the best estimate of their 
corrected gestational age. 
4. For subjects on adjunctive therapy, subject must be on a stable AED regimen (ie, a maximum 
of 2 AEDs) for the Selection and Evaluation Periods of the study. Minor adjustments to the 
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dose of current AEDs are allowed only prior to Visit 1. Monotherapy subjects must not 
receive AED treatment, receive temporary AED treatment, or switch an AED prior to Visit 1. 
5. Subject weighs ≥3.0kg. 
6. Subject may have Vagal Nerve Stimulation (VNS) which has been implanted for at least 
6 months prior to Visit 1; the settings must be stable for at least 2 months prior to Visit 1. 
Activated VNS must be counted as 1 of the 2 AEDs. 
7a. Subject must have experienced at least 2 observable partial seizures (ie, seizures of focal 
onset as determined by EEG), with or without secondary generalization during each 7-day 
period during the 2 weeks prior to Visit 1. This time period (the 2 weeks prior to Visit 1) will 
be referred to as the Retrospective Baseline Period. This seizure information (including type, 
frequency, and date) must have been recorded on a daily record card (DRC) in order to be 
acceptable. 
8.  Deleted. 
9. Deleted. 
10. If epilepsy surgery has been performed prior to study entry, subjects must have a documented 
failed epilepsy surgery outcome at least 4 weeks prior to Visit 1. 
11. The use of intermittent benzodiazepines, phenobarbitals, and phenytoins is allowed as long as 
the frequency is not greater than 1 single administration per week for at least 2 weeks prior to 
Visit 1 and throughout study participation. If benzodiazepines are used more than once a 
week, they must be considered as 1 of the AEDs. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has been taking any medication (other than their concomitant AEDs) that influences 
the central nervous system (CNS) for which they had not been on a stable regimen for at least 
1 month prior to Visit 1. 
2. Subject is taking any medication that may interfere with the absorption, distribution, 
metabolism, or excretion of the concomitant AEDs or LEV during the course of the study. 
3. Subject has received any investigational medication or device within 30 days prior to Visit 1. 
4. Subject has taken LEV prior to the study. 
5. Subjects using felbamate who have presented with clinically significant abnormalities for 
WBCs, RBCs, platelets, and/or hepatic function during felbamate treatment, and subjects 
who are taking felbamate <1year from the date of Visit 1. 
6. Subject has a history of status epilepticus requiring hospitalization during the 30 days prior to 
Visit 1, except for status epilepticus occurring during the first 10 days of life. 
7. Subject has a treatable seizure etiology (ie, febrile seizures). 
8. Subject is on a ketogenic diet (concomitantly or within 30 days prior to Visit 1). 
9. Subject has epilepsy secondary to progressing cerebral diseases. 
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10. Subject has a current diagnosis of Rasmussen’s syndrome, Landau-Kleffner disease or 
Lennox-Gastaut syndrome. 
11. Subject has clinically significant deviations from reference range values for renal function or 
any of the other laboratory parameters required for this study, as determined by the 
Investigator. 
12. Subject has any clinically significant acute or chronic illness (as determined during the 
physical examination or from other information available to the Investigator). 
13. Subject has an allergy to pyrrolidine derivatives or a history of multiple drug allergies. 
14. Subject is known to have a terminal illness. 
15. Subject has a disorder or condition that may interfere with the absorption, distribution, 
metabolism, or excretion of medications. 
16. Subject has a history of or presence of pseudoseizures. 
17. Subject has any medical condition that might interfere with the subject’s study participation 
(ie, serious infection, scheduled elective surgery, severe scalp eczema, etc.). 
18. Subject has ≥3x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. 
Subjects should be withdrawn from the study if any of the following events occur: 
1. Subject must be withdrawn if there is an occurrence of status epilepticus, seizure clustering, 
or generalized tonic-clonic seizure, if unknown for the subject. If seizure frequency is 
increased, subject can be withdrawn for safety reasons, at the discretion of the Investigator. 
2. Subject develops an illness that would interfere with his/her continued participation. 
3. Subject is noncompliant with the study procedures or medications in the opinion of the 
investigator. 
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4. Subject takes prohibited concomitant medications as defined in this protocol. 
5. Parent or legal guardian withdraws his/her consent. 
6. The sponsor or a regulatory agency requests withdrawal of the subject. 
7. Subject ≥6 years of age has active suicidal ideation without specific plan as indicated by a 
positive response (“Yes”) to question 4 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a Mental Healthcare Professional and may be 
withdrawn from the study based upon the investigator’s judgment of benefit/risk of 
continuing the subject in the study/on study medication. 
8. Subject ≥6 years of age has active suicidal ideation with a specific plan as indicated by a 
positive response (“Yes”) to question 5 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study. 
9. Subject who has cluster seizures prior to Visit 1 intermittently takes benzodiazepines, 
phenobarbitals, or phenytoins more than 1 single administration per week during the study 
period. 
10. Subject on monotherapy needs to add another AED during the First Period. 
Investigators should attempt to obtain information on subjects in the case of withdrawal. For 
subjects considered as lost to follow up, the investigator should make an effort (at least 1 phone 
call and 1 written message to the subject), and document his/her effort (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The CRF 
must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued. 
The PDILI criteria below require immediate and permanent discontinuation of IMP: 
• Subjects with either of the following: 
− ALT or AST ≥ 5xULN 
− ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of IMP: 
• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
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The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator. 
• Subjects with ALT or AST ≥3xULN (and ≥2x baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness). 
Evaluation of PDILI must be initiated as described in Section 11.2.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The CRF must document the primary 
reason for IMP discontinuation. 
7 
STUDY TREATMENT(S) 
7.1 
Description of investigational medicinal product 
Levetiracetam dry syrup 50% (white to off-white granules) for oral administration will be used in 
this study. Levetiracetam injection (100mg/mL) will also be used. 
7.2 
Treatments to be administered 
Each subject will be weighed in kg and will receive 2 equal oral doses of LEV dry syrup 50% 
dissolved in water; 1 in the morning and 1 in the evening. The weight obtained at every visit will 
be used to calculate the dose of study medication (mg per kg) for the entire study. 
If the subject cannot take LEV dry syrup under a fasting state during the First Period, LEV 
100mg/mL concentrate for solution for infusion (clear, colorless, sterile solution) can be used for 
a maximum of 4.5 consecutive days at each dose at the Investigator’s discretion. Levetiracetam 
injection is infused intravenously over 15 minutes per dose. 
The weight and amount of individual dose will be recorded in the CRF and in the drug 
accountability log for the site. Medication will be allocated by the IVRS. 
First Period 
Once the subject has fulfilled the eligibility criteria, the subject will enter the Evaluation Period. 
Study medication should be given as 2 equally divided doses administered twice daily. The first 
intake of newly dispensed study medication should occur at Visit 3. Subjects should take IMP 
according to instructions provided by the Investigator. 
Subjects aged 1 month to <6 months will be started on LEV 14mg/kg/day at Visit 3 (Week 0). 
The dose may be increased by LEV 14mg/kg/day for subjects aged 1 month to <6 months at 
2-week intervals to a maximum dose of LEV 42mg/kg/day. Subjects aged 6 months to <4 years 
will be started on LEV 20mg/kg/day at Visit 3 (Week 0). The dose may be increased by 
LEV 20mg/kg/day at 2-week intervals to a maximum dose of 60mg/kg/day. 
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At the end of the Evaluation Period, subjects will enter into the Second Period. Subjects who do 
not enter the Second Period will enter the Down-Titration Period, followed by the Safety 
Follow-Up Period. 
The Down-Titration Period (up to 4 weeks) will consist of the following: 
• The dose will be decreased by 14mg/kg/day for subjects aged 1 month to <6 months or by 
20mg/kg/day for subjects aged 6 months to <4 years at 2-week intervals to 0mg/kg/day. 
Figure 7‒1: Schematic for Down-Titration and Safety Follow-Up Periods 
 
EDV=Early Discontinuation Visit; SFU=Safety Follow-Up; V=Visit 
Note: The value in parentheses for dose is for subjects 1 month to <6 months of age. 
The down-titration procedure needs to be applied in case of early discontinuation. 
Second Period 
For continuing subjects, if a dose adjustment becomes necessary, the investigators will increase 
or decrease the dose by at least a 2-week interval. One increase or decrease in the dose should 
not exceed LEV 14mg/kg/day for subjects aged 1 month to <6 months or LEV 20mg/kg/day for 
subjects aged 6 months to <4 years for the 2-week interval. The dosage can be adjusted to 
LEV 14, 28 and 42mg/kg/day LEV for subjects aged 1 month to <6 months or LEV 20, 40 and 
60mg/kg/day for subjects aged 6 months to <4 years at the Investigator’s discretion for the 
benefit/risk for individual subjects. 
Subjects who withdraw or complete the Second Period will enter the Down-Titration Period, 
followed by the Safety Follow-Up Period. 
7.3 
Packaging 
A 100g-volume of LEV dry syrup 50% will be filled in a 250mL bottle. Each bottle will be 
packaged individually. The needed number of the bottles will be dispensed to each study site. 
Down-Titration (4, 2 or 0 weeks) and Safety Follow-up (2 weeks)
60 (42) mg/kg/day
40 (28) mg/kg/day
20 (14) mg/kg/day
Early Discontinuation Visit (EDV)
Early Discontinuation Visit (EDV)
Early Discontinuation Visit (EDV)
or First Period final dose
or First Period final dose
or First Period final dose
40 (28) mg/kg/day
20 (14) mg/kg/day
20 (14) mg/kg/day
0 (0) mg/kg/day
0 (0) mg/kg/day
0 (0) mg/kg/day
EDV
SFU*
EDV
SFU*
EDV
SFU*
*: Safety Follow-Up (SFU) is 2 weeks after final dose of study drug.
Week 0
Week 0
Week 2
Week 4
Week 0
Week 2
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The research pharmacist at the study site(s) will fill out each sachet with the prescribed amount 
of LEV dry syrup 50%. 
Levetiracetam injection (100mg/mL) will be packaged in 5mL glass vials (500mg/5mL). A dose 
of the drug (500mg to 1500 mg) must be diluted in 100mL of saline, lactate Ringer’s solution, or 
5% glucose solution. Consideration should be given to reducing the dilution volume for use in 
children by referring to the dilute concentration for adult use. The drug should be used 
immediately after dilution. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language. 
7.5 
Handling and storage requirements 
The investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label. 
7.6 
Drug accountability 
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the sponsor 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 IMP until returned or destroyed. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The investigator must ensure that the IMP is used only in accordance with the protocol. 
7.7 
Procedures for monitoring subject compliance 
At each visit after IMP is dispensed, subjects must return all unused IMP and empty IMP 
containers. Drug accountability must be done in the subject’s presence in order to obtain 
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explanations regarding discrepancies in compliance with the dosing regimen. Drug 
accountability must be recorded on the Drug Accountability form. 
If a subject is found to be persistently noncompliant (<80% or >120% compliant with the dosage 
schedule), the sponsor, in conjunction with the investigator, will make a decision as to whether 
the subject should be withdrawn from the study. 
7.8 
Concomitant medications/treatments 
An accurate record of treatments other than the IMP must be kept in the clinic chart (source 
documentation) and the Case Report form (CRF). This record should include the name of the 
medication, the dose, the date(s) of administration, and the indication for use. 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
First Period 
Subjects on adjunctive therapy must be on a stable regimen of 1 or a maximum of 2 other AEDs 
for the Selection and Evaluation Periods (Appendix 3 [Section 17.3]). No new AEDs may be 
added or current AEDs discontinued for at least 2 weeks prior to Visit 1. Minor adjustments to 
the dose of current AEDs are allowed prior to Visit 1 only. 
Subjects on adjunctive therapy who have VNS that have been implanted for at least 6 months 
prior to Visit 1 are allowed as long as the settings have been stable for at least 2 months prior to 
Visit 1. Activated VNS must be counted as 1 of the 2 AEDs. 
The use of intermittent benzodiazepines, phenobarbitals, and phenytoins is allowed as long as the 
frequency is not greater than 1 single administration per week for at least 2 weeks prior to Visit 1 
and during the First Period. If benzodiazepines are used more than once a week, they must be 
considered as 1 of the AEDs. 
Second Period 
The Investigator (or designee) will be allowed to change the type, dosage and administration, or 
discontinue/resume concomitant AEDs to optimize tolerability and seizure reduction for each 
subject after 3 months of the start of the Second Period. Changes in concomitant AED(s) will be 
allowed only if the dose of LEV has been stable for the previous 2 weeks; LEV dose must 
remain stable during changes to concomitant AED(s). Subjects may take no more than 
3 concomitant AEDs except when temporary (≤12 weeks) use of an additional AED is required 
to switch to a new AED (ie, taper from old AED during titration of new AED). New AED(s) 
may be added only when the subject has not optimally or adequately responded to a maximum 
tolerated dose of LEV. The concomitant AED(s) can be carefully tapered or discontinued at the 
discretion of the investigator. Monotherapy with LEV is permitted. Increasing the dose of LEV 
and/or concomitant AED(s), as well as addition of a new AED should be done at a visit 
(scheduled or unscheduled). There are no restrictions for concomitant AED(s) during the 
Down-Titration Period, considering subject safety. 
The use of intermittent benzodiazepines, phenobarbitals, and phenytoins is allowed as long as the 
frequency is not greater than 1 single administration per week during the Second Period. If 
benzodiazepines are used more than once a week, they must be considered as 1 of the AEDs. 
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7.8.2 
Prohibited concomitant treatments (medications and therapies) 
First Period 
Medications that may influence the central nervous system, ie, neuroleptics, antidepressants, 
psychostimulants, anticholinergics, tranquilizers, hypnotics, and narcotic analgesics should be 
avoided. If the use of CNS-influencing medication cannot be avoided, the subject must be on a 
stable regimen of the medication for at least 1 month prior to Visit 1. 
Second Period 
No concomitant treatments are prohibited during the Second Period. 
7.9 
Blinding 
This is an open-label study. 
7.10 
Randomization and numbering of subjects 
To enroll a subject (Visit 1), the Investigator or designee will contact the interactive response 
technology (IRT) and provide brief details about the subject to be enrolled. Each subject will 
receive a 5-digit number assigned at screening that serves as the subject identifier throughout the 
study. The subject number will be required in all communication between the Investigator or 
designee and the IRT regarding a particular subject. Subject numbers and kit numbers will be 
tracked via the IRT.  
8 
STUDY PROCEDURES BY VISIT 
The following will be obtained or assessed according to the Schedule of study assessments. Prior 
to any study activities, the subject’s legal representative will be asked to read and sign an 
Informed Consent form that has been approved by an IRB/IEC and which complies with 
regulatory requirements. The subject’s legal representative will be given adequate time to 
consider any information concerning the study, given to them by the Investigator or designee. As 
part of the informed consent procedure, the subject’s legal representative will be given the 
opportunity to ask the Investigator any questions regarding potential risks and benefits of 
participation in the study. 
8.1 
First Period 
See Section 5.2 for the schedule of assessments for the First Period. The visit window for Visit 4 
through Visit 6 is ±4 days. Visit 1 assessments will be performed for all subjects. 
8.1.1 
Selection Period 
8.1.1.1 
Visit 1/Day -9 to Day -2 (Screening) 
• Written informed consent 
• Register subject 
• Assess subject eligibility 
• Perform EEG (for subjects who have not had an EEG confirming the consistent with a 
diagnosis of localized epilepsy and the consistent with partial onset seizures.) 
• Collect demographic information 
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• Collect medical/procedures history, including AED and epilepsy history 
• Physical examination 
• Neurological examination 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count for seizures that occurred in the prior 2 weeks 
• Collect blood samples for safety laboratory assessments 
• Record body weight and height 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Perform ECG 
• Perform CT scan or MRI (for subjects who have not had a CT scan or MRI confirming the 
absence of a progressive lesion since being diagnosed with epilepsy, or have changes on 
physical examination that would suggest a lesion has occurred since the last imaging 
procedure. 
• Contact IVRS/IWRS 
• Dispense DRC 
• Dispense subject identification card 
8.1.1.2 
Visit 2/Day -2 to Day 0 
Not applicable. 
8.1.2 
Evaluation Period 
8.1.2.1 
Visit 3 (Week 0) 
• Register subject 
• Confirm subject eligibility 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count (record seizure count from after Visit 1 to Visit 3 based on the DRC) 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures from after 
Visit 1 to Visit 3 
• Record AEs from after Visit 1 to Visit 3 
• Dispense study drug 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
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8.1.2.2 
Visit 4 (Week 2) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Collect seizure count from DRC 
• Dispense/collect DRC 
• Study drug compliance 
• Confirm if fallback option is necessary and reason(s) to decrease the dosage 
• Contact IVRS/IWRS 
• Dispense/collect study drug 
8.1.2.3 
Visit 5 (Week 4) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Confirm if fallback option is necessary and reason(s) to decrease the dosage 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.1.3 
Visit 6 (Week 6) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level 
• Record body weight 
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• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Collect seizure count 
• Dispense/collect DRC 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect study drug 
8.2 
Second Period 
8.2.1 
Visit 7 (Week 8) 
Not applicable. 
8.2.2 
Visit 8 (Week 10) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood sample for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.2.3 
Visit 9 (Week 12) 
Not applicable. 
8.2.4 
Visit 10 (Week 14) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
• Collect blood sample for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
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• Dispense/collect study drug 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.2.5 
Visit 11 (Week 18) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood sample for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.2.6 
Visit 12 (Week 22) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood sample for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.2.7 
Visit 13 (Week 26) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
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• Collect blood sample for LEV plasma level 
• Record body weight and height 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Perform ECG 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.2.8 
Visit 14 (Week 32) 
Not applicable. 
8.2.9 
Visit 15 (Week 38) 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
8.2.10 
Visit 16 (Week 50) 
From Visit 16 onward, visits will occur every 12 weeks until approval or discontinuation of 
development. 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
• Record body weight 
• Record height (assessment will occur every 24 weeks during visits with even numbers) 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
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• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Perform ECG (assessment will occur every 24 weeks during visits with even numbers) 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
• C-SSRS (will be performed at each visit for subjects aged ≥6 years) 
8.3 
Direct Enrollment 
Not applicable. 
8.4 
Safety Follow-Up Visit (if applicable) 
The Safety Follow-Up Visit will occur 2 weeks after the final dose of study medication and will 
include the following assessments: 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
• Record body weight 
• Record height 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Perform ECG (to be performed only if abnormal at EDV) 
• Contact IVRS/IWRS 
• Collect DRC 
• C-SSRS (will be performed for subjects aged ≥6 years) 
8.5 
Early Discontinuation Visit 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments (at Week 0 only) 
• Record body weight 
• Record height (at Week 0 only) 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
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• Dispense/collect study drug 
• Study drug compliance 
• Perform ECG (at Week 0 only) 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
• C-SSRS (will be performed for subjects aged ≥6 years) 
8.6 
Unscheduled Visit (if applicable) 
Unscheduled visits can be conducted at the discretion of the investigator (eg, due to an AE). All 
information, including reasons for the visit, any information on AEs, etc, should be collected in 
the source documents and recorded in the appropriate sections of the eCRF. 
During the Unscheduled Visit, the following assessments will be performed: 
• Concomitant medications 
• Concomitant AEDs 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight 
• AE reporting 
• Review withdrawal criteria 
In addition to the required assessments listed above, additional assessments may be performed at 
the investigator’s discretion. 
9 
ASSESSMENT OF EFFICACY 
The primary and secondary efficacy variables are based on the partial seizure frequency per 
week as measured by patient diary. 
10 
ASSESSMENT OF PHARMACOKINETIC VARIABLE 
Blood samples for the determination of LEV plasma concentrations will be collected according 
to the tabular schedules of study procedures (see Section 5.2). Dose amounts, dosing dates, and 
times for the 3 previous LEV doses before blood sampling must be recorded in the eCRF. The 
date and time of blood sampling must be recorded. 
Actual sampling times will be recorded in the eCRF to the minute. 
Details of plasma sample collection and processing, sample labeling, and shipment will be 
provided in the laboratory manual. 
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11 
ASSESSMENT OF SAFETY 
11.1 
Adverse events 
11.1.1 
Definitions 
11.1.1.1 
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
investigator from the subject’s history or the Baseline Period. 
For results disclosure on public registries (eg, ClinicalTrials.gov), TEAEs and 
treatment-emergent SAEs will be published. 
11.1.1.2 
Serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
• Death 
• Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
• Significant or persistent disability/incapacity 
• Congenital anomaly/birth defect (including that occurring in a fetus) 
• Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 11.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.) 
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• Initial inpatient hospitalization or prolongation of hospitalization 
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
11.1.1.3 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow-up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
subject. 
11.1.2 
Procedures for reporting and recording adverse events 
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
11.1.2.1 
Description of adverse events 
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) 
are described in the eCRF Completion Guidelines. 
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11.1.2.2 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
11.1.2.3 
Additional procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database. 
An Investigator SAE report form will be provided to the investigator. The Investigator SAE 
Report form must be completed in English. 
It is important for the investigator, when completing the SAE report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information (eg, autopsy or laboratory reports) received by the investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE report form. 
The investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the investigator is certain that they are in no way associated with the IMP), up to 
<X days/weeks> from the end of the study for each subject, and to also inform participating 
subjects of the need to inform the investigator of any SAE within this period. Serious AEs that 
the investigator thinks may be associated with the IMP must be reported to UCB regardless of 
the time between the event and the end of the study. 
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure. 
11.1.3 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the investigator determines 
that it is no longer clinically significant, or the subject is lost to follow up. This follow-up 
requirement applies to AEs, SAEs, and AEs of special interest; further details regarding follow 
up of PDILI events is provided in Section 11.2.1.4. 
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If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
investigator must provide a justification. The follow up will usually be continued for 30 days 
after the subject has discontinued his/her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
11.1.4 
Suspected transmission of an infectious agent via a medicinal 
product 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
11.1.5 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
11.1.6 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or electrocardiogram [ECG] results) for which data will be periodically 
reviewed during the course of the study. 
11.2 
Laboratory measurements 
Blood specimens for routine assay of hematology and clinical chemistry testing will be collected 
according to the tabular schedule of study procedures (Section 5.2). A central laboratory will 
perform the routine analysis of blood specimens. The procedures for handling and shipping these 
specimens will be provided to the sites. 
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The following laboratory parameters will be measured: 
Table 11‒1: Laboratory measurements 
Hematology 
Chemistry 
Red blood cell count 
AST 
Hemoglobin 
ALT 
Hematocrit 
GGT 
Platelet count 
ALP 
White blood cell count 
Total bilirubin 
Neutrophil count 
BUN 
Lymphocyte count 
Creatinine 
Monocyte count 
Creatinine clearance 
Eosinophil count 
Sodium 
Basophil count 
Potassium 
Reticulocyte count 
Calcium 
MCV 
Total protein 
MCH 
Albumin 
MCHC 
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma-glutamyltransferase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; WBC=white blood cell 
11.2.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 11.1.1.3), and, if applicable, also reported as an 
SAE (see Section 11.1.1.2). 
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒2 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.2.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.2.1.4). 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
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All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 11.2.1.3 are met, rechallenge with IMP may be appropriate. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
The table below summarizes the approach to investigate PDILI. 
 
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Table 11‒2: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology consult.c 
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and subject 
discussed with 
Medical Monitor 
ASAP. 
Immediate, 
permanent IMP 
discontinuation. 
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 11.2.1.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, 
stabilize, or return to within 
baseline values.d 
≥8xULN 
NA 
NA 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥3xULN 
(and ≥2x 
baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met. 
Further 
investigation – 
immediate IMP 
discontinuation not 
required (see 
Section 11.2.1.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator). 
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Table 11‒2: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥5xULN 
(and ≥2x 
baseline) 
and 
<8xULN 
<2xULN 
No 
Hepatology consult 
if there is no 
evidence of 
resolution (see 
Follow up 
requirements).c 
 
Discussion with 
Medical Monitor 
required. 
IMP discontinuation 
required if any of 
the following occur: 
Subject cannot 
comply with 
monitoring 
schedule. 
Liver chemistry 
values continue to 
increase during 
2 week monitoring 
period. 
Liver chemistry 
values remain 
≥5xULN (and 
≥2x baseline) after 
2 week monitoring 
period. 
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
at the site with 
HCP (see 
Section 11.2.1.3). 
Monitoring of liver chemistry 
values at least twice per week 
for 2 weeks.d 
Immediate IMP discontinuation 
required if liver chemistry 
values continue to increase. 
After 2 weeks of monitoring 
liver chemistry values: 
Discontinue IMP if levels 
remain ≥5xULN (and ≥2x 
baseline); monitor until values 
normalize, stabilize, or return 
to within baseline values. d 
Continue IMP if levels are no 
longer ≥5xULN (and ≥2x 
baseline); continue to monitor 
at least twice per week until 
values normalize, stabilize, or 
return to within baseline 
values.d 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal 
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 11.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
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11.2.1.1 
Consultation with Medical Monitor and local hepatologist 
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 11.2.1.3) and SAE report (if applicable). 
11.2.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒2 for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
11.2.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 11‒3 (laboratory measurements) and Table 11‒4 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding CRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
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The following measurements are to be assessed: 
Table 11‒3: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgA antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation 
Additional 
Prothrombin time/INRa 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgA=immunoglobulin A; IgM=immunoglobulin M; INR=international 
normalized ratio; LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; 
RNA=ribonucleic acid; ULN=upper limit of normal 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
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The following additional information is to be collected: 
Table 11‒4: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”) 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
• 
Recent travel  
• 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, 
or rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
11.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in Section 
Section 11.2.1. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
11.3 
Other safety measurements 
11.3.1 
Physical examination 
A physical examination will be performed by medically qualified clinicians licensed to perform 
the examination at Visit 1. Height will be measured according to schedule of study assessments. 
11.3.2 
Neurological examination 
A neurological examination will be performed at Visit 1. The neurological examination should 
be conducted by a medically qualified clinician with documented training in the conduct of 
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neurological examinations. The investigator or subinvestigator is responsible for confirming the 
diagnosis of partial seizures or other epilepsy syndrome. 
11.3.3 
Vital signs and body weight 
Blood pressure (systolic and diastolic), pulse rate, and body temperature will be measured at all 
visits. Body weight will be determined according to the schedule of study assessments. 
11.3.4 
12-lead ECG 
Standard 12-lead ECGs will be performed according to the schedule of study assessments. 
11.3.5 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). For subjects ≥6 years of age, this scale will be used to assess suicidal 
ideation and behavior that may occur during the study. The C-SSRS will be completed according 
to the tabular schedule of study procedures. 
The C-SSRS is not validated and will not be used for subjects <6 years of age. Subjects should 
be monitored for any changes in mood, ideas, or behavior for warning signs of depression. The 
investigator should be aware of common warning signs that might be a signal for risk of 
depression. For common signs and symptoms of depression in children younger than 6 years old, 
reference should be made to the current version of the Diagnostic and Statistical Manual of 
Mental Disorders. Parents and caregivers should also be advised accordingly and effort should be 
made at clinic visits to specifically assess potential depression. 
12 
STUDY MANAGEMENT AND ADMINISTRATION 
12.1 
Adherence to protocol 
The investigator should not deviate from the protocol. However, the investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
After implementation of such measure, the investigator must notify the CPM of the sponsor 
within 24 hours and follow any local regulatory requirements. 
12.2 
Monitoring 
Monitoring of the study will be delegated by UCB to a CRO. The CRO will monitor the study to 
meet the CRO’s monitoring Standard Operating Procedures (SOPs), ICH GCP guideline, and 
applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are 
adequate. Monitoring of the study may be delegated by UCB to a CRO or a contract monitor. 
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
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The investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and investigator’s obligations are being fulfilled, 
and resolve any inconsistencies in the study records. 
12.2.1 
Definition of source data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. Source documents should be kept in a secure, limited access area. 
Original laboratory results, ECGs, and EEGs are considered as source documents and should be 
stored with the subject’s study information. Source documents that are computer generated and 
stored electronically must be printed for review by the monitor (eg, ECG reports). Once printed, 
these copies should be signed and dated by the investigator and become a permanent part of the 
subject’s source documents. The investigator will facilitate the process for enabling the monitor 
to compare the content of the printout and the data stored in the computer to ensure all data are 
consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
12.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 12.2.1. 
12.3 
Data handling 
12.3.1 
Case Report form completion 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the eCRF. 
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Detailed instructions will be provided in the eCRF Completion Guidelines. 
12.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. Case Report form data are entered into the clinical database using independent, 
double-data entry, with the exception of comment fields, which are verified by a second person. 
The data are entered into the eCRFs once and are subsequently verified if the study is performed 
using electronic data capture. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log. 
The investigator will keep a Subject Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each subject. 
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
12.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
12.5 
Archiving and data retention 
The investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
The record retainer at the study site and the IRB/IEC will retain the GCP-defined essential 
documents until at least 10 years after the discontinuation or completion of the study conduct. If 
UCB requires retention of these documents for longer period, the duration and method of 
retention will be decided upon discussion between UCB and study site. 
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It is responsibility of UCB (or designee) to inform the record retainer as to when the documents 
should no longer to be retained. The record retainer (or designee) 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 record retainer (or designee) will also notify UCB should 
he/she relocate or move the study related files to a location other than that specified in the 
sponsor’s trial master file. 
12.6 
Audit and inspection 
The investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities. 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory 
requirements. 
The investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the investigator will immediately 
inform UCB (or designee). 
12.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
13 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
13.1 
Definition of analysis sets 
The following sets are defined for this study: 
• Enrolled Set (ES) 
• Safety Sets: 
− SS_A (Safety Set [Adjunctive therapy]) 
− SS_M (Safety Set [Monotherapy]) 
• Full Analysis Sets: 
− FAS_A (Full Analysis Set [Adjunctive therapy]) 
− FAS_M (Full Analysis Set [Monotherapy]) 
• Pharmacokinetic Per-Protocol Set (PK-PPS) 
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If not stated otherwise, presentation of: 
• Disposition and important protocol deviations are based on the ES 
• Demographics, other baseline characteristics, safety, and exposure data are based on the 
SS_A and SS_M 
• Efficacy data are based on the FAS_A and FAS_M. 
13.1.1 
Enrolled Set 
The ES will consist of all subjects enrolled (which include all subjects screened) into the 
Selection Period. 
13.1.2 
Safety Set 
The SS_A will include all enrolled subjects on adjunctive therapy who receive at least 1 dose of 
study medication in the Evaluation Period. 
The SS_M will include all enrolled subjects on monotherapy who receive at least 1 dose of study 
medication in the Evaluation Period. 
13.1.3 
Full Analysis Set 
The FAS_A will consist of all subjects in the SS_A who have at least 1 post-Baseline efficacy 
assessment. 
The FAS_M will consist of all subjects in the SS_M who have at least 1 post-Baseline efficacy 
assessment. 
13.1.4 
Per Protocol Set 
Not applicable. 
13.1.5 
Other analysis sets 
The PK-PPS will consist of all subjects in the SS_A and SS_M for whom at least 1 valid LEV 
plasma concentration-time record and dosing information are available. 
13.2 
Handling of data for subjects who were enrolled prior to 
protocol amendment 3 
Subjects who were directly enrolled in the Second Period based on the protocol prior to 
Amendment 3 will also be included in the efficacy and safety analysis with remapping of visit 
numbers to correspond to the ones for subjects who enrolled in the First Period. Details will be 
found in the SAP. 
13.3 
General statistical considerations 
Descriptive statistics will be used to provide an overview of the primary and other variable 
results. For categorical parameters, the number and percentage of subjects in each category will 
be presented. The denominator for percentages will be based on the number of subjects 
appropriate for the purpose of analysis. For continuous parameters, descriptive statistics will 
include number of subjects, mean, standard deviation, median, minimum, and maximum. Unless 
otherwise specified, Baseline will refer to the Visit 1 to Visit 3 assessments or the last non-
missing data collected prior to the first dose of IMP. 
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13.4 
Planned efficacy analyses 
All efficacy analysis will be performed for the FAS_A or FAS_M depending on therapy. 
13.4.1 
Analysis of the primary efficacy variable for adjunctive treatment 
The percent reduction in partial seizures per week from Baseline to Visit 6 will be calculated as: 
Number of partial seizures per week at Baseline – Number of seizures per week at Visit 6 x 100 
Number of partial seizures per week at Baseline 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the percent reduction in partial seizure frequency per week from Visit 6 by 
age category (3 categories: 1 month to <1 year, 1 year to <2 years, and 2 years to <4 years), and 
for all subjects combined (overall). The corresponding 95% confidence interval for the median 
percent reduction at Visit 6 will also be provided by age category and overall. If the lower limit 
of the 95% confidence interval for overall is greater than the predefined threshold of 15.0%, the 
efficacy of LEV is significant. If this test shows a significant result, then it will be repeated for 
the corresponding Visit 4 and Visit 5 variable. In that case, the second test is also regarded as 
confirmatory as due to the hierarchical testing procedure no alpha adjustment is needed. 
There is no primary efficacy variable for subjects on monotherapy. 
13.4.2 
Other efficacy analyses 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the continuous secondary and other variables and absolute and relative 
frequencies will be calculated for the categorical secondary and other variables. 
13.5 
Planned safety and other analyses 
Safety summaries will be performed for SS_A and SS_M depending on the therapy. 
13.5.1 
Safety analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be summarized by MedDRA System Organ Class and 
Preferred Term. The incidence of SAEs, AEs leading to premature discontinuation, and related 
AEs, and the incidence of AEs by intensity will also be summarized for the First Period and the 
combined First and Second Periods. 
For laboratory evaluations and vital signs descriptive statistic on the observed values and the 
change from baseline will be computed by analysis visits. The number of subjects reporting at 
least one treatment-emergent possibly clinically significant (PCS) value will be computed by 
analysis visits. 
13.5.2 
Other analyses 
Descriptive statistics of plasma concentrations of LEV will be summarized by subgroups and 
total. Scatter plots of plasma LEV concentrations vs time after dosing will be produced by 
subgroups and total. In addition, these figures will be superimposed on scatter plots of plasma 
concentration vs time in N01223 and figures of LEV plasma concentration time profiles 
simulated based on the population PK model established in N01288. As needed, population PK 
analysis will be planned and described in a separate data analysis plan. 
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13.6 
Handling of protocol deviations 
Prior to taking a snapshot for the interim analysis for New Drug Application (NDA) submission, 
protocol deviations will be assessed if important or not important and if included into the 
relevant analysis set according to predefined specifications. 
13.7 
Handling of dropouts or missing data 
Days with missing seizure data will not be used for the calculation of seizure frequency per 
week. If subjects drop out, their seizure counts over the available period will be used and 
transformed into seizure frequency per week, by dividing the number of seizures during the 
available period by the number of days of that period, multiplied by 7. 
Safety variables will be analyzed insofar as they are available, without imputation or carrying 
values forward. 
13.8 
Planned interim analysis and data monitoring 
No interim analyses are planned for this study. For regulatory purposes, a planned data cutoff 
will be made when the final subject who completes the First Period reaches Visit 13. All the 
efficacy and safety analysis planned in this protocol will be performed for NDA submission 
using the interim cutoff data followed by additional cutoff and/or final analysis for long-term 
follow-up evaluation. 
13.9 
Determination of sample size 
Based on the previous placebo-controlled clinical studies for pediatric epilepsy patients that 
evaluated AEDs, the percent reduction in ADF of partial seizure frequency from Baseline for 
placebo is assumed to be no more than 10%. For the purposes of this study, a percent reduction 
in ADF of partial seizure frequency ≤10% is defined as non-effective. Therefore, when the lower 
limit of 95% confidence interval (CI) of median in the percent reduction in ADF of partial 
seizure frequency for LEV is greater than 10%, statistical significance is declared. Based on the 
N01009 data for the percent reduction in ADF of partial seizure frequency for LEV, a population 
of size N was randomly sampled with replacement repeatedly for 10,000 times for the sample 
size consideration. The probability was evaluated that the lower limit of 95% CI of median in the 
percent reduction in ADF of partial seizure frequency for LEV was greater than 10% by samples 
with size of N. A sample size of at least 34 subjects are required to obtain 90% power. Assuming 
10% of subjects will be nonevaluable, 38 subjects will be enrolled. 
Due to the change in the primary efficacy variable in Protocol Amendment 3, the sample size 
was reconsidered. When the placebo rate area is conservatively redefined as ≤15% and assuming 
there are no nonevaluable subjects, a sample size of 38 subjects will obtain ≥80% power. 
Therefore, no change in sample size is required. 
14 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
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Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the investigator. 
Prior to participation in the study, the Informed Consent form should be signed and personally 
dated by the subject, or his/her legal representative, and by the person who conducted the 
informed consent discussion (investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent form. As part of 
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. 
If the Informed Consent form is amended during the study, the investigator (or the sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form. 
14.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The investigator will fill in the subject identifying information and medical emergency contact 
information. The investigator will instruct the subject to keep the card with him/her at all times. 
14.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
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As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
14.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
14.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
15 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable. 
16 
REFERENCES 
Berg AT, Loddenkemper T, Baca CB. Diagnostic delays in children with early onset epilepsy: 
Impact, reasons, and opportunities to improve care. Epilepsia, 2014;55(1):123-32. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Inoue Y. Commission on Treatment Guidelines of the Japan Epilepsy Society. Report from 
Commission on Treatment Guidelines of the Japan Epilepsy Society. Guidelines for drug therapy 
in adult patients with epilepsy. J Japan Epilepsy Society. 2005;23:249-53. 
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Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 
2001; 357: 216-22. 
Ministry of Health, Labour and Welfare, Patient Survey, 2011. 
Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 
1996;61:433-43. 
Thurman DJ, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, et al. Standards for 
epidemiologic studies and surveillance of epilepsy. Epilepsia. 2011;52:2-26. 
Ueda Y. A new era of anti-epileptic drug (AED): expectation for a new-type medicine and 
combination therapy with existing AED. Nihon Yakurigaku Zasshi. 2007;129:116-
8.2007;129:116-8. 
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17 
APPENDICES 
17.1 
Appendix 1 
International Classification of Epileptic Seizures (1981) 
I. Partial seizures (focal, local) 
A. Simple partial seizures (consciousness not impaired) 
1. With motor signs 
a) Focal motor without march 
b) Focal motor with march (Jacksonian) 
c) Versive 
d) Postural 
e) Phonatory (vocalization or arrest of speech) 
2. With somatosensory or special sensory symptoms (simple hallucinations, eg, tingling, 
light flashes, buzzing) 
a) Somatosensory 
b) Visual 
c) Auditory 
d) Olfactory 
e) Gustatory 
f) Vertiginous 
3. With autonomic symptoms or signs (including epigastric sensation, pallor, sweating, 
flushing, piloerection, and pupillary dilatation) 
4. With psychic symptoms (disturbance of higher cerebral function). These  symptoms 
rarely occur without impairment of consciousness and are much more  commonly 
experienced as complex partial seizures. 
a) Dysphasic 
b) Dysmnesic (eg, déjà-vu) 
c) Cognitive (eg, dreamy states, distortions of time sense) 
d) Affective (fear, anger, etc.) 
e) Illusions (eg, macropsia) 
f) Structured hallucinations (eg, music, scenes) 
B. Complex partial seizures (with impairment of consciousness: may sometimes begin 
with simple symptomatology) 
1. Simple partial onset followed by impairment of consciousness 
a) With simple partial features followed by impaired consciousness (A.1. - A.4.) 
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b) With automatisms 
2. With impairment of consciousness at onset 
a) With impairment of consciousness only 
b) With automatisms 
C. Partial seizures evolving to secondarily generalized seizures (this may be generalized 
tonic-clonic, tonic, or clonic) 
1. Simple partial seizures (A) evolving to generalized seizures 
2. Complex partial seizures (B) evolving to generalized seizures 
3. Simple partial seizures evolving to complex partial seizures evolving to generalized 
seizures 
II. Generalized seizures (convulsive or non-convulsive) 
A. 1. Absence seizures 
a) Impairment of consciousness only 
b) With mild clonic components 
c) With atonic components 
d) With tonic components 
e) With automatisms 
f) With autonomic components 
(b through f may be used alone or in combination) 
2. Atypical absence 
May have: 
a) Changes in tone that are more pronounced than in A.1 
b) Onset and/or cessation that is not abrupt 
B. Myoclonic seizures - Myoclonic jerks (single or multiple) 
C. Clonic seizures 
D. Tonic seizures 
E. Tonic-clonic seizures 
F. Atonic seizures - (Astatic) 
(combinations of the above may occur, eg, B and F, B and D) 
Ш. Unclassified epileptic seizures 
Includes all seizures that cannot be classified because of inadequate or incomplete data and some 
that defy classification in hitherto described categories. This includes some neonatal seizures, eg, 
rhythmic eye movements, chewing, and swimming movements. 
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Status epilepticus (prolonged partial or generalized seizures without recovery between attacks) 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. 
Epilepsia. 1981;22:489-501. 
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17.2 
Appendix 2 
International Classification of Epilepsies and Epileptic Syndromes (1989) 
1. Localization-related (focal, local, partial) epilepsies and syndromes 
1.1 Idiopathic (with age-related onset) 
• Benign childhood epilepsy with centrotemporal spike 
• Childhood epilepsy with occipital paroxysms 
• Primary reading epilepsy 
1.2 Symptomatic 
• Chronic progressive epilepsia partialis continua of childhood (Rasmussen syndrome) 
• Syndromes characterized by seizures with specific modes of precipitation 
• Temporal lobe epilepsy 
• Frontal lobe epilepsy 
• Parietal lobe epilepsy 
• Occipital lobe epilepsy 
1.3 Cryptogenic 
2. Generalized epilepsies and syndromes 
2.1 Idiopathic (with age-related onset − listed in order of age) 
• Benign neonatal familial convulsions 
• Benign neonatal convulsions 
• Benign myoclonic epilepsy in infancy 
• Childhood absence epilepsy (pyknolepsy) 
• Juvenile absence epilepsy 
• Juvenile myoclonic epilepsy (impulsive petit mal) 
• Epilepsy with grand mal (GTCS) seizures on awakening 
• Other generalized idiopathic epilepsies not defined above 
• Epilepsies with seizures precipitated by specific modes of activation 
2.2 Cryptogenic or symptomatic (in order of age) 
• West syndrome (infantile spasms, Blitz-Nick-Salaam Krämpfe) 
• Lennox-Gastaut syndrome 
• Epilepsy with myoclonic-astatic seizures 
• Epilepsy with myoclonic absences 
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2.3 Symptomatic 
2.3.1 Non-specific etiology 
• Early myoclonic encephalopathy 
• Early infantile epileptic encephalopathy with suppression-burst 
• Other symptomatic generalized epilepsies not defined above 
2.3.2 Specific syndromes 
3. Epilepsies and syndromes undetermined whether focal or generalized 
3.1 With both generalized and focal seizures 
• Neonatal seizures 
• Severe myoclonic epilepsy in infancy 
• Epilepsy with continuous spikes-waves during slow wave sleep 
• Acquired epileptic aphasia (Landau-Kleffner-syndrome) 
• Other undetermined epilepsies not defined above 
3.2 Without unequivocal generalized or focal features 
4. Special syndromes 
4.1 Situation-related seizures (Gelegenheitsanfälle, Occasional seizures) 
• Febrile convulsions 
• Isolated seizures or isolated status epilepticus 
• Seizures occurring only when there is an acute metabolic or toxic event due to factors 
such as alcohol, drugs, eclampsia, nonketotic hyperglycemia 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 
1989;30:389-99. 
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17.3 
Appendix 3 
The following is a list of antiepileptic drugs (generic name): 
• Acetazolamide 
• Acetylpheneturide 
• Amino (diphenylhydantoin) valeric acid 
• Barbexaclone 
• Beclamide 
• Brivaracetam 
• Carbamazepine 
• Carisbamate 
• Clobazam 
• Clonazepam 
• Diclofenamide 
• Eslicarbazepine 
• Ethadione 
• Ethosuximide 
• Ethotoin 
• Felbamate 
• Fosphenytoin 
• Gabapentin 
• Ilepcimide 
• Lacosamide 
• Lamotrigine 
• Levetiracetam 
• Mesuximide 
• Metharbital 
• Methylphenobarbital 
• Mephenytoin 
• Nitrazepam 
• Oxcarbazepine 
• Paramethadione 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 70 of 157 
• Perampanel 
• Phenacemide 
• Pheneturide 
• Phenobarbital 
• Phensuximide 
• Phenytoin 
• Pregabalin 
• Primidone 
• Progabide 
• Retigabine 
• Rufinamide 
• Stiripentol 
• Sultiame 
• Tiagabine 
• Topiramate 
• Trimethadione 
• Valproic acid 
• Valpromide 
• Vigabatrin 
• Zonisamide 
 
Note: An AED that contains more than one compound in this list is not counted as 1 AED. 
The number of compounds contained in 1 AED is counted as the number of AED administered. 
 
It is prohibited that subjects take levetiracetam other than IMP during the study. Antiepileptic 
drugs that have not been approved in Japan are prohibited. 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
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Page 71 of 157 
17.4 
Protocol Amendment 1 
Rationale for the amendment 
The purpose of this amendment is the following: 
• Correct inconsistencies between Table 5-1, Table 5-2, and Section 8 
• Clarify permitted concomitant treatments 
• Clarify withdrawal criteria 
In addition, minor administrative edits including typographical changes for formatting and/or 
spelling errors have been made. 
The following shows the changes made in Amendment 1 compared to the original protocol, 
dated 06 Feb 2016. 
Modifications and changes 
Specific changes 
Change #1:  
 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 72 of 157 
Table 5‒1: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2  
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W5 
W62 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety  
assessment 
X 
Xh 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
Xi 
X 
Xi 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X 
 
Xj 
 
Concomitant AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medical 
procedures 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
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Page 73 of 157 
Table 5‒1: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2  
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W5 
W62 
Adverse events 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug 
 
 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CT scan/MRIl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEGm 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect DRC  
Xn 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fallback optiono 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
C-SSRSp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; EDV=Early 
Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have W6 evaluations and the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. At V2, V4, and V6, seizures will be counted by video-EEG and DRC. At all other visits, seizures 
will be counted by DRC only. 
g Recorded from end of V1 through V3. 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
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Page 74 of 157 
Table 5‒1: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2  
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W5 
W62 
h If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available prior 
to V2, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
i Blood samples will be obtained prior to receiving LEV and then at least 2h after dosing at V4 and V6. 
j Height to be collected every 24 weeks at even numbered visits. 
k Dispense study drug at V3. 
l Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
m All video-EEG data recording will be transmitted to a central reader for the purposes of data analysis. 
n Dispense DRC at V1. Confirm DRC at V2. 
o Fallback option is permitted. See Section 5.1.2 for details. 
p C-SSRS to be performed at each visit for subjects aged ≥6 years. 
Has been changed to 
 
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22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
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Page 75 of 157 
Table 5‒1: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2  
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W1
0 
W12 
W14 
W18 
W22 
W26 
W32 
W3
8 
W50… 
W62… 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety  
assessment 
X 
Xh 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
Xi 
X 
Xi 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Concomitant AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 76 of 157 
Table 5‒1: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2  
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W1
0 
W12 
W14 
W18 
W22 
W26 
W32 
W3
8 
W50… 
W62… 
Concomitant medical 
procedures 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CT scan/MRIk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEGl 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/collect DRC 
Xm 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fallback optionn 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
C-SSRSo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
Xo 
 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; 
EDV=Early Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have W6 evaluations and the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. At V2, V4, and V6, seizures will be counted by video-EEG and DRC. At all other visits, 
seizures will be counted by DRC only. 
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22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 77 of 157 
Table 5‒1: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2  
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W1
0 
W12 
W14 
W18 
W22 
W26 
W32 
W3
8 
W50… 
W62… 
g Recorded from end of V1 through V3. 
h If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available 
prior to V2, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
i Blood samples will be obtained prior to receiving LEV and then at least 2h after dosing at V4 and V6. 
j Dispense study drug at V3. 
k Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
l All video-EEG data recording will be transmitted to a central reader for the purposes of data analysis. 
m Dispense DRC at V1. Confirm DRC at V2. 
n Fallback option is permitted. See Section 5.1.2 for details. 
o C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
Change #2: 
 
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22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 78 of 157 
Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
Evaluation 
Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2 
D-2  
to D0 
 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44 
W56 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure counts 
Xf 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety 
assessment 
X 
Xh 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Concomitant AED(s) 
X 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 79 of 157 
Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
Evaluation 
Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2 
D-2  
to D0 
 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44 
W56 
Concomitant medical 
procedures 
X 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
CT scan/MRIk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect DRC 
Xl 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS m 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; EDV=Early 
Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f Collect seizure count for seizures that occurred in the prior 2 weeks. 
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application and any extensions or variations thereof. 


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22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 80 of 157 
Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
Evaluation 
Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2 
D-2  
to D0 
 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44 
W56 
g Seizures will be counted by video-EEG and DRC. 
h If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available prior 
to V6, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
i Recorded from end of V1 through V6. 
j Dispense study drug at V6. 
k Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
l Dispense DRC at V1. Confirm DRC at V2. 
m C-SSRS to be performed at each visit for subjects aged ≥6 years. 
Has been changed to 
 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 81 of 157 
Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
Evaluation 
Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44 
W56 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety 
assessment 
X 
Xg 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Concomitant AED(s) 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 82 of 157 
Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
Evaluation 
Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44 
W56 
Concomitant medical 
procedures 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
CT scan/MRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect DRC 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSl 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; EDV=Early 
Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. At V2, seizures will be counted by video-EEG and DRC. At all other visits, seizures will be 
counted by DRC only. 
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Table 5‒2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
Evaluation 
Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c 
V17d 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44 
W56 
g If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available prior 
to V6, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
h Recorded from end of V1 through V6. 
I Dispense study drug at V6. 
j Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
k Dispense DRC at V1. Confirm DRC at V2. 
l C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
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Change #3: 
Table 5‒3: 
Schedule of assessments for Down-Titration and SFU Periods 
Visit 
  Study Week 
EDVa 
SFUb 
W0 
W2  
W4 
 
Vital signsc 
X 
X 
X 
X 
Seizure counts 
X 
X 
X 
X 
Laboratory safety assessments 
X 
 
 
X 
Body weight  
X 
X 
X 
X 
Height 
X 
 
 
X 
Concomitant AED(s) 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
X 
X 
X 
Concomitant medical procedures 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
Dispense/return study drug 
X 
X 
X 
 
Study drug compliance 
X 
X 
X 
 
ECG 
X 
 
 
Xd 
IVRS/IWRS 
X 
X 
X 
X 
Dispense/collect DRC 
X 
X 
X 
Xe 
C-SSRSf 
X 
X 
X 
X 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily 
record card; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EEG=electroencephalogram; ID=identification; 
IVRS=interactive voice response system; IWRS=interactive web response system; LEV=levetiracetam; MRI=magnetic 
resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
a The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to <6 months or by LEV 20mg/kg/day for 
subjects aged 6 months to <4 years at 2-week intervals to 0mg/kg/day. 
b Two weeks after final dose of study drug. 
c Including temperature, blood pressure, and heart rate. 
d Performed only if abnormal at EDV. 
e Collect DRC. 
f C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
Has been changed to 
 
 
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Table 5‒3: 
Schedule of assessments for Down-Titration and SFU Periods 
Visit 
  Study Week 
EDVa 
SFUb 
W0 
W2  
W4 
 
Vital signsc 
X 
X 
X 
X 
Seizure counts 
X 
X 
X 
X 
Laboratory safety assessments 
X 
 
 
X 
Body weight  
X 
X 
X 
X 
Height 
X 
 
 
X 
Concomitant AED(s) 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
X 
X 
X 
Concomitant medical procedures 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
Dispense/return study drug 
X 
X 
X 
 
Study drug compliance 
X 
X 
X 
 
ECG 
X 
 
 
Xd 
IVRS/IWRS 
X 
X 
X 
X 
Dispense/collect DRC 
X 
X 
X 
Xe 
C-SSRSf 
Xf 
Xf 
Xf 
Xf 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily 
record card; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EEG=electroencephalogram; ID=identification; 
IVRS=interactive voice response system; IWRS=interactive web response system; LEV=levetiracetam; MRI=magnetic 
resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
a The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to <6 months or by LEV 20mg/kg/day for 
subjects aged 6 months to <4 years at 2-week intervals to 0mg/kg/day. 
b Two weeks after final dose of study drug. 
c Including temperature, blood pressure, and heart rate. 
d Performed only if abnormal at EDV. 
e Collect DRC. 
f C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
Change #4: 
6.1: Inclusion criteria 
6.   Subject may have Vagal Nerve Stimulation (VNS) which has been implanted for at least 
6 months prior to Day -1; the settings must be stable for at least 2 months prior to Visit 1. 
Activated VNS must be counted as 1 of the 2 AEDs. 
Has been changed to 
6.   Subject may have Vagal Nerve Stimulation (VNS) which has been implanted for at least 
6 months prior to Visit 1; the settings must be stable for at least 2 months prior to Visit 1. 
Activated VNS must be counted as 1 of the 2 AEDs. 
 
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Change #5: 
6.3: Withdrawal criteria 
10. Subject on monotherapy needs to add another AED. 
Has been changed to 
10. Subject on monotherapy needs to add another AED during the First Period. 
 
Change #6: 
7.2: Treatments to be administered 
If the subject cannot take LEV dry syrup under a fasting state during the First Period, LEV 
100mg/mL concentrate for solution for infusion (clear, colorless, sterile solution) can be used for 
a maximum of 4.5 consecutive days at each dose at the Investigator’s discretion. 
Has been changed to 
If the subject cannot take LEV dry syrup under a fasting state during the First Period, LEV 
100mg/mL concentrate for solution for infusion (clear, colorless, sterile solution) can be used for 
a maximum of 4.5 consecutive days at each dose at the Investigator’s discretion. Levetiracetam 
injection is infused intravenously over 15 minutes per dose. 
 
Change #7: 
7.2: Treatments to be administered 
The following administration details have been added. 
First Period 
. . . 
Subjects aged 1 month to <6 months will be started on LEV 14mg/kg/day at Visit 3 (Week 0). 
The dose may be increased by LEV 14mg/kg/day for subjects aged 1 month to <6 months at 
2-week intervals to a maximum dose of LEV 42mg/kg/day. Subjects aged 6 months to <4 years 
will be started on LEV 20mg/kg/day at Visit 3 (Week 0). The dose may be increased by 
LEV 20mg/kg/day at 2-week intervals to a maximum dose of 60mg/kg/day. 
 
Change #8:  
7.9.1: Permitted concomitant treatments (medications and therapies) 
First Period 
The use of intermittent benzodiazepines is allowed as long as the frequency is not greater than 
1 single administration per week for at least 2 weeks prior to Visit 1 and during the First Period. 
If benzodiazepines are used more than once a week, they must be considered as 1 of the AEDs. 
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Has been changed to 
The use of intermittent benzodiazepines, phenobarbitals, and phenytoins is allowed as long as the 
frequency is not greater than 1 single administration per week for at least 2 weeks prior to Visit 1 
and during the First Period. If benzodiazepines are used more than once a week, they must be 
considered as 1 of the AEDs. 
 
Change #9: 
7.8.1: Permitted concomitant treatments (medications and therapies) 
Second Period 
The use of intermittent benzodiazepines is allowed as long as the frequency is not greater than 
1 single administration per week during the Second Period. If benzodiazepines are used more 
than once a week, they must be considered as 1 of the AEDs. 
Has been changed to 
The use of intermittent benzodiazepines, phenobarbitals, and phenytoins is allowed as long as the 
frequency is not greater than 1 single administration per week during the Second Period. If 
benzodiazepines are used more than once a week, they must be considered as 1 of the AEDs. 
 
Change #10: 
8.2.10: Visit 16 (Week 50) 
The following text was added: 
• C-SSRS (will be performed at each visit for subjects aged ≥6 years) 
 
Change #11: 
8.3: Direct enrollment 
See Section 5.2 for the schedule of assessments for subjects who are 48h video-EEG failures at 
Visit 2. The C-SSRS will be performed at each visit for subjects aged ≥6 years. 
Has been changed to 
See Section 5.2 for the schedule of assessments for subjects who are 48h video-EEG failures at 
Visit 2. 
 
Change #12: 
8.4: Safety Follow Up Visit (if applicable) 
The following text was added: 
• Record height 
 
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Change #13: 
8.6: Unscheduled Visit (if applicable) 
• Vital signs (BP and pulse rate, including orthostatic assessments where feasible according to 
investigator judgment) 
Has been changed to 
• Vital signs (blood pressure, pulse rate, and body temperature) 
 
Change #14: 
Table 11‒3: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic acid; 
ULN=upper limit of normal 
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a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
 
Has been changed to 
Table 11‒3: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgA antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation 
Additional 
Prothrombin time/INRa 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgA=immunoglobulin A; IgM=immunoglobulin M; INR=international 
normalized ratio; LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; 
RNA=ribonucleic acid; ULN=upper limit of normal 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
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Change #15: 
Section 13.1: Definition of analysis sets 
The Safety Set (SS) will include all enrolled subjects in the First Period or the Second Period 
who will be administrated at least 1 dose of study medication. 
First Period 
The SS (for the First Period) will include all enrolled subjects in the First Period who receive at 
least 1 dose of study medication. The FAS (for the First Period and adjunctive therapy) will 
consist of all subjects in the SS who receive adjunctive therapy, have at least 24h of usable 
Selection Period video-EEG time, and have at least 1 post-baseline efficacy assessment from 
either the Evaluation Period video-EEG time or DRCs. 
. . .  
The Pharmacokinetic Per Protocol Set (PK-PPS) will consist of all subjects in the SS for whom 
at least 1 valid LEV plasma concentration-time record and dosing information are available. 
 
Has been changed to 
Section 13.1: Definition of analysis sets 
The Safety Set (SS) will include all enrolled subjects in the First Period or the Second Period 
who will be administrated at least 1 dose of study medication. 
The Pharmacokinetic Per Protocol Set (PK-PPS) will consist of all subjects in the SS for whom 
at least 1 valid LEV plasma concentration-time record and dosing information are available. 
First Period 
The SS (for the First Period) will include all enrolled subjects in the First Period who receive at 
least 1 dose of study medication. The FAS (for the First Period and adjunctive therapy) will 
consist of all subjects in the SS who receive adjunctive therapy, have at least 24h of usable 
Selection Period video-EEG time, and have at least 1 post-baseline efficacy assessment from 
either the Evaluation Period video-EEG time or DRCs. 
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17.5 
Protocol Amendment 2 
Rationale for the amendment 
The purpose of this amendment is to update the long-term efficacy and safety assessments so that 
they are more appropriate, taking into account 48h video-EEG failures. 
In addition, minor administrative edits including typographical changes for formatting have been 
made. 
The following shows the changes made in Protocol Amendment 2 compared to Protocol 
Amendment 1, dated 16 Jun 2017. 
Modifications and changes 
Specific changes 
Change #1: 
Section 3.2: 
Secondary objectives 
• To evaluate long-term safety and tolerability of LEV in the Second Period in pediatric 
epilepsy subjects aged 1 month to <4 years with partial seizures receiving long-term 
treatment with LEV at individualized doses 
• To evaluate the efficacy of LEV in the Second Period based on the daily record card (DRC) 
as monotherapy or adjunctive treatment in pediatric epilepsy subjects aged 1 month to  
<4 years with partial seizures 
Has been changed to 
Section 3.2: 
Secondary objectives 
• To evaluate long-term safety and tolerability of LEV in the combined First and Second 
Periods in pediatric epilepsy subjects aged 1 month to <4 years with partial seizures receiving 
long-term treatment with LEV at individualized doses 
• To evaluate the efficacy of LEV in the combined First and Second Periods based on the daily 
record card (DRC) as monotherapy or adjunctive treatment in pediatric epilepsy subjects 
aged 1 month to <4 years with partial seizures 
 
Change #2: 
Section 4.1: 
Efficacy Variables 
Section 4.1.1: Efficacy variables for subjects on adjunctive therapy 
Efficacy variables are defined separately for the First Period and the Second Period. 
Has been changed to 
Section 4.1: 
Efficacy variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
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Section 4.1.1: Efficacy variables for subjects on adjunctive therapy 
 
Change #3: 
Section 4.1.1.1.2: Second Period 
There is no primary efficacy variable for the Second Period. 
Has been changed to 
Section 4.1.1.1.2: Combined First and Second Periods 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
 
Change #4: 
Section 4.1.1.2.1: First Period 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, 50% to <75%, 75% to <100% and 100% on the Evaluation Period 48h 
video-EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 for the 
First Period 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
for the First Period 
Has been changed to 
Section 4.1.1.2.1: First Period 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, ≥50%, ≥75%, and 100% based on the Evaluation Period 48h video-
EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline at Visit 4, Visit 5, and Visit 6 
 
Change #5: 
Section 4.1.1.2.2: Second Period 
•  Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Maintenance Period for the Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 50% to <75%, 75% to 
<100%, and 100% during the Maintenance Period for the Second Period 
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Has been changed to 
Section 4.1.1.2.2: Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
Refer to Section 13.2 for the definition of each analysis visit. 
 
Change #6: 
Section 4.1.1.3.1: First Period 
•  Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 for the First Period 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 50% to <75%, 75% to <100%, 
and 100% on the Evaluation Period 48h video-EEG compared to the Selection Period 48h 
video-EEG at Visit 4 and Visit 6 for the First Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period for the First Period 
Has been changed to 
Section 4.1.1.3.1: First Period 
The other efficacy variables for the First Period are the following: 
• Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG compared to the Selection Period 48h video-EEG at 
Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period 
 
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Change #7: 
Section 4.1.1.3.2: Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline by visit during the Maintenance Period for the Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 50% to <75%, 75% to 
<100%, and 100% by visit during the Maintenance Period for the Second Period (A,M) 
Has been changed to 
Section 4.1.1.3.2: Combined First and Second Periods 
There are no other efficacy variables for the combined First and Second Periods. 
 
Change #8: 
Added new section: 
Section 4.1.2.1: 
Primary efficacy variable 
There is no primary efficacy variable for subjects on monotherapy. 
 
Change #9: 
Section 4.1.2.1: 
Secondary efficacy variables 
Section 4.1.2.1.1: First Period 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 for the First Period 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, 50% to <75%, 75% to <100% and 100% on the Evaluation Period 48h 
video-EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 for the 
First Period 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
for the First Period 
Has been changed to 
Section 4.1.2.2: 
Secondary efficacy variables 
Section 4.1.2.2.1: First Period 
The secondary efficacy variables for the First Period are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 
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• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, ≥50%, ≥75%, and 100% based on the Evaluation Period 48h video-
EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
 
Change #10: 
Section 4.1.2.1.2: Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Maintenance Period for the Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 50% to <75%, 75% to 
<100%, and 100% during the Maintenance Period for the Second Period 
• Subjects who are continuously 6-month seizure-free monitored by the patient diary during 
the Maintenance Period for the Second Period 
Has been changed to 
Section 4.1.2.2.2: Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
Refer to Section 13.2 for the definition of each analysis visit. 
 
Change #11: 
Section 4.1.2.1.3: Other efficacy variables 
Section 4.1.2.1.3.1: 
First Period 
•  Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 for the First Period 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 50% to <75%, 75% to <100%, 
and 100% on the Evaluation Period 48h video-EEG compared to the Selection Period 
48h video-EEG at Visit 4 and Visit 6 for the First Period 
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• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period for the First Period 
Has been changed to 
Section 4.1.2.3: 
Other efficacy variables 
Section 4.1.2.3.1: First Period 
The other efficacy variables for the First Period are the following: 
• Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG compared to the Selection Period 48h video-EEG at 
Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period 
 
Change #12: 
Section 4.1.2.1.3.2: 
Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline by visit during the Maintenance Period for the Second Period 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 50% to <75%, 75% to 
<100%, and 100% by visit during the Maintenance Period for the Second Period 
• Subjects who are continuously seizure-free monitored by the patient diary by analysis period 
during the Maintenance Period for the Second Period 
Section 4.1.2.1.3.3: 
First and Second Period Combined 
• Subjects who are continuously 6-month seizure-free monitored by the patient diary during 
the First Period and the Second Period 
Has been changed to 
Section 4.1.2.3.2: Combined First and Second Periods 
The other efficacy variable for the combined First and Second Periods is the following: 
• Subjects who are continuously 6-month seizure-free monitored by the patient diary during 
the combined Evaluation and Maintenance Periods for subjects who are not 48h video-EEG 
failures, and the combined Dose adjustment and Maintenance Periods for subjects who are 
48h video-EEG failures 
 
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Change #13: 
Added new section: 
Section 4.3.1: Primary safety variable 
There is no primary safety variable. 
 
Change #14: 
Section 4.3.1: Secondary safety variables 
• Incidence of TEAEs during the First Period 
• Incidence of SAEs during the First Period 
• Incidence of TEAEs led to discontinuation during the First Period 
• Incidence of TEAEs during the Second Period 
• Incidence of SAEs during the Second Period 
• Incidence of TEAEs leading to discontinuation during the Second Period 
 
Has been changed to 
Section 4.3.2: Secondary safety variables 
Section 4.3.2.1: 
First Period 
The secondary safety variables for the First Period are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs led to discontinuation 
Section 4.3.2.2: 
Combined First and Second Periods 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to discontinuation 
 
Change #15: 
Section 4.3.2: Other safety variables 
Has been changed to 
Section 4.3.3: Other safety variables 
The other safety variables are the following: 
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Change #16: 
 
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Table 5-2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44… 
W56… 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety 
assessment 
X 
Xg 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Concomitant AED(s) 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
non-AED(s) 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Has been changed to 
Concomitant medical 
procedures 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
CT scan/MRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect DRC 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS l 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; EDV=Early 
Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5-3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. . At V2, seizures will be counted by video-EEG and DRC. At all other visits, seizures will be 
counted by DRC only. 
g If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available prior 
to V6, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
h Recorded from end of V1 through V6. 
I Dispense study drug at V6. 
j Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
k Dispense DRC at V1. Confirm DRC at V2. 
l C-SSRS to be performed at each visit for subjects aged ≥6 years. 
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Table 5-2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
 
Dose Adjustment Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44… 
W56… 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety 
assessment 
X 
Xg 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Concomitant AED(s) 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 5-2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
 
Dose Adjustment Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44… 
W56… 
Concomitant 
non-AED(s) 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medical 
procedures 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
CT scan/MRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect DRC 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS l 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; EDV=Early 
Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5-3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
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Table 5-2: 
Schedule of assessments for subjects who are 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection 
Period 
 
Dose Adjustment Perioda 
Maintenance Perioda, b 
V1 
V2 
V3 to V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2  
to D0 
W0 
W2 
W4 
W6 
W8 
W12 
W16 
W20 
W26 
W32 
W44… 
W56… 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. At V2, seizures will be counted by video-EEG and DRC. At all other visits, seizures will be 
counted by DRC only. 
g If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available prior 
to V6, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
h Recorded from end of V1 through V6. 
I Dispense study drug at V6. 
j Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
k Dispense DRC at V1. Confirm DRC at V2. 
l C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
 
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Change #17: 
Figure 5-1: Schematic for subjects in the First and Second Periods 
 
 
 
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Has been changed to 
Figure 5-1: Schematic for subjects in the First and Second Periods 
 
 
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Change #18: 
Section 13.1: Definition of analysis sets 
The Safety Set (SS) will include all enrolled subjects in the First Period or the Second Period 
who will be administrated at least 1 dose of study medication. 
The Pharmacokinetic Per Protocol Set (PK-PPS) will consist of all subjects in the SS for whom 
at least 1 valid LEV plasma concentration-time record and dosing information are available. 
First Period 
The SS (for the First Period) will include all enrolled subjects in the First Period who receive at 
least 1 dose of study medication. 
The FAS (for the First Period and adjunctive therapy) will consist of all subjects in the SS who 
receive adjunctive therapy, have at least 24h of usable Selection Period video-EEG time, and 
have at least 1 post-baseline efficacy assessment from either the Evaluation Period video-EEG 
time or DRCs. 
The FAS (for the First Period and monotherapy) will consist of all subjects in the SS who receive 
monotherapy, have at least 24h of usable Selection Period video-EEG time, and have at least 
1 post-baseline efficacy assessment from either the Evaluation Period video-EEG time or DRCs. 
The Per-Protocol Set (PPS; for the First Period and adjunctive) will consist of all subjects in the 
FAS who have at least 24h of usable Evaluation Period video-EEG time and do not have 
important protocol deviations that affect the primary efficacy variable in the First Period. 
Second Period 
Safety Set 2 (SS2) (for the Second Period) will include all enrolled subjects in the Second Period 
who have receive at least 1 dose of study medication in the Second Period. 
The Full Analysis Set 2 (FAS2) (for the Second Period and adjunctive therapy) will consist of all 
subjects in the SS2 who receive adjunctive therapy, have an assessable baseline, and have at least 
1 post-baseline partial seizure from DRCs in the Second Period. 
The FAS2 (for the Second Period and monotherapy) will consist of all subjects in the SS2 who 
receive monotherapy, have an assessable baseline, and at least 1 post-baseline partial seizure 
from DRCs in the Second Period. 
The PPS is not defined for the Second Period. 
Both Periods 
The Full Analysis Set 3 (FAS3) (for both the First and Second Periods and monotherapy) will 
include all enrolled subjects in either the First Period or the Second Period who receive at least 
1 dose of study medication in the either the First Period or the Second Period, have an assessable 
baseline, and at least 1 post-baseline partial seizure from DRCs in the First Period or Second 
Period. 
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Has been changed to 
Section 13.1: Definition of analysis sets 
The following sets are defined for this study: 
• Enrolled Set (ES) 
• Safety Sets: 
− SS A1 (Safety Set [Adjunctive therapy, First Period], ie, Safety Set for subjects on 
Adjunctive Therapy during the First Period) 
− SS M1 (Safety Set [Monotherapy, First Period]) 
− SS A12 (Safety Set [Adjunctive therapy, combined First and Second Periods]) 
− SS M12 (Safety Set [Monotherapy, combined First and Second Periods]) 
• Full Analysis Sets: 
− FAS A1 (Full Analysis Set [Adjunctive therapy, First Period], ie, Full Analysis Set for 
subjects on Adjunctive Therapy during the First Period) 
− FAS M1 (Full Analysis Set [Monotherapy, First Period]) 
− FAS A12 (Full Analysis Set [Adjunctive therapy, combined First and Second Periods]) 
− FAS M12 (Full Analysis Set [Monotherapy, combined First and Second Periods]) 
• Per-Protocol Set (PPS) 
• Pharmacokinetic Per-Protocol Set (PK-PPS) 
If not stated otherwise, presentation of: 
• Disposition and important protocol deviations are based on the ES 
• Demographics, other baseline characteristics, safety, and exposure data are based on the 
SS A12 and SS M12 
• Efficacy data are based on the FAS A1, FAS M1, FAS A12, and FAS M12. Sensitivity 
analyses on the primary efficacy variable are repeated for the PPS. 
 
Change #19: 
Added new section: 
Section 13.1.1: 
Enrolled Set 
The ES will consist of all subjects enrolled (which include all subjects screened) into the 
Selection Period. 
 
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Change #20: 
Added new section: 
Section 13.1.2: 
Safety Set 
First Period: 
The SS A1 will include all enrolled subjects on adjunctive therapy in the First Period who 
receive at least 1 dose of study medication in the Evaluation Period. 
The SS M1 will include all enrolled subjects on monotherapy in the First Period who receive at 
least 1 dose of study medication in the Evaluation Period. 
Combined First and Second Periods: 
The SS A12 will include all enrolled subjects on adjunctive therapy in the Evaluation, Dose 
adjustment, and Maintenance Periods who receive at least 1 dose of study medication in the 
Evaluation, Dose adjustment, or Maintenance Periods. 
The SS M12 will include all enrolled subjects on monotherapy in the Evaluation, Dose 
adjustment, and Maintenance Periods who receive at least 1 dose of study medication in the 
Evaluation, Dose adjustment, or Maintenance Periods. 
 
Change #21: 
Added new section: 
Section 13.1.3: 
Full Analysis Set 
First Period: 
The FAS A1 will consist of all subjects in the SS A1 who entered the First Period, who receive 
adjunctive therapy, have at least 24h of usable video-EEG time in the Selection Period, with at 
least 2 partial seizures, and have at least 1 post-baseline efficacy assessment from the First 
Period video-EEG time or DRCs in the Evaluation Period. 
The FAS M1 will consist of all subjects in the SS M1 who entered the First Period, who receive 
monotherapy, have at least 24h of usable video-EEG time in the Selection Period, with at least 
2 partial seizures, and have at least 1 post-baseline efficacy assessment from the First Period 
video-EEG time or DRCs in the Evaluation Period. 
Combined First and Second Periods: 
The FAS A12 will consist of all subjects in the SS A12, who receive adjunctive therapy, have at 
least 24h of usable video-EEG time in the Selection Period, and have at least 1 post-baseline 
efficacy assessment from the First Period video-EEG time, or DRCs in the Evaluation, Dose-
adjustment, or Maintenance Period. 
The FAS M12 will consist of all subjects in the SS M12, who receive monotherapy, have at least 
24h of usable video-EEG time in the Selection Period, and have at least 1 post-baseline efficacy 
assessment from the First Period video-EEG time, or DRCs in the Evaluation, Dose-adjustment, 
or Maintenance Period. 
 
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Change #22: 
Added new section: 
Section 13.1.4: 
Per Protocol Set 
The PPS (Adjunctive therapy and First Period) will consist of all subjects in the FAS A1 who 
have at least 24h of usable video-EEG time in the First Period, and do not have important 
protocol deviations that affect the primary efficacy variable in the Evaluation Period. 
The PPS is not defined for the combined First and Second Periods. 
 
Change #23: 
Added new section: 
Section 13.1.5: 
Other analysis sets 
The PK-PPS will consist of all subjects in the SS A12 and SS M12 for whom at least 1 valid 
LEV plasma concentration-time record and dosing information are available. 
 
Change #24: 
Added new section: 
Section 13.2: Definition of analysis visits 
Table 13‒1 presents the mapping of study visits to analysis visits for subjects who are not 48h 
video-EEG failures and for subjects who are 48h video-EEG failures. Analysis visits will be used 
for analysis of long-term safety and efficacy data. 
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Table 13-1: Analysis visit mapping table 
Analysis 
Visit 
Week 
number 
Relative day 
since first study 
drug 
administration 
Analysis 
window 
Subjects who are 
not 48h video-
EEG failures 
Study Visit 
(Relative day) 
Subjects who are 
48h video-EEG 
failures 
Study Visit 
(Relative day) 
0 
0 
1 
- 
Visit 3 
Visit 6 
1 
2 
15 
2 – 22 
Visit 4 
Visit 7 
2 
4 
29 
23 – 36 
Visit 5 
Visit 8 
3 
6 
43 
37 – 50 
Visit 6 
Visit 9 
4 
8 
57 
51 – 64 
- 
Visit 10 
5 
10 
71 
65 – 78 
Visit 8 (Day 71#) 
- 
6 
12 
85 
79 – 95 
- 
Visit 11 (Day 85) 
7 
15 
106 
96 - 116 
Visit 10 (Day 99) 
Visit 12 (Day 113) 
8 
18 
127 
117 – 137 
Visit 11 (Day 127) 
- 
9 
21 
148 
138 – 158 
Visit 12 (Day 155) 
Visit 13 (Day 141) 
10 
24 
169 
159 – 179 
- 
- 
11 
27 
190 
180 – 200 
Visit 13 (Day 183) 
Visit 14 (Day 183) 
12 
30 
211 
201 – 231 
- 
Visit 15 (Day 225) 
13 
36 
253 
232 – 295 
Visit 15 (Day 267) 
- 
14 
48 
337 
296 – 379 
Visit 16 (Day 351) 
Visit 16 (Day 309) 
15 
60 
421 
380 – 463 
Visit 17 (Day 435) 
Visit 17 (Day 393) 
16 
72 
505 
464 – 547 
Visit 18 (Day 519) 
Visit 18 (Day 477) 
17 
84 
589 
548 – 631 
Visit 19 (Day 603) 
Visit 19 (Day 561) 
Every 12 weeks 
# Day relative to first study drug intake 
In the event that more than 1 assessment occurs within a given analysis visit window, the 
assessment closest to the target date will be used in summaries for the given visit. If 2 
assessments are equally close to the target day, the latest assessment will be used. 
 
Change #25: 
Section 13.3: Planned efficacy analyses 
All efficacy analysis will be performed for the FAS and also for the PPS as a supportive purpose 
for the First Period. The FAS2 will be utilized for efficacy analysis for the Second Period. 
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Has been changed to 
Section 13.4: Planned efficacy analyses 
All efficacy analysis will be performed for the FAS A1 or FAS M1 depending on therapy and 
also for the PPS as a supportive purpose for the First Period. The FAS A12 or FAS M12 will be 
utilized for efficacy analysis in the combined First and Second Periods. 
 
Change #26: 
Section 13.3.1: 
Analysis of the primary efficacy variable for adjunctive treatment 
First Period 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the percent reduction in ADF of partial seizures from the 48h Selection 
Period to the 48h Evaluation Period at Visit 6 by the age categories of 1 month to <6 months, 
6 months to <1 year, 1 year to <2 years, and 2 years to <4 years; the dose categories of 
LEV 14, 28, and 42mg/kg/day for subjects aged 1 month to <6 months, and LEV 20, 40, and 
60mg/kg/day for subjects aged 6 months to <4 years; and overall for the FAS. The corresponding 
95% confidence interval for the median percent reduction at Visit 6 will also be provided by the 
age categories, dose categories, and overall. If the lower limit of the 95% confidence interval for 
overall is greater than the predefined threshold of 10.0%, the efficacy of LEV is significant. If 
this test shows a significant result, then it will be repeated for the corresponding Visit 4 variable. 
In that case, the second test is also regarded as confirmatory as due to the hierarchical testing 
procedure no alpha adjustment is needed. The analysis will be repeated for PPS supportively. 
Has been changed to 
Section 13.4.1: 
Analysis of the primary efficacy variable for adjunctive treatment 
First Period 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the percent reduction in ADF of partial seizures from the 48h Selection 
Period to the 48h Evaluation Period at Visit 6 by age category (3 categories: 1 month to <1 year, 
1 year to <2 years, and 2 years to <4 years), and for all subjects combined (overall). The 
corresponding 95% confidence interval for the median percent reduction at Visit 6 will also be 
provided by age category and overall. If the lower limit of the 95% confidence interval for 
overall is greater than the predefined threshold of 10.0%, the efficacy of LEV is significant. If 
this test shows a significant result, then it will be repeated for the corresponding Visit 4 variable. 
In that case, the second test is also regarded as confirmatory as due to the hierarchical testing 
procedure no alpha adjustment is needed. The analysis will be repeated for PPS supportively. 
 
Change #27: 
Section 13.4: Planned safety and other analyses 
Safety summaries will be performed for SS, SS2, and SS3. 
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Has been changed to 
Section 13.5: Planned safety and other analyses 
Safety summaries will be performed for SS A1, SS M1, SS A12, and SS M12 depending on the 
therapy and period. 
 
Change #28: 
Section 13.4.1: 
Safety analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be summarized by MedDRA System Organ Class and 
Preferred Term. The incidence of SAEs, AEs leading to premature discontinuation, and related 
AEs, and the incidence of AEs by intensity will also be summarized by period. 
For laboratory evaluations and vital signs descriptive statistic on the observed values and the 
change from baseline will be computed by visits. The number of subjects reporting at least one 
treatment-emergent possibly clinically significant (PCS) value will be computed by periods and 
visits. 
Has been changed to 
Section 13.5.1: 
Safety analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be summarized by MedDRA System Organ Class and 
Preferred Term. The incidence of SAEs, AEs leading to premature discontinuation, and related 
AEs, and the incidence of AEs by intensity will also be summarized for the First Period and the 
combined First and Second Periods. 
For laboratory evaluations and vital signs descriptive statistic on the observed values and the 
change from baseline will be computed by analysis visits. The number of subjects reporting at 
least one treatment-emergent possibly clinically significant (PCS) value will be computed by 
analysis visits. 
 
Change #29: 
Section 13.5: Handling of protocol deviations 
Prior to unblinding, protocol deviations will be assessed if important or not important and if 
included into the relevant analysis set according to predefined specifications. 
Has been changed to 
Section 13.6: Handling of protocol deviations 
Prior to taking a snapshot for the interim analysis for New Drug Application (NDA) submission, 
protocol deviations will be assessed if important or not important and if included into the 
relevant analysis set according to predefined specifications. 
 
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Change #30: 
The following text has been added to the end of the section 
Section 13.8: Planned interim analysis and data monitoring 
All the efficacy and safety analysis planned in this protocol will be performed for NDA 
submission using the interim cutoff data followed by additional cutoff and/or final analysis for 
long-term follow-up evaluation. 
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17.6 
Protocol Amendment 3 
Rationale for the amendment 
The purpose of this amendment is to change the primary efficacy variable from daily partial 
seizure frequency monitored by 48h video-EEG to partial seizure frequency per week from 
Baseline to Visit 6 as agreed with PMDA. Text was revised throughout to reflect the change 
from 48h video-EEG to patient diary. 
In addition, minor administrative edits have been made. 
The following shows the changes made in Protocol Amendment 3 compared to Protocol 
Amendment 2, dated 28 Jun 2018. 
Modifications and changes 
Specific changes 
Change #1:  
Section 1: Summary 
EP0100 is an open-label, single-arm, multicenter study with levetiracetam (LEV) as 
monotherapy or adjunctive treatment to evaluate the efficacy and safety of LEV in Japanese 
subjects aged 1 month to <4 years with partial seizures. The study will consist of 2 periods. The 
First Period is designed to confirm efficacy of LEV, and the Second Period is designed to 
evaluate the long-term efficacy and safety of LEV. Subjects with uncontrolled partial seizures 
will be enrolled into the Selection Period of the First Period. Eligible subjects will be 
hospitalized, and a 48h video-electroencephalogram (EEG) will be performed. Subjects with at 
least 2 partial seizures during the 48h video-EEG will enter the Evaluation Period. Subjects with 
<2 partial seizures during the 48h video-EEG will directly enter the Second Period. 
Seizure counts during the 2 weeks prior to Visit 1 will be used as a Retrospective Baseline. All 
eligible subjects will enter a 6-week Evaluation Period. Subjects aged 1 month to <6 months will 
be started on LEV 14mg/kg/day at Visit 3 (Week 0). The dose may be increased by LEV 
14mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 
42mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20mg/kg/day at Visit 3 
(Week 0). The dose may be increased by LEV 20mg/kg/day at 2-week intervals to a maximum 
dose of 60mg/kg/day. A 48h video-EEG will be performed 2 days prior to Visit 4 (Week 2) and 
Visit 6 (Week 6). 
At Visit 6 (Week 6), subjects may enter the Second Period or enter the Down-Titration Period 
followed by a Safety Follow-Up Period. Subjects who do not enter the Second Period will be 
down-titrated. The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to 
<6 months or by LEV 20mg/kg/day for subjects aged 6 months to <4 years at 2-week intervals to 
0mg/kg/day. Subjects who withdraw from the study at the minimum age-related dose do not 
need to down-titrate. In order to provide LEV to subjects, the Second Period will be conducted 
until approval or the program is discontinued. 
All subjects who do not enter the Second Period will enter the Safety Follow-Up Period, 
regardless of whether they down-titrate LEV. 
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Subjects can be enrolled in the Second Period if 1 of the following is met: 
• Subject completes the First Period. 
• Subject fails Screening, defined as <2 partial seizures during 48h video EEG, or did not have 
at least 24h of readable video-EEG data, or not able to measure a video-EEG for 24h due to 
their disease severity. 
Subjects who fail Screening aged 1 month to <6 months will be started on LEV 14mg/kg/day at 
Visit 6 (Week 0). The dose may be increased by LEV 14mg/kg/day for subjects aged 1 month to 
<6 months at 2-week intervals to a maximum dose of LEV 42mg/kg/day. Subjects aged 
6 months to <4 years will be started on LEV 20mg/kg/day at Visit 6 (Week 0). The dose may be 
increased by LEV 20mg/kg/day at 2-week intervals to a maximum dose of LEV 60mg/kg/day. 
The primary objective of the study is to confirm the efficacy of LEV in the First Period based on 
48h video-EEG compared to an historical control as adjunctive treatment in pediatric Japanese 
epilepsy subjects aged 1 month to <4 years with partial seizures. 
Has been changed to 
EP0100 is an open-label, single-arm, multicenter study with levetiracetam (LEV) as 
monotherapy or adjunctive treatment to evaluate the efficacy and safety of LEV in Japanese 
subjects aged 1 month to <4 years with partial seizures. The study will consist of 2 periods. The 
First Period is designed to confirm efficacy of LEV, and the Second Period is designed to 
evaluate the long-term efficacy and safety of LEV. Subjects with uncontrolled partial seizures 
will be enrolled into the Selection Period of the First Period. 
Seizure counts during the 2 weeks prior to Visit 1 will be used as a Retrospective Baseline. All 
eligible subjects will enter a 6-week Evaluation Period. Subjects aged 1 month to <6 months will 
be started on LEV 14mg/kg/day at Visit 3 (Week 0). The dose may be increased by LEV 
14mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 
42mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20mg/kg/day at Visit 3 
(Week 0). The dose may be increased by LEV 20mg/kg/day at 2-week intervals to a maximum 
dose of 60mg/kg/day. 
At Visit 6 (Week 6), subjects may enter the Second Period or enter the Down-Titration Period 
followed by a Safety Follow-Up Period. Subjects who do not enter the Second Period will be 
down-titrated. The dose will be decreased by LEV 14mg/kg/day for subjects aged 1 month to 
<6 months or by LEV 20mg/kg/day for subjects aged 6 months to <4 years at 2-week intervals to 
0mg/kg/day. Subjects who withdraw from the study at the minimum age-related dose do not 
need to down-titrate. In order to provide LEV to subjects who completed the First Period, the 
Second Period will be conducted until approval or the program is discontinued. 
All subjects who do not enter the Second Period will enter the Safety Follow-Up Period, 
regardless of whether they down-titrate LEV. 
 
Change #2: 
Section 2: Introduction 
The following paragraph was added: 
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EP0100 was initially started with a design to evaluate the efficacy of LEV using the percent 
reduction from Baseline in partial seizure frequency based on the number of seizures recorded by 
video-electroencephalography (EEG) as the primary efficacy endpoint, but subject recruitment 
was extremely difficult. One of the major factors for the difficulty in recruitment was that the 
48h video-EEG measurement was to be performed 3 times at Baseline, Week 2, and Week 6, 
thus increasing the burden on the subject/guardian. As a result, consent to participate in the study 
was not obtained from the guardian, and many potential subjects could not be screened for entry 
into the study. After consultation with the PMDA, the method of recording seizures was changed 
to a conventional patient diary, and the primary endpoint was changed to percent reduction in 
partial seizure frequency based on the patient diary. The percent reduction in partial seizure 
frequency calculated from the 48h video-EEG is included as an “other” efficacy variable. 
 
Change #3: 
Section 3.1: 
Primary objectives 
The primary objective of this study is to confirm the efficacy of LEV in the First Period based on 
the 48h video-EEG compared to historical control as adjunctive treatment in pediatric epilepsy 
subjects aged 1 month to <4 years with partial seizures. 
Has been changed to 
The primary objective of this study is to confirm the efficacy of LEV in reducing seizure 
frequency in the First Period compared to historical control as adjunctive treatment in pediatric 
epilepsy subjects aged 1 month to <4 years with partial seizures. 
 
Change #4: 
Section 3.2: 
Secondary objectives 
The second and fourth bullets 
• To evaluate the efficacy of LEV in the First Period based on the 48h video-EEG compared to 
historical control as monotherapy in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures 
• To evaluate the efficacy of LEV in the combined First and Second Periods based on the daily 
record card (DRC) as monotherapy or adjunctive treatment in pediatric epilepsy subjects 
aged 1 month to <4 years with partial seizures 
Has been changed to 
• To evaluate the efficacy of LEV in reducing seizure frequency in the First Period compared 
to historical control as monotherapy in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures 
• To evaluate the efficacy of LEV in the combined First and Second Periods as monotherapy 
or adjunctive treatment in pediatric epilepsy subjects aged 1 month to <4 years with partial 
seizures 
 
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Change #5: 
Section 4.1: 
Efficacy variables 
4.1  
 
 
Efficacy variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
4.1.1  
 
Efficacy variables for subjects on adjunctive therapy 
4.1.1.1 
 
Primary efficacy variable 
4.1.1.1.1  
First Period 
The primary efficacy variable for the First Period for subjects on adjunctive therapy is the 
percent reduction in average daily frequency (ADF) of partial seizure frequency (ie, change from 
the Selection Period to the Evaluation Period in daily partial seizure frequency monitored by the 
48h video-EEG in their ADF) at Visit 6. 
4.1.1.1.2  
Combined First and Second Periods 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
4.1.1.2 
 
Secondary efficacy variables 
4.1.1.2.1  
First Period 
The secondary efficacy variables for the First Period are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, ≥50%, ≥75%, and 100% based on the Evaluation Period 48h video-
EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline at Visit 4, Visit 5, and Visit 6 
4.1.1.2.2  
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
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Refer to Section 13.2 for the definition of each analysis visit. 
4.1.1.3 
 
Other efficacy variables 
4.1.1.3.1  
First Period 
The other efficacy variables for the First Period are the following: 
• Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG compared to the Selection Period 48h video-EEG at 
Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period 
4.1.1.3.2  
Combined First and Second Periods 
There are no other efficacy variables for the combined First and Second Periods 
4.1.2  
 
Efficacy variables for subjects on monotherapy 
4.1.2.1 
 
Primary efficacy variable 
There is no primary efficacy variable for subjects on monotherapy. 
4.1.2.2 
 
Secondary efficacy variables  
4.1.2.2.1  
First Period 
The secondary efficacy variables for the First Period are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, ≥50%, ≥75%, and 100% based on the Evaluation Period 48h video-
EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
4.1.2.2.2  
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% during the combined Evaluation and Maintenance Periods for 
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subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
Refer to Section 13.2 for the definition of each analysis visit. 
4.1.2.3 
 
Other efficacy variables 
4.1.2.3.1  
First Period 
The other efficacy variables for the First Period are the following: 
• Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG compared to the Selection Period 48h video-EEG at 
Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period 
4.1.2.3.2 Combined First and Second Periods 
The other efficacy variable for the combined First and Second Periods is the following: 
• Subjects who are continuously 6-month seizure-free monitored by the patient diary during 
the combined Evaluation and Maintenance Periods for subjects who are not 48h video-EEG 
failures, and the combined Dose adjustment and Maintenance Periods for subjects who are 
48h video-EEG failures 
Has been changed to 
4.1  
 
 
Efficacy variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
4.1.1  
 
Efficacy variables for subjects on adjunctive therapy 
4.1.1.1 
 
Primary efficacy variable 
4.1.1.1.1  
First Period 
The primary efficacy variable for subjects on adjunctive therapy is the percent reduction in 
partial seizure frequency per week from Baseline to Visit 6. 
4.1.1.1.2  
Combined First and Second Periods 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
4.1.1.2 
 
Secondary efficacy variables 
4.1.1.2.1  
First Period 
The secondary efficacy variable for the First Period is the following: 
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• Percent reduction in partial seizure frequency per week from Baseline to Visit 4 and Visit 5 
4.1.1.2.2  
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in partial seizure frequency per week from Baseline 
• For each visit, percent reduction in partial seizure frequency per week monitored by the 
patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100%  
4.1.1.3 
 
Other efficacy variables 
4.1.1.3.1  
First Period 
The other efficacy variables for the First Period for the number of seizures based on the 48h 
video-EEG recorded through Protocol Amendment 2 are the following: 
• Percent reduction in average daily frequency (ADF) of partial seizure frequency monitored 
by the 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
4.1.1.3.2  
Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% 
4.1.2  
 
Efficacy variables for subjects on monotherapy 
4.1.2.1 
 
Primary efficacy variable 
There is no primary efficacy variable for subjects on monotherapy. 
4.1.2.2 
 
Secondary efficacy variables 
4.1.2.2.1  
First Period 
There is no secondary efficacy variable for the First Period. 
4.1.2.2.2  
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in partial seizure frequency per week from Baseline 
• For each visit, percent reduction in partial seizure frequency per week monitored by the 
patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% 
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4.1.2.3 
 
Other efficacy variables 
4.1.2.3.1  
First Period 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
4.1.2.3.2 Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all types of seizure frequency per week from Baseline 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% 
• Percentage of subjects who are continuously 6-month seizure-free monitored by the patient 
diary 4.3 
 
Change #6: 
Section 4.3: 
Safety variables 
4.3  
 
Safety variables 
4.3.1  
Primary safety variable 
There is no primary safety variable. 
4.3.2  
Secondary safety variables 
4.3.2.1 
First Period 
The secondary safety variables for the First Period are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs led to discontinuation 
4.3.2.2 
Combined First and Second Periods 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to discontinuation 
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4.3.3  
Other safety variables 
The other safety variables are the following: 
• Adverse events (variables other than secondary safety variables) 
• Laboratory tests (blood chemistry and hematology) 
• Vital signs 
• Body weight and height 
• Physical and neurological examination 
Has been changed to 
4.3  
 
Safety variables 
4.3.1  
Primary safety variable 
There is no primary safety variable. 
4.3.2  
Secondary safety variables 
4.3.2.1 
First Period 
The secondary safety variables for the First Period are the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of serious adverse events (SAEs) 
• Incidence of TEAEs leading to discontinuation from study medication 
4.3.2.2 
Combined First and Second Periods 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to discontinuation from study medication 
4.3.3  
Other safety variables 
The other safety variables are the following: 
• Adverse events (AEs) (variables other than secondary safety variables) 
• Laboratory tests (blood chemistry and hematology) 
• Vital signs 
• Body weight and height 
• Physical and neurological examination 
 
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Change #7: 
Section 5.1.1: Study description, Overall 
EP0100 is an open-label, single-arm, multicenter study with LEV as monotherapy or adjunctive 
treatment to evaluate the efficacy and safety of LEV (14mg/kg/day to 42mg/kg/day for subjects 
aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 6 months to 
<4 years) in the treatment of partial seizures over the 6-week Evaluation Period (First Period), 
followed by the long-term follow-up (Second Period) in pediatric subjects. 
Subjects with uncontrolled partial seizures will be enrolled into the Selection Period. If all 
inclusion criteria, with the exception of the seizure criterion for 48h video-EEG, and none of the 
exclusion criteria are met, eligible subjects will be hospitalized and a 48h video-EEG performed. 
Subjects with at least 2 partial seizures during the Selection Period 48h video-EEG will enter the 
Evaluation Period. Subjects with <2 partial seizures during the Selection Period 48h video-EEG 
will enter the Second Period. 
If a subject does not have at least 24h of data due to an electrode separation during a 
48h video-EEG, the electrode will be refitted, and the video-EEG recording will resume. In order 
to resume recording, the subject must be willing to continue, and it is safe to resume recording in 
the opinion of the investigator. In such cases, the subjects can enter the First Period only if at 
least a total of 24h of data from the additional video-EEG data are available at Visit 4. 
Has been changed to 
EP0100 is an open-label, single-arm, multicenter study with LEV as monotherapy or adjunctive 
treatment to evaluate the efficacy and safety of LEV (14mg/kg/day to 42mg/kg/day for subjects 
aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 6 months to 
<4 years) in the treatment of partial seizures over the First Period (6 weeks), followed by the 
long-term follow-up (Second Period) in pediatric subjects. 
 
Change #8: 
Section 5.1.2: First Period 
First and third paragraphs 
Eligible subjects will enter a 6-week Evaluation Period. Subjects aged 1 month to <6 months will 
be started on LEV 14mg/kg/day at Visit 3 (Week 0). The dose may be increased by LEV 
14mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 
LEV 42mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20mg/kg/day at 
Visit 3 (Week 0). The dose may be increased by LEV 20mg/kg/day at 2-week intervals to a 
maximum dose of 60mg/kg/day. The dose will be increased if seizure freedom has not been 
attained according to the patient diary. However, if there is a safety concern for the subject in the 
opinion of the investigator, the dose can be kept. 
… 
If an intolerable AE occurs during the First Period, the dose can be decreased only once as a 
fallback option. The dose will be decreased by LEV 14 mg/kg/day for subjects aged 1 month to 
<6 months or LEV 20mg/kg/day for subjects aged 6 months to <4 years. After decreasing the 
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dose, a re-increase will not be allowed during the First Period. The fallback option can be 
performed during the First Period; however, it cannot be performed within 2 days prior to the 
start of 48h video-EEG in order to maintain the steady-state LEV plasma concentration. 
Has been changed to 
Eligible subjects will enter the First Period (6 weeks). Subjects aged 1 month to <6 months will 
be started on LEV 14mg/kg/day at Visit 3 (Week 0). The dose may be increased by LEV 
14mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 
LEV 42mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20mg/kg/day at 
Visit 3 (Week 0). The dose may be increased by LEV 20mg/kg/day at 2-week intervals to a 
maximum dose of 60mg/kg/day. The dose will be increased if seizure freedom has not been 
attained according to the patient diary. However, if there is a safety concern for the subject in the 
opinion of the investigator, the dose can be kept. 
… 
If an intolerable AE occurs during the First Period, the dose can be decreased only once as a 
fallback option. The dose will be decreased by LEV 14 mg/kg/day for subjects aged 1 month to 
<6 months or LEV 20mg/kg/day for subjects aged 6 months to <4 years. After decreasing the 
dose, a re-increase will not be allowed during the First Period. 
 
Change #9: 
Section 5.1.3: Second Period 
Subjects can be enrolled in the Second Period if 1 of the following is met: 
• Subject completes the First Period 
• Subject fails Screening, defined as <2 partial seizures during 48h video EEG, or did not have 
at least 24h of readable video-EEG data, or not able to measure a video-EEG for 24h due to 
their disease severity. These subjects may directly enter the Second Period. 
Subjects aged 1 month to <6 months who complete the First Period will take LEV 14mg/kg/day 
to 42mg/kg/day during the Second Period. Subjects aged 6 months to <4 years who complete the 
First Period will take LEV 20mg/kg/day to 60mg/kg/day during Second Period. Subjects who 
directly enroll into the Second Period will enter the Dose Adjustment Period in order to adjust 
LEV dose in the same manner as in the First Period. These subjects will then enter the 
Maintenance Period. 
Subjects who complete the First Period will have a visit every 4 weeks ±7 days relative to the 
Visit 3 for the first 6 months of administration and then every 12 weeks ±14 days thereafter. 
Subjects will continue to receive LEV 14 to 42mg/kg/day in subjects aged 1 month to <6 months 
or LEV 20 to 60mg/kg/day for subjects aged ≥6 months <4 years at the discretion of the 
Investigator. 
When subjects aged <6 months at the time of study enrollment reach 6 months of age, they can 
take a maximum of LEV 60mg/kg/day. 
Subjects aged 1 month to <6 months who fail Screening will be started on LEV 14mg/kg/day at 
Visit 6 (Week 0). The dose may be increased by LEV 14mg/kg/day for subjects aged 1 month to 
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<6 months at 2-week intervals to a maximum dose of LEV 42mg/kg/day. Subjects aged 6 
months to <4 years who fail Screening will be started on LEV 20mg/kg/day at Visit 6 (Week 0). 
The dose may be increased by 20mg/kg/day at 2-week intervals to a maximum dose of LEV 
60mg/kg/day. 
A final visit will be required approximately 2 weeks ±7 days after the final dose of LEV, or 
sooner if the subject will continue LEV (prescribed by the primary care provider as commercial 
LEV) after study completion. 
Has been changed to 
Subjects who complete the First Period will have a visit every 4 weeks ±7 days relative to Visit 3 
for the first 6 months of administration and then every 12 weeks ±14 days thereafter. Subjects 
will continue to receive LEV 14 to 42mg/kg/day in subjects aged 1 month to <6 months or LEV 
20 to 60mg/kg/day for subjects aged ≥6 months <4 years at the discretion of the Investigator. 
When subjects aged <6 months at the time of study enrollment reach 6 months of age, they can 
take a maximum of LEV 60mg/kg/day. 
A final visit will be required 2 weeks ±7 days after the final dose of LEV, or sooner if the subject 
will continue LEV (prescribed by the primary care provider as commercial LEV) after study 
completion. 
 
Change #10: 
Section 5.1.4: Study duration per subject 
The study duration is as follows: 
Retrospective Baseline Period 
In order to evaluate LEV efficacy in the Second Period, seizure counts during the 2 weeks prior 
to Visit 1 will be used as a Retrospective Baseline Period. 
First Period 
• Selection Period (maximum of 9 days) 
• Evaluation Period (6 weeks) 
• Down-Titration Period (up to 4 weeks) 
• Safety Follow-Up Period (2 weeks) 
Second Period 
• Dose Adjustment Period (6 weeks) (for directly enrolled subjects [ie, 48h video-EEG 
failures]) 
• Maintenance Period (until approval or the program is discontinued) 
• Down-Titration Period (up to 4 weeks) 
• Safety Follow-Up Period (2 weeks) 
The end of the study is defined as the date of the final visit of the final subject in the study. 
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Has been changed to 
The study duration is as follows: 
Retrospective Baseline Period 
Seizure counts during the 2 weeks prior to Visit 1 will be used as a Retrospective Baseline 
Period. 
First Period 
• Selection Period (maximum of 9 days) 
• Evaluation Period (6 weeks) 
• Down-Titration Period (up to 4 weeks) 
• Safety Follow-Up Period (2 weeks) 
Second Period 
• Maintenance Period (until approval or the program is discontinued) 
• Down-Titration Period (up to 4 weeks) 
• Safety Follow-Up Period (2 weeks) 
The end of the study is defined as the date of the final visit of the final subject in the study. 
 
Change #11: 
Section 5.2: 
Schedule of study assessments 
For Visit 4 through Visit 6, planned clinic visits should be scheduled as indicated with a window 
of ±4 days relative to Visit 3. For Visit 8 through Visit 15, planned clinic visits should be 
scheduled as indicated with a window of ±7 days relative to Visit 3. From Visit 16 onward, 
planned clinic visits should be scheduled as indicated with a window of ±14 days relative to 
Visit 3. Subjects who fail the 48h video-EEG at Visit 2 will be directly enrolled. Directly 
enrolled subjects will skip Visit 3 to Visit 5 and will begin the Second Period at Visit 6. For 
Visit 7 through Visit 10, planned clinic visits should be scheduled as indicated with a window of 
±4 days relative to Visit 6. For Visit 11 through Visit 15, planned clinic visits should be 
scheduled as indicated with a window of ±7 days relative to Visit 6. From Visit 16 onward, 
planned clinic visits should be scheduled as indicated with a window of ±14 days relative to 
Visit 6. 
Has been changed to 
For Visit 4 through Visit 6, planned clinic visits should be scheduled as indicated with a window 
of ±4 days relative to Visit 3. For Visit 8 through Visit 15, planned clinic visits should be 
scheduled as indicated with a window of ±7 days relative to Visit 3. From Visit 16 onward, 
planned clinic visits should be scheduled as indicated with a window of ±14 days relative to 
Visit 3. 
 
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Change #12: 
Section 5.2: 
Schedule of study assessments 
 
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Table 5‒2: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety 
assessment 
X 
Xh 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
Xi 
X 
Xi 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Concomitant AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medical 
procedures 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 5‒2: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
Adverse events 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CT scan/MRIk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video-EEGl 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect DRC  
Xm 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fallback optionn 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
C-SSRSo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
Xo 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; 
EDV=Early Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have W6 evaluations and the EDV evaluations. 
b In the Maintenance Period, visits will occur every 2 weeks from V7 to V10, every 4 weeks from V11 to V13, every 6 weeks between V14 and V15, and every 12 weeks 
thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. At V2, V4, and V6, seizures will be counted by video-EEG and DRC. At all other visits, 
seizures will be counted by DRC only. 
g Recorded from end of V1 through V3. 
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Table 5‒2: 
Schedule of assessments for subjects who are not 48h video-EEG failures 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
h If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be available 
prior to V2, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
i Blood samples will be obtained prior to receiving LEV and then at least 2h after dosing at V4 and V6. 
j Dispense study drug at V3. 
k Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on physical 
examination which would suggest a lesion has occurred since the last imaging procedure. 
l All video-EEG data recording will be transmitted to a central reader for the purposes of data analysis. 
m Dispense DRC at V1. Confirm DRC at V2. 
n Fallback option is permitted. See Section 5.1.2 for details. 
o C-SSRS to be performed at each visit for subjects aged ≥6 years. 
Has been changed to 
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Table 5‒2: 
Schedule of assessments 
 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/procedures 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsf 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety  
assessment 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
LEV plasma level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Concomitant AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-
AED(s) 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 5‒2: 
Schedule of assessments 
 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
Concomitant medical 
procedures 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/return study 
drug  
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
CT scan/MRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEGk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense/collect DRC  
Xn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense subject’s ID 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fallback optionm 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
C-SSRSn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
Xo 
 
AED=antiepileptic drug; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; D=day; DRC=daily record card; ECG=electrocardiogram; 
EDV=Early Discontinuation Visit; EEG=electroencephalogram; ID=identification; IVRS=interactive voice response system; IWRS=interactive web response system; 
LEV=levetiracetam; MRI=magnetic resonance imaging; SFU=Safety Follow-Up; V=visit; W=week 
Note: See Table 5‒3 for the schedule of assessments for the Down-Titration and SFU Periods. 
a After beginning the study medication, subjects who withdraw prematurely must have W6 evaluations and the EDV evaluations. 
b In the Maintenance Period, visits will occur every 4 weeks from V8 to V13 and every 12 weeks thereafter. 
c Even numbered visits. 
d Odd numbered visits. 
e Including temperature, blood pressure, and heart rate. 
f At V1, collect seizure count for seizures that occurred in the prior 2 weeks. 
g Recorded from end of V1 through V3. 
 
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Table 5‒2: 
Schedule of assessments 
 
Visit 
  Study Week 
First Period 
Second Period 
Selection Period 
Evaluation Perioda 
Maintenance Periodb 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16c… 
V17d… 
D-9 to 
D-2 
D-2 to  
D0 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W18 
W22 
W26 
W32 
W38 
W50… 
W62… 
h If clinically significant laboratory abnormalities are present at V1, repeat samples must be obtained for blood chemistry and hematology. The results should be 
available prior to V2, and UCB or its designee should be contacted regarding clinically significant abnormalities. 
i Dispense study drug at V3. 
j Only for subjects who have not had a CT scan or MRI confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have changes on 
physical examination which would suggest a lesion has occurred since the last imaging procedure. 
k If the EEG exam was not performed prior to V1, the assessment needs to be completed, and results must be available prior to V3. 
l Dispense DRC. 
m Fallback option is permitted. See Section 5.1.2 for details. 
n C-SSRS to be performed at each visit for subjects aged ≥6 years. 
 
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Change #13: 
Section 5.2: 
Schedule of study assessments 
Table 5-2 has been deleted. 
 
Change #14: 
Section 5.3: 
Schematic diagram 
Figure 5-1: Schematic for subjects in the First and Second Periods 
 
 
Has been changed to 
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Figure 5-1: Schematic for subjects in the First and Second Periods 
 
6m admin=6 months of administration; D=day; DRC=daily record card; EEG=electroencephalogram; RBL=retrospective baseline; V=Visit; W=weeks 
Note: The value in parentheses for dose is for subjects 1 month to <6 months of age. 
 
60 (42) mg/kg/day
60 (42) mg/kg/day
40 (28) mg/kg/day
40 (28) mg/kg/day
6 month to <4 years (1month to < 6months)
20 (14) mg/kg/day
First period
Second period
Retrospective
Baseline
(Selection Period)
Evaluation Period
Maintenance Period
2W
FallBack option
20 (14) mg/kg/day
FallBack option
Subject’s DRC
DRC
(V2)
(V7)
(V9)
(V14)
V1
V3
V4
V5
V13
V15
Vx
Week 2
Week 4
Week 6
Week 10
V8
Week 14
V10
V11
V12
V6
Informed consent
Registration
6m admin
Every 12weeks
Week 18
Week 22
Week 26
Week 38
(V3  -9 to -2day)
Week 0
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Change #15 
Section 6.1: 
Inclusion criteria 
Inclusion criterion #1 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the parent(s) or legal representative. 
Has been changed to 
1a.  An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the parent(s) or legal representative. 
Subject/legal representative/caregiver is considered reliable and capable of adhering to the 
protocol (eg, able to understand and complete diaries), visit schedule, or medication intake 
according to the judgment of the Investigator. 
 
Change #16 
Section 6.1: 
Inclusion criteria 
Inclusion criterion #2 
2. Subject must have a diagnosis of epilepsy with partial onset seizures (ie, seizures of focal 
onset), whether or not secondarily generalized. 
Has been changed to 
2a. Subject must have a diagnosis of epilepsy with partial onset seizures (ie, seizures of focal 
onset), whether or not secondarily generalized. 
Subject has had an EEG and a brain computerized tomography (CT) scan or brain magnetic 
imaging (MRI) consistent with a diagnosis of localized epilepsy according to the 
International Classification of Epilepsies and Epileptic Syndromes (1989) (see Section 17.2) 
and consistent with partial onset seizures according to the Classification of Epileptic Seizures 
(1981) (see Section 17.1). If the EEG and brain CT scan and brain MRI were not performed 
prior to the Screening Visit (Visit 1), the assessment needs to be completed and results must 
be available prior to Visit 3. 
 
Change #17 
Section 6.1: 
Inclusion criteria 
Inclusion criterion #7 
7. Subject must have experienced at least 2 partial seizures (ie, seizures of focal onset as 
determined by EEG), with or without secondary generalization during each 7-day period 
during the 2 weeks prior to Visit 1. This time period (the 2 weeks prior to Visit 1) will be 
referred to as the Retrospective Baseline Period. This seizure information (including type, 
frequency, and date) must have been recorded on a DRC in order to be acceptable. 
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Has been changed to 
7a. Subject must have experienced at least 2 observable partial seizures (ie, seizures of focal 
onset as determined by EEG), with or without secondary generalization during each 7-day 
period during the 2 weeks prior to Visit 1. This time period (the 2 weeks prior to Visit 1) will 
be referred to as the Retrospective Baseline Period. This seizure information (including type, 
frequency, and date) must have been recorded on a daily record card (DRC) in order to be 
acceptable. 
 
Change #18 
Section 6.1: 
Inclusion criteria 
Inclusion criteria #8 and #9 have been deleted. 
 
Change #19 
Section 7.2: 
Treatments to be administered 
First Period 
Once the subject has fulfilled the eligibility criteria, he/she will be admitted to the clinic as an 
inpatient and the 48h video-EEG performed. After the Selection Period, the subject will enter the 
Evaluation Period. 
Figure 7-1: Schematic for Down-Titration and Safety Follow-Up Periods 
 
EDV=Early Discontinuation Visit; V=Visit 
The down-titration procedure needs to be applied in case of early discontinuation. 
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Second Period 
For continuing subjects, if a dose adjustment becomes necessary, the investigators will increase 
or decrease the dose by at least a 2-week interval. One increase or decrease in the dose should 
not exceed LEV 14mg/kg/day for subjects aged 1 month to <6 months or LEV 20mg/kg/day for 
subjects aged 6 months to <4 years for the 2-week interval. The dosage can be adjusted to 
LEV 14, 28 and 42mg/kg/day LEV for subjects aged 1 month to <6 months or LEV 20, 40 and 
60mg/kg/day for subjects aged 6 months to <4 years at the Investigator’s discretion for the 
benefit/risk for individual subjects. 
For directly enrolled subjects (ie, 48h video-EEG failures), LEV dose can be up-titrated to 
42mg/kg/day for subjects aged 1 month to <6 months or LEV 60mg/kg/day for subjects aged 
6 months to less than 4 years. The initial dose is LEV 14mg/kg/day for the first 2 weeks, 
followed by 28mg/kg/day and 42mg/kg/day or LEV 20mg/kg/day for the first 2 weeks, followed 
by 40mg/kg/day and 60mg/kg/day for 2 weeks, respectively. After up-titration, if a dose 
adjustment becomes necessary, the investigator will increase or decrease the dose by at least a 
2‑week interval. Each increase or decrease in dose should not exceed LEV 14mg/kg/day for 
subjects aged 1 month to <6 months and LEV 20mg/kg/day for subjects aged 6 months to  
<4 years for the 2-week interval. The dosage can be adjusted to LEV 14, 28, and 42mg/kg/day 
for subjects aged 1 month to <6 months and LEV 20, 40, and 60mg/kg/day for subjects aged 
6 months to <4 years at the Investigator’s discretion based on the benefit/risk for the individual 
subject. 
Subjects who withdraw or complete the Second Period will enter the Down-Titration Period, 
followed by the Safety Follow-Up Period. 
Has been changed to 
First Period 
Once the subject has fulfilled the eligibility criteria, the subject will enter the Evaluation Period. 
Study medication should be given as 2 equally divided doses administered twice daily. The first 
intake of newly dispensed study medication should occur at Visit 3 after the confirmation of 
seizure counts by 48h video-EEG. Subjects should take IMP according to instructions provided 
by Investigator. 
Subjects aged 1 month to <6 months will be started on LEV 14mg/kg/day at Visit 3 (Week 0). 
The dose may be increased by LEV 14mg/kg/day for subjects aged 1 month to <6 months at 
2-week intervals to a maximum dose of LEV 42mg/kg/day. Subjects aged 6 months to <4 years 
will be started on LEV 20mg/kg/day at Visit 3 (Week 0). The dose may be increased by 
LEV 20mg/kg/day at 2-week intervals to a maximum dose of 60mg/kg/day. 
At the end of the Evaluation Period, subjects will enter into the Second Period. Subjects who do 
not enter the Second Period will enter the Down-Titration Period, followed by the Safety 
Follow-Up Period. 
The Down-Titration Period (up to 4 weeks) will consist of the following: 
• The dose will be decreased by 14mg/kg/day for subjects aged 1 month to <6 months or by 
20mg/kg/day for subjects aged 6 months to <4 years at 2-week intervals to 0mg/kg/day. 
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Figure 7‒1: Schematic for Down-Titration and Safety Follow-Up Periods 
 
EDV=Early Discontinuation Visit; V=Visit 
Note: The value in parentheses for dose is for subjects 1 month to <6 months of age. 
The down-titration procedure needs to be applied in case of early discontinuation. 
Second Period 
For continuing subjects, if a dose adjustment becomes necessary, the investigators will increase 
or decrease the dose by at least a 2-week interval. One increase or decrease in the dose should 
not exceed LEV 14mg/kg/day for subjects aged 1 month to <6 months or LEV 20mg/kg/day for 
subjects aged 6 months to <4 years for the 2-week interval. The dosage can be adjusted to 
LEV 14, 28 and 42mg/kg/day LEV for subjects aged 1 month to <6 months or LEV 20, 40 and 
60mg/kg/day for subjects aged 6 months to <4 years at the Investigator’s discretion for the 
benefit/risk for individual subjects. 
Subjects who withdraw or complete the Second Period will enter the Down-Titration Period, 
followed by the Safety Follow-Up Period. 
 
Change #20 
Section 8.1: 
First Period 
See Section 5.2 for the schedule of assessments for the First Period. The visit window for Visit 4 
through Visit 6 is ±4 days. Visit 1 assessments will be performed for all subjects. Subjects who 
are 48h video-EEG failures will skip the Evaluation Period and will proceed to the Second 
Period. Subjects who are directly enrolled will skip Visit 2 through Visit 6 and start the study at 
Visit 7 (see Section 8.3). 
Down-Titration (4, 2 or 0 weeks) and Safety Follow-up (2 weeks)
60 (42) mg/kg/day
40 (28) mg/kg/day
20 (14) mg/kg/day
Early Discontinuation Visit (EDV)
Early Discontinuation Visit (EDV)
Early Discontinuation Visit (EDV)
or First Period final dose
or First Period final dose
or First Period final dose
40 (28) mg/kg/day
20 (14) mg/kg/day
20 (14) mg/kg/day
0 (0) mg/kg/day
0 (0) mg/kg/day
0 (0) mg/kg/day
EDV
SFU*
EDV
SFU*
EDV
SFU*
*: Safety Follow-Up (SFU) is 2 weeks after final dose of study drug.
Week 0
Week 0
Week 2
Week 4
Week 0
Week 2
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Has been changed to 
See Section 5.2 for the schedule of assessments for the First Period. The visit window for Visit 4 
through Visit 6 is ±4 days. Visit 1 assessments will be performed for all subjects. 
 
Change #21 
Section 8.1.1.1, Visit 1/Day -9 to Day -2 (Screening) 
The following bullet was added: 
• Perform EEG (for subjects who have not had an EEG confirming the consistent with a 
diagnosis of localized epilepsy and the consistent with partial onset seizures.) 
 
Change #22 
Section 8.1.1.2: 
Visit 2/Day -2 to Day 0 
This section has changed to “Not applicable.” 
 
Change #23 
Section 8.1.2.1: 
Visit 3 (Week 0) 
The following paragraph was deleted: 
Subjects who have at least 2 partial seizures during the 48h video-EEG will enter the Evaluation 
Period. Subjects who have 0 or 1 partial seizure during the 48h video-EEG will enter the Second 
Period (see Section 8.3). 
 
Change #24 
Section 8.1.2.2: 
Visit 4 (Week 2) 
For the 2 days prior to Visit 4, subjects will be inpatients at the clinic in order to have the 48h 
video-EEG performed. During this time, they will remain under close medical surveillance. 
Blood sampling for safety is allowed during measurement of the 48h video-EEG. Blood 
sampling for PK should be conducted during measurement of the 48h video-EEG. 
• Check the subject into the clinic 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level prior to receiving LEV dose and then at least 2h 
after dosing 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
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• Record AEs 
• Collect seizure count from DRC 
• Dispense/collect DRC 
• Study drug compliance 
• Perform 48h video-EEG. If a subject does not have at least 24h of data due to an electrode 
separation during the 48h video-EEG, the video-EEG may be continued without removing 
the electrodes if the subject is willing to continue the video-EEG and the video-EEG can be 
safely continued in the opinion of the investigator. 
• Confirm if fallback option is necessary and reason(s) to decrease the dosage 
• Contact IVRS/IWRS 
• Dispense/collect study drug 
Has been changed to 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Collect seizure count from DRC 
• Dispense/collect DRC 
• Study drug compliance 
• Confirm if fallback option is necessary and reason(s) to decrease the dosage 
• Contact IVRS/IWRS 
• Dispense/collect study drug 
 
Change #25 
Section 8.1.3: Visit 6 (Week 6) 
For the 2 days prior to Visit 6, subjects will be inpatients at the clinic in order to have the 48h 
video-EEG performed. During this time, they will remain under close medical surveillance. 
Blood sampling for safety is allowed during measurement of the 48h video-EEG. Blood 
sampling for PK should be conducted during measurement of the 48h video-EEG. 
• Check the subject into the clinic 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
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• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level prior to receiving LEV dose and then at least 2h 
after dosing  
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Collect seizure count 
• Dispense/collect DRC 
• Study drug compliance 
• Perform 48h video-EEG. If a subject does not have at least 24h of data due to an electrode 
separation during 48h video-EEG, the video-EEG may be continued without removing the 
electrodes if the subject is willing to continue the video-EEG and the video-EEG can be 
safely continued in the opinion of the investigator. 
• Contact IVRS/IWRS 
• Dispense/collect study drug 
Has been changed to 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect blood samples for safety laboratory assessments 
• Collect blood samples for LEV plasma level 
• Record body weight 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Collect seizure count 
• Dispense/collect DRC 
• Study drug compliance 
• Contact IVRS/IWRS 
• Dispense/collect study drug 
 
Change #26 
Section 8.2.1: Visit 7 (Week 8) 
This section has changed to “Not applicable.” 
 
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Change #27 
Section 8.2.3: Visit 9 (Week 12) 
This section has changed to “Not applicable.” 
 
Change #28 
Section 8.2.8: Visit 14 (Week 26) 
This section has changed to “Not applicable.” 
 
Change #29 
Section 8.3: 
Direct enrollment 
This section has changed to “Not applicable.” 
 
Change #30 
Section 8.5, Early discontinuation visit 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments 
• Record body weight and height 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Perform ECG 
• Contact IVRS/IXRS 
• Dispense/collect DRC 
• C-SSRS (will be performed for subjects aged ≥6 years) 
Has been changed to 
• Obtain vital sign measurements (blood pressure, pulse rate, and body temperature) 
• Collect seizure count 
• Collect blood samples for safety laboratory assessments (at Week 0 only) 
• Record body weight 
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• Record height (at Week 0 only) 
• Record concomitant medications (AEDs and non-AEDs) and medical procedures 
• Record AEs 
• Dispense/collect study drug 
• Study drug compliance 
• Perform ECG (at Week 0 only) 
• Contact IVRS/IWRS 
• Dispense/collect DRC 
• C-SSRS (will be performed for subjects aged ≥6 years) 
 
Change #31 
Section 9: Assessment of efficacy 
The primary and secondary efficacy variables are based on the ADF of partial seizures as 
measured by 48h video-EEG. Partial seizure count will be based on electrographic seizures with 
or without clinical correlate depending upon age as specified below. 
Partial seizure frequency for subjects aged ≥1 month to ≤6 months will be based on 
electrographic seizures. Partial seizure frequency for subjects aged >6 months to <4 years will be 
based on electrographic seizures with an accompanying clinical correlate. 
Electrographic seizures are defined as recognizable ictal patterns on an EEG involving 
≥2 contiguous electrodes. The seizures are initiated as a unilateral or strongly asymmetric 
abnormal epileptiform discharge lasting a total of >10 seconds. 
The video-EEG recordings will be evaluated by a central reader. 
The ADF is calculated by: 
ADF = 
# of partial seizures recorded on the # hour video-EEG 
 24 
# of hours 
In the above formula, 48h is used for Selection ADF. If the subjects complete the Evaluation 
Period, 48h is used for Evaluation ADF. For subjects who drop out during the Evaluation Period, 
the number of hours will be the time from the start of the Evaluation Period video-EEG to 
withdrawal (in hours). 
The video-EEG recordings from both the Selection and Evaluation Periods will be sent to a 
central reader for interpretation and recording of seizure frequency and type. In the event of a 
difference of opinion between the on-site epileptologist and the central reader, the central 
reader’s opinion will determine subject eligibility. 
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Has been changed to 
The primary and secondary efficacy variables are based on the partial seizure frequency per 
week as measured by patient diary. 
 
Change #32 
Section 11.3.5, Assessment of suicidality 
First paragraph 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). For subjects ≥6 years of age, this scale will be used for screening as well 
as to assess suicidal ideation and behavior that may occur during the study. The C-SSRS will be 
completed according to the tabular schedule of study procedures. 
Has changed to 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). For subjects ≥6 years of age, this scale will be used to assess suicidal 
ideation and behavior that may occur during the study. The C-SSRS will be completed according 
to the tabular schedule of study procedures. 
 
Change #33 
Section 13.1, Definition of analysis sets 
The following sets are defined for this study: 
• Enrolled Set (ES) 
• Safety Sets: 
− SS A1 (Safety Set [Adjunctive therapy, First Period], ie, Safety Set for subjects on 
Adjunctive Therapy during the First Period) 
− SS M1 (Safety Set [Monotherapy, First Period]) 
− SS A12 (Safety Set [Adjunctive therapy, combined First and Second Periods]) 
− SS M12 (Safety Set [Monotherapy, combined First and Second Periods]) 
• Full Analysis Sets: 
− FAS A1 (Full Analysis Set [Adjunctive therapy, First Period], ie, Full Analysis Set for 
subjects on Adjunctive Therapy during the First Period) 
− FAS M1 (Full Analysis Set [Monotherapy, First Period]) 
− FAS A12 (Full Analysis Set [Adjunctive therapy, combined First and Second Periods]) 
− FAS M12 (Full Analysis Set [Monotherapy, combined First and Second Periods]) 
• Per-Protocol Set (PPS) 
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• Pharmacokinetic Per-Protocol Set (PK-PPS) 
If not stated otherwise, presentation of: 
• Disposition and important protocol deviations are based on the ES 
• Demographics, other baseline characteristics, safety, and exposure data are based on the 
SS A12 and SS M12 
• Efficacy data are based on the FAS A1, FAS M1, FAS A12, and FAS M12. Sensitivity 
analyses on the primary efficacy variable are repeated for the PPS. 
Has been changed to 
The following sets are defined for this study: 
• Enrolled Set (ES) 
• Safety Sets: 
− SS_A (Safety Set [Adjunctive therapy]) 
− SS_M (Safety Set [Monotherapy) 
• Full Analysis Sets: 
− FAS_A (Full Analysis Set [Adjunctive therapy]) 
− FAS_M (Full Analysis Set [Monotherapy]) 
• Pharmacokinetic Per-Protocol Set (PK-PPS) 
If not stated otherwise, presentation of: 
• Disposition and important protocol deviations are based on the ES 
• Demographics, other baseline characteristics, safety, and exposure data are based on the 
SS A and SS M 
• Efficacy data are based on the FAS_A and FAS_M. 
 
Change #34 
Section 13.1.2, Safety Set 
First Period: 
The SS A1 will include all enrolled subjects on adjunctive therapy in the First Period who 
receive at least 1 dose of study medication in the Evaluation Period. 
The SS M1 will include all enrolled subjects on monotherapy in the First Period who receive at 
least 1 dose of study medication in the Evaluation Period. 
Combined First and Second Periods: 
The SS A12 will include all enrolled subjects on adjunctive therapy in the Evaluation, Dose 
adjustment, and Maintenance Periods who receive at least 1 dose of study medication in the 
Evaluation, Dose adjustment, or Maintenance Periods. 
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The SS M12 will include all enrolled subjects on monotherapy in the Evaluation, Dose 
adjustment, and Maintenance Periods who receive at least 1 dose of study medication in the 
Evaluation, Dose adjustment, or Maintenance Periods. 
Has been changed to 
First Period: 
The SS_A will include all enrolled subjects on adjunctive therapy in the First Period who receive 
at least 1 dose of study medication in the Evaluation Period. 
The SS_M will include all enrolled subjects on monotherapy in the First Period who receive at 
least 1 dose of study medication in the Evaluation Period. 
 
Change #35 
Section 13.1.3, Full Analysis Set 
First Period: 
The FAS A1 will consist of all subjects in the SS A1 who entered the First Period, who receive 
adjunctive therapy, have at least 24h of usable video-EEG time in the Selection Period, with at 
least 2 partial seizures, and have at least 1 post-baseline efficacy assessment from the First 
Period video-EEG time or DRCs in the Evaluation Period. 
The FAS M1 will consist of all subjects in the SS M1 who entered the First Period, who receive 
monotherapy, have at least 24h of usable video-EEG time in the Selection Period, with at least 
2 partial seizures, and have at least 1 post-baseline efficacy assessment from the First Period 
video-EEG time or DRCs in the Evaluation Period. 
Combined First and Second Periods: 
The FAS A12 will consist of all subjects in the SS A12, who receive adjunctive therapy, have at 
least 24h of usable video-EEG time in the Selection Period, and have at least 1 post-baseline 
efficacy assessment from the First Period video-EEG time, or DRCs in the Evaluation, Dose 
adjustment, or Maintenance Period. 
The FAS M12 will consist of all subjects in the SS M12, who receive monotherapy, have at least 
24h of usable video-EEG time in the Selection Period, and have at least 1 post-baseline efficacy 
assessment from the First Period video-EEG time, or DRCs in the Evaluation, Dose adjustment, 
or Maintenance Period. 
Has been changed to 
First Period: 
The FAS_A will consist of all subjects in the SS_A who have at least 1 post-Baseline efficacy 
assessment. 
The FAS_M will consist of all subjects in the SS_M who have at least 1 post-Baseline efficacy 
assessment. 
 
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Change #36 
Section 13.1.4, Per Protocol Set 
This section has changed to “Not applicable.” 
 
Change #37 
Section 13.1.5, Other analysis sets 
The PK-PPS will consist of all subjects in the SS A12 and SS M12 for whom at least 1 valid 
LEV plasma concentration-time record and dosing information are available. 
Has been changed to 
The PK-PPS will consist of all subjects in the SS_A and SS_M for whom at least 1 valid LEV 
plasma concentration-time record and dosing information are available. 
 
Change #38 
Section 13.2, Definitions of analysis visits 
Table 13-1 presents the mapping of study visits to analysis visits for subjects who are not 48h 
video-EEG failures and for subjects who are 48h video-EEG failures. Analysis visits will be used 
for analysis of long-term safety and efficacy data. 
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Table 13‒1: Analysis visit mapping table 
Analysis 
Visit 
Week 
number 
Relative day 
since first study 
drug 
administration 
Analysis 
window 
Subjects who are 
not 48h video-
EEG failures 
Study Visit 
(Relative day) 
Subjects who are 
48h video-EEG 
failures 
Study Visit 
(Relative day) 
0 
0 
1 
- 
Visit 3 
Visit 6 
1 
2 
15 
2 – 22 
Visit 4 
Visit 7 
2 
4 
29 
23 – 36 
Visit 5 
Visit 8 
3 
6 
43 
37 – 50 
Visit 6 
Visit 9 
4 
8 
57 
51 – 64 
- 
Visit 10 
5 
10 
71 
65 – 78 
Visit 8 (Day 71#) 
- 
6 
12 
85 
79 – 95 
- 
Visit 11 (Day 85) 
7 
15 
106 
96 - 116 
Visit 10 (Day 99) 
Visit 12 (Day 113) 
8 
18 
127 
117 – 137 
Visit 11 (Day 127) 
- 
9 
21 
148 
138 – 158 
Visit 12 (Day 155) 
Visit 13 (Day 141) 
10 
24 
169 
159 – 179 
- 
- 
11 
27 
190 
180 – 200 
Visit 13 (Day 183) 
Visit 14 (Day 183) 
12 
30 
211 
201 – 231 
- 
Visit 15 (Day 225) 
13 
36 
253 
232 – 295 
Visit 15 (Day 267) 
- 
14 
48 
337 
296 – 379 
Visit 16 (Day 351) 
Visit 16 (Day 309) 
15 
60 
421 
380 – 463 
Visit 17 (Day 435) 
Visit 17 (Day 393) 
16 
72 
505 
464 – 547 
Visit 18 (Day 519) 
Visit 18 (Day 477) 
17 
84 
589 
548 – 631 
Visit 19 (Day 603) 
Visit 19 (Day 561) 
Every 12 weeks 
# Day relative to first study drug intake 
In the event that more than 1 assessment occurs within a given analysis visit window, the 
assessment closest to the target date will be used in summaries for the given visit. If 
2 assessments are equally close to the target day, the latest assessment will be used. 
Has been changed to 
13.2 
Handling of data for subjects who were enrolled prior to protocol amendment 3 
Subjects who were directly enrolled in the Second Period based on the protocol prior to 
amendment 3 will also be included in the efficacy and safety analysis with remapping of visit 
numbers to correspond to the ones for subjects who enrolled in the First Period. Details will be 
found in the SAP. 
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Change #39 
Section 13.4: Planned efficacy analyses 
All efficacy analysis will be performed for the FAS A1 or FAS M1 depending on therapy and 
also for the PPS as a supportive purpose for the First Period. The FAS A12 or FAS M12 will be 
utilized for efficacy analysis in the combined First and Second Periods. 
Has been changed to 
All efficacy analysis will be performed for the FAS_A or FAS_M depending on therapy. 
 
Change #40 
Section 13.4.1: 
Analysis of the primary efficacy variable for adjunctive therapy 
First Period 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the percent reduction in ADF of partial seizures from the 48h Selection 
Period to the 48h Evaluation Period at Visit 6 by age category (3 categories: 1 month to <1 year, 
1 year to <2 years, and 2 years to <4 years), and for all subjects combined (overall). The 
corresponding 95% confidence interval for the median percent reduction at Visit 6 will also be 
provided by age category and overall. If the lower limit of the 95% confidence interval for 
overall is greater than the predefined threshold of 10.0%, the efficacy of LEV is significant. If 
this test shows a significant result, then it will be repeated for the corresponding Visit 4 variable. 
In that case, the second test is also regarded as confirmatory as due to the hierarchical testing 
procedure no alpha adjustment is needed. The analysis will be repeated for PPS supportively. 
Second Period 
Not applicable 
Has been changed to 
The percent reduction in partial seizures per week from Baseline to Visit 6 will be calculated as: 
Number of partial seizures per week at Baseline – Number of seizures per week at Visit 6 x 100 
Number of partial seizures per week at Baseline 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the percent reduction in partial seizure frequency per week from Visit 6 by 
age category (3 categories: 1 month to <1 year, 1 year to <2 years, and 2 years to <4 years), and 
for all subjects combined (overall). The corresponding 95% confidence interval for the median 
percent reduction at Visit 6 will also be provided by age category and overall. If the lower limit 
of the 95% confidence interval for overall is greater than the predefined threshold of 15.0%, the 
efficacy of LEV is significant. If this test shows a significant result, then it will be repeated for 
the corresponding Visit 4 variable. In that case, the second test is also regarded as confirmatory 
as due to the hierarchical testing procedure no alpha adjustment is needed. 
There is no primary efficacy variable for subjects on monotherapy. 
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Change #41 
Section 13.5: Planned safety analyses 
Safety summaries will be performed for SS A1, SS M1, SS A12, and SS M12 depending on the 
therapy and period. 
Has been changed to 
Safety summaries will be performed for SS_A and SS_M depending on the therapy. 
 
Change #42 
Section 13.7: Handling of dropouts or missing data 
For subjects with <24h of usable Evaluation Period video-EEG time including the subjects who 
discontinued without any Evaluation Period video-EEG time, partial seizure frequency in the 
Evaluation 48h video-EEG will be imputed by evaluable partial seizure frequency in Selection 
48h video-EEG (ie, Baseline Observation Carry Forward [BOCF]). From the results of N01009 
that the percent reduction from Selection in ADF was positive in most of subjects (>75%), 
BOCF imputation is considered as applicable. Other details about handling missing data will be 
defined in the SAP. 
Has been changed to 
Days with missing seizure data will not be used for the calculation of seizure frequency per 
week. If subjects drop out, their seizure counts over the available period will be used and 
transformed into seizure frequency per week, by dividing the number of seizures during the 
available period by the number of days of that period, multiplied by 7. 
Safety variables will be analyzed insofar as they are available, without imputation or carrying 
values forward 
 
Change #43 
Section 13.9: Determination of sample size 
The following paragraph was added: 
Due to the change in the primary efficacy variable in protocol amendment 3, the sample size was 
reconsidered. When the placebo rate area is conservatively redefined as ≤15% and assuming 
there are no nonevaluable subjects, a sample size of 38 subjects will obtain ≥80% power. 
Therefore, no change in sample size is required. 
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17.7 
Protocol Amendment 4 
Rationale for the amendment 
The purpose of this amendment is to comply with regulations in Japan for the conduct of 
postmarketing clinical studies. 
EP0100 will be conducted as a clinical study (Phase 3) until approval is obtained for the 
indication of LEV as monotherapy or adjunctive treatment in patients aged 1 month to <4 years 
with partial seizures, and will continue as a postmarketing clinical study (Phase 4) after the date 
of approval until the study participant is switched to commercial LEV as soon as possible, or 
until LEV is discontinued after a period of dose reduction. In Japan, the meaning and expressions 
related to "clinical study" shall automatically be read as "postmarketing clinical study" after the 
date of approval in Japan. 
In addition, minor administrative edits have been made. 
The following shows the changes made in Protocol Amendment 4 compared to Protocol 
Amendment 3, dated 29 Jan 2020. 
Modifications and changes 
Specific changes 
Change #1: 
Sponsor Study Physician 
Name: 
 
Phone: 
 
Has been changed to 
Name: 
 
Phone: 
 
 
Change #2: 
LIST OF ABBREVIATIONS 
The following abbreviation was added: 
GPSP 
Good Postmarketing Study Practice 
 
Change #3: 
Section 1: Summary 
The following paragraphs were added: 
After approval in Japan for the indication of LEV as monotherapy or adjunctive treatment in 
patients aged 1 month to <4 years with partial seizures, this clinical study (Phase 3) will be 
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continued as a postmarketing clinical study (Phase 4). All subjects who are still in the study as of 
the date of approval will be considered to have completed the study. After the date of approval, 
subjects should visit the investigational site as soon as possible to complete the study by 
switching to commercial LEV or discontinuing LEV after the assessment specified in Section 8.5 
“Early Discontinuation Visit” in the protocol. 
After the study is continued as a postmarketing clinical study (Phase 4), the LEV dry syrup 50% 
prescribed during the study period will continue to be used, and the labeling of the IMP will not 
be changed. There will also be no change in the handling and storage conditions of the IMP. 
After the date of approval, this clinical study shall be continued as a postmarketing clinical study 
(Phase 4), and the description of EP0100 in this protocol shall read as follows. The term "clinical 
study" should be replaced with "postmarketing clinical study," the term "clinical trial" should be 
replaced with "postmarketing clinical study", the term "this (clinical) study" should be replaced 
with "this postmarketing clinical study", the term "protocol" should be replaced with 
"postmarketing clinical study protocol", the term "investigator" should be replaced with 
"investigator for postmarketing clinical study", the term "subinvestigator" should be replaced 
with "subinvestigator for postmarketing clinical study", the term "IMP" should be replaced with 
"IMP for postmarketing clinical study ", the term "Investigator’s Brochure" should be replaced 
with "package insert or precautions information", the term "Phase 3" should be replaced with 
"Phase 4", the term "subject’s ID card" should be replaced with "subject’s ID card for 
postmarketing clinical study participation", and the term "Good Clinical Practice (GCP)" should 
be replaced with "GCP and Good Postmarketing Study Practice (GPSP)". 
 
Change #4: 
Section 4.3.2: Secondary safety variables 
Section 4.3.2.1: First Period 
• Incidence of serious adverse events (SAEs) 
Section 4.3.2.2: Combined First and Second Periods 
• Incidence of SAEs 
Has been changed to 
Section 4.3.2.1: First Period 
• Incidence of treatment-emergent serious adverse events (SAEs) 
Section 4.3.2.2: Combined First and Second Periods 
• Incidence of treatment-emergent SAEs 
 
Change #5: 
Section 11.1.1.1 Adverse event 
The following paragraph was added: 
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For results disclosure on public registries (eg, ClinicalTrials.gov), TEAEs and 
treatment-emergent SAEs will be published. 
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18 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract. 
Investigator: 
 
 
 
 
Printed name 
 
Date/Signature 
 
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19 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
ep0100-protocol-amendment-4
Version:
2. 0
Document Number:
CLIN-000214631
Title:
ep0100-protocol-amendment-4
Approved Date:
28 Feb 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Feb-2023 00:01:37 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Feb-2023 01:11:56 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 28-Feb-2023 03:11:32 GMT+0000
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SAP_001.pdf: 
UCB 
 
03 May 2022 
Statistical Analysis Plan 
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EP0100 
 
 
 
Confidential 
Page 1 of 122 
 
 
STATISTICAL ANALYSIS PLAN  
Study: EP0100 
Product: Levetiracetam 
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY OF LEVETIRACETAM 
AS MONOTHERAPY OR ADJUNCTIVE TREATMENT OF PARTIAL SEIZURES  
IN PEDIATRIC EPILEPTIC SUBJECTS RANGING FROM 1 MONTH TO  
LESS THAN 4 YEARS OF AGE 
 
 
SAP/Amendment Number Date 
SAP/Amendment 1  
04 Jun 2019 
SAP/Amendment 2 
18 Jun 2021 
SAP/Amendment 3 
03 May 2022 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
 
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EP0100 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF TABLES ..................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................... 8 
1 
INTRODUCTION ........................................................................................................... 10 
2 
PROTOCOL SUMMARY ............................................................................................... 10 
2.1 
Study Objectives .......................................................................................................... 10 
2.1.1 
Primary Objective ................................................................................................ 10 
2.1.2 
Secondary Objectives .......................................................................................... 10 
2.2 
Study Variables ............................................................................................................ 11 
2.2.1 
Efficacy Variables ............................................................................................... 11 
2.2.1.1 
Efficacy Variables for Subjects on Adjunctive Therapy ........................... 11 
2.2.1.2 
Efficacy Variables for Subjects on Monotherapy ..................................... 12 
2.2.2 
Pharmacokinetic/Pharmacodynamic Variable(s) ................................................. 13 
2.2.3 
Safety Variables ................................................................................................... 13 
2.2.3.1 
Primary Safety Variable ............................................................................ 13 
2.2.3.2 
Secondary Safety Variables ....................................................................... 13 
2.2.3.3 
Other Safety Variables .............................................................................. 13 
2.3 
Study Design and Conduct........................................................................................... 14 
2.3.1 
Study Periods ....................................................................................................... 14 
2.3.2 
Adjunctive Therapy and Monotherapy ................................................................ 15 
2.4 
Determination of Sample Size ..................................................................................... 15 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 15 
3.1 
General Presentation of Summaries and Analyses ...................................................... 15 
3.1.1 
Summarizing Categorical Variables .................................................................... 16 
3.1.2 
Summary Statistics for Continuous Variables ..................................................... 16 
3.1.3 
Table Presentation ............................................................................................... 16 
3.1.4 
Listing Presentation ............................................................................................. 16 
3.2 
General Study Level Definitions ................................................................................. 17 
3.2.1 
Analysis Time Points ........................................................................................... 17 
3.2.1.1 
Relative Day .............................................................................................. 17 
3.2.1.2 
End Date of the First/Second Period ......................................................... 17 
3.2.2 
Schedule of Study Assessments ........................................................................... 21 
3.2.3 
Unscheduled Visits .............................................................................................. 25 
3.2.4 
Mapping of Assessments Performed at Early Discontinuation Visit .................. 25 
3.2.5 
Age 25 
3.2.5.1 
Chronological Age .................................................................................... 25 
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3.2.5.2 
Adjusted Age ............................................................................................. 25 
3.2.5.3 
Age at Entry Into Study ............................................................................. 26 
3.2.6 
Body Mass Index ................................................................................................. 26 
3.2.7 
Exposure to Study Medication ............................................................................. 26 
3.3 
Definition of Baseline Values ...................................................................................... 26 
3.4 
Protocol Deviations ...................................................................................................... 26 
3.5 
Analysis Sets ................................................................................................................ 27 
3.5.1 
Enrolled Set ......................................................................................................... 27 
3.5.2 
Safety Set ............................................................................................................. 28 
3.5.3 
Full Analysis Set .................................................................................................. 28 
3.5.4 
Per Protocol Set ................................................................................................... 28 
3.5.5 
Other analysis sets ............................................................................................... 28 
3.6 
Treatment Assignment and Treatment Groups ............................................................ 28 
3.7 
Center pooling strategy ................................................................................................ 28 
3.8 
Coding dictionaries ...................................................................................................... 28 
3.9 
Changes to protocol-defined analyses ......................................................................... 28 
3.10 
Consideration for COVID-19 ...................................................................................... 29 
4 
STATISTICAL ANALYTICAL ISSUES ....................................................................... 29 
4.1 
Adjustments for Covariates.......................................................................................... 29 
4.2 
Handling of Dropouts or Missing Data ........................................................................ 29 
4.2.1 
General Imputation Rule for Incomplete Dates ................................................... 29 
4.2.2 
Handling of Incomplete Dates in Context of Concomitant Medications ............ 29 
4.2.3 
Handling of Adverse Events with Missing Data ................................................. 30 
4.2.4 
Handling of Study Medication with Missing data ............................................... 31 
4.3 
Interim Analyses and Data Monitoring........................................................................ 31 
4.4 
Multicenter Studies ...................................................................................................... 32 
4.5 
Multiple Comparisons/Multiplicity ............................................................................. 32 
4.6 
Use of an Efficacy Subset of Subjects ......................................................................... 32 
4.7 
Active-control studies intended to show equivalence .................................................. 32 
4.8 
Examination of Subgroups ........................................................................................... 32 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 32 
5.1 
Subject Disposition ...................................................................................................... 32 
5.1.1 
Definitions and Derivations ................................................................................. 33 
5.1.1.1 
Subject Status ............................................................................................ 33 
5.1.1.2 
Last Administration of Study Medication ................................................. 33 
5.1.1.3 
Time to Discontinuation from Study ......................................................... 33 
5.1.1.4 
Period Started/Ended ................................................................................. 33 
5.1.1.5 
Duration of a Period .................................................................................. 33 
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5.1.2 
Tables ................................................................................................................... 33 
5.1.3 
Listings ................................................................................................................ 35 
5.2 
Protocol Deviations ...................................................................................................... 37 
5.2.1 
Analysis Summary ............................................................................................... 37 
5.2.2 
Definitions and Derivations ................................................................................. 37 
5.2.3 
Tables ................................................................................................................... 37 
5.2.4 
Listings ................................................................................................................ 38 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 38 
6.1 
Demographics .............................................................................................................. 38 
6.1.1 
Definitions and Derivations ................................................................................. 39 
6.1.2 
Tables ................................................................................................................... 39 
6.1.3 
Listings ................................................................................................................ 39 
6.2 
ECG and CT Scan / MRI ............................................................................................. 39 
6.2.1.1 
Definitions and Derivations ....................................................................... 40 
6.2.1.2 
Tables ........................................................................................................ 40 
6.2.1.3 
Listings ...................................................................................................... 40 
6.3 
Neurological Examination ........................................................................................... 40 
6.3.1.1 
Definitions and Derivations ....................................................................... 41 
6.3.1.2 
Tables ........................................................................................................ 41 
6.3.1.3 
Listings ...................................................................................................... 41 
6.4 
Physical Examination................................................................................................... 41 
6.4.1.1 
Definitions and Derivations ....................................................................... 41 
6.4.1.2 
Tables ........................................................................................................ 41 
6.4.1.3 
Listings ...................................................................................................... 41 
6.5 
Other Baseline characteristics ...................................................................................... 42 
6.5.1.1 
Definitions and Derivations ....................................................................... 42 
6.5.1.2 
Tables ........................................................................................................ 42 
6.5.1.3 
Listings ...................................................................................................... 42 
6.6 
Epilepsy Background Variables ................................................................................... 42 
6.6.1 
Definitions and Derivations ................................................................................. 43 
6.6.1.1 
Epilepsy Duration and Age at Onset ......................................................... 43 
6.6.1.2 
Historical partial onset seizures and seizures of subtypes IA, IB, and IC 
during 2 weeks prior to Visit 1 .................................................................. 43 
6.6.1.3 
Historical Partial Onset Seizures (Type I) During 2 Weeks Prior to Visit 143 
6.6.1.4 
Historical Seizure Count for Partial Onset Seizures During 2 Weeks Prior 
to Visit 1 .................................................................................................... 43 
6.6.2 
Tables ................................................................................................................... 44 
6.6.3 
Listings ................................................................................................................ 45 
6.7 
Medical History and Concomitant Diseases ................................................................ 46 
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6.7.1 
Definitions and Derivations ................................................................................. 47 
6.7.2 
Tables ................................................................................................................... 47 
6.7.3 
Listings ................................................................................................................ 47 
6.8 
Prior and Concomitant Medications ............................................................................ 48 
6.8.1 
Definitions and derivations .................................................................................. 48 
6.8.2 
Tables ................................................................................................................... 50 
6.8.3 
Listings ................................................................................................................ 50 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 51 
7.1 
Definitions and Derivations ......................................................................................... 51 
7.2 
Tables ........................................................................................................................... 52 
7.3 
Listings ......................................................................................................................... 53 
8 
EFFICACY ANALYSES ................................................................................................ 53 
8.1 
Statistical Analysis of the Primary Efficacy Variable ................................................. 53 
8.1.1 
Primary Efficacy Variable for Adjunctive Therapy ............................................ 53 
8.1.2 
Primary Analysis Variable for Monotherapy ...................................................... 55 
8.1.3 
Sensitivity Analyses of the Primary Efficacy Variable ....................................... 55 
8.2 
Statistical Analysis of the Secondary Efficacy Variables ............................................ 55 
8.2.1 
Secondary Efficacy Variables for Adjunctive Therapy ....................................... 55 
8.2.2 
Secondary Efficacy Variables for Monotherapy ................................................. 56 
8.3 
Analysis of Other Efficacy Variables .......................................................................... 57 
8.3.1 
Derivations of Other Efficacy Variables ............................................................. 57 
8.3.2 
Other Efficacy Variables for Adjunctive therapy/Monotherapy ......................... 58 
8.4 
Listings ......................................................................................................................... 60 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 63 
9.1 
Pharmacokinetics ......................................................................................................... 63 
9.1.1 
Definitions and Derivations ................................................................................. 63 
9.1.2 
Tables and Figures ............................................................................................... 63 
9.1.3 
Listings ................................................................................................................ 64 
9.2 
Pharmacodynamics ...................................................................................................... 65 
10 SAFETY ANALYSES ..................................................................................................... 65 
10.1 
Extent of Exposure ....................................................................................................... 65 
10.1.1 
Definitions and Derivations ................................................................................. 65 
10.1.2 
Tables ................................................................................................................... 66 
10.1.3 
Listings ................................................................................................................ 66 
10.2 
Adverse Events ............................................................................................................ 66 
10.2.1 
Definitions and Derivations ................................................................................. 67 
10.2.1.1 
Categorization of AEs ............................................................................... 67 
10.2.1.2 
Assignment of AEs to Periods/Onset of AEs ............................................ 67 
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10.2.1.3 
AEs Leading to Discontinuation ............................................................... 67 
10.2.1.4 
Drug related AE ......................................................................................... 67 
10.2.1.5 
Dose at AE Onset ...................................................................................... 68 
10.2.1.6 
Incomplete Dates ....................................................................................... 68 
10.2.2 
Tables ................................................................................................................... 68 
10.2.3 
Listings ................................................................................................................ 69 
10.3 
Clinical Laboratory Evaluations .................................................................................. 69 
10.3.1 
Definitions and Derivations ................................................................................. 70 
10.3.1.1 
Blood Sample ............................................................................................ 70 
10.3.1.2 
Ordering of Laboratory Parameters ........................................................... 71 
10.3.2 
Tables ................................................................................................................... 71 
10.3.3 
Listings ................................................................................................................ 73 
10.4 
Vital signs, Physical Findings, and Other Observations Related to Safety ................. 74 
10.4.1 
Vital Signs ........................................................................................................... 74 
10.4.1.1 
Definitions and Derivations ....................................................................... 74 
10.4.1.2 
Tables ........................................................................................................ 75 
10.4.1.3 
Listings ...................................................................................................... 76 
10.4.2 
Electrocardiograms .............................................................................................. 76 
10.4.2.1 
Definitions and Derivations ....................................................................... 76 
10.4.2.2 
Tables ........................................................................................................ 76 
10.4.2.3 
Listings ...................................................................................................... 77 
10.4.3 
Body Weight and Height ..................................................................................... 77 
10.4.3.1 
Definitions and Derivations ....................................................................... 78 
10.4.3.2 
Tables ........................................................................................................ 78 
10.4.3.3 
Listings ...................................................................................................... 78 
10.4.4 
Concomitant Medical Procedures ........................................................................ 78 
10.4.4.1 
Definitions and Derivations ....................................................................... 78 
10.4.4.2 
Tables ........................................................................................................ 79 
10.4.4.3 
Listings ...................................................................................................... 79 
10.4.5 
Assessment of Suicidality .................................................................................... 79 
10.4.5.1 
Definitions and Derivations ....................................................................... 79 
10.4.5.2 
Tables ........................................................................................................ 79 
10.4.5.3 
Listings ...................................................................................................... 79 
11 REFERENCES ................................................................................................................ 80 
12 APPENDICES ................................................................................................................. 81 
12.1 
Order of Laboratory Variables in Tables and Listings ................................................ 81 
12.2 
Listing of AEDs ........................................................................................................... 83 
12.3 
Possibly Clinically Significant Treatment-Emergent Laboratory Values ................... 85 
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12.3.1 
Hematology .......................................................................................................... 85 
12.3.2 
Chemistry ............................................................................................................. 86 
12.3.3 
Required Investigations and follow up for PDILI ............................................... 88 
12.3.4 
PDILI Laboratory Measurements ........................................................................ 90 
12.4 
PDILI information to be collected ............................................................................... 91 
12.5 
Vital Signs Abnormality Criteria ................................................................................. 92 
12.6 
Body Weight Values .................................................................................................... 93 
13 EUDRACT TABLE ......................................................................................................... 95 
14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 96 
14.1 
Amendment 1 ............................................................................................................... 96 
14.2 
Amendment 2 ............................................................................................................... 96 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 122 
 
 
 
LIST OF TABLES 
Table 3‒1: 
Assessment Schedule ....................................................................................... 22 
Table 3‒2: 
Analysis Visit Mapping Table ......................................................................... 24 
Table 12‒1: 
PCST values for Hematology .......................................................................... 85 
Table 12‒2: 
PCST values for Chemistry ............................................................................. 86 
Table 12‒3: 
Vital Signs Abnormality Criteria ..................................................................... 92 
Table 12‒4: 
Body Weight Values (kg) by Age in Months/Years and Months for Males ... 93 
Table 12‒5: 
Body Weight Values (kg) by Age in Months/Years and Months for 
Females ............................................................................................................ 94 
Table 3‒1: 
Assessment Schedule ..................................................................................... 106 
Table 3‒2: 
Analysis Visit Mapping Table ....................................................................... 107 
Table 3‒1: 
Assessment Schedule ..................................................................................... 109 
Table 3‒2: 
Analysis Visit Mapping Table ....................................................................... 111 
 
 
 
LIST OF FIGURES 
Figure 6‒1: 
Past and Concomitant Medication ................................................................... 49 
 
 
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LIST OF ABBREVIATIONS 
 
ADF 
Average Daily Frequency 
AE 
Adverse Event 
AED 
Anti-Epileptic Drug 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
Body Mass Index 
CfB 
Change from Baseline 
CI 
Confidence Interval 
BLOCF 
Baseline Observation Carry Forward 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DEM 
Data Evaluation Meeting 
DRC 
Daily Record Card 
eCRF 
electronic Case Report Form 
ECG 
electrocardiogram 
EDV 
Early Discontinuation Visit 
EEG 
electroencephalogram 
FAS 
Full Analysis Set 
FAS_A 
Full Analysis Set (Adjunctive therapy) 
FAS_M 
Full Analysis Set (Monotherapy) 
ILAE 
International League Against Epilepsy 
IPD 
Important Protocol Deviations 
LEV 
Levetiracetam  
LLOQ 
Lower Limit Of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
M&S 
Modeling and Simulation 
NDA 
New Drug Application 
PCS 
Possibly Clinically Significant 
PCST 
Possibly Clinically Significant Treatment-emergent  
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PD 
Pharmacodynamic 
PDILI 
Potential Drug-Induced Liver Injury 
PK 
Pharmacokinetic 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PK-PPS_A 
Pharmacokinetic Per Protocol Set (Adjunctive therapy) 
PK-PPS_M 
Pharmacokinetic Per Protocol Set (Monotherapy) 
PPS 
Per Protocol Set 
PT 
Preferred Term 
Q1 
First quartile 
Q3 
Third quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SS 
Safety Set 
SS_A 
Safety Set (Adjunctive therapy) 
SS_M 
Safety Set (Monotherapy) 
TEAE 
Treatment-Emergent Adverse Event 
VNS 
Vagal Nerve Stimulation 
 
 
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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 clinical 
study report for EP0100. Unless specified below, the study will be analyzed as described in the 
most recent version of the protocol. If a future protocol amendment necessitates a substantial 
change to the statistical analysis of the study data, this SAP may be amended accordingly. If 
needed, revisions to the approved SAP may be made prior to the snapshot of the database needed 
for NDA submission. For regulatory purposes, two planned data cut-offs will be made when the 
final subject who completes the Evaluation Period reaches Visit 13 and Visit 16 in order to 
obtain 6-month and 12-month exposure data, respectively. 
 
In addition to above, an interim analysis (IA) was performed for providing PMDA with the latest 
information to discuss if the study can be discontinued and the application method can be 
changed to extrapolation strategy based on the results of the IA, which is based on the suggestion 
at the consultation meeting with PMDA held on 
. The IA was performed according 
to the eCRF snapshot on 04 Jun 2021, in which the data cut-off date was 30 Apr 2021.   
 
2 
PROTOCOL SUMMARY 
This is an open-label, single arm study which aims to study Levetiracetam as monotherapy or 
adjunctive treatment of partial seizures in pediatric epileptic subjects ranging from 1 month to 
less than 4 years of age. This SAP is based upon the final Protocol EP0100 Amendment 3: 
Protocol Date:  
06 Feb 2017 
Amendment 1:  
16 Jun 2017 
Amendment 2:  
28 Jun 2018 
Amendment 3:  
29 Jan 2020 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of this study is to confirm the efficacy of Levetiracetam (LEV) in 
reducing seizure frequency in the First Period compared to historical control as adjunctive 
treatment in pediatric epilepsy subjects aged 1 month to <4 years with partial seizures. 
2.1.2 
Secondary Objectives 
The secondary objectives are the following: 
• To evaluate the safety and tolerability of LEV in the First Period in pediatric epilepsy 
subjects aged 1 month to <4 years with partial seizures 
• To evaluate the efficacy of LEV in reducing seizure frequency in the First Period compared 
to historical control as monotherapy in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures 
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• To evaluate long-term safety and tolerability of LEV in the combined First and Second 
Periods in pediatric epilepsy subjects aged 1 month to <4 years with partial seizures receiving 
long-term treatment with LEV at individualized doses 
• To evaluate the efficacy of LEV in the combined First and Second Periods as monotherapy 
or adjunctive treatment in pediatric epilepsy subjects aged 1 month to <4 years with partial 
seizures 
• To characterize pharmacokinetics (PK) of LEV in the First and Second Periods in epileptic 
pediatric subjects aged 1 month to <4 years 
2.2 
Study Variables 
2.2.1 
Efficacy Variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
2.2.1.1 
Efficacy Variables for Subjects on Adjunctive Therapy 
2.2.1.1.1 
Primary Efficacy Variable 
First Period: 
The primary efficacy variable for subjects on adjunctive therapy is the percent reduction in 
partial seizure frequency per week from Baseline to Visit 6. 
Combined First and Second Periods: 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
2.2.1.1.2 
Secondary Efficacy Variables 
First Period: 
The secondary efficacy variable for the First Period is the following: 
• Percent reduction in partial seizure frequency per week from Baseline to Visit 4 and Visit 5 
Note: here and further on, percent reduction is percent reduction from Baseline. Visit, without 
analysis, refers to study visit. 
Combined First and Second Periods: 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week from Baseline  
• For each analysis visit, percent reduction in partial seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%  
For definition of analysis visit see Table 3‒2. 
2.2.1.1.3 
Other Efficacy Variables 
First Period 
The other efficacy variables for the First Period for the number of seizures based on the 48h 
video-EEG recorded  prior to Protocol Amendment 3 are the following: 
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• Percent reduction in average daily frequency (ADF) of partial seizure frequency monitored 
by the 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
Note: percent reduction is percent reduction from Baseline. 
Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline   
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%    
2.2.1.2 
Efficacy Variables for Subjects on Monotherapy 
2.2.1.2.1 
Primary Efficacy Variable 
There is no primary efficacy variable for subjects on monotherapy. 
2.2.1.2.2 
Secondary Efficacy Variables 
First Period: 
There is no secondary efficacy variable for the First Period. 
Combined First and Second Periods: 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week from Baseline 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100%  
Note: for definition of analysis visit see Table 3‒2. 
2.2.1.2.3 
Other Efficacy Variables 
First Period: 
The other efficacy variables for the First Period for the number of seizures based on the 48h 
video-EEG recorded prior to Protocol Amendment 3 are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
Note: percent reduction is percent reduction from Baseline. 
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Combined First and Second Periods: 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in all types of seizure frequency per week from 
Baseline   
• For each analysis visit, percent reduction in all types of seizure frequency per week from 
Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 
100% 
• Percentage of subjects who are continuously 6-month seizure-free monitored by the patient 
diary   
2.2.2 
Pharmacokinetic/Pharmacodynamic Variable(s) 
Levetiracetam (parent compound only) plasma level is defined as the other PK variable. 
2.2.3 
Safety Variables 
2.2.3.1 
Primary Safety Variable 
There is no primary safety variable. 
2.2.3.2 
Secondary Safety Variables 
The secondary safety variables for the First Period are the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of serious adverse events (SAEs) 
• Incidence of TEAEs leading to discontinuation from study medication 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to discontinuation from study medication 
2.2.3.3 
Other Safety Variables 
The other safety variables are the following: 
• Adverse events (variables other than secondary safety variables) 
• Laboratory tests (blood chemistry and hematology) 
• Vital signs 
• Body weight and height 
• Physical and neurological examination 
Additional details are mentioned in the safety analyses section. 
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2.3 
Study Design and Conduct 
EP0100 is a Phase 3, open-label, single-arm, multicenter study with LEV as monotherapy or 
adjunctive treatment to evaluate the efficacy and safety of LEV (14mg/kg/day to 42mg/kg/day 
for subjects aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 
6 months to <4 years) in the treatment of partial seizures over the First Period (6 weeks), 
followed by the long-term follow-up (Second Period) in pediatric subjects. 
First Period 
Eligible subjects will enter the First Period (6 weeks). For dosing scheme refer to the protocol, 
Section 5.1.2.  
At Visit 6 (Week 6), subjects may enter either the Second Period or the Down-Titration Period, 
followed by the Safety Follow-Up Period. Subjects who do not enter the Second Period will be 
down-titrated. 
Second Period 
Subjects who complete the First Period will have a visit every 4 weeks ±7 days relative to the 
Visit 3 for the first 6 months of administration and then every 12 weeks ±14 days thereafter.  
A final visit will be required approximately 2 weeks ±7 days after the final dose of LEV, or 
sooner if the subject will continue LEV (prescribed by the primary care provider as commercial 
LEV) after study completion. 
The end of the study is defined as the date of the final visit of the final subject in the study. 
The planned number of subjects to be enrolled in the First Period will be a total of 38 subjects for 
the primary efficacy analysis. Subjects will be enrolled into 4 age groups (1 month to <6 months, 
6 months to <1 year, 1 year to <2 years, and 2 years to <4 years), with a minimum of 5 subjects 
in each age group.  
The planned number of monotherapy subjects will be a total of 10 subjects. 
It is planned to have those subjects recruited in approximately 20 sites. 
 
2.3.1 
Study Periods 
• Retrospective Baseline Period 
Seizure counts during the 2 weeks prior to Visit 1 will be used as a Retrospective Baseline 
Period.  
• First Period 
− Selection Period (maximum of 9 days) 
− Evaluation Period (6 weeks) 
− Down-Titration Period (up to 4 weeks) 
− Safety Follow-Up Period (2 weeks) 
• Second Period 
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− Maintenance Period (until approval or the program is discontinued) 
− Down-Titration Period (up to 4 weeks) 
− Safety Follow-Up Period (2 weeks) 
2.3.2 
Adjunctive Therapy and Monotherapy 
Subject who took at least 1 AED at Visit 1 will be categorized as a subject on adjunctive therapy, 
otherwise the subject will be categorized as on monotherapy (See Section 6.8 for identification 
of AEDs).  
2.4 
Determination of Sample Size 
Based on the previous placebo-controlled clinical studies for pediatric epilepsy patients that 
evaluated AEDs, the percent reduction in ADF of partial seizure frequency from Baseline for 
placebo is assumed to be no more than 10%. For the purposes of this study, a percent reduction 
in ADF of partial seizure frequency ≤10% is defined as non-effective. Therefore, when the lower 
limit of 95% confidence interval (CI) of median in the percent reduction in ADF of partial 
seizure frequency for LEV is greater than 10%, statistical significance is declared. Based on the 
N01009 data for the percent reduction in ADF of partial seizure frequency for LEV, a population 
of size N was randomly sampled with replacement repeatedly for 10,000 times for the sample 
size consideration. The probability was evaluated that the lower limit of 95% Confidence 
Interval (CI) of median in the percent reduction in ADF of partial seizure frequency for LEV was 
greater than 10% by samples with size of N. A sample size of at least 34 subjects is required to 
obtain 90% power. Assuming 10% of subjects will be non-evaluable, 38 subjects will be 
enrolled. 
Due to the change in the primary efficacy variable in protocol amendment 3, the sample size was 
reconsidered. When the placebo rate area is conservatively redefined as ≤15% and assuming 
there are no nonevaluable subjects, a sample size of 38 subjects will obtain ≥80% power. 
Therefore, no change in sample size is required. 
 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General Presentation of Summaries and Analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
for the non-PK analysis will be performed using SAS Version 9.3 or higher.  
The study will enroll subjects from different age when entered into the study, see Section 4.8.  
The following subgroups are formed: 1 month to <6 months, 6 months to <1 year, 1 year to <2 
years and 2 years to <4 years. It is anticipated that a small number of subjects will be enrolled 
into the 1 month to <6 months and the 6 months to <1 year age categories. Hence, for analysis of 
the primary efficacy variable the data of the two youngest age categories will be pooled into one 
category resulting in three age categories:  1 month to <1 year, 1 year to <2 years, and 2 years to 
<4 years. 
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3.1.1 
Summarizing Categorical Variables 
For categorical parameters, the number and percentage of subjects will be presented. The 
denominator for percentages will be based on the number of subjects appropriate for the purpose 
of analysis. Unless otherwise noted, all percentages will be displayed to 1 decimal place. No 
percentage will be displayed for zero counts, and no decimal will be presented when the 
percentage is 100%.  
3.1.2 
Summary Statistics for Continuous Variables 
For continuous parameters, descriptive statistics will include number of subjects with available 
measurements (n), mean, standard deviation (SD), median, first and third quartiles (Q1, Q3), 
minimum, and maximum, unless otherwise stated. For the primary efficacy variable and one of 
the secondary efficacy variables also a 95% CI will be presented. For PK parameters, the 
coefficient of variation (CV) and geometric mean may also be presented. 
For reporting descriptive statistics of continuous parameters, the following rules will be applied: 
• Number of observations “n” will be an integer 
• Mean, SD, median, Q1, Q3 and upper and lower bound of 95% CI will use 1 additional 
decimal place compared to the original data 
• Coefficient of variance (CV [%]) will be presented with 1 decimal place 
• Minimum and maximum will have the same number of decimal places as the original value 
• Mean and median changes from Baseline lower than the minimal displayable change will be 
displayed without sign (eg, -0.00 is displayed as 0.00) 
A complete set of data listings containing all documented data and all calculated data (eg, change 
from Baseline) will be generated. 
3.1.3 
Table Presentation 
Tables will be presented for subjects on adjunctive therapy and for subjects on monotherapy, 
separately. 
3.1.4 
Listing Presentation 
Listings will be presented for subjects on adjunctive therapy and for subjects on monotherapy, 
separately. These listings will be ordered by age category and site-/subject number. 
The header information for listings related to safety assessments reflects Age Category, 
Region/Country/Site-/Subject Number, and Gender/Age/Race/Weight. 
Subject data listings are presented with the same number of decimal places for all values within 
one parameter. The number of decimal places within a listing of a variable is determined by the 
minimum absolute value across all subjects and visits, unless specified differently for individual 
variables. The number of decimal places is chosen so that the minimum value has 
• Three significant figures if <100 
• One decimal place if ≥100 
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The number of decimal places is restricted to a maximum of as many decimal places as are 
available in the original data. 
Date variables that were captured on a CRF are presented as documented without imputing 
incomplete dates. Imputed dates are listed separately. 
3.2 
General Study Level Definitions 
3.2.1 
Analysis Time Points 
3.2.1.1 
Relative Day 
Relative day is only defined for subjects who received study medication. 
The relative day for an assessment or start or end dates of events (eg, AEs) is calculated 
according to the following rules: 
• The relative day 1 indicates the date of the first dose of study medication 
• The relative day for an event on/after the day of first dose of study medication is calculated 
as: 
Assessment/Event date - date of the first dose of study medication +1 
• The relative day for an event before the day of first dose of study medication is calculated as: 
Assessment/Event date - date of the first dose of study medication 
In subject data listings the relative day is presented: 
• The relative day 1 (without any prefix) indicates the date of the first dose of study medication 
The relative day for an event on/after the day of first dose of study medication and on/before 
last dose of study medication is calculated as: 
Assessment/Event date - date of the first dose of study medication +1, the relative day will be 
presented without any prefix.  
• The relative day for an event before the day of first dose of study medication is calculated as: 
Assessment/Event date - date of the first dose of study medication, the relative day will be 
presented with a prefix “-“ to indicate number of days before first dose of study medication 
• The relative day for an event after the day of last dose of study medication is calculated as: 
Assessment/Event date - date of last dose of study medication, the relative day will be 
presented with a prefix “+” to indicate number of days since last dose of study medication 
For incomplete dates, no relative day is calculated. 
Note: Missing values for date of last administration of study medication are imputed as specified 
in Section 4.2.4. 
3.2.1.2 
End Date of the First/Second Period 
A subject is regarded to have started/ended a period as described below. For this, the start dates 
and end dates of study periods for each subject are defined in the following sections. 
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3.2.1.2.1 
Subjects enrolled prior to Protocol Amendment 3 who are not 48h 
video-EEG Failures and subjects enrolled according to Protocol 
Amendment 3 
3.2.1.2.1.1 
First period 
Selection Period: 
• Start: Day of Visit 1 
• End:  
− Subject does not discontinue from study: 1 day before Visit 3, or 
− Subject discontinues from study: “Date of last contact with Subject” on “Study 
Termination, Screen Failure Packet” CRF.  
Evaluation Period (only if subject does not discontinue before or at Visit 3): 
• Start: Day of Visit 3 
• End:   
First of: 
− Day of Visit 6, or 
− Day of first Early Discontinuation Visit.  
For subjects who do not enter the Second Period: 
Down-Titration Period (only when subject is not on minimum dose): 
• Start: 1 day after Day of End of Evaluation Period 
• End:  Day of Last Early Discontinuation Visit; if Day of Last Early Discontinuation Visit is 
missing,  the date of last dose of study medication will be used 
Followed by 
Safety Follow-Up Period (safety follow-up visit will take place when subject is 2 weeks off 
study drug, ie, on 0mg/kg dose): 
• Start: 1 day after Day of End of Down-Titration Period or 1 day after Day of End of 
Evaluation Period 
• End:  Day of Safety Follow-Up Visit 
3.2.1.2.1.2 
Second Period 
Maintenance period:  
• Start: 1 day after Day of Visit 6 
• End:  First of: 
− Day of first Early Discontinuation Visit, or 
− Day of End of Study*  
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* Day of End of Study as determined by sponsor, connected to market approval or 
completion of development of LEV in subjects 1 month to <4 years 
Down-Titration Period (only when subject is not on minimum dose): 
• Start: 1 day after Day of End of Maintenance Period 
• End:  Day of Last Early Discontinuation Visit; if Day of Last Early Discontinuation Visit is 
missing,  the date of last dose of study medication will be used  
Followed by 
Safety Follow-Up Period (safety follow-up visit will take place when subject is 2 weeks off 
study drug, ie, on 0mg/kg dose): 
• Start: 1 day after Day of End of Down-Titration Period or 1 day after Day of End of 
Maintenance Period 
• End:  Day of Safety Follow-Up Visit 
For subjects who did not discontinue from Maintenance Period:  
• The end date will be captured on “study termination” CRF.  
• No down-titration and Safety Follow-Up will be performed for these subjects. 
 
3.2.1.2.2 
Subjects enrolled prior to Protocol Amendment 3 who are 48h video-
EEG Failures  
3.2.1.2.2.1 
First period 
Selection Period: 
• Start: Day of Visit 1 
• End:   
− Subject dose not discontinue from study: 1 day before Visit 6, or 
− Subject discontinues from study: “Date of last contact with Subject” on “Study 
Termination, Screen Failure Packet” CRF. 
3.2.1.2.2.2 
Second Period  
For 48h video-EEG failures, the data will be re-mapped according to Table 3-2 and will be 
included in the efficacy and safety analysis.  
Dose Adjustment Period (only if subject does not discontinue at Visit 2): 
• Start: Day of Visit 6 
• End: First of: 
− Day of Visit 9, or 
− Day of first Early Discontinuation Visit 
1. For subjects who discontinued during the Dose Adjustment Period: 
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Down-Titration Period (only when subject is not on minimum dose): 
• Start: 1 day after Day of End of Dose Adjustment Period 
• End:  Day of Last Early Discontinuation Visit; if Day of Last Early Discontinuation Visit 
is missing,  the date of last dose of study medication will be used  
Followed by 
Safety Follow-Up Period (safety follow-up visit will take place when subject is 2 weeks 
off study drug, ie, on 0mg/kg dose): 
• Start: 1 day after Day of End of Down-Titration Period or 1 day after Day of End of Dose 
Adjustment Period  
• End:  Day of Safety Follow-Up Visit 
2. For subjects who did not discontinue during the Dose Adjustment Period: 
Maintenance Period: 
• Start: 1 day after Day of Visit 9 
• End:  First of: 
− Day of first Early Discontinuation Visit, or 
− Day of end of study*  
* Day of end of study as determined by sponsor, connected to market approval or 
completion of development of LEV in subjects 1 month to <4 years 
3. For subjects who discontinue from maintenance period: 
Down-Titration Period (only when subject is not on minimum dose): 
• Start: 1 day after Day of End of Maintenance Period 
• End:  Day of Last Early Discontinuation Visit; if Day of Last Early Discontinuation Visit 
is missing,  the date of last dose of study medication will be used  
Followed by 
Safety Follow-Up Period (safety follow-up visit will take place when subject is 2 weeks 
off study drug, ie, on 0mg/kg dose): 
• Start: 1 day after Day of End of Down-Titration Period or 1 day after Day of End of 
Maintenance Period 
• End:  Day of Safety Follow-Up Visit 
4. For subjects who did not discontinue from Maintenance Period:  
• The end date will be captured on “study termination” CRF.  
• No down-titration and Safety Follow-Up will be performed for these subjects. 
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3.2.2 
Schedule of Study Assessments 
The study protocol gives the overall study schedule and the permissible intervals for these visits 
expressed as the number of days relative to Visit 3: Section 5.2 of protocol. 
Subjects who were directly enrolled in the Second Period based on the protocol prior to 
Amendment 3 will also be included in the efficacy and safety analysis with remapping of visit 
numbers to correspond to the ones for subjects who enrolled in the First Period.  
Table 3‒1 presents the assessment schedule for subjects:  
• who are enrolled prior to Protocol Amendment 3 and are not 48h video-EEG failures; or   
• who are enrolled according to Protocol Amendment 3; or 
• who are enrolled prior to Protocol Amendment 3 and are 48h video-EEG failures  
 
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Table 3‒1: 
Assessment Schedule 
Study Visit 
Target day* 
Visit Window 
Week number 
Subjects: 
• 
who are enrolled prior to Protocol Amendment 3 and are not 48h video-EEG failures or 
• 
who are enrolled according to Protocol Amendment 3  
Evaluation Period 
Visit 3 
Day 1 
 
Week 0 
Visit 4 
Day 15 
Day 11 to Day 19 
Week 2 
Visit 5 
Day 29 
Day 25 to Day 33 
Week 4 
Visit 6 
Day 43 
Day 39 to Day 47 
Week 6 
Maintenance Period 
Visit 8 
Day 71 
Day 64 to Day 78 
Week 10 
Visit 10 
Day 99 
Day 92 to Day 106 
Week 14 
Visit 11  
Day 127 
Day 120 to Day 134 
Week 18 
Visit 12 
Day 155 
Day 148 to Day 162 
Week 22 
Visit 13 
Day 183 
Day 176 to Day 190 
Week 26 
Visit 15 
Day 267 
Day 260 to Day 274 
Week 38 
Visit 16 
Day 351 
Day 337 to Day 365 
Week 50 
Visit 17 
Day 435 
Day 421 to Day 449 
Week 62 
  Every 12 weeks 
 
 
 
Subjects:  
• 
who are enrolled prior to Protocol Amendment 3 and are 48h video-EEG failures  
Dose Adjustment Period 
Visit 6 
Day 1 
 
Week 0 
Visit 7 
Day 15 
Day 11 to Day 17 
Week 2 
Visit 8 
Day 29 
Day 25 to Day 33 
Week 4 
Visit 9 
Day 43 
Day 39 to Day 47 
Week 6 
Maintenance Period 
Visit 10 
Day 57 
Day 50 to Day 64 
Week 8 
Visit 11 
Day 85 
Day 78 to Day 92 
Week 12 
Visit 12 
Day 113 
Day 106 to Day 120 
Week 16 
Visit 13 
Day 141 
Day 134 to Day 148 
Week 20 
Visit 14 
Day 183 
Day 176 to Day 190 
Week 26 
Visit 15 
Day 225 
Day 221 to Day 232 
Week 32 
Visit 16 
Day 309 
Day 295 to Day 323 
Week 44 
Visit 17 
Day 393 
Day 379 to Day 407 
Week 56 
  Every 12 weeks 
 
 
 
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Table 3‒1: 
Assessment Schedule 
Study Visit 
Target day* 
Visit Window 
Week number 
Note: the day of the first dose of study medication is defined as Study Day 1, while the day before the date of first 
dose of study medication is defined as Study Day -1 (there is no Study Day 0).  
* Day relative to first study drug intake  
In the event that more than 1 assessment occurs within a given visit window, the assessment 
closest to the target date will be used in summaries for the given visit.  If 2 assessments are 
equally close to the target day, the latest assessment will be used. 
Table 3‒2 presents the mapping of Study Visits to Analysis Visits for subjects: 
• who are enrolled prior to Protocol Amendment 3 and are not 48h video-EEG failures; or  
• who are enrolled according to Protocol Amendment 3; or  
• who are enrolled prior to Protocol Amendment 3 and are 48h video-EEG failures  
Analysis visits will be used for analysis of long-term safety and efficacy data. 
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Table 3‒2: 
Analysis Visit Mapping Table 
Analysis 
Visit 
Week 
number 
Relative 
day since 
first study 
drug intake 
Analysis 
window 
Subjects enrolled 
prior to Protocol 
Amendment 3 and 
are not 48h video-
EEG failures; or 
subjects who are 
enrolled according 
to Protocol 
Amendment 3 
Study Visit 
(Target day[1]) 
Subjects enrolled 
prior to Protocol 
Amendment 3 and 
are 48h video-
EEG failures 
Study Visit 
(Target day[1]) 
Retrospective 
Baseline[2] 
 
- 
2 weeks prior to 
Visit 1 
 
 
Baseline Period 
-1 
-1 
-9 
-9 – 0 
Visit 1  
Visit 2[3] 
Visit 1 
Visit 2[3] 
Evaluation/Dose Adjustment/Maintenance Period 
0[4] 
0 
1 
 
Visit 3 
Visit 6 
1 
2 
15 
2 – 22 
Visit 4 
Visit 7 
2 
4 
29 
23 – 36 
Visit 5 
Visit 8 
3 
6 
43 
37 – 50 
Visit 6 
Visit 9 
4 
8 
57 
51 – 64 
- 
Visit 10 
5 
10 
71 
65 – 78 
Visit 8 (Day 71) 
- 
6 
12 
85 
79 – 95 
- 
Visit 11 (Day 85) 
7 
15 
106 
96 - 116  
Visit 10 (Day 99) 
Visit 12 (Day 
113) 
8 
18 
127 
117 – 137 
Visit 11 (Day 127) 
- 
9 
21 
148 
138 – 158 
Visit 12 (Day 155) 
Visit 13 (Day 
141) 
10 
24 
169 
159 – 179 
- 
- 
11 
27 
190 
180 – 200 
Visit 13 (Day 183) 
Visit 14 (Day 
183) 
12 
30 
211 
201 – 231 
- 
Visit 15 (Day 
225) 
13 
36 
253 
232 – 295 
Visit 15 (Day 267) 
- 
14 
48 
337 
296 – 379 
Visit 16 (Day 351) 
Visit 16 (Day 
309) 
15 
60 
421 
380 – 463 
Visit 17 (Day 435) 
Visit 17 (Day 
393) 
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16 
72 
505 
464 – 547 
Visit 18 (Day 519) 
Visit 18 (Day 
477) 
17 
84 
589 
548 – 631 
Visit 19 (Day 603) 
Visit 19 (Day 
561) 
Every 12 weeks 
Down-titration Period 
EDV/EOS 
- 
- 
 
 
 
Safety Follow-Up Period 
Safety 
Follow-Up 
- 
- 
 
 
 
EDV= Early Discontinuation Visit; EOS= End of Study 
[1] Day relative to first study drug intake 
[2] Retrospective Baseline is only applicable to seizure count data.  For other analyses the time window of “2 
weeks prior to Visit 1” for baseline is not applied.  
[3] Study Visit 2 is only applicable for those subjects enrolled prior to Protocol Amendment 3. 
[4] Analysis visit 0 is not applicable to laboratory test, since Week 0 is not scheduled for them. 
In the event that more than 1 assessment occurs within a given analysis visit window, the 
assessment closest to the target date will be used in summaries for the given visit. If 2 
assessments are equally close to the target day, the latest assessment will be used.  
3.2.3 
Unscheduled Visits 
If not otherwise stated, data from unscheduled visits are: 
• Not considered for by-visit presentations 
• Considered for a respective period depending on the date when the unscheduled visit 
occurred 
• Presented in subject data listings 
3.2.4 
Mapping of Assessments Performed at Early Discontinuation Visit 
Efficacy and safety assessments at an Early Discontinuation Visit (EDV) that correspond to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. In the event that the subject discontinues 
between two scheduled visits the data from the EDV are presented with data corresponding to 
the next scheduled visit for the subject.  For subjects who had more than one EDV because of the 
starting dose of the Down-Titration Period, only the first EDV will be mapped to the scheduled 
visit.  
3.2.5 
Age  
3.2.5.1 
Chronological Age 
For a given date, chronological age in months is defined as: ( Date – Date of birth ) / 30.4375, 
assuming that the date difference is given in days. 
3.2.5.2 
Adjusted Age 
Pre-Term birth will be accounted for by using the adjusted age which is defined as 
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• [ ( Date – Date of Birth ) – ( 36 – number of weeks pre-term ) x 7 ] / 30.4375 
for subjects of chronological age < 12 months and 
• Chronological age, otherwise 
If not specified otherwise, adjusted age at the date of the assessment is used for all analyses. 
3.2.5.3 
Age at Entry Into Study 
The adjusted age at entry into study is defined as the adjusted age at the screening date. This is 
also referred to as “Age at entry into study” 
3.2.6 
Body Mass Index 
Body Mass Index (BMI) will be calculated using the formula: 
 
BMI = weight (kg) / (height (m))2. 
3.2.7 
Exposure to Study Medication 
The date of first dose of study medication is defined as the first study medication dose date 
according to the First Administration CRF. 
The date of last dose of study medication is defined as the last dose of study medication reported 
on the standard Trial Termination CRF.  
The number of days of exposure is defined as the stop date minus the treatment start date +1 day. 
Days with unknown or zero dosing which occur prior to the last dose of study medication in the 
study will be included in the calculation. 
3.3 
Definition of Baseline Values 
For by-visit analysis, baseline is defined as following: 
For efficacy variables (except partial seizure frequency collected from DRC), safety variables, 
laboratory variables (blood chemistry, hematology), vital signs, and body weight, baseline is 
defined as the last value prior to the first dose of study medication (LEV). 
In general: Change from Baseline (CfB) is calculated as:  
 
CfB = Post-Baseline value – Baseline value. 
If not noted otherwise, change from Baseline is calculated for post Baseline visits according to 
the visit schedule including unscheduled visits and for Last Visit. 
For percent reduction in partial seizure frequency by DRC, a baseline value is calculated from 
retrospective baseline period + selection period. 
For by-analysis visit, baseline is calculated from Analysis Visit Baseline value. 
 
3.4 
Protocol Deviations 
After all CRFs have been retrieved and entered, all queries issued and answered to the extent 
possible, and prior to locking the database, a final Data Evaluation Meeting (DEM) will be held. 
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The meeting covers but is not limited to the following tasks: 
• Review and assessment of important protocol deviations 
• Agreement/confirmation of data handling rules 
• Evaluation of statistical methodology 
Important protocol deviations are to be classified into important for: 
• Efficacy 
• Conduct/Patient Management 
Criteria and rules for the identification and classification of important protocol deviations 
regarding their impact on study conduct/subject handling and/or the assessment of efficacy are to 
be setup and to be minuted. Decisions made during the meeting are minuted. 
3.5 
Analysis Sets 
The following sets are defined for this study: 
• Enrolled Set (ES) 
• Safety Sets:  
− SS_A (Safety Set [Adjunctive therapy]) 
− SS_M (Safety Set [Monotherapy]) 
• Full Analysis Sets:  
− FAS_A (Full Analysis Set [Adjunctive therapy]) 
− FAS_M (Full Analysis Set [Monotherapy]) 
• Pharmacokinetic Per-Protocol Set (PK-PPS) 
- 
PK-PPS_A [Pharmacokinetic-Per-Protocol Set (Adjunctive therapy)]  
- 
PK-PPS_M [Pharmacokinetic-Per-Protocol Set (Monotherapy)] 
If not stated otherwise, presentation of: 
• Disposition and important protocol deviations are based on the ES 
• Demographics, other baseline characteristics, safety, and exposure data are based on the 
SS_A and SS_M 
• Efficacy data are based on the FAS_A and FAS_M.  
 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all subjects enrolled (which include all subjects screened) 
into the Selection Period. 
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3.5.2 
Safety Set 
The SS_A will include all enrolled subjects on adjunctive therapy who receive at least 1 dose of 
study medication in the Evaluation Period. 
The SS_M will include all enrolled subjects on monotherapy who receive at least 1 dose of study 
medication in the Evaluation Period. 
For subjects who were directly enrolled in the Second Period based on the protocol prior to 
Amendment 3, after re-mapping they will be considered as entering in the Evaluation Period if 
they receive at least 1 dose of study medication in the Dose Adjustment Period. 
3.5.3 
Full Analysis Set 
The FAS_A will consist of all subjects in the SS_A who have at least 1 post-baseline efficacy 
assessment. 
The FAS_M will consist of all subjects in the SS_M who have at least 1 post-baseline efficacy 
assessment. 
3.5.4 
Per Protocol Set 
Not applicable.   
3.5.5 
Other analysis sets 
The PK-PPS_A will consist of all subjects in the SS_A for whom at least 1 valid LEV plasma 
concentration-time record and dosing information are available. 
The PK-PPS_M will consist of all subjects in the SS_M for whom at least 1 valid LEV plasma 
concentration-time record and dosing information are available. 
3.6 
Treatment Assignment and Treatment Groups 
This is an open-label study with a single treatment arm; hence subjects will not be randomized.  
3.7 
Center pooling strategy 
No pooling of centers is planned for this study.  
3.8 
Coding dictionaries 
Medical history and adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 23.0 that is released for execution at UCB/Designee.  
Medication including anti-epileptic drugs (AEDs) will be coded using the World Health 
Organization Drug Dictionary (WHO-DD) WHO-DD SEP/2017 that is released for execution at 
UCB/designee.  The applied version of the dictionaries will be explicitly mentioned in the 
respective tables and listings. 
3.9 
Changes to protocol-defined analyses 
Not applicable. 
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3.10 
Consideration for COVID-19 
Since the target population of this study is infants or young children in which the population is 
not considered will be impacted on the efficacy and safety evaluation due to COVID-19.  No 
additional amendment to CRF or analyses is required.   
 
4 
STATISTICAL ANALYTICAL ISSUES 
4.1 
Adjustments for Covariates 
This section is not applicable for this study. 
4.2 
Handling of Dropouts or Missing Data 
Days with missing seizure data will not be used for the calculation of seizure frequency per 
week. If subjects drop out, their seizure counts over the available period will be used and 
transformed into seizure frequency per week, by dividing the number of seizures during the 
available period by the number of days of that period, multiplied by 7. 
Safety variables will be analyzed insofar as they are available, without imputation or carrying 
values forward. 
Imputations for missing or partial values for dates for AEs and concomitant medications will be 
applied to determine if an event is to be considered treatment-emergent or concomitant. Across 
safety and PK analyses, only reported data will be used.  
4.2.1 
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 concomitant medication, Section 4.2.2 
• Start and stop dates of Adverse Events, Section 4.2.3 
Completely missing dates will not be replaced and the corresponding derived variables will be 
set to missing. 
4.2.2 
Handling of Incomplete Dates in Context of Concomitant Medications 
Any medications with incomplete start and/or end dates will be handled according to the 
following rules for classification as prior and concomitant and for the calculation of relative 
study days. Such imputations will only be performed for these classifications and calculations; in 
the listings all data will be shown as recorded on the eCRF. 
Imputation of Partial Start Dates: 
• If only the month and year are specified and the month and year of first dose of study 
medication are not the same as the month and year of the start date, then use the 1st of the 
month 
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• If only the month and year are specified and the month and year of first dose of study 
medication are the same as the month and year of the start date, then use the date of first dose 
of study medication 
• If only the year is specified, and the year of first dose is not the same as the year of the start 
date of study medication, then use January 1 of the year of the start date 
• If only the year is specified, and the year of first dose is the same as the year of the start date, 
then use the date of first dose of study medication 
• If the start date is completely unknown and the stop date is unknown or not prior to the date 
of first dose, then use the date of first dose of study medication 
Imputation of Partial Stop Dates: 
• If only the month and year are specified, then use the last day of the month 
• If only the year is specified, then use December 31 of that year 
• If the stop date is completely unknown, do not impute the stop date 
In the event of ambiguity or incomplete data which makes it impossible to determine whether a 
medication was concomitant or not, the medication will be considered as concomitant. 
4.2.3 
Handling of Adverse Events with Missing Data 
Any AEs with incomplete onset and outcome (end) dates/times will be handled according to the 
following rules for classification as treatment-emergent. Such imputations will only be 
performed for these classifications; in the listings all data will be shown as recorded on the 
eCRF.  
Imputation of Partial Onset Dates: 
• If only the month and year of onset are specified and the month and year of first dose of 
study medication are not the same as the month and year of onset, then use the 1st of the 
month 
• If only the month and year of onset are specified and the month and year of first dose of 
study medication are the same as the month and year of onset, then use the date/time of first 
dose of study medication 
• If only the year is specified, and the year of first dose of study medication is not the same as 
the year of onset, then use January 1 of the year of onset 
• If only the year is specified, and the year of first dose of study medication is the same as the 
year of onset, then use the date/time of first dose of study medication  
• If the onset date of the AE is completely unknown, then use the date\time of first dose of 
study medication 
Imputation of Partial End Dates: 
• If only the month and year are specified, then use the last day of the month 
• If only the year is specified, then use December 31 of that year 
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• If the AE resolved and the resolution date is completely unknown, then do not impute the 
resolution date 
• If the onset time of the event is unknown, impute it as 00:00 unless the known part of the 
onset date is the same as the date of first dose of study medication; in this case impute the 
time of first dose of study medication 
With respect to AEs, events with missing intensity will be assumed to be severe. Events with 
missing relationship to study medication per the investigator will be assumed to be related.  
Data handling for worsened AEs is provided below. The standard AE CRF has the outcome of 
“worsened” to be used when there is an increase in the intensity of an AE. The definition of 
“worsened” is when the AE is still present but at a heightened intensity. CRF instructions dictate 
to complete a new AE screen with the event term of the worsened event.   
Note that the outcome of “worsened” is not allowed terminology within the CDISC standards. In 
the SDTM.AE, the data is mapped to the outcome “Not Recovered/Not Resolved”. The outcome 
of “Worsened” will be kept in SDTM.SUPPAE. For subject data listings, the convention will be 
to use the mapped SDTM terminology of “Not Recovered/Not Resolved”.  
4.2.4 
Handling of Study Medication with Missing data 
No imputation should be performed for missing start dates of study medication. This field on the 
CRF should not be partial or missing. 
If a subject has missing last administration information from the Study Termination CRF page, 
the last available treatment date with nonzero total daily dose from Drug Dosing Log will be 
used for last administration date if it is not the same as the first administration date of the subject. 
If the subject does not have any available treatment date or the last available treatment date is the 
same as the first administration date from Drug Dosing Log and is missing last administration 
information from the Study Termination CRF page, the last contact date from CRF is used for 
the last administration date. 
Imputed date of last dose dates should only be used for calculation of the duration of exposure. 
The date as recorded on the CRF should be presented in subject data listings (no imputed dates 
should be included in subject data listings. 
4.3 
Interim Analyses and Data Monitoring 
No formal interim analysis is planned for this study. For regulatory purposes, two planned data 
cut-offs will be made when the final subject who completes the Evaluation Period reaches Visit 
13 and Visit 16 in order to obtain 6-month and 12-month exposure data, respectively.  All the 
efficacy and safety analysis planned in the protocol will be performed for NDA submission using 
the interim cut-off data followed by additional cut-off and/or final analysis for long-term follow-
up evaluation. 
In addition to above, an interim analysis (IA) was performed for providing PMDA with the latest 
information to discuss if the study can be discontinued and the application method can be 
changed to extrapolation strategy based on the results of the IA, which is based on the suggestion 
at the consultation meeting with PMDA held on 
 The IA was performed according 
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to the eCRF snapshot on 04 Jun 2021, in which the data cut-off date was 30 Apr 2021.  
 
4.4 
Multicenter Studies 
Since it is expected that there will be only a few subjects per age category and center 
combination, there are no plans to summarize data by age category and center. Summary tables 
will be presented pooled for all centers. 
4.5 
Multiple Comparisons/Multiplicity 
If the primary analysis of the primary variable (median percent reduction for adjunctive therapy) 
at Study Visit 6 is not significant, the statistical testing will stop.  If testing at Study Visit 6 is 
significant, the analysis will be repeated for Study Visit 4.  If testing at Study Visit 4 is also 
significant, the analysis will be repeated for Study Visit 5.   In that case, the second and the third 
analyses are also regarded as confirmatory as due to the hierarchical testing procedure no alpha 
adjustment is needed. 
4.6 
Use of an Efficacy Subset of Subjects 
No additional efficacy subset is used. 
4.7 
Active-control studies intended to show equivalence 
No comparator and no testing for equivalence in this study, hence this section is not applicable 
for this study. 
4.8 
Examination of Subgroups 
In this study 4 age categories will be investigated: 1 month to <6 months, 6 months to <1 year, 
1 year to <2 years, and 2 years to <4 years. For the primary efficacy variable the data of the two 
youngest age categories will be pooled and data of the primary efficacy variable will be 
summarized by the so-obtained 3 age-categories and overall. 
Note: for the age classification, the age at entry into study is used (Section 3.2.5.3). 
 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject Disposition 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
Disposition related tables cover a presentation of screen failure reasons, frequencies of 
completed and discontinued subjects including reason for discontinuation overall and by video-
EEG status (video-EEG failures and video-EEG non-failures for subjects enrolled prior to 
Protocol Amendment 3 and subjects enrolled following Protocol Amendment 3), attendance at 
visits and periods, study duration as well as analysis sets. In addition, information on number of 
subjects enrolled (ie, Enrolled Set), and being in the Safety Sets, Full Analysis Sets, and 
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Pharmacokinetic Per-Protocol Sets is presented overall and by investigator site together with the 
date of first subject in and last subject out.  
The following listings will be provided: study eligibility criteria text; subjects who did not meet 
study eligibility criteria; subject disposition; study discontinuation; visit dates; study periods; and 
subject analysis sets. 
5.1.1 
Definitions and Derivations 
5.1.1.1 
Subject Status 
Subject status regarding completion is taken from the Study Termination CRF. 
5.1.1.2 
Last Administration of Study Medication 
Missing values for date of last administration of study medication are imputed as specified in 
Section 4.2.4. 
5.1.1.3 
Time to Discontinuation from Study 
 
An event in the sense of the variable Time to Discontinuation from Study is observed if for a 
subject on the Study Termination CRF Subject status at study termination is “Dropout”. 
In case of an event, 
 
Time to Discontinuation from Study [months] =  
12 x (Date of premature study termination [Study Termination CRF] -  
date of enrolment) / 365.25. 
This observation is not censored. 
In case of no event, 
 
Time to Discontinuation from Study [months] =  
12 x (Date of last visit – date of enrolment) / 365.25. 
This observation is censored. 
5.1.1.4 
Period Started/Ended 
A subject is regarded to have started / ended period as described in Section 3.2.1.2. 
5.1.1.5 
Duration of a Period 
The duration of a period is not shown in context of disposition. The duration of a period is used 
as the duration of exposure to study medication, see Section 3.2.7. 
5.1.2 
Tables 
A table Reasons for Screen Failures for the ES presents, for subjects on adjunctive therapy and 
for subjects on monotherapy, separately: 
• Number of screened subjects and number and percentage of screen failures. 
• Number and percentage of screen failures by primary reason for screen failure. 
The table is presented for subjects across all age categories. 
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A table Disposition of Subjects Screened for the ES presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately: 
• Number of subjects screened, treated, being in the FAS_A, FAS_M, SS_A, SS_M, and PK-
PPS_A and PK-PPS_M , by age category and for all subjects 
• The date of first subject in (defined as date of first screening visit) and last subject out 
(defined as date of last visit for the last subject) 
Subject disposition is presented for subjects across all age categories by investigator site and 
overall. 
A table Disposition and Discontinuation Reasons for SS presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately: 
• Number and percentage of subjects who started and completed the study 
• Number and percentage of subjects discontinuing the study including primary reason for 
discontinuation 
For the whole table, percentages are based on the number of the SS. 
Subject disposition and the reason for discontinuation is presented overall and by study period. 
Also number and percentage of subjects continuing treatment after the study is presented. 
A table Attendance at Analysis Visits for the SS presents for subjects on adjunctive therapy and 
for subjects on monotherapy, separately: 
• Number and percentage of subjects at a visit 
A table Disposition of Analysis Sets presents for the ES the frequency distribution (number and 
percentage of subjects) per analysis set, ie,: 
• For subjects on adjunctive therapy: 
− ES 
− SS_A 
− FAS_A 
− PK-PPS_A 
and 
• For subjects on monotherapy: 
− ES 
− SS_M 
− FAS_M 
− PK-PPS_M 
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5.1.3 
Listings 
A listing Study Eligibility Criteria Text (for the ES1) presents: 
• Protocol/Amendment Number 
• Criteria/Number 
• Description 
1 Analysis set is specified only for technical reasons as content-wise this is unnecessary.. 
A listing Therapy presents: 
• Site-/Subject Number  
• Therapy 
A subject data listing Subjects Who Did Not Meet Study Eligibility Criteria for the ES presents 
for subjects on adjunctive therapy and for subjects on monotherapy, separately, for subjects that 
do not comply with at least one study eligibility criteria: 
• Age Category 
• Site/Subject Number 
• Protocol dated 
• Protocol/Amendment Number 
• Inclusion Criteria Not Met 
• Exclusion Criteria Met 
A subject data listing Subject Disposition for the ES presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately: 
• Protocol/Amendment Number 
• Age Category 
• Site/Subject Number 
• Subject Status 
• Date of Informed Consent 
• Date of First Study Medication/Last Study Medication including relative day/Imputed Last 
Study Medication including relative day 
Note: Imputation rule for missing Last Study Medication date is given in Section 4.2.4. 
• Date of Premature Study Termination/Final Contact (For screen failure subjects, this is the 
date of screen failure.) 
• Primary Reason for Premature Study Termination (For screen failure subjects, this is the 
reason for screen failure.) 
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A subject data listing Study Discontinuation for ES presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately, for subjects who discontinued the study the reason 
for discontinuation including: 
• Protocol/Amendment Number 
• Age Category 
• Site/Subject Number 
• Reason for Discontinuation 
• Period 
• Dose from which was discontinued 
• Days on dose from which was discontinued 
• Total Days on Study Medication 
A subject data listing Visit Dates for ES presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately, visit dates including: 
• Age Category 
• Site/Subject Number 
• Visit 
• Analysis Visit 
• Visit Date 
• Relative Day 
A subject data listing Study Periods for ES presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Period 
• Start Date Period 
• End Date Period 
A subject data listing Subject Analysis Sets for the ES presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately, the analysis set that a certain subject 
belongs to: 
• For subjects on adjunctive therapy  
− Age Category 
− Site/Subject Number 
− ES 
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− SS_A 
− FAS_A 
− PK-PPS_A 
• For subjects on monotherapy 
− Age Category 
− Site/Subject Number 
− ES 
− SS_M 
− FAS_M 
− PK-PPS_M 
5.2 
Protocol Deviations 
Prior to database lock, protocol deviations will be assessed if important or not important and if 
included into the relevant analysis set according to predefined specifications. 
5.2.1 
Analysis Summary 
Important protocol deviations (IPD) defined in the protocol-specific document, and additionally 
identified at the data evaluation meetings, will be listed. In addition, the number and percentage 
of subjects with at least one important protocol deviation will be summarized overall and by 
category of important protocol deviation for the ES. The number and percentage of subjects with 
no important protocol deviations will also be summarized for the ES. These will be summarized 
by age category and for all subjects combined. A listing of important protocol deviations will be 
provided. 
5.2.2 
Definitions and Derivations 
The category, type, description, and action resulting from important protocol deviations are 
derived in accordance with the Specifications of Important Protocol Deviations document and 
decisions made on the DEM. 
5.2.3 
Tables 
A table Important Protocol Deviations presents, for subjects on adjunctive therapy and for 
subjects on monotherapy, separately, the number and percentage of subjects with: 
• No important protocol deviation 
• At least one important protocol deviation 
Percentages are based on the number of subjects in the ES, whereby subjects can have more than 
1 important protocol deviation. 
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5.2.4 
Listings 
A subject data listing Important Protocol Deviations presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately, for subjects with at least 1 important protocol 
deviation the following information: 
• Protocol/Amendment Number 
• Age Category 
• Site/Subject Number 
• Start Date of Deviation (if applicable) 
• Deviation Category (efficacy, conduct/patient management) 
• Deviation Type (eg, inclusion criteria, exclusion criteria, treatment non-compliance) 
• Deviation Description (giving details) 
Deviation category, deviation type, deviation description and action are in accordance with the 
IPD. 
A subject data listing Subjects Excluded from Efficacy Analysis presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately, the following information: 
• Age Category 
• Site/Subject Number 
• Excluded from Analysis Set 
• Reason for Exclusion from Analysis Set 
 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
6.1 
Demographics 
The variables to be considered are: 
• Age at entry into study (as defined in Section 3.2.5.3) – continuous and categorized as: 
1 month to <6 months, 6 months to <1 year, 1 year to <2 years, and 2 years to <4 years 
• Gender 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) (as defined in Section 3.2.6) 
• Ethnicity 
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• Race (American Indian/Alaskan Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, and Other/Mixed) 
• Ethnic subgroup (Japan, Other) 
6.1.1 
Definitions and Derivations 
For definition of age, see Section 3.2.5. 
6.1.2 
Tables 
A table Demographics presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Summary statistics on age at entry into study, weight, height, BMI 
• Frequency distribution (number and percentage of subjects) for age (1 month to <6 months, 6 
months to <1 year, 1 year to <2 years, and 2 years to <4 years)  
• Frequency distribution (number and percentage of subjects) on gender, race and ethnic 
subgroup 
Missing is presented as category only if this is applicable for a certain variable. 
6.1.3 
Listings 
A subject data listing Demographics presents for subjects on adjunctive therapy and for subjects 
on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Date of Birth 
• Age at entry into Study 
• Adjusted Age 
• Gender 
• Race 
• Ethnicity 
• Ethnic subgroup 
• Height  
• Weight  
• BMI 
 
6.2 
ECG and CT Scan / MRI 
A CT scan or MRI will be performed only for those subjects who have not had a CT scan or MRI 
confirming the absence of a progressive lesion since being diagnosed with epilepsy, or have 
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changes on physical examination which would suggest a lesion has occurred since the last 
imaging procedure. 
6.2.1.1 
Definitions and Derivations 
Not applicable. 
6.2.1.2 
Tables 
A table CT/MRI Interpretation at Baseline presents, for subjects on adjunctive therapy and for 
subjects on monotherapy, separately, a frequency distribution (number and percentage of 
subjects) for: 
• CT/MRI (CT performed; MRI performed; Not performed) 
• CT/MRI Result (Normal; Abnormal, not clinically significant; Abnormal, clinically 
significant; Not performed) 
 
6.2.1.3 
Listings 
A subject data listing CT Scan/MRI presents for subjects on adjunctive therapy and for subjects 
on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Was CT scan / MRI image taken 
• Type of Image (CT/MRI) 
• Date/Relative Day of Image  
• Result of Image 
A subject data listing Baseline ECG Interpretation presents: 
• Age Category 
• Site/Subject Number 
• Date/Relative Day of ECG 
• Result of ECG 
6.3 
Neurological Examination 
A complete neurological examination will be performed at the Screening Visit according to the 
protocol schedule of study assessments. The complete neurological examination will include 
selected assessment of general neurological status (level of consciousness, mental status, 
speech), cranial nerves, reflexes, motor system (general motor status, muscle strength, muscle 
tone), coordination/cerebellar function, and sensation.  
Clinically significant neurological findings will be reported as AEs. Also, any change to 
clinically significant neurological findings that was not the same at baseline will be provided. 
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A listing of neurological examination abnormalities from the complete neurological examination 
will be provided. 
6.3.1.1 
Definitions and Derivations 
Not applicable. 
6.3.1.2 
Tables 
Not applicable. 
6.3.1.3 
Listings 
A listing Neurological Examination presents for subjects on adjunctive therapy and for subjects 
on monotherapy, separately, for each abnormal finding noted during neurological examinations: 
• Age Category 
• Site/Subject Number 
• Visit 
• Date/Relative Day 
• Abnormality as domain concatenated with the examination parameter that led to the 
abnormal finding 
• Clinical Significance 
6.4 
Physical Examination 
A complete physical examination will be performed at the Screening Visit according to the 
protocol schedule of study assessments. 
6.4.1.1 
Definitions and Derivations 
Not applicable. 
6.4.1.2 
Tables 
None. 
6.4.1.3 
Listings 
A listing Physical Examination Abnormalities presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately, for each abnormal finding noted during physical 
examination: 
• Age Category 
• Site/Subject Number 
• Visit Done/Not done 
• Date/Relative Day 
• Abnormality 
• Clinical Significance 
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6.5 
Other Baseline characteristics 
Subject data listings are presented for other baseline characteristics data of lifestyle, pre-term 
birth status and family medical history. 
6.5.1.1 
Definitions and Derivations 
Not applicable. 
6.5.1.2 
Tables 
None. 
6.5.1.3 
Listings 
A listing Lifestyle Status presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Did the Subject use alcohol within the past 6 months  
• Did the Subject use illicit drugs within the past 6 months  
A listing Pre-Term Birth Status presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Was Subject Pre-Term Infant 
• If Yes, Number of Weeks Pre-Term 
A listing Family Medical History presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• System Organ Class 
• Preferred Term 
• Reported condition 
• Start date and stop date of reported condition. 
6.6 
Epilepsy Background Variables 
Epilepsy related tables will present summary statistics for: diagnosis of epilepsy (age at onset, 
duration of epilepsy at study entry, historical seizure counts overall and by seizure type) as well 
as frequency distributions for etiology, and ILAE seizure classification.  
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In addition, the interpretation of baseline EEG and CT/MRI (normal, not clinically relevant 
abnormal, and clinically relevant abnormal) will be presented. 
Details on epilepsy related information are provided in subject data listing. 
6.6.1 
Definitions and Derivations 
6.6.1.1 
Epilepsy Duration and Age at Onset 
Date of first onset of epilepsy is documented in the Diagnosis of Epilepsy CRF. Based on this 
date, the duration of epilepsy and the age at onset is derived as followers: 
• Epilepsy duration [months] = (date of Visit 1 – date of first seizure) / 30.4375 
• Age at onset of epilepsy [months] = (date of first seizure – date of birth) / 30.4375. 
6.6.1.2 
Historical partial onset seizures and seizures of subtypes IA, IB, and 
IC during 2 weeks prior to Visit 1 
The information if a subject experienced any seizures (note: this includes seizures other than 
partial onset seizures) is captured in the Historical Seizure Count CRF. 
A subject is regarded as having experienced any simple partial seizures (subtype IA) during the 
past 2 weeks to Visit 1, if the number of simple partial seizures in the Historical Seizure Count is 
>0 for the past 2 weeks prior to Visit 1, otherwise the subject is regarded as not having 
experienced simple partial seizures during the past 2 weeks prior to Visit 1. 
Analogously, this is done for: 
• Experiencing complex partial seizures (subtype IB) during the past 2 weeks prior to Visit 1 
• Experiencing partial evolving to secondarily generalized seizures (subtype IC) during the 
past 2 weeks prior to Visit 1 
• Experiencing Generalized seizures (subtype II) during the past 2 weeks prior to Visit 1 
• Experiencing unclassified epileptic seizures (subtype III) during the past 2 weeks prior to 
Visit 1. 
6.6.1.3 
Historical Partial Onset Seizures (Type I) During 2 Weeks Prior to 
Visit 1 
A subject is regarded as having experienced any partial onset seizures (any subtype) during the 
past 2 weeks prior to Visit 1, if they experienced any simple partial seizures (subtype IA), 
complex partial seizures (subtype IB) or partial evolving to secondarily generalized seizures 
(subtype IC) during the past 2 weeks prior to Visit 1, otherwise they are not regarded as having 
had any partial onset seizures during the past 2 weeks prior to Visit 1. 
6.6.1.4 
Historical Seizure Count for Partial Onset Seizures During 2 Weeks 
Prior to Visit 1 
The information regarding ILAE historical seizure count is captured on the “ILAE Seizure 
Classification History” CRF. 
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The number of simple partial seizures (subtype IA), number of complex partial seizures (subtype 
IB) and number of partial evolving to secondarily generalized seizures (subtype IC) during 2 
weeks prior to Visit 1 is captured in the Historical Seizure Count CRF. 
The number of partial onset seizures (any subtype) during the past 2 weeks prior to Visit 1 will 
be derived as the sum of the number of:  
• Simple partial seizures during the past 2 weeks prior to Visit 1 
• Complex partial seizures during the past 2 weeks prior to Visit 1 
• Partial evolving to secondarily generalized seizures during the past 2 weeks prior to Visit 1 
6.6.2 
Tables 
A table Diagnosis of Epilepsy presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Summary statistics for age (months) at onset of epilepsy 
• Summary statistics for duration (months) of epilepsy at study entry 
A table ILAE Seizure Classification History presents a frequency distribution (number and 
percentage of subjects) for: 
• Partial onset seizures (I), Total and in ILAE sub-classes as specified in the CRF (seizure 
description and ILAE seizure code) (eg, Simple partial (IA), Complex partial (IB), …) 
• Generalized seizures (II), Total and in ILAE sub-classes 
• Unclassified epileptic seizures (III) 
A subject can appear in more than 1 category. 
A table Historical Seizure Count, Number and Percentage of Subjects presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately: 
• Frequency distribution (number and percentage of subjects) for experiencing any seizure 
during the 2 weeks prior to Visit 1 
• Frequency distribution (number and percentage of subjects) for experiencing any partial 
onset seizures 
• Frequency distribution (number and percentage of subjects) for experiencing partial onset 
seizure subtypes (simple partial, complex partial, partial evolving to secondarily generalized) 
• Frequency distribution (number and percentage of subjects) for experiencing any generalized 
seizures 
• Frequency distribution (number and percentage of subjects) for experiencing any unclassified 
epileptic seizures 
A table Historical Seizure Count, Descriptive Statistics presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately: 
• Summary statistics for the number of any seizures during the 2 weeks prior to Visit 1 
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• Summary statistics for the number of partial onset seizures 
• Summary statistics for the number of partial onset seizure subtypes (simple partial, complex 
partial, partial evolving to secondarily generalized) 
• Summary statistics for the number of generalized seizures 
• Summary statistics for the number of unclassified epileptic seizures 
A table Classifications of Epileptic Syndromes presents for subjects on adjunctive therapy and 
for subjects on monotherapy, separately, a frequency distribution (number and percentage of 
subjects) for: 
• Localization related classifications (with subdivisions) 
• Generalized classifications (with subdivisions) 
• Epilepsies and syndromes undetermined (with subdivisions) 
• Special syndromes 
6.6.3 
Listings 
A subject data listing Diagnosis of Epilepsy presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Date of first diagnosis 
• Age at first diagnosis 
• Duration of epilepsy at study entry 
• History of status epilepticus requiring hospitalization during the 30 days prior to Visit 1, 
except for status epilepticus occurring during the first 10 days of life 
• Diagnosis of epilepsy with partial onset seizures whether or not secondarily generalized  
• History of epilepsy secondary to progressing cerebral diseases 
• Treatable seizure etiology (ie, febrile seizures) 
• Current diagnosis of Rasmussen's syndrome, Landau-Kleffner disease or Lennox-Gastaut 
syndrome 
A subject data listing ILAE Seizure Classification History presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Ever Experienced a Seizure or a Cluster 
• Description (Partial onset seizures, Generalized seizures, Unclassified epileptic 
seizures)/Subtype Description 
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• ILAE Seizure Code (IA, IB, IC, other) 
A subject data listing Historical Seizure Count presents for subjects on adjunctive therapy and 
for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Any seizures during the 2 weeks prior to Visit 1 
• Number of seizures during the 2 weeks prior to Visit 1 
• Number of seizures of ILAE class IA, IB, IC, during the 2 weeks prior to Visit 1 
A subject data listing Classifications of Epileptic Syndromes presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Classification of Epileptic Syndromes 
• Sub-Classification of Epileptic Syndromes 
A subject data listing Classification of Epileptic Syndromes – Details on Generalized Syndromes 
presents for subjects on adjunctive therapy and for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Classification of Generalized Epileptic Syndrome 
• Details on Generalized Syndrome 
• Result 
6.7 
Medical History and Concomitant Diseases 
Tables are presented separately for past diseases and concomitant diseases. The number and 
percentage of subjects with diseases will be summarized by age category, for subjects on 
adjunctive therapy only, overall and by system organ class (SOC) and preferred term (PT) on the 
SS_A  and on the SS_M. 
Tables will be sorted alphabetically by SOC and within SOC by descending frequency of PT for 
the “all subjects combined” group in all subjects group. 
Data on “Family members who experienced any previous or ongoing DILI- relevant medical 
conditions or have any DILI-relevant inheritable disorders” will be summarized in the same way 
as for past diseases.  
The following listings will be provided: previous and ongoing medical history glossary, and 
previous and ongoing medical history conditions.  
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6.7.1 
Definitions and Derivations 
Medical conditions at study entry are documented on the Medical History CRF and are to be 
categorized as past or concomitant: 
• Past diseases: Medical conditions which are not specified as ongoing (response to item 
"Ongoing?"="No") 
• Concomitant diseases: Medical conditions which are specified as ongoing 
("Ongoing?"="Yes") or missing status information 
Start and stop date are documented partially with month and year only. No date imputation is 
foreseen. 
6.7.2 
Tables 
A table Past Medical History Conditions (except epilepsy) presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately: 
• Any Medical Condition 
Number and percentage of subjects reporting at least one medical condition. 
• By System Organ Class 
Number and percentage of subjects reporting at least one medical condition within a SOC. 
• By Preferred Term 
Number and percentage of subjects reporting at least one medical condition of that PT within 
its SOC. 
The table is repeated for: 
• Concomitant Diseases (except epilepsy) 
No table is presented for Procedure History. 
6.7.3 
Listings 
A listing Previous and Ongoing Medical History Glossary – All Conditions represents the 
mapping of reported terms to preferred terms and system organ class based on the MedDRA 
coding dictionary: 
• System Organ Class 
• Preferred Term 
• Reported Abnormality/Symptom 
A subject data listing Previous and Ongoing Medical History Conditions presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• System Organ Class/Preferred Term 
• Reported Condition 
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• Information about the condition being past or concomitant 
• Start Date/Stop Date 
A subject data listing Procedure History presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately: 
• Age Category  
• Site/Subject Number 
• Procedure (Reported Term) 
• Date of Procedure 
6.8 
Prior and Concomitant Medications 
Tables present past AEDs, past Non-AEDs, concomitant AEDs, and concomitant Non-AEDs, 
separately. 
Past and concomitant non AED medications are coded with WHO-DD, and will be summarized 
by Anatomical Main Group (ATC level 1), Pharmacological Subgroup (ATC level 3) and 
preferred term, by age category and for all subjects combined for the SS_A and for the SS_M.  
Past and concomitant AED medications are also coded with WHO-DD, and will be summarized 
by Chemical Subgroup (ATC level 4) and preferred term, by age category and for all subjects 
combined for the SS_A and for the SS_M. 
The following listings will be provided: prior and concomitant medications non-AEDs, glossary 
of prior and concomitant non-AED medications with verbatim term coded into ATC levels 1 and 
3, prior and concomitant medications AEDs, glossary of prior and concomitant AED medications 
with verbatim term coded into ATC level 4 and preferred term. 
6.8.1 
Definitions and derivations 
Medications documented on the Prior and Concomitant Medications CRF and are categorized as 
follows (see Figure 6.1): 
• Past medication 
Medication that stopped prior to the first dose of study medication. 
• Concomitant medication 
Medication with at least 1 day in common with the dosing period, ie, either 
− starts before first dose of study medication and is ongoing at day of first dose of study 
medication 
OR 
− starts on or after first dose of study medication  
Medication with a missing start date and missing information regarding “ongoing” status and 
medication with a missing start and missing end date are conservatively considered 
“concomitant”. 
 
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Figure 6‒1: Past and Concomitant Medication 
 
Past or concomitant medication is assigned to each study period the subject goes through based 
on the start and end date of the past or concomitant medication. For the definitions of study 
periods, please refer to Section 2.3.1. If intake is documented outside of any study period defined 
in Section 2.3.1, then for this part the period is given as “Not applicable” in the period column of 
the corresponding listings. 
Identification of AEDs 
Medications are regarded as potential AED if they meet one of the following criteria: 
• On the Prior and Concomitant Medications CRF the item “Core AED?” is checked 
• The medication is documented on the History of Previous Antiepileptic Drug Treatment CRF 
module 
Based on the criteria above, UCB will perform the manual review to the name, frequency and 
formulation of the medications and to identify the AEDs in an external file which is regularly 
updated in the course of the study.  
Subjects taking the same medication multiple times will be counted once per medication and 
investigational period.  A medication which can be classified into several chemical and/or 
therapeutic subgroups is presented in all chemical and therapeutic subgroups. 
Concomitant AEDs are captured on the Prior and Concomitant Medications (AEDs and non-
AEDs) eCRF. Concomitant AEDs will be summarized separately by level 4 ATC code and 
preferred medication name. If a medication identified as an AED does not code to a level 4 ATC 
code, the highest level of coding will be displayed along with the preferred drug name. 
Summaries of AEDs will be presented separately from other concomitant medications by 
infusion duration and overall.  
Handling of prior and concomitant medications missing data is described in the Section 4.2.2.  
1st study med. 
Last study med. 
Past 
Concomitant 
Concomitant 
Concomitant 
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6.8.2 
Tables 
For non-AEDs, tables are sorted alphabetically by Anatomical Main group (ATC level 1) and 
Pharmacological Subgroup (ATC level 3) and within level 3 by descending frequency of PT in 
the all subjects group.  
For AEDs, tables are sorted alphabetically by Chemical Subgroup (ATC level 4) and within level 
4 by descending frequency of preferred term in the all subjects group.  
The following tables will be provided: 
• Past Anti-Epileptic Drugs 
• Concomitant Anti-Epileptic Drugs 
• Anti-Epileptic Drugs at Study Visit 1 
• Past Medications (Non-AEDs) 
• Concomitant Medications (Non-AEDs) 
6.8.3 
Listings 
A listing Medication Glossary represents the mapping of reported terms to preferred terms and 
WHO-DD coding. 
• Anatomical Main Group, Level 1 
• Pharmacological Subgroup, Level 3 
• Preferred Term 
• Reported Term 
• AED Flag 
A subject data listing Past and Concomitant Medications (Non AEDs) presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately: 
• Age Category  
• Site/Subject Number 
• Anatomical Main Group (Level 1)/Pharmacological Subgroup (Level 3)/Preferred 
Term/Reported Term 
• Dose per Intake and Unit 
• Frequency/Formulation 
• Indication 
• Past / Concomitant medication 
• Start Date (Relative Day)/Stop Date (Relative Day) 
This listing is repeated for: 
• Concomitant Anti-Epileptic Drugs 
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• Changes in Concomitant AEDs – AEDs that started on or after First Dose of Study 
Medication 
A subject data listing Past Anti-Epileptic Drugs presents for subjects on adjunctive therapy and 
for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Anatomical Main Group (Level 1)/Pharmacological Subgroup (Level 3)/Preferred 
Term/Reported Term 
• Maximum Daily Dose and Unit 
• Start Date (Relative Day)/Stop Date (Relative Day) 
• Reason for Discontinuation 
 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
7.1 
Definitions and Derivations 
Since derivations for compliance is connected to derivations for exposure, derivation to both 
topics are described here. 
Date of first dose of study medication is documented in the “First Administration” CRF. 
Missing values for date of last administration of study medication are imputed as specified in 
Section 4.2.4. 
Details on study medication administration are recorded on the CRFs: First Administration; 
Study Medication Administration – Dry Syrup; and Study Medication Administration – IV.  
Overall compliance with Levetiracetam, administered once in the morning and once in the 
evening, will be examined for subjects whose total study medication administration and first and 
last days of treatment in the first and/or second period are known:  
• First Period, Treatment compliance (%) will be calculated as follows:  
Compliance (%) = 
∑
(# of actual administrations
𝑙𝑎𝑠𝑡 𝑑𝑎𝑦
𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑦
 per day)
total # of administrations planned during the first period  x 100 
where “total # of administrations planned during the first period” is equal to the total number 
of administrations planned during first administration of study medication to last planned 
administration in Evaluation Period, or day of discontinuation, which will be calculated as 
the duration of Evaluation Period in days ×2.  In consideration of whether the first 
administration is taken in the morning or in the evening, please see Section 10.1.1. 
• Second Period, Treatment compliance (%) will be calculated as follows:  
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Compliance (%) = 
∑
(# of actual administrations per day
𝑙𝑎𝑠𝑡 𝑑𝑎𝑦
𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑦
)
total # of administrations planned during the time the subject was in second period  x 100 
where “total # of administrations planned during the time the subject was in the second 
period” is equal to the total number of administrations planned during first planned 
administration of study medication and last planned administration in Maintenance Period, or 
day of discontinuation, which will be calculated as the duration of Maintenance Period in 
days ×2.  In consideration of whether the first administration is taken in the morning or in the 
evening, please see Section 10.1.1. 
• Overall Period, Treatment compliance (%) will be calculated as follows:  
Compliance (%) = 
∑
(# of actual administrations per day
𝑙𝑎𝑠𝑡 𝑑𝑎𝑦
𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑦
)
total # of administrations planned during the time the subject was in the study  x 100 
where “total # of administrations planned during the time the subject was in the study” is 
equal to the total number of administrations planned during first planned administration of 
study medication and last planned administration, or day of discontinuation which will be 
calculated as the duration of exposure to study medication in days ×2.  In consideration of 
whether the first administration is taken in the morning or in the evening, please see Section 
10.1.1. 
 
Percent overall compliance for study medication will be summarized for the Evaluation and 
Maintenance Period in two ways: 
● 
Descriptive statistics will be presented by age category and overall. 
● 
Percent compliance data will be summarized by age category and overall, and will be 
categorized according to the following categories: 
- 
< 80% 
- 
80 – 120% 
- 
> 120%. 
Summary statistics will be based on the SS_A and SS_M. 
 
7.2 
Tables 
A table Study Medication Compliance presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately:  
• Summary statistics on compliance 
• Frequency distribution (<80%, 80-120%, >120%). 
 
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7.3 
Listings 
A subject data listing Study Medication Compliance presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately:  
• Age Category 
• Site/Subject Number 
• Period 
• Formulation (IV or Dry Syrup) 
• Number of administrations 
• Target number of administrations 
• Study Medication Compliance (%) 
 
8 
EFFICACY ANALYSES 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be calculated 
for the continuous secondary efficacy variables and absolute and relative frequencies will be 
calculated for the categorical efficacy variables. 
The primary efficacy variable and potentially the two secondary efficacy variables will be 
compared with a threshold in a confirmatory way according to the hierarchical testing procedure 
(see Section 4.5).  All efficacy variables which are not tested as confirmatory in the course of the 
hierarchical testing procedure will be analyzed exploratively only. Descriptive summaries will be 
created for all these variables irrespective of this.  
 
8.1 
Statistical Analysis of the Primary Efficacy Variable  
8.1.1 
Primary Efficacy Variable for Adjunctive Therapy 
First Period 
The primary efficacy variable for subjects on adjunctive therapy for the First Period is the 
percent reduction in partial seizure frequency per week from Baseline to Study Visit 6. In order 
to include the EEG failures subjects who were enrolled prior to Protocol Amendment 3, analysis 
visit will be used therefore the primary efficacy variable is presented as the percent reduction in 
partial seizure frequency per week from Baseline to Analysis Visit 3. 
The percent reduction in partial seizures per week from Baseline to Study Visit 6 (Analysis Visit 
3) will be calculated as: 
Number of partial seizures per week at Baseline – Number of seizures per week at Analysis Visit 3 
Number of partial seizures per week at Baseline 
 x100 
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The number of partial seizures per week at Baseline will be based on the Retrospective Baseline 
seizure counts (during the 2 weeks prior to Study Visit 1) + Selection Period (Study Visit 1 and 
Study Visit 2*), see Section 3.3, and will be calculated as: 
[total number of partial seizures entered on the DRC starting at the 2 weeks prior to Study 
Visit 1 until Study Visit 3 divided by the number of days on which data was entered on the 
DRC] × 7. 
*Study Visit 2 is only applicable for those subjects enrolled prior to Protocol Amendment 3.  
The number of seizures per week at Study Visit 6 (Analysis Visit 3) will be based on the seizure 
count from Analysis Visit 2 to Analysis Visit 3 and will be calculated as: 
[total number of partial seizures entered on the DRC during the period starting 1 day after 
Study Visit 5 (Analysis Visit 2) through Study Visit 6 (Analysis Visit 3) divided by the 
number of days, within this period, on which data was entered on the DRC] × 7     
Those seizure free days (ie, seizure count is 0 and there is no entry of DRC data) will be included 
into denominator. Data was NOT entered on DRC only refer to the situation that “Not Done” 
was ticked on CRF “Seizure Count” page 
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) 
will be calculated for the percent reduction in partial seizure frequency per week from Study 
Visit 6 (Analysis Visit 3) by Baseline age category (3 categories: 1 month to <1 year, 1 year to 
<2 years, and 2 years to <4 years), and for all subjects combined (overall). The corresponding 
95% CI for the median percent reduction at Study Visit 6 (Analysis Visit 3) will be provided by 
age category and overall. The 95% CI will be derived from a distribution-free method based on 
order statistics. For example, under the assumption that data does not follow a Gaussian 
distribution the 95% CI might be calculated by using the UNIVARIATE procedure from SAS® 
with ciquantdf (alpha=.05) as specification [1]. If the lower limit of the 95% confidence interval 
for overall is greater than the predefined threshold of 15.0%, the efficacy of LEV is shown 
significant. If this test shows a significant result, then it will be repeated for the corresponding 
Study Visit 4 (Analysis Visit 1) and Study Visit 5 (Analysis Visit 2) variable hierarchically (see 
Section 8.2.1).  In that case, the second and the third test is also regarded as confirmatory as due 
to the hierarchical testing procedure no alpha adjustment is needed (see Section 4.5).     
A summary table based on the FAS_A will be presented: 
- Percent Reduction in Partial Seizure Frequency per Week from Baseline to Visit 6 (Analysis 
Visit 3), by Age Category, Adjunctive Therapy Subjects  
 
Combined First and Second Periods 
There is no primary efficacy variable for subjects on adjunctive therapy for the combined First 
and Second Periods. 
 
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8.1.2 
Primary Analysis Variable for Monotherapy  
There is no primary efficacy variable for subjects on monotherapy. 
 
8.1.3 
Sensitivity Analyses of the Primary Efficacy Variable 
For the subjects who have important protocol deviations who are considered with impact on 
efficacy, BLOCF (Baseline Observation Carried Forward) will be applied for the post-baseline 
value. 
A summary table based on the FAS_A will be presented: 
- Percent Reduction in Partial Seizure Frequency per Week from Baseline to Visit 6 (Analysis 
Visit 3), by Age Category, Adjunctive Therapy Subjects, (BLOCF)  
 
8.2 
Statistical Analysis of the Secondary Efficacy Variables 
8.2.1 
Secondary Efficacy Variables for Adjunctive Therapy 
First Period: 
The secondary efficacy variable for subjects on adjunctive therapy for the First Period is the 
percent reduction in partial seizure frequency per week from Baseline to Study Visit 4 (Analysis 
Visit 1) and Study Visit 5 (Analysis Visit 2).  
Percent reduction in partial seizure frequency per week from Baseline to Study Visit X will be 
calculated as: 
Number of partial seizures per week at Baseline – Number of seizures per week at Study Visit X  
Number of partial seizures per week at Baseline 
 ×100 
 
If the analysis of the primary efficacy variable, see Section 8.1.1, shows a significant result 
(lower limit of the 95% confidence interval for the overall group is greater than the predefined 
threshold of 15.0%), the lower limit of the 95% CI of the median percent reduction in partial 
seizure frequency at Study Visit 4 (Analysis Visit 1) and Study Visit 5 (Analysis Visit 2) will 
also be compared with the predefined threshold of 15.0%.   
The following summary tables based on the FAS_A will be presented: 
- Percent Reduction in Partial Seizure Frequency per Week from Baseline to Visit 4 (Analysis 
Visit 1), by Age Category, Adjunctive Therapy Subjects 
- Percent Reduction in Partial Seizure Frequency per Week from Baseline to Visit 5 (Analysis 
Visit 2), by Age Category, Adjunctive Therapy Subjects 
 
Combined First and Second Periods: 
The secondary efficacy variables for subjects on adjunctive therapy for the combined First and 
Second Periods are: 
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• For each analysis visit, percent reduction in partial seizure frequency per week from 
Baseline. 
Note: This is combined over the age categories. 
• For each analysis visit, percent reduction in partial seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%  
Note: This is combined over the age categories. 
Percent reduction in partial seizures per week from Baseline at Analysis Visit X will be 
calculated as:  
 
Number of partial seizures per week at Baseline − Number of partial seizures per week at Analysis Visit X
Number of partial seizures per week at Baseline
 x100 
 
The calculation of number of partial seizures per week at Baseline is the same as aforementioned 
(see Section 8.1.1).     
Number of partial seizure frequency per week, as collected on the DRC, is calculated at Analysis 
Visit x, x=1, 2, 3, 4, …, as: 
Number of partial seizures per week at Analysis Visit x = [total number of partial seizures 
entered on the DRC during the period starting 1 day after Analysis Visit x-1 through Study Day 
of Analysis Visit x divided by the number of days, within this period, on which data was entered 
on the DRC] x 7. Those seizure free days (i.e. seizure count is 0 and there is no entry of DRC 
data) will be included into denominator. Data was NOT entered on DRC only refer to the 
situation that “Not Done” was ticked on CRF “Seizure Count” page. 
The following summary tables based on the FAS_A will be presented: 
- Percent Reduction in Seizure Frequency per Week, by Analysis Visit, Adjunctive Therapy 
Subjects 
- Percent Reduction in Seizure Frequency per Week Grouped into 6 Categories by Analysis 
Visit, Adjunctive Therapy Subjects 
 
8.2.2 
Secondary Efficacy Variables for Monotherapy 
First Period: 
There is no secondary efficacy variable for subjects on monotherapy for the First Period. 
 
Combined First and Second Periods: 
The secondary efficacy variables for subjects on monotherapy for the combined First and Second 
Periods are: 
• For each analysis visit, percent reduction in partial seizure frequency per week from 
Baseline. 
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Number of partial seizure frequency per week, as collected on the patient dairy form, will be 
calculated for each Analysis Visit as described in Section 8.2.1 Combined First and Second 
Periods. 
A table Percent Reduction in Seizure Frequency per Week, by Analysis Visit, Monotherapy 
Subjects presents summary statistics of subjects for each analysis visit on the FAS_M .  
Note: This is combined over the age categories. 
• For each analysis visit, percent reduction in partial seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% during 
the combined First and Second Periods. 
A table Percent Reduction in Seizure Frequency per Week, Grouped into 6 Categories, by 
Analysis Visit, Monotherapy Subjects presents the number and percentage of subjects within 
each of the above defined six categories for all analysis visits on the FAS_M.  
Note: This is combined over the age categories. 
 
8.3 
Analysis of Other Efficacy Variables 
8.3.1 
Derivations of Other Efficacy Variables 
The average daily frequency (ADF) of partial seizures as measured by 48h video-EEG will be 
included as an “other” efficacy variable. Partial seizure count will be based on electrographic 
seizures with or without clinical correlate depending upon age as specified below. Partial 
seizures have ILAE seizure code: IA, IB or IC, other seizure codes will not be included in the 
analysis. 
Partial seizure frequency for subjects: 
• Aged ≥1 month to ≤6 months will be based on electrographic seizures with an accompanying 
clinical correlate: item: “Number of electrographic seizures (Partial Onset Seizure only)” and 
“Number of electro-clinical seizures (Partial Onset Seizure only)” respectively, from Video-
EEG CRF. Aged >6 months to <4 years will be based electro-clinical seizures: item “Number 
of electro-clinical seizures (Partial Onset Seizure only)” from Video-EEG CRF.  
 
The ADF (partial seizures) at Analysis Visit x is defined as: 
 # of partial seizures recorded during the 48 hr video EEG collection period at Analysis Visit x
 # hours of useable video −EEG time at Analysis Visit x
 x 24, 
where:  
• x = -1 (Baseline), 1, or 3; and 
• number of hours of useable video-EEG time = total video-EEG time – disconnection time. 
Total video-EEG time is defined as the difference between the end and the start of recording 
date and time. Disconnection time is obtained from the “Video-EEG” CRF (item “Total 
Disconnect Time”). 
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Percent reduction in ADF of partial seizure frequency at Analysis Visit 3 (Study Visit 6) 
compared to Baseline (Study Visit 2) is defined as: 
ADF (partial seizures) at Study Visit 2 − ADF (partial seizures) at Analysis Visit 3 (Study Visit 6)
ADF (partial seizures) at Baseline Period
 x 100  
where Baseline Period (representing the whole 48 hours video-EEG data collection period) is 
the visit just before start of administration of study medication (Baseline). 
 
8.3.2 
Other Efficacy Variables for Adjunctive therapy/Monotherapy 
First Period: 
The other efficacy variables for the First Period for the number of seizures based on the 48h  
video-EEG recorded  prior to Protocol Amendment 3 are: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Analysis Visit 1 (Study Visit 4) and at Analysis Visit 3 (Study Visit 6) compared to Baseline. 
Percent reduction in ADF of partial seizure frequency will be summarized at Study Visit 4 
and Study Visit 6 for all subjects combined. 
A table Percent Reduction in Average Daily Frequency (ADF) of Partial Seizure Frequency 
at Analysis Visit 1(Study Visit 4) and Analysis Visit 3 (Study Visit 6), Adjunctive Therapy 
Subjects, presents summary statistics of subjects on adjunctive therapy for Analysis Visit 1 
and Analysis Visit 3 on the FAS_A.  
Note: This is combined over the age categories. 
A table Percent Reduction in Average Daily Frequency (ADF) of Partial Seizure Frequency 
at Analysis Visit 1 (Study Visit 4) and Analysis Visit 3 (Study Visit 6), Monotherapy 
Subjects, presents summary statistics of subjects on monotherapy for Analysis Visit 1 and 
Analysis Visit 3 on the FAS_M.  
Note: This is combined over the age categories. 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Analysis Visit 1 (Study Visit 4) and Analysis 
Visit 3 (Study Visit 6) compared to Baseline. 
A table Percent Reduction in Average Daily Frequency (ADF) of Partial Seizure Frequency 
Grouped into 6 Categories, Adjunctive Therapy Subjects, presents the number and 
percentage of subjects, on adjunctive therapy, for Analysis Visit 1 and Analysis Visit 3 
within each of the above defined six categories for all analysis visits on the FAS_A.  
Note: This is combined over the age categories. 
A table Percent Reduction in Average Daily Frequency (ADF) of Partial Seizure Frequency 
Grouped into 6 Categories, Monotherapy Subjects, presents the number and percentage of 
subjects on monotherapy, for Analysis Visit 1 (Study Visit 4) and Analysis Visit 3 (Study 
Visit 6), within each of the above defined six categories for all analysis visits on the FAS_M.  
Note: This is combined over the age categories. 
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Combined First and Second Periods: 
The other efficacy variables for the combined First and Second Periods are: 
• For each analysis visit, percent reduction in all types of seizure frequency per week from 
Baseline. 
A table Percent Reduction in All Types of Seizure Frequency per Week during Combined 
First and Second Periods, Adjunctive Therapy Subjects presents summary statistics of 
subjects on adjunctive therapy, for each analysis visit on the FAS_A.  
Note: This is combined over the age categories. 
A table Percent Reduction in All Types of Seizure Frequency per Week during Combined 
First and Second Periods, Monotherapy Subjects presents summary statistics of subjects, on 
monotherapy, for each analysis visit on the FAS_M.  
Note: This is combined over the age categories. 
• For each analysis visit, percent reduction in all type of seizure frequency per week from 
Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 
100%. 
A table Percent Reduction in All Types of Seizure Frequency per Week Grouped into 6 
Categories During Combined First and Second Periods, Adjunctive Therapy Subjects, 
presents the number and percentage of subjects on adjunctive therapy within each of the 
above defined six categories for all analysis visits on the FAS_A.  
Note: This is combined over the age categories. 
A table Percent Reduction in All Types of Seizure Frequency per Week Grouped into 6 
Categories During Combined First and Second Periods, Monotherapy Subjects, presents the 
number and percentage of subjects on monotherapy within each of the above defined six 
categories for all analysis visits on the FAS_M.  
Note: This is combined over the age categories. 
The following other efficacy variable is only applicable to Monotherapy: 
• Percent of subjects who are continuously 6-months seizure-free monitored by the patient 
diary. 
A subject is considered 6-months seizure free if they are seizure free for at least 26 x 7 = 182 
consecutive days during the combined period of Evaluation Period + Dose adjustment Period 
+ Maintenance Period, otherwise they are not considered seizure free. 
The seizure free time interval must not contain days for which seizure data are missing, ie, 
“Not done” was checked on the Seizure Count CRF or seizure information is missing 
otherwise, eg because the complete and required CRF module was not filled out for a certain 
visit. 
Subjects who received less than 182 days study medication are counted as not having 
achieved 6-months seizure freedom. 
Missing seizure dates and dates for “not done” rows (in the following both are called “row”) 
are handled as follows: 
− If the row date is missing completely (no entry), two cases can occur 
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1. The missing row date is the in the first row of the CRF.  
In this case, the visit date of the visit before the documentation visit is imputed. 
2. The missing row date is not the first row of the CRF. 
In this case, the date of the day after the last entry in the rows before the row with the 
missing date is imputed. 
− If the row date is missing completely (“UNK”, ie, unknown), then the date of the visit 
before the documentation visit is imputed, independent of the row being the first row or a 
later one. 
− If the year and month of a row date is present but the day is missing, then the same 
imputation as for a completely missing row date is performed first. If the imputed date is 
before the first of the month that is documented, then then first day of the month is used. 
− If the year of a row date is present but the month is missing, then the same imputation as 
for a completely missing date is performed first. If the imputed date is before the first of 
the year that is documented, then then first day of the year is used. 
A table Percent and Number of Subjects Who are continuously 6-Months Seizure-Free 
Monitored by Patient Diary During the Evaluation, Dose-adjustment and Maintenance Period 
presents the number and percentage of subject on monotherapy who are continuously 6-
months seizure-free on the FAS_M.  
Note: This is combined over the age categories. 
8.4 
Listings 
A Listing of Partial Seizures Occurrence Recorded on Daily Record Cards presents for subjects 
in ES for adjunctive therapy: 
• Age category 
• Site-Subject Number 
• Study Visit 
• Collection Date  
• Number of Partial Seizures  
Same listing will be repeated for subjects in ES for monotherapy therapy.  
A Listing of Seizures Count by Type of Seizures for subjects in ES for adjunctive therapy: 
• Age category 
• Site-Subject Number 
• Analysis Visit 
• Seizure Type (IA, IB, IC, II, III) 
• Number of Partial Seizures  
Same listing will be repeated for subjects in ES for monotherapy therapy. 
A Listing of Partial Seizure Frequency per Week and Percent Reduction of Partial Seizures, as 
Recorded on Daily Record Cards in FAS_A: 
• Age category 
• Site-Subject Number 
• Retrospective + Selection Period Baseline Value 
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• Value / Reduction at Visit 4 (Analysis Visit 1)  
• Value / Reduction at Visit 5 (Analysis Visit 2) 
• Value / Reduction at Visit 6 (Analysis Visit 3) 
Same listing will be repeated for subjects in FAS_M. 
A Listing of Partial Seizure Frequency per Week and Percent Reduction from Baseline, as 
Recorded on Daily Record Cards for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Analysis Visit Number 
• Study Visit  
• Baseline Seizure Frequency per Week  
• Seizure Frequency per Week at Visit  
• Result 
• Percent Reduction  
Same listing will be repeated for subjects in FAS_M. 
The following listings based on the 48h video-EEG will only be applicable to the subjects 
enrolled prior to Protocol Amendment 3: 
A Listing Video EEG Part 1 presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Study Visit 
• Start date/time monitoring 
• Stop date/Time monitoring 
• Total connect time 
• Type of EEG performed 
• If other 
Same listing will be prepared for subjects in FAS_M. 
A Listing Video EEG Part 2 presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Study Visit 
• Was sleep included 
• EEG pattern 
• Spasms present 
Same listing will be prepared for subjects in FAS_M. 
A Listing Video EEG Number of Seizures presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Study Visit 
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• Non-IS seizures present 
• Number of electrographic seizures (Partial Onset Seizure only) 
• Number of electro-clinical seizures (Partial Onset Seizure only) 
• Number of partial onset seizures (ILAE code I) 
• Number of primary generalized seizures (ILAE code II) 
• Number of primary generalized seizures (ILAE code II) 
Same listing will be prepared for subjects in FAS_M. 
A Listing Video EEG Number of Clusters presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Study Visit 
• Non-IS Seizures Present 
• Number of Partial Onset Seizures (ILAE code I) 
• Number of Generalized Onset Seizures (ILAE code II) 
• Number of Unclassified Epileptic Seizures (ILAE code III) 
Same listing will be prepared for subjects in FAS_M. 
A Listing Average Daily Frequency (ADF) and Percent Reduction of Partial Seizures as 
Measured by 48 hour Video-EEG presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Study Visit 
• Number of Partial Seizures  
• Average Daily Frequency 
• Percent Reduction in Average Daily Frequency 
Same listing will be prepared for subjects in FAS_M. 
A Listing Average Daily Frequency (ADF) and Percent Reduction of Electro-Clinical Partial 
Seizure Frequency as Measured by 48 hour Video-EEG presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
• Study Visit 
• Number of Electro-Clinical Partial Seizures 
• Average Daily Frequency 
• Percent Reduction in Average Daily Frequency 
Same listing will be prepared for subjects in FAS_M. 
 
A Listing Average Daily Frequency (ADF) and Percent Reduction of Partial Seizures, as 
Recorded on Daily Record Cards presents for subjects in FAS_A: 
• Age category 
• Site-Subject Number 
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• Analysis Visit number (Week number) 
• Result 
• Percent reduction 
Same listing will be prepared for subjects in FAS_M. 
 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS  
Results of observed plasma concentrations and dose-normalized LEV plasma concentrations will 
be presented. Listings will be presented for subjects on adjunctive therapy and for subjects on 
monotherapy, separately.  
9.1 
Pharmacokinetics 
9.1.1 
Definitions and Derivations 
For the calculation of descriptive statistics, a LEV plasma concentration below the lower limit of 
quantification (LLOQ) will be substituted by LLOQ/2. 
Dose-normalized (to 10mg/kg for aged subjects of 6 months and above, or 7mg/kg for age less 
than 6 months) LEV plasma concentrations are derived as follows: 
Dose-normalized LEV plasma concentrations = LEV observed plasma concentration / actual 
dose given (mg/kg) × 10 (mg/kg) or 7 (mg/kg). 
9.1.2 
Tables and Figures 
Descriptive statistics of LEV observed and dose-normalized plasma concentrations will be 
summarized per defined time window post-dose by age category (1 month<=Age<6 months, 6 
months<=Age<1 year, 1 year<=Age<2 years, 2 years<=Age<4 years) and dose level per 
administration (10mg/kg, 20mg/kg, 30mg/kg in aged subjects of 6 months and above, 7mg/kg, 
14mg/kg, 21mg/kg in aged subjects less than 6 months) in PK-PPS_A and PK-PPS_M. The 
statistics are calculated only if at least 2/3 of the individual data at a specific sampling point are 
above or equal to the LLOQ. 
Scatter plots of LEV observed plasma concentrations vs. time after last dosing will be presented 
by age category and dose level.  Scatter plots for LEV observed plasma concentrations vs time 
after last dosing by dose level will be superposed with different symbols in a single graph for 
each age category.  
Scatter plots of LEV observed plasma concentrations vs. time after last dosing will be presented 
by age category and dose group.  Scatter plots for LEV observed plasma concentrations vs time 
post dose by dose group will be superposed with different symbols in a single graph for each 
dose group.  The dose groups are defined as: 
o low dose group, 7mg/kg in aged subjects less than 6 months and 10mg/kg in aged 
subjects of 6 months and above;  
o middle dose group, 14mg/kg in aged subjects less than 6 months and 20mg/kg in aged 
subjects of 6 months and above;  
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o high dose group, 21mg/kg in aged subjects less than 6 months and 30mg/kg in aged 
subjects of 6 months and above 
Scatter plots of LEV dose-normalized plasma concentrations vs. time after last dosing will be 
presented by age category and dose level.  Scatter plots for LEV dose-normalized plasma 
concentrations vs time after last dosing by dose level will be superposed with different symbols 
in a single graph for each age category.  
 
Another scatter plot for LEV dose-normalized plasma concentrations vs time after last dosing 
will be presented by age category and AED category with different symbols in a single graph.  
Scatter plots for LEV dose-normalized plasma concentrations vs time post dose by age category 
will be superposed with a scatter plot for LEV dose-normalized plasma concentrations vs time 
pose dose in N01223 with different symbols in a single graph. Dose-normalization of LEV 
plasma concentrations in N01223 will be performed to 10mg/kg for a subject with a body weight 
less than 50kg and to 500mg for a subject with a body weight more than or equal to 50kg.  
In addition, scatter plots for LEV dose-normalized plasma concentrations vs time pose dose will 
be superposed with simulated LEV plasma concentration-time profiles based on the population 
PK model established in N01288 by age category. The data of LEV plasma concentrations and 
times in N01223 and N01288 are provided from data management group in UCB. 
 
9.1.3 
Listings 
A subject data listing LEV Plasma Concentration Monitoring will present for subjects on 
adjunctive therapy and for subjects on monotherapy, separately: 
• Treatment Group 
• Region/Country/Site-Subject Number 
• Gender/Age(years)/ Weight(kg) 
• Visit 
• Not Done (with a flag ‘N’) 
• Last Study Medication prior to Blood Sampling Datetime (YYYY-MM-DDThh:mm)/ 
Relative Day 
• Blood Sampling Date time (YYYY-MM-DDThh:mm:ss)/Relative Hours to Last Medication 
• Last Dosage (mg/intake) 
• Plasma LEV Concentration (µg/ml) 
• Time Window [-0 (Just before dosing), >0-1, >1-2, >2-4, >4-8, >8-12, and >12 hours post 
dosing] 
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• Dose Normalized Plasma Level (µg/ml): equivalent to 10mg/kg/administration for aged 
subjects of 6 months and above or 7mg/kg/administration for aged subjects less than 
6 months 
9.2 
Pharmacodynamics 
Not applicable. 
 
10 
SAFETY ANALYSES 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
Summaries will be presented for: AEs, ECG data, vital signs and weight (continuous) data, and 
PCS data. 
Safety data will be summarized for the Safety Sets, see Section 3.5.2.  
10.1 
Extent of Exposure 
The duration of exposure to LEV, as defined in Section 3.2.7, will be summarized as a 
continuous parameter (in days). Descriptive statistics for the duration of exposure to study 
medication in days will be presented by age category and overall. Handling of missing study 
medication data is described in Section 4.2.4. 
The following listings will be provided: study medication administration and exposure to study 
medication.  
10.1.1 
Definitions and Derivations 
Duration in days of exposure to study medication is calculated as: 
Start date = Date of first administration of study medication 
End date  = Date of last administration of study medication 
A) Start Date (Morning) and End Date (Evening) then Duration=End date - Start date + 1 
B) Start Date (Morning) and End Date (Morning) then Duration=End date - Start date + 0.5  
C) Start Date (Evening) and End Date (Evening) then Duration=End date - Start date + 0.5 
D) Start Date (Evening) and End Date (Morning) then Duration=End date - Start date. 
Note: The date of the first and last administration of study medication is recorded on the “First 
Administration” and the “Study Termination” eCRFs, respectively. 
Note: Missing values for date of last administration of study medication are imputed as specified 
in Section 4.2.4.  
The exposure duration in days for a period is assumed to be equal to the duration of the 
respective period except for the Down-titration Period. For the Down-titration Period the 
exposure duration is calculated as: 
Date of last administration of study medication – Date of first day of period +1. 
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If date of last administration of study medication is missing, the last complete administration 
date will be used.  
For start and end dates of periods see Section 2.3.1 and Section 5.1.1.4 . 
Details on study medication administration are recorded on the “Study Medication 
Administration – IV” and “Study Medication Administration – Dry Syrup” eCRFs. 
The modal dose is calculated using the daily dose (morning dose + evening dose).  If there are 
tied cases, the later dose will be the modal dose.  
10.1.2 
Tables 
A table Study Medication Duration presents for subjects on adjunctive therapy and for subjects 
on monotherapy, separately: 
• Summary statistics on study medication duration  
A table Study Medication Administration presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately: 
• Summary statistics on mean daily dose and modal dose of study medication  
10.1.3 
Listings 
A subject data listing Exposure to Study Medication presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Period 
• Date of First Dose 
• Date of Last Dose 
• Study Medication Duration (days) 
• Mean daily dose 
10.2 
Adverse Events 
An overview of AEs presents number and percent of subjects with any TEAE, serious TEAEs, 
TEAEs leading to discontinuation, TEAEs requiring dose change, any drug-related TEAEs, 
severe TEAEs, as well as deaths together with the number of individual occurrences in those 
categories. 
Incidences of TEAEs by SOC and PT are presented together with the number of individual 
occurrences for , TEAEs, , serious TEAEs and serious drug-related TEAEs, and TEAEs leading 
to discontinuation of study drug.  
Additional tables are presented for TEAEs by intensity and for a subset of TEAEs occurring in at 
least 5% of subjects. 
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Secondary safety variables for the First Period are: Incidence of TEAEs, Incidence of SAEs, and 
Incidence of TEAEs leading to discontinuation 
Secondary safety variables for the combined First and Second Periods are: Incidence of TEAEs 
during the combined First and Second Periods, Incidence of SAEs during the combined First and 
Second Periods, and Incidence of TEAEs leading to discontinuation during the combined First 
and Second Periods. 
Presentations are done for subjects on adjunctive therapy and for subjects on monotherapy, 
separately. 
Subject data listings also cover the verbatim term and further details like start and end date, if 
applicable. 
10.2.1 
Definitions and Derivations 
The treatment-emergent adverse events (TEAEs) are defined as those events that started on or 
after the date (and time) of first dose of study medication, or adverse events whose intensity 
worsened on or after the date (and time) of first dose of study medication. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). 
10.2.1.1 
Categorization of AEs 
Adverse events are categorized as pre-treatment and treatment-emergent: 
• Pre-treatment: Onset date before first dose of study medication 
• Treatment-emergent: Onset date (including severity-worsening) on or after first dose of study 
medication 
10.2.1.2 
Assignment of AEs to Periods/Onset of AEs  
An AE is assigned to that study period the subject is in during onset of the AE. For the 
definitions of study periods see Section 2.3.1. 
10.2.1.3 
AEs Leading to Discontinuation 
AEs leading to discontinuation are identified using information documented on the AE CRF. 
Both of the following needs to be documented for an event being classified as leading to 
discontinuation: 
• Item “Action Taken with Study Medication” is specified as “Drug permanently withdrawn” 
• Item “Did Adverse Event Lead to Dropout?” is specified with “Yes” 
10.2.1.4 
Drug related AE 
A drug-related TEAE is defined as any TEAE with ”Relationship to Study Medication” recorded 
as “related” on the CRF as assessed by the investigator or with missing assessment of the causal 
relationship.  
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10.2.1.5 
Dose at AE Onset 
As a conservative approach, in case an AE has onset date on a day with 2 different total daily 
doses, the lower dose is used. 
10.2.1.6 
Incomplete Dates 
Data handling rules for management of missing or partial start or stop dates for adverse events 
should follow those defined in the Section 4.2.3.  
10.2.2 
Tables 
Tables will be presented for subjects on adjunctive therapy and for subjects on monotherapy, 
separately. 
AE Summaries 
For the First Period all TEAE summaries will be presented for all age categories combined on 
the SS_A and SS_M.  
For the combined First and Second Period all TEAE summaries will be presented for all age 
categories combined on the SS_A and SS_M. 
The following summaries will be produced, for the First, and for the combined First and Second 
Periods): 
• Number and percent of subjects with AEs – Overview.  
Overview of the Incidence of AEs will include all subjects with at least one TEAE, serious 
TEAEs, subject discontinuations due to TEAEs, drug-related TEAEs, severe TEAEs, and all 
deaths (AEs leading to death). 
• Incidence of AEs – Overview  
• Number and percent of subjects with TEAEs, and Incidence of TEAEs 
• Number and percent of subjects with serious TEAEs, and Incidence of serious TEAEs 
• Number and percent of subjects with TEAEs by relationship to study medication, and 
Incidence of TEAEs by relationship to study medication 
• Number and percent of subjects with serious TEAEs by relationship to study medication, and 
Incidence of serious TEAEs by relationship to study medication 
• Number and percent of subjects with serious drug-related TEAE 
• Number and percent of subjects with TEAEs by Intensity, and Incidence of TEAEs by 
Intensity 
• Number and percent of subjects with serious TEAEs occurring in at least 5% of the subjects, 
and Incidence of serious TEAEs occurring in at least 5% of the subjects 
• Number and percent of subjects with TEAEs leading to (permanent) discontinuation of study 
medication 
Note: permanent discontinuation: when in the Adverse Event CRF the item “Action taken 
with study Medication” is answered with “Drug Permanently Withdrawn”. And Incidence of 
TEAEs leading to (permanent) discontinuation of study medication 
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AEs will be summarized by MedDRA SOC and MedDRA PT. The number and percentage of 
subjects experiencing each event at least once will be summarized.  
10.2.3 
Listings 
A listing TEAE Glossary represents the mapping of reported terms to preferred terms and system 
organ class based on the MedDRA coding dictionary: 
• System Organ Class 
• Preferred Term 
• Reported Term 
A subject data listing All Adverse Events presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately: 
• Age Category 
• Region/Country/Site/Subject Number 
• Gender/Age/Race/Weight 
• System Organ Class/Preferred Term/Reported Term 
• AE Onset Date (Relative Day)/AE Outcome Date (Relative Day)/Period 
• AE Duration/Dose at Onset/Days on Dose at Onset/Total Days on Treatment 
• Seriousness/Intensity 
• Pattern of Event 
• AE Led to Dropout? 
• Relationship to Study Medication/Action Taken with Study Medication/Other Action Taken / 
AE Outcome 
The listing is repeated for: 
• Treatment Emergent AEs Leading to Discontinuation 
• Deaths and Other Serious TEAEs 
10.3 
Clinical Laboratory Evaluations 
All laboratory data summaries will be presented by analysis visit.  
Shifts from baseline to end of treatment based on the normal range (ie, low, normal, high, and 
missing) for each hematology and clinical chemistry lab parameter will be presented.  
The number and percentage of subjects with possibly clinically significant treatment-emergent 
laboratory values (hematology and clinical chemistry) as defined in Section 12.3.1 and 
Section 12.3.2, respectively, will be summarized. Possibly clinically significant treatment-
emergent laboratory values are those that are observed during the defined treatment period at 
scheduled or unscheduled visits and were not observed at any visit during the Baseline period. A 
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subject number table will be presented for subjects with laboratory assessments meeting the 
marked abnormality criteria.  
Individual subject data listings present laboratory data including change from Baseline and flags 
for abnormal and PCS values. 
Subjects who meet one or more of the criteria presented in Appendix 12.3.3 for potential drug-
induced liver injury (PDILI) at any time-point (from both scheduled and unscheduled visits) will 
be listed. The listing will display only visits for which at least one of the above criteria was 
fulfilled for a given subject, and will display all results obtained at that visit for the specified 
variables. Potential Hy’s law cases will be flagged. If applicable, a summary of subjects who met 
the criteria for PDILI will be presented separately from all relevant data collected.  
PDILI laboratory results and additional PDILI information will be listed. If specific PDILI 
information collected separately is matching to the entries in the standard eCRF pages collected 
for all subjects, the specific PDILI information will be added to the corresponding listing for the 
standard eCRF information (eg, lifestyle information is collected for all study subjects, the 
additional PDILI information for alcohol and illicit drug use will be included in the listings for 
lifestyle). For information collected on top (eg, family history of PDILI) a new listing will be 
generated. 
10.3.1 
Definitions and Derivations 
For continuous laboratory variables (hematology and clinical chemistry) summary statistics of 
actual values and change from Baseline values will be presented.  
In tables that are provided by period, percentages are based on the number of subjects who are at 
risk for a certain period per age category in the respective analysis set. Subjects who entered a 
period are regarded as "at risk" for this period. 
The list of laboratory variables is given in Section 12.1. 
10.3.1.1 
Blood Sample  
Blood samples are analyzed by a central laboratory and data are available electronically 
including SI units as well as an assessment of abnormality based on normal ranges (eg, high, 
low; adjusted for age and gender where applicable). 
Change from Baseline (see Section 3.3) is calculated for each post Baseline visit according to the 
visit schedule including unscheduled visits and for the Last Visit. 
A variable representing categories for possibly clinically significant treatment-emergent (PCST) 
abnormal values is created for selected hematology and blood chemistry parameters (Table 12‒1 
and Table 12‒2): 
• Too low 
• Not PCS 
• Too high 
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PCST abnormal values are defined as any treatment emergent laboratory values meeting the 
criteria (UCB 2012, GUIDANCE DOCUMENT, Clinical and Laboratory Possibly Clinically 
Significant Treatment Emergent (PCST) Criteria For Clinical Development Programs in TA 
CNS). 
10.3.1.2 
Ordering of Laboratory Parameters 
The tables and listings, parameters are presented in the following order (Section 12.1): 
• Hematology 
Quantitative data: Red Blood Cell (RBC, also called erythrocytes) count, hemoglobin, 
hematocrit, platelets, White Blood Cell (WBC, also called leukocytes) count, differential 
blood count, (basophil, eosinophil, neutrophil, lymphocyte, monocyte), reticulocyte count, 
MCV, MCH, and MCHC 
• Blood chemistry 
Quantitative data: AST, ALT, GGT, ALP, Total bilirubin, Creatinine, Creatinine clearance, 
Sodium, Potassium, Calcium, Total protein, and Albumin, BUN,. 
10.3.2 
Tables 
A table Hematology Observed Values and Changes from Baseline presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately per analysis visit summary 
statistics: 
• For absolute values 
• For Change from Baseline values. 
This by visit presentation includes scheduled visits and Last Visit. 
The table is repeated for: 
• Blood Chemistry Observed Values and Changes from Baseline values. 
 
A table Hematology: Shift from Baseline to End of Treatment presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately the number of shifts from:  
• “Low” at Baseline and “Low” at End of Treatment 
• “Low” at Baseline and “Normal” at End of Treatment 
• “Low” at Baseline to “High” at End of Treatment  
• “Normal” at Baseline to “Low” at End of Treatment  
• “Normal” at Baseline to “Normal” at End of Treatment 
• “Normal” at Baseline to “High” at End of Treatment  
• “High” at Baseline to “High” at End of Treatment 
• “High” at Baseline to “Normal” at End of Treatment 
• “High” at Baseline to “Low” at End of Treatment  
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The table is repeated for: 
• Blood Chemistry.  
 
A table Treatment-emergent PCS Hematology by Analysis Visit presents the number and 
percentage of subjects with treatment-emergent PCS criteria (Too low, Too high) for each of the 
respective parameters. Tables will be presented for subjects on adjunctive therapy and for 
subjects on monotherapy, separately. 
Note: Category “Not PCS” is omitted due to limited usefulness. 
Frequencies are presented as: 
• n over Nobs with n being the number of subjects with PCS criterion for the respective 
variable at least at one visit during that period and Nobs being the number of subjects with at 
least 1 non-missing measurement for respective variable during that period. 
• Percentage (%) based on Nobs 
The table is repeated for: 
• Blood Chemistry PCS Data. 
 
A table Hematology PCS Shift from Baseline presents, for each period and for the combined 
periods changes from Baseline in the PCS abnormality category at any time during the respective 
period and overall. Tables will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
The table presents the following settings: 
• “Too low” at Baseline and “Too low” at least at one visit during that period 
• Shifts from “Too low” at Baseline to “Too high” at least at one visit during that period 
• Shifts from “Not PCS” at Baseline to “Too low” at least at one visit during that period 
• Shifts from “Not PCS” at Baseline to “Too high” at least at one visit during that period 
• “Too high” at Baseline and “Too high” at least at one visit during that period 
• Shifts from “Too high” at Baseline to “Too low” at least at one visit during that period 
• “Too low”, “Not PCS”, and “Too high” at Baseline for those subjects having at least one 
measurement during that period. 
Note: Shifts to status “No PCS” are omitted due to limited usefulness. 
Frequencies are presented as: 
• n over Nobs with n being the number of subjects with at least one measurement during that 
period meeting the criteria for the respective variable and Nobs being the number of subjects 
with at least one non-missing measurement for the respective variable during that period and 
at baseline. 
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• Percentage (%) based on Nobs 
For this table a subject can appear in more than one shift. 
The table is repeated for: 
• Blood Chemistry PCS Shifts. 
 
A table Potential Drug Induced Liver Injury (PDILI) Data presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately, the number and percentage of subjects with 
the following criteria: 
• ALT or AST ≥ 5xULN 
• ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
Frequencies are presented as: 
• n over Nobs with n being the number of subjects with at least one measurement during that 
period meeting the criteria for the respective variable and Nobs being the number of subjects 
with at least one non-missing measurement for the respective variable during that period and 
at baseline. 
• Percentage (%) based on Nobs 
10.3.3 
Listings 
A subject data listing Hematology Laboratory Results presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately: 
• Age Category 
• Region/Country/Site/Subject Number 
• Gender/Age/Race/Weight 
• Laboratory Function Panel 
• Variable 
• Normal Range 
• Analysis Visit 
• Lab Not Done 
• Date Sample Taken/Relative Day 
• Fasting? 
• Result / Flag 
• Change from Baseline / Flag 
• Abnormal 
The column “Abnormal” represents the PCS criterion that is met, if applicable. 
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The subject data listing is repeated for: 
• Blood Chemistry Laboratory Values. 
 
A listing of Subjects with Potential Drug-Induced Liver Injury presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately: 
• Age Category 
• Region/Country/Site/Subject Number 
• Gender/Age/Weight 
• Analysis Visit 
• ALT value 
• AST value 
• Bilirubin value 
Note: Potential Drug-Induced Liver Injury criteria presented are:  
(ALT >3 x ULN or AST >3 x ULN) and Bilirubin >2 x ULN, and  
(ALT >5 x ULN or AST >5 x ULN), where ULN=Upper Limit of Normal Range 
 
10.4 
Vital signs, Physical Findings, and Other Observations Related 
to Safety 
10.4.1 
Vital Signs 
PCST abnormal vital sign values are any treatment emergent parameters meeting the criteria as 
described in the UCB guidance document.  
For each scheduled post-Baseline visit and for Last Visit descriptive statistics for observed 
values and change from Baseline values are presented for each vital sign parameter. In addition, 
number and percent of subjects with PCS values are presented by visit and by period for vital 
sign parameters. In addition, a table presents per period and overall changes from Baseline in the 
PCS category. 
Individual subject data listings present vital sign data including change from Baseline and flags 
for PCS values. 
10.4.1.1 
Definitions and Derivations 
Vital signs parameters are documented in the Vital signs CRF. 
Change from Baseline (CfB) is calculated for each post Baseline visit according to the visit 
schedule including unscheduled visits and for Last Visit:  
CfB= Post-baseline value – Baseline value. 
The vital signs abnormality criteria are defined as presented in Section 12.5. 
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A variable representing categories for possibly clinically significant treatment-emergent (PCST) 
abnormal values is created for vital sign parameters pulse rate, systolic blood pressure, diastolic 
blood pressure, and temperature: 
• Too low 
• Not PCS 
• Too high 
PCST abnormal values are any treatment emergent vital sign values meeting the criteria (UCB 
2012, GUIDANCE DOCUMENT, Clinical and Laboratory Possibly Clinically Significant 
Treatment Emergent Criteria (PCST) Criteria for Clinical Development Programs in TA CNS). 
In tables that are provided by period, percentages are based on the number of subjects who are at 
risk for a certain period per age category in the respective analysis set. Subjects who entered a 
period are regarded as "at risk" for this period. 
10.4.1.2 
Tables 
A table Vital Signs Observed Values and Changes from Baseline presents for subjects on 
adjunctive therapy and for subjects on monotherapy, separately, per analysis visit summary 
statistics: 
• For observed values (systolic blood pressure, diastolic blood pressure, pulse rate) 
• For Change from Baseline in vital sign parameters. 
This by analysis visit presentation includes scheduled visits and Last Visit. 
A table Post-baseline PCS Vital Signs by Analysis Visit presents for subjects on adjunctive 
therapy and for subjects on monotherapy, separately, per analysis visit and overall the number 
and percentage of subjects with PCS criteria (Too low, Too high) for each of the following 
parameters: 
• Systolic blood pressure 
• Diastolic blood pressure 
• Pulse rate 
• Temperature 
Note: Category “Not PCS” is omitted due to limited usefulness. 
Frequencies are presented as 
• n over Nobs with n being the number of subjects with PCS criterion for the respective 
variable at least at one visit and Nobs being the number of subjects with at least one non-
missing measurement. 
• Percentage (%) based on Nobs. 
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10.4.1.3 
Listings 
A subject data listing Vital Signs presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Age Category 
• Region/Country/Site/Subject Number 
• Gender/Age/Race/Weight 
• Vital sign variable 
• Analysis Visit 
• Date/Relative Day 
• Result 
• Change from Baseline 
• Abnormal 
The column “Abnormal” represents the PCS category, if applicable. 
10.4.2 
Electrocardiograms  
A summary of ECG data will be presented by visit. A frequency distribution on the abnormality 
status of the ECG assessment is presented by visit. In addition, a table presents changes from 
Baseline in the abnormality assessment of ECG. 
10.4.2.1 
Definitions and Derivations 
The overall result of the ECG is documented in the 12-Lead ECG Interpretation CRF as: 
• Normal 
• Abnormal, not clinically significant 
• Abnormal, clinically significant. 
No individual ECG parameter is documented in the CRF or is available for data analysis 
10.4.2.2 
Tables 
A table 12-lead ECG Report by Analysis Visit presents for subjects on adjunctive therapy and 
for subjects on monotherapy, separately, for each analysis visit the frequency distribution on the 
abnormality status of the ECG assessment: 
• Normal 
• Abnormal, not clinically significant 
• Abnormal, clinically significant 
Frequencies are presented as: 
• n over Nobs with n being the number of subjects with an assessment in that category at that 
visit and Nobs being the number of subjects with a non-missing ECG report at that visit 
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• Percentage (%) based on Nobs 
A table 12-lead ECG Shifts from Baseline by Analysis Visit presents for each analysis visit 
changes in the abnormality assessment from baseline: 
The table presents the following settings: 
• “Normal” at Baseline and at the respective post-baseline visit 
• Shifts from “Normal” to “Abnormal, not clinically significant” or “Abnormal, clinically 
significant” 
• “Abnormal, not clinically significant” at Baseline and at the respective post-baseline visit 
• Shifts from “Abnormal, not clinically significant” to “Normal” or “Abnormal, clinically 
significant” 
• “Abnormal, clinically significant” at Baseline and at the respective post-baseline visit 
• Shifts from “Abnormal, clinically significant” to “Normal” or “Abnormal, not clinically 
significant” 
Frequencies are presented as: 
• n over Nobs with n being the number of subjects with an assessment in that category and 
Nobs being the number of subjects with a non-missing ECG report at baseline and that visit 
• Percentage (%) based on Nobs 
10.4.2.3 
Listings 
The subject data listing 12-Lead ECG Findings presents for subjects on adjunctive therapy and 
for subjects on monotherapy, separately: 
• Age Category 
• Region/Country/Site/Subject Number 
• Gender/Age/Race/Weight 
• Analysis Visit 
• ECG Date and Time/Relative Day 
• ECG evaluated by (investigator/cardiologist) 
• Finding 
• Abnormal Result 
The column “Abnormal results” represents the pre-defined categorization given in the respective 
ECG CRF and only abnormal findings are listed. 
10.4.3 
Body Weight and Height 
A summary of body weight and height data, including change from baseline data, will be 
presented by visit. A frequency distribution on the abnormality status of the weight data will be 
presented by visit. 
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10.4.3.1 
Definitions and Derivations 
A variable representing categories for PCST abnormal values is created for body weight: 
• Too low 
• Not PCS 
• Too high 
(see Table 12‒3, Table 12‒4 and Table 12‒5) 
In tables that are provided by period, percentages are based on the number of subjects who are at 
risk for a certain period per age category in the respective analysis set. Subjects who entered a 
period are regarded as "at risk" for this period. 
10.4.3.2 
Tables 
A table Weight and Height presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately: 
• Summary statistics on weight and height by visit 
• Summary statistics on change from baseline on weight and height by post-baseline visit 
Missing is presented as category only if this is applicable for a certain variable. 
A table Post-baseline PCS Weight by Analysis Visit presents for subjects on adjunctive therapy 
and for subjects on monotherapy, separately, per analysis visit the number and percentage of 
subjects with PCS criteria (Too low, Not PCS, Too high) for the following parameter: 
• Body Weight 
10.4.3.3 
Listings 
A subject data listing Weight and Height presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately: 
• Age Category 
• Site/Subject Number 
• Analysis Visit 
• Date and Relative Day 
• Height 
• Weight 
• Abnormal (weight) 
10.4.4 
Concomitant Medical Procedures 
Concomitant medical procedures will be listed.  
10.4.4.1 
Definitions and Derivations 
Not applicable. 
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10.4.4.2 
Tables 
None. 
10.4.4.3 
Listings 
Procedure names are not coded, therefore only a listing is presented. 
A listing Concomitant Medical Procedures presents for subjects on adjunctive therapy and for 
subjects on monotherapy, separately for each concomitant medical procedure: 
• Age Category 
• Site/Subject Number 
• Date of Procedure/Relative Day 
• Procedure (Reported Term) 
• Procedure related to (Epilepsy, Lack of Efficacy, Adverse Event, Elective Procedure, Other) 
10.4.5 
Assessment of Suicidality 
Data listings of the data for the C-SSRS will be provided. No summaries of these results are 
planned. 
10.4.5.1 
Definitions and Derivations 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This will be completed according to the protocol schedule of study 
assessments. The C-SSRS is not validated and will not be used for subjects <6 years of age.  
10.4.5.2 
Tables 
Not applicable. 
10.4.5.3 
Listings 
Data as recorded on the “C-SSRS (Since Last Visit)” will be presented by subject number. 
A listing C-SSRS Suicidality presents for subjects on adjunctive therapy and for subjects on 
monotherapy, separately the following: 
• Age Category 
• Site/Subject Number 
• Visit 
• Assessment Date/Relative Day 
• Module 
• Time point 
• Question 
• Response 
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11 
REFERENCES 
[1] Hahn G.J. and Meeker W.Q., Statistical Intervals: A Guide for Practitioners, 1991, New 
York: John Wiley & Son 
[2] GUIDANCE DOCUMENT, Clinical and Laboratory Possibly Clinically Significant 
Treatment Emergent Criteria (PCST) Criteria For Clinical Development Programs in TA 
CNS (UCB 14JUN2012) 
 
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12 
APPENDICES 
12.1 
Order of Laboratory Variables in Tables and Listings 
For tables and listings the order for hematology variables is: 
1. Red blood cell count (also called erythrocytes) 
2. Hemoglobin 
3. Hematocrit 
4. Platelet count 
5. White blood cell count (also called leukocytes) 
6. Basophil count  
7. Basophils/Leukocytes (%) 
8. Eosinophil count  
9. Eosinophils/Leukocytes (%) 
10. Neutrophil count  
11. Neutrophils/Leukocytes (%) 
12. Lymphocyte count  
13. Lymphocytes/Leukocytes (%) 
14. Monocyte count  
15. Monocytes/Leukocytes (%) 
16. Reticulocyte count 
17. Mean Corpuscular Volume (MCV) 
18. Mean Corpuscular Hemoglobin (MCH) 
19. Mean Corpuscular HGB Concentration (MCHC) 
For tables and listings the order for blood chemistry variables is: 
1. Aspartate Aminotransferase (AST) 
2. Alanine Aminotransferase (ALT) 
3. Gamma Glutamyl Transferase (GGT) 
4. Alkaline Phosphatase (ALP) 
5. Total Bilirubin 
6. Creatinine 
7. Creatinine Clearance 
8. Sodium 
9. Potassium 
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10. Calcium 
11. Total Protein 
12. Albumin 
13. Blood Urea Nitrogen (BUN) 
 
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12.2 
Listing of AEDs 
The following is a list of antiepileptic drugs (generic name): 
• Acetazolamide 
• Acetylpheneturide 
• Amino (diphenylhydantoin) valeric acid 
• Barbexaclone 
• Beclamide 
• Brivaracetam 
• Carbamazepine 
• Carisbamate 
• Clobazam 
• Clonazepam 
• Diclofenamide 
• Eslicarbazepine 
• Ethadione 
• Ethosuximide 
• Ethotoin 
• Felbamate 
• Fosphenytoin 
• Gabapentin 
• Ilepcimide 
• Lacosamide 
• Lamotrigine 
• Levetiracetam 
• Mesuximide 
• Metharbital 
• Methylphenobarbital 
• Mephenytoin 
• Nitrazepam 
• Oxcarbazepine 
• Paramethadione 
• Perampanel 
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• Phenacemide 
• Pheneturide 
• Phenobarbital 
• Phensuximide 
• Phenytoin 
• Pregabalin 
• Primidone 
• Progabide 
• Retigabine 
• Rufinamide 
• Stiripentol 
• Sultiame 
• Tiagabine 
• Topiramate 
• Trimethadione 
• Valproic acid 
• Valpromide 
• Vigabatrin 
• Zonisamide 
Note: An AED that contains more than one compound in this list is not counted as 1 AED. 
The number of compounds contained in 1 AED is counted as the number of AED administered. 
It is prohibited that subjects take levetiracetam other than IMP during the study. Antiepileptic 
drugs that have not been approved in Japan are prohibited. 
 
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12.3 
Possibly Clinically Significant Treatment-Emergent Laboratory 
Values 
The following two tables are obtained from [2]. 
12.3.1 
Hematology 
Table 12‒1: PCST values for Hematology 
Parameter 
Age range 
Unit 
(conventional) 
Abnormality 
Criteria 
(conventional) 
Unit 
Abnormality 
Criteria 
(standard) 
Red blood 
<2 years 
1012/L 
< 3.0 
T/L 
< 3.0 
cell count 
≥2 years 
 
< 3.5 
 
< 3.5 
Hematocrit 
<2 years 
% 
≤ 27 
% 
≤ 27 
 
 
 
> 45 
 
> 45 
 
≥2 y - <18 y 
 
≤ 29 
 
≤ 29 
 
 
 
> 47 
 
> 47 
Hemoglobin 
<2 years 
g/dL 
≤ 9.0 
g/L 
≤ 90 
 
 
 
> 15.0 
 
> 150 
 
≥2 y – <18 y 
 
≤ 9.5 
 
≤ 95 
 
 
 
> 16.0 
 
> 160 
Platelets 
>1 month 
109/L 
≤ 100 
G/L 
≤ 100 
 
 
 
> 600 
 
> 600 
White blood  
<12 years 
109/L 
< 3.5 
G/L 
< 3.5 
cell count 
 
 
> 15.0 
 
> 15.0 
Neutrophil 
count 
>1 month 
109/L 
< 1.5 
G/L 
< 1.5 
Lymphocyte  
<6 months 
% 
≤ 30.0 
% 
≤ 30.0 
 
6 m - <6 y 
 
≤ 22.0 
 
≤ 22.0 
Monocyte  
>1 month 
% 
≥ 20.0 
% 
≥ 20.0 
 
 
 
 
 
 
Eosinophil  
>1 month 
% 
≥ 10.0 
% 
≥ 10.0 
Basophil 
>1 month 
% 
≥ 3.0 
% 
≥ 3.0 
Reticulocyte 
 
 
$ 
 
$ 
MCV 
 
 
$ 
 
$ 
MCH 
 
 
$ 
 
$ 
MCHC 
 
 
$ 
 
$ 
Abbreviations: dL = deciliter; L = liter; m: month; mg = milligram; mmol = millimoles; μmol = 
micromoles; U = unit; y: year 
MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume 
$ Not presented in reference [2] 
Note: The adjusted age (Section 3.2.5.2) at the assessment/visit will be used to determine within 
which percentile the subject is included. 
 
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12.3.2 
Chemistry 
Table 12‒2: PCST values for Chemistry 
Parameter 
Age range 
Unit 
(conventional) 
Abnormality 
Criteria 
(conventional) 
Unit 
Abnormality 
Criteria 
(standard) 
AST 
<14 years 
U/L 
> 180 
U/L 
> 180 
ALT 
<1 year  
U/L 
$ 
U/L 
$ 
 
1 yr - <18 y 
 
> 90 
 
> 90 
GGT 
<6 month 
U/L 
> 522 
U/L 
> 522 
 
6 m - <1 y 
 
> 279 
 
> 279 
 
1 y - < 13 y 
 
> 66 
 
> 66 
Alkaline  
<4 year 
U/L 
> 690 
U/L 
> 690 
Phosphatase 
4 y - <10 y 
 
> 834 
 
> 834 
Total Bilirubin 
> 1 month 
mg/dl 
≥ 1.5 
μmol/L 
≥ 25.656 
BUN 
<1 year 
mg/dl 
> 21 
mmol/L 
> 7.497 
 
≥1 year 
 
> 30 
 
> 10.71 
Creatinine 
<1 year 
mg/dL 
$ 
μmol/L 
$ 
 
1 y - <10 y 
 
> 0.9 
 
> 79.56 
Creatinine  
All 
ml/min 
< 70 
mL/s 
< 1.169 
Clearance # 
 
 
 
 
 
Sodium 
> 1 month 
mEq/L 
≤ 130 
mmol/L 
≤ 130 
 
 
 
≥ 150 
 
≥ 150 
Potassium 
< 1 year 
mEq/L 
< 3.0 
mEq/L 
< 3.0 
 
 
 
> 6.5 
 
> 6.5 
 
≥ 1 year 
 
< 3.0 
 
< 3.0 
 
 
 
> 5.8 
 
> 5.8 
Calcium 
< 1 year 
mg/dL 
< 6.9 
mmol/L 
< 1.725 
 
 
 
> 12.2 
 
> 3.05 
 
1 y - <18 y 
 
< 7.4 
 
< 1.85 
 
 
 
> 11.7 
 
> 2.925 
Total Protein 
<2 months 
g/dL 
$  
g/L 
$  
 
2 m - <1 yr 
 
< 3.0 
 
< 30 
 
 
 
> 10.0 
 
> 100 
 
≥1 year 
 
< 4.3 
 
< 43 
 
 
 
> 10.0 
 
> 100 
Albumin 
<1 year 
g/dL 
< 1.6 
g/L 
< 16 
 
 
 
> 6.0 
 
> 60 
 
≥1 year 
 
< 2.4 
 
< 24 
 
 
 
> 7.0 
 
> 70 
Abbreviations: ALT= alanine aminotransferase; AST = aspartate aminotransferase; GGT: gamma-glutamyl 
transferase; BUN = blood urea nitrogen; dL = deciliter; L = liter; mg = milligram; mmol = millimoles; μmol = 
micromoles; U = unit; m=month (a month is defined as 30 days); y = years (a year is defined as 365.25 days) 
$ Not presented in reference [2] 
# Schwartz equation (patients <12):  Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine  
  Cockroft equation (patients >12): Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum 
  creatinine); Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85 
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Note: The adjusted age (Section 3.2.5.2) at the assessment/visit will be used to determine within 
which percentile the subject is included. 
 
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12.3.3 
Required Investigations and follow up for PDILI 
 
 
 
 
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12.3.4 
PDILI Laboratory Measurements 
 
 
Virology-related 
Hepatitis E IgM antibody 
HBsAg 
Hepatitis A IgA antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophil antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing 
transaminase elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; HBsAg=hepatitis B 
surface antigen; IgA=immunoglobulin A; IgM=immunoglobulin M; INR=international 
normalized ratio; LDH=lactate dehydrogenase; PDILI=potential drug-induced liver injury; 
PK=pharmacokinetic; RNA=ribonucleic acid; ULN=upper limit of normal  
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right 
upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, 
and fever (without clear alternative cause). 
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12.4 
PDILI information to be collected 
 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies,  
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty liver 
disease”) 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
• 
Recent travel 
• Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea,  
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or  
rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
 
 
 
 
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12.5 
Vital Signs Abnormality Criteria 
Table 12‒3: Vital Signs Abnormality Criteria 
Parameter 
Age Range 
Abnormality Criteria 
Pulse Rate 
(beats/minute) 
<6 months  
< 100 bpm  
> 180 bpm 
6 months - <3 years 
< 90 bpm  
> 150 bpm 
3 years to <12 years 
< 60 bpm 
> 130 bpm 
Systolic Blood Pressure 
(mmHg) 
<6 months  
< 60 mmHg  
> 100 mmHg 
6 months - <3 years 
< 70 mmHg  
> 120 mmHg 
3 years to <12 years 
< 80 mmHg  
> 140 mmHg 
Diastolic Blood Pressure 
(mmHg) 
<6 months  
< 40 mmHg 
> 65 mmHg 
6 months - <3 years 
< 45 mmHg 
> 75 mmHg 
3 years to < 12 years 
< 50 mmHg 
> 80 mmHg 
Temperature 
>1 month 
>101 ºF (38.3 ºC) 
Body Weight 
1 month - <17 years 
<3% or 97% of the normal body weight 
growth curve ranges based on gender and the 
age of subject on date of weight assessmenta 
a  For centiles see Table 12‒4 and Table 12‒5  
A month is defined as 30 days; a year is defined as 365.25 days.  
Data obtained from: GUIDANCE DOCUMENT, Clinical and Laboratory Possibly Clinically 
Significant Treatment Emergent Criteria (PCST) Criteria For Clinical Development Programs in TA 
CNS (UCB 14JUN2012) 
Note: The adjusted age (Section 3.2.5.2) at the assessment/visit will be used to determine within 
which percentile the subject is included. 
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12.6 
Body Weight Values 
Table 12‒4: Body Weight Values (kg) by Age in Months/Years and Months for Males 
Age 
Percentile 
3 
10 
25 
50 
75 
90 
97 
6 to <7 months 
6.44 
6.94 
7.44 
8.00 
8.56 
9.07 
9.57 
7 to <8 months 
6.73 
7.21 
7.71 
8.27 
8.84 
9.36 
9.87 
8 to <9 months 
6.96 
7.44 
7.94 
8.50 
9.08 
9.61 
10.14 
9 to <10 months 
7.16 
7.64 
8.13 
8.70 
9.29 
9.83 
10.37 
10 to <11 months 
7.34 
7.81 
8.31 
8.88 
9.48 
10.03 
10.59 
11 to <12 months 
7.51 
7.98 
8.48 
9.06 
9.67 
10.23 
10.82 
1 yr and 0 to <1 month 
7.68 
8.15 
8.65 
9.24 
9.86 
10.44 
11.04 
1 yr and 1 to <2 months 
7.85 
8.32 
8.83 
9.42 
10.05 
10.65 
11.28 
1 yr and 2 to <3 months 
8.02 
8.49 
9.00 
9.60 
10.25 
10.86 
11.51 
1 yr and 3 to <4 months 
8.19 
8.67 
9.18 
9.79 
10.44 
11.08 
11.75 
1 yr and 4 to <5 months 
8.36 
8.84 
9.35 
9.97 
10.64 
11.29 
11.98 
1 yr and 5 to <6 months 
8.53 
9.01 
9.53 
10.16 
10.84 
11.51 
12.23 
1 yr and 6 to <7 months 
8.70 
9.18 
9.71 
10.35 
11.04 
11.73 
12.47 
1 yr and 7 to <8 months 
8.86 
9.35 
9.89 
10.53 
11.25 
11.95 
12.71 
1 yr and 8 to <9 months 
9.03 
9.52 
10.06 
10.72 
11.45 
12.17 
12.96 
1 yr and 9 to <10 months 
9.19 
9.69 
10.24 
10.91 
11.65 
12.39 
13.20 
1 yr and 10 to <11 months 
9.36 
9.86 
10.41 
11.09 
11.85 
12.61 
13.45 
1 yr and 11 to <12 months 
9.52 
10.03 
10.59 
11.28 
12.06 
12.83 
13.69 
2 yrs and 0 to <6 months 
10.06 
10.60 
11.19 
11.93 
12.76 
13.61 
14.55 
2 yrs and 6 to <12 months 
10.94 
11.51 
12.17 
12.99 
13.93 
14.90 
16.01 
3 yrs and 0 to <6 months 
11.72 
12.35 
13.07 
13.99 
15.04 
16.15 
17.43 
3 yrs and 6 to <12 months 
12.42 
13.10 
13.89 
14.90 
16.08 
17.34 
18.82 
4 yrs and 0 to <6 months 
13.07 
13.80 
14.65 
15.76 
17.08 
18.51 
20.24 
4 yrs and 6 to <12 months 
13.71 
14.50 
15.42 
16.62 
18.09 
19.71 
21.72 
5 yrs and 0 to <6 months 
14.37 
15.23 
16.24 
17.56 
19.17 
20.95 
23.15 
5 yrs and 6 to < 2 months 
15.03 
16.02 
17.17 
18.63 
20.36 
22.19 
24.33 
6 yrs and 0 to <6 months 
15.55 
16.84 
18.24 
19.91 
21.70 
23.43 
25.25 
 
 
 
 
 
 
 
 
Note: The adjusted age (Section 3.2.5.2 ) at the assessment/visit will be used to determine within 
which percentile the subject is included 
 
 
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Table 12‒5: Body Weight Values (kg) by Age in Months/Years and Months for Females 
Age 
Percentile 
3 
10 
25 
50 
75 
90 
97 
6 to <7 months 
6.06 
6.49 
6.95 
7.47 
8.02 
8.53 
9.05 
7 to <8 months 
6.32 
6.75 
7.21 
7.75 
8.31 
8.83 
9.37 
8 to <9 months 
6.53 
6.97 
7.43 
7.97 
8.54 
9.08 
9.63 
9 to <10 months 
6.71 
7.15 
7.62 
8.17 
8.74 
9.29 
9.85 
10 to <11 months 
6.86 
7.31 
7.78 
8.34 
8.93 
9.49 
10.06 
11 to <12 months 
7.02 
7.46 
7.95 
8.51 
9.11 
9.68 
10.27 
1 yr and 0 to <1 month 
7.16 
7.62 
8.11 
8.68 
9.29 
9.87 
10.48 
1 yr and 1 to <2 months 
7.31 
7.77 
8.27 
8.85 
9.47 
10.07 
10.69 
1 yr and 2 to <3 months 
7.46 
7.93 
8.43 
9.03 
9.66 
10.27 
10.90 
1 yr and 3 to <4 months 
7.61 
8.08 
8.60 
9.20 
9.85 
10.47 
11.12 
1 yr and 4 to <5 months 
7.75 
8.24 
8.76 
9.38 
10.04 
10.67 
11.33 
1 yr and 5 to <6 months 
7.90 
8.39 
8.93 
9.55 
10.23 
10.87 
11.55 
1 yr and 6 to <7 months 
8.05 
8.55 
9.09 
9.73 
10.42 
11.08 
11.77 
1 yr and 7 to <8 months 
8.20 
8.71 
9.26 
9.91 
10.61 
11.28 
11.99 
1 yr and 8 to <9 months 
8.34 
8.86 
9.43 
10.09 
10.81 
11.49 
12.21 
1 yr and 9 to <10 months 
8.49 
9.02 
9.59 
10.27 
11.00 
11.70 
12.44 
1 yr and 10 to <11 months 
8.64 
9.18 
9.76 
10.46 
11.20 
11.92 
12.67 
1 yr and 11 to <12 months 
8.78 
9.34 
9.93 
10.64 
11.40 
12.13 
12.90 
2 yrs and 0 to <6 months 
9.30 
9.89 
10.53 
11.29 
12.11 
12.90 
13.73 
2 yrs and 6 to <12 months 
10.18 
10.85 
11.56 
12.43 
13.36 
14.27 
15.23 
3 yrs and 0 to <6 months 
11.04 
11.76 
12.56 
13.53 
14.59 
15.64 
16.76 
3 yrs and 6 to <12 months 
11.83 
12.61 
13.49 
14.56 
15.75 
16.95 
18.27 
4 yrs and 0 to <6 months 
12.56 
13.39 
14.33 
15.51 
16.84 
18.21 
19.73 
4 yrs and 6 to <12 months 
13.27 
14.15 
15.15 
16.41 
17.89 
19.43 
21.20 
5 yrs and 0 to <6 months 
14.01 
14.92 
15.97 
17.32 
18.93 
20.65 
22.69 
5 yrs and 6 to <12 months 
14.81 
15.75 
16.84 
18.27 
20.00 
21.91 
24.22 
6 yrs and 0 to <6 months 
15.71 
16.68 
17.81 
19.31 
21.15 
23.21 
25.77 
Note: The adjusted age (Section 3.2.5.2) at the assessment/visit will be used to determine within 
which percentile the subject is included. 
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13 
EudraCT TABLE 
A table Discontinuation due to AEs for the ES presents the number and percentage of subjects 
reporting an AE leading to discontinuation in the following categories: 
• Total 
• Serious fatal AE(s) 
• Non-serious fatal AE(s) 
• Non-fatal SAE(s) 
• Non-serious non-fatal AE(s) 
• Fatal SAE(s) and non-serious fatal AE(s) 
• Fatal SAE(s) and non-fatal SAE(s) 
• Fatal SAE(s) and non-serious non-fatal AE(s) 
• Non-serious fatal AE(s) and non-fatal SAE(s) 
• Non-serious fatal AE(s) and non-serious non-fatal AE(s) 
• Non-fatal SAE(s) and non-serious non-fatal AE(s) 
• Fatal SAE(s) and non-serious fatal AE(s) and non-fatal SAE(s) 
• Fatal SAE(s) and non-serious fatal AE(s) and non-serious non-fatal AE(s) 
• Fatal SAE(s) and non-fatal SAE(s) and non-serious non-fatal AE(s) 
• Non-serious fatal AE(s) and non-fatal SAE(s) and non-serious non-fatal AE(s) 
• Fatal SAE(s) and non-serious fatal AE(s) and non-fatal SAE(s) and non-serious non-fatal 
AE(s) 
Note: A subject can only appear in 1 category. One subject can have more than 1 AE leading to 
discontinuation and therefore several criteria might have been met. 
Note: This table uses AEs, not TEAEs. 
Note: This table, with all the above categories, was created additionally to meet EudraCT 
requirements. 
Note: this table will use data from subjects on adjunctive therapy as well as from subjects on 
monotherapy. 
 
 
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14 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP) 
14.1 
Amendment 1 
The main purpose for the SAP amendment 1 is to apply the modifications according to the draft 
Protocol Amendment 3 dated on 04 Jun 2019. Moreover, many technical and detailed 
descriptions for executing the statistical analysis have been added in existing or new sections. 
 
14.2 
Amendment 2 
Rationale for the amendment: 
The SAP amendment 2 is aimed to apply the updates according to the final Protocol Amendment 
3 dated on 29 Jan 2020.   The purpose of  Protocol Amendment 3 is to change the primary 
efficacy variable from daily partial seizure frequency monitored by 48h video-EEG to partial 
seizure frequency per week from Baseline to Visit 6 as agreed with PMDA.  
Modifications and changes: 
Change #1: 
Section 1: Introduction 
…. For regulatory purposes, a planned data cut-off will be made when the final subject who 
completes the Evaluation Period reaches Visit 13 and the final subject who directly enrolled in 
the Maintenance Period reaches Visit 14 in order to obtain 6-month exposure data. 
Has been changed to 
… For regulatory purposes, a planned data cut-off will be made when the final subject who 
completes the Evaluation Period reaches Visit 13 and the final subject who directly enrolled in 
the Maintenance Period reaches Visit 14 in order to obtain 6-month exposure data. 
 
Change #2: 
Section 2: Protocol Summary 
Amendment 3:  
04 Jun 2019 
Has been changed to 
Amendment 3:  
29 Jan 2020 
 
Change #3: 
Section 2.1.1 Primary Objective 
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The primary objective of this study is to confirm the efficacy of Levetiracetam (LEV) in the First 
Period based on the 48h video-EEG compared to historical control as adjunctive treatment in 
pediatric epilepsy subjects aged 1 month to <4 years with partial seizures. 
Has been changed to 
The primary objective of this study is to confirm the efficacy of Levetiracetam (LEV) in 
reducing seizure frequency in the in the First Period based on the 48h video-EEG compared to 
historical control as adjunctive treatment in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures. 
 
Change #4: 
Section 2.1.2 Secondary Objective 
The second and fourth bullets 
• To evaluate the efficacy of LEV in the First Period based on the 48h video-EEG compared to 
historical control as monotherapy in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures 
• To evaluate the efficacy of LEV in the combined First and Second Periods based on the daily 
record card (DRC) as monotherapy or adjunctive treatment in pediatric epilepsy subjects 
aged 1 month to <4 years with partial seizures 
Has been changed to 
• To evaluate the efficacy of LEV in reducing seizure frequency in the First Period compared 
to historical control as monotherapy in pediatric epilepsy subjects aged 1 month to <4 years 
with partial seizures 
• To evaluate the efficacy of LEV in the combined First and Second Periods as monotherapy 
or adjunctive treatment in pediatric epilepsy subjects aged 1 month to <4 years with partial 
seizures 
 
Change #5: 
Section 2.2: 
Efficacy variables 
2.2.1   
 
Efficacy variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
2.2.1.1  
 
 
Efficacy variables for subjects on adjunctive therapy 
2.2.1.1.1  
Primary efficacy variable 
First Period 
The primary efficacy variable for the First Period for subjects on adjunctive therapy is the 
percent reduction in average daily frequency (ADF) of partial seizure frequency (ie, change from 
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the Selection Period to the Evaluation Period in daily partial seizure frequency monitored by the 
48h video-EEG in their ADF) at Visit 6. 
Combined First and Second Periods 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
2.2.1.1.2  
Secondary efficacy variables 
First Period 
The secondary efficacy variables for the First Period are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, ≥50%, ≥75%, and 100% based on the Evaluation Period 48h video-
EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline at Visit 4, Visit 5, and Visit 6 
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
2.2.1.1.3   
Other efficacy variables 
First Period 
The other efficacy variables for the First Period are the following: 
• Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG compared to the Selection Period 48h video-EEG at 
Visit 4 and Visit 6 
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• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period 
Combined First and Second Periods 
There are no other efficacy variables for the combined First and Second Periods 
2.2.1.2 
 
 
Efficacy variables for subjects on monotherapy 
2.2.1.2.1  
Primary efficacy variable 
There is no primary efficacy variable for subjects on monotherapy. 
2.2.1.2.2  
Secondary efficacy variables  
First Period 
The secondary efficacy variables for the First Period are the following: 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 
• Percent reduction in ADF of partial seizure frequency grouped into 6 categories: <0%, 0% to 
<25%, 25% to <50%, ≥50%, ≥75%, and 100% based on the Evaluation Period 48h video-
EEG compared to the Selection Period 48h video-EEG at Visit 4 and Visit 6 
• Percent reduction in ADF of electro-clinical partial seizure frequency at Visit 4 and Visit 6 
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
• For each analysis visit, percent reduction in partial seizure frequency per week monitored by 
the patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100% during the combined Evaluation and Maintenance Periods for 
subjects who are not 48h video-EEG failures, and the combined Dose adjustment and 
Maintenance Periods for subjects who are 48h video-EEG failures 
2.2.1.2.3  
Other efficacy variables 
First Period 
The other efficacy variables for the First Period are the following: 
• Percent reduction in ADF of all types of seizure frequency monitored by the 48h video-EEG 
at Visit 4 and Visit 6 
• Percent reduction in ADF of all type of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG compared to the Selection Period 48h video-EEG at 
Visit 4 and Visit 6 
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• Percent reduction in partial seizure frequency per week monitored by the patient diary from 
Baseline during the Evaluation Period 
Combined First and Second Periods 
The other efficacy variable for the combined First and Second Periods is the following: 
• Subjects who are continuously 6-month seizure-free monitored by the patient diary during 
the combined Evaluation and Maintenance Periods for subjects who are not 48h video-EEG 
failures, and the combined Dose adjustment and Maintenance Periods for subjects who are 
48h video-EEG failures 
Has been changed to 
2.2.1   
 
Efficacy variables 
Efficacy variables are defined separately for the First Period and the combined First and Second 
Periods, and for the type of therapy, if applicable. 
2.2.1.1  
 
 
Efficacy variables for subjects on adjunctive therapy 
2.2.1.1.1  
Primary efficacy variable 
First Period 
The primary efficacy variable for subjects on adjunctive therapy is the percent reduction in 
partial seizure frequency per week from Baseline to Visit 6. 
Combined First and Second Periods 
There is no primary efficacy variable for the combined First and Second Periods for subjects on 
adjunctive therapy. 
2.2.1.1.2  
Secondary efficacy variables 
First Period 
The secondary efficacy variable for the First Period is the following: 
• Percent reduction in partial seizure frequency per week from Baseline to Visit 4 and Visit 5 
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in partial seizure frequency per week from Baseline 
• For each visit, percent reduction in partial seizure frequency per week monitored by the 
patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100%  
2.2.1.1.3  
Other efficacy variables 
First Period 
The other efficacy variables for the First Period for the number of seizures based on the 48h 
video-EEG recorded through Protocol Amendment 2 are the following: 
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• Percent reduction in average daily frequency (ADF) of partial seizure frequency monitored 
by the 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline 
Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all type of seizure frequency per week from Baseline  
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%   
2.2.1.2 
 
 
Efficacy variables for subjects on monotherapy 
2.2.1.2.1  
Primary efficacy variable 
There is no primary efficacy variable for subjects on monotherapy. 
2.2.1.2.2  
Secondary efficacy variables  
First Period 
There is no secondary efficacy variable for the First Period. 
Combined First and Second Periods 
The secondary efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in partial seizure frequency per week from Baseline  
• For each visit, percent reduction in partial seizure frequency per week monitored by the 
patient diary from Baseline grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, 
≥50%, ≥75%, and 100%  
2.2.1.2.3  
Other efficacy variables 
First Period 
• Percent reduction in ADF of partial seizure frequency monitored by the 48h video-EEG at 
Visit 4 and Visit 6 compared to Baseline 
• Percent reduction in ADF of partial of seizure frequency monitored by the 48h video-EEG 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100% based 
on the Evaluation Period 48h video-EEG at Visit 4 and Visit 6 compared to Baseline  
Combined First and Second Periods 
The other efficacy variables for the combined First and Second Periods are the following: 
• For each visit, percent reduction in all types of seizure frequency per week from Baseline  
• For each visit, percent reduction in all type of seizure frequency per week from Baseline 
grouped into 6 categories: <0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%   
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• Percentage of subjects who are continuously 6-month seizure-free monitored by the patient 
diary 4.3 
 
Change #6:  
Section 4.3: 
Safety variables 
2.2.3  
 
Safety variables  
2.2.3.1 
 
Primary safety variable 
There is no primary safety variable. 
2.2.3.2 
 
Secondary safety variables 
The secondary safety variables for the First Period are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs led to discontinuation 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to discontinuation 
2.2.3.3 
 
Other safety variables 
The other safety variables are the following: 
• Adverse events (variables other than secondary safety variables) 
• Laboratory tests (blood chemistry and hematology) 
• Vital signs 
• Body weight and height 
• Physical and neurological examination 
Has been changed to 
2.2.3  
 
Safety variables  
2.2.3.1 
 
Primary safety variable 
There is no primary safety variable. 
2.2.3.2 
 
Secondary safety variables 
The secondary safety variables for the First Period are the following: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of serious adverse events (SAEs) 
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• Incidence of TEAEs leading to discontinuation from study medication 
The secondary safety variables for the combined First and Second Periods are the following: 
• Incidence of TEAEs 
• Incidence of SAEs 
• Incidence of TEAEs leading to discontinuation from study medication 
2.2.3.3 
 
Other safety variables 
The other safety variables are the following: 
• Adverse events (AEs) (variables other than secondary safety variables) 
• Laboratory tests (blood chemistry and hematology) 
• Vital signs 
• Body weight and height 
• Physical and neurological examination 
 
Change #7:  
Section 2.3: 
Study Design and Conduct 
EP0100 is an open-label, single-arm, multicenter study with LEV as monotherapy or adjunctive 
treatment to evaluate the efficacy and safety of LEV (14mg/kg/day to 42mg/kg/day for subjects 
aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 6 months to 
<4 years) in the treatment of partial seizures over the 6-week Evaluation Period (First Period), 
followed by the long-term follow-up (Second Period) in pediatric subjects. 
Subjects with uncontrolled partial seizures will be enrolled into the Selection Period. If all 
inclusion criteria, with the exception of the seizure criterion for 48h video-EEG, and none of the 
exclusion criteria are met, eligible subjects will be hospitalized and a 48h video-EEG performed. 
Subjects with at least 2 partial seizures during the Selection Period 48h video-EEG will enter the 
Evaluation Period. Subjects with <2 partial seizures during the Selection Period 48h video-EEG 
will enter the Maintenance Period. 
… 
No interim analysis is planned. 
 
Has been changed to 
EP0100 is an open-label, single-arm, multicenter study with LEV as monotherapy or adjunctive 
treatment to evaluate the efficacy and safety of LEV (14mg/kg/day to 42mg/kg/day for subjects 
aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 6 months to 
<4 years) in the treatment of partial seizures over the First Period (6 weeks), followed by the 
long-term follow-up (Second Period) in pediatric subjects. 
… 
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No interim analysis is planned. 
 
Change #8: 
2.3.1 Study Periods 
Retrospective Baseline Period 
In order to evaluate the efficacy of LEV by the patient diary, seizure counts during the 2 weeks 
prior to Visit 1 will be used as a Retrospective Baseline Period. 
• 
First Period 
- Selection Period (maximum of 9 days) 
- Evaluation Period (6 weeks) 
At Visit 6 the subject may enter the Second Period, or enter the Down Titration Period followed 
by the Safety Follow-Up Period: 
- Down-Titration Period (up to 4 weeks) 
- Safety Follow-Up Period (2 weeks) 
• 
Second Period 
- Dose adjustment Period (6 weeks) (only for directly enrolled subjects [ie, 48h video-EEG 
failures]) 
- Maintenance Period (until approval or the program is discontinued) 
- Down-Titration Period (up to 4 weeks) 
- Safety Follow-Up Period (2 weeks) 
Has been changed to 
2.3.1 Study Periods 
Retrospective Baseline Period 
In order to evaluate the efficacy of LEV by the patient diary, Seizure counts during the 2 weeks 
prior to Visit 1 will be used as a Retrospective Baseline Period. 
• 
First Period 
- Selection Period (maximum of 9 days) 
- Evaluation Period (6 weeks) 
At Visit 6 the subject may enter the Second Period, or enter the Down Titration Period followed 
by the Safety Follow-Up Period: 
- Down-Titration Period (up to 4 weeks) 
- Safety Follow-Up Period (2 weeks) 
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• 
Second Period 
- Dose adjustment Period (6 weeks) (only for directly enrolled subjects [ie, 48h video-EEG 
failures]) 
- Maintenance Period (until approval or the program is discontinued) 
- Down-Titration Period (up to 4 weeks) 
- Safety Follow-Up Period (2 weeks) 
 
Change #9: 
2.4  
Determination of Sample Size 
… 
The planned number of monotherapy subjects will be a total of 10 subjects. 
Has been changed to 
2.4  
Determination of Sample Size 
… 
The planned number of monotherapy subjects will be a total of 10 subjects. 
Due to the change in the primary efficacy variable in protocol amendment 3, the sample size was 
reconsidered. When the placebo rate area is conservatively redefined as ≤15% and assuming 
there are no nonevaluable subjects, a sample size of 38 subjects will obtain ≥80% power. 
Therefore, no change in sample size is required. 
 
Change #10: 
3.2.2 Schedule of Study Assessments 
The study protocol gives the overall study schedule and the permissible intervals for these visits 
expressed as the number of days relative to Visit 3: Section 5.2 of protocol. 
Table 3‒1 presents the assessment schedule for subjects who are not 48h video-EEG failures and 
who are 48h video-EEG failures. 
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Table 14‒1: Assessment Schedule 
Study Visit 
Target day* 
Visit Window 
Week number 
Subjects who are not 48h video-EEG failures 
Evaluation Period 
Visit 3 
Day 1 
 
Week 0 
Visit 4 
Day 15 
Day 11 to Day 19 
Week 2 
Visit 5 
Day 29 
Day 25 to Day 33 
Week 4 
Visit 6 
Day 43 
Day 39 to Day 47 
Week 6 
Maintenance Period 
Visit 8 
Day 71 
Day 64 to Day 78 
Week 10 
Visit 10 
Day 99 
Day 92 to Day 106 
Week 14 
Visit 11  
Day 127 
Day 120 to Day 134 
Week 18 
Visit 12 
Day 155 
Day 148 to Day 162 
Week 22 
Visit 13 
Day 183 
Day 176 to Day 190 
Week 26 
Visit 15 
Day 267 
Day 260 to Day 274 
Week 38 
Visit 16 
Day 351 
Day 337 to Day 365 
Week 50 
Visit 17 
Day 435 
Day 421 to Day 449 
Week 62 
  Every 12 weeks 
 
 
 
Subjects who are 48h video-EEG failures  
Dose Adjustment Period 
Visit 6 
Day 1 
 
Week 0 
Visit 7 
Day 15 
Day 11 to Day 17 
Week 2 
Visit 8 
Day 29 
Day 25 to Day 33 
Week 4 
Visit 9 
Day 43 
Day 39 to Day 47 
Week 6 
Maintenance Period 
Visit 10 
Day 57 
Day 50 to Day 64 
Week 8 
Visit 11 
Day 85 
Day 78 to Day 92 
Week 12 
Visit 12 
Day 113 
Day 106 to Day 120 
Week 16 
Visit 13 
Day 141 
Day 134 to Day 148 
Week 20 
Visit 14 
Day 183 
Day 176 to Day 190 
Week 26 
Visit 15 
Day 225 
Day 221 to Day 232 
Week 32 
Visit 16 
Day 309 
Day 295 to Day 323 
Week 44 
Visit 17 
Day 393 
Day 379 to Day 407 
Week 56 
  Every 12 weeks 
 
 
 
Note: the day of the first dose of study medication is defined as Study Day 1, while the day before the date of first 
dose of study medication is defined as Study Day -1 (there is no Study Day 0).  
* Day relative to first study drug intake  
 
 
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In the event that more than 1 assessment occurs within a given visit window, the assessment 
closest to the target date will be used in summaries for the given visit.  If 2 assessments are 
equally close to the target day, the latest assessment will be used. 
Table 3‒2 presents the mapping of Study Visits to Analysis Visits for subjects who are not 48h 
video-EEG failures and for subjects who are 48h video-EEG failures. Analysis visits will be used 
for analysis of long-term safety and efficacy data. 
Table 14‒2: Analysis Visit Mapping Table 
Analysis 
Visit 
Week 
number 
Relative day 
since first 
study drug 
intake 
Analysis 
window 
Subjects who are 
not 48h video-EEG 
failures 
Study Visit 
(Target day*) 
Subjects who are 
48h video-EEG 
failures 
Study Visit 
(Target day*) 
Baseline 
 
 
Until Relative Day 
1 
 
 
Evaluation/Dose Adjustment/Maintenance Period 
0 
0 
1 
 
Visit 3 
Visit 6 
1 
2 
15 
2 – 22 
Visit 4 
Visit 7 
2 
4 
29 
23 – 36 
Visit 5 
Visit 8 
3 
6 
43 
37 – 50 
Visit 6 
Visit 9 
4 
8 
57 
51 – 64 
- 
Visit 10 
5 
10 
71 
65 – 78 
Visit 8 (Day 71) 
- 
6 
12 
85 
79 – 95 
- 
Visit 11 (Day 85) 
7 
15 
106 
96 - 116  
Visit 10 (Day 99) 
Visit 12 (Day 113) 
8 
18 
127 
117 – 137 
Visit 11 (Day 127) 
- 
9 
21 
148 
138 – 158 
Visit 12 (Day 155) 
Visit 13 (Day 141) 
10 
24 
169 
159 – 179 
- 
- 
11 
27 
190 
180 – 200 
Visit 13 (Day 183) 
Visit 14 (Day 183) 
12 
30 
211 
201 – 231 
- 
Visit 15 (Day 225) 
13 
36 
253 
232 – 295 
Visit 15 (Day 267) 
- 
14 
48 
337 
296 – 379 
Visit 16 (Day 351) 
Visit 16 (Day 309) 
15 
60 
421 
380 – 463 
Visit 17 (Day 435) 
Visit 17 (Day 393) 
16 
72 
505 
464 – 547 
Visit 18 (Day 519) 
Visit 18 (Day 477) 
17 
84 
589 
548 – 631 
Visit 19 (Day 603) 
Visit 19 (Day 561) 
Every 12 weeks 
Down-titration Period 
EDV/EOS 
- 
- 
 
 
 
Safety Follow-Up Period 
SFU 
- 
- 
 
 
 
* Day relative to first study drug intake 
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In the event that more than 1 assessment occurs within a given analysis visit window, the 
assessment closest to the target date will be used in summaries for the given visit. If 2 
assessments are equally close to the target day, the latest assessment will be used.  
 
Has been changed to 
3.2.2 Schedule of Study Assessments 
The study protocol gives the overall study schedule and the permissible intervals for these visits 
expressed as the number of days relative to Visit 3: Section 5.2 of protocol. 
Subjects who were directly enrolled in the Second Period based on the protocol prior to 
Amendment 3 will also be included in the efficacy and safety analysis with remapping of visit 
numbers to correspond to the ones for subjects who enrolled in the First Period.  
Table 3‒1 presents the assessment schedule for subjects:  
• 
who are enrolled prior to Protocol Amendment 3 and are not 48h video-EEG failures; or   
• 
who are enrolled according to Protocol Amendment 3; or 
• 
who are enrolled prior to Protocol Amendment 3 and are 48h video-EEG failures 
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Table 14‒1: Assessment Schedule 
Study Visit 
Target day* 
Visit Window 
Week number 
Subjects: 
• 
who are enrolled prior to Protocol Amendment 3 and are not 48h video-EEG failures or 
• 
who are enrolled according to Protocol Amendment 3  
Evaluation Period 
Visit 3 
Day 1 
 
Week 0 
Visit 4 
Day 15 
Day 11 to Day 19 
Week 2 
Visit 5 
Day 29 
Day 25 to Day 33 
Week 4 
Visit 6 
Day 43 
Day 39 to Day 47 
Week 6 
Maintenance Period 
Visit 8 
Day 71 
Day 64 to Day 78 
Week 10 
Visit 10 
Day 99 
Day 92 to Day 106 
Week 14 
Visit 11  
Day 127 
Day 120 to Day 134 
Week 18 
Visit 12 
Day 155 
Day 148 to Day 162 
Week 22 
Visit 13 
Day 183 
Day 176 to Day 190 
Week 26 
Visit 15 
Day 267 
Day 260 to Day 274 
Week 38 
Visit 16 
Day 351 
Day 337 to Day 365 
Week 50 
Visit 17 
Day 435 
Day 421 to Day 449 
Week 62 
  Every 12 weeks 
 
 
 
Subjects:  
• 
who are enrolled prior to Protocol Amendment 3 and are 48h video-EEG failures  
Dose Adjustment Period 
Visit 6 
Day 1 
 
Week 0 
Visit 7 
Day 15 
Day 11 to Day 17 
Week 2 
Visit 8 
Day 29 
Day 25 to Day 33 
Week 4 
Visit 9 
Day 43 
Day 39 to Day 47 
Week 6 
Maintenance Period 
Visit 10 
Day 57 
Day 50 to Day 64 
Week 8 
Visit 11 
Day 85 
Day 78 to Day 92 
Week 12 
Visit 12 
Day 113 
Day 106 to Day 120 
Week 16 
Visit 13 
Day 141 
Day 134 to Day 148 
Week 20 
Visit 14 
Day 183 
Day 176 to Day 190 
Week 26 
Visit 15 
Day 225 
Day 221 to Day 232 
Week 32 
Visit 16 
Day 309 
Day 295 to Day 323 
Week 44 
Visit 17 
Day 393 
Day 379 to Day 407 
Week 56 
  Every 12 weeks 
 
 
 
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Table 14‒1: Assessment Schedule 
Study Visit 
Target day* 
Visit Window 
Week number 
Note: the day of the first dose of study medication is defined as Study Day 1, while the day before the date of first 
dose of study medication is defined as Study Day -1 (there is no Study Day 0).  
* Day relative to first study drug intake  
In the event that more than 1 assessment occurs within a given visit window, the assessment 
closest to the target date will be used in summaries for the given visit.  If 2 assessments are 
equally close to the target day, the latest assessment will be used. 
Table 3‒2 presents the mapping of Study Visits to Analysis Visits for subjects : 
• 
who are enrolled prior to Protocol Amendment 3 and are not 48h video-EEG failures and for 
subjects ; or  
• 
who are enrolled according to Protocol Amendment 3; or  
• 
who are enrolled prior to Protocol Amendment 3 and are 48h video-EEG failures.   
Analysis visits will be used for analysis of long-term safety and efficacy data. 
 
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Table 14‒2: Analysis Visit Mapping Table 
Analysis 
Visit 
Week 
number 
Relative 
day since 
first study 
drug intake 
Analysis 
window 
Subjects enrolled 
prior to Protocol 
Amendment 3 and 
are not 48h video-
EEG failures; or 
subjects who are 
enrolled according 
to Protocol 
Amendment 3 
Study Visit 
(Target day[1]) 
Subjects enrolled 
prior to Protocol 
Amendment 3 and 
are 48h video-
EEG failures 
Study Visit 
(Target day[1]) 
Retrospective 
Baseline[2] 
 
- 
2 weeks prior to 
Visit 1 
 
 
Baseline Period 
-1 
-1 
-9 
-9 – 0 
Visit 1  
Visit 2[3] 
Visit 1 
Visit 2[3] 
Evaluation/Dose Adjustment/Maintenance Period 
0[4] 
0 
1 
 
Visit 3 
Visit 6 
1 
2 
15 
2 – 22 
Visit 4 
Visit 7 
2 
4 
29 
23 – 36 
Visit 5 
Visit 8 
3 
6 
43 
37 – 50 
Visit 6 
Visit 9 
4 
8 
57 
51 – 64 
- 
Visit 10 
5 
10 
71 
65 – 78 
Visit 8 (Day 71) 
- 
6 
12 
85 
79 – 95 
- 
Visit 11 (Day 85) 
7 
15 
106 
96 - 116  
Visit 10 (Day 99) 
Visit 12 (Day 
113) 
8 
18 
127 
117 – 137 
Visit 11 (Day 127) 
- 
9 
21 
148 
138 – 158 
Visit 12 (Day 155) 
Visit 13 (Day 
141) 
10 
24 
169 
159 – 179 
- 
- 
11 
27 
190 
180 – 200 
Visit 13 (Day 183) 
Visit 14 (Day 
183) 
12 
30 
211 
201 – 231 
- 
Visit 15 (Day 
225) 
13 
36 
253 
232 – 295 
Visit 15 (Day 267) 
- 
14 
48 
337 
296 – 379 
Visit 16 (Day 351) 
Visit 16 (Day 
309) 
15 
60 
421 
380 – 463 
Visit 17 (Day 435) 
Visit 17 (Day 
393) 
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16 
72 
505 
464 – 547 
Visit 18 (Day 519) 
Visit 18 (Day 
477) 
17 
84 
589 
548 – 631 
Visit 19 (Day 603) 
Visit 19 (Day 
561) 
Every 12 weeks 
Down-titration Period 
EDV/EOS 
- 
- 
 
 
 
Safety Follow-Up Period 
Safety 
Follow-Up 
- 
- 
 
 
 
EDV= Early Discontinuation Visit; EOS= End of Study 
[1] Day relative to first study drug intake 
[2] Retrospective Baseline is only applicable to seizure count data.  For other analyses the time window of “2 
weeks prior to Visit 1” for baseline is not applied.  
[3] Study Visit 2 is only applicable for those subjects enrolled prior to Protocol Amendment 3. 
[4] Analysis visit 0 is not applicable to laboratory test since Week 0 is not scheduled for laboratory test. 
 
Change #11: 
3.2.4 Mapping of Assessments Performed at Early Discontinuation Visit 
Efficacy and safety assessments at an Early Discontinuation Visit (EDV) that correspond to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. In the event that the subject discontinues 
between two scheduled visits the data from the EDV are presented with data corresponding to 
the next scheduled visit for the subject.  
Has been changed to 
3.2.4 Mapping of Assessments Performed at Early Discontinuation Visit 
Efficacy and safety assessments at an Early Discontinuation Visit (EDV) that correspond to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. In the event that the subject discontinues 
between two scheduled visits the data from the EDV are presented with data corresponding to 
the next scheduled visit for the subject.  For subjects who had more than one EDV because of the 
starting dose of the Down-Titration Period, only the first EDV will be mapped to the scheduled 
visit. 
 
Change 12: 
3.5 Analysis Sets 
The following sets are defined for this study: 
• 
Enrolled Set (ES) 
• 
Safety Sets:  
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- 
SS A1 [Safety Set (Adjunctive therapy, First Period), i.e. Safety Set for subjects on 
Adjunctive therapy during the First Period]  
- 
SS M1 [Safety Set (Monotherapy, First Period)]  
- 
SS A12 [Safety Set (Adjunctive therapy, combined First and Second Periods)]  
- 
SS M12 [Safety Set (Monotherapy, combined First and Second Periods)] 
• 
Full Analysis Sets:  
- 
FAS A1 [Full Analysis Set (Adjunctive therapy, First Period), i.e., Full Analysis Set for 
subjects on Adjunctive therapy during the First Period]  
- 
FAS M1 [Full Analysis Set (Monotherapy, First Period)]  
- 
FAS A12 [Full Analysis Set (Adjunctive therapy, combined First and Second Periods)]  
- 
FAS M12 [Full Analysis Set (Monotherapy, combined First and Second Periods)] 
• 
Per Protocol Set (PPS) 
• 
Pharmacokinetic Per-Protocol Set (PK-PPS) 
- 
PK-PPS A12 [Pharmacokinetic-Per-Protocol Set (Adjunctive therapy, combined First and 
Second Periods)]  
- 
PK-PPS M12 [Pharmacokinetic-Per-Protocol Set (Monotherapy, combined First and Second 
Periods)] 
If not stated otherwise, presentation of: 
• 
Disposition and important protocol deviations are based on the ES 
• 
Demographics, other baseline characteristics, safety, and exposure data are based on the SS 
A12 and SS M12 
• 
Efficacy data are based on the FAS A1, FAS M1, FAS A12, and FAS M12. Sensitivity 
analyses on the primary efficacy variable are repeated for the PPS 
3.5.1 Enrolled Set 
The Enrolled Set (ES) will consist of all subjects enrolled (which include all subjects screened) 
into the Selection Period. 
3.5.2 Safety Set 
First Period: 
The SS A1 will include all enrolled subjects on adjunctive therapy in the First Period who 
receive at least 1 dose of study medication in the Evaluation Period. 
The SS M1 will include all enrolled subjects on monotherapy in the First Period who receive at 
least 1 dose of study medication in the Evaluation Period. 
Combined First and Second Periods: 
The SS A12 will include all enrolled subjects on adjunctive therapy in the Evaluation, Dose 
adjustment and Maintenance Period who receive at least 1 dose of study medication in the 
Evaluation, Dose adjustment or Maintenance Period. 
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The SS M12 will include all enrolled subjects on monotherapy in the Evaluation, Dose 
adjustment and Maintenance Period who receive at least 1 dose of study medication in the 
Evaluation, Dose adjustment or Maintenance Period. 
3.5.3 Full Analysis Set 
First Period: 
The FAS A1 will consist of all subjects in the SS A1 who entered the First Period, who receive 
adjunctive therapy, have at least 24h of usable video-EEG time in the Selection Period, with at 
least 2 partial seizures, and have at least 1 post-baseline efficacy assessment from the First 
Period video-EEG time or DRCs in the Evaluation Period. 
The FAS M1 will consist of all subjects in the SS MM who entered the First Period, who receive 
monotherapy, have at least 24h of usable video-EEG time in the Selection Period, with at least 2 
partial seizures, and have at least 1 post-baseline efficacy assessment from the First Period 
video-EEG time or DRCs in the Evaluation Period. 
Combined First and Second Periods: 
The FAS A12 will consist of  all subjects in the SS A12 AND, (all subjects in the FAS A1 OR 
subjects who have at least baseline efficacy assessment and 1 post-baseline efficacy assessment 
from DRCs in the Dose-adjustment or Maintenance Period). 
The FAS M12 will consist of all subjects in the SS M12 AND, (all subjects in the FAS A1 OR 
subjects who have at least baseline efficacy assessment and 1 post-baseline efficacy assessment 
from DRCs in the Dose-adjustment or Maintenance Period). 
3.5.4 Per Protocol Set 
The Per-Protocol Set (Adjunctive therapy and First Period) will consist of all subjects in the FAS 
A1 who have at least 24h of usable video-EEG time in the First Period, and do not have 
important protocol deviations that affect the primary efficacy variable in the Evaluation Period. 
The PPS is not defined for monotherapy and first period, and for the combined first and second 
Periods. 
3.5.5 Other analysis sets 
The PK-PPS A12 will consist of all subjects in the SS A12 for whom at least 1 valid LEV 
plasma concentration-time record and dosing information are available. 
The PK-PPS M12 will consist of all subjects in the SS M12 for whom at least 1 valid LEV 
plasma concentration-time record and dosing information are available. 
 
Has been changed to 
3.5 Analysis Sets 
The following sets are defined for this study: 
• 
Enrolled Set (ES) 
• 
Safety Sets:  
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- 
SS_A (Safety Set [Adjunctive therapy]) 
- 
SS_M (Safety Set [Monotherapy]) 
• 
Full Analysis Sets:  
- 
FAS_A (Full Analysis Set [Adjunctive therapy]) 
- 
FAS_M (Full Analysis Set [Monotherapy]) 
• 
Pharmacokinetic Per-Protocol Set (PK-PPS) 
- 
PK-PPS_A [Pharmacokinetic-Per-Protocol Set (Adjunctive therapy)]  
- 
PK-PPS_M [Pharmacokinetic-Per-Protocol Set (Monotherapy)] 
If not stated otherwise, presentation of: 
• 
Disposition and important protocol deviations are based on the ES 
• 
Demographics, other baseline characteristics, safety, and exposure data are based on the 
SS_A and SS_M 
• 
Efficacy data are based on the FAS_A and FAS_M.  
3.5.1 Enrolled Set 
The Enrolled Set (ES) will consist of all subjects enrolled (which include all subjects screened) 
into the Selection Period. 
3.5.2 Safety Set 
The SS_A will include all enrolled subjects on adjunctive therapy who receive at least 1 dose of 
study medication in the Evaluation Period. 
The SS_M will include all enrolled subjects on monotherapy who receive at least 1 dose of study 
medication in the Evaluation Period. 
For subjects who were directly enrolled in the Second Period based on the protocol prior to 
Amendment 3, after re-mapping they will be considered as entering in the Evaluation Period if 
they receive at least 1 dose of study medication in the Dose Adjustment Period. 
3.5.3 Full Analysis Set 
The FAS_A will consist of all subjects in the SS_A who have at least 1 post-baseline efficacy 
assessment. 
The FAS_M will consist of all subjects in the SS_M who have at least 1 post-baseline efficacy 
assessment. 
3.5.4 Per Protocol Set 
Not applicable.   
3.5.5 Other analysis sets 
The PK-PPS_A will consist of all subjects in the SS_A for whom at least 1 valid LEV plasma 
concentration-time record and dosing information are available. 
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The PK-PPS_M will consist of all subjects in the SS_M for whom at least 1 valid LEV plasma 
concentration-time record and dosing information are available. 
Moreover, many technical and detailed descriptions for executing the statistical analysis have 
been added in existing or new sections. 
 
Change 13: 
Section 6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
For subjects on adjunctive therapy, summary of demographic data and data from other baseline 
characteristics will be presented for not 48h Video-EEG failures and for 48h Video-EEG failures 
by age category and for all subjects combined (overall). 
For subjects on monotherapy, summary of demographic data and data from other baseline 
characteristics will be presented for not 48h Video-EEG failures and for 48h Video-EEG failures 
for all subjects combined (overall). 
Has been changed to 
Section 6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Summary tables and listings will be presented for subjects on adjunctive therapy and for subjects 
on monotherapy, separately. 
For subjects on adjunctive therapy, summary of demographic data and data from other baseline 
characteristics will be presented for not 48h Video-EEG failures and for 48h Video-EEG failures 
by age category and for all subjects combined (overall). 
For subjects on monotherapy, summary of demographic data and data from other baseline 
characteristics will be presented for not 48h Video-EEG failures and for 48h Video-EEG failures 
for all subjects combined (overall). 
 
Change 14: 
Section 6.8.1 Definitions and derivations 
Identification of AEDs 
Medications are regarded as AED if they meet one of the following criteria: 
• At least one of the possible level 2 ATC codes is 
 
• On the Prior and Concomitant Medications CRF the item “Indication” contains one of the 
following text (case insensitive): 
- 
epilepsy 
- 
epileptic (except for the case that indication is “status epilepticus”, i.e. 
CMINDC=”STATUS EPILEPTICUS”) 
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• On the Prior and Concomitant Medications CRF the item “Core AED?” is checked 
• The medication is documented on the History of Previous Antiepileptic Drug Treatment CRF 
module 
Has been changed to 
Identification of AEDs 
Medications are potentially regarded as potential AED if they meet one of the following criteria: 
• At least one of the possible level 2 ATC codes is 
 
• On the Prior and Concomitant Medications CRF the item “Indication” contains one of the 
following text (case insensitive): 
- 
epilepsy 
- 
epileptic (except for the case that indication is “status epilepticus”, i.e. 
CMINDC=”STATUS EPILEPTICUS”) 
• On the Prior and Concomitant Medications CRF the item “Core AED?” is checked 
• The medication is documented on the History of Previous Antiepileptic Drug Treatment CRF 
module 
Based on the criteria above, UCB will perform the manual review to the name, frequency and 
formulation of the medications and to identify the AEDs in an external file which is regularly 
updated in the course of the study.  
 
Change 15: 
Section 7.1 
Definitions and Derivations 
Overall Period treatment compliance is added: 
• Overall Period, Treatment compliance (%) will be calculated as follows:  
Compliance (%) = 
∑
(# of actual administrations per day
𝑙𝑎𝑠𝑡 𝑑𝑎𝑦
𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑦
)
total # of administrations planned during the time the subject was in the study  x 100 
where “total # of administrations planned during the time the subject was in the study” is 
equal to the total number of administrations planned during first planned administration of 
study medication and last planned administration, or day of discontinuation which will be 
calculated as the duration of exposure to study medication in days ×2.  In consideration of 
whether the first administration is taken in the morning or in the evening, please see Section 
10.1.1. 
 
Change 16: 
8 EFFICACY ANALYSES 
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Global updates to change the primary efficacy variable from daily partial seizure frequency 
monitored by 48h video-EEG to partial seizure frequency per week from Baseline to Visit 6 as 
agreed with PMDA. 
 
Change 17: 
9 PHARMACOKINETICS AND PHARMACODYNAMICS 
9.1.2 Tables and Figures 
Descriptive statistics of LEV observed plasma concentrations and dose-normalized LEV plasma 
concentrations are summarized per defined time window post-dose by age categories (1 
month<=Age<6 months, 6 months<=Age<1 year, 1 year<=Age<2 years, 2 years<=Age<4 years) 
and dose levels per administration (10 mg/kg, 20 mg/kg, 30 mg/kg in aged subjects of 6 months 
and above, 7 mg/kg, 14 mg/kg, 21 mg/kg in aged subjects less than 6 months) for observed 
concentrations or all dose levels for dose-normalized concentrations in PK-PPS. The statistics 
are calculated only if at least 2/3 of the individual data at a specific sampling point are above or 
equal to the LLOQ. 
Figures of the geometric means of LEV observed plasma concentrations vs. defined time 
window post-dose are presented by age categories and dose levels. These figures by dose levels 
are superimposed in a same graph for each age categories. 
Figures of the geometric means of LEV dose-normalized plasma concentrations vs. defined time 
window post-dose are presented by age categories in a same graph.  
Scatter plots of LEV observed plasma concentrations vs. time after dosing are presented by age 
categories and dose levels. In addition, these figures are superimposed on scatter plots of plasma 
concentration vs. time in N01223 and figures of LEV plasma concentration time profiles 
simulated based on the population PK model established in N01288. The data of LEV plasma 
concentrations and times in N01223 are provided from data management group in UCB and the 
simulated median, and 5 percentile and 95 percentile of LEV plasma concentrations and times 
are provided from M&S group in UCB to reconstruct N01223 graphs and N01288 simulated 
graphs. 
As needed, population PK analysis will be planned and described in a separate data analysis 
plan. 
Has been changed to 
Descriptive statistics of LEV observed and dose-normalized plasma concentrations will be 
summarized per defined time window post-dose by age category (1 month<=Age<6 months, 6 
months<=Age<1 year, 1 year<=Age<2 years, 2 years<=Age<4 years) and dose level per 
administration (10mg/kg, 20mg/kg, 30mg/kg in aged subjects of 6 months and above, 7mg/kg, 
14mg/kg, 21mg/kg in aged subjects less than 6 months) in PK-PPS_A and PK-PPS_M. The 
statistics are calculated only if at least 2/3 of the individual data at a specific sampling point are 
above or equal to the LLOQ. 
Scatter plots of LEV observed plasma concentrations vs. time after last dosing will be presented 
by age category and dose level.  Scatter plots for LEV observed plasma concentrations vs time 
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after last dosing by dose level will be superposed with different symbols in a single graph for 
each age category.  
Scatter plots of LEV observed plasma concentrations vs. time after last dosing will be presented 
by age category and dose group.  Scatter plots for LEV observed plasma concentrations vs time 
post dose by dose group will be superposed with different symbols in a single graph for each 
dose group.  The dose groups are defined as: 
o low dose group, 7mg/kg in aged subjects less than 6 months and 10mg/kg in aged 
subjects of 6 months and above;  
o middle dose group, 14mg/kg in aged subjects less than 6 months and 20mg/kg in aged 
subjects of 6 months and above;  
o high dose group, 21mg/kg in aged subjects less than 6 months and 30mg/kg in aged 
subjects of 6 months and above 
Scatter plots of LEV dose-normalized plasma concentrations vs. time after last dosing will be 
presented by age category and dose level.  Scatter plots for LEV dose-normalized plasma 
concentrations vs time after last dosing by dose level will be superposed with different symbols 
in a single graph for each age category.  
 
Another scatter plot for LEV dose-normalized plasma concentrations vs time after last dosing 
will be presented by age category and AED category with different symbols in a single graph.  
Scatter plots for LEV dose-normalized plasma concentrations vs time post dose by age category 
will be superposed with a scatter plot for LEV dose-normalized plasma concentrations vs time 
pose dose in N01223 with different symbols in a single graph. Dose-normalization of LEV 
plasma concentrations in N01223 will be performed to 10mg/kg for a subject with a body weight 
less than 50kg and to 500mg for a subject with a body weight more than or equal to 50kg.  
In addition, scatter plots for LEV dose-normalized plasma concentrations vs time pose dose will 
be superposed with simulated LEV plasma concentration-time profiles based on the population 
PK model established in N01288 by age category. The data of LEV plasma concentrations and 
times in N01223 and N01288 are provided from data management group in UCB. 
 
Change 18: 
10.1.1 Definitions and Derivations 
… 
Date of last administration of study medication – Date of first day of period +1. 
If date of last administration of study medication is missing, the last complete administration 
date will be used.  
For start and end dates of periods see Section 2.3.1 and Section 5.1.1.4 . 
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Details on study medication administration are recorded on the “Study Medication 
Administration – IV” and “Study Medication Administration – Dry Syrup” eCRFs. 
Has been changed to: 
Date of last administration of study medication – Date of first day of period +1. 
If date of last administration of study medication is missing, the last complete administration 
date will be used.  
For start and end dates of periods see Section 2.3.1 and Section 5.1.1.4 . 
Details on study medication administration are recorded on the “Study Medication 
Administration – IV” and “Study Medication Administration – Dry Syrup” eCRFs. 
The modal dose is calculated using the daily dose (morning dose + evening dose).  If there are 
tied cases, the later dose will be the modal dose.  
 
Change 19: 
Section 10.2 Adverse Events 
An overview of AEs presents number and percent of subjects with any TEAE, serious TEAEs, 
TEAEs leading to discontinuation, TEAEs requiring dose change, any ADR, severe TEAEs, as 
well as deaths together with the number of individual occurrences in those categories. 
Incidences of TEAEs by SOC and PT are presented together with the number of individual 
occurrences for pre-treatment, TEAEs, ADRs, TEAEs and ADRs leading to temporary and/or 
permanent discontinuation, serious TEAEs and ADRs. 
Additional tables are presented for TEAEs by intensity and for a subset of TEAEs occurring in at 
least 5% of subjects. 
Has been changed to: 
Section 10.2 Adverse Events 
An overview of AEs presents number and percent of subjects with any TEAE, serious TEAEs, 
TEAEs leading to discontinuation, TEAEs requiring dose change, any drug-related TEAEs, 
severe TEAEs, as well as deaths together with the number of individual occurrences in those 
categories. 
Incidences of TEAEs by SOC and PT are presented together with the number of individual 
occurrences for , TEAEs, , serious TEAEs and serious drug-related TEAEs, and TEAEs leading 
to discontinuation of study drug.  
Additional tables are presented for TEAEs by intensity and for a subset of TEAEs occurring in at 
least 5% of subjects. 
 
Change 19: 
10.2.1.5 
Adverse Drug Reactions 
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Adverse drug reactions (ADRs), a subset of TEAEs, are identified using information documented 
on the AE CRF. “Relationship to Study Medication” is documented as “related” or missing. 
Has been changed to: 
This section is removed from the SAP Amendment 2.  
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
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Approval Signatures
Name:
EP0100-SAP Amendment 3
Version:
1. 0
Document Number:
CLIN-000188865
Title:
EP0100-SAP Amendment 3
Approved Date:
05 May 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-May-2022 02:06:04 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-May-2022 13:23:21 GMT+0000
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