An Open-Label, Multicenter, Follow-up Study to Evaluate the Long-Term Safety and Efficacy of Brivaracetam Used as Adjunctive Treatment in Subjects >=16 Years of Age With Partial Seizures With or Without Secondary Generalization
Phase: PHASE3
Conditions: Partial Seizures With or Without Secondary Generalization, Epilepsy
Sponsor: UCB Biopharma SRL

UCB 
15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
EP0085 
Confidential  
Page 1 of 115 
PROTOCOL EP0085 AMENDMENT 4.0 
AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND EFFICACY OF 
BRIVARACETAM USED AS ADJUNCTIVE TREATMENT IN 
SUBJECTS ≥16 YEARS OF AGE WITH PARTIAL SEIZURES 
WITH OR WITHOUT SECONDARY GENERALIZATION 
PHASE 3 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
22 Nov 2016 
Not applicable 
Protocol Amendment 1 
26 Jul 2017 
Non-substantial 
Protocol Amendment 2 
28 Jan 2019 
Substantial 
Protocol Amendment 3 
20 Nov 2019 
Substantial 
Protocol Amendment 3.1 (Japan) 
09 Feb 2021 
Substantial 
Protocol Amendment 4 
15 Mar 2023 
Substantial 
Confidential Material 
Confidential 
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reproduced, published, or otherwise used without the express permission of UCB. 
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Clinical Study Protocol 
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EP0085 
 
 
 
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STUDY CONTACT INFORMATION 
Sponsor/Local Legal Representatives 
UCB BIOPHARMA SRL 
UCB Japan Co. Ltd. 
UCB Trading (Shanghai) Co., 
Ltd. 
Allée de la Recherche 60 
Shinjuku Grand Tower  
317 Room No.
 
8-17-1 Nishi-Shinjuku 
Futexi Yi road, China 
(Shanghai) 
Shinjuku-ku 
Pilot Free Trade Zone 
1070 Brussels 
Tokyo 160-0023 
Shanghai 200131 
BELGIUM 
JAPAN 
PRC 
Medical Expert in Japan 
Name: 
 
Affiliation: 
National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological 
Disorders 
Address: 
886 Urushiyama, Aoi-Ku, Shizuoka-Shi, Shizuoka 420-8688, JAPAN 
Phone: 
Fax: 
Sponsor Study Physician 
Name: 
 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Phone: 
 
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Clinical Study Protocol 
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EP0085 
 
 
 
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Clinical Project Managers 
Name: 
 
Address: 
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku, 
Tokyo, 160-0023, JAPAN 
Phone: 
Fax: 
Name: 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Phone: 
Fax: 
Clinical Trial Biostatistician 
Name: 
 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200040 PRC 
Phone: 
Fax: 
Clinical Monitoring Contract Research Organization (Ireland) 
Name: 
PAREXEL International (IRL) Limited 
Address: 
70 Sir John Rogerson’s Quay, Dublin 2,  
Ireland 
Phone: 
Fax: 
Other study contact information will be provided in separate documents. 
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Clinical Study Protocol 
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EP0085 
 
 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24 hours) for Japan 
Fax 
UCB Japan: +81 3 6864 7400 
Email 
UCB Japan: JDSO@ucb.com 
Serious adverse event reporting (24 hours) for China 
Fax 
UCB China: +86-21-23210206 
Email 
UCB China: ds.China@ucb.com 
 
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Clinical Study Protocol 
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EP0085 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 9 
1 
SUMMARY ..................................................................................................................... 11 
2 
INTRODUCTION ........................................................................................................... 12 
2.1 Background and epidemiology of targeted disease.......................................................... 12 
2.2 Background information regarding product ..................................................................... 13 
2.3 Efficacy with BRV in long-term follow-up studies in subjects with partial seizure ....... 14 
2.4 Safety with BRV .............................................................................................................. 14 
2.5 Rationale for the study ..................................................................................................... 14 
3 
STUDY OBJECTIVES .................................................................................................... 15 
3.1 Primary objective ............................................................................................................. 15 
3.2 Secondary objective ......................................................................................................... 15 
4 
STUDY VARIABLES ..................................................................................................... 15 
4.1 Safety variables ................................................................................................................ 15 
4.1.1 
Primary safety variables ...................................................................................... 15 
4.1.2 
Other safety variables .......................................................................................... 15 
4.1.3 
Efficacy variables ................................................................................................ 15 
5 
STUDY DESIGN ............................................................................................................. 16 
5.1 Study description ............................................................................................................. 16 
5.1.1 
Study duration per subject ................................................................................... 17 
5.1.2 
Planned number of subjects and sites .................................................................. 18 
5.1.3 
Anticipated regions and countries ....................................................................... 18 
5.2 Schedule of study assessments ......................................................................................... 18 
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 Eligibility criteria in Japan ............................................................................................... 27 
6.1.1 
Inclusion criteria for all subjects .......................................................................... 27 
6.1.2 
Additional inclusion criteria for rollover subjects ............................................... 28 
6.1.3 
Additional inclusion criteria for directly enrolled subjects ................................. 28 
6.1.4 
Exclusion criteria for all subjects ........................................................................ 28 
6.1.5 
Additional exclusion criteria for rollover subjects .............................................. 29 
6.1.6 
Additional exclusion criteria for directly enrolled subjects ................................. 29 
6.2 Eligibility criteria in China .............................................................................................. 30 
6.2.1 
Inclusion criteria .................................................................................................. 30 
6.2.2 
Exclusion criteria ................................................................................................. 31 
6.3 Withdrawal criteria .......................................................................................................... 31 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 32 
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7 
STUDY TREATMENTS ................................................................................................. 33 
7.1 Description of investigational medicinal products .......................................................... 33 
7.2 Treatments to be administered ......................................................................................... 33 
7.3 Packaging ......................................................................................................................... 34 
7.4 Labeling ........................................................................................................................... 34 
7.5 Handling and storage requirements.................................................................................. 34 
7.6 Drug accountability .......................................................................................................... 34 
7.7 Procedures for monitoring subject compliance ................................................................ 34 
7.8 Concomitant medications/treatments ............................................................................... 35 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 35 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 35 
7.8.3 
Rescue medication ............................................................................................... 36 
7.9 Blinding ............................................................................................................................ 36 
7.10 Randomization and numbering of subjects ...................................................................... 36 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 36 
8.1 Screening Visit (for direct enrollers in Japan only) ......................................................... 36 
8.2 Entry Visit (for direct enrollers in Japan only) ................................................................ 37 
8.3 Entry Visit (rollovers from China and Japan) .................................................................. 38 
8.4 Minimal Evaluation Visits (all subjects) .......................................................................... 39 
8.5 Full Evaluation Visits (all subjects) ................................................................................. 40 
8.6 Yearly Evaluation Visit (all subjects) .............................................................................. 40 
8.7 End of Study Visit or Early Discontinuation Visit (all subjects) ..................................... 41 
8.8 Final Visit (all subjects) ................................................................................................... 42 
8.9 Unscheduled Visit (all subjects) ...................................................................................... 43 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 43 
9.1 Additional efficacy measures ........................................................................................... 43 
9.1.1 
Medical procedures .............................................................................................. 43 
10 ASSESSMENT OF SAFETY .......................................................................................... 44 
10.1 Adverse events ................................................................................................................. 44 
10.1.1 
Definitions ........................................................................................................... 44 
10.1.1.1 
Adverse event ............................................................................................ 44 
10.1.1.2 
Serious adverse event ................................................................................ 44 
10.1.1.3 
Adverse events of special interest ............................................................. 45 
10.1.2 
Procedures for reporting and recording AEs ....................................................... 45 
10.1.2.1 
Description of AEs .................................................................................... 46 
10.1.2.2 
Rule for repetition of an AE ...................................................................... 46 
10.1.2.3 
Additional procedures for reporting SAEs ................................................ 46 
10.1.3 
Follow up of AEs ................................................................................................. 47 
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10.1.4 
Pregnancy ............................................................................................................ 47 
10.1.5 
Suspected transmission of an infectious agent via a medicinal product .............. 48 
10.1.6 
Overdose of investigational medicinal product ................................................... 48 
10.1.7 
Safety signal detection ......................................................................................... 48 
10.2 Laboratory measurements ................................................................................................ 49 
10.2.1 
Evaluation of PDILI ............................................................................................ 51 
10.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 55 
10.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 55 
10.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 55 
10.2.1.4 
Follow-up evaluation ................................................................................. 57 
10.3 Other safety measurements .............................................................................................. 57 
10.3.1 
ECG ..................................................................................................................... 57 
10.3.2 
Vital signs ............................................................................................................ 58 
10.3.3 
Physical examination ........................................................................................... 58 
10.3.4 
Neurological examination .................................................................................... 58 
10.3.5 
Body weight and height ....................................................................................... 58 
10.3.6 
Assessment of suicidality .................................................................................... 58 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 59 
11.1 Adherence to protocol ...................................................................................................... 59 
11.2 Monitoring ....................................................................................................................... 59 
11.2.1 
Definition of source data ..................................................................................... 59 
11.2.2 
Source data verification ....................................................................................... 60 
11.3 Data handling ................................................................................................................... 60 
11.3.1 
Case Report form completion .............................................................................. 60 
11.3.2 
Database entry and reconciliation ........................................................................ 60 
11.3.3 
Subject Enrollment log/Subject Identification Code list ..................................... 60 
11.4 Termination of the study .................................................................................................. 61 
11.5 Archiving and data retention ............................................................................................ 61 
11.6 Audit and inspection ........................................................................................................ 61 
11.7 Good Clinical Practice ..................................................................................................... 61 
12 STATISTICS ................................................................................................................... 61 
12.1 Definition of analysis sets ................................................................................................ 62 
12.2 General statistical considerations ..................................................................................... 62 
12.3 Planned efficacy analyses ................................................................................................ 62 
12.4 Planned safety analyses .................................................................................................... 63 
12.5 Handling of protocol deviations ....................................................................................... 63 
12.6 Handling of dropouts or missing data .............................................................................. 63 
12.7 Planned interim analysis and data monitoring ................................................................. 63 
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12.8 Determination of sample size ........................................................................................... 63 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 64 
13.1 Informed consent ............................................................................................................. 64 
13.2 Subject identification cards .............................................................................................. 64 
13.3 Institutional Review Boards and Independent Ethics Committees .................................. 64 
13.4 Subject privacy ................................................................................................................. 65 
13.5 Protocol amendments ....................................................................................................... 65 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 65 
15 REFERENCES ................................................................................................................ 66 
16 APPENDICES ................................................................................................................. 67 
16.1 Appendix 1 - International Classification of Epileptic Seizures ...................................... 67 
16.2 Appendix 2 - International Classification of Epilepsies and Epileptic Syndromes ......... 70 
16.3 Appendix 3 - List of antiepileptic drugs .......................................................................... 72 
16.4 Appendix 4 - Protocol Amendment 1 .............................................................................. 74 
16.5 Appendix 5 - Protocol Amendment 2 .............................................................................. 79 
16.6 Appendix 6 - Protocol Amendment 3 .............................................................................. 84 
16.7 Appendix 7 – Protocol Amendment 3.1 (Japan) .............................................................. 90 
16.8 Appendix 8 – Protocol Amendment 4 ........................................................................... 107 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 114 
18 SPONSOR DECLARATION ........................................................................................ 115 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of study assessments for subjects transitioning from EP0083 
and N01379 ...................................................................................................... 19 
Table 5-2: 
Schedule of study assessments for subjects directly enrolled into EP0085 
in Japan ............................................................................................................ 22 
Table 5‒3: 
Full visit schedule ............................................................................................ 26 
Table 10‒1: 
Laboratory measurements ................................................................................ 50 
Table 10‒2: 
Required investigations and follow up for PDILI............................................ 52 
Table 10‒3: 
PDILI laboratory measurements ...................................................................... 56 
Table 10‒4: 
PDILI information to be collected ................................................................... 57 
 
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Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BRV 
brivaracetam 
CDMS 
clinical data management system 
CLcr 
creatinine clearance 
CPM 
Clinical Project Manager 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DEM 
data evaluation meeting 
DRC 
daily record card 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EDC 
electronic data capture 
EDV 
Early Discontinuation Visit 
EEG 
electroencephalogram 
EV 
Entry Visit 
FEV 
Full Evaluation Visits 
FV 
Final Visit 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IVRS/IWRS 
interactive voice response system/interactive web response system 
LEV 
levetiracetam 
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LTFU 
long-term follow-up 
MEV 
Minimal Evaluation Visits 
MedDRA 
Medical Dictionary for Regulatory Activities 
PBO 
placebo 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic 
PS 
Patient Safety 
SAE 
serious adverse event 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SV 
Screening Visit 
SV2A 
synaptic vesicle protein 2A 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UV 
Unscheduled Visit 
VNS 
vagal nerve stimulation 
YEV 
Yearly Evaluation Visit 
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EP0085 
 
 
 
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1 
SUMMARY 
EP0085 is an open-label, multicenter, follow-up study to evaluate the long-term safety and 
efficacy of brivaracetam (BRV) used as adjunctive treatment in subjects ≥16 years with partial 
seizures with or without secondary generalization. The primary objective is to evaluate the 
long-term safety and tolerability of BRV in focal epilepsy subjects with partial seizures. The 
secondary objective is to evaluate the maintenance of efficacy of BRV over time. 
The subject population will be subjects with partial seizures with or without secondary 
generalization. Subjects of a minor age are included only where legally permitted and ethically 
accepted.  
Rollover subjects from EP0083 must complete the Treatment and Transition Period of EP0083 
prior to enrollment into EP0085. Japanese subjects participating in N01379, the long-term 
open-label extension to the Phase 3, placebo-controlled study N01358, can enter into this study.  
In addition, for accumulating safety data, subjects in Japan that have well-characterized focal 
epilepsy with seizures that are uncontrolled in spite of treatment with at least 1 permitted 
anti-epileptic drug (AED), having experienced 1 to <8 partial seizures within the 8 weeks prior to 
BRV administration may be directly enrolled. 
Directly enrolled subjects and subjects from EP0083 will be started on oral BRV at a dose of 
100mg/day (2 equally divided doses administered twice daily) at study entry and should be 
maintained at this dose for at least 2 weeks, unless the subject is unable to tolerate treatment. 
Subjects from N01379 can enter EP0085 at a dose up to 200mg/day. 
The BRV dose can be adjusted based on the individual subject’s seizure control and tolerability 
between 50mg/day and 200mg/day during the study and must always be administered in equal 
morning and evening doses except the last week of down-titration. Of note, decreasing the dose 
should not exceed 50mg/day. Study medication in the last week of down-titration is given only in 
the morning. 
Upon completion or early discontinuation from EP0085, there will be a Down-Titration Period, 
followed by a 2-week Study Drug-Free Period during which the subject will not receive study 
drug. 
The primary safety variable is treatment-emergent adverse events (TEAEs). Other safety 
variables include safety laboratory tests (blood chemistry, hematology, and urinalysis), vital 
signs, body weight, electrocardiograms (ECGs), physical and neurological examinations. 
Efficacy variables for rollover subjects include: 
• Percent reduction in partial seizure frequency per 28 days from Baseline of EP0083 or 
N01358 to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from Baseline 
Period of EP0083 or N01358 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized, and unclassified epileptic seizure) for at least 6 months and at least 
12 months during the Evaluation Period 
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• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
Efficacy variables for directly enrolled subjects in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 weeks 
prior to BRV administration 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized, and unclassified epileptic seizure) for at least 6 months and at least 
12 months during the Evaluation Period 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
Overall, approximately 217 subjects are planned for enrollment. In Japan, it is estimated that 
approximately 127 subjects will enter the study, based on the assumption that at least 90% of 
randomized Japanese subjects will complete EP0083 (approximately 90 subjects) or enroll from 
N01379 sites in Japan (7 subjects) and the plan that 30 Japanese subjects will be directly enrolled 
in this study. Likewise, at least 90% of randomized Chinese subjects will be assumed to 
complete EP0083 (approximately 90 subjects). 
2 
INTRODUCTION 
2.1 
Background and epidemiology of targeted disease 
Epilepsy is one of the most common and challenging neurological disorders. It has been 
estimated that over 50 million people are affected worldwide (Engel and Pedley, 1998; Sander 
and Shorvon, 1996; Hauser et al, 1993; Loiseau et al, 1990). The prevalence of epilepsy is 
around 1%. The annual incidence in developed countries is approximately 50 to 70 cases per 
100,000. In developing countries, the figure is higher due to more limited obstetric services and 
the greater likelihood of cerebral infection and trauma. 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. Sudden unexpected death, a complication of great concern, 
occurs in 1 to 5 per 1000 patient years, particularly if the seizure disorder remains uncontrolled. 
The treatment for epilepsy remains difficult, and there is an ongoing medical need for new 
AEDs. For a considerable proportion of patients (up to 30%), seizure freedom can still not be 
reached with currently available AEDs (Nasreddine et al, 2010; Kwan and Brodie, 2001). 
Diagnosis of epilepsy is based on the recurrence of seizures. Seizures may be caused by an 
underlying brain disorder or lesion or due to genetic conditions. Characterization of the epileptic 
syndrome has profound implications for treatment and prognosis. The major dichotomy for the 
diagnosis of epilepsy being the differentiation between focal epilepsies (ie, related to a focal 
brain dysfunction) which are the most frequent and account for approximately 60 to 70% of all 
cases, and generalized epilepsy syndromes which represent approximately 25 to 30% of all 
epilepsy syndromes. In about 10% of cases, other specific syndromes are classified or the 
classification remains uncertain. 
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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 on the other 
hand 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 16.1]). 
Likewise, the classification of epilepsy syndromes will be used according to the 1989 
ILAE-publication (ILAE, 1989, Appendix 2 [Section 16.2]). 
2.2 
Background information regarding product 
Brivaracetam is a chemical relative of the AED levetiracetam (LEV [Keppra®/E-Keppra®]). 
Like LEV, BRV displays a high and selective interaction with a novel brain-specific binding site 
synaptic vesicle protein 2A (SV2A). However, the binding affinity of BRV for SV2A is 
approximately 10 fold higher. This binding site appears to be the major target for its 
pharmacological activity. Unlike LEV, BRV also reduces voltage-dependent sodium currents. 
Brivaracetam also reverses the inhibitory effects of negative allosteric modulators on gamma-
aminobutyric acid- and glycine induced currents. Brivaracetam is extensively metabolized, but 
seizure protection appears to be associated with the parent compound. 
Brivaracetam is rapidly and completely absorbed throughout the gastrointestinal tract. The extent 
of BRV absorption is not affected by food. The pharmacokinetics (PK) is dose-proportional (at 
least from 10mg to 600mg). Brivaracetam is weakly bound to plasma proteins (≤20%). The 
volume of distribution is 0.5L/kg, a value that is close to that of total body water. The plasma 
half-life of BRV is approximately 8 hours in young healthy male adults. The main metabolic 
pathway of BRV is by hydrolysis of the acetamide group to the corresponding carboxylic acid, 
while a second pathway is the ω1-hydroxylation mediated by cytochrome P450 (CYP)2C19 
(with contributions of several other isoenzymes). The combination of these 2 pathways results in 
the hydroxyacid terminal metabolite. These metabolites are not pharmacologically active. There 
is no evidence of chiral inversion of BRV. Brivaracetam is eliminated primarily by metabolism 
and by excretion in the urine. More than 95% of the dose, with less than 9% as unchanged BRV, 
is excreted in urine within 72 hours after dosing. 
Pharmacokinetic studies in elderly and in subjects with renal impairment showed a similar PK 
profile of BRV compared to that in healthy subjects while the elimination of the metabolites was 
markedly slowed down. A PK study in subjects with hepatic impairment showed a 50% increase 
in exposure to BRV associated with decreased hydroxylation. 
Brivaracetam does not impair the efficacy of oral contraceptives containing 30µg ethinylestradiol 
and 150µg levonorgestrel. Brivaracetam does not induce CYP3A4 using midazolam as a marker 
probe. Brivaracetam has no interaction on lamotrigine and topiramate. Brivaracetam plasma 
concentration is not increased by gemfibrozil, a selective CYP2C8/9 inhibitor but is increased in 
a nonclinically relevant manner in Japanese subjects possessing defective CYP2C19 mutations. 
Brivaracetam clearance is doubled by rifampicin, a potent CYP inducer. 
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Trough levels of concomitant AEDs were monitored in all efficacy trials. No significant change 
from Baseline nor dose-related trend was observed for the plasma concentrations of 
carbamazepine, lamotrigine, LEV, oxcarbazepine metabolite, phenobarbital, phenytoin, 
topiramate, valproate, zonisamide. Carbamazepine epoxide was significantly increased from 
Baseline at all BRV doses greater than 20mg/day, nearly reaching the upper limit of normal 
(3.0μg/mL) at BRV doses of 100 and 150mg/day. 
2.3 
Efficacy with BRV in long-term follow-up studies in subjects 
with partial seizure 
Subjects who completed 1 of the primary efficacy studies (N01358, N01252, or N01253) or 1 of 
the supporting efficacy studies (N01114, N01193, or N01254) had the option to participate in 
open-label extension studies (N01125, N01199, and N01379) to further evaluate the safety and 
efficacy of BRV. In the long-term follow-up (LTFU) studies, in which physicians could increase 
or decrease BRV doses as needed, modal doses of 100mg/day, 150mg/day, and 200mg/day were 
reported for 22.4%, 46.5%, and 14.7% of subjects with ≥12 months exposure, respectively. 
Similar findings were reported for subjects with ≥24 months exposure. 
The long-term follow-up studies indicate a consistently high percentage of subjects continued to 
receive BRV and clinically relevant efficacy was maintained over time across all regions. 
2.4 
Safety with BRV 
In the BRV clinical development program, 3970 subjects were exposed to BRV (unique 
exposures) as of 14 Jan 2019. 
In Phase 2/3 studies, a favorable safety and tolerability profile has been demonstrated for BRV. 
The discontinuation rate and the discontinuation rate due to TEAEs were low and similar to PBO 
for all studies. The most common adverse drug reactions in subjects with partial seizures were 
somnolence, sedation, dizziness, fatigue, and nausea/vomiting. The overall incidence of serious 
adverse events (SAEs) was low and similar to placebo (PBO). There were no clinically relevant 
changes in laboratory values, vital signs or ECG abnormalities. 
In addition, the safety of BRV as long-term adjunctive treatment is being evaluated in 5 ongoing 
LTFU studies in adults (N01125, N01199, N01315, N01379, and N01372). The safety profile in 
the open-label extension studies (up to 8 years) was consistent to that observed in the short-term, 
placebo-controlled studies. 
For additional details on safety and efficacy of BRV, please refer to the Investigator’s Brochure 
(IB). 
2.5 
Rationale for the study 
EP0085 will explore the long-term safety and efficacy of BRV in subjects in Japan and China. 
EP0085 will include subjects who have completed EP0083, Japanese subjects from N01379, and 
directly enrolled Japanese subjects.  
The proposed study is intended to provide evidence of the long-term safety and efficacy of BRV 
as adjunctive therapy in subjects with partial seizures. In alignment with the doses previously 
assessed in the feeder studies, doses of BRV 50 to 200mg/day will be assessed in EP0085. 
EP0083 is an adequate and well-controlled study to provide additional data confirming the 
efficacy and safety of BRV as an AED in subjects (≥16 to 80 years of age) with partial seizures 
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with or without secondary generalization. N01379 is an open-label, multicenter, long-term 
follow up study for N01358 which is the pivotal global efficacy study for BRV used as 
adjunctive treatment in adult subjects (≥16 to 80 years of age) with partial seizures with or 
without secondary generalization. For sites in Japan, subjects with uncontrolled seizures treated 
by at least 1 permitted concomitant AED may be directly enrolled in order to provide additional 
safety and efficacy data with BRV. 
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
The primary objective is to evaluate the long-term safety and tolerability of BRV in focal 
epilepsy subjects with partial seizures. 
3.2 
Secondary objective 
The secondary objective is to evaluate the maintenance of efficacy of BRV over time. 
4 
STUDY VARIABLES 
4.1 
Safety variables 
4.1.1 
Primary safety variables 
The primary safety variable is TEAEs. 
4.1.2 
Other safety variables 
The other safety variables are as follows: 
• Laboratory tests (blood chemistry, hematology, and urinalysis) 
• Vital signs 
• Body weight  
• ECG 
• Physical examination  
• Neurological examination 
4.1.3 
Efficacy variables 
The efficacy variables for rollover subjects include: 
• Percent reduction in partial seizure frequency per 28 days from Baseline of EP0083 or 
N01358 to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from Baseline 
Period of EP0083 or N01358 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized, and unclassified epileptic seizure) for at least 6 months and at least 12 
months during the Evaluation Period 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
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Efficacy variables for directly enrolled subjects in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 weeks 
prior to BRV administration 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized, and unclassified epileptic seizure) for at least 6 months and at least 12 
months during the Evaluation Period 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
5 
STUDY DESIGN 
5.1 
Study description 
EP0085 is a Phase 3, open-label, LTFU, multicenter, noncomparative, and dose flexible study to 
be conducted in Japan and China. The population will be subjects (≥16 years of age) with partial 
seizures with or without secondary generalization. Subjects of a minor age are included only 
where legally permitted and ethically accepted. In Japan, subjects meeting the inclusion and 
exclusion criteria as specified in Section 6.1 may be directly enrolled. Rollover subjects must 
complete the Treatment and Transition Period of EP0083 prior to enrollment into EP0085.  
In addition, Japanese subjects participating in N01379, the long-term open-label extension to the 
Phase 3, placebo-controlled study N01358, may enter this study. Upon completion or early 
discontinuation from EP0085, there will be a Down-Titration Period, followed by a 2-week 
Study Drug-Free Period during which the subject will not receive study drug. 
Directly enrolled subjects in Japan and rollover subjects from EP0083 will be started on oral 
BRV at a dose of 100mg/day (2 equally divided doses administered twice daily) at study entry 
and should be maintained at this dose for at least 2 weeks, unless the subject is unable to tolerate 
treatment.  
Japanese subjects from N01379 can enter EP0085 at a dose up to 200mg/day. After Visit 1, the 
next visit for subjects entering from N01379 will be Visit 4 (Visit 2 and Visit 3 will not be 
conducted). Subsequent visits will be conducted according to the visit schedule provided in 
Table 5‒3. The BRV dose can be adjusted based on the individual subject’s seizure control and 
tolerability between 50mg/day and 200mg/day during the study and must always be administered 
as a symmetrical morning and evening dose except the last week of down-titration. Of note, 
decreasing the dose should not exceed 50mg/day. Study medication in the last week of down-
titration is given only in the morning. 
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5.1.1 
Study duration per subject 
The following study periods are defined: 
• Screening Visit (Visit 0, up to 3 weeks before the Entry Visit (EV) for direct enrollers in 
Japan only) 
• Evaluation Period (Visit 1 to End of Study Visit or Early Discontinuation Visit [EDV]): 
Subjects who enroll in EP0083 and N01379 will enter the Evaluation Period. 
• Down-Titration Period (up to 4 weeks) 
− If the subject is discontinuing study drug, the Investigator will first plan an EDV 
followed by the progressive down-titration of study drug. 
− During the Down-Titration Period, the BRV dose may be decreased in steps of a 
maximum of 50mg/day on a weekly basis. A last down-titration step at 25mg/day for 1 
week should be included prior to the 2-week Study Drug-Free Period. 
• 2-week Study Drug-Free Period: After completion of the Down-Titration Period, or for those 
subjects who for extenuating circumstances do not complete a Down-Titration Period, the 
subject will be required to enter a 2-week Study Drug-Free Period, followed by a Final Visit 
(FV). 
Visits should occur on the specified Visit/Week. A ±7 day window for each specified Visit/Week 
is allowed, provided the subject has adequate investigational medicinal product (IMP) to sustain 
the visit window. The end of the study is defined as the date of the last visit of the last subject in 
the study. 
EP0085 will continue until the market approval of BRV, or until the sponsor decides to close the 
study, whichever comes first. In the event that market approval is not requested or obtained in 
the participant country, the subject will be able to continue in EP0085 for two years after 
entering EP0085. 
In Japan, EP0085 will continue as a postmarketing clinical study until approximately 6 months 
after the date of BRV approval for the partial seizure indication. 
At selected sites in Japan, Japanese subjects may participate in an additional study (EP0118) 
with the intravenous formulation of BRV without withdrawing from EP0085. Ten evaluable 
subjects are planned for EP0118, and the total duration in the study for each subject is 7 days. 
The study period of EP0118 will be included in that of EP0085. Subjects will continue to receive 
their current dose of BRV at the time of entry and it will remain stable for the duration of 
EP0118. Subjects who complete or withdraw from EP0118 will resume their participation in 
EP0085 with oral BRV treatment. In the event that a subject withdraws from EP0118 and is 
required to down-titrate BRV treatment, the subject will return to EP0085 and down-titrate using 
BRV tablets. Treatment-emergent AEs and concomitant treatment(s)/medication(s) that occur or 
are administered during EP0118 will be recorded in EP0118. Ongoing TEAEs and concomitant 
medication(s)/medical procedure(s) originating from EP0118 will be recorded and followed in 
EP0085 until resolution or until the status of the TEAE and/or concomitant medications are 
stable. All other data reported for EP0118 will be captured in the EP0118 database. Per the 
EP0118 protocol, the study (EP0118) will require hospitalization. Hospitalization for study 
participation does not need to be reported as an SAE. 
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5.1.2 
Planned number of subjects and sites 
Overall, approximately 217 subjects are planned for enrollment. In Japan, it is estimated that 
approximately 127 subjects will enter the study. This estimate assumes that at least 90% of 
randomized Japanese subjects will complete EP0083 (approximately 90 subjects) or enroll from 
N01379 sites in Japan (7 subjects) and the plan that 30 Japanese subjects will be directly enrolled 
in this study.  
In China Mainland, it is estimated that approximately 90 subjects will enter the study, based on 
the assumption that at least 90% of randomized Chinese subjects will complete EP0083. 
It is estimated that approximately 50 Japan sites and 25 China Mainland sites will participate in 
the study. 
5.1.3 
Anticipated regions and countries 
The study is planned to be conducted in Japan and China Mainland. 
5.2 
Schedule of study assessments 
The schedule of study assessments for subjects transitioning from EP0083 and N01379 is 
provided in Table 5‒1. The schedule of study assessments for subjects directly enrolled into 
EP0085 in Japan is provided in Table 5-2.  
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Table 5‒1: 
Schedule of study assessments for subjects transitioning from EP0083 and N01379 
Assessments 
EV 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V1 
V2a, V4, V6, V8, 
V10… 
V3a, V5, V9… 
V7, V11… 
NA 
NA 
Month  
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
Written informed consent 
Xb 
 
 
 
 
 
Subject identification card 
dispensed 
X 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Medical/procedures history 
Xc 
 
 
 
 
 
Epilepsy history 
Xc 
 
 
 
 
 
AED history 
Xc 
 
 
 
 
 
Vital signs 
X* 
X 
X 
X 
X 
X 
Body weight and heightd 
X*d  
X 
X 
X 
X 
X 
Physical examination 
X* 
 
X 
X 
X 
X 
Neurological examination 
X* 
 
X 
X 
X 
X 
12-lead ECGe 
X* 
 
X 
X 
X 
X 
IVRS/IWRS  
X 
X 
X 
X 
X 
X 
Subject's DRC dispensed 
X 
X 
X 
X 
X 
 
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Table 5‒1: 
Schedule of study assessments for subjects transitioning from EP0083 and N01379 
Assessments 
EV 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V1 
V2a, V4, V6, V8, 
V10… 
V3a, V5, V9… 
V7, V11… 
NA 
NA 
Month  
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
Subject's DRC retrieval 
 
X 
X 
X 
X 
X 
Seizure countsf 
X* 
X 
X 
X 
X 
X 
Laboratory safety assessmentsg 
X* 
Xe 
X 
X 
X 
Xg 
Pregnancy testh 
X* 
X 
X 
X 
X 
X 
AE reporting 
X* 
X 
X 
X 
X 
X 
C-SSRS 
X* 
X 
X 
X 
X 
X 
Medical procedures 
X* 
X 
X 
X 
X 
X 
Concomitant AEDs 
X* 
X 
X 
X 
X 
X 
Concomitant non-AEDs 
X* 
X 
X 
X 
X 
X 
Study drug dispensing 
X 
X 
X 
X 
X 
 
Study drug return/accountability 
 
X 
X 
X 
X 
X 
End of study statusi 
 
 
 
 
X 
X 
AE=adverse event; AED=antiepileptic drug; BRV=brivaracetam; C-SSRS=Columbia-Suicide Severity Rating Scale; DRC=daily record card; 
ECG=electrocardiogram; eCRF=electronic case report form; EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final 
Visit; IVRS=interactive voice response system; IWRS= interactive web response system; M=Month; MEV=Minimal Evaluation Visit; NA=not applicable; 
V=Visit; W=week; YEV= Yearly Evaluation Visit 
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Table 5‒1: 
Schedule of study assessments for subjects transitioning from EP0083 and N01379 
Assessments 
EV 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V1 
V2a, V4, V6, V8, 
V10… 
V3a, V5, V9… 
V7, V11… 
NA 
NA 
Month  
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
Note: For subjects who have completed EP0083 or N01379, assessments marked (*) should have already been completed during the last visit of the previous 
protocol and do not need to be repeated at Visit 1. 
a After Visit 1, for subjects entering from N01379 V2 and V3 will not be conducted. Subsequent visits will be conducted according to the visit schedule 
provided in Table 5‒3. 
b Informed consent must be obtained during the previous study. 
c General medical and procedures history, AED history, and epilepsy history will be obtained from the Baseline of EP0083 or Baseline of N01358 (for 
subjects entering from N01379) and do not need to be recorded on the eCRF for this study. 
d Height will be recorded at V1 only. 
e At the FV, a 12-lead ECG is mandatory, except if the FV follows an EDV where ECG results were normal. 
f Seizure counts are collected on the subject's daily record card on a daily basis. 
g Laboratory safety assessment will not be performed at MEV. Only liver function tests will be performed at the MEV in Visit 4 (M3) and Visit 6 (M9).  
Laboratory safety assessment is mandatory at the FV, except if the FV follows an EDV where laboratory results were normal. The result of the calculated 
creatinine clearance will be provided by the central laboratory.  
h A urine pregnancy test will be done for female subjects with childbearing potential. 
i End of study status will be completed at the FV for subjects having performed an EDV and down-titration of BRV (discontinued subjects) and for subjects 
leaving the study at the end of the program (completed subjects). Alternatively, end of study status will be completed at the End of Study Visit for subjects 
who will be converted without down-titration to commercial BRV if, when, and where available. 
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Table 5-2: 
Schedule of study assessments for subjects directly enrolled into EP0085 in Japan 
Assessments 
SV 
 
EV 
 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V0 
V1 
V2, V4, V6, V8, 
V10… 
V3, V5, V9… 
V7, V11… 
NA 
NA 
Month  
- 
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
(-2 to -21 
days) 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
Written informed consent 
X 
 
 
 
 
 
 
Subject identification card 
dispensed 
X 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical/procedures history 
X 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
Birth control 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Body weight and heighta 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
X 
X 
X 
X 
Neurological examination 
X 
 
 
X 
X 
X 
X 
12-lead ECGb 
X 
 
 
X 
X 
X 
X 
EEGc 
X 
 
 
 
 
 
 
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Table 5-2: 
Schedule of study assessments for subjects directly enrolled into EP0085 in Japan 
Assessments 
SV 
 
EV 
 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V0 
V1 
V2, V4, V6, V8, 
V10… 
V3, V5, V9… 
V7, V11… 
NA 
NA 
Month  
- 
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
(-2 to -21 
days) 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
Neuro-imaging procedured 
X 
 
 
 
 
 
 
IVRS/IWRS  
X 
X 
X 
X 
X 
X 
X 
Subject's DRC dispensed 
 
X 
X 
X 
X 
X 
 
Subject's DRC retrieval 
 
 
X 
X 
X 
X 
X 
Seizure countse 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety assessmentsf 
X 
X 
X 
X 
X 
X 
Xf 
Pregnancy testg 
X 
X 
X 
X 
X 
X 
X 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
Medical procedures 
X 
X 
X 
X 
X 
X 
X 
Concomitant AEDsh  
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AEDs 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X 
X 
X 
X 
X 
 
Study drug 
return/accountability 
 
 
X 
X 
X 
X 
X 
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Table 5-2: 
Schedule of study assessments for subjects directly enrolled into EP0085 in Japan 
Assessments 
SV 
 
EV 
 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V0 
V1 
V2, V4, V6, V8, 
V10… 
V3, V5, V9… 
V7, V11… 
NA 
NA 
Month  
- 
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
(-2 to -21 
days) 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
End of study statusi 
 
 
 
 
 
X 
X 
AE=adverse event; AED=antiepileptic drug; BRV=brivaracetam; C-SSRS=Columbia-Suicide Severity Rating Scale; DE=Direct Enrollment; DRC=daily record 
card; ECG=electrocardiogram; eCRF=electronic case report form; EDV=Early Discontinuation Visit; EEG=electroencephalogram; EV=Entry Visit; FEV=Full 
Evaluation Visit; FV=Final Visit; IVRS=interactive voice response system; IWRS= interactive web response system; M=Month; MEV=Minimal Evaluation 
Visit; NA=not applicable; SV=Screening Visit; V=Visit; W=week; YEV= Yearly Evaluation Visit 
Note: Other than the SV and EV, the same study assessment will be performed at subsequent visits for all subjects. Subsequent visits will be conducted according 
to the visit schedule provided in Table 5‒3. 
a Height will be recorded at the SV only. 
b At the FV, a 12-lead ECG is mandatory, except if the FV follows an EDV where ECG results were normal. 
c If no appropriate EEG result (within the last 10 years) is available, the EEG must be scheduled at the SV and the results received before the EV. 
d A neuro-imaging procedure (brain magnetic resonance imaging/brain computerized tomography scan or any other imaging test) should be performed if no 
report is available within the previous 2 years. If there is not a known history and clinical signs or suspicion of brain tumor, performing a neuro-imaging 
procedure for the purpose of the study is not mandatory. If the investigator can judge a participant's eligibility by his/her own medical judgement without 
performing neuro-imaging procedure, it is also acceptable. However, if the etiology of epilepsy is a brain tumor, or the participant has any intracranial 
structural abnormality as documented by a previous neuro-imaging procedure, the participant needs to have documentation of a neuro-imagining procedure 
which is no older than 2 years. 
e At the SV and EV (For DE), historical seizure information (including type, frequency, and date) should be checked. Historical seizure information must have 
been prospectively recorded on a subject’s own document (eg, DRC). After the EV, seizure counts are collected on the subject’s DRC on a daily basis 
f Laboratory safety assessment will not be performed at MEV. Only liver function tests will be performed at the MEV in Visit 4 (M3) and Visit 6 (M9).  
Laboratory safety assessment is mandatory at the FV, except if the FV follows an EDV where laboratory results were normal. The result of the calculated 
creatinine clearance will be provided by the central laboratory.  
g At the SV, a serum pregnancy test will be performed for female subjects with childbearing potential. At all subsequent visits, a urine pregnancy test will be 
performed 
h Concomitant levetiracetam is permitted for directly enrolled subjects in Japan, but not allowed for subjects transitioning from EP0083 and N01379. 
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Table 5-2: 
Schedule of study assessments for subjects directly enrolled into EP0085 in Japan 
Assessments 
SV 
 
EV 
 
MEV 
FEV 
YEV 
End of Study 
Visit or EDV 
FV 
Visit  
V0 
V1 
V2, V4, V6, V8, 
V10… 
V3, V5, V9… 
V7, V11… 
NA 
NA 
Month  
- 
M0 
M1, M3, M9, 
M15, M21… 
M2, M6, M18… 
M12, M24… 
NA 
NA 
Week 
(-2 to -21 
days) 
W0 
W4, W12, W36, 
W60, W84… 
W8, W24, W72… 
W48, W96… 
NA 
NA 
i End of study status will be completed at the FV for subjects having performed an EDV and down-titration of BRV (discontinued subjects) and for subjects 
leaving the study at the end of the program (completed subjects). Alternatively, end of study status will be completed at the End of Study Visit for subjects who 
will be converted without down-titration to commercial BRV if, when, and where available. 
 
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5.3 
Schematic diagram 
A full visit schedule is presented in Table 5‒3. 
Table 5‒3: 
Full visit schedule 
First year follow-up 
Month (Week) 
Visit 
Type of visit 
-2 to -21 days 
V0 
SVa 
M0 (W0) 
V1 
EV 
M1 (W4) 
V2c 
MEVb 
M2 (W8) 
V3c 
FEV 
M3 (W12) 
V4 
MEVb 
M4 (W16) 
- 
- 
M5 (W20) 
- 
- 
M6 (W24) 
V5 
FEV 
M7 (W28) 
- 
- 
M8 (W32) 
- 
- 
M9 (W36) 
V6 
MEVb 
M10 (W40) 
- 
- 
M11 (W44) 
- 
- 
M12 (W48) 
V7 
YEV 
Second year follow-up c 
Month 
Visit 
Type of visit 
M15 (W60) 
V8 
MEVb 
M18 (W72) 
V9 
FEV 
M21 (W84) 
V10 
MEVb 
M24 (W96) 
V11 
YEV 
EV=Entry Visit; FEV=Full Evaluation Visit; M=month; MEV=Minimal Evaluation Visit; SV=Screening Visit; 
V=Visit; W=Week; YEV=Yearly Evaluation Visit 
Note: A dash (-) denotes that no visit is scheduled in that month. 
a For subjects directly enrolled into EP0085 in Japan only. 
b Laboratory safety assessments will not be performed at MEV. Only liver function tests will be performed at 
MEV in the first year (V4 and V6). 
c Subsequent years will follow the same visit schedule. 
 
 
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5.4 
Rationale for study design and selection of dose 
Directly enrolled subjects and subjects from EP0083 will be started on a BRV dose of 
100mg/day (2 equally divided doses administered twice daily) at study entry and should be 
maintained at this dose for at least 2 weeks, unless the subject is not able to tolerate treatment. 
Subjects who entered from N01379 can enter EP0085 at a dose up to 200mg/day. The BRV 50 to 
200mg/day is approved as the effective dose of BRV for adults in EU/US without titration. The 
BRV dose can be adjusted based on the individual subject’s seizure control and tolerability 
between 50mg/day and 200mg/day during the study and must always be administered in equal 
morning and evening doses except the last week of down-titration. Of note, decreasing the dose 
should not exceed 50mg/day. Study medication in the last week of down-titration is given only in 
the morning. 
In Phase 2/3 studies for partial seizures with BRV doses up to 200mg/day, BRV had a low 
dropout rate and was generally well tolerated. The most frequently reported TEAEs were 
headache, somnolence, dizziness, and fatigue. The starting dose of BRV 100mg/day was selected 
from N01358 efficacy results that were numerically similar between 100 and 200mg/day, and the 
starting dose in US and EU labeling. The BRV dose can be adjusted based on the individual 
subject’s seizure control and/or tolerability after the first 2 weeks, up to a maximum dose of 
BRV 200mg/day. 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Eligibility criteria in Japan 
6.1.1 
Inclusion criteria for all subjects 
To be eligible to participate in this study, all of the following criteria must be met for all subjects 
in Japan: 
1. An IRB/IEC approved written informed consent signed and dated by the subject or by 
parent(s) or legally representative. The consent form or a specific assent form, where 
required, will be signed and dated by minors. 
2. Male/female subject from 16 years of age or older. Subjects who are not legal adults may 
only be included where legally permitted and ethically accepted. 
4. Subject for whom the Investigator believes a reasonable benefit from the long-term 
administration of BRV may be expected. 
5. Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral 
oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive method. 
Oral or depot contraceptive treatment with at least approved dosage of ethinylestradiol per 
intake in each country where this study is conducted (if subjects is taking any enzyme 
inducer such as carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. 
John’s Wort or rifampicin, the dosage of ethinylestradiol should have been modified 
according to the guidelines for contraceptive treatment in each country), monogamous 
relationship with vasectomized partner, or barrier contraception are acceptable methods. The 
subject must understand the consequences and potential risks of inadequately protected 
sexual activity, be educated about and understand the proper use of contraceptive methods, 
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and undertake to inform the Investigator of any potential change in status. Abstinence will be 
considered as an acceptable method of contraception if the Investigator can document that 
the subject agrees to be compliant. 
6. Subject/legally representative considered as reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries and questionnaires), visit schedule, or 
medication intake according to the judgment of the Investigator. 
6.1.2 
Additional inclusion criteria for rollover subjects 
In addition to the inclusion criteria for all subjects in Japan (Section 6.1.1), the following criteria 
must also be met for rollover subjects in Japan:  
3. Subject completed the Treatment Period and Transition Period of EP0083 or is ongoing in 
N01379 sites in Japan. 
6.1.3 
Additional inclusion criteria for directly enrolled subjects 
In addition to the inclusion criteria for all subjects in Japan (Section 6.1.1), the following criteria 
must also be met for directly enrolled subjects in Japan:  
7. Subject has a body weight ≥40kg at the Screening Visit (SV). 
8. Subject has well-characterized focal epilepsy/epileptic syndrome according to the 1989 ILAE 
classification. 
9. Subject has had an electroencephalogram (EEG) reading compatible with the clinical 
diagnosis of focal epilepsy within the last 10 years. If there is no appropriate EEG available 
within the last 10 years, a Baseline EEG must be scheduled at the SV and the results received 
before the EV. 
10. Subject has 1 to <8 partial seizures (according to the 1981 ILAE classification) during the 
8 weeks prior to BRV administration. 
11. Subject’s seizures are uncontrolled while treated by at least 1 permitted concomitant AED. 
Vagal nerve stimulation (VNS) will be allowed and counted as a concomitant AED. 
6.1.4 
Exclusion criteria for all subjects 
Subjects in Japan are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has developed hypersensitivity to any components of the IMP or comparative drugs 
as stated in this protocol during the course of the core study. 
2. Severe medical, neurological or psychiatric disorders, or laboratory values which may have 
an impact on the safety of the subject. 
4. Planned participation in any other clinical study of another investigational drug or device 
during this study. 
5. Pregnant or lactating woman. 
6. Any medical condition which, in the Investigator’s opinion, warrants exclusion. 
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6.1.5 
Additional exclusion criteria for rollover subjects 
In addition to the exclusion criteria for all subjects in Japan (Section 6.1.4), the following 
exclusion criteria also apply for rollover subjects in Japan: 
3. Poor compliance with the visit schedule or medication intake in the previous BRV studies. 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS at the Entry Visit 
(EV). 
8. Subject has >2xULN of any of the following at the EV: ALT, AST, ALP, or >ULN total 
bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). 
If subject has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate 
bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
6.1.6 
Additional exclusion criteria for directly enrolled subjects 
In addition to the exclusion criteria for all subjects in Japan (Section 6.1.4), the following 
exclusion criteria also apply for directly enrolled subjects in Japan: 
9. Subject has participated in another study of an investigational medication (or a medical 
device) within the last 30 days or is currently participating in another study of an 
investigational medication (or a medical device). 
10. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (”Yes”) to either Question 4 or Question 5 of the C-SSRS at the SV. 
11. Subject has >2xULN of any of the following at the SV: ALT, AST, ALP, or >ULN total 
bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). 
If subject has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate 
bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For 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. 
12. Subject previously enrolled in this study or any other prior study with BRV as a dosing arm. 
13. Subject has experienced febrile seizures exclusively. The occurrence of febrile seizures in 
addition to other unprovoked seizures is not exclusionary. 
14. Subject/legal representative is not able to read and understand the Informed Consent form 
(ICF), Assent form, or daily record card (DRC) instructions. 
15. Subject has a history or presence of status epilepticus during the 30 days preceding the SV. 
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16. Subject has a history or presence of known psychogenic nonepileptic seizures. 
17. Study participant has been treated with vigabatrin and has visual field defects. 
18. Subject is taking any drug that significantly influences the metabolism of BRV (cytochrome 
P450 strong inducers such as rifampin/rifampicin) except if the dose has been kept stable at 
least 4 weeks before the SV. 
19. Subject has presence of any sign (clinical or imaging techniques) suggesting rapidly 
progressing (ie, not expected to stay stable during study participation) brain disorder or brain 
tumor per investigator assessment. Stable arteriovenous malformations, meningiomas, or 
other benign tumors may be acceptable. 
20. Subject has any clinical conditions (eg, bone marrow suppression, severe renal impairment) 
which, per investigator discretion, impair reliable participation in the study or necessitate the 
use of medication not allowed by protocol. 
21. Subject has the presence of a terminal illness. 
22. Subject has the presence of a serious infection. 
23. Subject has clinically significant laboratory abnormality that may increase the risk associated 
with study participation or may interfere with the interpretation of study results, according to 
the Investigator. 
24. Subject has clinically significant ECG abnormalities according to the Investigator. 
25. Subject has known alcohol or drug addiction or abuse within the last 2 years.  
6.2 
Eligibility criteria in China 
6.2.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met for subjects in 
China: 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent signed and dated by the subject or by parent(s) or legally representative. 
The consent form or a specific assent form, where required, will be signed and dated by 
minors. 
2. Male/female subject from 16 years of age or older. Subjects who are not legal adults may 
only be included where legally permitted and ethically accepted. 
3. Subject completed the Treatment Period and Transition Period of EP0083. 
4. Subject for whom the Investigator believes a reasonable benefit from the long-term 
administration of BRV may be expected. 
5. Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral 
oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive method. 
Oral or depot contraceptive treatment with at least approved dosage of ethinylestradiol per 
intake in each country where this study is conducted (if subjects is taking any enzyme 
inducer such as carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. 
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John’s Wort or rifampicin, the dosage of ethinylestradiol should have been modified 
according to the guidelines for contraceptive treatment in each country), monogamous 
relationship with vasectomized partner, or barrier contraception are acceptable methods. The 
subject must understand the consequences and potential risks of inadequately protected 
sexual activity, be educated about and understand the proper use of contraceptive methods, 
and undertake to inform the Investigator of any potential change in status. Abstinence will be 
considered as an acceptable method of contraception if the Investigator can document that 
the subject agrees to be compliant. 
6. Subject/legally representative considered as reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries and questionnaires), visit schedule, or 
medication intake according to the judgment of the Investigator. 
6.2.2 
Exclusion criteria 
Subjects in China are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has developed hypersensitivity to any components of the IMP or comparative drugs 
as stated in this protocol during the course of the core study. 
2. Severe medical, neurological or psychiatric disorders, or laboratory values which may have 
an impact on the safety of the subject. 
3. Poor compliance with the visit schedule or medication intake in the previous BRV studies. 
4. Planned participation in any other clinical study of another investigational drug or device 
during this study. 
5. Pregnant or lactating woman. 
6. Any medical condition which, in the Investigator’s opinion, warrants exclusion. 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the EV. 
8. Subject has >2 x upper limit of normal (ULN) of any of the following at the EV: 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%). 
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: 
• Withdrawal for safety reasons by the Investigator such as a worsening of the seizure profile, 
eg, occurrence of status epilepticus, seizure clustering or generalized tonic-clonic seizure, if 
unknown for the subject 
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• Subject develops an illness that would interfere with his/her continued participation. 
• Subject is noncompliant with the study procedures or medications in the opinion of the 
Investigator. 
• Subject takes prohibited concomitant medications as defined in this protocol. 
• Subject or legal guardian withdraws his/her consent. 
• There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
• The sponsor or a regulatory agency requests withdrawal of the subject. 
• In the event of a suicide attempt, the subject should be referred immediately to a Mental 
Healthcare Professional and must be withdrawn from the study. 
Subject 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. 
Subject 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. 
Investigators should attempt to obtain information on subjects, in the case of withdrawal or 
discontinuation. The Investigator should make 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 eCRF must document the primary 
reason for withdrawal or discontinuation. 
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: 
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• Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
Investigator. 
• Subjects with ALT or AST ≥3xULN (and ≥2x Baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness). 
Evaluation of PDILI must be initiated as described in Section 10.2.1. 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 eCRF must document the primary 
reason for IMP discontinuation. 
7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal products 
Oral film-coated tablets of BRV 25mg and BRV 50mg will be used in this study. 
7.2 
Treatments to be administered 
Directly enrolled subjects in Japan and subjects rolling over from EP0083 will be started on a 
BRV dose of 100mg/day (2 equally divided doses administered twice daily) at study entry and 
should be maintained at this dose for at least 2 weeks, unless the subject is not able to tolerate 
treatment.  
Subjects from Japan who entered from N01379 can enter EP0085 at a dose up to 200mg/day. 
The BRV dose can be adjusted based on the individual subject’s seizure control and tolerability 
between 50mg/day and 200mg/day during the study and must always be administered in equal 
morning and evening doses except the last week of down-titration. Of note, decreasing the dose 
should not exceed 50mg/day. 
For all subjects, the first intake of study medication should occur in the evening of the day of the 
EV. Subjects should take tablets according to instructions provided by the Investigator. 
During the Down-Titration Period, the BRV dose may be decreased in steps of a maximum of 
50mg/day on a weekly basis. A last down-titration step at 25mg/day for 1 week should be 
included prior to the 2-week Study Drug-Free Period. The subject will be required to enter a 
2-week Study Drug-Free Period for 2 weeks, followed by a FV. 
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7.3 
Packaging 
Brivaracetam tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice guidelines and applicable laws or regulations. The IMP is suitably packaged in such a 
way as to protect the IMP from deterioration during transport and storage. 
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 (or designee) 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. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and returned 
to UCB (or designee) preferably in the original package. Investigational medicinal product 
intended for the study cannot be used for any other purpose than that described in this protocol. 
7.7 
Procedures for monitoring subject compliance 
The IMP will be supplied to the subject/parent(s)/legal representative(s) at protocol specified 
time points provided in Table 5‒1 and Table 5-2). 
The Investigator will instruct the subject/parent(s)/legal representative(s) to bring back at each 
visit the kits (even empty) dispensed at the previous visit and containing all the remaining tablets 
of study medication. 
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The subject/parent(s)/legal representative(s) must record the situation of medication compliance 
every time the subject takes an IMP. 
Drug accountability must be done in the subject/parent(s)/legal representative(s) presence in 
order to obtain explanations regarding discrepancies in compliance with the dosing regimen. 
Drug accountability must be recorded on the Drug Accountability form. 
Compliance with investigational product is defined as investigational product consumption by 
the subject within 80% and 120% of the prescribed dosage. If a subject is found to be persistently 
noncompliant (<80% or >120%), the Sponsor in conjunction with the Investigator will make a 
decision as to whether the subject should be withdrawn from the study. 
The number of tablets dispensed and returned must be recorded in the source documents. 
7.8 
Concomitant medications/treatments 
For any treatment other than the IMP, including over-the-counter products, an accurate record 
must be kept in the source documents and in the eCRF. 
All concomitant medications should be recorded in the eCRF at the EV and subsequently be 
recorded only if there is a change regarding the administration of the medication. For all 
subjects, new medications should be recorded in the eCRF at only the first visit at which they are 
reported and subsequently only if there is a change. For any change, the start date corresponding 
to the date of change in administration should be recorded in the eCRF. 
For all subjects, all changes in concomitant AEDs and non-AEDs will be recorded on the AED 
or non-AED concomitant medication page, respectively, in the eCRF. This record should include 
the name of the drug (preferably the brand name), the dose, the date(s) of administration, 
formulation(s), and the indication for use. 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
At the beginning of EP0085, the concomitant AEDs that were used in EP0083 and N01379 are 
permitted for rollover subjects. Subjects directly enrolled into EP0085 in Japan will enter the 
study receiving at least 1 permitted concomitant AED.  
The investigator (or designee) will be allowed to change the type, dosage and administration, or 
discontinuation/resumption of concomitant AEDs to optimize tolerability and seizure reduction 
for each subject. Antiepileptic drugs (Appendix 3 [Section 16.3]) are permitted during the study. 
Changes in concomitant AEDs will be allowed only if the dose of BRV has been stable for the 
previous 4 weeks; BRV dose must remain stable during changes to concomitant AEDs. New 
AEDs may be added only when the subject has not optimally or adequately responded to a 
maximum tolerated dose of BRV. The concomitant AEDs can be carefully tapered or 
discontinued at the discretion of the investigator. 
Monotherapy with BRV is permitted. Increasing the dose of BRV and/or concomitant AEDs, as 
well as addition of a new AED should be done at a visit (scheduled or unscheduled). There are 
no restrictions for concomitant AEDs during the Taper Period, considering subject safety.  
Vagal nerve stimulation (VNS) is allowed and will be counted as a concomitant AED. 
7.8.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications/treatments are prohibited during the study: 
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− BRV (other than IMP) 
− LEV (LEV is not prohibited for directly enrolled subjects in Japan) 
− Potassium bromide, sodium bromide, and calcium bromide  
− Other investigational products and drugs and medical devices that have not been 
approved in each country 
− Brain surgery (including surgery for examination purposes). 
7.8.3 
Rescue medication 
The rescue medication(s) which the dosage form is suppository, injection, and enema preparation 
are permitted during the study for sudden aggravation or cluster seizures, and if the subject’s 
condition requires rescue medication(s) during minor surgical procedures in a relatively short 
time. The use of rescue medication is permitted only once a week for a maximum of 4 weeks to 
control seizures; if the frequency exceeds once a week, the subject will be discontinued from the 
study. 
7.9 
Blinding 
This is an open-label LTFU study of the preceding double-blind study EP0083 and open-label 
study N01379, thus, subjects are not blinded. 
7.10 
Randomization and numbering of subjects 
Since EP0085 is an open-label LTFU study for EP0083 and open-label study N01379, subjects 
will not be randomized to any treatment groups. Subjects from EP0083 will start with a dose of 
BRV 100mg/day (2 equally divided doses administered twice daily) and will be maintained on 
that dose for at least 2 weeks, unless they are unable to tolerate the dose. Subjects from Japan 
who participated in N01379 can enter EP0085 at a dose up to 200mg/day. 
Subjects from EP0083 and N01379 will continue with the 5-digit subject numbers assigned by 
the IVRS/IWRS in the preceding studies. Directly enrolled subjects will receive a 5-digit number 
assigned by the IVRS/IWRS at Screening that serves as the subject identifier throughout the 
study. 
8 
STUDY PROCEDURES BY VISIT  
Prior to any study activities, the subject/parent(s)/legal representative(s) will be asked to read and 
sign an ICF that has been approved by an IRB/IEC and which complies with regulatory 
requirements. The subject/parent(s)/legal representative(s) 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/parent(s) or legal representative(s) will be 
given the opportunity to ask the Investigator any questions regarding potential risks and benefits 
of participation in the study. Additionally, if applicable (according to subject’s age and local 
requirements), the subject will sign an IRB/IEC-approved Assent form. 
8.1 
Screening Visit (for direct enrollers in Japan only) 
The following tasks and procedures are to be performed between Day -21 and Day -2, prior to 
Visit 1 (EV) for direct enrollers in Japan: 
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• Written informed consent 
• Subject identification card dispensed 
• Eligibility assessment 
• Demography 
• Medical/procedures history 
• Epilepsy history 
• AED history 
• Birth control 
• Vital signs 
• Body weight 
• Height 
• Physical examination 
• Neurological examination 
• 12-lead ECG 
• EEG (if no EEG result within the previous10 years is available) 
• Neuro-imaging procedure (per Investigator discretion) 
• IVRS/IWRS  
• Seizure counts (prospectively recorded historical seizure information) 
• Laboratory safety assessments including hematology, blood chemistry, and urinalysis  
• Serum pregnancy test 
• AE reporting 
• C-SSRS 
• Medical procedures 
• Concomitant AEDs 
• Concomitant non-AEDs 
8.2 
Entry Visit (for direct enrollers in Japan only) 
The EV assessments for direct enrollers in Japan are as follows: 
• Eligibility assessment 
• Vital signs 
• Body weight 
• IVRS/IWRS  
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• Subject's daily record card (DRC) dispensed 
• Seizure counts (prospectively recorded historical seizure information) 
• Laboratory safety assessments including hematology, blood chemistry, urinalysis and urine 
pregnancy test (if applicable) 
• AE reporting 
• C-SSRS 
• Medical procedures 
• Concomitant AEDs 
• Concomitant non-AEDs 
• Study drug dispensing 
8.3 
Entry Visit (rollovers from China and Japan) 
The following tasks and procedures are to be performed at this visit (for subjects who have 
completed EP0083 and N01379, assessments marked [*] should have already been completed 
during the last visit of the previous protocol and do not need to be repeated at Visit 1). 
The EV assessments are as follows: 
• Written informed consent (must be obtained during the previous study) 
• Subject identification card dispensed 
• Eligibility assessment 
• Demography 
• Vital signs* 
• Body weight* 
• Height 
• Physical examination* 
• Neurological examination* 
• 12-lead ECG* 
• IVRS/IWRS  
• Subject's daily record card (DRC) dispensed 
• Seizure counts* 
• Laboratory safety assessments including hematology, blood chemistry, urinalysis and urine 
pregnancy test (if applicable)* 
• AE reporting* 
− Ongoing AEs at the time of subject completion of EP0083 or N01379 will be obtained 
from the database for EP0083 or N01379 and should not be recorded on the eCRF for 
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EP0085, unless there is a change in intensity or seriousness. In this event, the AE should 
be recorded on the eCRF for EP0085 with the onset date corresponding to the date of 
change in condition. 
• C-SSRS* 
• Medical procedures* 
• Concomitant AEDs* 
− Ongoing medications (AEDs and non-AEDs) at the time of subject completion of 
EP0083 or N01379 will be obtained from the database for EP0083 or N01379 and should 
not be recorded on the eCRF for EP0085, unless there is a change regarding the 
administration of the medication. In this event, the medication should be recorded on the 
eCRF for EP0085 with the start date corresponding to the date of change in 
administration. 
• Concomitant non-AEDs* 
• Study drug dispensing 
The following data will be obtained from the Baseline of EP0083 or N01358 (for subjects 
entering from N01379) and do not need to be recorded on the eCRF for this study. 
• General medical and procedures history 
• AED history  
• Epilepsy history. 
8.4 
Minimal Evaluation Visits (all subjects) 
After V1 for subjects entering from N01379, V2 will not be conducted). Subsequent visits will 
be conducted according to the visit schedule provided in Table 5‒3. 
At the Minimal Evaluation Visits (MEV) assessments are as follows: 
• Vital signs 
• Body weight  
• IVRS/IWRS  
• Subject's DRC dispensed 
• Subject's DRC retrieval 
• Seizure counts (collected on the subject’s DRC on a daily basis) 
• Urine pregnancy test (if applicable) 
• Liver function tests will be performed in V4 (M) and V6 (M 9) as described in Section 10.2. 
• AE reporting 
• C-SSRS 
• Medical procedures 
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• Concomitant AEDs 
• VNS settings 
• Concomitant non-AEDs 
• Study drug dispensing 
• Study drug return/accountability 
8.5 
Full Evaluation Visits (all subjects) 
After V1 for subjects entering from N01379, V3 will not be conducted. Subsequent visits will be 
conducted according to the visit schedule provided in Table 5‒2. 
At the Full Evaluation Visits (FEV) assessments are as follows: 
• Vital signs 
• Body weight  
• Physical examination 
• Neurological examination 
• 12-lead ECG 
• IVRS/IWRS  
• Subject's DRC dispensed 
• Subject's DRC retrieval 
• Seizure counts (collected on the subject’s DRC on a daily basis) 
• Laboratory safety assessments including hematology, blood chemistry, urinalysis and urine 
pregnancy test (if applicable) 
• AE reporting 
• C-SSRS 
• Medical procedures 
• Concomitant AEDs 
• VNS settings 
• Concomitant non-AEDs 
• Study drug dispensing 
• Study drug return/accountability 
8.6 
Yearly Evaluation Visit (all subjects) 
At the Yearly Evaluation Visit (YEV) assessments are as follows: 
• Vital signs 
• Body weight  
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• Physical examination 
• Neurological examination 
• 12-lead ECG 
• IVRS/IWRS  
• Subject's DRC dispensed 
• Subject's DRC retrieval 
• Seizure counts (collected on the subject’s DRC on a daily basis) 
• Laboratory safety assessments including hematology, blood chemistry, urinalysis and urine 
pregnancy test (if applicable) 
• AE reporting 
• C-SSRS 
• Medical procedures 
• Concomitant AEDs 
• VNS settings 
• Concomitant non-AEDs 
• Study drug dispensing 
• Study drug return/accountability 
8.7 
End of Study Visit or Early Discontinuation Visit (all subjects) 
At the End of Study Visit or Early Discontinuation Visit (EDV) assessments are as follows: 
• Vital signs 
• Body weight  
• Physical examination 
• Neurological examination 
• 12-lead ECG 
• IVRS/IWRS  
• Subject's DRC dispensed 
• Subject's DRC retrieval 
• Seizure counts (collected on the subject’s DRC on a daily basis) 
• Laboratory safety assessments including hematology, blood chemistry, urinalysis and urine 
pregnancy test (if applicable) 
• AE reporting 
• C-SSRS 
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• Medical procedures 
• Concomitant AEDs 
• VNS settings 
• Concomitant non-AEDs 
• Study drug dispensing 
• Study drug return/accountability 
• End of study status (end of study status will be completed at the End of Study Visit for 
subjects who will be converted without down-titration to commercial BRV if, when, and 
where available). 
8.8 
Final Visit (all subjects) 
At the Final Visit (FV) assessments are as follows: 
• Vital signs 
• Body weight  
• Physical examination 
• Neurological examination 
• 12-lead ECG (mandatory, except if the FV follows an EDV where ECG results were normal) 
• IVRS/IWRS  
• Subject's DRC retrieval 
• Seizure counts (collected on the subject’s DRC on a daily basis) 
• Laboratory safety assessments (mandatory, except if the FV follows an EDV where 
laboratory results were normal): hematology, blood chemistry, urinalysis, and urine 
pregnancy test (if applicable) 
• AE reporting 
• C-SSRS 
• Medical procedures 
• Concomitant AEDs 
• VNS settings 
• Concomitant non-AEDs 
• Study drug return/accountability 
• End of study status 
The FV is not applicable to subjects who convert to commercial BRV (if, when, and where 
available). 
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8.9 
Unscheduled Visit (all subjects) 
At any time, the subject may have an additional study visit if the Investigator or the subject 
and/or legal representative deem it necessary. All information, including reason for visit, any 
information on AEs, etc, should be collected in the source documents and recorded in the 
appropriate sections of the eCRF. 
If an Unscheduled Visit (UV) is conducted due to safety or efficacy reasons, a C-SSRS 
assessment will be performed with the subject during the visit. If a UV is conducted for reasons 
other than safety or efficacy concerns (eg, replacement of lost medication, repeated collection of 
a laboratory specimen due to collection or analysis issues), a C-SSRS will not be required at 
these visits. 
9 
ASSESSMENT OF EFFICACY 
Efficacy variables will be assessed using the seizure count information recorded on the DRC.  
At each visit, the subject will receive a DRC, to be filled in on days on which a seizure occurs, 
and to be returned at the next visit. No DRC will be dispensed at the UV or the FV. 
The date, the symptom and the number of epileptic seizures will be recorded on the DRC, as well 
as individual description of seizures, intake of IMP, undesirable events with start and end dates,  
and changes in concomitant medication, if applicable.  
The written information will be discussed with the subject at each visit in order to ensure 
completeness and accuracy. As a result of the discussion, the Investigator will assess the seizures 
according to the ILAE codes and record the seizure types and frequency on the DRC and eCRF; 
he/she will also confirm the presence of AEs (if applicable). The concomitant medication 
changes, healthcare provider consultations not foreseen per protocol, and AEs will be reported 
by the Investigator on the specific pages of the eCRF. 
The DRC will be considered as source documentation. The subject should be educated to 
complete the DRC (eg, when taking evening tablets). Substantial noncompliance with DRC 
(seizures recording) may result in subject discontinuation from the study at any time by the 
Investigator or the Sponsor. 
9.1 
Additional efficacy measures 
9.1.1 
Medical procedures 
Data on medical procedures (surgery, therapeutic and/or diagnostic) undertaken during the study 
will be collected and recorded in the eCRF. Electrocardiograms specific to this study will not be 
recorded on the medical procedures page of the eCRF, but in the modules specifically designed 
for this purpose. 
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10 
ASSESSMENT OF SAFETY 
10.1 
Adverse events 
10.1.1 
Definitions 
10.1.1.1 
Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no 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. 
10.1.1.2 
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 10.1.1.3], 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.) 
• Initial inpatient hospitalization or prolongation of hospitalization 
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(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
10.1.1.3 
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. The procedure for reporting AEs of special interest 
is the same as that for reporting SAEs (Section 10.1.2.3).  
The following Preferred Terms are considered as AEs of special interest: 
• autoimmune nephritis 
• nephritis 
• nephritis allergic 
• tubulointerstitial nephritis 
• uveitis syndrome 
• Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of special interest (ie, without 
waiting for any additional etiologic investigations to have been concluded). Follow-up 
information should then be reported if an alternative etiology is identified during 
investigation and monitoring of the subject. 
10.1.2 
Procedures for reporting and recording AEs 
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, DRC) employed 
in the study. 
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10.1.2.1 
Description of AEs 
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, DRC) 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. 
10.1.2.2 
Rule for repetition of an AE 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
• The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
• The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
10.1.2.3 
Additional procedures for reporting SAEs 
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. 
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 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the Investigator of any SAE within this period. Serious AEs that the 
Investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study. 
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the IB. 
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10.1.3 
Follow up of AEs 
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 10.2.1.4 . 
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. 
10.1.4 
Pregnancy 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see SERIOUS ADVERSE EVENT 
REPORTING information at the beginning of this protocol). The subject should be withdrawn 
from the study as soon as pregnancy is known (by positive pregnancy test), and the following 
should be completed: 
• The subject should return for an early discontinuation visit. 
• The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the early discontinuation visit.  
• A Safety Follow-Up Visit should be scheduled 2 weeks after the subject has discontinued her 
IMP. 
The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the Investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
be available in the Investigator site file. In case of questions about the consent process, the 
Investigator may contact the UCB/contract research organization (CRO) contract monitor for the 
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study. The Investigator will complete the Pregnancy Report and Outcome form and send it to 
UCB’s PS department (for contact details see Serious Adverse Event reporting information at the 
beginning of this protocol) only after the partner has agreed that additional information can be 
captured and has provided the signed Partner Pregnancy Consent form. UCB’s PS department is 
also the primary contact for any questions related to the data collection for the partner pregnancy, 
eventual birth, and follow up. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form. 
10.1.5 
Suspected transmission of an infectious agent via a medicinal 
product 
A suspected transmission of infectious agent is defined as any infection that is temporally related 
to the administration of the medicinal product with no other likely cause. The Medical Monitor 
should be contacted immediately. No further medicinal product from that specific batch should 
be administered. Infections should be treated according to normal clinical practice. 
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. 
10.1.6 
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). 
10.1.7 
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 ECG results) for which data will be periodically reviewed during the course 
of the study. 
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10.2 
Laboratory measurements 
Laboratory assessments will be conducted using standard methods at a central laboratory with 
the exception of urine pregnancy tests (which will be performed at the unit by clinical study 
personnel). The central laboratory will provide the Investigator with dedicated, standardized 
sampling equipment (labels, needles, tubes), and a study-specific laboratory manual, which will 
explain how to use the equipment and how to ship the samples to the central laboratory. 
The total blood volume drawn for clinical laboratory assessments will be a maximum of 4.5mL 
by sampling, which includes 2mL for hematology and 2.5mL for blood chemistry.  
The subject must be preferably fasting, but study medication intake must not be delayed. The 
following safety laboratory parameters will be measured: 
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Table 10‒1: Laboratory measurements 
Hematology 
Biochemistry 
Urinalysis 
Pregnancy 
WBC 
Glucose 
Glucose 
β-hCG urine/serum 
RBC 
Sodium 
Ketones 
 
Hemoglobin 
Potassium 
Occult blood 
Hematocrit 
Calcium 
Protein 
MCV 
Chloride 
Nitrites 
MCH 
Bicarbonate 
Leukocytes 
MCHC 
Phosphorus (inorganic) 
Microscopic 
examinationb 
Platelet count 
Total protein 
 
Lymphocytes (number, %) Albumin 
Monocytes (number, %) 
Total bilirubina 
Neutrophils (number, %) 
ALPa 
Eosinophils (number, %) 
AST (SGOT)a 
Basophils (number, %) 
ALT (SGPT)a 
 
GGTa 
Uric acid 
Urea 
Creatinine 
Triglycerides 
Cholesterol 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
β-hCG=beta-human chorionic gonadotropin; GGT=gamma-glutamyltransferase; MCH=mean corpuscular 
hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; 
MEV=Minimal Evaluation Visits; RBC=red blood cell; SGOT=serum glutamic oxaloacetic transaminase; 
SGPT=serum glutamic pyruvic transaminase; WBC=white blood cell 
a This assessment is used for hepatic monitoring. Liver function tests will be assessed at MEVs (Visit 4 and 
Visit 6) during the first year in addition to the full laboratory assessments described in Section 8. 
 b Includes bacteria, cells, casts, and crystals for all samples. 
The creatinine clearance (CLcr) will be calculated over time by the central laboratory using their 
current methods.  
The subject’s age, body weight, and gender must be recorded on the laboratory requisition form. 
The result of the calculated CLcr will be provided by the central laboratory for all assessments.  
For rollover subjects in China and Japan, laboratory safety assessments at the EV will be taken 
from the last visit of EP0083 or N01379 and do not need to be recorded on the eCRF. Laboratory 
safety assessments will be performed at time points specified in the schedules of study 
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assessments (Table 5‒1 and Table 5-2). In addition, liver function tests will be performed at 
MEVs (Visit 4 and Visit 6) during the first year. Laboratory assessments will also be mandatory 
at the FV, except if the FV follows an EDV where laboratory results were normal. 
Where applicable, females of childbearing potential), a blood pregnancy test (beta-human 
chorionic gonadotropin level) or urine pregnancy test will be included in the laboratory safety 
assessments. If pregnancy is suspected at any time during the study, an interim test should be 
performed. Results for hematology, biochemistry, urinalysis, and pregnancy tests will be 
provided by fax to the Investigator within 72 hours after sample receipt. 
10.2.1 
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 10.1.1.3), and, if applicable, also reported as an 
SAE (see Section 10.1.1.2). 
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 10‒2 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.2.1.1 ). 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 10.2.1.4 ). 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the Investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. Table 10‒2 summarizes the approach to investigate PDILI. 
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Table 10‒2: 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 10.2.1.3); 
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 
 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥5xULN 
(and ≥2x 
Baseline)  
<2xULN 
No 
Discussion with 
Medical Monitor 
required. 
Hepatology consult 
required if ALT/AST 
≥8xULN 
Immediate IMP 
discontinuation 
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
at the site with 
HCP (see 
Section 10.2.1.3). 
 
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Table 10‒2: 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 
(and ≥2x 
Baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met. 
 
Further 
investigation – 
immediate IMP 
discontinuation not 
required (see 
Section 10.2.1.2). 
IMP discontinuation 
required if any of 
the following occur: 
Subject cannot 
comply with 
monitoring 
schedule.  
Liver chemistry 
values continue to 
increase. 
Liver chemistry 
values remain 
≥3xULN (and 
≥2xBaseline) after 
2 week monitoring 
without stabilization 
or evidence of 
resolution. 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
Investigator 
Monitoring of liver chemistry 
values at least twice per week 
for 2 weeksd 
Immediate IMP discontinuation 
required if:  
Liver chemistry values 
continue to increase. 
After 2 weeks of monitoring 
liver chemistry values: 
Liver chemistry values remain 
≥3xULN (and ≥2x Baseline) 
after 2 weeks of monitoring 
without stabilization or 
evidence of resolution    
Continue to monitor until 
values normalize, stabilize, or 
return to within Baseline 
valuesd 
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Table 10‒2: 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 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 10.2.1.1 . 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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10.2.1.1 
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 10.2.1.3) and SAE report (if applicable). 
10.2.1.2 
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 10‒2 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. 
10.2.1.3 
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 10‒3 (laboratory measurements) and Table 10‒4 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
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Table 10‒3: 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 
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 10‒4: 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 
10.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 10‒2. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the Investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
10.3 
Other safety measurements 
Other safety measurements include 12-lead ECGs, vital signs, physical examinations, 
neurological examination, body weight and height, and assessment of suicidality. 
10.3.1 
ECG 
A standard 12-lead ECG will be performed at protocol specified time points according to the 
schedules of study assessments  
(Table 5‒1 and Table 5-2). For rollover subjects in China and Japan, data will be obtained from 
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the last visit of the previous study and should not be recorded in the eCRF at the EV. At the FV, 
a 12-lead ECG is mandatory for all subjects, except if the FV follows an EDV where ECG 
results were normal. The Investigator will determine whether the results of the ECG are normal 
or abnormal and assess the clinical significance of any abnormalities. 
The original 12-lead ECG tracing will be signed or initialed and dated by the Investigator and 
will be retained as part of the source data.  
10.3.2 
Vital signs 
Vital signs, including measurements of blood pressure and supine or sitting pulse rate will be 
performed after 5 minutes of rest at time points specified in the schedules of study assessments 
(Table 5‒1 and Table 5-2). 
For rollover subjects in China and Japan, data will be obtained from the last visit of the previous 
study and should not be recorded in the eCRF at the EV. 
The vital signs measurements will be repeated after 30 minutes if unusual values were observed 
at the initial reading. 
10.3.3 
Physical examination 
A standard physical examination will be performed at time points specified in the schedules of 
study assessments (Table 5‒1 and Table 5-2). 
 For rollover subjects in China and Japan, data will be obtained from the last visit of the previous 
study and should not be recorded in the eCRF at the EV. Clinically significant new or worsened 
abnormalities will have to be reported as AEs. 
10.3.4 
Neurological examination 
A standard neurological examination will be performed at time points specified in the schedules 
of study assessments (Table 5‒1 and Table 5-2). 
For rollover subjects in China and Japan, data will be obtained from the last visit of the previous 
study and should not be recorded in the eCRF at the EV. Clinically significant new or worsened 
abnormalities will have to be reported as AEs. 
10.3.5 
Body weight and height 
Body weight (subject wearing light clothing without shoes and rounded to the nearest kilogram) 
will be measured at time points specified in the schedules of study assessments (Table 5‒1 and 
Table 5-2).  
For rollover subjects in China and Japan, height will be obtained from Visit 1 in EP0085. For 
direct enrollers in Japan, height will be obtained at the SV only. 
10.3.6 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS. This scale will be used 
for Baseline/Selection as well as to assess suicidal ideation and behavior that may occur during 
the study. The C-SSRS will be completed at time points specified in the schedules of study 
assessments (Table 5‒1 and Table 5-2).  
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11 
STUDY MANAGEMENT AND ADMINISTRATION  
11.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
After implementation of such measure, the Investigator must notify the Clinical Project Manager 
(CPM) of the sponsor within 24 hours and follow any local regulatory requirements. 
11.2 
Monitoring 
UCB (or designee) will monitor the study to meet the sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a CRO or a contract monitor. 
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The Investigator will allow UCB (or designee) to periodically review all 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. 
11.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Source documents should be kept in a secure, limited access area. 
Original laboratory results, ECGs, and electroencephalograms 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 
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Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
11.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 11.2.1. 
11.3 
Data handling 
11.3.1 
Case Report form completion 
This study will be performed using electronic data capture (EDC). 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
11.3.2 
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. The data are entered into the eCRFs once and are subsequently verified if the study is 
performed using EDC. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
11.3.3 
Subject Enrollment log/Subject Identification Code list 
The subject’s enrollment will be recorded in the Subject 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. 
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11.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
11.5 
Archiving and data retention 
The record retainer at the study site and the IRB/IEC will retain the GCP defined essential 
document 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. 
It is responsibility of UCB (or designee) to inform the record retainer as to when the documents 
should no longer to be retained. 
11.6 
Audit and inspection 
The Investigator or head of the participating study site 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 or head of the participating study site will provide direct access to all study 
documents, source records, and source data. If an inspection by a regulatory authority is 
announced, the Investigator will immediately inform UCB (or designee). 
11.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
12 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
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For subjects from EP0083, subgroup analyses for Japanese and Chinese subjects will be 
conducted as well as analyses for the entire population. 
Subjects from N01379 and direct enrollers from Japan will be analyzed separately. 
12.1 
Definition of analysis sets 
Analysis populations will be defined as follows: 
The Safety Set (SS) will consist of all subjects who took at least 1 dose of study medication. 
The Full Analysis Set (FAS) will consist of all subjects who took at least 1 dose of study 
medication and have at least 1 seizure record on DRC during the Evaluation Period. 
12.2 
General statistical considerations 
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 
75th percentile, minimum value, and maximum value for quantitative variables, and counts and 
percentages for categorical variables, will be provided. Summary statistics will be presented for 
all subjects. 
12.3 
Planned efficacy analyses 
All efficacy outcomes will be summarized with descriptive statistics only on the FAS.  
The 28-day adjusted seizure frequency will be calculated by dividing the number of partial 
seizures by the number of days for which the DRC was completed and multiplying by 28. 
Planned efficacy analyses for rollover subjects in China and Japan include: 
• Percent reduction in partial seizure frequency per 28 days from Baseline of EP0083 or 
N01358 to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from Baseline 
Period of EP0083 or N01358 
Planned efficacy analyses for directly enrolled subjects in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 weeks 
prior to BRV administration 
Planned efficacy analyses for all subjects (directly enrolled in Japan and rollovers in China and 
Japan) include: 
• Seizure frequency per 28 days for partial seizures by 3-month periods over the Evaluation 
Period. 
• Seizure frequency per 28 days for all seizure types (partial, generalized and unclassified 
epileptic seizure) by 3-month periods over the Evaluation Period. 
• Percentages of subjects continuously seizure-free for partial seizure and all seizure types for 
at least 6 months and at least 12 months during the Evaluation Period. 
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• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period. 
12.4 
Planned safety analyses 
The long-term safety of BRV at individualized doses will be evaluated by means of the safety 
analyses. Summary tables will be presented over the Evaluation Period as well as 
Down-Titration Period for all subjects. 
All safety variables will be analyzed by descriptive methods on the SS. Treatment-emergent 
adverse events will be summarized in incidence tables by Medical Dictionary for Regulatory 
Activities (MedDRA®) Primary System Organ Class and Preferred Term. Separate tables will be 
provided for AEs leading to withdrawal from the study and SAEs. 
Laboratory values, vital signs, and weight will be summarized by period and visit. Possibly 
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and 
weight will be listed and summarized by period and visit. Electrocardiogram abnormalities will 
also be listed by period and visit. 
12.5 
Handling of protocol deviations 
After all CRFs have been retrieved and entered and queries addressed, and prior to locking the 
clinical database a Data Evaluation Meeting (DEM) will be held. The purpose of this DEM will 
be to assess the quality of the data for subsequent database lock, identify protocol deviations, and 
finalize analysis populations. 
12.6 
Handling of dropouts or missing data 
Safety and efficacy variables will be analyzed as they are available. Days with missing 
information will be ignored in the calculation of the seizure frequency. 
Since subjects will drop out at different times from the study, results will be presented by overall 
and by 6 month periods. 
12.7 
Planned interim analysis and data monitoring 
No formal interim analysis is planned. However, data will be reported prior to the completion of 
this study to support regulatory submissions. At a minimum, 2 interim reports are planned after 
all ongoing subjects have completed Visit 5 (Week 24) and after all ongoing subjects have 
completed Visit 7 (Week 48). Regular monitoring of safety data collected during clinical studies 
will be performed by medically qualified Sponsor personnel or equivalent designee(s). 
12.8 
Determination of sample size 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. Overall, approximately 
217 subjects are planned for enrollment. In Japan, it is estimated that approximately 127 subjects 
will enter the study. This estimate assumes that at least 90% of randomized Japanese 
subjects will complete EP0083 (approximately 90 subjects) or enroll from N01379 sites in Japan 
(7 subjects) and the plan that 30 Japanese subjects will be directly enrolled in this study. 
Likewise, at least 90% of randomized Chinese subjects will be assumed to complete EP0083 
(approximately 90 subjects). 
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13 
ETHICS AND REGULATORY REQUIREMENTS 
13.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
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 ICF should be signed and personally dated by the subject, 
or his/her legal representative, and by the person who conducted the informed consent discussion 
(Investigator or designee). The subject or his/her legal representative must receive a copy of the 
signed and dated ICF. As part of the consent process, each subject must consent to direct access 
to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and 
regulatory inspection. 
If the ICF is amended during the study, the Investigator (or the sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form. 
13.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The Investigator will fill in the subject identifying information and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with him/her at all times. 
13.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, IB, 
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. 
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The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
13.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
13.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
14 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable. 
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15 
REFERENCES 
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. 
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. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Engel J, Pedley TA. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott Raven; 1998. 
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing 
clinical evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, 07/2009.  
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34:453-68. 
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255-60. 
Loiseau J, Loiseau P, Guyot M, Duche B, Dartigues JF, Aublet B. Survey of seizure disorders in 
the French southwest. I. Incidence of epileptic syndromes. Epilepsia. 1990;31:391-6. 
Nasreddine W, Beydoun A, Atweh S, Abou-Khalil B. Emerging drugs for partial onset seizures. 
Expert Opin Emerg Drugs. 2010;15:415-31. 
Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 
1996;61:433-43. 
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16 
APPENDICES 
16.1 
Appendix 1 - International Classification of Epileptic Seizures 
 International Classification of Epileptic Seizures (1981) 
I. 
Partial seizures (focal, local) 
A. 
Simple partial seizures (consciousness not impaired) 
9. 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) 
10. 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 
11. With autonomic symptoms or signs (including epigastric sensation, pallor,  
sweating, 
flushing, piloerection, and pupillary dilatation) 
12. 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) 
13. 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 
14. 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) 
III 
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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16.2 
Appendix 2 - International Classification of Epilepsies and Epileptic 
Syndromes 
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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16.3 
Appendix 3 - List of antiepileptic drugs 
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 
*Concomitant LEV is allowed only for direct enrollment participants. In that case, LEV is 
counted as 1 AED. 
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 AEDs administered. 
It is prohibited that subjects take BRV other than IMP, during the study. 
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16.4 
Appendix 4 - Protocol Amendment 1 
Rationale 
This protocol has been amended to update descriptions in study duration per subject visit, 
treatments administered, and a few subject visits to provide a greater level of clarity. 
In addition, minor administrative edits including typographical changes for formatting have been 
made. 
Modifications and changes 
Global changes 
There were no global changes to the protocol for this amendment. 
Specific changes 
Change #1 
LIST OF ABBREVIATIONS  
The following abbreviation definitions were updated and corrected, respectively: 
DEM 
Data Evaluation Meeting 
ILAE 
International League Against Epilepsy 
Change #2 
Section 5.1.1  Study duration per subject 
Additional text was added: 
Visits should occur on the specified Visit/Week. A ±7 day window for each specified Visit/Week 
is allowed, provided the subject has adequate investigational medicinal product (IMP) to sustain 
the visit window. 
Change #3 
Table 5-1  Schedule of study assessments (EP0085) 
For body weight and height at EV footnote (c) was added. For Laboratory safety assessments at 
MEV and FV footnote (e) was added. 
Footnote (e) 
e Laboratory safety assessment includes hematology, blood chemistry, and urinalysis. Liver 
function tests will be performed at the MEV in Visit 4 (M3) and Visit 6 (M9). Laboratory 
assessment will not be performed at MEV from the 2nd year, and is mandatory at the FV, except 
if the FV follows an EDV where laboratory results were normal. 
Has been changed to: 
e Laboratory assessment will not be performed at MEV. Only liver function tests will be 
performed at the MEV in Visit 4 (M3) and Visit 6 (M9).  Laboratory safety assessment is 
mandatory at the FV, except if the FV follows an EDV where laboratory results were normal. 
The result of the calculated creatinine clearance will be provided by the central laboratory. 
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Footnote (g) 
g End of study status will be completed at the FV for subjects having performed an EDV and 
down-titration of BRV (discontinued subjects) and for subjects leaving the study at the end of the 
program (completed subjects). Alternatively, end of study status will be completed at the EDV 
for subjects who will be converted without down-titration to commercial BRV if, when, and 
where available. 
Has been changed to: 
g End of study status will be completed at the FV for subjects having performed an EDV and 
down-titration of BRV (discontinued subjects) and for subjects leaving the study at the end of the 
program (completed subjects). Alternatively, end of study status will be completed at the End of 
Study Visit for subjects who will be converted without down-titration to commercial BRV if, 
when, and where available. 
Change #4 
Table 5-2  Full visit schedule 
In the Visit column for V2 and V3 footnote (c) was added. In the Type of visit column to all 
MEV added footnote (b). 
Footnote (b) 
b Liver function tests will be performed at MEV in the first year (V4 and V6). Laboratory safety 
assessments will not be performed at MEV from the second year. 
Has been changed to: 
b Laboratory safety assessments will not be performed at MEV. Only liver function tests will be 
performed at MEV in the first year (V4 and V6). 
Change #5 
Section 7.2  Treatments to be administered 
During the Down-Titration Period, the BRV dose may be decreased in steps of a maximum of 
50mg/day on a weekly basis. Subjects who are treating with BRV 50mg/day at the 
discontinuation decision by Investigator enter the 2-week Study Drug-Free Period after 1 week at 
25mg/day. The subject will be required to enter a 2-week Study Drug-Free Period for 2 weeks, 
followed by a FV. 
Has been changed to: 
During the Down-Titration Period, the BRV dose may be decreased in steps of a maximum of 
50mg/day on a weekly basis. A last down-titration step at 25mg/day for 1 week should be 
included prior to the 2-week Study Drug-Free Period. The subject will be required to enter a 
2-week Study Drug-Free Period for 2 weeks, followed by a FV. 
Change #6 
Section 7.6  Drug accountability 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and either 
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destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee) preferably in the original package. 
Has been changed to: 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and returned 
to UCB (or designee) preferably in the original package. 
Change #7 
Section 7.10  Randomization and numbering of subjects 
Since EP0085 is an open-label LTFU study for EP0083, subjects will not be randomized to any 
treatment groups. 
Has been changed to: 
Since EP0085 is an open-label LTFU study for EP0083 and open-label study N01379, subjects 
will not be randomized to any treatment groups. 
Change #8 
Section 8.1  Entry visit 
• AE reporting* 
Ongoing AEs at the time of subject completion of EP0083 or N01379 will be obtained from the 
database for EP0083 or N01379 and should not be recorded on the eCRF for EP0085, unless 
there is a change in intensity or seriousness. In this event, the AE should be recorded on the 
eCRF for N01379 with the onset date corresponding to the date of change in condition. 
Has been changed to: 
• AE reporting* 
Ongoing AEs at the time of subject completion of EP0083 or N01379 will be obtained from the 
database for EP0083 or N01379 and should not be recorded on the eCRF for EP0085, unless 
there is a change in intensity or seriousness. In this event, the AE should be recorded on the 
eCRF for EP0085 with the onset date corresponding to the date of change in condition 
Change #9 
Section 8.2  Minimal Evaluation Visits 
The following assessment was added: 
• Urine pregnancy test (if applicable) 
The following text was removed: 
Laboratory safety assessments including hematology, blood chemistry, urinalysis and urine 
pregnancy test (if applicable); 
Change #10 
Section 8.3  Full Evaluation Visits 
The following assessment was removed: 
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• Mental and psychiatric status 
Change #11 
Section 8.5  End of study Visit or Early Discontinuation Visit 
End of study status (end of study status will be completed at the EDV for subjects who will be 
converted without down-titration to commercial BRV if, when, and where available). 
Has been changed to: 
End of study status (end of study status will be completed at the End of Study Visit for subjects 
who will be converted without down-titration to commercial BRV if, when, and where 
available). 
Change #12 
Section 10.1.2.3  Additional procedures for reporting serious adverse events 
The following text has been removed: 
An Investigator SAE report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English. 
Change #13 
Table 10-1  Laboratory measurements 
In the Biochemistry column for GGT footnote (b) was removed and footnote (a) was added. 
Change #14 
Table 10-2  Required investigations and follow up for PDILI 
In the Evaluation column: 
Monitoring of liver chemistry values at least twice per week for 2 weeksc 
Immediate IMP discontinuation required if:  
• Liver chemistry values continue to increase. 
After 2 weeks of monitoring liver chemistry values: 
• Liver chemistry values remain ≥3xULN (and ≥2x Baseline) after 2 weeks of monitoring 
without stabilization or evidence of resolution    
Continue to monitor until values normalize, stabilize, or return to within Baseline valuesc 
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Has been changed to: 
Monitoring of liver chemistry values at least twice per week for 2 weeksd 
Immediate IMP discontinuation required if:  
• Liver chemistry values continue to increase. 
After 2 weeks of monitoring liver chemistry values: 
• Liver chemistry values remain ≥3xULN (and ≥2x Baseline) after 2 weeks of monitoring 
without stabilization or evidence of resolution 
Continue to monitor until values normalize, stabilize, or return to within Baseline valuesd 
Change #15 
Section 10.3  Other safety measurements  
Other safety measurements include 12-lead ECGs, vital signs, physical examinations, 
neurological examination, psychiatric and mental status, body weight and height, and assessment 
of suicidality. 
Has been changed to: 
Other safety measurements include 12-lead ECGs, vital signs, physical examinations, 
neurological examination, body weight and height, and assessment of suicidality. 
Change #16 
Section 10.3.2  Vital signs 
Vital signs, including measurements of blood pressure, supine or sitting pulse rate, and body 
temperature, will be performed after 5 minutes of rest at time points specified in the schedule of 
study assessments (Table 5‒1). 
Has been changed to: 
Vital signs, including measurements of blood pressure and supine or sitting pulse rate will be 
performed after 5 minutes of rest at time points specified in the schedule of study assessments 
(Table 5‒1). 
Change #17 
Section 10.3.5  Body weight and height 
Body weight (subject wearing light clothing without shoes and rounded to the nearest kilogram 
or pound) will be measured at time points specified in the schedule of study assessments. 
Has been changed to: 
Body weight (subject wearing light clothing without shoes and rounded to the nearest kilogram) 
will be measured at time points specified in the schedule of study assessments. 
Change #18 
Section 12.5  Handling of protocol deviations 
Throughout the section, DRM was changed to DEM. 
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16.5 
Appendix 5 - Protocol Amendment 2 
Rationale 
This purpose of this protocol amendment is to update the following: 
• Update the number of subjects based on randomization of EP0083 and N01379 sites in Japan 
• Update safety variables 
• Update participating countries  
• Include Independent Ethics Committee  
In addition, minor administrative edits including typographical changes for formatting have been 
made. 
Modifications and changes 
Global changes 
The Independent Ethics Committee (IEC) was added where IRB was mentioned throughout the 
document. 
Specific changes 
Change #1 
Protocol Title 
AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO EVALUATE THE LONG-
TERM SAFETY AND EFFICACY OF BRIVARACETAM USED AS ADJUNCTIVE 
TREATMENT IN JAPANESE SUBJECTS ≥16 YEARS OF AGE WITH PARTIAL SEIZURES 
WITH OR WITHOUT SECONDARY GENERALIZATION 
Has been changed to: 
AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO EVALUATE THE LONG-
TERM SAFETY AND EFFICACY OF BRIVARACETAM USED AS ADJUNCTIVE 
TREATMENT IN SUBJECTS ≥16 YEARS OF AGE WITH PARTIAL SEIZURES WITH OR 
WITHOUT SECONDARY GENERALIZATION 
Change #2 
IEC was added to the list of abbreviations 
Change #3 
Section 1 Summary 
EP0085 is an open-label, multicenter, follow-up study to evaluate the long-term safety and 
efficacy of brivaracetam (BRV) used as adjunctive treatment in Japanese subjects ≥16 years with 
partial seizures with or without secondary generalization. The primary objective is to evaluate 
the long-term safety and tolerability of BRV in focal epilepsy subjects with partial seizures. The 
secondary objective is to evaluate the maintenance of efficacy of BRV over time. 
The subject population will be Japanese subjects with partial seizures with or without secondary 
generalization. 
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The primary safety variables include adverse events (AEs), withdrawals due to AEs, and 
occurrence of serious adverse events (SAEs). Other safety variables include safety laboratory 
tests (blood chemistry, hematology, and urinalysis), vital signs, body weight, electrocardiograms 
(ECGs), and physical and neurological examinations. 
Have been changed to: 
EP0085 is an open-label, multicenter, follow-up study to evaluate the long-term safety and 
efficacy of brivaracetam (BRV) used as adjunctive treatment in subjects ≥16 years with partial 
seizures with or without secondary generalization. The primary objective is to evaluate the long-
term safety and tolerability of BRV in focal epilepsy subjects with partial seizures. The 
secondary objective is to evaluate the maintenance of efficacy of BRV over time. 
The subject population will be subjects with partial seizures with or without secondary 
generalization. 
The primary safety variable is adverse events (AEs). Exploratory safety variables include safety 
laboratory tests (blood chemistry, hematology, and urinalysis), vital signs, body weight, 
electrocardiograms (ECGs), physical and neurological examinations, and mental and 
psychiatric status. 
Change #4 
Section 1 Summary 
It is estimated that approximately 124 subjects will enter the study, based on the assumption that 
at least 90% of randomized subjects will complete EP0083 or enroll from N01379 sites in Japan.  
Has been changed to: 
Approximately 227 subjects in total are expected to enter the study based on the assumption that 
90% of randomized subjects will complete EP0083 in all participating countries or enroll from 
N01379 sites in Japan. It is estimated that approximately 124 Japanese subjects will enter the 
study, based on the assumption that at least 90% of randomized Japanese subjects will complete 
EP0083 or enroll from N01379 sites in Japan. 
Change #5 
Section 2.5 Rationale for the study 
EP0085 will explore the long-term safety and efficacy of BRV in Japanese subjects. EP0085 will 
include Japanese subjects who have completed EP0083 and will also provide the opportunity for 
Japanese subjects from N01379 continue BRV treatment. The proposed study is intended to 
provide evidence of the long-term safety and efficacy of BRV as adjunctive therapy in Japanese 
subjects with partial seizures. Doses of BRV 50 to 200mg/day will be assessed with reference to 
EP0083. EP0083 is an adequate and well-controlled study to provide additional data confirming 
the efficacy and safety of BRV as an AED in Asian subjects (≥16 to 80 years of age) with partial 
seizures with or without secondary generalization. N01379 is an open-label, multicenter, 
long-term follow up study for N01358 which is the pivotal global efficacy study for BRV used as 
adjunctive treatment in adult subjects (≥16 to 80 years of age) with partial seizures with or 
without secondary generalization. 
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Has been changed to: 
EP0085 will explore the long-term safety and efficacy of BRV in subjects. EP0085 will include 
subjects who have completed EP0083 and will also provide the opportunity for Japanese subjects 
from N01379 to continue BRV treatment. The proposed study is intended to provide evidence of 
the long-term safety and efficacy of BRV as adjunctive therapy in subjects with partial seizures. 
Doses of BRV 50 to 200mg/day will be assessed with reference to EP0083. EP0083 is an 
adequate and well-controlled study to provide additional data confirming the efficacy and safety 
of BRV as an AED in subjects (≥16 to 80 years of age) with partial seizures with or without 
secondary generalization. N01379 is an open-label, multicenter, long-term follow up study for 
N01358 which is the pivotal global efficacy study for BRV used as adjunctive treatment in adult 
subjects (≥16 to 80 years of age) with partial seizures with or without secondary generalization. 
Change #6 
Section 4 Study variables 
4.1 Safety variables 
4.1.1 Primary safety variables 
The primary safety variables include: 
• AEs 
• Withdrawal due to AEs 
• Occurrence of SAEs 
4.1.2 Secondary safety variables 
The secondary safety variables include: 
• Laboratory tests (blood chemistry, hematology, and urinalysis) 
• Vital signs 
• Body weight  
• ECG 
• Physical examination  
• Neurological examination 
Have been changed to: 
4.1 Safety variables 
4.1.1 Primary safety variables 
The primary safety variable is AEs. 
4.1.2 Exploratory safety variables 
The exploratory safety variables are as follows: 
• Laboratory tests (blood chemistry, hematology, and urinalysis) 
• Vital signs 
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• Body weight  
• 12-lead ECG 
• Physical examination  
• Neurological examination 
• Mental status  
• Psychiatric status  
Change #7 
Section 5.1 Study description 
The subject population will be Japanese subjects (≥16 years of age) with partial seizures with or 
without secondary generalization. 
Subjects from N01379 can enter EP0085 at a dose up to 200mg/day. After Visit 1, the next visit 
for subjects entering from N01379 will be Visit 4 (Visit 2 and Visit 3 will not be conducted). 
Have been changed to: 
The subject population will be subjects (≥16 years of age) with partial seizures with or without 
secondary generalization. 
Japanese subjects from N01379 can enter EP0085 at a dose up to 200mg/day. After Visit 1, the 
next visit for subjects entering from N01379 will be Visit 4 (Visit 2 and Visit 3 will not be 
conducted). 
Change #8 
Section 5.1.1 Study duration per subject 
EP0085 will continue until the date of the market approval of BRV, or until the sponsor decides 
to close the study or until BRV development is stopped by the sponsor. EP0085 will continue as 
a postmarketing clinical study until approximately 6 months after the date of BRV approval for 
the partial seizure indication.  
Have been changed to: 
EP0085 will continue until the later date on which the date of the market approval of BRV or 
one year after each subject has entered into EP0085, or until the sponsor decides to close the 
study. In the event that market approval is not obtained in the participant country, the 
subject will be able to continue in EP0085 for two years after entering EP0085. 
In Japan, EP0085 will continue as a postmarketing clinical study until approximately 6 months 
after the date of BRV approval for the partial seizure indication.  
Change #9 
Section 5.1.2 Planned number of subjects and sites 
It is estimated that approximately 124 subjects will enter the study, based on the assumption that 
at least 90% of randomized subjects will complete EP0083 or enroll from N01379 sites in Japan.  
It is estimated that 30 sites will participate in the study. 
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Has been changed to: 
Approximately 227 subjects in total are expected to enter the study based on the 
assumption that 90% of randomized subjects will complete EP0083 in all participating 
countries or enroll from N01379 sites in Japan. 
It is estimated that approximately 124 Japanese subjects will enter the study, based on the 
assumption that at least 90% of randomized Japanese subjects will complete EP0083 or enroll 
from N01379 sites in Japan.  
It is estimated that 65 sites will participate in the study. 
Change #10 
Section 5.1.3 Anticipated regions and countries 
All sites in this study will be conducted in Japan. 
Has been changed to: 
The study is planned to be conducted in Japan, South Korea, Bulgaria, and Poland with 
possible extension to other countries or regions. 
Change #11 
Section 12 Statistics 
The following sentence was added: 
For subjects from EP0083, subgroup analyses for Japanese and non-Japanese subjects will 
be conducted as well as analyses for the entire population. 
Change #12 
Section 12.8 Determination of sample size 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. It is estimated that 
approximately 124 subjects will enter the study based on the assumption that at least 90% of 
randomized subjects will complete EP0083 or enter from N01379 sites in Japan. 
Has been changed to: 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. Approximately 227 
subjects in total are expected to enter the study based on the assumption that 90% of 
randomized subjects will complete EP0083 in all participating countries or enroll from 
N01379 sites in Japan. It is estimated that approximately 124 Japanese subjects will enter the 
study based on the assumption that at least 90% of randomized Japanese subjects will complete 
EP0083 or enter from N01379 sites in Japan. 
 
 
 
 
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16.6 
Appendix 6 - Protocol Amendment 3 
Rationale 
The purpose of this protocol amendment is to update the following: 
• Update the Sponsor/Local Legal Representatives 
• Add China as a participating country 
• Include SAE reporting information for China 
• Update the number of subjects expected to enter the study  
• Change exploratory safety variable to other safety variable 
In addition, minor administrative edits including typographical changes for formatting have been 
made. 
Modifications and changes 
Global Changes 
The “exploratory safety variable” language was changed to “other safety variable” throughout 
the protocol. 
Specific changes 
Change #1 
STUDY CONTACT INFORMATION, Sponsor/Local Legal Representative 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
JAPAN 
Has been changed to: 
UCB BIOPHARMA SPRL 
UCB Japan Co. Ltd. 
UCB Trading (Shanghai) Co., 
Ltd. 
Allée de la Recherche 60 
Shinjuku Grand Tower  
317 Room No.
 
8-17-1 Nishi-Shinjuku 
Futexi Yi road, China 
(Shanghai) 
Shinjuku-ku 
Pilot Free Trade Zone 
1070 Brussels 
Tokyo 160-0023 
Shanghai 200131 
BELGIUM 
JAPAN 
PRC 
 
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Change #2 
STUDY CONTACT INFORMATION  
Medical Expert 
Has been changed to: 
Medical Expert in Japan 
Change #3 
STUDY CONTACT INFORMATION 
A placeholder was added for the National Principal Investigator in China 
Change #4 
STUDY CONTACT INFORMATION, Sponsor Study Physician 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Has been changed to: 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Change #5 
STUDY CONTACT INFORMATION, 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: 
Has been changed to: 
Name: 
 
Address: 
Allée de la Recherche 60 
B- 1070 Brussels, BELGIUM 
Phone: 
Fax: 
Change #6 
The following serious adverse event reporting information was added for China 
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Serious adverse event reporting (24 hours) for China 
Fax 
UCB China: +86-21-23210206 
Email 
UCB China: ds.China@ucb.com 
Change #7 
Summary, third paragraph, last sentence 
The following sentence was removed. 
In the event that subjects are converted to commercial BRV, they may complete the study 
without down-titration if, when, and where available. 
Change #8 
Summary, sixth paragraph, second sentence 
Exploratory safety variables include safety laboratory tests (blood chemistry, hematology, and 
urinalysis), vital signs, body weight, electrocardiograms (ECGs), physical and neurological 
examinations, and mental and psychiatric status. 
Has been changed to: 
Other safety variables include safety laboratory tests (blood chemistry, hematology, and 
urinalysis), vital signs, body weight, electrocardiograms (ECGs), physical and neurological 
examinations, and mental and psychiatric status. 
Change #9 
Summary, last two paragraphs 
Approximately 227 subjects in total are expected to enter the study based on the assumption that 
90% of randomized subjects will complete EP0083 in all participating countries or enroll from 
N01379 sites in Japan.  
 It is estimated that approximately 124 subjects will enter the study, based on the assumption that 
at least 90% of Japanese randomized subjects will complete EP0083 or enroll 
Has been changed to: 
Approximately 227 subjects in total are expected to enter the study based on the assumption that 
90% of randomized subjects will complete EP0083 in all participating countries or enroll from 
N01379 sites in Japan.  
 In Japan, it is estimated that approximately 124 subjects will enter the study, based on the 
assumption that at least 90% of Japanese randomized subjects will complete EP0083 or enroll 
from N01379 sites in Japan.  Likewise, at least 90% of randomized Chinese subjects will be 
assumed to complete EP0083. 
Change #10 
Section 2.4 Safety with BRV 
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In the BRV clinical development program, 3822 subjects were exposed to BRV (unique 
exposures) as of 14 Jul 2016. 
Has been changed to: 
In the BRV clinical development program, 3970 subjects have been exposed to BRV (unique 
exposures) as of 14 Jan 2019.  
Change #11 
Section 2.5 Rationale for the study 
EP0085 will explore the long-term safety and efficacy of BRV in subjects. EP0085 will include 
subjects who have completed EP0083 and will also provide the opportunity for Japanese subjects 
from N01379 to continue BRV treatment. 
Has been changed to: 
EP0085 will explore the long-term safety and efficacy of BRV in subjects in Japan and China. 
EP0085 will include subjects who have completed EP0083.  In addition, the study will also 
provide the opportunity for Japanese subjects from N01379 to continue BRV treatment.  
Change #12 
Section 4.1.2 Exploratory safety variables 
The exploratory safety variables are as follows: 
Has been changed to: 
Section 4.1.2 Other safety variables 
The other safety variables are as follows: 
Change #13 
Section 5.1 Study description, first sentence 
EP0085 is a Phase 3, open-label, LTFU, multicenter, noncomparative, and dose flexible study. 
Has been changed to: 
EP0085 is a Phase 3, open-label, LTFU, multicenter, noncomparative, and dose flexible study to 
be conducted in Japan and China. 
Change #14 
Section 5.1.1 Study duration per subject, last two paragraphs 
EP0085 will continue until the later date on which the date of the market approval of BRV or one 
year after each subject has entered into EP0085, or until the sponsor decides to close the study. 
In the event that market approval is not obtained in the participant country, the subject will be 
able to continue in EP0085 for two years after entering EP0085. 
In Japan, EP0085 will continue as a postmarketing clinical study until approximately 6 months 
after the date of BRV approval for the partial seizure indication. 
Has been changed to: 
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EP0085 will continue until the later date on which the date of the market approval of BRV or one 
year after each subject has entered into EP0085, or until the sponsor decides to close the study, 
whichever comes first. In the event that market approval is not obtained in the participant 
country, the subject will be able to continue in EP0085 for two years after entering EP0085. 
In Japan and China, EP0085 will continue as a postmarketing clinical study until approximately 
6 months after the date of BRV approval for the partial seizure indication. 
Change #15 
Section 5.1.2 Planned number of subjects and sites, second paragraph 
Approximately 227 subjects in total are expected to enter the study based on the assumption that 
90% of randomized subjects will complete EP0083 in all participating countries or enroll from 
N01379 sites in Japan. 
It is estimated that approximately 124 Japanese subjects will enter the study, based on the 
assumption that at least 90% of randomized Japanese subjects will complete EP0083 or enroll 
from N01379 sites in Japan. 
It is estimated that 65 sites will participate in the study. 
Has been changed to: 
Approximately 227 subjects in total are expected to enter the study based on the assumption that 
90% of randomized subjects will complete EP0083 in all participating countries or enroll from 
N01379 sites in Japan. 
In Japan, it is estimated that approximately 124 subjects will enter the study, based on the 
assumption that at least 90% of randomized Japanese subjects will complete EP0083 or enroll 
from N01379 sites in Japan.  Likewise, at least 90% of randomized Chinese subjects will be 
assumed to complete EP0083. 
In China Mainland, it is estimated that approximately 90 subjects will enter the study, 
based on the assumption that at least 90% of randomized Chinese subjects will complete 
EP0083. 
It is estimated that approximately 50 Japan sites and 25 China Mainland sites will participate 
in the study. 
Change #16 
Section 5.1.3 Anticipated regions and countries 
The study is planned to be conducted in Japan, South Korea, Bulgaria, and Poland with possible 
extension to other countries or regions. 
Has been changed to: 
The study is planned to be conducted in Japan and China Mainland. 
Change #17 
Section 7.2 Treatments to be administered, second paragraph 
Subjects who entered from N01379 can enter EP0085 at a dose up to 200mg/day. 
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Has been changed to: 
Subjects from Japan who entered from N01379 can enter EP0085 at a dose up to 200mg/day. 
Change #18 
Section 7.10 Randomization and numbering of subjects, last sentence in first 
paragraph 
Subjects from N01379 can enter EP0085 at a dose up to 200mg/day. 
Has been changed to: 
Subjects from Japan who participated in N01379 can enter EP0085 at a dose up to 200mg/day. 
Change #19 
Section 12 Statistics, second sentence 
For subjects from EP0083, subgroup analyses for Japanese and non-Japanese subjects will be 
conducted as well as analyses for the entire population. 
Has been changed to: 
For subjects from EP0083, subgroup analyses for Japanese and Chinese subjects will be 
conducted as well as analyses for the entire population. 
Change #20 
Section 12.8 Determination of sample size, second sentence 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. Approximately 227 
subjects in total are expected to enter the study based on the assumption that 90% of randomized 
subjects will complete EP0083 in all participating countries or enroll from N01379 sites in 
Japan. It is estimated that approximately 124 Japanese subjects will enter the study based on the 
assumption that at least 90% of randomized Japanese subjects will complete EP0083 or enter 
from N01379 sites in Japan. 
Has been changed to: 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. In Japan, it is 
estimated that approximately 124 Japanese subjects will enter the study, based on the assumption 
that at least 90% of randomized Japanese subjects will complete EP0083 or enroll from N01379 
sites in Japan. Likewise, at least 90% of randomized Chinese subjects will be assumed to 
complete EP0083.
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16.7 
Appendix 7 – Protocol Amendment 3.1 (Japan) 
Rationale 
The purpose of this local protocol amendment is to update the following: 
• Add a cohort of directly enrolled subjects for sites in Japan. 
• Add inclusion criteria for direct enrollers to avoid overlap with the patient population of 
EP0083. 
• Remove LEV from the list of prohibited concomitant medications for directly enrolled 
subjects in Japan. 
In addition, minor administrative edits including typographical changes for formatting have been 
made. 
Global Changes 
In Japan, a cohort of direct enrollers was added. 
Modifications and changes 
Specific changes 
Change #1 
Study contact information 
The National Leading Principal Investigator in China information was removed for this local 
protocol amendment for Japan. 
A fax number was added for the Clinical Project Manager 
Change #2 
Summary, third and fourth paragraphs 
In addition, Japanese subjects participating in N01379, the long-term open-label extension to the 
Phase 3, placebo-controlled study N01358, can enter into this study. Upon completion or early 
discontinuation from EP0085, there will be a Down-Titration Period, followed by a 2-week 
Study Drug-Free Period during which the subject will not receive study drug.  
Subjects from EP0083 will be started on oral BRV at a dose of 100mg/day (2 equally divided 
doses administered twice daily) at study entry and should be maintained at this dose for at least 
2 weeks, unless the subject is unable to tolerate treatment. Subjects from N01379 can enter 
EP0085 at a dose up to 200mg/day. 
Have been changed to: 
Japanese subjects participating in N01379, the long-term open-label extension to the Phase 3, 
placebo-controlled study N01358, can enter into this study. Upon completion or early 
discontinuation from EP0085, there will be a Down-Titration Period, followed by a 2-week 
Study Drug-Free Period during which the subject will not receive study drug.  
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In addition, for accumulating safety data, subjects in Japan that have well-characterized 
focal epilepsy with seizures that are uncontrolled in spite of treatment with at least 
1 permitted AED, having experienced 1 to <8 partial seizures within the 8 weeks prior to 
BRV administration may be directly enrolled. 
Directly enrolled subjects and subjects from EP0083 will be started on oral BRV at a dose of 
100mg/day (2 equally divided doses administered twice daily) at study entry and should be 
maintained at this dose for at least 2 weeks, unless the subject is unable to tolerate treatment. 
Subjects from N01379 can enter EP0085 at a dose up to 200mg/day. 
Change #3 
Summary, bulleted list of efficacy variables 
The following efficacy variables for directly enrolled subjects in Japan were added: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 
8 weeks prior to BRV administration 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized, and unclassified epileptic seizure) for at least 6 months and at 
least 12 months during the Evaluation Period 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
Change #4 
Summary, last paragraph 
In Japan, it is estimated that approximately 124 subjects will enter the study, based on the 
assumption that at least 90% of randomized Japanese subjects will complete EP0083 or enroll 
from N01379 sites in Japan. Likewise, at least 90% of randomized Chinese subjects will be 
assumed to complete EP0083. 
Has been changed to: 
Overall, approximately 217 subjects are planned for enrollment. In Japan, it is estimated that 
approximately 127 subjects will enter the study, based on the assumption that at least 90% of 
randomized Japanese subjects will complete EP0083 (approximately 90 subjects) or enroll 
from N01379 sites in Japan (7 subjects) and the plan that approximately 30 Japanese 
subjects will be directly enrolled in this study. Likewise, at least 90% of randomized Chinese 
subjects will be assumed to complete EP0083 (approximately 90 subjects). 
Change #5 
Section 2.5, Rationale for the study 
EP0085 will explore the long-term safety and efficacy of BRV in subjects in Japan and China. 
EP0085 will include subjects who have completed EP0083.  In addition, the study will also 
provide the opportunity for Japanese subjects from N01379 to continue BRV treatment.  
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The proposed study is intended to provide evidence of the long-term safety and efficacy of BRV 
as adjunctive therapy in subjects with partial seizures. Doses of BRV 50 to 200mg/day will be 
assessed with reference to EP0083. EP0083 is an adequate and well-controlled study to provide 
additional data confirming the efficacy and safety of BRV as an AED in subjects (≥16 to 
80 years of age) with partial seizures with or without secondary generalization. N01379 is an 
open-label, multicenter, long-term follow up study for N01358 which is the pivotal global 
efficacy study for BRV used as adjunctive treatment in adult subjects (≥16 to 80 years of age) 
with partial seizures with or without secondary generalization. 
Has been changed to: 
EP0085 will explore the long-term safety and efficacy of BRV in subjects in Japan and China. 
EP0085 will include subjects who have completed EP0083, Japanese subjects from N01379, and 
directly enrolled Japanese subjects.  
The proposed study is intended to provide evidence of the long-term safety and efficacy of BRV 
as adjunctive therapy in subjects with partial seizures. Doses of BRV 50 to 200mg/day will be 
assessed with reference to EP0083. EP0083 is an adequate and well-controlled study to provide 
additional data confirming the efficacy and safety of BRV as an AED in subjects (≥16 to 
80 years of age) with partial seizures with or without secondary generalization. N01379 is an 
open-label, multicenter, long-term follow up study for N01358 which is the pivotal global 
efficacy study for BRV used as adjunctive treatment in adult subjects (≥16 to 80 years of age) 
with partial seizures with or without secondary generalization. For sites in Japan, subjects with 
uncontrolled seizures treated by at least 1 permitted concomitant AED may be directly 
enrolled in order to provide additional safety and efficacy data with BRV. 
Change #6 
Section 4.1.3, Efficacy variables 
The following efficacy variables for directly enrolled subjects in Japan were added: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 
weeks prior to BRV administration 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized, and unclassified epileptic seizure) for at least 6 months and at 
least 12 months during the Evaluation Period 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
Change #7 
Section 5.1, Study description, first 3 paragraphs 
EP0085 is a Phase 3, open-label, LTFU, multicenter, noncomparative, and dose flexible study to 
be conducted in Japan and China. The subject population will be subjects (≥16 years of age) with 
partial seizures with or without secondary generalization. Subjects of a minor age are included 
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only where legally permitted and ethically accepted. Subjects must complete the Treatment and 
Transition Period of EP0083 prior to enrollment into EP0085.  
In addition, Japanese subjects participating in N01379, the long-term open-label extension to the 
Phase 3, placebo-controlled study N01358, can enter into this study. Upon completion or early 
discontinuation from EP0085, there will be a Down-Titration Period, followed by a 2-week 
Study Drug-Free Period during which the subject will not receive study drug. 
Subjects from EP0083 will be started on oral BRV at a dose of 100mg/day (2 equally divided 
doses administered twice daily) at study entry and should be maintained at this dose for at least 
2 weeks, unless the subject is unable to tolerate treatment.  
Have been changed to: 
EP0085 is a Phase 3, open-label, LTFU, multicenter, noncomparative, and dose flexible study to 
be conducted in Japan and China. The population will be subjects (≥16 years of age) with partial 
seizures with or without secondary generalization. Subjects of a minor age are included only 
where legally permitted and ethically accepted. In Japan, subjects meeting the inclusion and 
exclusion criteria as specified in Section 6.1 may be directly enrolled. Rollover subjects must 
complete the Treatment and Transition Period of EP0083 prior to enrollment into EP0085.  
In addition, Japanese subjects participating in N01379, the long-term open-label extension to the 
Phase 3, placebo-controlled study N01358, may enter this study. Upon completion or early 
discontinuation from EP0085, there will be a Down-Titration Period, followed by a 2-week 
Study Drug-Free Period during which the subject will not receive study drug. 
Directly enrolled subjects in Japan and rollover subjects from EP0083 will be started on oral 
BRV at a dose of 100mg/day (2 equally divided doses administered twice daily) at study entry 
and should be maintained at this dose for at least 2 weeks, unless the subject is unable to tolerate 
treatment.  
Change #8 
Section 5.1.1, Study duration per subject 
Text added to define the Screening Visit for direct enrollers in Japan: 
• Screening Visit (Visit 0, up to 3 weeks before the Entry Visit (EV) for direct enrollers in 
Japan only) 
Change #9 
Section 5.1.2, Planned number of subjects and sites, first paragraph 
In Japan, it is estimated that approximately 124 subjects will enter the study, based on the 
assumption that at least 90% of randomized Japanese subjects will complete EP0083 or enroll 
from N01379 sites in Japan. Likewise, at least 90% of randomized Chinese subjects will be 
assumed to complete EP0083. 
Has been changed to: 
Overall, approximately 217 subjects are planned for enrollment. In Japan, it is estimated that 
approximately 127 subjects will enter the study. This estimate assumes that at least 90% of 
randomized Japanese subjects will complete EP0083 (approximately 90 subjects) or enroll 
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from N01379 sites in Japan (7 subjects) and the plan that 30 Japanese subjects will be 
directly enrolled in this study.  
Change #10 
Section 5.2, Schedule of study assessments 
The title of Table 5-1 has been changed to: 
Schedule of study assessments for subjects transitioning from EP0083 to N01379 
Table 5-2 has been added, presenting the schedule of study assessments for directly 
enrolled subjects in Japan. 
Change #11 
Section 5.3, Schematic diagram 
Table 5-3, Full visit schedule, was revised to add the Screening Visit for directly enrolled 
subjects in Japan. 
Change #12 
Section 5.4, Rationale for study design and selection of dose, first paragraph 
Subjects from EP0083 will be started on a BRV dose of 100mg/day (2 equally divided doses 
administered twice daily) at study entry and should be maintained at this dose for at least 
2 weeks, unless the subject is not able to tolerate treatment. Subjects who entered from N01379 
can enter EP0085 at a dose up to 200mg/day. The BRV 50 to 200mg/day is approved as the 
effective dose of BRV for adults in EU/US without titration. The BRV dose can be adjusted 
based on the individual subject’s seizure control and tolerability between 50mg/day and 
200mg/day during the study and must always be administered as a symmetrical morning and 
evening dose except the last week of down-titration. Of note, decreasing the dose should not 
exceed 50mg/day. Study medication in the last week of down-titration is given only in the 
morning. 
Has been changed to: 
Directly enrolled subjects and subjects from EP0083 will be started on a BRV dose of 
100mg/day (2 equally divided doses administered twice daily) at study entry and should be 
maintained at this dose for at least 2 weeks, unless the subject is not able to tolerate treatment. 
Subjects who entered from N01379 can enter EP0085 at a dose up to 200mg/day. The BRV 50 to 
200mg/day is approved as the effective dose of BRV for adults in EU/US without titration. The 
BRV dose can be adjusted based on the individual subject’s seizure control and tolerability 
between 50mg/day and 200mg/day during the study and must always be administered in equal 
morning and evening doses except the last week of down-titration. Of note, decreasing the dose 
should not exceed 50mg/day. Study medication in the last week of down-titration is given only in 
the morning. 
Change #13 
Section 6, Selection and withdrawal of subjects 
The inclusion and exclusion criteria were reorganized to present them separately for China 
and Japan. Criteria for the directly enrolled cohort was added. 
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Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent signed and dated by the subject or by parent(s) or legally representative. 
The consent form or a specific assent form, where required, will be signed and dated by 
minors. 
2. Male/female subject from 16 years of age or older. Subjects who are not legal adults may 
only be included where legally permitted and ethically accepted. 
3. Subject completed the Treatment Period and Transition Period of EP0083 or is ongoing in 
N01379 sites in Japan. 
4. Subject for whom the Investigator believes a reasonable benefit from the long-term 
administration of BRV may be expected. 
5. Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral 
oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive method. 
Oral or depot contraceptive treatment with at least approved dosage of ethinylestradiol per 
intake in each country where this study is conducted (if subjects is taking any enzyme 
inducer such as carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. 
John’s Wort or rifampicin, the dosage of ethinylestradiol should have been modified 
according to the guidelines for contraceptive treatment in each country), monogamous 
relationship with vasectomized partner, or barrier contraception are acceptable methods. The 
subject must understand the consequences and potential risks of inadequately protected 
sexual activity, be educated about and understand the proper use of contraceptive methods, 
and undertake to inform the Investigator of any potential change in status. Abstinence will be 
considered as an acceptable method of contraception if the Investigator can document that 
the subject agrees to be compliant. 
6. Subject/legally representative considered as reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries and questionnaires), visit schedule, or 
medication intake according to the judgment of the Investigator. 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has developed hypersensitivity to any components of the IMP or comparative drugs 
as stated in this protocol during the course of the core study. 
2. Severe medical, neurological or psychiatric disorders, or laboratory values which may have 
an impact on the safety of the subject. 
3. Poor compliance with the visit schedule or medication intake in the previous BRV studies. 
4. Planned participation in any other clinical study of another investigational drug or device 
during this study. 
5. Pregnant or lactating woman. 
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6. Any medical condition which, in the Investigator’s opinion, warrants exclusion. 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the Entry Visit (EV). 
8. Subject has >2 x upper limit of normal (ULN) of any of the following at the EV: 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%. 
Have been changed to:  
Eligibility criteria in Japan 
Inclusion criteria for all subjects 
To be eligible to participate in this study, all of the following criteria must be met for all 
subjects in Japan: 
1. An IRB/IEC approved written informed consent signed and dated by the subject or by 
parent(s) or legally representative. The consent form or a specific assent form, where required, 
will be signed and dated by minors. 
2. Male/female subject from 16 years of age or older. Subjects who are not legal adults may 
only be included where legally permitted and ethically accepted. 
4. Subject for whom the Investigator believes a reasonable benefit from the long-term 
administration of BRV may be expected. 
5. Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral 
oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive method. 
Oral or depot contraceptive treatment with at least approved dosage of ethinylestradiol per 
intake in each country where this study is conducted (if subjects is taking any enzyme 
inducer such as carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. 
John’s Wort or rifampicin, the dosage of ethinylestradiol should have been modified 
according to the guidelines for contraceptive treatment in each country), monogamous 
relationship with vasectomized partner, or barrier contraception are acceptable methods. The 
subject must understand the consequences and potential risks of inadequately protected 
sexual activity, be educated about and understand the proper use of contraceptive methods, 
and undertake to inform the Investigator of any potential change in status. Abstinence will be 
considered as an acceptable method of contraception if the Investigator can document that 
the subject agrees to be compliant. 
6. Subject/legally representative considered as reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries and questionnaires), visit schedule, or 
medication intake according to the judgment of the Investigator. 
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Additional inclusion criteria for rollover subjects 
In addition to the inclusion criteria for all subjects in Japan (Section 6.1.1), the following 
criteria must also be met for rollover subjects in Japan:  
3. Subject completed the Treatment Period and Transition Period of EP0083 or is ongoing in 
N01379 sites in Japan. 
Additional inclusion criteria for directly enrolled subjects 
In addition to the inclusion criteria for all subjects in Japan (Section 6.1.1), the following 
criteria must also be met for directly enrolled subjects in Japan:  
7. Subject has a body weight ≥40kg at the Screening Visit (SV). 
8. Subject has well-characterized focal epilepsy/epileptic syndrome according to the 1989 
ILAE classification. 
9. Subject has had an electroencephalogram (EEG) reading compatible with the clinical 
diagnosis of focal epilepsy within the last 10 years. If there is no appropriate EEG 
available within the last 10 years, a Baseline EEG must be scheduled at the SV and the 
results received before the EV. 
10. Subject has 1 to <8 partial seizures (according to the 1981 ILAE classification) during 
the 8 weeks prior to BRV administration. 
11. Subject’s seizures are uncontrolled while treated by at least 1 permitted concomitant 
AED. Vagal nerve stimulation (VNS) will be allowed and counted as a concomitant 
AED. 
Exclusion criteria for all subjects 
Subjects in Japan are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has developed hypersensitivity to any components of the IMP or comparative drugs 
as stated in this protocol during the course of the core study. 
2. Severe medical, neurological or psychiatric disorders, or laboratory values which may have 
an impact on the safety of the subject. 
4. Planned participation in any other clinical study of another investigational drug or device 
during this study. 
5. Pregnant or lactating woman. 
6. Any medical condition which, in the Investigator’s opinion, warrants exclusion. 
Exclusion criteria for rollover subjects 
In addition to the exclusion criteria for all subjects in Japan (Section 6.1.4), the following 
exclusion criteria also apply for rollover subjects in Japan: 
3. Poor compliance with the visit schedule or medication intake in the previous BRV studies. 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
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positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS at the Entry Visit 
(EV). 
8. Subject has >2xULN of any of the following at the EV: ALT, AST, ALP, or >ULN total 
bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). 
If subject has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate 
bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
Exclusion criteria for directly enrolled subjects 
In addition to the exclusion criteria for all subjects in Japan (Section 6.1.4), the following 
exclusion criteria also apply for directly enrolled subjects in Japan: 
9. Subject has participated in another study of an investigational medication (or a medical 
device) within the last 30 days or is currently participating in another study of an 
investigational medication (or a medical device). 
10. Subject has a lifetime history of suicide attempt (including an active attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months 
as indicated by a positive response (”Yes”) to either Question 4 or Question 5 of the C-
SSRS at the SV. 
11. Subject has >2xULN of any of the following at the SV: ALT, AST, ALP, or >ULN total 
bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). 
If subject has elevations only in total bilirubin that are >ULN and <1.5xULN, 
fractionate bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct 
bilirubin <35%). 
For 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. 
12. Subject previously enrolled in this study or any other prior study with BRV as a dosing 
arm. 
13. Subject has experienced febrile seizures exclusively. The occurrence of febrile seizures 
in addition to other unprovoked seizures is not exclusionary. 
14. Subject/legal representative is not able to read and understand the Informed Consent 
form (ICF), Assent form, or daily record card (DRC) instructions. 
15. Subject has a history or presence of status epilepticus during the 30 days preceding the 
SV. 
16. Subject has a history or presence of known psychogenic nonepileptic seizures. 
17. Study participant has been treated with vigabatrin and has visual field defects. 
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18. Subject is taking any drug that significantly influences the metabolism of BRV 
(cytochrome P450 strong inducers such as rifampin/rifampicin) except if the dose has 
been kept stable at least 4 weeks before the SV. 
19. Subject has presence of any sign (clinical or imaging techniques) suggesting rapidly 
progressing (ie, not expected to stay stable during study participation) brain disorder or 
brain tumor per investigator assessment. Stable arteriovenous malformations, 
meningiomas, or other benign tumors may be acceptable. 
20. Subject has any clinical conditions (eg, bone marrow suppression, severe renal 
impairment) which, per investigator discretion, impair reliable participation in the 
study or necessitate the use of medication not allowed by protocol. 
21. Subject has the presence of a terminal illness. 
22. Subject has the presence of a serious infection. 
23. Subject has clinically significant laboratory abnormality that may increase the risk 
associated with study participation or may interfere with the interpretation of study 
results, according to the Investigator. 
24. Subject has clinically significant ECG abnormalities according to the Investigator. 
25. Subject has known alcohol or drug addiction or abuse within the last 2 years.  
Eligibility criteria in China 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met for subjects in 
China: 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent signed and dated by the subject or by parent(s) or legally representative. 
The consent form or a specific assent form, where required, will be signed and dated by 
minors. 
2. Male/female subject from 16 years of age or older. Subjects who are not legal adults may 
only be included where legally permitted and ethically accepted. 
3. Subject completed the Treatment Period and Transition Period of EP0083. 
4. Subject for whom the Investigator believes a reasonable benefit from the long-term 
administration of BRV may be expected. 
5. Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral 
oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive method. 
Oral or depot contraceptive treatment with at least approved dosage of ethinylestradiol per 
intake in each country where this study is conducted (if subjects is taking any enzyme 
inducer such as carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. 
John’s Wort or rifampicin, the dosage of ethinylestradiol should have been modified 
according to the guidelines for contraceptive treatment in each country), monogamous 
relationship with vasectomized partner, or barrier contraception are acceptable methods. The 
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subject must understand the consequences and potential risks of inadequately protected 
sexual activity, be educated about and understand the proper use of contraceptive methods, 
and undertake to inform the Investigator of any potential change in status. Abstinence will be 
considered as an acceptable method of contraception if the Investigator can document that 
the subject agrees to be compliant. 
6. Subject/legally representative considered as reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries and questionnaires), visit schedule, or 
medication intake according to the judgment of the Investigator. 
Exclusion criteria 
Subjects in China are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has developed hypersensitivity to any components of the IMP or comparative drugs 
as stated in this protocol during the course of the core study. 
2. Severe medical, neurological or psychiatric disorders, or laboratory values which may have 
an impact on the safety of the subject. 
3. Poor compliance with the visit schedule or medication intake in the previous BRV studies. 
4. Planned participation in any other clinical study of another investigational drug or device 
during this study. 
5. Pregnant or lactating woman. 
6. Any medical condition which, in the Investigator’s opinion, warrants exclusion. 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the EV. 
8. Subject has >2 x upper limit of normal (ULN) of any of the following at the EV: 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%). 
Change #14 
Section 7.2, Treatments to be administered, paragraphs 1, 2, and 3 
Subjects will be started on a BRV dose of 100mg/day (2 equally divided doses administered 
twice daily) at study entry and should be maintained at this dose for at least 2 weeks, unless the 
subject is not able to tolerate treatment.  
Subjects from Japan who entered from N01379 can enter EP0085 at a dose up to 200mg/day. 
The BRV dose can be adjusted based on the individual subject’s seizure control and tolerability 
between 50mg/day and 200mg/day during the study and must always be administered as a 
symmetrical morning and evening dose except the last week of down-titration. Of note, 
decreasing the dose should not exceed 50mg/day. 
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The first intake of study medication should occur in the evening of the day of the EV. Subjects 
should take tablets according to instructions provided by the Investigator. 
Has been changed to: 
Directly enrolled subjects in Japan and subjects rolling over from EP0083 will be started on 
a BRV dose of 100mg/day (2 equally divided doses administered twice daily) at study entry and 
should be maintained at this dose for at least 2 weeks, unless the subject is not able to tolerate 
treatment.  
Subjects from Japan who entered from N01379 can enter EP0085 at a dose up to 200mg/day. 
The BRV dose can be adjusted based on the individual subject’s seizure control and tolerability 
between 50mg/day and 200mg/day during the study and must always be administered in equal 
morning and evening doses except the last week of down-titration. Of note, decreasing the dose 
should not exceed 50mg/day. 
For all subjects, the first intake of study medication should occur in the evening of the day of 
the EV. Subjects should take tablets according to instructions provided by the Investigator. 
Change #15 
Section 7.8.1, Permitted concomitant treatments, first paragraph 
At the beginning of EP0085, the concomitant AEDs that were used in EP0083 and N01379 are 
permitted. 
Has been changed to:  
At the beginning of EP0085, the concomitant AEDs that were used in EP0083 and N01379 are 
permitted for rollover subjects. Subjects directly enrolled into EP0085 in Japan will enter 
the study receiving at least 1 permitted concomitant AED.  
Change #16 
Section 7.8.2, Prohibited concomitant treatments 
Additional text was added to note that LEV is permitted for directly enrolled subjects in Japan 
only. 
− LEV (LEV is not prohibited for directly enrolled subjects in Japan) 
Change #17 
Section 8.1, Screening Visit (for direct enrollers in Japan only) 
New section added to describe the tasks and procedures to be performed during the 
Screening Visit for direct enrollers. 
Change #18 
Section 8.2, Entry Visit (for direct enrollers in Japan only) 
New section added to describe the tasks and procedures to be performed during the Entry 
Visit for direct enrollers. 
Change #19 
Section 8.3, Entry Visit (rollovers from China and Japan only) 
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Section heading revised to clarify the information presented describing the Entry Visit is 
for rollover subjects only. 
Change #20 
Section 8.4, Minimal Evaluation Visits (all subjects) 
Section heading revised to clarify the information presented describing the MEV is for all 
subjects. 
Change #21 
Section 8.5, Full Evaluation Visits (all subjects) 
Section heading revised to clarify the information presented describing the FEV is for all 
subjects. 
Change #22 
Section 8.6, Yearly Evaluation Visits (all subjects) 
Section heading revised to clarify the information presented describing the YEV is for all 
subjects. 
Change #23 
Section 8.7, End of Study Visit or Early Discontinuation Visit (all subjects) 
Section heading revised to clarify the information presented describing the EOS or EDV is 
for all subjects. 
Change #24 
Section 8.8, Final Visit (all subjects) 
Section heading revised to clarify the information presented describing the FV is for all 
subjects. 
Change #25 
Section 8.9, Unscheduled Visit (all subjects) 
Section heading revised to clarify the information presented describing the UV is for all 
subjects. 
Change #26 
Section 10.2, Laboratory measurements, seventh paragraph 
Laboratory safety assessments at the EV will be taken from the last visit of EP0083 or N01379 
and do not need to be recorded on the eCRF. Laboratory safety assessments will be performed at 
time points specified in the schedule of study assessments (Table 5‒1). 
Has been changed to: 
For rollover subjects in China and Japan, laboratory safety assessments at the EV will be 
taken from the last visit of EP0083 or N01379 and do not need to be recorded on the eCRF. 
Laboratory safety assessments will be performed at time points specified in the schedules of 
study assessments (Table 5‒1 and Table 5-2).  
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Change #27 
Section 10.3.1, ECG, first paragraph 
A standard 12-lead ECG will be performed at protocol specified time points according to the 
Study schedule of assessments (Table 5‒1). At the EV, data will be obtained from the last visit of 
the previous study and should not be recorded in the eCRF. At the FV, a 12-lead ECG is 
mandatory, except if the FV follows an EDV where ECG results were normal. The Investigator 
will determine whether the results of the ECG are normal or abnormal and assess the clinical 
significance of any abnormalities. 
Has been changed to: 
A standard 12-lead ECG will be performed at protocol specified time points according to the 
schedules of study assessments (Table 5‒1 and Table 5-2).  
For rollover subjects in China and Japan, data will be obtained from the last visit of the 
previous study and should not be recorded in the eCRF at the EV. At the FV, a 12-lead ECG is 
mandatory for all subjects, except if the FV follows an EDV where ECG results were normal. 
The Investigator will determine whether the results of the ECG are normal or abnormal and 
assess the clinical significance of any abnormalities. 
Change #28 
Section 10.3.2, Vital signs, first paragraph 
Vital signs, including measurements of blood pressure and supine or sitting pulse rate will be 
performed after 5 minutes of rest at time points specified in the schedule of study assessments 
(Table 5‒1). At the EV, data will be obtained from the last visit of the previous study and should 
not be recorded in the eCRF. 
Has been changed to: 
Vital signs, including measurements of blood pressure and supine or sitting pulse rate will be 
performed after 5 minutes of rest at time points specified in the schedules of study assessments 
(Table 5‒1 and Table 5-2).  
For rollover subjects in China and Japan, data will be obtained from the last visit of the 
previous study and should not be recorded in the eCRF at the EV. 
Change #29 
Section 10.3.3, Physical examination 
A standard physical examination will be performed at time points specified in the schedule of 
study assessments (Table 5‒1). At the EV, data will be obtained from the last visit of the 
previous study and should not be recorded in the eCRF. Clinically significant new or worsened 
abnormalities will have to be reported as AEs. 
Has been changed to 
A standard physical examination will be performed at time points specified in the schedules of 
study assessments (Table 5‒1 and Table 5-2).   
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For rollover subjects in China and Japan, data will be obtained from the last visit of the 
previous study and should not be recorded in the eCRF at the EV. Clinically significant new or 
worsened abnormalities will have to be reported as AEs. 
Change #30 
Section 10.3.4, Neurological examination 
A standard neurological examination will be performed at time points specified in the schedule 
of study assessments (Table 5‒1). At the EV, data will be obtained from the last visit of the 
previous study and should not be recorded in the eCRF. Clinically significant new or worsened 
abnormalities will have to be reported as AEs. 
Has been changed to: 
A standard neurological examination will be performed at time points specified in the schedules 
of study assessments (Table 5‒1 and Table 5-2).   
For rollover subjects in China and Japan, data will be obtained from the last visit of the 
previous study and should not be recorded in the eCRF at the EV. Clinically significant new or 
worsened abnormalities will have to be reported as AEs. 
Change #31 
Section 10.3.5, Body weight and height 
Body weight (subject wearing light clothing without shoes and rounded to the nearest kilogram) 
will be measured at time points specified in the schedule of study assessments (Table 5‒1). 
Height will be obtained from Visit 1 in EP0085. 
Has been changed to: 
Body weight (subject wearing light clothing without shoes and rounded to the nearest kilogram) 
will be measured at time points specified in the schedules of study assessments (Table 5‒1 and 
Table 5-2).   
For rollover subjects in China and Japan, height will be obtained from Visit 1 in EP0085. For 
direct enrollers in Japan, height will be obtained at the SV only. 
Change #32 
Section 12, Statistics, third paragraph 
Subjects from N01379 will be analyzed separately. 
Has been changed to: 
Subjects from N01379 and direct enrollers from Japan will be analyzed separately. 
Change #33 
Section 12.3, Planned efficacy analyses 
All efficacy outcomes will be summarized with descriptive statistics only on the FAS.  
The 28-day adjusted seizure frequency will be calculated by dividing the number of partial 
seizures by the number of days for which the DRC was completed and multiplying by 28. 
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• Percent reduction in partial seizure frequency per 28 days from Baseline of the preceding 
study to the Evaluation Period. The efficacy variable will be summarized by 3-month periods 
over the Evaluation Period. 
• Seizure frequency per 28 days for partial seizures by 3-month periods over the Evaluation 
Period. 
• Seizure frequency per 28 days for all seizure types (partial, generalized and unclassified 
epileptic seizure) by 3-month periods over the Evaluation Period. 
• Responder rate in partial seizure frequency by 3-month periods per 28 days over the 
Evaluation Period. A responder is defined as a subject with a ≥50% reduction in seizure 
frequency from the Baseline Period of EP0083 or N01358. 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized and unclassified epileptic seizure) by 3-month periods over the 
Evaluation Period. 
• Percentages of subjects continuously seizure-free for partial seizure and all seizure types for 
at least 6 months and at least 12 months during the Evaluation Period. 
• Proportion of seizure-free days for partial seizure and all seizure types by 3-month periods 
over the Evaluation Period. 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period. 
Has been changed to:  
Planned efficacy analyses for rollover subjects in China and Japan include: 
• Percent reduction in partial seizure frequency per 28 days from Baseline of EP0083 or 
N01358 to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from Baseline 
Period of EP0083 or N01358 
Planned efficacy analyses for directly enrolled subjects in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 
weeks prior to BRV administration 
Planned efficacy analyses for all subjects (directly enrolled in Japan and rollovers in China 
and Japan) include: 
• Seizure frequency per 28 days for partial seizures by 3-month periods over the Evaluation 
Period. 
• Seizure frequency per 28 days for all seizure types (partial, generalized and unclassified 
epileptic seizure) by 3-month periods over the Evaluation Period. 
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• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized and unclassified epileptic seizure) by 3-month periods over the 
Evaluation Period. 
• Percentages of subjects continuously seizure-free for partial seizure and all seizure types for 
at least 6 months and at least 12 months during the Evaluation Period. 
• Proportion of seizure-free days for partial seizure and all seizure types by 3-month periods 
over the Evaluation Period. 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period. 
Change #34 
Section 12.8, Determination of sample size 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. In Japan, it is estimated 
that approximately 124 subjects will enter the study, based on the assumption that at least 90% of 
randomized Japanese subjects will complete EP0083 or enroll from N01379 sites in Japan. 
Likewise, at least 90% of randomized Chinese subjects will be assumed to complete EP0083. 
Has been changed to: 
For this open-label LTFU study, no sample size calculation will be performed. The sample size 
will depend upon recruitment into and completion of the previous study. Overall, 
approximately 217 subjects are planned for enrollment. In Japan, it is estimated that 
approximately 127 subjects will enter the study. This estimate assumes that at least 90% of 
randomized Japanese subjects will complete EP0083 (approximately 90 subjects) or enroll 
from N01379 sites in Japan (7 subjects) and the plan that 30 Japanese subjects will be 
directly enrolled in this study. Likewise, at least 90% of randomized Chinese subjects will be 
assumed to complete EP0083 (approximately 90 subjects). 
Change #35 
Section 16.3, Appendix 3- List of antiepileptic drugs 
Text was added to clarify that LEV is permitted only for directly enrolled subjects in Japan. 
• Levetiracetam * 
*Concomitant LEV is allowed only for direct enrollment participants. In that case, LEV is 
counted as 1 AED. 
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16.8 
Appendix 8 – Protocol Amendment 4 
Rationale 
The purpose of this protocol amendment is to update the following: 
• Update the Study Contact Information 
• Change the primary safety variable from AEs to TEAEs, in alignment with other studies 
across the BRV development program 
• Delete mental status/psychiatric status from the list of other safety variables to be collected; 
abnormal findings upon physical or neurological examination will be recorded as AEs 
• Change the planned duration of EP0085 to allow participants to continue in the study until 
market approval in countries where market approval will be requested and for 2 years in 
countries where market approval will not be requested or obtained  
• Add details regarding EP0085 subjects’ participation in EP0118 for clarification purposes 
• Add to the study withdrawal criteria that a suicide attempt will necessitate a subject’s 
withdrawal from the study. This will eliminate the risk of another suicide attempt or 
completed suicide during the study in cases where the participant’s recent suicidal ideation 
was not accurately reflected by the C-SSRS.  
• Add information regarding numbering of directly enrolled subjects entering the study 
• Add a statement for TEAE and SAE disclosure on public registries per the current UCB 
protocol template 
• Remove 2 efficacy analyses from the previous list of analyses planned for all subjects per 
SAP amendments implemented following EP0085 protocol approval 
• Correct the handling of protocol deviations text as there was no pooling of stratification 
levels for statistical analysis and there were no statistical assumptions for the primary 
analysis for this study.  
In addition, minor clarifications and administrative edits including typographical changes for 
formatting have been made. 
Modifications and changes 
Global changes 
References to AEs was changed to TEAEs to clarify that treatment-emergent AEs were to be 
collected during the study. 
Specific changes 
Change #1 
STUDY CONTACT INFORMATION 
Sponsor Study Physician 
Name: 
  
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Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Phone: 
Fax: 
Has been changed to: 
Name: 
 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Phone: 
 
Clinical Project Manager 
Name: 
 
Address: 
Allée de la Recherche 60 
B- 1070 Brussels, BELGIUM 
Phone: 
Fax: 
Has been changed to: 
Name: 
 
Address: 
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku, 
Tokyo, 160-0023, JAPAN 
Phone: 
Fax: 
Name: 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Phone: 
Fax: 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku, 
Tokyo, 160-0023, JAPAN 
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Clinical Study Protocol 
Brivaracetam 
 
EP0085  
 
 
 
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Phone: 
Fax: 
Has been changed to: 
Name: 
 
Address: 
Suite 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200040 PRC 
Phone: 
Fax: 
Change #2, Section 4.1.1 Primary safety variables 
The primary safety variable is AEs. 
Has been changed to: 
The primary safety variable is TEAEs. 
Change #3, Section 4.1.2 Other safety variables 
The other safety variables are as follows: 
• Laboratory tests (blood chemistry, hematology, and urinalysis) 
• Vital signs 
• Body weight  
• ECG 
• Physical examination  
• Neurological examination 
• Mental status 
• Psychiatric status 
Has been changed to: 
• Laboratory tests (blood chemistry, hematology, and urinalysis) 
• Vital signs 
• Body weight  
• ECG 
• Physical examination  
• Neurological examination 
Change #4, Section 5.1.1 Study duration per subject 
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Clinical Study Protocol 
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EP0085  
 
 
 
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EP0085 will continue until the market approval of BRV or one year after each subject has 
entered into EP0085, or until the sponsor decides to close the study, whichever comes first. In 
the event that market approval is not obtained in the participant country, the subject will be able 
to continue in EP0085 for two years after entering EP0085. 
In Japan and China, EP0085 will continue as a postmarketing clinical study until approximately 
6 months after the date of BRV approval for the partial seizure indication. 
Has been changed to: 
EP0085 will continue until the market approval of BRV, or until the sponsor decides to close the 
study, whichever comes first. In the event that market approval is not requested or obtained in 
the participant country, the subject will be able to continue in EP0085 for two years after 
entering EP0085. 
At selected sites in Japan, Japanese subjects may participate in an additional study (EP0118) 
with the intravenous formulation of BRV without withdrawing from EP0085. Ten evaluable 
subjects are planned for EP0118, and the total duration in the study for each subject is 7 days. 
The study period of EP0118 will be included in that of EP0085. Subjects will continue to receive 
their current dose of BRV at the time of entry and it will remain stable for the duration of 
EP0118. Subjects who complete or withdraw from EP0118 will resume their participation in 
EP0085 with oral BRV treatment. In the event that a subject withdraws from EP0118 and is 
required to down-titrate BRV treatment, the subject will return to EP0085 and down-titrate using 
BRV tablets. Treatment-emergent AEs and concomitant treatment(s)/medication(s) that occur or 
are administered during EP0118 will be recorded in EP0118. Ongoing TEAEs and concomitant 
medication(s)/medical procedure(s) originating from EP0118 will be recorded and followed in 
EP0085 until resolution or until the status of the TEAE and/or concomitant medications are 
stable. All other data reported for EP0118 will be captured in the EP0118 database. Per the 
EP0118 protocol, the study (EP0118) will require hospitalization. Hospitalization for study 
participation does not need to be reported as an SAE. 
Change #4, Section 6.3 Withdrawal criteria 
• Subject 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. 
Subject 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. 
Has been changed to: 
• In the event of a suicide attempt, the subject should be referred immediately to a Mental 
Healthcare Professional and must be withdrawn from the study. 
Subject 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 
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15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
 
EP0085  
 
 
 
Confidential                                           
Page 111 of 115 
 
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. 
Subject 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. 
Change #5, Section 7.10 Randomization and numbering of subjects 
Subjects will continue with the 5-digit subject numbers assigned by the IVRS/IWRS in the 
preceding studies. 
Has been changed to: 
Subjects from EP0083 and N01379 will continue with the 5-digit subject numbers assigned by 
the IVRS/IWRS in the preceding studies. Directly enrolled subjects will receive a 5-digit number 
assigned by the IVRS/IWRS at Screening that serves as the subject identifier throughout the 
study. 
Change #6, Section 10.1.1.1 Adverse events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no 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. 
Has been changed to: 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures 
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Clinical Study Protocol 
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EP0085  
 
 
 
Confidential                                           
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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. 
Change #7, Section 12.3 Planned efficacy analyses 
All efficacy outcomes will be summarized with descriptive statistics only on the FAS.  
The 28-day adjusted seizure frequency will be calculated by dividing the number of partial 
seizures by the number of days for which the DRC was completed and multiplying by 28. 
Planned efficacy analyses for rollover subjects in China and Japan include: 
• Percent reduction in partial seizure frequency per 28 days from Baseline of EP0083 or 
N01358 to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from Baseline 
Period of EP0083 or N01358 
Planned efficacy analyses for directly enrolled subjects in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 weeks 
prior to BRV administration 
Planned efficacy analyses for all subjects (directly enrolled in Japan and rollovers in China and 
Japan) include: 
• Seizure frequency per 28 days for partial seizures by 3-month periods over the Evaluation 
Period. 
• Seizure frequency per 28 days for all seizure types (partial, generalized and unclassified 
epileptic seizure) by 3-month periods over the Evaluation Period. 
• Percentage of subjects continuously seizure-free for partial seizure and all seizure types 
(partial, generalized and unclassified epileptic seizure) by 3-month periods over the 
Evaluation Period. 
• Percentages of subjects continuously seizure-free for partial seizure and all seizure types for 
at least 6 months and at least 12 months during the Evaluation Period. 
• Proportion of seizure-free days for partial seizure and all seizure types by 3-month periods 
over the Evaluation Period. 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period. 
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Clinical Study Protocol 
Brivaracetam 
 
EP0085  
 
 
 
Confidential                                           
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Has been changed to: 
All efficacy outcomes will be summarized with descriptive statistics only on the FAS.  
The 28-day adjusted seizure frequency will be calculated by dividing the number of partial 
seizures by the number of days for which the DRC was completed and multiplying by 28. 
Planned efficacy analyses for rollover subjects in China and Japan include: 
• Percent reduction in partial seizure frequency per 28 days from Baseline of EP0083 or 
N01358 to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from Baseline 
Period of EP0083 or N01358 
Planned efficacy analyses for directly enrolled subjects in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
• Responder rate in partial seizure frequency per 28 days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from 8 weeks 
prior to BRV administration 
Planned efficacy analyses for all subjects (directly enrolled in Japan and rollovers in China and 
Japan) include: 
• Seizure frequency per 28 days for partial seizures by 3-month periods over the Evaluation 
Period. 
• Seizure frequency per 28 days for all seizure types (partial, generalized and unclassified 
epileptic seizure) by 3-month periods over the Evaluation Period. 
• Percentages of subjects continuously seizure-free for partial seizure and all seizure types for 
at least 6 months and at least 12 months during the Evaluation Period. 
• Seizure freedom (partial, all epileptic seizure) during the Evaluation Period. 
Change #8, Section 12.5 Handling of protocol deviations 
After all CRFs have been retrieved and entered and queries addressed, and prior to locking the 
clinical database a Data Evaluation Meeting (DEM) will be held. The purpose of this DEM will 
be to assess the quality of the data for subsequent database lock, identify protocol deviations, 
finalize analysis populations, reach agreement on the pooling of stratification levels for statistical 
analysis, and verify that the statistical assumptions for the primary analysis are appropriate. 
Has been changed to: 
After all CRFs have been retrieved and entered and queries addressed, and prior to locking the 
clinical database a Data Evaluation Meeting (DEM) will be held. The purpose of this DEM will 
be to assess the quality of the data for subsequent database lock, identify protocol deviations, and 
finalize analysis populations. 
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Clinical Study Protocol 
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EP0085  
 
 
 
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17 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract. 
Investigator: 
 
 
 
 
Printed name  
 
Date/Signature 
 
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Clinical Study Protocol 
Brivaracetam 
 
EP0085  
 
 
 
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18 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
ep0085-protocol-amend-4
Version:
1. 0
Document Number:
CLIN-000215404
Title:
EP0085 Protocol Amendment 4
Approved Date:
16 Mar 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Mar-2023 02:11:29 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Mar-2023 02:28:36 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Mar-2023 14:56:42 GMT+0000
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