Clinical trial NCT03250377
Conditions: Partial Seizures With or Without Secondary Generalization Epilepsy
Keywords: Brivaracetam Epilepsy Partial seizures with or without secondary generalization Briviact
Sponsor: UCB Biopharma SRL
Start date: 2017-08-05; Completion date: 2024-12-24
Enrollment: 207 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the long-term safety and tolerability of Brivaracetam (BRV) in focal epilepsy subjects with partial seizures and to evaluate the maintenance of efficacy of BRV over time.

Detailed description:

Arms: arm 1: Subjects randomized to this arm will receive open-label Brivaracetam
Interventions: intervention 1: Brivaracetam
Intervention descriptions: intervention 1: * Pharmaceutical form: Film-coated tablet
* Concentration: 25 mg and 50 mg
* Route of administration: Oral use

Protocol documents:
Prot_000.pdf: 
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 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Clinical Study Protocol 
Brivaracetam 
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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15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
Confidential                                           
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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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15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
Confidential                                           
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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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15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
Confidential                                           
Page 5 of 115 
 
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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15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
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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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Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
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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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Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
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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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15 Mar 2023 
Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
Confidential                                           
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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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Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
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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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Clinical Study Protocol 
Brivaracetam 
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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Clinical Study Protocol 
Brivaracetam 
EP0085 
 
 
 
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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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EP0085 
 
 
 
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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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EP0085 
 
 
 
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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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Clinical Study Protocol 
Brivaracetam 
 
EP0085  
 
 
 
Confidential                                           
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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 
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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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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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Clinical Study Protocol 
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EP0085  
 
 
 
Confidential                                           
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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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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 
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EP0085  
 
 
 
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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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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 
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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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SAP_001.pdf: 
UCB 
03 Feb 2025 
Statistical Analysis Plan 
Brivaracetam 
EP0085 
Confidential 
Page 1 of 100 
STATISTICAL ANALYSIS PLAN 
Study: EP0085 
Product: Brivaracetam 
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 
SAP/Amendment Number Date 
Final SAP 
26 SEP 2017 
SAP Amendment 1 
16 NOV 2021 
SAP Amendment 2 
17 JAN 2023 
SAP Amendment 3 
05 JUL 2023 
SAP Amendment 4 
03 FEB 2025 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Statistical Analysis Plan 
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EP0085 
 
 
 
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Page 2 of 100 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 6 
2 
PROTOCOL SUMMARY ................................................................................................. 6 
2.1 
Study objectives ............................................................................................................. 6 
2.1.1 
Primary objectives ................................................................................................. 6 
2.1.2 
Secondary objective ............................................................................................... 6 
2.2 
Study variables ............................................................................................................... 6 
2.2.1 
Safety variables ...................................................................................................... 6 
2.2.1.1 
Primary safety variables .............................................................................. 6 
2.2.1.2 
Other safety variables .................................................................................. 6 
2.2.2 
Efficacy variables .................................................................................................. 6 
2.3 
Study design and conduct .............................................................................................. 7 
2.4 
Determination of sample size ....................................................................................... 10 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 10 
3.1 
General presentation of summaries and analyses ........................................................ 10 
3.2 
Analysis time points ..................................................................................................... 10 
3.2.1 
First and last dose of BRV ................................................................................... 10 
3.2.2 
Relative day ......................................................................................................... 11 
3.2.3 
Screening Visit ..................................................................................................... 11 
3.2.4 
Entry Visit ............................................................................................................ 11 
3.2.5 
Study periods ....................................................................................................... 12 
3.2.6 
Monthly time intervals ......................................................................................... 13 
3.2.7 
Last Value on BRV Treatment ............................................................................ 14 
3.3 
Definition of Baseline values ....................................................................................... 14 
3.4 
Protocol deviations....................................................................................................... 14 
3.5 
Analysis sets................................................................................................................. 14 
3.5.1 
Enrolled Set ......................................................................................................... 14 
3.5.2 
Safety Set ............................................................................................................. 14 
3.5.3 
Full Analysis Set .................................................................................................. 15 
3.6 
Treatment assignment and study groups ...................................................................... 15 
3.7 
Coding dictionaries ...................................................................................................... 15 
3.8 
Changes to protocol-defined analyses ......................................................................... 16 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 16 
4.1 
Handling of missing data ............................................................................................. 16 
4.2 
Interim analyses and data monitoring .......................................................................... 16 
4.3 
Multicenter studies ....................................................................................................... 16 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 16 
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Statistical Analysis Plan 
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5.1 
Subject disposition ....................................................................................................... 16 
5.2 
Protocol deviations....................................................................................................... 17 
5.3 
Consideration for COVID-19 ...................................................................................... 17 
5.4 
Time to BRV discontinuation ...................................................................................... 17 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................... 18 
6.1 
Demographics .............................................................................................................. 18 
6.2 
History of epilepsy ....................................................................................................... 18 
6.3 
Medical history conditions and procedure history ....................................................... 19 
6.3.1 
Previous and ongoing medical history conditions ............................................... 19 
6.3.2 
Procedure history and concomitant procedures ................................................... 19 
6.4 
Prior and concomitant medications .............................................................................. 19 
6.4.1 
Non-AEDs taken at study entry ........................................................................... 19 
6.4.2 
History of previous AED use ............................................................................... 20 
6.4.3 
Number of previous AEDs .................................................................................. 20 
6.4.4 
AEDs taken at study entry ................................................................................... 20 
6.5 
Potential drug-induced liver injury (PDILI) related information ................................ 21 
6.6 
Neuro-imaging procedure ............................................................................................ 21 
6.7 
Electroencephalogram.................................................................................................. 21 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 21 
8 
EFFICACY ANALYSES ................................................................................................ 21 
8.1 
Derivations of efficacy variable(s)............................................................................... 21 
8.1.1 
28-day adjusted seizure frequency ....................................................................... 21 
8.1.2 
Percent reduction of 28-day adjusted partial seizure frequency .......................... 22 
8.1.3 
Responder rate of 28DPSF .................................................................................. 22 
8.1.4 
Seizure freedom (partial, all epileptic seizure) .................................................... 22 
8.2 
Analysis of the efficacy variables ................................................................................ 22 
8.2.1 
Analysis of seizure frequency per 28 day ............................................................ 22 
8.2.2 
Analysis of percent reduction of 28DPSF ........................................................... 22 
8.2.3 
Analysis for responder rate of 28DPSF ............................................................... 23 
8.2.4 
Analysis of seizure freedom ................................................................................ 23 
8.2.4.1 
The percentage of subjects continuously seizure-free ............................... 23 
8.2.4.2 
Seizure Freedom ........................................................................................ 23 
9 
SAFETY ANALYSES ..................................................................................................... 23 
9.1 
Extent of exposure ....................................................................................................... 23 
9.1.1 
Study medication duration and total study medication duration in subject-years 23 
9.1.2 
Study medication dose ......................................................................................... 24 
9.2 
Primary safety variables ............................................................................................... 24 
9.2.1 
Definition of treatment-emergent adverse events ................................................ 24 
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Statistical Analysis Plan 
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Page 4 of 100 
9.2.2 
Summaries of TEAEs .......................................................................................... 24 
9.2.2.1 
Incidence of treatment-emergent adverse events ...................................... 25 
9.2.2.2 
Withdrawal due to adverse events ............................................................. 26 
9.2.2.3 
Serious adverse events ............................................................................... 26 
9.2.2.4 
Adverse events of special interest ............................................................. 26 
9.2.2.5 
Relationship of adverse events to study drug ............................................ 26 
9.2.2.6 
Intensity of adverse event .......................................................................... 26 
9.2.2.7 
Adverse event requiring dose change ........................................................ 27 
9.2.2.8 
Adverse events related to COVID-19 vaccination .................................... 27 
9.3 
Other safety variables .................................................................................................. 27 
9.3.1 
Laboratory measurements .................................................................................... 27 
9.3.1.1 
Hematology, biochemistry and urinalysis parameters .............................. 27 
9.3.1.2 
PDILI laboratory measurements................................................................ 27 
9.3.2 
Vital signs ............................................................................................................ 27 
9.3.3 
Body weight ......................................................................................................... 28 
9.3.4 
Electrocardiograms (ECG) .................................................................................. 28 
9.3.5 
Physical examination ........................................................................................... 28 
9.3.6 
Neurological examination .................................................................................... 28 
9.3.7 
Columbia-suicide severity rating scale ................................................................ 28 
10 PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 28 
11 REFERENCES ................................................................................................................ 29 
12 APPENDICES ................................................................................................................. 30 
12.1 
PCST criteria ................................................................................................................ 30 
12.1.1 
Laboratory assessments - PCST .......................................................................... 30 
12.1.1.1 
Hematology ............................................................................................... 30 
12.1.1.2 
Blood chemistry ........................................................................................ 31 
12.1.1.3 
Urinalysis ................................................................................................... 34 
12.1.2 
Vital sign assessments – abnormal ...................................................................... 35 
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 38 
13.1 
Amendment 1 ............................................................................................................... 38 
13.2 
Amendment 2 ............................................................................................................... 72 
13.3 
Amendment 3 ............................................................................................................... 94 
13.4 
Amendment 4 ............................................................................................................... 98 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 100 
 
 
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Statistical Analysis Plan 
Brivaracetam 
 
EP0085 
 
 
 
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Page 5 of 100 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AED 
Antiepileptic Drug 
BMI 
Body Mass Index 
BRV 
Brivaracetam 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computerized Tomography 
DEM 
Data Evaluation Meeting 
DRC 
Daily Record Card 
ECG 
Electrocardiogram 
EDV 
Early Discontinuation Visit 
EEG 
Electroencephalogram 
ES 
Enrolled Set  
FAS 
Full Analysis Set 
IMP 
Investigational Medicinal Product 
LTFU 
Long-Term Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
PCST 
Possibly Clinically Significant Treatment-emergent 
PDILI 
Potential Drug-Induced Liver Injury 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
VNS 
Vagus Nerve Stimulation 
WHODD 
World Health Organization Drug Dictionary  
28DPSF 
28-Day Adjusted Partial Seizure Frequency 
 
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Statistical Analysis Plan 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report (CSR). The SAP is based on the following study document: Protocol 
Amendment 4.1 and Case Report Form (CRF) version 8.0. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objectives 
The primary objective is to evaluate the long-term safety and tolerability of BRV in focal 
epilepsy subjects with partial seizures. 
2.1.2 
Secondary objective 
The secondary objective is to evaluate the maintenance of efficacy of BRV over time. 
2.2 
Study variables 
2.2.1 
Safety variables 
2.2.1.1 
Primary safety variables 
The primary safety variable is treatment-emergent adverse events (TEAEs). 
2.2.1.2 
Other safety variables 
The other safety variables are as follows: 
• Laboratory tests (blood chemistry, hematology, and urinalysis) 
• Vital signs 
• Body weight 
• 12-lead electrocardiogram (ECG) 
• Physical examination 
• Neurological examination 
2.2.2 
Efficacy variables 
The efficacy variables 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 partial seizure frequency from 
the Baseline Period of EP0083 or N01358 
Efficacy variables for direct enrollers in Japan include: 
• Percent reduction in partial seizure frequency per 28 days from 8 weeks prior to BRV 
administration to the Evaluation Period 
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Statistical Analysis Plan 
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EP0085 
 
 
 
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Page 7 of 100 
• 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 partial seizure frequency from 
8 weeks prior to BRV administration 
Efficacy variables for all subjects (rollovers in China and Japan and direct enrollers in Japan): 
• Percentage of subjects continuously seizure-free for partial seizures 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 
2.3 
Study design and conduct 
EP0085 is a Phase 3, open-label, long-term follow-up (LTFU), multicenter, noncomparative, and 
dose flexible study being conducted in Japan and China. The population are 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 the study protocol can be directly enrolled.  
Rollover subjects must complete the Treatment and Transition Period of EP0083 prior to 
enrolment 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 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 will have their eligibility confirmed at the Screening Visit 
(SV). SV occurs -2 to -21 days before BRV administration.  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.   
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 according to EP0085 study 
protocol. (see Table 1). 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 drug in the last week of down-
titration is given only in the morning. 
The study duration per subject is defined as follows:  
• 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):  
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- 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).  
Subjects who will be converted to the commercial BRV product will complete an End of Study 
Visit without entering the Down-Titration Period or the 2-week Study Drug-Free Period and will 
not complete an 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 (Phase 4) after the date of 
approval of BRV 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. TEAEs 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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Table 1: 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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2.4 
Determination of sample size 
For this open-label LTFU study, no sample size calculation was performed. The sample size 
will depend upon recruitment into and completion of the previous studies. 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 that 30 Japanese subjects will be directly 
enrolled in this study. Likewise, this estimate assumes that at least 90% of randomized 
Chinese subjects will complete EP0083 (approximately 90 subjects). 
3 
DATA ANALYSIS CONSIDERATIONS  
3.1 
General presentation of summaries and analyses 
For the analysis purposes, “core study” in this plan refers to the study where the subjects 
were firstly enrolled.  For rollover subjects, the core study is N01358 (for rollover subjects 
from N01379) or EP0083 (for rollover subjects from EP0083).  For direct enrollers EP0085 
is the core study.  
Statistical analysis and generation of tables, figures, subject data listings, and statistical 
output will be performed using SAS® Version 9.3 or higher.  
Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. The denominator for percentages will be based on the number of subjects 
appropriate for the purpose of analysis. Unless otherwise noted, all percentages will be 
displayed to 1 decimal place. No percentage will be displayed for zero counts, and no 
decimal will be presented when the percentage is 100%.  
For continuous parameters, descriptive statistics will include number of subjects with 
available measurements (n), mean, standard deviation (SD), median, minimum, and 
maximum. Decimal places for descriptive statistics will always apply the following rules: 
• 
“n” will be an integer. 
• 
Mean, SD and median will use 1 additional decimal place compared to the original data. 
• 
Minimum and maximum will have the same number of decimal places as the original 
value. 
All summaries will be descriptive; no statistical hypothesis testing is planned. 
Subject data listings will be provided and will present source data and key derived variables 
for statistical analyses. 
3.2 
Analysis time points 
3.2.1 
First and last dose of BRV 
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first 
dose of BRV during EP0085 (ie, not the first dose of BRV from the previous study in which 
subjects participated in prior to EP0085). Unless otherwise noted, all references to the last 
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known dose of BRV in this SAP refer to the last dose of BRV taken across any study periods 
(ie, the last dose of BRV across both the Evaluation and Down-Titration Periods). 
3.2.2 
Relative day 
Relative day will be calculated as follows: 
- 
For days prior to the first dose of BRV, the relative day is the current date minus the 
date of first dose of BRV. The relative day prior to first dose will be Day -1. 
- 
For days on or after the first dose of BRV and on or prior to the last dose of BRV, the 
relative day is the current date minus the date of first dose of BRV plus 1.  The 
relative day of first dose will be Day 1. 
- 
For days after the last dose of BRV, the relative day is the current date minus the date 
of last dose of BRV.  The relative day will include a “+” to denote post treatment 
days (eg, the day after the last dose will be Day +1). 
Relative day will not be calculated for partial or missing dates. 
3.2.3 
Screening Visit  
The SV only applies to direct enrollers in Japan and will be performed between Day -21 and 
Day -2 prior to Visit 1 (EV).  The following assessments will be performed at SV: 
Study 
Visit 
Assessments 
EP0085 
direct 
enrollers in 
Japan  
Visit 0 
Demography, medical history, epilepsy history, AED history, 
vital signs, body weight, physical examination, neurological 
examination, 12-lead ECG, electroencephalogram (EEG), 
neuro-imaging procedure (per Investigator discretion), 
laboratory safety assessments, seizure counts, ongoing AE 
reporting (see more information in Section 9.2), C-SSRS, 
medical procedures, ongoing concomitant medications 
(including AEDs and non-AEDS).  
3.2.4 
Entry Visit 
The EV corresponds to the assessments performed at the time of entry into EP0085. For 
direct enrollers in Japan, the EV will be performed at Visit 1 and the relevant assessments 
will be performed according to the study protocol.  For rollover subjects from EP0083 and 
N01379, the following assessments will be completed during the last visit of the previous 
study and do not need to be repeated at Visit 1:  
Study 
Visit 
Assessments 
EP0083 
Visit 8 
vital signs, body weight, physical 
examination, neurological examination, 
12-lead ECG, laboratory safety 
assessments, seizure counts, ongoing 
AE reporting (see more information in 
N01379 
Last Evaluation Period Visit or 
Early Discontinuation Visit 
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Section 9.2), C-SSRS, medical 
procedures, ongoing concomitant 
medications (including AEDs and non-
AEDS).  
3.2.5 
Study periods 
The following study periods are defined for the classification in summary that are based on 
the study design: 
Baseline Period  
For rollover subjects from EP0083, the Baseline Period 
corresponds to the Baseline Period of EP0083 and is 
defined as study days on or after EP0083 Visit 1 date and 
prior to EP0083 Visit 3 date.   
For rollover subjects from N01379, the Baseline Period 
corresponds to the Baseline Period of N01379 and is 
defined as study days on or after N01358 Visit 1 date and 
prior to N01358 Visit 3 date.  
For direct enrollers, except for seizure outcome the 
Baseline Period is defined as study days on or after EP0085 
Visit 0 date and prior to EP0085 Visit 1 date. The Baseline 
Period for seizure outcome is defined as 8 weeks prior to 
the first BRV administration (see section 8.1.2). 
Evaluation Period 
The Evaluation Period starts on the date of Visit 1 and the 
following algorithm is used to determine the end date: 
If the subjects enter the Down-Titration Period: 
- 
for completed subjects, which is indicated by the 
CRF “Study Termination” form (Complete subject), 
the Evaluation Period ends on the date of End of 
Study Visit date. 
- 
for discontinued subjects, which is indicated by the 
CRF “Study Termination” form (Dropout), the 
Evaluation Period ends on the date of EDV date.  
If the subjects do not enter the Down-Titration Period: 
For complete / discontinued subjects who do not enter the 
Down-Titration Period, the end of Evaluation Period will 
be the date of last dose of BRV.  
Down-Titration Period (up 
to 4 weeks) 
If the subject is discontinuing BRV, the Investigator will 
first plan an EDV followed by the progressive down-
titration of study drug. 
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A subject is considered entering Down-Titration Period 
only if the subject has an EDV and has at least 1 dose of 
study drug after the date of EDV, the start date of Down-
Titration Period is set as 1 day after the date of EDV, and 
the Down-Titration Period ends on date of last dose of 
BRV. A subject without an EDV but having a termination 
CRF or with an EDV but without any dosing of study drug 
after the EDV will not have the Down-Titration Period, and 
no artificial Down-Titration Period will be created for 
analysis. 
Study Drug-Free Period (2 
weeks) 
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 enter a 
2-week Study Drug-Free Period, followed by a Final Visit. 
A subject is considered entering the Study Drug-Free 
Period if the subject has at least 1 contact (scheduled visit, 
unscheduled visit, or telephone contact) after the date of 
last dose of BRV. The 2-week Study Drug-Free Period 
starts 1 day after the date of last dose of BRV and ends on 
the date of Final Visit, irrespective of entering the Down-
Titration Period.  
 
A subject is considered as completed if this subject completes all scheduled visits as defined 
in the protocol or converts to commercial BRV without a Down-Titration Period (where 
commercial BRV is available). 
3.2.6 
Monthly time intervals 
In terms of the analysis, a month is defined as 30 days and time intervals based on monthly 
durations are defined as a multiple of 30 days (eg, 12 months is defined as 360 days). The 
following definitions of 3‑month intervals are based on 30-day months where the date of first 
dose of BRV is Day 1: 
Interval  
Duration Definition  
3-month interval 
 
Month 1-3 
Day 1-90  
Month 4-6 
Day 91-180   
Month 7-9 
Day 181-270  
Month 10-12 
Day 271-360 
Subsequent 3-month intervals are defined in a similar manner.  Three-month intervals will be 
used for analyses of efficacy (except for continuously seizure-free) and TEAE summaries.  
For the analysis of efficacy outcomes, a subject is included in the analysis of a 3-month 
interval if the last dose of study drug during the Evaluation Period of EP0085 is equal or 
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greater than the last day of the 3-month time interval and the seizure diary was completed for 
at least 1 day during the 3-month interval over the Evaluation Period.  
For TEAE summaries, a subject is included in the analysis of a 3-month interval if the last 
dose of study drug in whole period of EP0085 is equal or greater than the first day of the 3-
month time interval (as N for the time interval) and with at least one specified TEAE within 
the 3-month interval (as n in the summary tables according to the AE onset date).  
3.2.7 
Last Value on BRV Treatment  
Last Value for clinical laboratory parameters, vital signs, and ECGs is the last available result 
obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All 
scheduled and unscheduled assessments within this time period will be considered. Last 
Value will be determined separately for each laboratory parameter.  
3.3 
Definition of Baseline values 
Unless otherwise specified, Baseline for all safety and efficacy variables will be based on 
baseline of the core study.   
For rollover subjects, the baseline value for all safety and efficacy variables is defined as the 
last non-missing data collected prior to the first dose of study medication in the core study 
(EP0083 or N01358), unless addressed otherwise for a specific type of data.  Baseline seizure 
frequency will be obtained from the core study (EP0083 or N01358). 
For direct enrollers in Japan, the baseline value is defined as the last non-missing data 
collected prior to the first dose of study medication in study EP0085, unless addressed 
otherwise. For seizure frequency, the baseline is defined as the seizure counts collected from 
8 weeks prior to the first BRV administration. This baseline seizure frequency for direct 
enrollers is consisted of subject's own document (eg, DRC) and the data in DRC for EP0085 
between SV and EV. 
3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on the evaluation of safety and efficacy outcome. Protocol deviations will 
be identified during ongoing data monitoring and cleaning process and will be reviewed in 
the Data Cleaning Meetings. The impact of the protocol deviations to the analysis will be 
discussed in Data Evaluation Meeting.   
3.5 
Analysis sets 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) will consist of subjects who signed an informed consent form in 
EP0085, enrolling from study EP0083 or from study N01379 or are directly enrolled into 
EP0085 in Japan. This analysis set is also referred to as “All Subjects Screened”. 
3.5.2 
Safety Set 
The Safety Set (SS) will consist of all subjects in the ES who took at least 1 dose of study 
medication in EP0085. All safety variables will use SS for presentation. In addition, 
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demographic data, baseline characteristics, medical history, prior and concomitant 
medications and study drug exposure will use SS for presentation as well. 
3.5.3 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects in the ES who took at least 1 dose of 
study medication and have at least 1 seizure record on Daily Record Card (DRC) during the 
Evaluation Period. All efficacy variables will use FAS for presentation. 
3.6 
Treatment assignment and study groups 
This is an uncontrolled study in which all subjects receive BRV in doses that are optimally 
adjusted for each subject. It is expected that subjects will receive treatment in accordance 
with the study design.  
Rollover subjects from N01379, EP0083, and directly enrolled subjects need to be analyzed 
separately. For rollovers from EP0083 a detailed segmentation by randomized drug group in 
EP0083 is necessary.  Unless otherwise specified, results will be presented for each grouping 
described below:  
For tables and figures the study groups will be presented as follows: 
• EP0083 Placebo  
• EP0083 BRV All 
• EP0083 Total 
• N01379 
• Direct Enrollers  
• All Subjects 
For subject listings, the study group will be presented as follows: 
• EP0083 Placebo  
• EP0083 BRV 50mg/day 
• EP0083 BRV 200mg/day 
• N01379 
• Direct Enrollers  
For submission purpose, the subgroup tables and figures will be presented by Japan.  In 
Japan subgroup tables and figures, the study groups will be presented in the same manner as 
overall.   
3.7 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1. Prior and concomitant medications will be coded using 
the World Health Organization Drug Dictionary (WHODD) version September 2017. 
Medical procedures or medical devices will not be coded. 
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3.8 
Changes to protocol-defined analyses 
Not applicable.   
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Handling of missing data 
No rule for handling of missing data will be applied for this LTFU study. Safety and efficacy 
variables will be analyzed as available. Days with missing information will be ignored in the 
calculation of the seizure frequency. 
Since subjects may drop out from the study at different times, selected summaries will be 
presented by time interval. 
Subjects participating in EP0118 while also enrolled in EP0085 will have missing data for 
seizure frequency and drug dosing while participating in the EP0118 study. As the duration 
of the EP0118 study will be short (3-7 days), no imputation for data missing due to 
participation in EP0118 will be performed. Subjects will be assigned the same dose in 
EP0118 as that assigned in EP0085 for the two weeks prior to the start of EP0118. As such, 
time during the EP0118 study will not be subtracted from the exposure calculations (eg, 
exposure will be from the start of BRV treatment in the EP0085 study until the date of last 
dose of BRV in EP0085).  
For the calculation of variables related to seizure frequency, the dates during participation in 
EP0118 will be considered as not done for the purpose of efficacy analyses for EP0085 
according to the Seizure Count form entry (eg, these dates will not be considered as days 
evaluated for seizure frequency).  
4.2 
Interim analyses 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).  There are no statistical concerns with such interim 
reports for this open-label LTFU study. 
4.3 
Multicenter studies 
The disposition of subject by study center will present in the summary table by study center. 
The information of study centers will also be identified in the Subject Disposition listing. 
Efficacy and safety outcomes will not be assessed for individual study center due to the low 
expected number for enrollment within each study center. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
The number of screen failures and the primary reason for screen failure will be summarized 
for all subjects screened. The number and percentage of subjects who started, completed and 
discontinued will be presented by study period, 6-month periods over the Evaluation Period 
and study group.  
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The number of subjects by site will be provided in a separate summary table for the ES. The 
number and percentage of subjects in different analysis sets will be provided based on the 
ES. The summary of subjects in the SS who discontinued the study due to AE will be 
presented in a separate table.  
All subject disposition related information and subjects who did not meet the 
inclusion/exclusion criteria will be provided in the subject listings. 
5.2 
Protocol deviations 
The number and percentage of subjects with at least one important protocol deviation will be 
summarized by main category of protocol deviation by study group. The percentage will be 
based on the Safety Set. 
The assignment of subjects to each of the analysis sets will be listed for all subjects enrolled.  
5.3 
Consideration for COVID-19 
A new Coronavirus Disease 2019 (COVID-19) CRF to evaluate the impact of global 
pandemic was created and implemented to collect the information on impacted visit, impact 
category, and relationship to COVID-19.  
The relationship to COVID-19 global pandemic will be assessed and captured as: confirmed 
COVID-19 infection, suspected COVID-19 infection, general circumstances around COVID-
19 without infection or any other deviation from the protocol due to COVID-19. 
Summary and listing to describe the impact of COVID-19 will be performed.  AE related to 
COVID-19 vaccination will be flagged in the AE listings (see section 9.2.2.8).   
5.4 
Time to BRV discontinuation 
As an additional assessment, the time to BRV discontinuation will be evaluated for both the 
overall study population and the Japanese subpopulation. 
The time to BRV discontinuation will be calculated as follows: 
(Date of last dose of BRV – date of first dose of BRV +1) / 30 (in month) 
The time to BRV discontinuation will be analyzed using Kaplan-Meier method.  The median 
time, 25% percentile, and 75% percentile of time to BRV discontinuation will be calculated 
based on SS.  Additionally, the cumulative number of events, number at risk, and survival 
estimate at month 12, 24, 36, 48, 60, 72, 84, and 96 will be provided.   
Subjects who discontinued BRV for any reason will be considered as an event.  All other 
subjects will be censored at the date of the last dose of BRV.   
In addition to analyzing BRV discontinuation due to any reason, the time to BRV 
discontinuation will be separately analyzed for the following specific reasons: 
• Due to TEAE 
• Due to lack of efficacy 
• Due to lack of efficacy or TEAE 
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For each of the BRV discontinuation reason, a summary table will be provided by study 
group.  Additionally, a Kaplan-Meier figure will be provided combing all discontinuation 
reasons and presented, by study group.   
 
6 
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS 
All summaries for subject characteristics will be based on SS. Unless otherwise specified, all 
demographics and other baseline characteristics summaries will be based on data collected in 
the core study.  
6.1 
Demographics 
Age, age category, gender, racial group, ethnicity, ethnicity subgroup (Japan or China), body 
weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI category will be 
summarized by study group for the Safety Set.  
The age will be categorized according to the following categories: 
- 
Standard for BRV adult studies: <17, 17 to <65, and ≥65 years 
- 
EudraCT: 12 to <18, 18 to <65, 65 to <85, and ≥85 years 
- 
clinicaltrials.gov: ≤18, 19 to <65 and ≥65 years 
The BMI will be categorized according to the following category: 
- 
<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40 
Age will be calculated based on the date of informed consent in EP0085 and date of birth.  
The result will be kept as integer and the unit of age is years. A birth date of each subject 
provided from the core studies is imputed to be born on the first day of that month (yyyy-
mm-01).  Except for age, all other demographic variables will be based on data from baseline 
of core study. 
The demographic variables will be listed by subject.  
6.2 
History of epilepsy  
The following epilepsy-related background variables will be summarized by study group 
based on the Safety Set: 
• Epileptic seizure profile: the number and percentage of subjects experiencing each 
seizure type at any time based on the Classification of Epileptic Seizures (ILAE,1981) 
prior to the core study entry will be summarized. 
• History of epileptic seizures at the core study: the number and percentage of subjects with 
a history of status epilepticus and quantitative summaries of epilepsy duration, age at 
time of first diagnosis of seizure, and percent of life with epilepsy, will be summarized.  
Percent of life with epilepsy will be calculated as 100 times epilepsy duration relative to 
the first diagnosis date and divided by the subject’s age at the core study entry. 
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• Classification of epileptic syndrome collected at the core study: the number and 
percentage of subjects with each epileptic syndrome will be summarized. 
• Baseline seizure type and partial seizure frequency collected at the core study: the 
number and percentage of subjects who experienced each seizure type during the 
Baseline Period of core study will be presented. Baseline partial seizure frequency will be 
summarized descriptively for subjects who experienced at least one seizure of type I, IA, 
IB or IC during the Baseline Period of core study. 
For rollover subjects, the data will be obtained from the Baseline Period of N01358 and 
EP0083.  For direct enrollers, the data will be obtained from EP0085 Screening Visit CRF 
forms.  
All above-mentioned baseline characteristics will be listed by subject. 
6.3 
Medical history conditions and procedure history 
For rollover subjects, the medical history conditions and procedure history will be obtained 
directly from the Medical History CRFs and the Procedure History CRFs of the EP0083 and 
N01358 (for rollover subjects from N01379). If there is any new medical history condition, it 
will be collected in the Medical History Update form in EP0085.  For direct enrollers, the 
medical history conditions and procedure history will be obtained from the Medical History 
CRFs and the Procedure History CRFs of EP0085.  Reported medical history conditions are 
coded according with MedDRA version 18.1. Medical procedures are not coded. Start and 
stop date are documented partially with month and year only (yyyy-mm). No date imputation 
is foreseen. 
6.3.1 
Previous and ongoing medical history conditions 
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions, will be summarized by study group by the primary System 
Organ Class (SOC) and Preferred Term (PT). 
A listing of subjects with previous and ongoing medical history conditions will be provided. 
6.3.2 
Procedure history and concomitant procedures 
A listing of subjects with procedure history and concomitant procedures will be provided. 
6.4 
Prior and concomitant medications 
All prior and concomitant medications will be coded according to the WHODD version 
September 2017. Medications taken at study entry are the ongoing medications at the study 
entry of the core study.  Previous medications are medications taken and discontinued prior 
to entry into the core study. Concomitant medications are medications taken during 
administration of BRV in EP0085 study. Previous AEDs and AED taken at core study entry 
will follow the AED definition according to the respective core study.  
6.4.1 
Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AEDs at study entry will be summarized 
for the Safety Set by primary therapeutic group (Anatomic Therapeutic Class [ATC] level 1), 
therapeutic subgroup (ATC level 2), and preferred drug name.  
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Non-AED taken at study entry refers to the core study entry.  The non-AEDs at core study 
entry will follow the AED definition according to the respective core study. For rollover 
subjects the information will be obtained from CRF form “Prior and Concomitant 
Medications (including AEDs)” from EP0083 and CRF form “Prior and Concomitant 
Medications” from N01358 (for subjects from N01379).  For direct enrollers the information 
will be obtained from EP0085 CRF form “Concomitant Medications (including AEDs)”. 
6.4.2 
History of previous AED use 
The number and percentage of subjects who had taken at least 1 previous AED prior to entry 
into the core study will be summarized overall and by preferred drug name for the Safety Set.  
For rollover subjects the information will be obtained from CRF form “History of Previous 
Antiepileptic Drug Treatment” from EP0083 and N01358 (for subjects from N01379).  For 
direct enrollers the information will be obtained from EP0085 CRF form “History of 
Previous Antiepileptic Drug Treatment”. Different with the core study N01358, for core 
study EP0083 (for the rollover subjects from EP0083) and EP0085 (for the direct enrollers), 
the history of previous AED was recorded in accordance with the list of AEDs as indicated in 
Appendix 3 of the study protocol, however, the Investigator’s judgement was prioritized and 
taken into consideration.  
6.4.3 
Number of previous AEDs 
The number and percentage of previous AEDs will be summarized based on the following 
categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.   The definition of previous AED use 
will be the same as section 6.4.2.   
6.4.4 
AEDs taken at study entry  
The number and percentage of subjects taking AEDs at the core study entry visit will be 
summarized by preferred drug name for the Safety Set.  
AED taken at study entry refers to the core study entry.  The AEDs at core study entry will 
follow the AED definition according to the respective core study. Different with the core 
study N01358, for core study EP0083 (for the rollover subjects from EP0083) and EP0085 
(for the direct enrollers), the AEDs taken at study entry was recorded in accordance with the 
list of AEDs as indicated in Appendix 3 of the study protocol and was captured according to 
the CRF “Core AED?” based on the Investigator’s judgement.  
For rollover subjects the information will be obtained from CRF form “Prior and 
Concomitant Medications (including AEDs)” from EP0083 and CRF form “Prior and 
Concomitant Medications (AEDs only)” from N01358 (for subjects from N01379).  For 
direct enrollers the information will be obtained from EP0085 CRF form “Concomitant 
Medications (including AEDs)”.  
6.4.5 
Concomitant AEDs 
A concomitant AED is an AED which was taken during administration of BRV in EP0085 
study, regardless of the start and stop date of the AED. Concomitant AEDs will be recorded 
in accordance with the list of AEDs as indicated in Appendix 3 of the study protocol and will 
be captured according to the CRF “Core AED?” based on the investigator’s judgement.  The 
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number and percentage of subjects taking concomitant AEDs will be summarized by 
preferred drug name for the Safety Set.  
6.4.6 
Vagus nerve stimulation (VNS) 
For all subjects, the VNS information will be obtained from EP0085 CRF form: Vagus Nerve 
Stimulation Status at Screening/Baseline.  The number and percentage of subject who had 
VNS at Screening/Baseline of EP0085 will be summarized in a table.  A listing of VNS 
status at study entry and VNS setting at the subsequent visits will be provided.   
6.5 
Potential drug-induced liver injury (PDILI) related information 
Subjects with potential drug-induced liver injury (PDILI) will be assessed to determine if 
IMP must be discontinued.  If PDILI occurs, additional lifestyle and family medical history 
information will be collected.  Listings of lifestyle and family medical history will be 
provided only if any subject reporting PDILI. 
6.6 
Neuro-imaging procedure  
A neuro-imaging procedure, including brain magnetic resonance imaging (MRI), brain 
computerized tomography (CT) scan or other imaging test will be performed for direct 
enrollers at Screening Visit per Investigator discretion.  A listing of  CT and MRI data will 
be provided.  
6.7 
Electroencephalogram 
For direct enrollers, 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.  A listing 
of EEG interpretation data will be provided.  
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Study drug compliance will not be calculated because the planned dose information is not 
collected and also due to the complexity associated with the interpretation of study drug 
compliance for this study. However, study drug compliance will be evaluated during the 
review of important protocol deviation.  Study drug dosing will be provided in subject data 
listings.   
8 
EFFICACY ANALYSES 
All efficacy outcomes will be summarized with descriptive statistics only on the FAS.  All 
efficacy analyses to the Evaluation Period will be based on the seizure records during the 
Evaluation Period on/after the first dose of BRV.     
8.1 
Derivations of efficacy variable(s) 
The derivation and definition of efficacy variables in this study are addressed in this section.  
8.1.1 
28-day adjusted seizure frequency 
The 28-Day Adjusted Partial Seizure Frequency (28DPSF) 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, eg, as following equation: 
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28DPSF =
 Number of partial seizures
Number of days completed in the DRC × 28 
For the 28-day adjusted frequency of all seizure types (partial, generalized and unclassified 
epileptic seizure), the number of numerator will include partial, generalized and unclassified 
epileptic seizure. 
8.1.2 
Percent reduction of 28-day adjusted partial seizure frequency  
Percent reduction of 28DPSF from Baseline is defined as the percentage reduction of 
28DPSF for a designated post-baseline period in EP0085 compared with the Baseline 
28DPSF in the core study. This variable will be derived as following equation: 
Percent reduction = Baseline 28DPSF −Post Baseline 28DPSF
Baseline 28DPSF
× 100 
For rollover subjects the Baseline seizure will be obtained from EP0083 and N01358 study.  
For direct enrollers, the Baseline seizure counts will be collected from 8 weeks prior to the 
first BRV administration (see section 3.3) and the number of days during the Baseline Period 
will be set as 56 days.   
8.1.3 
Responder rate of 28DPSF 
A responder is defined as a subject with a ≥50% reduction of 28DPSF from the Baseline to 
the designated period. 
8.1.4 
Seizure freedom (partial, all epileptic seizure) 
A subject is defined as seizure free for a designated period during the Evaluation Period if 
they meet all of the following criteria:  
• Criteria 1: the subject completed the designated period during the Evaluation Period  
• Criteria 2: the subject has at least 90% non-missing diary days during the period of time 
• Criteria 3: the subject did not report any seizures during the period 
8.2 
Analysis of the efficacy variables 
8.2.1 
Analysis of seizure frequency per 28 day 
Based on the definition in the Section 8.1.1, the partial seizure and all type seizures 
frequency per 28 days will be summarized by descriptive statistics for continuous parameters 
by study group. The analysis time intervals will be 3-month periods over the Evaluation 
Period. In addition, the partial seizure and all type seizures frequencies per 28 days all over 
the Evaluation Period will be summarized in the same way. 
8.2.2 
Analysis of percent reduction of 28DPSF 
The percent reduction of 28DPSF from Baseline will be summarized by descriptive statistics 
as continuous parameters (refer to the Section 3.1) by study group. The analysis time 
intervals will be 3-month periods over the Evaluation Period. In addition, the percent 
reduction of 28DPSF all over the Evaluation Period will be summarized in the same way. 
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8.2.3 
Analysis for responder rate of 28DPSF 
The number and percentage of responders will be summarized by study group. The analysis 
time intervals will be 3-month periods over the Evaluation Period.  The denominator of 
percentage will be based on the total number of subjects with at least 1 seizure assessment 
during the time interval. The numerator will be the number of responders.  
8.2.4 
Analysis of seizure freedom 
Based on the definition of seizure free in the Section 8.1.4, the parameters in the following 
sub-sections will be analyzed respectively. 
8.2.4.1 
The percentage of subjects continuously seizure-free 
The number and percentage of subjects who have been continuously seizure-free for partial 
seizure and all seizure types for at least 6 months and at least 12 months during the 
Evaluation Period will be summarized.  
In addition to the 6 months and 12 months of intervals of continuously seizure-free, 
subsequent 6-month intervals will be summarized in a similar manner.   
The percentage of subjects with continuously seizure-free will be based on the number of 
subjects exposed to BRV for at least the specific time interval.  
8.2.4.2 
Seizure Freedom  
The number and percentage of subjects with seizure-freedom (partial, all epileptic seizure) 
during the Evaluation Period will be summarized by study group.   
9 
SAFETY ANALYSES 
All safety analysis will be based on SS. 
9.1 
Extent of exposure 
9.1.1 
Study medication duration and total study medication duration in 
subject-years 
Duration of exposure to study medication is defined as the total number of days a subject is 
exposed to study medication and will be calculated as the date of last dose in EP0085 minus 
date of first dose in EP0085 plus one in days.  If the last dose date on the Study Termination / 
Early Discontinuation page is missing the last dose date will be captured from the Drug 
Dosing Log CRF.  Gaps in BRV treatment or days on the Drug Dosing Log CRF with 
unknown dosing and/or partial missing exposure date will not be subtracted from the total 
duration of exposure. 
Total study medication duration in subject-years will be calculated as the total duration of 
exposure in days divided by 365.25. 
The duration of exposure to study medication will be summarized by study group for all 
subjects in the SS and will be presented in a table by summary statistics.  
The subject cumulative exposure duration will then be classified into one of the following 
categories: >0 month, ≥3 months, ≥6 months, ≥12 month, ≥18 month, ≥24 months, ≥ 36 
months, ≥ 48 months, and so forth in 12-month increments up to the maximum duration of 
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exposure and will be presented as the number and percentage of subjects in each duration 
category by BRV overall and by modal dose group. Percentages for BRV overall will be 
computed based on the Safety Set. Percentages for the modal dose group will be computed 
based on the number of subjects exposed overall or within each duration of exposure. 
9.1.2 
Study medication dose 
The total cumulative dose will be defined as the sum of the doses across all study days. The 
mean daily dose is defined as cumulative dose divided by total days on study medication.  
The modal daily dose will be calculated across all study days on or after the day of first dose 
of BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during the study. In the event of a tie, the modal dose will be set 
to the lower of the tied doses. Modal daily dose will be categorized as follows: 
 
 
Category  
 
Definition 
5 mg/day  
 
<20mg/day 
20mg/day         
≥20mg/day to <50mg/day  
50mg/day  
 
≥50mg/day to <100mg/day 
100mg/day 
 
≥100mg/day to <150mg/day 
150mg/day 
 
≥150mg/day to <200mg/day 
200mg/day 
 
≥200mg/day 
The mean daily dose, modal daily dose, and modal daily dose category will be summarized 
using descriptive summary statistics by study group. 
A summary of each subject’s exposure will be presented in a listing.   
9.2 
Primary safety variables 
9.2.1 
Definition of treatment-emergent adverse events 
AEs will be classified as either pre-treatment or treatment-emergent. Pre-treatment AEs are 
defined as AEs which had onset prior to the date of the first dose of BRV in EP0085 study. 
Treatment-emergent AEs (TEAEs) are defined as AEs that had onset on or after the day of 
first BRV dose in EP0085 study.  AEs with an incomplete onset date will be classified as 
TEAEs if the month and year of onset (when only the month and year are specified) is the 
same as the month and year of the first BRV dose or the year of onset (when only year is 
specified) is the same as the year of first BRV dose. 
9.2.2 
Summaries of TEAEs 
Pre-treatment AEs will be provided in a subject data listing; no summary of pre-treatment 
AEs are planned.  Summaries will be for TEAEs and will be provided overall by combining 
Evaluation Period, Down-Titration Period, and Study Drug-Free Period unless otherwise 
indicated. 
The following summary of TEAEs will be provided: 
• Incidence of TEAEs – overview (overall and by study periods) 
The following summaries of TEAEs will be provided by MedDRA SOC and PT:  
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• Incidence of TEAE (overall and by study periods) 
• Incidence of TEAEs by safety time interval (overall) 
• Incidence of TEAEs above reporting threshold of 5% of subjects (overall)  
• Incidence of non-serious TEAEs above reporting threshold of 5% of subjects 
(overall) 
• Incidence of TEAEs by maximum intensity (overall and by study periods) 
• Incidence of TEAEs by relationship (overall and by study periods) 
• Incidence of TEAEs leading to permanent discontinuation of study drug (overall) 
• Incidence of treatment-emergent SAE (overall and by study periods)     
• Incidence of treatment-emergent SAE by relationship (overall)     
• Incidence of fatal TEAEs by relationship (overall)   
• Incidence of TEAEs of special interest (overall and by study periods) 
• Incidence of TEAEs requiring dose change (overall and by study periods) 
• Incidence of TEAEs related to COVID-19 vaccination (overall and by study periods) 
For by-study period summary tables, TEAEs will be attributed according to the onset date.   
Three-month safety time interval will be used to summarize data up to and including the 
maximum duration of exposure to BRV. TEAEs which had onset prior to or on the date of 
the last dose of BRV are included in summaries by 3-month time intervals. A subject is 
included in a 3-month interval if the subject was receiving BRV at any time during that 
interval based on their duration of exposure to BRV (eg, a subject with exposure for 91 days 
is included in the time interval for Months 1-3 and Months 4-6). Summaries of AEs by 3-
month intervals will include all subjects who are classified into each time interval as defined 
above as the denominator and TEAEs reported within the specific time interval according to 
the onset date as the nominator. 
9.2.2.1 
Incidence of treatment-emergent adverse events 
TEAEs will be presented by SOC and PT. The incidence of TEAE table will include the 
number and percentage of subjects and number of events by SOC and PT. For the number of 
subjects by SOC/PT, if a subject experiences the same SOC/PT multiple times during the 
period, then that PT will only be incremented by one since subject counts will be presented. 
Percentages will be calculated out of the number of subjects in the SS. The number of events 
at each level of SOC and PT will also be summarized.  
The summary of AEs will be presented in alphabetical order by SOC. Within each SOC, PTs 
will be sorted by descending order of total frequency (ie, frequency across all study groups). 
If the total frequency for any two or more PTs is equal within a SOC, the PTs will be 
presented in alphabetical order. 
All TEAEs will be presented in a listing with a glossary. 
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9.2.2.2 
Withdrawal due to adverse events  
All TEAEs collected with a study drug action taken as “Drug permanently withdrawn” will 
be summarized in a table by SOC and PT in a manner similar to that described in the Section 
9.2.2.1. All AE leading to study discontinuation or permanently withdrawal of study drug 
will be listed by subject. 
9.2.2.3 
Serious adverse events 
Serious TEAEs will be presented in a table by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. All SAE will be listed by subject. 
9.2.2.4 
Adverse events of special interest  
The following AEs are considered as AEs of special interest: 
• autoimmune nephritis 
• nephritis 
• nephritis allergic 
• tubulointerstitial nephritis 
• uveitis syndrome 
• Potential Hy’s Law 
The TEAE of special interest, which will be captured on the CRF page, will be categorized 
and presented by SOC and PT in a manner similar to that described in the Section 9.2.2.1. 
9.2.2.5 
Relationship of adverse events to study drug 
The relationships of TEAE will be either “Related” or “Not Related” according to the CRF 
entry. AEs with missing relationship will be presented in the summary table as “Related” but 
will be presented in the data listing with a missing relationship.  
The AE data will be categorized and presented by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. 
9.2.2.6 
Intensity of adverse event 
Summary of TEAEs will be presented by maximum intensity: 
In the TEAE by maximum intensity table, if a subject experiences multiple occurrences 
within the SOC and PT during that period, the subject is counted only once according to the 
maximum intensity within that SOC or PT (severe > moderate > mild). 
AEs with missing intensity will be presented on tables as “Severe” but will be presented in 
the data listing with a missing intensity.  
The AE data will be categorized and presented by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. 
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9.2.2.7 
Adverse event requiring dose change 
All TEAEs collected with a study drug action taken as “Dose reduced”, "Dose increased" or 
"Drug temporary interrupted" will be summarized in a table by SOC and PT. 
9.2.2.8 
Adverse events related to COVID-19 vaccination 
The TEAE related to COVID-19 vaccination, which will be captured on the CRF page, will 
be categorized and presented by SOC and PT in a manner similar to that described in the 
Section 9.2.2.1. 
9.3 
Other safety variables 
Unless otherwise indicated baseline is defined as the last non-missing data collected prior to 
the first dose of study medication (including Placebo and BRV) in core study. Core study is 
defined as the first study a study participant was enrolled in. 
9.3.1 
Laboratory measurements 
9.3.1.1 
Hematology, biochemistry and urinalysis parameters 
All summaries will be based on the standard international units.  
The observed values and change from baseline will be presented descriptively for 
hematology and biochemistry assessments with numeric values by study group for each 
scheduled visit (not including EV) and for Last Value. Change from baseline will be 
presented for each scheduled post-baseline visit and Last Value. Last Value is the last 
available assessment during treatment with BRV. 
For the qualitative urinalysis parameters, the number and percentage of subjects with each 
response category will be summarized for Baseline, scheduled visits and Last Value.  
Possibly clinically significant treatment-emergent (PCST) abnormalities for laboratory values 
will be summarized by visit and at Last Value as stated above. The PCST abnormality will 
also summarized with shift tables of post-baseline results versus baseline results. Details of 
PCST criteria are available in Section 12.1. 
Urine pregnancy test results will not be summarized but will be provided in a subject data 
listing. 
9.3.1.2 
PDILI laboratory measurements 
The number and percentage of subjects with PDILI will be summarized in table by study 
group. In addition, the number and percentage of subjects meeting ALT or AST or both, total 
bilirubin and symptoms criteria will be summarized in table. 
Listings of subjects with PDILI include alcohol use within past 6 months, the laboratory 
results for ALT, AST and Total bilirubin, symptoms of hepatitis or hypersensitivity, action 
and follow up will be provided only if any subject reporting PDILI. 
9.3.2 
Vital signs 
The observed value and change from baseline for vital signs parameters will be presented at 
each scheduled visit and Last Value by study group.  
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The number and percentage of subjects with any PCST values, any PCST low values, and 
any PCST high value will be summarized. Percentages will be relative to the number of 
subjects with an assessment within each visit. Details of PCST criteria are available in 
Section 12.1.2. 
9.3.3 
Body weight 
Same analyses stated for vital signs will be applied. The results will be reported as an item of 
vital signs. 
9.3.4 
Electrocardiograms (ECG)  
As for the reported ECG parameters, the observed values and change from baseline will be 
presented descriptively by study group for each scheduled visit and for Last Value. 
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding will be summarized for Baseline, each 
visit during the Evaluation Period for which an ECG is scheduled to be performed, and Last 
Value. Percentages will be relative to the number of subjects with an ECG assessment at each 
time point. Same summary will be provided to ECG classification of QTc.    
A listing of subjects will be provided, in which details of abnormality and ECG reader 
(investigator or cardiologist) will be included.  Subjects with QTc results >= 500 msec or 
QTc change from Baseline >= 60 msec will be flagged.  
9.3.5 
Physical examination 
A standard physical examination will be performed at time points specified in the protocol. 
No summaries of physical examination are planned because physical examination findings 
were not recorded on the CRF, and clinically significant new or worsened abnormalities will 
have to be reported as AEs.  
9.3.6 
Neurological examination 
A listing of abnormal neurological examination findings or examination that was not done 
will be provided; no summaries of neurological examination findings are planned because 
clinically significant new or worsened abnormalities will have to be reported as AEs. 
9.3.7 
Columbia-suicide severity rating scale  
Suicidality will be assessed by trained study personnel using the Columbia-Suicide Severity 
Rating Scale (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 schedule of study assessments. Because clinical 
events of interest will be recorded as AEs or serious AEs, no study variable is defined for this 
assessment and no summary analyses are planned for the C-SSRS within the context of this 
study. However, subject data listings of the data for the C-SSRS will be provided. 
10 
PHARMACOKINETICS AND PHARMACODYNAMICS  
Not applicable for this study. 
 
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11 
REFERENCES 
Not applicable 
 
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12 
APPENDICES 
12.1 
PCST criteria 
12.1.1 
Laboratory assessments - PCST  
The following criteria will be applied in the determination of PCST laboratory assessment values. 
12.1.1.1 
Hematology 
Table 2: 
Hematology PCST criteria 
PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
Hematocrit 
<2y 
% 
≤27, >45 
 
2y - <18y 
 
≤29, >47 
 
≥18y 
 
≤85% of LLN, ≥115% of ULN 
Hemoglobin 
<2y 
g/L 
≤90, >150 
 
2y - <18y 
 
≤95, >160 
 
≥18y 
 
≤85% of LLN, ≥115% of ULN 
WBC/Leukocytes 
<12y 
G/L 
<3.5, >15.0 
 
≥12y 
 
<3.0, >12.0 
Neutrophils Absolute 
>1m 
G/L 
<1.5 
Lymphocytes 
<6m 
% 
≤30.0 
 
6m - <6y 
 
≤22.0 
 
6y - <18y 
 
≤12.0, ≥80.0 
 
≥18y 
 
≤10.0, ≥80.0 
Basophils 
>1m 
% 
≥3.0 
Eosinophils 
>1m 
% 
≥10.0 
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PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
Monocytes 
>1m 
% 
≥20.0 
Platelets 
>1m 
G/L 
≤100, >600 
RBC/ Erythrocytes 
<2y 
T/L 
<3.0 
 
≥2y 
 
<3.5 
Abbreviations: F=female; M=male; m=month; PCST=possibly clinically significant treatment-emergent; y= year. A month is defined as 30 days; a year is 
defined as 365.25 days. 
12.1.1.2 
Blood chemistry  
Table 3: 
Chemistry PCST criteria 
PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
AST (SGOT) 
<14y 
U/L 
>180 
 
≥14y 
 
>144 
ALT (SGPT) 
1y - <18y 
U/L 
>90 
 
≥18y 
 
>123 
Alkaline Phosphatase 
<4y 
U/L 
>690 
 
4y - <10y 
 
>834 
 
10y - <18y 
 
>1174 
 
≥18y 
 
>432 (F), >933 (M) 
GGT 
<6m 
U/L 
>522 
 
6m - <1y 
 
>279 
 
1y - <13y 
 
>66 
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PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
 
13y - <18y 
 
>126 
 
≥18y 
 
>255 
Total Bilirubin 
>1m 
umol/L 
≥25.656 
Total Protein 
2m-<1y 
g/L 
<30, >100 
 
≥1y 
 
<43, >100 
Albumin 
<1y 
g/L 
<16, >60 
 
≥1y 
 
<24, >70 
BUN 
<1y 
mmol/L 
>7.497 
 
≥1y 
 
>10.71 
Urea 
<1y 
mmol/L 
>7.014 
 
≥1y 
 
>10.02 
Creatinine 
1y - <10y 
umol/L 
>79.56 
 
10y - <16y 
 
>123.76 
 
≥16y 
 
>141.44 
Creatinine Clearance * 
All 
mL/s 
<1.169 
Calcium 
<1y 
mmol/L 
<1.725, >3.05 
 
1y - <18y 
 
<1.85, >2.925 
 
≥18y 
 
≤1.975, ≥2.775 
Phosphorous 
<1y 
mmol/L 
<0.5814, >2.6486 
 
≥1y 
 
<0.5814, >2.3902 
Potassium 
<1y 
mmol/L 
<3.0, >6.5 
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PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
 
≥1y 
 
<3.0, >5.8 
Sodium 
>1m 
mmol/L 
≤130, ≥150 
Glucose 
>1m 
mmol/L 
<2.775, >9.99 
Total Cholesterol 
1y - <18y 
mmol/L 
>6.475 
 
≥18y 
 
>7.77 
LDL (calculated) 
1y - <18y 
mmol/L 
>3.626 
 
≥18y 
 
>5.18 
HDL 
≤2y 
mmol/L 
<0.259 
 
>2y 
 
<0.518 
Triglycerides 
<1y 
mmol/L 
>8.475 
 
≥1y 
 
>2.825 
Uric Acid 
<1y 
umol/L 
>457.996 
 
1y - <13y 
 
>386.62 
 
13y - <18y 
 
>511.528 
 
≥18y 
 
>404.464 (F), >571.008 (M) 
Thyroxine (T4) 
<1y 
nmol/L 
≤55.3453, ≥236.8264 
 
≥1y 
 
≤48.9098, ≥173.7585 
Globulin 
<1y 
g/L 
<10, >38 
 
≥1y 
 
<12, >44 
Abbreviations: ALT= alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; Cr CL=creatinine clearance; dL = deciliter; 
F=female; GGT: gamma-glutamyltransferase; HDL = high density lipoprotein; LDL = low density lipoprotein; L = liter; M=male; m = month (a month is defined 
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as 30 days) mg = milligram; mmol = millimoles; μg = microgram; PCST=possibly clinically significant treatment-emergent; U = unit; ULN = upper limit of 
normal; y = years (a year is defined as 365.25 days) 
* Schwartz equation (patients <12): Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine; Cockroft equation (patients >12): Male: Cr Cl ml/min = [(140-age)  
body weight (kg)] / (72  serum creatinine); Female: Cr Cl ml/min = [(140-age)  body weight (kg)] / (72  serum creatinine)]  0.85 
 
12.1.1.3 
Urinalysis 
Qualitative urine parameters are generally reported by a descriptive score, which differs among laboratories. For data analysis 
purpose, a 4-point scale is used. Five-point, 6-point, or 7-point scales will be collapsed into a 4-point scale first. A value is considered 
possibly clinically significant treatment-emergent abnormal if an upward shift of at least 2 degrees from the baseline occurs under 
investigational treatment. To collapse the results in a 5-point scale into a 4-point scale, the lowest 2 positive results will be combined 
(see example below). For results reported with a scale of more than 5-point, please consult your study physician for how to collapse 
into 4-point scale. 
Original 5-point Scale 
4-point Scale 
Negative/None 
Negative/None 
Trace/Rare/Mild/A Few 
Trace/1+/Rare/Mild/A Few 
1+ 
 
2+/Mod 
2+/Mod 
3+/Sev 
3+/Sev 
Table 4: 
Urinalysis 4-point scales for PCST criteria 
PARAMETER 
Original Scale 
4-point Scale for PCST 
Protein 
Negative, Trace, 30mg/dL, 100mg/dL, 
≥300mg/dL, ≥1000mg/dL 
Negative, (Trace, 30mg/dL), 100mg/dL, 
(≥300mg/dL, ≥1000mg/dL) 
Glucose 
Negative, 100mg/dL, 250mg/dL, 
500mg/dL, ≥1000mg/dL 
Negative, (100mg/dL, 250mg/dL), 
500mg/dL, ≥1000mg/dL 
Ketones 
Negative, Trace, 15mg/dL, 40mg/dL, 
≥80mg/dL, ≥160mg/dL 
Negative, (Trace, 15mg/dL), 40mg/dL, 
(≥80mg/dL, ≥160mg/dL) 
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PARAMETER 
Original Scale 
4-point Scale for PCST 
Hemoglobin 
(Occult blood) 
Negative, Trace, Small, Moderate, Large 
Negative, (Trace, Small), Moderate, 
Large 
Leukocyte 
Esterase 
Negative, Trace, Small, Moderate, Large 
Negative, (Trace, Small), Moderate, 
Large 
 
12.1.2 
Vital sign assessments – abnormal 
Abnormality criteria to be applied in the assessment of vital signs parameter values are given below. 
Table 5: 
Vital sign PCST criteria 
PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
Pulse Rate 
(beats/minute) 
<6m 
<100, >180 
 
6m - <3y 
<90, >150 
 
3y - <12y 
<60, >130 
 
12y - <17y 
<50, >120 
 
≥17y 
<50 and a decrease from Baseline of ≥15, >120 and an increase from Baseline of ≥15 
Systolic Blood Pressure 
(mmHg) 
<6m 
<60, >100 
 
6m - <3y 
<70, >120 
 
3y - <12y 
<80, >140 
 
12y - <17y 
<90, >160 
 
≥17y 
≤ 90 and a decrease from Baseline of ≥20, ≥ 180 and an increase from Baseline of ≥20 
Diastolic Blood Pressure 
(mmHg) 
<6m 
<40, >65 
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PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
 
6m - <3y 
<45, >75 
 
3y - <12y 
<50, >80 
 
12y - <17y 
<50, >105 
 
≥17y 
<50 and a decrease from Baseline of ≥15, >105 and an increase from Baseline of ≥ 15 
Respiratory Rate 
(breaths/minute) 
<6m 
<25, >55 
 
6m - <3y 
<20, >45 
 
3y - <12y 
<15, >35 
 
≥12y 
<10, >25 
Temperature 
>1m 
>101°F (38.3°C) 
Body Weight 
1m - <17y 
<3% or 97% of the normal body weight growth curve ranges based on gender and the age of 
subject on date of weight assessment a 
 
≥17y 
≥ 10% change from Baseline (an increase or a decrease) a 
Abbreviations: m = month, y = year. A month is defined as 30 days; a year is defined as 365.25 days. 
a source: http://www.cdc.gov/growthcharts/: Once the subject reaches 17 years of age use the body curve criteria of a 17-year-old regardless of their age in the 
study. 
The following table is used to judge PCST regarding body weight. 
Body weight (kg) at the 3 and 97 percentiles of the distribution at each age in Japanese children 
Age  
(years-months) 
16-0 
16-1 
16-2 
16-3 
16-4 
16-5 
16-6 
16-7 
16-8 
16-9 
16-10 
16-11 
17-0 
Male 
3% 
45.66 
45.89 
46.11 
46.33 
46.53 
46.73 
46.93 
47.11 
47.29 
47.47 
47.64 
47.80 
47.97 
97% 
83.83 
84.08 
84.32 
84.57 
84.82 
85.07 
85.31 
85.56 
85.79 
86.02 
86.24 
86.45 
86.64 
Female 
3% 
41.04 
41.11 
41.18 
41.25 
41.31 
41.37 
41.43 
41.49 
41.55 
41.60 
41.66 
41.71 
41.76 
97% 
69.91 
69.98 
70.05 
70.12 
70.19 
70.25 
70.31 
70.36 
70.41 
70.46 
70.51 
70.55 
70.59 
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Source: The Japanese Society for Pediatric Endocrinology: [homepage on the Internet]. Available from: http://jspe.umin.jp/pdf/fuhyo2.pdf 
 
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13 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP)  
13.1 
Amendment 1 
Rationale for the amendment 
The main purpose of this amendment is to align the SAP with Protocol Amendment 3 and 
Protocol Amendment 3.1 (Japan). 
Modifications and changes 
Global changes 
In Japan, a cohort of direct enrollers was added. 
Specific changes 
Change #1 
Study 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 JAPANESE SUBJECTS ≥16 YEARS OF AGE WITH 
PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALIZATION 
 
Change #2 
1 INTRODUCTION (last sentence) 
… The SAP is based on the following study document: Final Protocol Amendment 1 26 July 
2017 and CRF version 2.0. 
Has been changed to: 
… The SAP is based on the following study document: Protocol Amendment 3 and Protocol 
Amendment 3.1 (Japan) and Case Report Form (CRF) version 8.0. 
 
Change #3 
2.2.1 Safety variables 
2.2.1.1 Primary Safety variables 
The primary safety variables include: 
• 
AEs 
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• 
Withdrawal due to AEs 
• 
Occurrence of SAEs 
2.2.1.2 Secondary Safety variables 
The secondary safety variables include: 
• 
Laboratory tests (blood chemistry, hematology, and urinalysis) 
…  
Has been changed to: 
2.2.1.1 Primary Safety variables 
The primary safety variable is AEs. 
2.2.1.2 Other safety variables 
The other safety variables are as follows: 
• 
Laboratory tests (blood chemistry, hematology, and urinalysis) 
…  
 
Change #4 
2.2.2 Efficacy variables 
The efficacy variables 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 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. 
• 
Percentage 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 
Has been changed to: 
2.2.2 Efficacy variables 
The efficacy variables 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 
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• 
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 partial seizure frequency from the 
Baseline Period of EP0083 or N01358 
Efficacy variables for direct enrollers 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 partial seizure frequency from 8 
weeks prior to BRV administration 
Efficacy variables for all subjects (rollovers in China and Japan and direct enrollers in 
Japan): 
• 
Percentage of subjects continuously seizure-free for partial seizure for at least 6 months 
during the Evaluation Period 
• 
Percentage of subjects continuously seizure-free for partial seizure for at least 12 months 
during the Evaluation Period 
• 
Percentage of subjects continuously seizure-free for all seizure types (partial, generalized 
and unclassified epileptic seizure) for at least 6 months during the Evaluation Period 
• 
Percentage of subjects continuously seizure-free for all seizure types (partial, generalized 
and unclassified epileptic seizure) for at least 12 months during the Evaluation Period 
• 
Seizure freedom (partial, all epileptic seizure) during the Evaluation Period 
 
Change #5 
2.3 Study design and conduct 
EP0085 is a Phase 3, open-label, LTFU, multicentre, noncomparative, and dose flexible 
study. The subject population will be Japanese subjects (≥16 years of age) with partial 
seizures with or without secondary generalization. Subjects must complete the Treatment and 
Transition Period of EP0083 prior to enrolment 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 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. 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 protocol Section 5.3, Table 5‒2 
(final version, 22 Nov 2016). 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 
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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 
drug in the last week of down-titration is given only in the morning. 
The study duration per subject is based on the definition of the following periods:  
• 
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). 
Has been changed to: 
2.3 Study design and conduct 
EP0085 is a Phase 3, open-label, long-term follow-up (LTFU), multicenter, noncomparative, 
and dose flexible study being conducted in Japan and China. The population are 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 the study protocol can be 
directly enrolled.  Rollover subjects must complete the Treatment and Transition Period of 
EP0083 prior to enrolment 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 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 will have their eligibility confirmed at the Screening Visit 
(SV). SV occurs -2 to -21 days before BRV administration.  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.   
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 according to 
EP0085 study protocol. (see Table 1). 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 
drug in the last week of down-titration is given only in the morning. 
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The study duration per subject is defined as follows:  
• 
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 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. 
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 that will remain stable for the duration 
of EP0118. Subjects who complete or withdraw from EP0118 will be given the opportunity 
to resume their participation in EP0085 with oral BRV treatment. In the event that a subject 
withdraws from EP0118 and is required to taper off BRV, the subject will return to EP0085 
and taper using BRV tablets. Adverse events and concomitant treatment(s)/medication(s) that 
occur or are administered during EP0118 will be recorded in EP0118.  Ongoing AEs and 
concomitant medication(s)/medical procedure(s) originating from the EP0118 will be 
recorded and followed in EP0085 until resolution or until the status of AE 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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Change #6 
 2.4 
Determination of sample size 
For this open-label LTFU study, no sample size calculation was performed. The sample size 
will depend upon recruitment into and completion of the previous studies. 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: 
2.4 Determination of sample size 
For this open-label LTFU study, no sample size calculation was performed. The sample size 
will depend upon recruitment into and completion of the previous studies. 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 that 30 Japanese subjects will be directly 
enrolled in this study. Likewise, this estimate assumes that at least 90% of randomized 
Chinese subjects will complete EP0083 (approximately 90 subjects). 
 
Change #7 
 3 DATA ANALYSIS CONSIDERATIONS 
The statistical analysis details are addressed in following sections. Subjects from N01379 and 
from EP0083 will be analysed separately as well as pooled as an overall study population, no 
comparison will be performed. 
Has been changed to: 
3 DATA ANALYSIS CONSIDERATIONS 
The statistical analysis details are addressed in following sections. Subjects from N01379 and 
from EP0083 will be analysed separately as well as pooled as an overall study population, no 
comparison will be performed. 
 
Change #8 
 
3.1 General presentation of summaries and analyses 
 
… 
For continuous parameters, descriptive statistics will include number of subjects with 
available measurements (n), mean, standard deviation (SD), median, 25th percentile, 75th 
percentile, minimum, and maximum. Decimal places for descriptive statistics will always 
apply the following rules: 
• 
“n” will be an integer. 
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• 
Mean, SD and median will use 1 additional decimal place compared to the original data. 
• 
Minimum and maximum will have the same number of decimal places as the original 
value. 
A complete set of data listings containing all documented data and all calculated data (eg, 
change from Baseline) will be generated. 
Summaries for the subject disposition, demographics, baseline characteristics, medical 
history, protocol deviation, prior and concomitant medications and study drug exposure will 
present results for study groups described in the later Section 3.2.2, respectively. All the 
safety variables and efficacy variables will present results for study groups, respectively.  
Statistical outliers are defined as values that are discordant with other values and are 
clinically implausible. Any outliers will be reviewed during the data evaluation meeting 
(DEM) prior to database lock or in an interim report.  
Subject data listings will be provided and will present source data and key derived variables 
for statistical analyses. 
Has been changed to:  
3.1 General presentation of summaries and analyses 
 
… 
For continuous parameters, descriptive statistics will include number of subjects with 
available measurements (n), mean, standard deviation (SD), median, 25th percentile, 75th 
percentile, minimum, and maximum. Decimal places for descriptive statistics will always 
apply the following rules: 
• 
“n” will be an integer. 
• 
Mean, SD and median will use 1 additional decimal place compared to the original data. 
• 
Minimum and maximum will have the same number of decimal places as the original 
value. 
All summaries will be descriptive; no statistical hypothesis testing is planned. 
A complete set of data listings containing all documented data and all calculated data (eg, 
change from Baseline) will be generated. 
Summaries for the subject disposition, demographics, baseline characteristics, medical 
history, protocol deviation, prior and concomitant medications and study drug exposure will 
present results for study groups described in the later Section 3.2.2, respectively. All the 
safety variables and efficacy variables will present results for study groups, respectively.  
Statistical outliers are defined as values that are discordant with other values and are 
clinically implausible. Any outliers will be reviewed during the data evaluation meeting 
(DEM) prior to database lock or in an interim report.  
Subject data listings will be provided and will present source data and key derived variables 
for statistical analyses. 
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Change #9 
3.2.1 Analysis time points 
3.2.1.1 Relative day 
Relative day will be calculated as the current date minus the date of first dose of study drug 
plus 1 for days on treatment. The day prior to first dose will be Day -1, the day of first dose 
in this study will be Day 1. The days during BRV treatment will be Day plus a positive 
integer (eg, Day 2, 28). 
For days after the last dose of study drug (in Down-Titration Period and 2-week Study Drug-
Free Period), the relative day will be calculated as the current date minus the date of last dose 
of study drug including a “+” to denote post treatment days (eg, the day after the last dose 
will be Day +1).  
Relative day will not be calculated for partial dates. 
Has been changed to: 
3.2 Analysis time points 
3.2.1 First and last dose of BRV 
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first 
dose of BRV during EP0085 (ie, not the first dose of BRV from the previous study in which 
subjects participated in prior to EP0085). Unless otherwise noted, all references to the last 
known dose of BRV in this SAP refer to the last dose of BRV taken across any study periods 
(ie, the last dose of BRV across both the Evaluation and Down-Titration Periods). 
3.2.2 Relative day 
Relative day will be calculated as follows: 
- 
For days prior to the first dose of BRV, the relative day is the current date minus the date 
of first dose of BRV. The relative day prior to first dose will be Day -1. 
- 
For days on or after the first dose of BRV and on or prior to the last dose of BRV, the 
relative day is the current date minus the date of first dose of BRV plus 1.  The relative day 
of first dose will be Day 1. 
- 
For days after the last dose of BRV, the relative day is the current date minus the date of 
last dose of BRV.  The relative day will include a “+” to denote post treatment days (eg, the 
day after the last dose will be Day +1). 
Relative day will not be calculated for partial or missing dates. 
 
Change #10 
A new section has been added: 
3.2.3 Screening Visit  
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The SV only applies to direct enrollers in Japan and will be performed between Day -21 and 
Day -2 prior to Visit 1 (EV).  The following assessments will be performed at SV: 
Study 
Visit 
Assessments 
EP0085 
direct 
enrollers in 
Japan  
Visit 0 
Demography, medical history, epilepsy history AED 
history, vital signs, body weight, physical 
examination, neurological examination, 12-lead ECG, 
laboratory safety assessments, seizure counts, ongoing 
AE reporting (see more information in Section 9.2), 
C-SSRS, medical procedures, ongoing concomitant 
medications (including AEDs and non-AEDS).  
 
Change #11 
 3.2.2 Study periods 
The following study periods are defined for the classification in summary that are based on 
the study design: 
Evaluation Period 
The Evaluation Period starts on the date of Visit 1 and ends on 
the date of End of Study Visit for subjects who completed 
study or were converted to commercial BRV or on the date of 
EDV for discontinued subjects. 
Treatment Period 
This period comprises the duration from the day of the first 
dose to the day of last the last dose throughout the Evaluation 
Period and the Down-Titration Period. 
Down-Titration Period 
(up to 4 weeks) 
The Down-Titration Period starts with the first dose date of 
decreasing dose to the last day within the 4 weeks, or the date 
of discontinuation during the Down-Titration Period. 
Study Drug-Free Period 
(2 weeks) 
The 2-week Study Drug-Free Period starts with the first day 
after the last dose of Down-Titration Period up to two week 
later or the last following up date. 
Has been changed to: 
3.2.5 Study periods 
The following study periods are defined for the classification in summary that are based on 
the study design: 
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Baseline Period  
For rollover subjects from EP0083, the Baseline Period is 
defined as study days on or after EP0083 Visit 1 date and 
prior to EP0083 Visit 3 date.   
For rollover subjects from N01379, the Baseline Period is 
defined as study days on or after N01358 Visit 1 date and 
prior to N01358 Visit 3 date.  
For direct enrollers, the Baseline Period is defined as study 
days on or after EP0085 Visit 0 date and prior to EP0085 
Visit 1 date.  
Evaluation Period 
The Evaluation Period starts on the date of Visit 1 and the 
following algorithm is used to determine the end date: 
If the subjects enter the Down-Titration Period: 
- 
for completed subjects, which is indicated by the 
CRF “Study Termination” form (Complete subject), 
the Evaluation Period ends on the date of End of 
Study Visit date. 
- 
for discontinued subjects, which is indicated by the 
CRF “Study Termination” form (Dropout), the 
Evaluation Period ends on the date of EDV date.  
If the subjects do not enter the Down-Titration Period: 
For complete / discontinued subjects who do not enter the 
Down-Titration Period, the end of Evaluation Period will 
be the date of last dose of BRV.  
Down-Titration Period 
(up to 4 weeks) 
If the subject is discontinuing BRV, the Investigator will 
first plan an EDV followed by the progressive down-
titration of study drug. 
A subject is considered entering Down-Titration Period 
only if the subject has an EDV and has at least 1 dose of 
study drug after the date of EDV, the start date of Down-
Titration Period is set as 1 day after the date of EDV, and 
the Down-Titration Period ends on date of last dose of 
BRV. A subject without an EDV but having a termination 
CRF or with an EDV but without any dosing of study drug 
after the EDV will not have the Down-Titration Period, and 
no artificial Down-Titration Period will be created for 
analysis. 
Study Drug-Free Period 
(2 weeks) 
After completion of the Down-Titration Period, or for those 
subjects who for extenuating circumstances do not 
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complete a Down-Titration Period, the subject will enter a 
2-week Study Drug-Free Period, followed by a Final Visit. 
A subject is considered entering the Study Drug-Free 
Period if the subject has at least 1 contact (scheduled visit, 
unscheduled visit, or telephone contact) after the date of 
last dose of BRV. The 2-week Study Drug-Free Period 
starts 1 day after the date of last dose of BRV and ends on 
the date of Final Visit.  
For complete / discontinued subjects who do not enter the 
Down-Titration Period, the Study Drug-Free Period starts 1 
day after the last dose of BRV and ends on the date of Final 
Visit. 
 
Change #12 
 3.2.3 Study groups 
Subjects from N01379 and EP0083 need to be analyzed separately. For EP0083 a detailed 
segmentation by dose group is necessary. All relevant Tables, Figures and Listings will 
present the group titles as: 
• 
EP0083 Placebo  
• 
EP0083 BRV 50mg/day 
• 
EP0083 BRV 200mg/day 
• 
EP0083 BRV all 
• 
EP0083 Total 
• 
N01379 
• 
All Subjects 
Unless otherwise specified, results will be presented for each grouping described above. 
Has been moved to: 
3.6 Treatment assignment and study groups 
It is expected that subjects will receive treatment as assigned in accordance with the study 
design.  
Rollover subjects from N01379, EP0083, and directly enrolled subjects need to be analyzed 
separately. For EP0083 a detailed segmentation by drug group is necessary.  Unless 
otherwise specified, results will be presented for each grouping described below:  
For tables and figures the study groups will be presented as follows: 
• 
EP0083 Placebo  
• 
EP0083 BRV All 
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• 
EP0083 Total 
• 
N01379 
• 
Direct Enrollers  
• 
All Subjects 
For subject listings, the study group will be presented as follows: 
• 
EP0083 Placebo  
• 
EP0083 BRV 50mg/day 
• 
EP0083 BRV 200mg/day 
• 
N01379 
• 
Direct Enrollers  
For submission purpose, the subgroup tables and figures will be presented by Japan and 
China.  In Japan subgroup tables and figures, the study groups will be presented in the same 
manner as overall.  In China subgroup tables and figure, given that only the EP0083 rollover 
subjects will be enrolled from China, the study group will be presented as follows: 
• 
EP0083 Placebo  
• 
EP0083 BRV All 
• 
All Subjects 
 
Change #13 
 A new section 3.2.6 Monthly time intervals has been added: 
3.2.6 Monthly time intervals 
In terms of the analysis, a month is defined as 30 days and time intervals based on monthly 
durations are defined as a multiple of 30 days (eg, 12 months is defined as 360 days). The 
following definitions of 3‑month and 6-month intervals are based on 30-day months where 
the date of first dose of BRV is Day 1: 
 
Interval  
Duration Definition  
Month 1-3 
Day 1-90  
Month 4-6 
Day 90-180   
Month 7-9 
Day 181-270  
Month 10-12 
Day 271-360 
Month 13-15 
Day 361-450 
Month 16-18 
Day 451-540 
Month 19-21 
Day 541-630 
Month 22-24 
Day 631-720 
 
 
Month 1-6 
Day 1-180 
Month 7-12 
Day 181-360 
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Month 13-18 
Day 361-540 
Month 19-24 
Day 541-720 
 
Change #14 
 3.2.4 Mapping of assessments performed at Early Discontinuation Visit 
Efficacy and safety assessments at an Early Discontinuation Visit (EDV) that correspond to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. Such assessments will also be considered for 
Last Value. 
In particular, clinical laboratory parameters, vital signs, and body weight are assessed at all 
Treatment Period visits, and so all assessments of these variables at EDVs corresponding to a 
scheduled visit will be mapped to the corresponding scheduled visit. 
The results of unscheduled visit will only be presented in subject listing for safety and 
efficacy variables. 
Has been changed to: 
3.2.4 Mapping of assessments performed at Early Discontinuation Visit 
Efficacy and safety assessments at an Early Discontinuation Visit (EDV) that correspond to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. Such assessments will also be considered for 
Last Value. 
In particular, clinical laboratory parameters, vital signs, and body weight are assessed at all 
Treatment Period visits, and so all assessments of these variables at EDVs corresponding to a 
scheduled visit will be mapped to the corresponding scheduled visit. 
The results of unscheduled visit will only be presented in subject listing for safety and 
efficacy variables. 
A new section 3.2.7 is added: 
3.2.7 Last Value on BRV Treatment  
Last Value for clinical laboratory parameters, vital signs, and ECGs is the last available result 
obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All 
scheduled and unscheduled assessments within this time period will be considered. Last 
Value will be determined separately for each laboratory parameter. 
 
Change #15 
 3.3 
Definition of Baseline values 
The baseline value for all safety and efficacy variables is defined as the last non-missing data 
collected prior to the first dose of study medication in study EP0083 or N01358, unless 
addressed otherwise for a specific type of data. 
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Has been changed to: 
3.3 Definition of Baseline values 
For rollover subjects, the baseline value for all safety and efficacy variables is defined as the 
last non-missing data collected prior to the first dose of study medication in study EP0083 or 
N01358, unless addressed otherwise for a specific type of data. 
For direct enrollers in Japan, the baseline value is defined as the last non-missing data 
collected prior to the first dose of study medication in study EP0085, unless addressed 
otherwise.  For seizure frequency, the baseline is defined as the seizure counts collected from 
8 weeks prior to the first BRV administration. This baseline seizure frequency for direct 
enrollers is consisted of subject's own document (eg, DRC) and the data in DRC for EP0085 
between SV and EV. 
 
Change #16 
 3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on the evaluation of safety and efficacy outcome. Protocol deviations will 
be identified during ongoing data monitoring process. All potential protocol deviation will be 
reviewed at the DEM. In the DEM the important protocol deviation will be identified on a 
subject level. 
Has been changed to: 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on the evaluation of safety and efficacy outcome. Protocol deviations will 
be identified during ongoing data monitoring and cleaning process and All potential protocol 
deviation will be reviewed in the Data Cleaning Meetings . The impact of the protocol 
deviations to the analysis will be discussed in Data Evaluation Meeting.   
 
Change #17 
 3.5.1 Enrolled Set 
The Enrolled Set (ES) will consist of subjects who signed an informed consent form, 
enrolling from either study EP0083 or from study N01379.  Subject disposition will be based 
on ES for presentation. This analysis set is referred to as “All Subjects Screened”. 
Has been changed to: 
3.5.1 Enrolled Set 
The Enrolled Set (ES) will consist of subjects who signed an informed consent form in 
EP0085, enrolling from study EP0083 or from study N01379 or are directly enrolled into 
EP0085 in Japan.  This analysis set is also referred to as “All Subjects Screened”. 
 
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Change #18 
3.8 Changes to protocol-defined analyses 
No applicable. 
Has been changed to: 
3.8 Changes to protocol-defined analyses 
According to the Protocol Amendment 3 and Protocol Amendment 3.1 (Japan), the mental 
and psychiatric status are included as the other safety variables.  However, both variables are 
not collected in EP0085 CRF and will be removed in the future protocol amendment.  The 
relevant analysis will not be conducted.    
 
Change #19 
The following new paragraphs are added to section 4.1 Handling of missing data: 
Subjects participating in EP0118 while also enrolled in EP0085 will have missing data for 
seizure frequency and drug dosing while participating in the EP0118 trial. As the duration of 
the EP0118 study will be short (3-7 days), no imputation for data missing due to participation 
in EP0118 will be performed. Subjects will be assigned the same dose in EP0118 as that 
assigned in EP0085 for the two weeks prior to the start of EP0118. As such, time during the 
EP0118 study will not be subtracted from the exposure calculations (eg, exposure will be 
from the start of BRV treatment in the EP0085 study until the date of last dose of BRV in 
EP0085).  
For the calculation of variables related to seizure frequency, the dates during participation in 
EP0118 will be considered as not done for the purpose of efficacy analyses for trial EP0085 
(eg, these dates will not be considered as days evaluated for seizure frequency). Due to the 
short nature of the EP0118 study, only a few days of seizure frequency data are expected to 
be missing due to participation in EP0118 unless otherwise specified (eg, for the evaluation 
of seizure freedom). 
 
Change #20 
 4.3 
Multicenter studies 
The disposition of subject by study center will present in the summary table by study center. 
The information of study centers will also be identified in the Subject Disposition listing. 
Has been changed to: 
4.3 Multicenter studies 
The disposition of subject by study center will present in the summary table by study center. 
The information of study centers will also be identified in the Subject Disposition listing. 
Efficacy and safety outcomes will not be assessed for individual study center due to the low 
expected number for enrollment within each study center. 
 
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Change #21 
 A new section regarding COVID-19 has been added: 
A new Coronavirus Disease 2019 (COVID-19) CRF to evaluate the impact of global 
pandemic was created and implemented to collect the information on impacted visit, impact 
category, and relationship to COVID-19.  
The impact on study conduct of the COVID-19 global pandemic will be assessed and 
captured as: confirmed COVID-19 infection, suspected COVID-19 infection, general 
circumstances around COVID-19 without infection or any other deviation from the protocol 
due to COVID-19. 
Summary and listing (see section 9.2.2.9) to describe the impact on the interpretability of 
efficacy and safety endpoint due to COVID-19 will be performed.  AE related to COVID-19 
vaccination will be flagged in the AE listings.   
 
Change #22 
 6.1 
Demographics 
The age, weight and height as continuous variables, the age classifications and the sex as 
categorical variables will be summarized by study group.  
The age of subject will be derived as following: 
Age[years] =INT [ (The date of signed informed consent - The date of birth)/365.25] 
The result from above derivation will be kept as integer and the unit of age is years. 
The demographic variables will be listed by subject. 
Has been changed to: 
6.1 Demographics 
Age, age category, gender, racial group, ethnicity, ethnicity subgroup (Japan or China), body 
weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI category will be 
summarized by study group for the Safety Analysis Set.  
The age will be categorized according to the following categories: 
- 
Standard for BRV adult studies: <17, 17 to <65, and ≥65 years 
- 
EudraCT: 12 to <18, 18 to <65, 65 to <85, and ≥85 years 
- 
clinicaltrials.gov: ≤18, 19 to <65 and ≥65 years 
The BMI will be categorized according to the following category: 
- 
<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40 
Age will be calculated based on the date of informed consent and date of birth.  The result 
will be kept as integer and the unit of age is years.  
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A birth date of each subject provided from the feeder studies is imputed to be born on the 
first day of that month (yyyy-mm-01).  
The demographic variables will be listed by subject. 
 
Change #23 
 6.2 
Other Baseline characteristics 
The following epilepsy-related background variables will be summarized by study group: 
• 
Vagal nerve stimulation  
• 
Etiology of epilepsy   
• 
Epileptic seizure profile   
• 
Classification of epileptic syndrome  
• 
Focus localization   
• 
History of epileptic seizures   
• 
Seizure types during Baseline   
• 
Baseline partial seizure frequency 
The number and percentage of subject who had vagal nerve stimulation (VNS) at baseline 
will be summarized in a table. 
All above-mentioned baseline characteristics of study EP0083 and N01358 will be listed by 
subject. 
In addition, childbearing potential and lifestyle-related variables for PDILI (potential drug-
induced liver injury) assessment will be listed by subject. 
Has been changed to: 
6.2 History of epilepsy  
The following epilepsy-related background variables will be summarized by study group: 
• 
Vagus nerve stimulation (VNS) at Screening/Baseline  
• 
History of epileptic seizures   
• 
Classification of epileptic syndrome  
• 
Baseline seizure type and partial seizure frequency 
For all subjects, the VNS information will be obtained from EP0085 CRF form: Vagus Nerve 
Stimulation Status at Screening/Baseline.  The number and percentage of subject who had 
VNS at study entry will be summarized in a table.  A listing of VNS status at study entry and 
VNS setting at the subsequent visits will be provided.   
For rollover subjects, the history of epileptic seizures, classification of epileptic syndrome, 
seizure types during Baseline, and Baseline partial seizure frequency, the data will be 
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obtained from the EP0083 study and N01358 study (for subjects from N01379).  For direct 
enrollers, the data will be obtained from EP0085 CRF forms.  
All above-mentioned baseline characteristics will be listed by subject. 
 
Change #24 
 6.3 
Medical history and concomitant diseases 
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions at the time of study entry, will be summarized by study 
group by the primary system organ class (SOC) and preferred term (PT) according with 
MedDRA version 18.1. Additionally, the number and percentage of subjects with 
concomitant diseases and conditions will be summarized by SOC and PT. 
A listing of subjects with concomitant medical procedures will be provided. 
Has been changed to: 
6.3 Medical history conditions and procedure history 
For rollover subjects, the medical history conditions and procedure history will be obtained 
directly from the Medical History CRFs and the Procedure History CRFs of the EP0083 and 
N01358 (for rollover subjects from N01379). If there is any new medical history condition, it 
will be collected in the Medical History Update form in EP0085.  For direct enrollers, the 
medical history conditions and procedure history will be obtained from the Medical History 
CRFs and the Procedure History CRFs of EP0085.  Reported medical history conditions are 
coded according with MedDRA version 18.1 Medical procedures are not coded. Start and 
stop date are documented partially with month and year only (yyyy-mm). No date imputation 
is foreseen. 
6.3.1 Previous and ongoing medical history conditions 
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions, will be summarized by study group by the primary System 
Organ Class (SOC) and Preferred Term (PT). 
A listing of subjects with previous and ongoing medical history conditions will be provided. 
6.3.2 Procedure history and concomitant procedures 
A listing of subjects with procedure history and concomitant procedures will be provided. 
 
Change #25 
 6.3 
Medical history and concomitant diseases 
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions at the time of study entry, will be summarized by study 
group by the primary system organ class (SOC) and preferred term (PT) according with 
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MedDRA version 18.1. Additionally, the number and percentage of subjects with 
concomitant diseases and conditions will be summarized by SOC and PT. 
A listing of subjects with concomitant medical procedures will be provided. 
 
6.4 Prior and concomitant medications 
All prior and concomitant medications will be coded according to the WHODD version 
September 2015. A prior medication is defined as any medication with a stop date prior to 
the first dose of study drug. A concomitant medication is defined as any ongoing medication 
or with a stop date on or after the first dose of study drug. 
If necessary, the same imputation rules for incomplete dates as for AEs will be applied. 
Please refer to Section 9.1.1. 
The number and percentage of subjects taking prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) class and preferred term by study 
group using the SS as follows; 
• 
History of antiepileptic drugs (AEDs) use prior to entry into the feeder study (EP0083 or 
N01358) 
• 
Number of previous AEDs at the feeder study (EP0083 or N01358) entry 
• 
AEDs taken at study entry 
• 
Concomitant AEDs 
• 
Non-AEDs taken at study entry 
Has been changed to: 
6.4 Prior and concomitant medications 
All prior and concomitant medications will be coded according to the WHODD version 
September 2017.  The AED is defined according to the list of antiepileptic drug as indicated 
in Appendix 3 of the study protocol.   
6.4.1 Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AEDs at study entry will be summarized 
for Safety Set by primary therapeutic group (Anatomic Therapeutic Class [ATC] level 1), 
therapeutic subgroup (ATC level 2), and preferred drug name for the Safety Analysis Set. 
For rollover subjects the medications will be the non-AEDs taken at study entry of the 
previous feeder study and the information will be obtained from CRF form “Prior and 
Concomitant Medications (including AEDs)” from EP0083 and CRF form “Prior and 
Concomitant Medications ” from N01358 (for subjects from N01379).  For direct enrollers 
the medication will be the non-AEDs taken at study entry of EP0085 and the information will 
be obtained from EP0085 CRF form “Concomitant Medications (including AEDs)”. 
6.4.2 History of previous AED use 
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The number and percentage of subjects who had taken at least 1 previous AED will be 
summarized overall and by preferred drug name for the Safety Set.  For rollover subjects the 
previous AEDs are AEDs taken and discontinued prior to entry into the previous feeder study 
and the information will be obtained from CRF form “History of Previous Antiepileptic Drug 
Treatment” from EP0083 and N01358 (for subjects from N01379).  For direct enrollers the 
previous AEDs are AEDs taken and discontinued prior to EP0085 and the information will 
be obtained from EP0085 CRF form “History of Previous Antiepileptic Drug Treatment”.  
6.4.3 Number of previous AEDs 
The number and percentage of previous AEDs will be summarized based on the following 
categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.   The definition of previous AED use 
will be the same as section 6.4.2.   
6.4.4 AEDs taken at study entry  
The number and percentage of subjects taking AEDs at study entry visit will be summarized 
by preferred drug name for the Safety Set. For rollover subjects the medications will be the 
AEDs taken at study entry of the previous feeder study and the information will be obtained 
from CRF form “Prior and Concomitant Medications (including AEDs)” from EP0083 and 
CRF form “Prior and Concomitant Medications(AEDs only)” from N01358 (for subjects 
from N01379).  For direct enrollers the medication will be the AEDs taken at study entry of 
EP0085 and the information will be obtained from EP0085 CRF form “Concomitant 
Medications (including AEDs)”. 
6.4.5 Concomitant AEDs 
A concomitant AED is an AED which was taken during administration of BRV in EP0085 
study, regardless of the start and stop date of the AED. The number and percentage of 
subjects taking concomitant AEDs will be summarized by preferred drug name for the Safety 
Set. 
6.5 Potential drug-induced liver injury (PDILI) 
Subjects with potential drug-induced liver injury (PDILI) will be assessed to determine if 
IMP must be discontinued.  If PDILI occurs, additional lifestyle and family medical history 
information will be collected.  The number and percentage of subjects with PDILI using 
laboratory criteria will be summarized.  Listings of lifestyle and family medical history will 
be provided for subjects with PDILI. 
 
Change #26 
7 MEASUREMENTS OF TREATMENT COMPLIANCE 
7.1 Treatment compliance and modifications 
Study drug compliance will be calculated for each subject by taking into account whether a 
subject takes all doses of study drug as instructed. The number of tablets taken will be 
calculated by subtracting the number of tablets returned from the number of tablets 
dispensed.   
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The study drug compliance (%) for each visit will be calculated by dividing the total number 
of tablets taken up to the next visit by the total number of tablets prescribed at each visit and 
then multiplying by 100.  The overall study drug compliance (%) will be calculated by 
dividing the total number of tablets taken at all visits by the total number of tablets prescribed 
for all visits and then multiplying by 100.  [Example: Compliance (%) = [(total no. of tablets 
dispensed – total no. of tablets returned) / (No. of days in visit interval *No. of tablets 
prescribed per day)] * 100]. It is assumed that half of the daily dose should be consumed on 
the first day and last day of a duration of administration.   
 
The study drug compliance will be summarized by study group and study period using the 
descriptive statistics. For the Evaluation Period, the statistics will be calculated not only 
overall but also by 3-month period. 
Summary statistics on percentage of treatment compliance as well as the number and 
percentage of subjects in each compliance category (<80%, 80-120% and greater than 120% 
compliant) will be presented with the same specification stated above. Percentages will be 
calculated out of the number of subjects who were dosed at that dosing period. 
Has been changed to: 
7 MEASUREMENTS OF TREATMENT COMPLIANCE 
Study drug compliance will not be assessed due to the complexities associated with the 
calculation and interpretation of study drug compliance for this study. Study drug dosing will 
be provided in subject data listings. 
 
Change #27 
 8 EFFICACY ANALYSES 
All efficacy outcomes will be summarized with descriptive statistics only on the FAS. 
Has been changed to: 
8 EFFICACY ANALYSES 
All efficacy outcomes for all study periods will be summarized with descriptive statistics 
only on the FAS.  All efficacy analyses to the Evaluation Period will be based on the seizure 
records during the Evaluation Period on/after the first dose of BRV.     
 
Change #28 
 8.1.2 Percent reduction of 28-day adjusted partial seizure frequency 
Percent reduction of 28DPSF is defined as the percentage reduction of 28DPSF at post-
baseline point compared with the baseline 28DPSFduring the Evaluation Period. This 
variable will be derived as following equation: 
 Percent reduction =
Baseline 28DPSF−Post Baseline 28DPSF
Baseline 28DPSF
 
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Has been changed to: 
Percent reduction of 28DPSF is defined as the percentage reduction of 28DPSF for a 
designated post-baseline period compared with the Baseline 28DPSF. This variable will be 
derived as following equation: 
Percent reduction = Baseline 28DPSF −Post Baseline 28DPSF
Baseline 28DPSF
× 100 
For rollover subjects the Baseline seizure will be obtained from EP0083 and N01358 study.  
For direct enrollers, the Baseline seizure counts will be collected from 8 weeks prior to the 
first BRV administration (see section 3.3) and the number of days during the Baseline Period 
will be set as 56 days.   
 
Change #29 
 8.1.4 Seizure free 
A subject is defined as seizure free during the Evaluation Period if they meet all of the 
following criteria:  
• 
Criteria 1: the subject completed the Evaluation Period 
• 
Criteria 2: the subject did not have more than 90% missing diary days during the 
Evaluation Period 
• 
Criteria 3: the subject did not report any seizures during the Evaluation Period 
Specific algorithmic rules for each of the above are defined as follows: 
• 
Criteria 1: A subject who completed study or were converted to commercial BRV is 
defined as completing the Evaluation Period if End of Study Visit is completed. A subject 
who discontinued study is defined as completing the Evaluation Period if EDV is completed. 
• 
Criteria 2: A subject who meet the criteria 2 is defined as if more than 90% of the seizure 
diary was completed from the day after Visit 1 up to the day prior to the end date of the 
Evaluation Period.  
• 
Criteria 3: A subject who meets criteria 3 is defined as if there are no diary records from 
the day after Visit 1 up to and including the end date of the Evaluation Period with either a 
count >0 or a reported seizure code with an unknown or missing seizure count. 
Has been changed to: 
8.1.4 Seizure freedom (partial, all epileptic seizure) 
A subject is defined as seizure free for a designated period during the Evaluation Period if 
they meet all of the following criteria:  
• 
Criteria 1: the subject completed the designated period during the Evaluation Period  
• 
Criteria 2: the subject has at least 90% non-missing diary days during the period of time 
• 
Criteria 3: the subject did not report any seizures during the period 
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Specific algorithmic rules for each of the above are defined as follows: 
• 
Criteria 1: A subject who completed study or were converted to commercial BRV is 
defined as completing the Evaluation Period if End of Study Visit is completed. A subject 
who discontinued study is defined as completing the Evaluation Period if EDV is completed. 
• 
Criteria 2: A subject who meet the criteria 2 is defined as if more than 90% of the seizure 
diary was completed from the day after Visit 1 up to the day prior to the end date of the 
Evaluation Period.  
• 
Criteria 3: A subject who meets criteria 3 is defined as if there are no diary records from 
the day after Visit 1 up to and including the end date of the Evaluation Period with either a 
count >0 or a reported seizure code with an unknown or missing seizure count. 
 
Change #30 
8.2.4 Analysis of seizure free 
Based on the definition of seizure free in the Section 8.1.4, the parameters in the following 
sub-sections will be analyzed respectively. 
8.2.4.1 The percentage of subjects continuously seizure-free 
The below variables will be summarized as categorical parameters by study group: 
• 
The number and percentage of subjects who have been continuously seizure-free for 
partial seizure by 3-month periods over the Evaluation Period 
• 
The number and percentage of subjects who have been continuously seizure-free for all 
seizure types by 3-month periods over the Evaluation Period 
The denominator of percentage for every 3-month period will be based on the total number 
of subjects for whom seizure assessment during the every 3-month period were performed 
satisfying the criteria 1 and 2 in 8.1.4. 
• 
The number and percentage of subjects who have been continuously partial seizure-free 
at least 6 months during the Evaluation Period 
• 
The number and percentage of subjects who have been continuously partial seizure-free 
at least 12 months during the Evaluation Period 
• 
The number and percentage of subjects who have been continuously all types seizure-free 
at least 6 months during the Evaluation Period 
• 
The number and percentage of subjects who have been continuously all types seizure-free 
at least 12 months during the Evaluation Period 
The percentage for above four variables will be based on the FAS. 
Has been changed to: 
8.2.4 Analysis of seizure freedom 
Based on the definition of seizure free in the Section 8.1.4, the parameters in the following 
sub-sections will be analyzed respectively. 
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8.2.4.1 The percentage of subjects continuously seizure-free 
The below variables will be summarized as categorical parameters by study group: 
• 
The number and percentage of subjects who have been continuously seizure-free for 
partial seizure by 3-month periods over the Evaluation Period 
• 
The number and percentage of subjects who have been continuously seizure-free for all 
seizure types by 3-month periods over the Evaluation Period 
The denominator of percentage for every 3-month period will be based on the total number 
of subjects for whom seizure assessment during the every 3-month period were performed 
satisfying the criteria 1 and 2 in 8.1.4. 
 
• 
The number and percentage of subjects who have been continuously partial seizure-free 
at least 6 months during the Evaluation Period 
• 
The number and percentage of subjects who have been continuously partial seizure-free 
at least 12 months during the Evaluation Period 
• 
The number and percentage of subjects who have been continuously all types seizure-free 
at least 6 months during the Evaluation Period 
• 
The number and percentage of subjects who have been continuously all types seizure-free 
at least 12 months during the Evaluation Period 
The percentage for above four variables will be based on the FAS. 
 
Change #31 
8.2.4.2 Proportion of seizure-free days  
The proportion of seizure-free days for partial seizure by 3-month periods over the 
Evaluation Period will be calculated based on the following equation:  
Proportion of partial seizure free days (%)=(Partial seizure free days during 3 months)/(Total 
days during 3 months)×100  
For the seizure-free days for all seizure types by 3-month periods over the Evaluation Period 
will be calculate as: 
Proportion of all types seizure free days (%)=(All seizures free days during 3 months)/(Total 
days during 3 months)×100  
The proportion of seizure-free days for partial seizure and all seizure types will be 
summarized by descriptive statistics by study group. The analysis time durations will be 3-
month periods over the Evaluation Period. 
In addition, the total days of partial seizure-free and all seizure types over the Evaluation 
Period will be summarized by 3-month periods and for the overall period. 
The time to the first partial seizure and all types seizure will be presented graphically in 
Kaplan-Meier plots by study group during the Evaluation Period. In the analyses, first partial 
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seizure and all types seizure will be analyzed as events and discontinuation (or data-cutoff) 
during the period and completion of the period will be treated as censors. The duration (days) 
of partial seizure-free and all types seizure-free will be presented in box plots by study group 
during the Evaluation Period. 
Has been changed to: 
The analysis of proportion of seizure-free days has been removed since it is not included in 
the protocol.  
 
Change #32 
 8.2.4.3 
Subject with Seizure Freedom  
The number and percentage of subjects who have been any types seizure-free over the 
Evaluation Period will be summarized by 3-month periods and overall period by study group.  
Additionally, as a sensitivity analysis, the number and percentage of subjects meeting criteria 
2 and 3 but not meeting criterion 1 will be summarized by 3-month periods and overall 
period by study group. 
Has been changed to: 
8.2.4.2 Subject with Seizure Freedom  
The number and percentage of subjects who have been any types seizure-free over the 
Evaluation Period will be summarized by 3-month periods and overall period by study group. 
Additionally, as a sensitivity analysis, the number and percentage of subjects meeting criteria 
2 and 3 but not meeting criterion 1 will be summarized by 3-month periods and overall 
period by study group. 
 
Change #33 
 9.1.1 Study drug duration 
Duration of exposure to study drug is defined as the total number of days a subject is exposed 
to study drug and will be presented as the total number of days from the first dose date (Day 
1) to the last dose date as recorded on the Study Termination/Early Discontinuation page on 
the CRF.  If the last dose date on the Study Termination/Early Discontinuation page is 
missing or a subject is lost to follow-up, but the drug accountability log confirms that the 
subject has taken study drug, the visit date following the last completed drug accountability 
log will be used. Days under the study drug exposure will be calculated as date of last dose 
minus date of first dose plus one. 
The duration of exposure to study drug will be summarized by study group for all subjects in 
the SS and will be presented in a table by summary statistics. Total time at risk is defined as 
the total subject-years during the study. Total study drug duration is a subset of total time at 
risk excluding non-treated periods. The total time at risk and the total study drug duration of 
subject-year will be summarized. 
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Has been changed to: 
Duration of exposure to study drug is defined as the total number of days a subject is exposed 
to study drug and will be presented as the total number of days from the first dose date of 
EP0085 to the last dose date during the Treatment Period (i.e., last dose of study drug minus 
the date of first dose of study drug plus 1 day). If the last dose date on the Study 
Termination/Early Discontinuation page is missing or a subject is lost to follow-up, but the 
drug accountability log confirms that the subject has taken study drug, the visit date 
following the last completed drug accountability log will be used. Days under the study drug 
exposure will be calculated as date of last dose minus date of first dose plus one. 
The duration of exposure to study drug will be summarized by study group for all subjects in 
the SS and will be presented in a table by summary statistics. Total time at risk is defined as 
the total subject-years during the study. Total study drug duration is a subset of total time at 
risk excluding non-treated periods. The total time at risk and the total study drug duration of 
subject-year will be summarized. 
 
Change #34 
 9.1.2 Study drug dose 
The total cumulative dose will be defined as the sum of the doses across all study days. The 
mean daily dose is cumulative dose divided by total days on study.  The mean daily dose and 
modal dose will be summarized using descriptive summary statistics by study group and 
study period. 
A summary of each subject’s exposure will be presented in a listing.   
Has been changed to: 
9.1.2 Study drug dose 
The total cumulative dose will be defined as the sum of the doses across all study days. The 
mean daily dose is defined as cumulative dose divided by total days on study.  
The modal daily dose will be calculated across all study days on or after the day of first dose 
of BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during this period. In the event of a tie, the modal dose will be set 
to the lower of the tied doses. Modal daily dose will be categorized as follows: 
 
 
Category  
 
Definition 
5 mg/day  
 
<20mg/day 
20mg/day         
≥20mg/day to <50mg/day  
50mg/day  
 
≥50mg/day to <100mg/day 
100mg/day 
 
≥100mg/day to <150mg/day 
150mg/day 
 
≥150mg/day to <200mg/day 
200mg/day 
 
≥200mg/day 
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The mean daily dose, modal daily dose, and modal daily dose category will be summarized 
using descriptive summary statistics by study group and study period. 
A summary of each subject’s exposure will be presented in a listing.   
 
Change #35 
 9.2.1 Definition of treatment-emergent adverse events 
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined 
as AEs which had onset prior to the date of the first dose of BRV. Treatment-emergent AEs 
(TEAEs) are defined as AEs that had onset on or after the day of first BRV dose. 
Has been changed to: 
9.2.1 Definition of treatment-emergent adverse events 
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined 
as AEs which had onset prior to the date of the first dose of BRV in EP0085 study. 
Treatment-emergent AEs (TEAEs) are defined as AEs that had onset on or after the day of 
first BRV dose in EP0085 study.  AEs with an incomplete onset date will be classified as 
TEAEs if the month and year of onset (when only the month and year are specified) is the 
same as the month and year of the first BRV dose or the year of onset (when only year is 
specified) is the same as the year of first BRV dose. 
 
Change #36 
 9.2.2 Analysis of the primary safety variables 
An overview summary of the number and percentage of subjects with any TEAEs, serious 
TEAEs, subject discontinuations due to TEAEs, permanent withdrawal of study medication 
due to TEAEs, TEAEs requiring dose change, drug-related TEAEs, severe TEAEs, all deaths 
(AEs leading to death), and deaths (TEAEs leading to death) will be provided by study 
group. 
Has been changed to: 
9.2.2 Summaries of TEAEs 
Pre-study AEs will be provided in a subject data listing; no summary of pre-treatment AEs 
are planned.  Summaries will be for TEAEs and will be provided overall by combining 
Evaluation Period, Down-Titration Period, and Study Drug-Free Period unless otherwise 
indicated. 
The following summary of TEAEs will be provided: 
• 
Incidence of TEAEs – overview  
The following summaries of TEAEs will be provided by MedDRA SOC and PT:  
• 
Incidence of TEAE (overall and by study periods) 
• 
Incidence of TEAEs by safety time interval (overall) 
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• 
Incidence of TEAEs above reporting threshold of 5% of subjects (overall) 
• 
Incidence of non-serious TEAEs above reporting threshold of 5% of subjects (overall) 
• 
Incidence of TEAEs by maximum intensity (overall and by study periods) 
• 
Incidence of TEAEs by maximum relationship (overall and by study periods) 
• 
Incidence of TEAEs leading to permanent discontinuation of study drug (overall and by 
study periods) 
• 
Incidence of treatment-emergent SAE (overall and by study periods)     
• 
Incidence of TEAEs of special interest (overall and by study periods) 
• 
Incidence of TEAEs requiring dose change (overall and by study periods) 
• 
Incidence of TEAEs related to COVID-19 vaccination (overall and by study periods) 
A subject is included in a 3 month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above as the denominator and TEAEs reported within the specific time interval as 
the nominator. 
 
Change #37 
 9.2.2.1 
Incidence of Adverse Events 
Summaries of the total number of TEAEs and number and percentage of subjects with at 
least one TEAE will be provided by study group.  TEAEs will be presented by SOC and PT.  
The incidence of TEAEs table will include the number and percentage of subjects and 
number of events by SOC and PT.  For the number of subjects by PT, if a subject experiences 
the same PT multiple times during the period, then that PT will only be incremented by one 
since subject counts will be presented.  As with the PT, for the number of subjects by SOC, if 
a subject experiences multiple AEs within the same SOC during the period, then that SOC 
will only be incremented by one since subject counts will be presented.  Percentages will be 
calculated out of the number of subjects at risk in the SS. The number of events at each level 
of SOC and PT will also be summarized.   
A summary of AEs will also be presented in descending order from the SOC with the highest 
total incidence (that is, summed across all study groups) to the SOC with the lowest total 
incidence by study group.  If the total incidence for any two or more SOCs is equal, the 
SOCs will be presented in alphabetical order. Within each SOC, the PTs will be presented in 
descending order of total incidence. 
In addition, a table for incidence of TEAEs per 100 subject-years will be provided. 
All TEAEs will be presented in a listing with a glossary. 
Has been changed to: 
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9.2.2.1 Incidence of adverse events 
TEAEs will be presented by SOC and PT. The incidence of TEAE table will include the 
number and percentage of subjects and number of events by SOC and PT. For the number of 
subjects by PT, if a subject experiences the same PT multiple times during the period, then 
that PT will only be incremented by one since subject counts will be presented. As with the 
PT, for the number of subjects by SOC, if a subject experiences multiple AEs within the 
same SOC during the period, then that SOC will only be incremented by one since subject 
counts will be presented. Percentages will be calculated out of the number of subjects in the 
SS. The number of events at each level of SOC and PT will also be summarized.  
The summary of AEs will be presented in alphabetical order by SOC. Within each SOC, PTs 
will be sorted by descending order of total frequency (ie, frequency across all study groups) . 
If the total frequency for any two or more PTs is equal within a SOC, the PTs will be 
presented in alphabetical order. 
A subject is included in a 3 month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above as the denominator and TEAEs reported within the specific time interval as 
the nominator. 
A table for incidence of non-serious TEAEs above reporting threshold of 5% of subjects will 
be provided in the same manner. 
The above summaries will be based on all TEAEs and additionally summaries of the 
incidence of TEAEs would be provided for each of the Evaluation, Down-Titration, and 
Study Drug-Free Periods. 
All TEAEs will be presented in a listing with a glossary. 
 
Change #38 
 9.2.2.5 
Relationship of Adverse Events to Study drug 
A summary of TEAEs by relationship to study drug will be presented in a table by incidence 
of occurrence.  The relationships will be collected as the possibility that the study drug 
caused the event.  The possible relationships are “Related” and “Not Related.  In the AE 
relationship table, if a subject experiences multiple occurrences within each SOC and PT 
during that period, each subject is counted once according to the maximum relationship for 
all TEAEs within that SOC or PT. AE that is missing relationship will be presented in the 
summary table as “Related” but will be presented in the data listing with a missing 
relationship.  Percentages will be calculated out of the number of subjects at risk in the SS. 
The AE data will be categorized and presented by SOC, PT and relationship in a manner 
similar to that described in the Section 9.2.2.1. 
Has been changed to: 
9.2.2.5 Relationship of adverse events to study drug 
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A summary of TEAEs by relationship to study drug will be presented in a table by incidence 
of occurrence.  The relationships will be collected as the possibility that the study drug 
caused the event.  The possible relationships of TEAE are “Related” and “Not Related. In the 
TEAE by relationship table, If a subject experiences multiple occurrences within the SOC 
and PT during that period, the subject is counted separately according to each relationship to 
study drug within that SOC or PT.  
In the TEAE by maximum relationship table, if a subject experiences multiple occurrences 
within the SOC and PT during that period, the subject is counted only once according to the 
maximum relationship to study drug within that SOC or PT.  
AEs with missing relationship will be presented in the summary table as “Related” but will 
be presented in the data listing with a missing relationship.  
Percentages will be calculated out of the number of subjects in the SS.  
The AE data will be categorized and presented by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. 
 
Change #39 
 9.2.2.6 
Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table.  The severity that will be 
presented represents the most extreme severity captured on the CRF page.  The possible 
severities are “Mild”, “Moderate”, and “Severe”.  In the AE severity table, if a subject 
reported multiple occurrences of the same AE, only the most severe will be presented.  AEs 
that are missing severity will be presented on tables as “Severe” but will be presented in the 
data listing with a missing severity.  Percentages will be calculated out of the number of 
subjects at risk in the SS. 
The AE data will be categorized and presented by SOC, PT and severity in a manner similar 
to that described in the Section 9.2.2.1. 
Has been changed to: 
9.2.2.6 Intensity of adverse event 
Summary of TEAEs will be presented by intensity and maximum intensity: 
In the TEAE by intensity table, If a subject experiences multiple occurrences within the SOC 
and PT during that period, the subject is counted separately according to each intensity 
within that SOC or PT.  
In the TEAE by maximum intensity table, if a subject experiences multiple occurrences 
within the SOC and PT during that period, the subject is counted only once according to the 
maximum intensity within that SOC or PT (severe > moderate > mild). 
AEs with missing intensity will be presented on tables as “Severe” but will be presented in 
the data listing with a missing intensity. Percentages will be calculated out of the number of 
subjects in the SS. 
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The AE data will be categorized and presented by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. 
 
Change #40 
A new section 9.2.2.8 regarding the adverse events related to COVID-19 vaccination is 
added: 
9.2.2.8 Adverse events related to COVID-19 vaccination 
The TEAE related to COVID-19 vaccination, which will be captured on the CRF page, will 
be categorized and presented by SOC and PT in a manner similar to that described in the 
Section 9.2.2.1. 
 
Change #41 
 9.3.1.1 
Hematology Biochemistry and Urinalysis parameters 
All summaries will be based on the standard international units.  
The observed values and change from baseline will be presented descriptively for 
hematology and biochemistry assessments with numeric values by study group for each 
scheduled visit and for Last Value. Change from baseline will be presented for each 
scheduled post-baseline visit and Last Value. 
Outcomes from the clinical laboratory tests which will be classified as Low, Normal, or High 
according to the reference ranges will be summarized in shift tables comparing those at the 
extreme (either minimum or maximum) post-baseline value with those at the baseline value. 
For the qualitative urinalysis parameters, the number and percentage of subjects with each 
response category will be summarized for Baseline, scheduled visits and Last Value. 
Additionally, this ordered categorical data will be summarized with shift tables in the same 
manner as stated above. 
… 
Has been changed to: 
9.3.1.1 Hematology Biochemistry and Urinalysis parameters 
All summaries will be based on the standard international units.  
The observed values and change from baseline will be presented descriptively for 
hematology and biochemistry assessments with numeric values by study group for each 
scheduled visit and for Last Value. Change from baseline will be presented for each 
scheduled post-baseline visit and Last Value. 
Outcomes from the clinical laboratory tests which will be classified as Low, Normal, or High 
according to the reference ranges will be summarized in shift tables comparing those at the 
extreme (either minimum or maximum) post-baseline value with those at the baseline value. 
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For the qualitative urinalysis parameters, the number and percentage of subjects with each 
response category will be summarized for Baseline, scheduled visits and Last Value. 
Additionally, this ordered categorical data will be summarized with shift tables in the same 
manner as stated above. 
… 
 
Change #42 
 9.3.4 Electrocardiograms (ECG)  
As for the reported ECG parameters, the observed values and change from baseline will be 
presented descriptively by study group for each scheduled visit and for Last Value. 
Categorical analyses with appropriate classification in accordance with ICH E14 guidance 
will be conducted.  
For the result of ECG abnormality, the number and percentage of subjects will be 
summarized for each scheduled visit and Last Value by study group. Additionally, shift table 
of Last Value versus baseline will be provided. 
A listing of subjects will be provided, in which details of abnormality and ECG reader 
(investigator or cardiologist) will be included. 
Has been changed to: 
9.3.4 Electrocardiograms (ECG)  
As for the reported ECG parameters, the observed values and change from baseline will be 
presented descriptively by study group for each scheduled visit and for Last Value. 
Categorical analyses with appropriate classification in accordance with ICH E14 guidance 
will be conducted.  
For the result of ECG abnormality The number and percentage of subjects with no 
abnormality, an abnormal but not clinically significant finding, and a clinically significant 
finding will be summarized for Baseline, each visit during the Evaluation Period for which 
an ECG is scheduled to be performed, and Last Value. Percentages will be relative to the 
number of subjects with an ECG assessment at each time point. Same summary will be 
provided to ECG classification of QTc.    
A listing of subjects will be provided, in which details of abnormality and ECG reader 
(investigator or cardiologist) will be included. 
 
Change #43 
 9.3.5 Physical examination 
A standard physical examination will be performed at time points specified in the protocol.  
Clinically significant new 
Has been changed to: 
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9.3.5 Physical examination 
A standard physical examination will be performed at time points specified in the protocol. 
No summaries of physical examination are planned because clinically significant new or 
worsened abnormalities will have to be reported as AEs. 
 
Change #44 
The following possibly clinically significant treatment-emergent (PCST) criteria are newly 
added to the section 12 Appendices: 
Table 4: 
Urinalysis 4-point scales for PCST criteria 
 
PARAMET
ER 
Original Scale 
4-point Scale for PCST 
Protein 
Negative, Trace, 30mg/dL, 
100mg/dL, ≥300mg/dL, ≥1000mg/dL 
Negative, (Trace, 30mg/dL), 
100mg/dL, (≥300mg/dL, ≥1000mg/dL) 
Glucose 
Negative, 100mg/dL, 250mg/dL, 
500mg/dL, ≥1000mg/dL 
Negative, (100mg/dL, 250mg/dL), 
500mg/dL, ≥1000mg/dL 
Ketones 
Negative, Trace, 15mg/dL, 40mg/dL, 
≥80mg/dL, ≥160mg/dL 
Negative, (Trace, 15mg/dL), 40mg/dL, 
(≥80mg/dL, ≥160mg/dL) 
Hemoglobin 
(Occult blood) 
Negative, Trace, Small, Moderate, 
Large 
Negative, (Trace, Small), Moderate, 
Large 
Leukocyte 
Esterase 
Negative, Trace, Small, Moderate, 
Large 
Negative, (Trace, Small), Moderate, 
Large 
 
Table 5: 
Vital sign PCST criteria 
PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
Pulse Rate 
(beats/minute) 
<6m 
<100, >180 
 
6m - <3y 
<90, >150 
 
3y - <12y 
<60, >130 
 
12y - <17y 
<50, >120 
 
≥17y 
<50 and a decrease from Baseline of ≥15, >120 and an 
increase from Baseline of ≥15 
Systolic Blood 
Pressure 
(mmHg) 
<6m 
<60, >100 
 
6m - <3y 
<70, >120 
 
3y - <12y 
<80, >140 
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PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
 
12y - <17y 
<90, >160 
 
≥17y 
≤ 90 and a decrease from Baseline of ≥20, ≥ 180 and an 
increase from Baseline of ≥20 
Diastolic Blood 
Pressure 
(mmHg) 
<6m 
<40, >65 
 
6m - <3y 
<45, >75 
 
3y - <12y 
<50, >80 
 
12y - <17y 
<50, >105 
 
≥17y 
<50 and a decrease from Baseline of ≥15, >105 and an 
increase from Baseline of ≥ 15 
Respiratory 
Rate 
(breaths/minute) 
<6m 
<25, >55 
 
6m - <3y 
<20, >45 
 
3y - <12y 
<15, >35 
 
≥12y 
<10, >25 
Temperature 
>1m 
>101°F (38.3°C) 
Body Weight 
1m - <17y 
<3% or 97% of the normal body weight growth curve 
ranges based on gender and the age of subject on date of 
weight assessment a 
 
≥17y 
≥ 10% change from Baseline (an increase or a decrease) a 
 Abbreviations: m = month, y = year. A month is defined as 30 days; a year is defined as 365.25 days. 
 
a source: http://www.cdc.gov/growthcharts/: Once the subject reaches 17 years of age use the body curve criteria 
of a 17-year-old regardless of their age in the study. 
The following table is used to judge PCST regarding body weight. 
Body weight (kg) at the 3 and 97 percentiles of the distribution at each age in Japanese children 
Age  
(years-
months) 
16-0 
16-1 
16-2 
16-3 
16-4 
16-5 
16-6 
16-7 
16-8 
16-9 16-10 16-11 17-0 
Male 
3% 
45.66 
45.89 
46.11 
46.33 
46.53 
46.73 
46.93 
47.11 
47.29 
47.47 
47.64 
47.80 
47.97 
97% 
83.83 
84.08 
84.32 
84.57 
84.82 
85.07 
85.31 
85.56 
85.79 
86.02 
86.24 
86.45 
86.64 
Female 3% 
41.04 
41.11 
41.18 
41.25 
41.31 
41.37 
41.43 
41.49 
41.55 
41.60 
41.66 
41.71 
41.76 
97% 
69.91 
69.98 
70.05 
70.12 
70.19 
70.25 
70.31 
70.36 
70.41 
70.46 
70.51 
70.55 
70.59 
Source: The Japanese Society for Pediatric Endocrinology: [homepage on the Internet]. Available from: 
http://jspe.umin.jp/pdf/fuhyo2.pdf 
 
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13.2 
Amendment 2 
Rationale for the amendment 
The main purpose of this amendment is to remove the China subgroup analysis and to achieve 
consistency with other SAPs of the program. 
Modifications and changes 
Specific changes 
Change #1 
2.2.2 Efficacy variables 
… 
Efficacy variables for all subjects (rollovers in China and Japan and direct enrollers in 
Japan):  
•  Percentage of subjects continuously seizure-free for partial seizure for at least 6 months 
during the Evaluation Period  
•  Percentage of subjects continuously seizure-free for partial seizure for at least 12 months 
during the Evaluation Period  
•  Percentage of subjects continuously seizure-free for all seizure types (partial, generalized 
and unclassified epileptic seizure) for at least 6 months during the Evaluation Period  
•  Percentage of subjects continuously seizure-free for all seizure types (partial, generalized 
and unclassified epileptic seizure) for at least 12 months during the Evaluation Period  
Has been changed to: 
2.2.2 Efficacy variables 
… 
Efficacy variables for all subjects (rollovers in China and Japan and direct enrollers in 
Japan):  
•  Percentage of subjects continuously seizure-free for partial seizures for at least 6 months 
and at least 12 months during the Evaluation Period  
•  Percentage of subjects continuously seizure-free for all seizure types (partial, generalized 
and unclassified epileptic seizure) for at least 6 months and at least 12 months during the 
Evaluation Period  
 
Change #2 
2.3 Study design and conduct 
… 
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. 
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Has been changed to: 
2.3 Study design and conduct 
… 
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 #3 
The following new paragraph is added to section 3.1 General presentation of summaries and 
analyses: 
For the analysis purposes, “core study” in this plan refers to the study where the subjects 
were firstly enrolled.  For rollover subjects, the core study is N01358 (for rollover subjects 
from N01379) or EP0083 (for rollover subjects from EP0083).  For direct enrollers EP0085 
is the core study. 
 
Change #4 
3.2.4  Entry Visit  
For rollover subjects from EP0083 and N01379, the following assessments will be completed 
during the last visit of the previous study and do not need to be repeated at Visit 1 (EV):   
Has been changed to: 
3.2.4  Entry Visit  
The EV corresponds to the assessments performed at the time of entry into EP0085. For 
direct enrollers in Japan, the EV will be performed at Visit 1 and the relevant assessments 
will be performed according to the study protocol.  For rollover subjects from EP0083 and 
N01379, the following assessments will be completed during the last visit of the previous 
study and do not need to be repeated at Visit 1 (EV): 
 
Change #5 
3.2.5  Study periods 
Baseline Period 
For rollover subjects from EP0083, the Baseline Period is defined 
as study days on or after EP0083 Visit 1 date and prior to EP0083 
Visit 3 date.  For rollover subjects from N01379, the Baseline 
Period is defined as study days on or after N01358 Visit 1 date and 
prior to N01358 Visit 3 date. For direct enrollers, the Baseline 
Period is defined as study days on or after EP0085 Visit 0 date and 
prior to EP0085 Visit 1 date.   
Has been changed to: 
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3.2.5  Study periods 
Baseline Period 
For rollover subjects from EP0083, the Baseline Period 
corresponds to the Baseline Period of EP0083 and is defined as 
study days on or after EP0083 Visit 1 date and prior to EP0083 
Visit 3 date.   
For rollover subjects from N01379, the Baseline Period 
corresponds to the Baseline Period of N01379 and is defined as 
study days on or after N01358 Visit 1 date and prior to N01358 
Visit 3 date.  
For direct enrollers, except for seizure outcome the Baseline 
Period is defined as study days on or after EP0085 Visit 0 date and 
prior to EP0085 Visit 1 date. The Baseline Period for seizure 
outcome is defined as 8 weeks prior to the first BRV 
administration (see section 8.1.2). 
 
Change #6 
3.2.5  Study periods 
Study Drug-Free 
Period (2 weeks) 
… 
A subject is considered entering the Study Drug-Free Period if the 
subject has at least 1 contact (scheduled visit, unscheduled visit, or 
telephone contact) after the date of last dose of BRV. The 2-week 
Study Drug-Free Period starts 1 day after the date of last dose of 
BRV and ends on the date of Final Visit.   
For complete / discontinued subjects who do not enter the Down-
Titration Period, the Study Drug-Free Period starts 1 day after the 
last dose of BRV and ends on the date of Final Visit. 
 
Has been changed to: 
3.2.5  Study periods 
Study Drug-Free 
Period (2 weeks) 
… 
A subject is considered entering the Study Drug-Free Period if the 
subject has at least 1 contact (scheduled visit, unscheduled visit, or 
telephone contact) after the date of last dose of BRV. The 2-week 
Study Drug-Free Period starts 1 day after the date of last dose of 
BRV and ends on the date of Final Visit, irrespective of entering 
the Down-Titration Period.   
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For complete / discontinued subjects who do not enter the Down-
Titration Period, the Study Drug-Free Period starts 1 day after the 
last dose of BRV and ends on the date of Final Visit. 
 
Change #7 
3.2.5  Study periods 
… 
A subject is considered as completed if this subject completes all scheduled visits as defined 
in the protocol or convert to commercial BRV. 
Has been changed to: 
… 
A subject is considered as completed if this subject completes all scheduled visits as defined 
in the protocol or converts to commercial BRV without a Down-Titration Period (where 
commercial BRV is available). 
 
Change #8 
3.2.6 Monthly time intervals 
In terms of the analysis, a month is defined as 30 days and time intervals based on monthly 
durations are defined as a multiple of 30 days (eg, 12 months is defined as 360 days). The 
following definitions of 3‑month and 6-month intervals are based on 30-day months where 
the date of first dose of BRV is Day 1: 
Interval  
Duration Definition  
Month 1-3 
Day 1-90  
Month 4-6 
Day 90-180   
Month 7-9 
Day 181-270  
Month 10-12 
Day 271-360 
Month 13-15 
Day 361-450 
Month 16-18 
Day 451-540 
Month 19-21 
Day 541-630 
Month 22-24 
Day 631-720 
 
 
Month 1-6 
Day 1-180 
Month 7-12 
Day 181-360 
Month 13-18 
Day 361-540 
Month 19-24 
Day 541-720 
Has been changed to: 
3.2.6 Monthly time intervals 
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In terms of the analysis, a month is defined as 30 days and time intervals based on monthly 
durations are defined as a multiple of 30 days (eg, 12 months is defined as 360 days). The 
following definitions of 3‑month and 6-month intervals are based on 30-day months where 
the date of first dose of BRV is Day 1: 
Interval  
Duration Definition  
3-month interval 
 
Month 1-3 
Day 1-90  
Month 4-6 
Day 91-180   
Month 7-9 
Day 181-270  
Month 10-12 
Day 271-360 
Subsequent 3-month intervals are defined in a similar manner.  Three-month intervals will be 
used for analyses of efficacy (except for continuously seizure-free) and TEAE summaries.  
For the analysis of efficacy outcomes, a subject is included in the analysis of a 3-month 
interval if the last dose of study drug during the Evaluation Period of EP0085 is equal or 
greater than the last day of the 3-month time interval and the seizure diary was completed for 
at least 1 day during the 3-month interval over the Evaluation Period.  
For TEAE summaries, a subject is included in the analysis of a 3-month interval if the last 
dose of study drug in whole period of EP0085 is equal or greater than the first day of the 3-
month time interval (as N for the time interval) and with at least one specified TEAE within 
the 3-month interval (as n in the summary tables according to the AE onset date). 
 
Change #9 
3.3 Definition of Baseline values  
For rollover subjects, the baseline value for all safety and efficacy variables is defined as the 
last non-missing data collected prior to the first dose of study medication in study EP0083 or 
N01358, unless addressed otherwise for a specific type of data. 
Has been changed to: 
3.3 Definition of Baseline values 
Unless otherwise specified, Baseline for all safety and efficacy variables will be based on 
baseline of the core study.   
For rollover subjects, the baseline value for all safety and efficacy variables is defined as the 
last non-missing data collected prior to the first dose of study medication in the core study 
(EP0083 or N01358,), unless addressed otherwise for a specific type of data.  Baseline 
seizure frequency will be obtained from the core study (EP0083 or N01358). 
 
Change #10 
3.6  Treatment assignment and study groups  
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It is expected that subjects will receive treatment as assigned in accordance with the study 
design.   
Rollover subjects from N01379, EP0083, and directly enrolled subjects need to be analyzed 
separately. For EP0083 a detailed segmentation by drug group is necessary.  Unless 
otherwise specified, results will be presented for each grouping described below: 
… 
Has been changed to: 
3.6 Treatment assignment and study groups 
This is an uncontrolled study in which all subjects receive BRV in doses that are optimally 
adjusted for each subject. It is expected that subjects will receive treatment as assigned in 
accordance with the study design.  
Rollover subjects from N01379, EP0083, and directly enrolled subjects need to be analyzed 
separately. For rollovers from EP0083 a detailed segmentation by randomized drug group in 
EP0083 is necessary.  Unless otherwise specified, results will be presented for each grouping 
described below: 
… 
 
Change #11 
3.6  Treatment assignment and study groups 
… 
For submission purpose, the subgroup tables and figures will be presented by Japan and 
China.  In Japan subgroup tables and figures, the study groups will be presented in the same 
manner as overall.  In China subgroup tables and figure, given that only the EP0083 rollover 
subjects will be enrolled from China, the study group will be presented as follows:  
•  EP0083 Placebo   
•  EP0083 BRV All  
•  All Subjects 
Has been changed to: 
3.6  Treatment assignment and study groups 
… 
For submission purpose, the subgroup tables and figures will be presented by Japan and 
China.  In Japan subgroup tables and figures, the study groups will be presented in the same 
manner as overall.  In China subgroup tables and figure, given that only the EP0083 rollover 
subjects will be enrolled from China, the study group will be presented as follows:  
•  EP0083 Placebo   
•  EP0083 BRV All  
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•  All Subjects 
 
Change #12 
4.1  Handling of missing data  
No rule for handling of missing data will be applied for this LTFU study. Safety and efficacy 
variables will be analyzed as available. Days with missing information will be ignored in the 
calculation of the seizure frequency.  
Since subjects may drop out from the study at different times, results will be presented 
overall, by study period, and by 6-month period during the Evaluation Period.  
Missing data related to AEs and seizure frequency will be assessed in the DEM prior to 
database lock or interim report to ensure an acceptable level of protocol compliance.   
Has been changed to: 
4.1  Handling of missing data  
No rule for handling of missing data will be applied for this LTFU study. Safety and efficacy 
variables will be analyzed as available. Days with missing information will be ignored in the 
calculation of the seizure frequency.  
Since subjects may drop out from the study at different times, selected summaries will be 
presented by time interval. 
Missing data related to AEs and seizure frequency will be assessed in the DEM prior to 
database lock or interim report to ensure an acceptable level of protocol compliance.   
 
Change #13 
4.1  Handling of missing data 
… 
For the calculation of variables related to seizure frequency, the dates during participation in 
EP0118 will be considered as not done for the purpose of efficacy analyses for trial EP0085 
(eg, these dates will not be considered as days evaluated for seizure frequency). Due to the 
short nature of the EP0118 study, only a few days of seizure frequency data are expected to 
be missing due to participation in EP0118 unless otherwise specified (eg, for the evaluation 
of seizure freedom). 
Has been changed to: 
4.1  Handling of missing data 
… 
For the calculation of variables related to seizure frequency, the dates during participation in 
EP0118 will be considered as not done for the purpose of efficacy analyses for trial EP0085 
according to the Seizure Count form entry (eg, these dates will not be considered as days 
evaluated for seizure frequency). Due to the short nature of the EP0118 study, only a few 
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days of seizure frequency data are expected to be missing due to participation in EP0118 
unless otherwise specified (eg, for the evaluation of seizure freedom). 
 
Change #14 
4.2  Interim analyses 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 required number of ongoing subjects have completed Visit 5 (Week 24) and after 
required number of ongoing subjects have completed Visit 7 (Week 48).    
Has been changed to: 
4.2  Interim analyses 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 required number of all ongoing subjects have completed Visit 5 (Week 24) and after 
required number of ongoing subjects have completed Visit 7 (Week 48).  There are no 
statistical concerns with such interim reports for this open-label LTFU study. 
 
Change #15 
5.1  Subject disposition 
…  The summary of subjects in the SS who discontinued the study due to AE will be 
presented in a separate table. The percentages will be based on the number of patients in the 
SS. 
Has been changed to: 
5.1  Subject disposition 
…  The summary of subjects in the SS who discontinued the study due to AE will be 
presented in a separate table. The percentages will be based on the number of patients in the 
SS. 
 
Change #16 
5.2  Protocol deviations 
… 
The assignment of subjects to each of the analysis sets will be listed for all subjects enrolled. 
In addition, the reasons for exclusion will be provided in the listing. 
Has been changed to: 
5.2  Protocol deviations 
… 
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The assignment of subjects to each of the analysis sets will be listed for all subjects enrolled. 
In addition, the reasons for exclusion will be provided in the listing. 
 
Change #17 
6  CHARACTERISTICS  
All summaries for subject characteristics will be based on SS. 
Has been changed to: 
6 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
All summaries for subject characteristics will be based on SS. Unless otherwise specified, all 
demographics and other baseline characteristics summaries will be based on data collected in 
the core study. 
 
Change #18 
6.1  Demographics 
Age will be calculated based on the date of informed consent and date of birth.  The result 
will be kept as integer and the unit of age is years.   
A birth date of each subject provided from the feeder studies is imputed to be born on the 
first day of that month (yyyy-mm-01).   
The demographic variables will be listed by subject.    
Has been changed to: 
6.1  Demographics 
Age will be calculated based on the date of informed consent in EP0085 and date of birth.  
The result will be kept as integer and the unit of age is years.  A birth date of each subject 
provided from the core studies is imputed to be born on the first day of that month (yyyy-
mm-01).  Except for age, all other demographic variables will be based on data from baseline 
of core study. 
A birth date of each subject provided from the feeder studies is imputed to be born on the 
first day of that month (yyyy-mm-01).   
The demographic variables will be listed by subject.    
 
Change #19 
6.2  History of epilepsy   
The following epilepsy-related background variables will be summarized by study group:  
•  Vagus nerve stimulation (VNS) at Screening/Baseline   
•  History of epileptic seizures    
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•  Classification of epileptic syndrome   
•  Baseline seizure type and partial seizure frequency 
Has been changed to: 
6.2  History of epilepsy   
The following epilepsy-related background variables will be summarized by study group 
based on the Safety Set:  
•  Vagus nerve stimulation (VNS) at Screening/Baseline   
•  History of epileptic seizures    
• 
Epileptic seizure profile: the number and percentage of subjects experiencing each 
seizure type at any time based on the Classification of Epileptic Seizures (ILAE,1981) prior 
to the core study entry will be summarized. 
• 
History of epileptic seizures at the core study: the number and percentage of subjects with 
a history of status epilepticus and quantitative summaries of epilepsy duration, age at time of 
first diagnosis of seizure, and percent of life with epilepsy, will be summarized.  Percent of 
life with epilepsy will be calculated as 100 times epilepsy duration relative to the first 
diagnosis date and divided by the subject’s age at the core study entry. 
•  Classification of epileptic syndrome collected at the core study: the number and percentage 
of subjects with each epileptic syndrome will be summarized. 
•  Baseline seizure type and partial seizure frequency collected at the core study: the number 
and percentage of subjects who experienced each seizure type during the Baseline Period of 
core study will be presented. Baseline partial seizure frequency will be summarized 
descriptively for subjects who experienced at least one seizure of type I, IA, IB or IC during 
the Baseline Period of core study. 
 
Change #20 
6.4  Prior and concomitant medications  
All prior and concomitant medications will be coded according to the WHODD version 
September 2017.  The AED is defined according to the list of antiepileptic drug as indicated 
in Appendix 3 of the study protocol.    
Has been changed to: 
6.4 Prior and concomitant medications 
All prior and concomitant medications will be coded according to the WHODD version 
September 2017. The AED is defined according to the list of antiepileptic drug as indicated 
in Appendix 3 of the study protocol. Medications taken at study entry are the ongoing 
medications at the study entry of the core study.  Previous medications are medications taken 
and discontinued prior to entry into the core study. Concomitant medications are medications 
taken during administration of BRV in EP0085 study. Previous AEDs and AED taken at core 
study entry will follow the AED definition according to the respective core study. 
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Change #21 
6.4.1  Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AEDs at study entry will be summarized 
for Safety Set by primary therapeutic group (Anatomic Therapeutic Class [ATC] level 1), 
therapeutic subgroup (ATC level 2), and preferred drug name for the Safety Analysis Set.  
For rollover subjects the medications will be the non-AEDs taken at study entry of the 
previous feeder study and the information will be obtained from CRF form “Prior and 
Concomitant Medications (including AEDs)” from EP0083 and CRF form “Prior and 
Concomitant Medications ” from N01358 (for subjects from N01378).  For direct enrollers 
the medication will be the non-AEDs taken at study entry of EP0085 and the information will 
be obtained from EP0085 CRF form “Concomitant Medications (including AEDs)”. 
Has been changed to: 
6.4.1  Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AEDs at study entry will be summarized 
for Safety Set by primary therapeutic group (Anatomic Therapeutic Class [ATC] level 1), 
therapeutic subgroup (ATC level 2), and preferred drug name for the Safety Analysis Set.  
Non-AED taken at study entry refers to the core study entry.  The non-AEDs at core study 
entry will follow the AED definition according to the respective core study. For rollover 
subjects the medications will be the non-AEDs taken at study entry of the previous feeder 
study and the information will be obtained from CRF form “Prior and Concomitant 
Medications (including AEDs)” from EP0083 and CRF form “Prior and Concomitant 
Medications ” from N01358 (for subjects from N01378).  For direct enrollers the medication 
will be the non-AEDs taken at study entry of EP0085 and the information will be obtained 
from EP0085 CRF form “Concomitant Medications (including AEDs)”. 
 
Change #22 
6.4.2  History of previous AED use  
The number and percentage of subjects who had taken at least 1 previous AED will be 
summarized overall and by preferred drug name for the Safety Set.  For rollover subjects the 
previous AEDs are AEDs taken and discontinued prior to entry into the previous feeder study 
and the information will be obtained from CRF form “History of Previous Antiepileptic Drug 
Treatment” from EP0083 and N01358 (for subjects from N01378).  For direct enrollers the 
previous AEDs are AEDs taken and discontinued prior to EP0085 and the information will 
be obtained from EP0085 CRF form “History of Previous Antiepileptic Drug Treatment”.   
Has been changed to: 
6.4.2  History of previous AED use  
The number and percentage of subjects who had taken at least 1 previous AED prior to entry 
into the core study will be summarized overall and by preferred drug name for the Safety Set.  
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For rollover subjects the previous AEDs are AEDs taken and discontinued prior to entry into 
the previous feeder study and the information will be obtained from CRF form “History of 
Previous Antiepileptic Drug Treatment” from EP0083 and N01358 (for subjects from 
N01378).  For direct enrollers the previous AEDs are AEDs taken and discontinued prior to 
EP0085 and the information will be obtained from EP0085 CRF form “History of Previous 
Antiepileptic Drug Treatment”.  Different with the core study N01358, for core study 
EP0083 (for the rollover subjects from EP0083) and EP0085 (for the direct enrollers), the 
history of previous AED was recorded in accordance with the list of AEDs as indicated in 
Appendix 3 of the study protocol, however, the Investigator’s judgement was prioritized and 
taken into consideration. 
 
Change #23 
6.4.4  AEDs taken at study entry   
The number and percentage of subjects taking AEDs at study entry visit will be summarized 
by preferred drug name for the Safety Set. For rollover subjects the medications will be the 
AEDs taken at study entry of the previous feeder study and the information will be obtained 
from CRF form “Prior and Concomitant Medications (including AEDs)” from EP0083 and 
CRF form “Prior and Concomitant Medications(AEDs only)” from N01358 (for subjects 
from N01378).  For direct enrollers the medication will be the AEDs taken at study entry of 
EP0085 and the information will be obtained from EP0085 CRF form “Concomitant 
Medications (including AEDs)”. 
Has been changed to: 
6.4.4  AEDs taken at study entry   
The number and percentage of subjects taking AEDs at study entry visit will be summarized 
by preferred drug name for the Safety Set. For rollover subjects the medications will be the  
AED taken at study entry refers to the core study entry.  The AEDs at core study entry will 
follow the AED definition according to the respective core study. Different with the core 
study N01358, for core study EP0083 (for the rollover subjects from EP0083) and EP0085 
(for the direct enrollers), the AEDs taken at study entry was recorded in accordance with the 
list of AEDs as indicated in Appendix 3 of the study protocol and was captured according to 
the CRF “Core AED?” based on the Investigator’s judgement.  
For rollover subjects the information will be obtained from CRF form “Prior and 
Concomitant Medications (including AEDs)” from EP0083 and CRF form “Prior and 
Concomitant Medications (AEDs only)” from N01358 (for subjects from N01379).  For 
direct enrollers the information will be obtained from EP0085 CRF form “Concomitant 
Medications (including AEDs)”. 
 
Change #24 
6.4.5  Concomitant AEDs  
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A concomitant AED is an AED which was taken during administration of BRV in EP0085 
study, regardless of the start and stop date of the AED. The number and percentage of 
subjects taking concomitant AEDs will be summarized by preferred drug name for the Safety 
Set. 
Has been changed to: 
6.4.5  Concomitant AEDs  
A concomitant AED is an AED which was taken during administration of BRV in EP0085 
study, regardless of the start and stop date of the AED.  Concomitant AEDs will be recorded 
in accordance with the list of AEDs as indicated in Appendix 3 of the study protocol and will 
be captured according to the CRF “Core AED?” based on the investigator’s judgement. The 
number and percentage of subjects taking concomitant AEDs will be summarized by 
preferred drug name for the Safety Set. 
 
Change #25 
The following new section is added: 
6.4.6 Vagus nerve stimulation (VNS) 
For all subjects, the VNS information will be obtained from EP0085 CRF form: Vagus Nerve 
Stimulation Status at Screening/Baseline.  The number and percentage of subject who had 
VNS at Screening/Baseline of EP0085 will be summarized in a table.  A listing of VNS 
status at study entry and VNS setting at the subsequent visits will be provided.   
 
Change #26 
6.5  Potential drug-induced liver injury (PDILI)  
Subjects with potential drug-induced liver injury (PDILI) will be assessed to determine if 
IMP must be discontinued.  If PDILI occurs, additional lifestyle and family medical history 
information will be collected.  The number and percentage of subjects with PDILI using 
laboratory criteria will be summarized.  Listings of lifestyle and family medical history will 
be provided for subjects with PDILI. 
Has been changed to: 
6.5  Potential drug-induced liver injury (PDILI) related information 
Subjects with potential drug-induced liver injury (PDILI) will be assessed to determine if 
IMP must be discontinued.  If PDILI occurs, additional lifestyle and family medical history 
information will be collected.  The number and percentage of subjects with PDILI using 
laboratory criteria will be summarized.  Listings of lifestyle and family medical history will 
be provided if any subject reporting PDILI. 
 
Change #27 
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7  MEASUREMENTS OF TREATMENT COMPLIANCE  
Study drug compliance will not be assessed due to the complexities associated with the 
calculation and interpretation of study drug compliance for this study. Study drug dosing will 
be provided in subject data listings. 
Has been changed to: 
7  MEASUREMENTS OF TREATMENT COMPLIANCE  
Study drug compliance will not be assessed calculated because the planned dose information 
is not collected and also due to the complexity associated with the calculation and 
interpretation of study drug compliance for this study. However, study drug compliance will 
be evaluated during the review of important protocol deviation.  Study drug dosing will be 
provided in subject data listings. 
 
Change #28 
8  EFFICACY ANALYSES  
All efficacy outcomes for all study periods will be summarized with descriptive statistics 
only on the FAS.  All efficacy analyses to the Evaluation Period will be based on the seizure 
records during the Evaluation Period on/after the first dose of BRV.      
Has been changed to: 
8  EFFICACY ANALYSES  
All efficacy outcomes for all study periods will be summarized with descriptive statistics 
only on the FAS.  All efficacy analyses to the Evaluation Period will be based on the seizure 
records during the Evaluation Period on/after the first dose of BRV.      
 
Change #29 
8.1.2  Percent reduction of 28-day adjusted partial seizure frequency   
Percent reduction of 28DPSF is defined as the percentage reduction of 28DPSF for a 
designated post-baseline period compared with the Baseline 28DPSF. This variable will be 
derived as following equation: … 
Has been changed to: 
8.1.2  Percent reduction of 28-day adjusted partial seizure frequency   
Percent reduction of 28DPSF from Baseline is defined as the percentage reduction of 
28DPSF for a designated post-baseline period in EP0085 compared with the Baseline 
28DPSF in the core study. This variable will be derived as following equation: … 
 
Change #30 
8.2.3  Analysis for responder rate of 28DPSF  
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The number and percentage of responders will be summarized by study group. The summary 
will be presented by study visit and all over the Evaluation Period.  The denominator of 
percentage will be based on the total number of subjects with at least 1 seizure assessment 
during the time interval. The numerator will be the number of responders.   
Has been changed to: 
8.2.3  Analysis for responder rate of 28DPSF  
The number and percentage of responders will be summarized by study group. The summary 
analysis time intervals will be 3-month periods presented by study visit and all over the 
Evaluation Period.  The denominator of percentage will be based on the total number of 
subjects with at least 1 seizure assessment during the time interval. The numerator will be the 
number of responders.   
 
Change #31 
8.2.4.1  The percentage of subjects continuously seizure-free  
•  The number and percentage of subjects who have been continuously partial seizure-free at 
least 6 months during the Evaluation Period  
•  The number and percentage of subjects who have been continuously partial seizure-free at 
least 12 months during the Evaluation Period  
•  The number and percentage of subjects who have been continuously all types seizure-free 
at least 6 months during the Evaluation Period 
•  The number and percentage of subjects who have been continuously all types seizure-free 
at least 12 months during the Evaluation Period  
The percentage for above four variables will be based on the FAS. 
Has been changed to: 
8.2.4.1  The percentage of subjects continuously seizure-free 
The number and percentage of subjects who have been continuously seizure-free for partial 
seizure and all seizure types for at least 6 months and at least 12 months during the 
Evaluation Period will be summarized.  
In addition to the 6 months and 12 months of intervals of continuously seizure-free, 
subsequent 6-month intervals will be summarized in a similar manner.   
The percentage of subjects with continuously seizure-free will be based on the number of 
subjects exposed to BRV for at least the specific time interval. 
 
Change #32 
8.2.4.2  Subject with Seizure Freedom   
The number and percentage of subjects who have been any types seizure-free over the 
Evaluation Period will be summarized by study group.   
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Has been changed to: 
8.2.4.2 Seizure Freedom  
The number and percentage of subjects with seizure-freedom (partial, all epileptic seizure) 
during the Evaluation Period will be summarized by study group. 
 
Change #33 
9.1.1  Study drug duration  
Duration of exposure to study drug is defined as the total number of days a subject is exposed 
to study drug and will be presented as the total number of days from the first dose date of 
EP0085 to the last dose date during the Treatment Period (i.e., last dose of study drug minus 
the date of first dose of study drug plus 1 day). If the last dose date on the Study 
Termination/Early Discontinuation page is missing or a subject is lost to follow-up, but the 
drug accountability log confirms that the subject has taken study drug, the visit date 
following the last completed drug accountability log will be used. Days under the study drug 
exposure will be calculated as date of last dose minus date of first dose plus one.  
The duration of exposure to study drug will be summarized by study group for all subjects in 
the SS and will be presented in a table by summary statistics.   
The subject exposure duration will then be classified into one of the following categories: >0 
month, ≥3 months, ≥6 months, ≥12 month, ≥18month, and ≥24 months and will be presented 
as the number and percentage of subjects in each duration category. Percentages will be 
computed based on the number of subjects in the SS. 
Has been changed to: 
9.1.1 Study medication duration and total study medication duration in subject-years 
Duration of exposure to study medication is defined as the total number of days a subject is 
exposed to study medication and will be calculated as the date of last dose in EP0085 minus 
date of first dose in EP0085 plus one in days.  If the last dose date on the Study Termination / 
Early Discontinuation page is missing the last dose date will be captured from the Drug 
Dosing Log CRF.  Gaps in BRV treatment or days on the Drug Dosing Log CRF with 
unknown dosing and/or partial missing exposure date will not be subtracted from the total 
duration of exposure. 
Total study medication duration in subject-years will be calculated as the total duration of 
exposure in days divided by 365.25. 
The duration of exposure to study medication will be summarized by study group for all 
subjects in the SS and will be presented in a table by summary statistics.  
The subject cumulative exposure duration will then be classified into one of the following 
categories: >0 month, ≥3 months, ≥6 months, ≥12 month, ≥18 month, ≥24 months, ≥ 36 
months, ≥ 48 months, and so forth in 12-month increments up to the maximum duration of 
exposure and will be presented as the number and percentage of subjects in each duration 
category by BRV overall and by modal dose group. Percentages for BRV overall will be 
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computed based on the Safety Set. Percentages for the modal dose group will be computed 
based on the number of subjects exposed overall or within each duration of exposure. 
 
Change #34 
9.2.2  Summaries of TEAEs 
… 
The following summary of TEAEs will be provided: 
• 
Incidence of TEAEs – overview  
… 
•  Incidence of TEAEs by maximum relationship (overall and by study periods) 
•  Incidence of TEAEs leading to permanent discontinuation of study drug (overall and by 
study periods) 
A subject is included in a 3 month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above as the denominator and TEAEs reported within the specific time interval as 
the nominator. 
Has been changed to: 
9.2.2  Summaries of TEAEs 
… 
The following summary of TEAEs will be provided: 
• 
Incidence of TEAEs – overview (overall and by study periods) 
… 
•  Incidence of TEAEs by maximum relationship (overall and by study periods) 
•  Incidence of TEAEs leading to permanent discontinuation of study drug (overall and by 
study periods) 
• 
Incidence of treatment-emergent SAE by relationship (overall)     
• 
Incidence of fatal TEAEs by relationship (overall)   
For by-study period summary tables, TEAEs will be attributed according to the onset date.   
Three-month safety time interval will be used to summarize data up to and including the 
maximum duration of exposure to BRV. TEAEs which had onset prior to or on the date of 
the last dose of BRV are included in summaries by 3-month time intervals. A subject is 
included in a 3-month interval if the subject was receiving BRV at any time during that 
interval based on their duration of exposure to BRV (eg, a subject with exposure for 91 days 
is included in the time interval for Months 1-3 and Months 4-6). Summaries of AEs by 3-
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month intervals will include all subjects who are classified into each time interval as defined 
above as the denominator and TEAEs reported within the specific time interval according to 
the onset date as the nominator. 
 
Change #35 
9.2.2.1  Incidence of adverse events 
TEAEs will be presented by SOC and PT. The incidence of TEAE table will include the 
number and percentage of subjects and number of events by SOC and PT. For the number of 
subjects by PT, if a subject experiences the same PT multiple times during the period, then 
that PT will only be incremented by one since subject counts will be presented. As with the 
PT, for the number of subjects by SOC, if a subject experiences multiple AEs within the 
same SOC during the period, then that SOC will only be incremented by one since subject 
counts will be presented. Percentages will be calculated out of the number of subjects in the 
SS. The number of events at each level of SOC and PT will also be summarized.   
The summary of AEs will be presented in alphabetical order by SOC. Within each SOC, PTs 
will be sorted by descending order of total frequency (ie, frequency across all study groups). 
If the total frequency for any two or more PTs is equal within a SOC, the PTs will be 
presented in alphabetical order.  
A subject is included in a 3-month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above as the denominator and TEAEs reported within the specific time interval as 
the nominator.  
A table for incidence of non-serious TEAEs above reporting threshold of 5% of subjects will 
be provided in the same manner.  
The above summaries will be based on all TEAEs and additionally summaries of the 
incidence of TEAEs would be provided for each of the Evaluation, Down-Titration, and 
Study Drug-Free Periods.  
All TEAEs will be presented in a listing with a glossary. 
Has been changed to: 
9.2.2.1  Incidence of adverse events 
TEAEs will be presented by SOC and PT. The incidence of TEAE table will include the 
number and percentage of subjects and number of events by SOC and PT. For the number of 
subjects by SOC/PT, if a subject experiences the same PT multiple times during the period, 
then that PT will only be incremented by one since subject counts will be presented. As with 
the PT, for the number of subjects by SOC, if a subject experiences multiple AEs within the 
same SOC during the period, then that SOC will only be incremented by one since subject 
counts will be presented. Percentages will be calculated out of the number of subjects in the 
SS. The number of events at each level of SOC and PT will also be summarized.   
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The summary of AEs will be presented in alphabetical order by SOC. Within each SOC, PTs 
will be sorted by descending order of total frequency (ie, frequency across all study groups). 
If the total frequency for any two or more PTs is equal within a SOC, the PTs will be 
presented in alphabetical order.  
A subject is included in a 3-month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above as the denominator and TEAEs reported within the specific time interval as 
the nominator.  
A table for incidence of non-serious TEAEs above reporting threshold of 5% of subjects will 
be provided in the same manner.  
The above summaries will be based on all TEAEs and additionally summaries of the 
incidence of TEAEs would be provided for each of the Evaluation, Down-Titration, and 
Study Drug-Free Periods.  
All TEAEs will be presented in a listing with a glossary. 
 
Change #36 
9.2.2.3  Occurrence of serious adverse events  
Serious TEAEs will be presented in a table by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. The table of serious TEAEs will include only one 
occurrence of a PT per subject. If a subject experiences the same SAE PT multiple times 
during the period, then that PT will only be incremented by one since subject counts will be 
presented. As with the PT, if a subject experience multiple SAEs within the same SOC, then 
that SOC will only be incremented by one since subject counts will be presented. Percentages 
will be calculated out of the number of subjects in the SS.    
Has been changed to: 
9.2.2.3  Occurrence of serious adverse events  
Serious TEAEs will be presented in a table by SOC and PT in a manner similar to that 
described in the Section 9.2.2.1. The table of serious TEAEs will include only one 
occurrence of a PT per subject. If a subject experiences the same SAE PT multiple times 
during the period, then that PT will only be incremented by one since subject counts will be 
presented. As with the PT, if a subject experience multiple SAEs within the same SOC, then 
that SOC will only be incremented by one since subject counts will be presented. Percentages 
will be calculated out of the number of subjects in the SS.    
 
Change #37 
9.2.2.5  Relationship of adverse events to study drug  
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The possible relationships of TEAE are “Related” and “Not Related. If a subject experiences 
multiple occurrences within the SOC and PT during that period, the subject is counted 
separately according to each relationship to study drug within that SOC or PT.   
In the TEAE by maximum relationship table, if a subject experiences multiple occurrences 
within the SOC and PT during that period, the subject is counted only once according to the 
maximum relationship to study drug within that SOC or PT.   
Has been changed to: 
9.2.2.5  Relationship of adverse events to study drug  
The possible relationships of TEAE are “Related” and “Not Related. If a subject experiences 
multiple occurrences within the SOC and PT during that period, the subject is counted 
separately according to each relationship to study drug within that SOC or PT.   
In the TEAE by maximum relationship table, if a subject experiences multiple occurrences 
within the SOC and PT during that period, the subject is counted only once according to the 
maximum relationship to study drug within that SOC or PT.   
The relationships of TEAE will be either “Related” or “Not Related” according to the CRF 
entry. AEs with missing relationship will be presented in the summary table as “Related” but 
will be presented in the data listing with a missing relationship. 
 
Change #38 
9.3  Statistical analysis of the other safety variables 
Has been changed to: 
9.3  Other safety variables 
Unless otherwise indicated baseline is defined as the last non-missing data collected prior to 
the first dose of study medication (including Placebo and BRV) in core study. Core study is 
defined as the first study a study participant was enrolled in. 
 
Change #39 
9.3.1.1  Hematology, biochemistry and urinalysis parameters 
… The observed values and change from baseline will be presented descriptively for 
hematology and biochemistry assessments with numeric values by study group for each 
scheduled visit and for Last Value. Change from baseline will be presented for each 
scheduled post-baseline visit and Last Value. 
… 
Possibly clinically significant treatment-emergent (PCST) abnormalities for laboratory values 
will be summarized by visit and at Last Value as stated above. Additionally, it will be 
analyzed for the worst value which is either a minimum value for a downward criterion or a 
maximum value for an upward criterion. The PCST abnormality will also summarized with 
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shift tables of post-baseline results versus baseline results. Details of PCST criteria are 
available in Section 12.1. 
Has been changed to: 
9.3.1.1  Hematology, biochemistry and urinalysis parameters 
… The observed values and change from baseline will be presented descriptively for 
hematology and biochemistry assessments with numeric values by study group for each 
scheduled visit and for Last Value. Change from baseline will be presented for each 
scheduled post-baseline visit and Last Value. Last Value is the last available assessment 
during treatment with BRV. 
… 
Possibly clinically significant treatment-emergent (PCST) abnormalities for laboratory values 
will be summarized by visit and at Last Value as stated above. Additionally, it will be 
analyzed for the worst value which is either a minimum value for a downward criterion or a 
maximum value for an upward criterion. The PCST abnormality will also summarized with 
shift tables of post-baseline results versus baseline results. Details of PCST criteria are 
available in Section 12.1. 
 
Change #40 
9.3.1.2  PDILI laboratory measurements  
The number and percentage of subjects with PDILI will be summarized in table by study 
group for each scheduled visit and for Last Value. In addition, the number and percentage of 
subjects meeting ALT or AST or both, total bilirubin and symptoms criteria will be 
summarized in table. 
Listings of subjects with PDILI include alcohol use within past 6 months, the laboratory 
results for ALT, AST and Total bilirubin, symptoms of hepatitis or hypersensitivity, action 
and follow up will be provided. 
Has been changed to: 
9.3.1.2  PDILI laboratory measurements  
The number and percentage of subjects with PDILI will be summarized in table by study 
group for each scheduled visit and for Last Value. In addition, the number and percentage of 
subjects meeting ALT or AST or both, total bilirubin and symptoms criteria will be 
summarized in table. 
Listings of subjects with PDILI include alcohol use within past 6 months, the laboratory 
results for ALT, AST and Total bilirubin, symptoms of hepatitis or hypersensitivity, action 
and follow up will be provided only if any subject reporting PDILI. 
 
Change #41 
9.3.2  Vital signs  
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The observed value and change from baseline for vital signs parameters will be presented at 
each scheduled visit and Last Value by study group.   
PCST abnormalities for vital signs will be summarized as stated in Section 9.3.1.1. 
Has been changed to: 
9.3.2  Vital signs  
The observed value and change from baseline for vital signs parameters will be presented at 
each scheduled visit and Last Value by study group.   
PCST abnormalities for vital signs will be summarized as stated in Section 9.3.1.1. 
The number and percentage of subjects with any PCST values, any PCST low values, and 
any PCST high value will be summarized. Percentages will be relative to the number of 
subjects with an assessment within each visit. Details of PCST criteria are available in 
Section 12.1.2 
 
Change #42 
9.3.5  Physical examination  
A standard physical examination will be performed at time points specified in the protocol. 
No summaries of physical examination are planned because clinically significant new or 
worsened abnormalities will have to be reported as AEs.   
Has been changed to: 
9.3.5  Physical examination  
A standard physical examination will be performed at time points specified in the protocol. 
No summaries of physical examination are planned because physical examination findings 
were not recorded on the CRF, and clinically significant new or worsened abnormalities will 
have to be reported as AEs.   
 
Change #43 
9.3.6  Neurological examination  
A listing of abnormal neurological examination findings will be provided; no summaries of 
neurological examination findings are planned because clinically significant new or 
worsened abnormalities will have to be reported as AEs. 
Has been changed to: 
9.3.6  Neurological examination  
A listing of abnormal neurological examination findings or examination that was not done 
will be provided; no summaries of neurological examination findings are planned because 
clinically significant new or worsened abnormalities will have to be reported as AEs. 
 
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13.3 
Amendment 3 
Rationale for the amendment 
The main purpose of this amendment is to align the SAP with the Protocol Amendment 4. 
Modifications and changes 
Specific changes 
Change #1 
1  INTRODUCTION  
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a  
detailed description of statistical methodology for the statistical analyses to support the final  
clinical study report (CSR). The SAP is based on the following study document: Protocol  
Amendment 3 and Protocol Amendment 3.1 (Japan) and Case Report Form (CRF) version 
8.0. 
Has been changed to: 
1  INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report (CSR). The SAP is based on the following study document: Protocol 
Amendment 4 and Case Report Form (CRF) version 8.0. 
 
Change #2 
2.2.1.1  Primary safety variables  
The primary safety variable is adverse events (AEs). 
Has been changed to: 
2.2.1.1  Primary safety variables  
The primary safety variable is treatment-emergent adverse events (TEAEs). 
 
Change #3 
 
2.2.2  Efficacy variables 
 
… 
Efficacy variables for all subjects (rollovers in China and Japan and direct enrollers in 
Japan):  
•  Percentage of subjects continuously seizure-free for partial seizures for at least 6 
months and at least 12 months during the Evaluation Period  
•  Percentage of subjects continuously seizure-free for 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 
Has been changed to: 
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Efficacy variables for all subjects (rollovers in China and Japan and direct enrollers in 
Japan): 
• Percentage of subjects continuously seizure-free for partial seizures 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 
 
2.3  Study design and conduct 
 
… 
 
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, 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 that will remain stable for the duration 
of EP0118. Subjects who complete or withdraw from EP0118 will be given the opportunity 
to resume their participation in EP0085 with oral BRV treatment. In the event that a subject 
withdraws from EP0118 and is required to taper off BRV, the subject will return to EP0085 
and taper using BRV tablets. Adverse events and concomitant treatment(s)/medication(s) that 
occur or are administered during EP0118 will be recorded in EP0118. Ongoing AEs and 
concomitant medication(s)/medical procedure(s) originating from the EP0118 will be 
recorded and followed in EP0085 until resolution or until the status of AE 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. 
 
 
Has been changed to: 
2.3  Study design and conduct 
 
… 
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.  
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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 be given the 
opportunity to 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. TEAEs 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 #5 
3.8  Changes to protocol-defined analyses  
According to the Protocol Amendment 3 and Protocol Amendment 3.1 (Japan), the mental 
and psychiatric status are included as the other safety variables.  However, both variables are 
not collected in EP0085 CRF.  The relevant analysis will not be conducted.     
Has been changed to: 
 
3.8  Changes to protocol-defined analyses 
 
Not applicable.   
 
Change #6 
The following new section is added: 
6.6 Neuro-imaging procedure  
A neuro-imaging procedure, including brain magnetic resonance imaging (MRI), brain 
computerized tomography (CT) scan or other imaging test will be performed for direct 
enrollers at Screening Visit per Investigator discretion.  A listing of  CT and MRI data will be 
provided.    
 
Change #7 
The following new section is added: 
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6.7 Electroencephalogram 
For direct enrollers, 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.  A listing 
of EEG interpretation data will be provided. 
 
Change #8 
9.2.1 Definition of treatment-emergent adverse events 
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined 
as AEs which had onset prior to the date of the first dose of BRV in EP0085 study.  
… 
Has been changed to: 
9.2.1 Definition of treatment-emergent adverse events 
AEs will be classified as either pre-treatment or treatment-emergent. Pre-treatment AEs are 
defined as AEs which had onset prior to the date of the first dose of BRV in EP0085 study.  
… 
 
Change #9 
9.2.2 Summaries of TEAEs 
Pre-study AEs will be provided in a subject data listing; no summary of pre-treatment AEs 
are planned.  Summaries will be for TEAEs and will be provided overall by combining 
Evaluation Period, Down-Titration Period, and Study Drug-Free Period unless otherwise 
indicated.  
… 
Has been changed to: 
9.2.2 Summaries of TEAEs 
Pre-treatment AEs will be provided in a subject data listing; no summary of pre-treatment 
AEs are planned.  Summaries will be for TEAEs and will be provided overall by combining 
Evaluation Period, Down-Titration Period, and Study Drug-Free Period unless otherwise 
indicated.  
… 
 
Change #10 
9.3.4 Electrocardiograms (ECG) 
… 
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A listing of subjects will be provided, in which details of abnormality and ECG reader 
(investigator or cardiologist) will be included.  Subjects with QTc results > 500 msec or QTc 
change from Baseline > 60 msec will be flagged.  
Has been changed to: 
9.3.4 Electrocardiograms (ECG) 
… 
A listing of subjects will be provided, in which details of abnormality and ECG reader 
(investigator or cardiologist) will be included.  Subjects with QTc results >= 500 msec or 
QTc change from Baseline >= 60 msec will be flagged.  
 
13.4 
Amendment 4 
Rationale for the amendment 
The main purpose of this amendment are  
(1) To align the SAP with the protocol amendment 4.1. This Japan-specific protocol amendment 
is to update the terminology “clinical study” to “postmarketing clinical study” and related 
text that describes the continuing of EP0085 in Japan after the date of approval in Japan. 
(2) To add time to BRV discontinuation analyses  
 
Modifications and changes 
Specific changes 
Change #1 
1 INTRODUCTION  
…The SAP is based on the following study document: Protocol Amendment 4 and Case 
Report Form (CRF) version 8.0. 
Has been changed to: 
1 INTRODUCTION  
…The SAP is based on the following study document: Protocol Amendment 4.1 and Case 
Report Form (CRF) version 8.0. 
 
Change #2 
The following new paragraph is added to section 2.3 Study design and conduct: 
Subjects who will be converted to the commercial BRV product will complete an End of 
Study Visit without entering the Down-Titration Period or the 2-week Study Drug-Free 
Period and will not complete an FV. 
 
Change #3 
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Section 2.3 Study design and conduct 
… 
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: 
 
…  
In Japan, EP0085 will continue as a postmarketing clinical study (Phase 4) after the date of 
approval of BRV for the partial seizure indication until approximately 6 months after the date 
of BRV approval for the partial seizure indication. 
 
Change #4 
The following new section is added for time to BRV discontinuation analysis: 
5.4 Time to BRV discontinuation  
As an additional assessment, the time to BRV discontinuation will be evaluated for both the 
overall study population and the Japanese subpopulation. 
The time to BRV discontinuation will be calculated as follows: 
(Date of last dose of BRV – date of first dose of BRV +1) / 30 (in month) 
The time to BRV discontinuation will be analyzed using Kaplan-Meier method.  The median 
time, 25% percentile, and 75% percentile of time to BRV discontinuation will be calculated 
based on SS.  Additionally, the cumulative number of events, number at risk, and survival 
estimate at month 12, 24, 36, 48, 60, 72, 84 and 96 will be provided.   
Subjects who discontinued BRV for any reason will be considered as an event.  All other 
subjects will be censored at the date of the last dose of BRV.   
In addition to analyzing BRV discontinuation due to any reason, the time to BRV 
discontinuation will be separately analyzed for the following specific reasons: 
• 
Due to TEAE 
• 
Due to lack of efficacy 
• 
Due to lack of efficacy or TEAE 
For each of the BRV discontinuation reason, a summary table will be provided by study 
group.  Additionally, a Kaplan-Meier figure will be provided combing all discontinuation 
reasons and presented, by study group.   
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
 
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Approval Signatures
Name:
ep0085-sap-amend-4
Version:
1. 0
Document Number:
CLIN-000272131
Title:
ep0085-sap-amend-4
Approved Date:
05 Feb 2025
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-Feb-2025 02:43:17 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-Feb-2025 14:37:48 GMT+0000
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