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: PHASE3
Conditions: Partial Seizures
Sponsor: UCB Japan Co. Ltd.

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
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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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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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Clinical Study Protocol 
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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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Clinical Study Protocol 
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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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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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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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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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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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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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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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Clinical Study Protocol 
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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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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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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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• 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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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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22 Feb 2023 
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 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
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. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
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 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
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 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
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. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
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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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
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 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
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. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
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 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
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 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
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: 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 155 of 157 
For results disclosure on public registries (eg, ClinicalTrials.gov), TEAEs and 
treatment-emergent SAEs will be published. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 156 of 157 
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 
 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

UCB 
 
22 Feb 2023 
Clinical Study Protocol 
Levetiracetam 
EP0100 
 
 
 
Confidential 
Page 157 of 157 
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. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof. 

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
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.