Clinical trial NCT03083665
Conditions: Partial Seizures With or Without Secondary Generalization Epilepsy
Keywords: Epilepsy Partial seizures with or without secondary generalization Brivaracetam Briviact
Sponsor: UCB Biopharma SRL
Start date: 2017-08-22; Completion date: 2022-06-30
Enrollment: 449 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the efficacy of brivaracetam (BRV) compared to placebo (PBO) as adjunctive treatment in subjects (\>=16 to 80 years of age) with partial seizures with or without secondary generalization despite current treatment with 1 or 2 concomitant antiepileptic drugs (AEDs) and to assess the safety and tolerability of BRV in subjects \>= 16 years to 80 years of age.

Detailed description:

Arms: arm 1: * 12 weeks Treatment Period: Subjects will receive Placebo
* 4 weeks Down-Titration Period: Subjects will receive Placebo arm 2: 12 weeks Treatment Period: Subjects will receive BRV 50 mg/day

\- Subjects entering into the Long term follow up (LTFU) study or managed access program (MAP): 2 weeks Transition Period: Subjects will receive BRV 50 mg/day followed by LTFU or MAP: Subjects will receive BRV 100 mg/day

\- Subjects not entering into the LTFU study or MAP: 4 weeks Down-Titration Period: Subjects will receive BRV 25 mg/day for 1 week followed by Placebo for 3 weeks, followed by a Study Drug-Free Period arm 3: 12 weeks Treatment Period: Subjects will receive BRV 200 mg/day

\- Subjects entering into the Long term follow up (LTFU) study or managed access program (MAP): 2 weeks Transition Period: Subjects will receive BRV 150 mg/day followed by LTFU or MAP: Subjects will receive BRV 100 mg/day

\- Subjects not entering into the LTFU study or MAP: 4 weeks Down-Titration Period: Subjects will receive BRV 150 mg/day for 1 week followed by BRV 100 mg/day for 1 week, followed by BRV 50 mg/day for 1 week, followed by BRV 25 mg/day for 1 week followed by a Study Drug-Free Period
Interventions: intervention 1: Placebo intervention 2: Brivaracetam
Intervention descriptions: intervention 1: * Pharmaceutical form: Film-coated tablets
* Route of administration: Oral use intervention 2: * Pharmaceutical form: Film-coated tablets
* Concentration: 25 mg tablets and 50 mg tablets
* Route of administration: Oral use

Protocol documents:
Prot_000.pdf: 
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PROTOCOL EP0083 AMENDMENT 4 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER, PARALLEL-GROUP STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF ADJUNCTIVE 
BRIVARACETAM IN SUBJECTS (≥16 TO 80 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 
17 Oct 2016 
Not applicable 
Protocol Amendment 1 
12 May 2017 
Non-substantial 
Protocol Amendment 2 
11 July 2017 
Non-substantial 
Protocol Amendment 3 
01 Feb 2019 
Substantial 
Protocol Amendment 4 
10 Jan 2020 
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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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  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
317 Room No.439, 
Futexi Yi road, China 
(Shanghai) 
Pilot Free Trade Zone 
1070 Brussels 
Tokyo 160-0023 
Shanghai 200131 
BELGIUM 
JAPAN 
PRC 
Medical expert  
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: 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Phone: 
 
Fax: 
 
Clinical Project Manager 
Name: 
 
Address: 
Allée de la Recherche 60 
1070 Brussels, BELGIUM 
Phone: 
 
Fax: 
  
 
 
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Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku, 
Tokyo, 160-0023, JAPAN 
Phone: 
 
Fax: 
 
Clinical Monitoring Contract Research Organization (Ireland) 
Name: 
PAREXEL International (IRL) Limited 
Address: 
70 Sir John Rogerson’s Quay, Dublin 2,  
Ireland 
Phone: 
+353 -1-473 9500 
Fax: 
+353-1- 473 9501 
Other study contact information will be provided in separate documents. 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24 hours) 
Fax 
UCB Japan: +81 3 6864 7400 
Email 
UCB Japan: JDSO@ucb.com 
Serious adverse event reporting (24 hours) for China only 
Fax 
UCB China: +86-21-23210206 
Email 
UCB China: ds.China@ucb.com 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 13 
2.1 Background and epidemiology of targeted disease.......................................................... 13 
2.2 Background information regarding product ..................................................................... 14 
2.3 Efficacy with BRV in fixed-dose Phase 2/3 studies in subjects with partial seizures ..... 15 
2.4 Safety with BRV .............................................................................................................. 15 
2.5 Study rationale ................................................................................................................. 15 
3 
STUDY OBJECTIVE(S) ................................................................................................. 16 
3.1 Primary objective ............................................................................................................. 16 
3.2 Secondary objective ......................................................................................................... 16 
4 
STUDY VARIABLES ..................................................................................................... 16 
4.1 Efficacy variable .............................................................................................................. 16 
4.1.1 
Primary efficacy variable ..................................................................................... 16 
4.1.2 
Secondary efficacy variables ............................................................................... 16 
4.2 Pharmacokinetic variable ................................................................................................. 17 
4.3 Safety variables ................................................................................................................ 17 
4.3.1 
Primary safety variables ...................................................................................... 17 
4.3.2 
Other safety variables .......................................................................................... 17 
5 
STUDY DESIGN ............................................................................................................. 17 
5.1 Study description ............................................................................................................. 17 
5.1.1 
Study duration per subject ................................................................................... 18 
5.1.2 
Planned number of subjects and sites .................................................................. 18 
5.1.3 
Anticipated regions and countries ....................................................................... 19 
5.2 Schedule of study assessments ......................................................................................... 20 
5.3 Schematic diagram ........................................................................................................... 23 
5.4 Rationale for study design and selection of dose ............................................................. 24 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 24 
6.1 Inclusion criteria .............................................................................................................. 24 
6.2 Exclusion criteria ............................................................................................................. 25 
6.3 Withdrawal criteria .......................................................................................................... 27 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 28 
7 
STUDY TREATMENT(S) .............................................................................................. 29 
7.1 Description of investigational medicinal product(s) ........................................................ 29 
7.2 Treatment(s) to be administered ...................................................................................... 29 
7.3 Packaging ......................................................................................................................... 29 
7.4 Labeling ........................................................................................................................... 30 
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7.5 Handling and storage requirements.................................................................................. 30 
7.6 Drug accountability .......................................................................................................... 30 
7.7 Procedures for monitoring subject compliance ................................................................ 30 
7.8 Concomitant medication(s)/treatment(s).......................................................................... 31 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 31 
7.8.2 
Prohibited concomitant treatments (medication and therapies) ........................... 31 
7.8.3 
Restricted concomitant treatments (medications and therapies).......................... 32 
7.8.4 
Rescue medication ............................................................................................... 32 
7.9 LEV use ........................................................................................................................... 32 
7.10 Blinding ............................................................................................................................ 32 
7.10.1 
Procedures for maintaining and breaking the treatment blind ............................. 33 
7.10.1.1 
Maintenance of study treatment blind ....................................................... 33 
7.10.1.2 
Breaking the treatment blind in an emergency situation ........................... 33 
7.11 Randomization and numbering of subjects ...................................................................... 33 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 34 
8.1 Visit 1 (Week -8) Baseline ............................................................................................... 34 
8.2 Visit 2 (Week -4) ............................................................................................................. 35 
8.3 Visit 3 (Week 0) Randomization ..................................................................................... 35 
8.4 Visits 4 and 5 (Weeks 2 and 4) ........................................................................................ 36 
8.7 Early Discontinuation Visit (before randomization) ........................................................ 38 
8.8 Early Discontinuation Visit (after randomization)........................................................... 38 
8.9 Visit 8 (Transition Period) ............................................................................................... 39 
8.9.1 
Visit 8 (Down-Titration Period) .......................................................................... 40 
8.10 Safety Visit (Study Drug-Free Period)............................................................................. 40 
8.11 Unscheduled Visit (if applicable) .................................................................................... 41 
8.12 Handling of biological samples ....................................................................................... 41 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 41 
9.1 Additional efficacy assessments ...................................................................................... 42 
9.1.1 
Medical procedures .............................................................................................. 42 
10 ASSESSMENT OF PHARMACOKINETICS ................................................................ 42 
11 ASSESSMENT OF SAFETY .......................................................................................... 42 
11.1 Adverse events ................................................................................................................. 42 
11.1.1 
Definitions ........................................................................................................... 42 
11.1.1.1 
Adverse event ............................................................................................ 42 
11.1.1.2 
Serious adverse event ................................................................................ 43 
11.1.1.3 
Adverse events of special interest ............................................................. 43 
11.1.2 
Procedures for reporting and recording adverse events ....................................... 44 
11.1.2.1 
Description of adverse events .................................................................... 44 
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11.1.2.2 
Rule for repetition of an adverse event...................................................... 44 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 44 
11.1.3 
Follow up of adverse events ................................................................................ 45 
11.1.4 
Pregnancy ............................................................................................................ 45 
11.1.5 
Suspected transmission of an infectious agent via a medicinal product .............. 46 
11.1.6 
Overdose of investigational medicinal product ................................................... 47 
11.1.7 
Safety signal detection ......................................................................................... 47 
11.2 Laboratory measurements ................................................................................................ 47 
11.2.1 
Evaluation of PDILI ............................................................................................ 49 
11.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 53 
11.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 53 
11.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 53 
11.2.1.4 
Follow-up evaluation ................................................................................. 55 
11.3 Other safety measurements .............................................................................................. 55 
11.3.1 
ECG ..................................................................................................................... 55 
11.3.2 
Vital signs ............................................................................................................ 56 
11.3.3 
Physical examinations ......................................................................................... 56 
11.3.4 
Neurological examination .................................................................................... 56 
11.3.5 
Psychiatric and mental status ............................................................................... 56 
11.3.6 
Body weight and height ....................................................................................... 56 
11.3.7 
Neuro-imaging procedure .................................................................................... 56 
11.3.8 
Assessment of suicidality .................................................................................... 56 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 56 
12.1 Adherence to protocol ...................................................................................................... 56 
12.2 Monitoring ....................................................................................................................... 57 
12.2.1 
Definition of source data ..................................................................................... 57 
12.2.2 
Source data verification ....................................................................................... 57 
12.3 Data handling ................................................................................................................... 58 
12.3.1 
Case Report form completion .............................................................................. 58 
12.3.2 
Database entry and reconciliation ........................................................................ 58 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 58 
12.4 Termination of the study .................................................................................................. 58 
12.5 Archiving and data retention ............................................................................................ 59 
12.6 Audit and inspection ........................................................................................................ 59 
12.7 Good Clinical Practice ..................................................................................................... 59 
13 STATISTICS ................................................................................................................... 59 
13.1 Definition of analysis sets ................................................................................................ 59 
13.2 General statistical considerations ..................................................................................... 60 
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13.3 Planned efficacy analyses ................................................................................................ 60 
13.3.1 
Analysis of the primary efficacy variable ............................................................ 60 
13.3.2 
Analyses of secondary efficacy variables ............................................................ 61 
13.4 Planned safety and other analyses .................................................................................... 61 
13.4.1 
Safety analyses ..................................................................................................... 61 
13.4.2 
Pharmacokinetic analyses .................................................................................... 61 
13.5 Handling of protocol deviations ....................................................................................... 61 
13.6 Handling of dropouts or missing data .............................................................................. 62 
13.7 Planned interim analysis and data monitoring ................................................................. 62 
13.8 Determination of sample size ........................................................................................... 62 
13.9 Management of LEV cap ................................................................................................. 62 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 63 
14.1 Informed consent ............................................................................................................. 63 
14.2 Subject identification cards .............................................................................................. 63 
14.3 Institutional Review Boards and Independent Ethics Committees .................................. 63 
14.4 Subject privacy ................................................................................................................. 64 
14.5 Protocol amendments ....................................................................................................... 64 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 64 
16 REFERENCES ................................................................................................................ 65 
17 APPENDIX ...................................................................................................................... 66 
17.1 Appendix 1 - International Classification of Epileptic Seizures ...................................... 66 
17.2 Appendix 2 - International Classification of Epilepsies and Epileptic Syndromes ......... 69 
17.3 Appendix 3 - List of Antiepileptic Drugs ........................................................................ 71 
17.4 Appendix 4 - Protocol Amendment 1 .............................................................................. 73 
17.5 Appendix 5 – Protocol Amendment 2 ............................................................................. 84 
17.6 Appendix 6 – Protocol Amendment 3 ............................................................................. 86 
17.7 Appendix 7 – Protocol Amendment 4 ............................................................................. 87 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ....................................... 95 
19 SPONSOR DECLARATION .......................................................................................... 96 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of study assessments......................................................................... 20 
Table 11‒1: 
Laboratory measurements ................................................................................ 48 
Table 11‒2: 
Required investigations and follow-up for PDILI ........................................... 51 
Table 11‒3: 
PDILI laboratory measurements ...................................................................... 54 
Table 11‒4: 
PDILI information to be collected ................................................................... 55 
 
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LIST OF FIGURES 
Figure 5‒1: 
Schematic diagram ........................................................................................... 23 
 
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Brivaracetam 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BRV 
brivaracetam 
CDMS 
clinical data management system 
CLcr 
creatinine clearance 
CL/F 
plasma clearance 
CNS 
central nervous system 
CPM 
Clinical Project Manager 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CYP 
cytochrome P450  
DEM 
data evaluation meeting 
DRC 
daily record card 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EDV 
Early Discontinuation Visit 
FAS 
Full Analysis Set 
EEG 
electroencephalogram 
eCRF 
electronic Case Report form 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
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IRB 
Institutional Review Board 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LEV 
levetiracetam 
LTFU 
long-term follow-up 
MAP 
managed access program 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PBO 
placebo 
PDILI 
potential drug-induced liver injury 
PK  
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PPS 
Per-Protocol Set 
PS 
Patient Safety 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SV2A 
synaptic vesicle protein 2A 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VNS 
vagal nerve stimulation 
 
 
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1 
SUMMARY 
This is a randomized, double-blind, placebo (PBO)-controlled, multicenter, parallel-group study 
designed to evaluate the efficacy and safety of adjunctive brivaracetam (BRV) in subjects (≥16 
to 80 years of age) with partial seizures. The primary objective is to evaluate the efficacy of BRV 
compared to PBO as adjunctive treatment in adult and adolescent focal epilepsy subjects with 
partial seizures not fully controlled despite current treatment with 1 or 2 concomitant 
antiepileptic drugs (AEDs). Secondary objectives are to assess the safety and tolerability of BRV 
and to characterize the steady-state pharmacokinetics (PK) of BRV in subjects from ≥16 to 80 
years of age. 
This study will enroll subjects ≥16 years to 80 years of age with partial seizures with or without 
secondary generalization. Subjects who are not legal adults will be included only where legally 
permitted and ethically accepted. Subjects will complete an 8-week prospective Baseline Period, 
followed by a 12-week Treatment Period. Subjects may be eligible for conversion to a long-term 
follow-up (LTFU) study or managed access program (MAP) upon completion of the Treatment 
and Transition Period. There is a 4-week Down-Titration Period followed by a 2-week Study 
Drug-Free Period for subjects not entering the LTFU study or MAP. If BRV is commercially 
available upon subject completion of the Treatment and Transition Period, subjects will receive 
BRV directly without entering the LTFU study or MAP. 
A 1:1:1 central randomization (random permuted blocks) stratified for country, levetiracetam 
(LEV) use (LEV naïve vs prior LEV use) and number of AEDs previously used but discontinued 
prior to study entry (≤2 vs >2 AEDs) will be used to ensure the balance across treatment groups 
(PBO, BRV 50mg/day, BRV 200mg/day) within each combination of stratification levels. 
Randomization will not be stratified by study center due to the expected small number of 
randomized subjects per study center. 
The primary efficacy variable is the partial seizure frequency per 28 days during the 12-week 
Treatment Period. The primary efficacy outcome is the percent reduction in partial seizure 
frequency over PBO based on analysis of covariance (ANCOVA). 
The secondary efficacy variables are as follows:  
 The 50% responder rate based on percent reduction in partial seizure frequency from 
Baseline to the 12-week Treatment Period  
 Percent reduction in partial-seizure frequency per 28 days from Baseline to the 12-week 
Treatment Period  
 Categorized percent reduction in partial-seizure frequency per 28 days from Baseline to the 
12-week Treatment Period  
 All seizure frequency (partial, generalized, and unclassified epileptic seizures) per 28 days 
during the 12-week Treatment Period  
 Seizure freedom (partial, all epileptic seizures) during the 12-week Treatment Period  
 Time to nth (n=1, 5, 10) partial seizure during the 12-week Treatment Period 
 
Pharmacokinetic variable is BRV (parent compound only) plasma levels. 
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Safety variables include incidence of treatment-emergent adverse events (TEAEs), incidence of 
TEAEs leading to study withdrawal, incidence of treatment-emergent serious adverse events 
(SAEs), changes in clinical laboratory test parameters (blood chemistry, hematology, urinalysis), 
electrocardiogram (ECG) parameters and findings, changes in vital signs (SBP, DBP, and pulse 
rate), changes in body weight, physical and neurological examinations, and mental and 
psychiatric status. 
The planned number of evaluable subjects will be a total of 444 (148 subjects per treatment 
group) for the primary efficacy analysis. The number of prior LEV use subjects will be limited to 
30% of the total study population. It is planned to have those subjects recruited in approximately 
95 centers. 
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. 
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 17.1]). 
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Likewise, the classification of epilepsy syndromes will be used according to the 1989 
ILAE-publication (ILAE,1989, Appendix 2 [Section 17.2]). 
2.2 
Background information regarding product 
Brivaracetam is a chemical relative of the AED LEV (Keppra®/E-Keppra®). Like LEV, BRV 
displays a high and selective interaction with a novel brain-specific binding site SV2A (synaptic 
vesicle protein 2A). 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 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 CYP2C19 (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 cytochrome P450 (CYP) 3A4 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. 
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 
(ULN) (3.0μg/mL) at BRV doses of 100 and 150mg/day. 
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2.3 
Efficacy with BRV in fixed-dose Phase 2/3 studies in subjects 
with partial seizures 
The efficacy of BRV for adjunctive therapy in partial seizure was established in 3 randomized, 
double-blind, PBO-controlled, fixed-dose studies (N01252, N01253, and N01358) in subjects 
≥16 years of age. Adjunctive BRV administration at doses of 50mg/day to 200mg/day resulted in 
statistically significant and clinically relevant reductions in seizure frequency. Brivaracetam was 
well tolerated at these therapeutic doses.  
2.4 
Safety with BRV 
In the BRV clinical development program, 3970 subjects have been 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 treatment-emergent adverse events 
(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 
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 has been evaluated in 5 LTFU 
studies (N01125, N01379, N01199, N01315, and N01372). The safety profile in the open-label 
extension studies (up to 8 years) was consistent to that observed in the short-term, PBO-
controlled studies. 
For additional details on safety and efficacy of BRV, please refer to the Investigator’s Brochure 
(IB). 
2.5 
Study rationale 
This adequate and well-controlled study will be performed to provide data confirming the 
efficacy and safety of BRV as an AED and to support a new drug application in Japan and China 
for BRV in the indication of adjunctive treatment in subjects (≥16 to 80 years of age) with partial 
seizures with or without secondary generalization.  
Studies using BRV as adjunctive therapy in partial seizures in adults have shown the results in 
terms of both efficacy and safety. Well-controlled confirmatory studies N01252, N01253, and 
N01358 were designed to assess the efficacy and safety of BRV as adjunctive treatment in 
refractory epilepsy subjects with partial seizures: N01253 assessed BRV doses of 5, 20, and 
50mg/day and provided statistically significant and clinically relevant evidence of efficacy of 
BRV 50mg/day; N01252 assessed BRV doses of 20, 50, and 100mg/day. Although N01252 was 
not positive for the primary analysis due to predefined sequential testing, it provided supporting 
evidence for the efficacy of BRV 100mg/day; and N01358 assessed BRV doses of 100 and 
200mg/day and provided statistically significant and clinically relevant evidence of efficacy of 
BRV 100 and 200mg/day.  
A Phase 1, PBO-controlled, single and multiple rising dose study in Japanese healthy subjects 
(N01209), has shown that the disposition of BRV was similar to that in overseas populations. 
Brivaracetam was well tolerated and displayed linear and dose-proportional PK. No new 
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observations were made relative to the known safety and tolerability profile of BRV. The main 
metabolism pathway of BRV is by hydrolysis of the amide function, and a secondary pathway is 
hydroxylation mediated by the CYP2C19 isoenzyme. In Japanese subjects bearing 
2 nonfunctional alleles of the gene coding for the CYP2C19 isoenzyme (namely, *2/*2, *2/*3 or 
*3/*3; representing 25% of the study population), formation of the inactive hydroxy metabolite 
was decreased 10-fold but the plasma clearance (CL/F) of BRV was only decreased by 30% 
(0.70 mL/min/kg compared to 0.99 mL/min/kg in *1/*1 homozygous extensive metabolisers). It 
was concluded that no BRV dose adaptation is necessary in Japanese subjects compared to 
overseas populations and in particular no dose reduction is needed for subjects bearing 
CYP2C19 mutations.  
The proposed study is intended to provide evidence of efficacy, safety, and PK for BRV as 
adjunctive therapy in subjects with partial seizures. Doses of BRV 50 and 200mg/day will be 
assessed in EP0083. 
3 
STUDY OBJECTIVE(S) 
3.1 
Primary objective 
To evaluate the efficacy of BRV compared to PBO as adjunctive treatment in subjects (≥16 to 
80 years of age) with partial seizures with or without secondary generalization despite current 
treatment with 1 or 2 concomitant AEDs. 
3.2 
Secondary objective 
The secondary objectives are to assess the safety and tolerability of BRV in subjects ≥16 years to 
80 years of age. 
4 
STUDY VARIABLES 
4.1 
Efficacy variable 
4.1.1 
Primary efficacy variable 
The primary efficacy variable is the partial seizure frequency per 28 days during the 12-week 
Treatment Period.  
4.1.2 
Secondary efficacy variables 
Secondary efficacy variables are as follows:  
 The 50% responder rate based on percent reduction in partial seizure frequency per 28 days 
from Baseline to the 12-week Treatment Period  
 Percent reduction in partial seizure frequency per 28 days from Baseline to the 12-week 
Treatment Period  
 Categorized percent reduction in partial seizures frequency per 28 days from Baseline to the 
12-week Treatment Period  
 All seizure frequency (partial, generalized, and unclassified epileptic seizures) per 28 days 
during the 12-week Treatment Period  
 Seizure freedom (partial, all epileptic seizure) during the 12-week Treatment Period  
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 Time to nth (n=1, 5, 10) partial seizure during the 12-week Treatment Period 
4.2 
Pharmacokinetic variable 
The PK variable is BRV (parent compound only) plasma levels. 
4.3 
Safety variables 
4.3.1 
Primary safety variables 
 Incidence of TEAEs 
 Incidence of TEAEs leading to study withdrawal 
 Incidence of treatment-emergent serious adverse events (SAEs) 
4.3.2 
Other safety variables 
The other safety variables are as follows: 
 Changes in clinical laboratory test parameters (blood chemistry, hematology, urinalysis)  
 ECG parameters and findings 
 Changes in vital signs (SBP, DBP, and pulse rate) 
 Changes in body weight 
 Physical examination  
 Neurological examination  
 Mental status  
 Psychiatric status  
5 
STUDY DESIGN 
5.1 
Study description 
This is a randomized, double-blind, PBO-controlled, multicenter, therapeutic confirmatory study 
evaluating 2 doses of BRV. The subject population will be subjects (≥16 to 80 years of age) with 
partial seizures with or without secondary generalization. Subjects who are not legal adults will 
be included only where legally permitted and ethically accepted. Subjects will complete an 8-
week prospective Baseline Period, followed by a 12-week Treatment Period.  
Subjects may be eligible for conversion to a LTFU study or MAP upon completion of the 
Treatment and Transition Period. There is a 4-week Down-Titration Period followed by a 2-week 
Study Drug-Free Period for subjects not entering the LTFU study or MAP. If BRV is 
commercially available upon subject completion of the Treatment and Transition Period, subjects 
will receive BRV directly without entering the LTFU study or MAP.  
A 1:1:1 central randomization (random permuted blocks) stratified for country, LEV use (LEV 
naïve vs prior LEV use), and number of AEDs previously used but discontinued prior to study 
entry (≤2 vs >2 AEDs) will be used to ensure the balance across treatment groups (PBO, BRV 
50mg/day, BRV 200mg/day) within each combination of stratification levels. Randomization 
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will not be stratified by study center due to the expected small number of randomized subjects 
per study center. 
No restrictions are placed on the proportion of randomized subjects within each stratification 
level, either overall or on a regional basis. 
5.1.1 
Study duration per subject 
The total duration of the study will be up to approximately 26 weeks with a maximum 16-weeks 
exposure to BRV consisting of the following study periods: 
 Baseline Period (8 weeks) 
 Treatment Period (12 weeks) 
 Down-Titration Period (4 weeks)  
 Study Drug-Free Period (2 weeks)  
 Transition Period (2 weeks) (required for subjects participating in the LTFU study or MAP) 
Ideally, visits should occur on the specified Visit/Week. A ±3 day window for each specified 
Visit/Week is allowed, provided the subject has adequate investigational medicinal product 
(IMP) to sustain the visit window. 
 For the subject who has completed the Treatment Period, the Investigator will decide whether 
the subject would benefit or not from continuing the treatment with BRV at the end of the 
Treatment Period (Visit 7). If the investigator decides the subject would benefit from 
continued BRV treatment and the subject desires to continue treatment, the subject will enter 
the LTFU study or MAP. 
 Prior to entry into LTFU study or MAP, the informed consent, where applicable, should be 
obtained from the subject at the end of Treatment Period (Visit 7). Subsequently, the subject 
will go through the Transition Period, and will be dosed in a double-blind manner in order to 
maintain the blind. 
 As a procedure of MAP, the import license of medication for MAP is necessary. The process 
to obtain the import license starts after patient enrollment and can on occasions take a long 
time. To avoid a scenario where a subject cannot enter MAP due to the delayed importation 
of medication, a temporary period for providing BRV will be prepared as the rescue. Once 
medication for MAP is ready, a subject can start MAP. 
The end of the study is defined as the date of the last visit of the last subject in the study. 
5.1.2 
Planned number of subjects and sites 
The planned number of evaluable subjects for the primary efficacy analysis will be a total of 444 
(148 subjects per treatment group). The number of prior LEV use subjects will be limited to 30% 
of the total study population as referenced in Section 13.9.  
Considering an anticipated screen failure rate of approximately 20%, approximately 555 subjects 
will be screened. It is planned to have those subjects recruited in approximately 95 sites (50 
Japan sites, 20 Southeast Asia sites in countries and regions specified in Section 5.1.3, and 25 
China Mainland sites).  
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5.1.3 
Anticipated regions and countries 
The study is being conducted in Japan, Taiwan, China Mainland, Philippines, Thailand, 
Singapore, and Malaysia.  
 
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5.2 
Schedule of study assessments 
Table 5‒1: 
Schedule of study assessments 
Assessments 
 
Prospective Baseline 
Period 
(8 weeks) 
Treatment Period 
(12 weeks) 
Early 
discontinuation 
Transition 
Period 
(2 weeks)/ 
Down 
Titration 
Period 
(4 weeks) 
Study 
Drug-Free 
Period  
(2 weeks)a 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
EDV 
V8 
Safety Visit 
W -8 
W -4 
W 0 
W 2 
W 4 
W 8 
W 12 
 
W 14/W 16 
W 18 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Subject ID Card dispense 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
Xb 
Xb 
Xb 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical/procedures history 
X 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
Lifetime AED history 
X 
 
 
 
 
 
 
 
 
 
Birth control 
X 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and heighte 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
X 
 
 
 
X 
Xd 
X 
X 
Neurological examination 
X 
 
X 
 
 
 
X 
Xd 
X 
X 
Psychiatric and mental status 
X 
 
X 
 
 
 
X 
Xd 
X 
X 
ECG 
Xf 
 
 
X 
X 
 
X 
Xd 
Xk 
X 
EEG 
Xg 
 
 
 
 
 
 
 
 
 
CT scan/MRI 
Xh 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Subject DRC dispensed 
X 
X 
X 
X 
X 
X 
X 
Xd 
Xo 
 
Subject DRC returned and 
reviewed 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Seizure countsi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 5‒1: 
Schedule of study assessments 
Assessments 
 
Prospective Baseline 
Period 
(8 weeks) 
Treatment Period 
(12 weeks) 
Early 
discontinuation 
Transition 
Period 
(2 weeks)/ 
Down 
Titration 
Period 
(4 weeks) 
Study 
Drug-Free 
Period  
(2 weeks)a 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
EDV 
V8 
Safety Visit 
W -8 
W -4 
W 0 
W 2 
W 4 
W 8 
W 12 
 
W 14/W 16 
W 18 
Laboratory safety assessmentsj 
X 
 
X 
X 
X 
X 
X 
Xd 
X 
X 
Pregnancy testl 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
X 
BRV plasma levelm 
 
 
 
X 
X 
X 
X 
Xd 
Xn 
 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant AED(s)/VNS 
settings 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP dispensing 
 
 
X 
X 
X 
X 
X 
Xd 
 
 
IMP return/accountability 
 
 
 
X 
X 
X 
X 
Xd 
X 
 
End of study status 
 
 
 
 
 
 
 
X 
Xk 
X 
AE=adverse event; AED=antiepileptic drug; BRV=brivaracetam; C-SSRS=Columbia-Suicide Severity Rating Scale; CT=computed tomography; DRC=daily record card; 
ECG=electrocardiogram; eCRF=electronic case report form; EDV=early discontinuation visit EEG=electroencephalogram; ID=identification card; IMP=investigational medicinal 
product; IVRS/IWRS=interactive voice response system/interactive web response system; MAP=managed access program; MRI=magnetic resonance imaging; LTFU=long term 
follow-up; W=week; V=Visit; VNS=vagal nerve stimulation 
Note: Prior to entry into LTFU or MAP, the informed consent should be obtained from the subject at the end of Treatment Period (Visit 7) (Section 5.1.1). 
   a Safety Visit is not needed for subjects who discontinued before randomization. 
   b Subject is randomized at V3 once all inclusion/exclusion criteria are met. 
   c Vital signs (supine or sitting pulse rate and blood pressure after 5 minutes rest). 
d Assessment to be conducted in subjects who discontinued after randomization. 
e Height will be recorded at V1 only. 
f Baseline ECG has to be scheduled and results received before V3. An ECG at the Safety Visit will be performed only if abnormal at V7/EDV.  
g Baseline EEG has to be scheduled and results received before V3 if no appropriate EEG available within the last 5 years.  
h A CT scan or MRI has to be scheduled and results received before V3 if no previous CT scan or MRI available within the last 2 years.  
i Seizure counts are collected on the subject’s DRC on a daily basis.  
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j Laboratory assessment: safety assessment includes hematology, blood chemistry, and urinalysis. Eligibility of subjects will be based on laboratory samples collected at V1. The 
result of the creatinine clearance will be provided by the central laboratory for all visits and the results at V1 will be used to determine eligibility of the subject. 
k Only Transition Period  
l Serum pregnancy at V1 only. Urine pregnancy test will be used at other visits. 
m Concentrations of BRV will be determined in plasma samples. Date and time of sampling will be recorded. Dosing dates and times for the actual 3 previous BRV doses will be 
recorded in the eCRF.  
n At V8, concentrations of BRV will be evaluated only in the Transition Period. 
o If subjects will not enter to LTFU or MAP, a DRC is dispensed. 
 
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5.3 
Schematic diagram 
Figure 5‒1: Schematic diagram 
 
Baseline Period 
(8 weeks) 
Treatment Period 
(12 weeks) 
Down-Titration Period* 
(4 weeks) 
 
Study 
Drug Free 
Period* 
(2 weeks) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1w) 
(1w) 
(1w) (1w) 
 
 
 
 
 
 
200mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
150mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
50mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25mg/day 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V1 
W -8 
V2 
W -4 
V3 
W 0 
V4 
W2 
V5 
W4 
V6 
W8 
 
V7 
W12 
 
 
 
V8 
W16 
Safety Visit 
W18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transition 
Period 
(2 weeks) 
Long-term Follow-up Study 
or MAP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
200mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
150mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
100mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
50mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V7 
W12 
V8 
W14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDV=early discontinuation visit, V=visit, MAP=managed access program, W=week,  
* Subjects with an EDV at any time during the Treatment Period should proceed through the 4-week Down-Titration Period and 2-week Study Drug-Free Period 
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5.4 
Rationale for study design and selection of dose 
Consistent with the previous fixed dose Phase 3 studies N01253, N01252 and N01358 in EU/US, 
EP0083 will include an 8-week Baseline Period and a 12-week Treatment Period. The primary 
efficacy variable is the partial seizure frequency per 28 days during the 12-week Treatment 
Period. 
Brivaracetam 50 to 200mg/day is approved as the effective dose for adults in EU/US. The 
treatment arms of EP0083 have been decided from the minimum/maximum dose approved. 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
After the number of prior LEV use subjects are randomized to 30% of the total study population, 
only LEV naive subjects will be entered in EP0083.  
6.1 
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 form is signed and dated by the subject or by the parent(s) or 
legal representative. The Informed Consent form or a specific Assent form, where required, 
will be signed and dated by minors. 
2. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries), visit schedule, or medication intake 
according to the judgment of the Investigator. 
3. Subjects (male or female) from 16 to 80 years of age at Visit 1, both inclusive. Subjects 
who are not legal adults may only be included where legally permitted and ethically 
accepted. 
4. Subjects with a body weight ≥40kg during Baseline Period. 
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. Well-characterized focal epilepsy/epileptic syndrome according to the 1989 ILAE 
classification. 
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7. Presence of an electroencephalogram (EEG) reading compatible with the clinical diagnosis 
of focal epilepsy within the last 5 years. Baseline EEG has to be scheduled and results 
received before Visit 3 if no appropriate EEG available within the last 5 years. 
8. Presence of a brain magnetic resonance imaging (MRI)/computed tomography (CT) scan 
performed within the last 2 years. A CT scan or MRI has to be scheduled and results 
received before Visit 3 if no previous CT scan or MRI available within the last 2 years. 
9. Subjects having at least 8 partial seizures (according to the 1981 ILAE classification) 
during the 8-Week Baseline Period with at least 2 partial seizures during each 4-week 
interval of the Baseline Period. 
10. Subjects having at least 2 partial seizures whether or not secondary generalization per 
month during the 3 months preceding Visit 1. 
11. Subjects uncontrolled while treated by 1 or 2 permitted concomitant AED(s). Vagal Nerve 
Stimulation (VNS) is allowed and will be counted as a concomitant AED. 
12. Permitted concomitant AED(s) and VNS being stable and at optimal dosage for the subject 
from at least 4 weeks (12 weeks for phenobarbital, phenytoin, and primidone) before Visit 
1 and expected to be kept stable during whole study period. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met:  
1. Subject previously randomized within this study or any other prior study with BRV as a 
dosing arm.  
2. Simple partial seizure (1981 ILAE classification) nonmotor as only seizure type.  
3. Subject has experienced febrile seizures exclusively. The occurrence of febrile seizures in 
addition to other unprovoked seizures is not exclusionary.  
4. 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).  
5. Subject is currently treated with LEV.  
6. Subject has taken LEV within 90 days prior to Visit 1.  
7. Subject has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the subject’s ability to participate in this study.  
8. Subject has a known hypersensitivity to any components of the IMP, or any of its 
excipients.  
9. Subject/legal representative not able to read and understand the Informed Consent form, 
Assent form, or daily record card (DRC) instructions.  
10. Subject has severe cognitive impairment or mental retardation as per Investigator 
assessment 
11. Subject whose seizures could not be reliably counted on a regular basis due to their fast and 
repetitive occurrence (clusters or flurries).  
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12. Subject has history or presence of status epilepticus during the year preceding Visit 1 or 
during Baseline.  
13. Subject has history or presence of known psychogenic nonepileptic seizures.  
14. Subject has taken vigabatrin for 24 weeks prior to Visit 1. Subject with history of 
vigabatrin use but either no visual fields examination report available including standard 
static (Humphrey or Octopus) or kinetic perimetry (Goldman) or results of these 
examinations are abnormal, even though vigabatrin was stopped before 24 weeks.  
15. Subject taking any drug with possible central nervous system (CNS) effects except if stable 
from at least 4 weeks before Visit 1 and expected to be kept stable during whole study 
period.  
16. Subject 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 Visit 1, and is expected to be kept stable during the Treatment Period.  
17. Subject has history of cerebrovascular accident, including transient ischemic attack, in the 
last 24 weeks.  
18. Subject has severe cardiovascular disease or peripheral vascular disease.  
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. Stable arteriovenous malformations, meningiomas, or other benign tumors 
may be acceptable.  
20a. Subject has any clinical conditions (eg, bone marrow suppression, severe renal 
impairment with creatinine clearance [CLcr] <30 ml/min/1.73 m2) which impair reliable 
participation in the study or necessitate the use of medication not allowed by protocol.  
21. Subject has chronic hepatic disease.  
22. Subject has presence of a terminal illness.  
23. Subject has presence of a serious infection.  
24. Subject has history of severe adverse hematologic reaction to any drug.  
25. Subject has severe disturbance of hemostasis. 
26. Subject has >2xULN of any of the following: alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), or >ULN total bilirubin (≥1.5xULN 
total bilirubin if known Gilbert’s syndrome). 
If subject has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate 
bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%) 
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a Baseline diagnosis and/or the cause of any clinically meaningful elevation must 
be understood and recorded in the electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
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relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor.  
27a. 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 judgment of the Investigator.  
28. Subject has clinically significant ECG abnormalities according to the Investigator.  
29. 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 Visit 1.  
30. Subject has known multiple drug allergies or severe drug allergy.  
31. Subject is pregnant or lactating.  
32. Subject has known alcohol or drug addiction or abuse within the last 2 years.  
33. Investigators, co-Investigators, their spouses or children, or any study collaborators. If the 
Investigator has any other doubts concerning the eligibility, he/she should consult UCB 
Study Physician or representative for clarification. 
 
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  
 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.  
 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.  
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 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. For 
subjects considered as lost to follow-up, the Investigator should make an effort (at least 1 phone 
call and 1 written message to the subject), and document his/her effort (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The eCRF 
must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
 Subjects with either of the following: 
 ALT or AST ≥5xULN 
 ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN  
The PDILI criterion below requires immediate discontinuation of IMP: 
 Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without clear 
alternative cause), rash, or eosinophilia (ie, >5%). 
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
Investigator.  
 Subjects with ALT or AST ≥3xULN (and ≥2x Baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis (eg, 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness). 
Evaluation of PDILI must be initiated as described in Section 11.2.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
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7 
STUDY TREATMENT(S) 
7.1 
Description of investigational medicinal product(s) 
Oral film-coated tablets of BRV 25mg, BRV 50mg, and matching PBO tablets will be used in 
this study.  
7.2 
Treatment(s) to be administered 
After an 8-Week Baseline Period and once the subject has fulfilled the eligibility criteria, he/she 
will be randomized to 50mg/day group, 200mg/day group or PBO group, and enter the 
double-blind Treatment Period (Visit 3 to Visit 7).  
During the Treatment Period, subjects will be treated with BRV 50mg/day, BRV 200mg/day, or 
the matching PBO tablets in a double-blinded manner. Study medication should be given as 
2 equally divided doses administered twice daily except the last week of down-titration. Study 
medication in the last week of down-titration is given only in the morning. The first intake of 
newly dispensed study medication should occur in the evening of each visit. Subjects should take 
IMP according to instructions provided by Investigator.  
At the end of the Treatment Period (Visit 7), the subjects entering into the LTFU study or MAP 
will enter the Transition Period or the subjects not entering into the LTFU study or MAP will 
enter the Down-Titration Period followed by a Study Drug-Free Period.  
The Transition Period (2 weeks) will consist of the following:  
 For subjects randomized to BRV 50mg/day group or PBO group, keep same dose as 
Treatment Period during the Transition Period.  
 For subjects randomized to BRV 200mg/day group, the Transition Period will consist of the 
following: 2 weeks at BRV 150mg/day.  
The Down-Titration Period (4 weeks) will consist of the following:  
 For subjects randomized to PBO group, keep PBO during the Down-Titration Period.  
 For subjects randomized to BRV 50mg/day group, the Down-Titration Period will consist of 
the following: 1 week at BRV 25mg/day followed by 3 weeks at PBO.  
 For subjects randomized to BRV 200mg/day group, the Down-Titration Period will consist 
of the following: 1 week at BRV 150mg/day, 1 week at BRV 100mg/day, 1 week at BRV 
50mg/day, followed by 1 week at BRV 25mg/day.  
The down-titration procedure needs to be applied in case of early discontinuation or completion 
without conversion to the LTFU study or MAP. 
7.3 
Packaging 
Brivaracetam tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) 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.  
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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 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 (oral tablets) will be supplied to the subject/parent(s)/legal representative(s) at protocol 
specified time points according to the study schedule of assessments (Table 5‒1).  
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. 
The subjects/parent(s)/legal representative must record the situation of medication compliance 
every time the subjects take 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. 
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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 medication(s)/treatment(s) 
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 Screening Visit 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) 
All subjects will take 1 or 2 concomitant AEDs (Appendix 3 [Section 17.3]). Only oral-daily use 
is permitted (any other use or route of administration is prohibited, except when it is used as 
rescue medication). 
All concomitant AEDs except the ones specified in Section 7.8.2 are permitted during the study. 
All AEDs need to be at a stable dose for at least 4 weeks prior to Visit 1 and kept stable over the 
whole study period. 
If the subject discontinues from the study, the above limitation is not required after the Early 
discontinuation Visit (EDV), considering subject safety. 
Drugs with no CNS effects, which are not strong enzyme inducers/inhibitors, are allowed. 
Vagal nerve stimulation is allowed and will be counted as a concomitant AED.  
7.8.2 
Prohibited concomitant treatments (medication and therapies) 
The following concomitant medications/treatments are prohibited during the study: 
 LEV 
 BRV (other than IMP) 
 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). 
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7.8.3 
Restricted concomitant treatments (medications and therapies) 
The following concomitant medications/treatments are restricted during the study: 
 Drugs with possible CNS effects (anxiolytics, hypnotic, and neuropsychiatric agents) 
including benzodiazepines are allowed if at stable dose from at least 4 weeks prior to Visit 1 
and during the entire study period. In case of as-needed use, it is allowed the frequency is up 
to once a week in this study. However, it is prohibited to take more than once a week in this 
study. Any drug where the route of administration is not oral, except when it is used as 
rescue medication.  
 Any drug that significantly influences the metabolism of BRV (cytochrome P450 strong 
inducers such as rifampin/rifampicin) are allowed if at stable dose from at least 4 weeks prior 
to Visit 1 and during the entire study period. 
7.8.4 
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. In addition, the use of anticonvulsants is permitted as rescue medication. 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.Prior  
7.9 
LEV use 
Levetiracetam use within 90 days prior to Visit 1 [(Week -8) Baseline] is prohibited. If a subject 
has been treated with LEV in the past, in order to participate in the study: 
 oral LEV must be discontinued ≥91 days prior to Visit 1, or 
 intravenous (iv) LEV must have been administered ≥91 days prior to Visit 1. 
The management of LEV cap is specified in Section 13.9. 
7.10 
Blinding 
Brivaracetam and matching placebo and their accompanying packaging will be identical in 
appearance (size and color), so that neither the investigator nor the subject is able to tell whether 
the subject is receiving BRV or placebo. 
At UCB Clinical Trial Supply, kit numbers will be allocated according to the package list 
generated by a validated program by UCB. This list will be provided to the IVRS/IWRS. 
The treatment randomization schedule will be generated by UCB (or designee) in a manner that 
will ensure that the study team remains blinded, in accordance with current Standard Operating 
Procedures (SOPs). The randomization schedule will be maintained in a secure location until the 
study is unblinded for the final statistical analysis. 
All sponsor, Investigator sites, and contract research organization (CRO) staff involved with the 
study will be blinded to the treatment code with the following exceptions: 
 Sponsor personnel and its subcontractors directly involved in the packaging of the IMP or in 
the management of the IVRS/IWRS.  
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 Sponsor Patient Safety (PS) staff will receive separate access to the IVRS/IWRS in order to 
meet their requirements for SAE reporting to regulatory authorities. 
 Central laboratory staff assaying study drug. However, no randomization list will be 
provided. 
7.10.1 
Procedures for maintaining and breaking the treatment blind 
7.10.1.1 
Maintenance of study treatment blind 
All subject treatment details will be allocated and maintained by the IVRS/IWRS. 
7.10.1.2 
Breaking the treatment blind in an emergency situation 
In the event of an emergency, it will be possible to determine to which treatment arm and dose 
the subject has been allocated by contacting the IVRS/IWRS. All sites will be provided with 
details of how to contact the system for code breaking at the start of the study. The Medical 
Monitor or equivalent should be consulted prior to unblinding, whenever possible. 
The Clinical Project Manager (CPM) or designee will be informed immediately via the 
IVRS/IWRS when a code is broken, but will remain blinded to specific treatment information. 
Any unblinding of the IMP performed by the Investigator must be recorded in the source 
documents and on the Study Termination eCRF page. 
7.11 
Randomization and numbering of subjects 
A 1:1:1 central randomization (random permuted blocks) will be stratified for the following to 
ensure the balance across treatment groups (PBO, BRV 50mg/day, BRV 200mg/day) within each 
combination of stratification levels. 
 Country 
 LEV use (LEV naïve vs prior LEV use) 
 Number of prior AEDs (≤2/>2) based on AEDs previously used and discontinued prior to 
Visit 1.  
An IVRS/IWRS will be used for assigning eligible subjects to a treatment regimen (as 
applicable) based on a predetermined production randomization and/or packaging schedule 
provided by UCB (or designee). The randomization schedule will be produced by the 
IVRS/IWRS vendor. The IVRS/IWRS will generate individual assignments for subject kits of 
IMP, as appropriate, according to the visit schedule. 
To enroll a subject (Visit 1), the Investigator or designee will contact the IVRS/IWRS and 
provide brief details about the subject to be enrolled. Each subject will receive a 5-digit number 
assigned at screening that serves as the subject identifier throughout the study. The subject 
number will be required in all communication between the Investigator or designee and the 
IVRS/IWRS regarding a particular subject. Subject numbers and kit numbers will be tracked via 
the IVRS/IWRS.  
To randomize a subject (Visit 3), the Investigator or designee will contact the IVRS/IWRS and 
provide brief details about the subject to be randomized. The IVRS/IWRS will automatically 
inform the Investigator or designee of the subject’s randomization number. The IVRS/IWRS will 
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allocate kit numbers to the subject based on the subject number during the course of the study. 
The randomization number must be incorporated into the eCRF.  
8 
STUDY PROCEDURES BY VISIT  
The informed consent procedure, as described in Section 14.1, must be completed prior to 
initiating any other study-specific activities. 
A ±3 day window for each specified Visit/Week is allowed, provided the subject has adequate 
IMP to sustain the visit window. 
8.1 
Visit 1 (Week -8) Baseline 
Visit 1 assessments are as follows: 
 Written informed consent 
 Subject identification (ID) Card dispense 
 Eligibility assessment (verification of inclusion and exclusion criteria) 
 Demography 
 Medical/procedures history 
 Epilepsy history 
 Lifetime AED history 
 Birth control 
 Vital signs (blood pressure and pulse rate) 
 Body weight and height 
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 ECG (Baseline ECG has to be done to ensure results received before Visit 3) 
 EEG (to be performed before Visit 3 if no previous report available within last 5 years) 
 CT scan/MRI (to be performed before Visit 3 if no previous report available within last 
2 years) 
 IVRS/ IWRS 
 Subject DRC dispensed 
 Laboratory safety assessments  
 Pregnancy test (serum) 
 AE reporting 
 C-SSRS  
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 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
8.2 
Visit 2 (Week -4) 
Visit 2 assessments are as follows: 
 Eligibility assessment (verification of inclusion and exclusion criteria) 
 Vital signs 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Pregnancy test (urine) 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
8.3 
Visit 3 (Week 0) Randomization 
Visit 3 assessments are as follows: 
 Eligibility assessment (verification of inclusion and exclusion criteria) 
 Vital signs 
 Body weight  
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 IVRS/IWRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
 AE reporting 
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 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
 IMP dispensing 
8.4 
Visits 4 and 5 (Weeks 2 and 4) 
Visit 4 and 5 assessments are the same and as follows: 
 Vital signs 
 Body weight  
 ECG 
 IVRS/IWRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
 BRV plasma level 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s) 
 Concomitant non-AED(s)/VNS settings 
 IMP dispensing 
 IMP return/accountability 
8.5 
Visit 6 (Week 8) 
Visit 6 assessments are as follows: 
 Vital signs 
 Body weight  
 IWRS/IVRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
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 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
 BRV plasma level 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
 IMP dispensing 
 IMP return/accountability 
8.6 
Visit 7 (Week 12) 
Visit 7 assessments are as follows: 
 Vital signs 
 Body weight  
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 ECG 
 IVRS/IWRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
 BRV plasma level 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
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 IMP dispensing 
 IMP return/accountability 
Prior to entry into LTFU or MAP, the informed consent should be obtained from the subject. 
8.7 
Early Discontinuation Visit (before randomization) 
Assessments for subjects who are discontinued from the study before randomization as follows: 
 IVRS/IWRS 
 Subject DRC returned and reviewed  
 AE reporting 
 End of study status 
As for the other assessments, these are not required but still recommended to complete if 
possible: 
 Vital signs  
 Body weight  
 Seizure counts  
 C-SSRS  
 Medical procedures  
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s)  
8.8 
Early Discontinuation Visit (after randomization) 
Assessments for subjects that discontinue the study early are as follows: 
 Vital signs 
 Body weight  
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 ECG 
  IVRS/IWRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
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 BRV plasma level 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
 IMP dispensing 
 IMP return/accountability 
8.9 
Visit 8 (Transition Period) 
Assessments for the Transition Period are as follows: 
 Vital signs 
 Body weight  
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 ECG 
 IVRS/IWRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
 BRV plasma level 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
 IMP return/accountability 
 End of study status 
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8.9.1 
Visit 8 (Down-Titration Period)  
Assessments during the Down-Titration Visit are as follows: 
 Vital signs 
 Body weight  
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 IVRS/IWRS 
 Subject DRC dispensed 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
 Pregnancy test (urine) 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
 IMP return/accountability 
8.10 
Safety Visit (Study Drug-Free Period)  
Assessments for the Safety Follow-Up Visit are as follows: 
(Safety Visit is not needed for subjects that discontinued before randomization) 
 Vital signs 
 Body weight 
 Physical examination  
 Neurological examination 
 Psychiatric and mental status 
 ECG (to be performed only if abnormal at Visit 7/EDV) 
 Subject DRC returned and reviewed 
 Seizure counts 
 Laboratory safety assessments 
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 Pregnancy test (urine) 
 AE reporting 
 C-SSRS 
 Medical procedures 
 Concomitant AED(s)/VNS settings 
 Concomitant non-AED(s) 
 End of study status 
8.11 
Unscheduled Visit (if applicable) 
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 is conducted due to safety or efficacy reasons, a C-SSRS assessment will 
be performed with the subject during the visit. If an Unscheduled Visit 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. 
8.12 
Handling of biological samples 
The safety samples (hematology, biochemistry, urinalysis, and serum pregnancy test) will be 
routinely assayed and the results sent by fax to the Investigator as specified in Section 11.2.  
The central lab will keep plasma samples for BRV plasma level determinations in freezers 
at -20°C until assayed as well as 1 plasma back-up sample until database lock. These back-up 
samples can only be destroyed following written authorization from the Clinical Project 
Manager. Results will only be communicated to the Investigator and study team after database 
lock. 
Methods for collecting, processing, storing, and shipping laboratory samples for determination of 
BRV plasma levels are described in Section 11.2. 
9 
ASSESSMENT OF EFFICACY 
At each visit the subject will receive a DRC with assistance of the parent(s) or legal 
representative when needed, to be filled in daily for each occurrence of events and to be returned 
at the next visit. At Visit 8, a DRC will be dispensed for the subjects not willing to enter the 
LTFU study or MAP. No DRC will be dispensed at the Safety Visit. 
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 concomitant IMPs, 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; 
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he/she will also confirm the presence of AEs (if applicable). The concomitant medication 
changes, and AEs will be reported by the Investigator on the specific pages of the eCRF 
At Visit 3, the 2 DRCs from Baseline must be reviewed for seizure data to confirm that the 
subject meets eligibility criteria before randomization. 
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. The copy of DRC will be retained 
by Sponsor. 
9.1 
Additional efficacy assessments 
9.1.1 
Medical procedures 
From Visit 1 onwards, 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. Electroencephalogram and brain CT scan (or 
MRI where legally required) performed before randomization in order to meet inclusion criteria 
will be recorded in the modules specifically designed for this purpose. 
10 
ASSESSMENT OF PHARMACOKINETICS  
Plasma concentrations of BRV will be determined. Methods for collecting, processing, storing, 
and shipping laboratory samples for determination of BRV plasma are described in Section 11.2. 
11 
ASSESSMENT OF SAFETY 
11.1 
Adverse events 
11.1.1 
Definitions 
11.1.1.1 
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 Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the subject’s history or the Baseline Period. 
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11.1.1.2 
Serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
 Death 
 Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
 Significant or persistent disability/incapacity 
 Congenital anomaly/birth defect (including that occurring in a fetus) 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 11.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.) 
 Initial inpatient hospitalization or prolongation of hospitalization 
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
11.1.1.3 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. The procedure for reporting AEs of special interest 
is the same as that for reporting SAEs (Section 11.1.2.3). 
The following are AEs of special interest:  
 autoimmune nephritis 
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 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. 
11.1.2 
Procedures for reporting and recording adverse events 
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the Investigator should review any self-assessment procedures (eg, DRC) employed 
in the study. 
11.1.2.1 
Description of adverse events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, DRC) and the corresponding medical terminology should be clarified 
in the source documentation. 
Details for completion of the AE eCRF (including judgment of relationship to IMP) are 
described in the eCRF Completion Guidelines. 
11.1.2.2 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
 The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
 The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
11.1.2.3 
Additional procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The Investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database. 
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An Investigator SAE report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English, with the exception of Japanese reports. 
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. 
11.1.3 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events is provided in Section 11.2.1.4.  
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
Investigator must provide a justification. The follow up will usually be continued for 30 days 
after the subject has discontinued his/her IMP.  
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
11.1.4 
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 EDV. 
 The subject should immediately stop the intake of the IMP or be down-titrated as instructed 
at the EDV.  
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 A Safety 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/ CRO contract monitor for the 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 a serious adverse event (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. 
11.1.5 
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. 
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11.1.6 
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). 
11.1.7 
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. 
11.2 
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 10.5mL 
by sampling, which includes 2mL for hematology, 2.5mL for blood chemistry, and 6mL for 
BRV plasma level measurements.  
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 11‒1: 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; 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. 
b Includes bacteria, cells, casts, and crystals for all samples. 
The 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. 
The results of all safety assessments obtained from the blood sample collected at Visit 1 will be 
used to determine the eligibility of the subject.  
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Laboratory safety assessments will be performed at timepoints specified in the schedule of study 
assessments (Table 5‒1). The decision for the treatment at Visit 3 will be based on the results of 
the laboratory safety sample analysis obtained at Visit 1.  
Where applicable females of childbearing potential, a blood pregnancy test (beta-human 
chorionic gonadotropin [β-hCG] 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 serum pregnancy tests will 
be provided by fax to the Investigator within 72 hours after sample receipt. 
BRV Plasma Levels 
For BRV plasma levels, the date and time of the last 3 actual intakes will be recorded in the 
source documentation and eCRF.  
One blood sample per visit should be obtained for BRV plasma levels at Visit 4, Visit 5, Visit 6, 
Visit7, and Visit 8 (Transition Period) or EDV. The Investigator should attempt as far as 
practically feasible to collect the sample at different times postdose in order to cover the 0 to 
12 hour dosing interval (for example, between 0 to 2 hours postdose, 2 to 4 hours postdose, 4 to 
8 hours postdose, and 8 to 12 hours postdose). 
Brivaracetam plasma levels will be assayed in batch runs. Results of BRV plasma level 
measurements will only be communicated to the Investigator and UCB study team after database 
lock. 
11.2.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 11.1.1.3), and, if applicable, also reported as an 
SAE (see Section 11.1.1.2).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒2 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.2.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.2.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and sponsor. 
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 
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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 11‒2 summarizes the approach to investigate PDILI. 
 
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Table 11‒2: Required investigations and follow-up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology consult.c 
Medical Monitor must be 
notified within 24 hours 
(eg, by laboratory alert) 
and subject discussed with 
Medical Monitor ASAP. 
Immediate, permanent 
IMP discontinuation. 
 
Essential: Must have 
repeat liver chemistry 
values and additional 
testing completed 
ASAP (see 
Section 11.2.1.3); 
recommended to 
occur at the site with 
HCP. 
Monitoring of liver chemistry values at 
least twice per week until values 
normalize, stabilize, or return to within 
baseline values.d 
 
≥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 11.2.1.3). 
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Table 11‒2: Required investigations and follow-up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
(and ≥2x 
Baseline) 
and <5xULN 
<2xULN 
No 
Discussion with Medical 
Monitor required if the 
criterion that allows for 
IMP continuation is met. 
 
 Further investigation – 
immediate IMP 
discontinuation not 
required (see Section 
11.2.1.2). 
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 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a  Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 11.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the Investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
Investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
 
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11.2.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the Investigator must discuss the case with the Medical 
Monitor as soon as possible. If required, the Investigator must also discuss the case with the local 
hepatologist. The local hepatologist is the expert usually consulted by the treating physician for 
assessment and management of potential hepatic disease. This would usually be a hepatologist, 
but may be a gastroenterologist. If determined necessary, this discussion should be followed by a 
full hepatology assessment (see Section 11.2.1.3) and SAE report (if applicable). 
11.2.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒2 for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The Investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
11.2.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 11‒3 (laboratory measurements) and Table 11‒4 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding 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 11‒3: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing) 
Immunology 
Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic acid; 
ULN=upper limit of normal 
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). 
The following additional information is to be collected: 
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Table 11‒4: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”) 
 
Adverse reactions to drugs 
 
Allergies 
 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
 
Recent travel  
 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
11.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 11‒2. 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. 
11.3 
Other safety measurements 
11.3.1 
ECG 
A standard 12-lead ECG will be performed at time points specified in the schedule of study 
assessments (Table 5‒1).  
Baseline (Visit 1) results must be received before Visit 3 randomization. The Investigator will 
determine whether the results of the ECG are normal or abnormal and assess the clinical 
significance of any abnormalities. 
The original ECG tracing will be signed or initialed and dated by the Investigator and will be 
retained as part of the source data.  
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11.3.2 
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 schedule of study assessments 
(Table 5‒1).  
The vital signs measurements will be repeated after 30 minutes if unusual values were observed 
at the initial reading. 
11.3.3 
Physical examinations  
A standard physical examination will be performed at time points specified in the schedule of 
study assessments (Table 5‒1). Clinically significant new or worsened abnormalities will have to 
be reported as AEs. 
11.3.4 
Neurological examination 
A standard neurological examination will be performed at time points specified in the schedule 
of study assessments (Table 5‒1). Clinically significant new or worsened abnormalities will have 
to be reported as AEs. 
11.3.5 
Psychiatric and mental status 
Psychiatric and mental status will be reported by recording the presence or absence of psychiatric 
symptoms, mental impairment, and behavioral problems at time points specified in the schedule 
of study assessments (Table 5‒1). Clinically significant new or worsened abnormalities will have 
to be reported as AEs. 
11.3.6 
Body weight and height 
At all visits, body weight (subject wearing light clothing without shoes) will be measured. 
Subjects with a body weight ≥40kg during Baseline Period will be eligible. Height will be 
recorded at Baseline (Visit 1) only.  
11.3.7 
Neuro-imaging procedure 
A brain MRI, brain CT scan should be performed during the Baseline Period if no previous 
report is available within the last 2 years. 
11.3.8 
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 schedule of study 
assessments (Table 5‒1). 
12 
STUDY MANAGEMENT AND ADMINISTRATION  
12.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor. 
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12.2 
Monitoring 
UCB (or designee) will monitor the study to meet the sponsor’s monitoring 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. 
12.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of CRFs 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 EEGs are considered as source documents and should be 
stored with the subject’s study information. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the subject’s source documents. The 
Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records as applicable, such as Holter monitor records or EEG records, must be 
saved and stored as instructed by UCB (or designee). 
12.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 12.2.1. 
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12.3 
Data handling 
12.3.1 
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. 
12.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. Case Report form data are entered into the clinical database using independent, 
double-data entry, with the exception of comment fields, which are verified by a second person. 
The data are entered into the eCRF 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. 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log. 
The Investigator will keep a Subject Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each subject. 
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
12.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
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requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
12.5 
Archiving and data retention 
The 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. 
12.6 
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). 
12.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
13 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
13.1 
Definition of analysis sets 
Analysis populations will be defined as follows: 
The Safety Set (SS) will include all randomized subjects who will take at least 1 dose of study 
medication.  
The Full Analysis Set (FAS) will consist of all randomized subjects who receive at least 1 dose 
of study medication and have at least 1 post-Baseline seizure DRC data.  
The Per-Protocol Set (PPS) will consist of all subjects in the FAS who do not have a major 
protocol deviation impacting the primary efficacy variable.  
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The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects who took at least 
1 dose of BRV and for whom at least 1 valid BRV plasma concentration-time record and dosing 
information are available.  
All efficacy analyses will primarily be carried out using the FAS. In order to verify the 
robustness of the efficacy results, the primary efficacy variable will also be analyzed using the 
PPS. Safety analyses will be carried out using the SS.  
All analyses will be based on randomized treatment assignment. Incorrectly treated subjects will 
be evaluated during the blinded data evaluation meeting (DEM) to assess the potential impact of 
such cases and any special analysis considerations. 
13.2 
General statistical considerations 
Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 75th 
percentile, minimum value, and maximum value for quantitative variables, and counts and 
percentages for categorical variables, will be provided. Key supporting data will be provided in 
data listings. All statistical testing will be carried out at a 2-sided 0.05 significance level unless 
otherwise indicated. 
Statistical outliers are defined as values that are discordant with other values and are clinically 
implausible. Exclusion of outliers from an analysis requires thorough justification based on 
statistical and clinical grounds. Any outliers will be reviewed during the blinded DEMs (see 
Section 13.5). 
13.3 
Planned efficacy analyses 
13.3.1 
Analysis of the primary efficacy variable 
The primary analysis will be based on ANCOVA with log-transformed [log(x+1)] Treatment 
Period adjusted partial seizure frequency per 28 days as the outcome and effects for treatment 
group and stratification effects and log-transformed Baseline partial seizure frequency as a 
continuous covariate, where log represents the natural logarithm function. Seizure frequency 
within each study period will be standardized to a 28-day duration. Treatment effects will be 
characterized using percent reduction over PBO based on back-transformation of least squares 
means. A non-parametric analysis will be carried out to assess the robustness of the parametric 
ANCOVA results.  
This study is stratified by country, LEV use (LEV naïve vs prior LEV use), and number of 
previously used AEDs (≤2 vs >2). Some combinations of stratification levels may have few 
subjects. The general rules for pooling stratification levels for statistical analyses will be 
provided in the SAP, with finalization of any pooling during the blinded DEM.  
Statistical testing will be based on the comparison of each BRV treatment group (BRV 50mg/day 
and 200mg/day) to PBO with control of overall Type I error rate based on the Hochberg 
procedure. The Hochberg procedure does not require a pre-specified order of testing for BRV 
dose groups vs PBO. In a setting with a comparison of 2 active groups to PBO, the Hochberg 
procedure is applied by first testing the BRV group with the larger p-value at the 0.05 level. If 
statistical significance is achieved at this step, then the study is positive and both BRV dose 
groups are declared statistically different from PBO. If the largest p-value is not significant at the 
0.05 level, then the Hochberg procedure steps to the smaller p-value and tests at the 0.025 level. 
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If statistical significance is achieved at this step, then the study is positive and the BRV dose 
group associated with the smaller p-value is declared statistically different from PBO. If the 
smaller p-value is not significant at the 0.025 level, then neither BRV group is statistically 
different from PBO and the study is not positive. 
13.3.2 
Analyses of secondary efficacy variables 
The secondary efficacy variables will be analyzed with statistical testing at the nominal 
0.05 level without adjusting multiplicities.  
For treatment and stratification effects, 50% responder rate will be analyzed using a logistic 
regression with effects for treatment and stratification effects and log-transformed Baseline 
partial seizure frequency per 28 days as a continuous covariate.  
With regard to stratification, the same rule with the Section 13.3.1 will be applied.  
Median percent reduction in partial seizure frequency per 28 days from Baseline to the 
Treatment Period will be compared between each BRV group and PBO using a Wilcoxon-Mann-
Whitney test. Hodges Lehmann non-parametric effect estimates and corresponding 95% 
confidence intervals will be provided. Categorized percent reduction (<-25%, -25% to <25%, 
25% to <50%, 50% to <75%, 75% to <100%, and 100%) in partial seizure frequency from 
Baseline to the Treatment Period will be summarized descriptively with comparisons between 
each BRV group and PBO carried out using a Mantel-Haenszel test for comparison of row mean 
scores. Seizure freedom rates will be compared between each BRV group and PBO using 
Fisher’s Exact Test. To be considered seizure-free, a subject must not report seizures of any type 
and must complete the Treatment Period without any missing seizure DRC days.  
All seizure frequency (partial, generalized, and unclassified epileptic seizure) per 28 days over 
the Treatment Period will be analyzed in a manner similar to the primary ANCOVA analysis.  
Time to nth (n=1, 5, 10) partial seizure will be compared between each BRV group and PBO 
using a semi-parametric proportional hazards model with an effect for treatment and 
log-transformed Baseline partial seizure frequency as a continuous covariate. 
13.4 
Planned safety and other analyses 
13.4.1 
Safety analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be summarized by MedDRA System Organ Class (SOC) and 
Preferred Term. The incidence of SAEs, AEs leading to premature discontinuation, and related 
AEs, and the incidence of AEs by maximum intensity will also be summarized. 
13.4.2 
Pharmacokinetic analyses 
Descriptive statistics of plasma concentrations of BRV will be summarized by subgroups and 
total. Figures of BRV plasma concentration vs time profile will be produced by subgroups and 
total. As needed, population PK and/or PK analyses will be planned and described in a separate 
data analysis plan. 
13.5 
Handling of protocol deviations 
After all eCRFs have been retrieved and entered and queries addressed, and prior to locking the 
clinical database and unblinding the study, a blinded DEM will be held. The purpose of this 
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blinded 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. 
13.6 
Handling of dropouts or missing data 
Subjects who provide at least 1 complete daily seizure record for the Treatment Period will be 
included in the primary analysis. Seizure frequency standardized to a 28-day duration will be 
computed over non-missing DRC days during each study period; missing seizure DRC days will 
not be considered in the calculation of seizure frequency. Similarly, if a subject prematurely 
discontinues before the end of the Treatment Period, then the seizure information collected up 
until the time of discontinuation will be used to calculate seizure frequency over the Treatment 
Period. The preceding assumes that seizure frequency during the missing DRC days is equal to 
the daily seizure frequency computed over non-missing days. Sensitivity analyses will be 
considered to assess the impact of these assumptions. 
13.7 
Planned interim analysis and data monitoring 
No formal interim analysis is planned. However, an informal analysis is planned post data 
collection during the double-blind period of the study to support regulatory submissions. Prior to 
the analysis, an official unblinding will be completed. At a minimum, one interim report is 
planned. Regular monitoring of safety data collected during clinical studies will be performed by 
medically qualified Sponsor personnel or equivalent designee(s). 
13.8 
Determination of sample size 
A total of 148 analyzable subjects per treatment group will provide at least 80% power to 
simultaneously detect differences between each BRV treatment group (BRV 50mg/day group 
and BRV 200mg/day group) and the PBO group at the 1-sided 0.025 significance level. This 
sample size assumes treatment differences of 0.221 and 0.285 in means on the log-transformed 
scale and a common SD of 0.66. The estimates of 0.221 and 0.285 correspond to reductions of 
19.8% and 24.8% of BRV over PBO after back-transformation, respectively. The percent 
reduction of 24.8% is obtained from BRV 200mg/day in the N01358 study and assuming the 
LEV cap of 30% is reached overall. Based on a similar result from the Integrated Summary of 
Efficacy and again assuming the LEV cap of 30% is reached overall, a 19.8% reduction of BRV 
50mg/day over PBO can be estimated. The SD of 0.66 is based on the observed SD from all 
treatment groups in N01358.The sample size calculation accounts for the correlation of the test 
statistics (same placebo group is compared to each BRV dose) as well as the planned Hochberg 
procedure.  A total of 444 (148×3) analyzable subjects in the study is calculated as a target 
number. 
13.9 
Management of LEV cap 
The number of prior LEV users will be limited to 30% of the total study population.  The system 
cap will be managed in IWRS.  Operational aspects of the LEV cap will be specified in the 
Monitoring Plan.   
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14 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the Investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the Investigator. 
Prior to participation in the study, the Informed Consent form should be signed and personally 
dated by the subject, or his/her legal representative, and by the person who conducted the 
informed consent discussion (Investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent form. Additionally, 
if applicable (according to subject’s age and local requirements), the subject will sign an 
IRB/IEC-approved Assent form. As part of the consent process, each subject must consent to 
direct access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, 
and regulatory inspection. 
If the Informed Consent form is amended during the study, the Investigator (or the sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form. 
14.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The Investigator will fill in the subject identifying information and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with him/her at all times. 
14.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
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The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
14.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
14.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
15 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable. 
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16 
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. 
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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17 
APPENDIX  
17.1 
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) 
1. With motor signs 
a) Focal motor without march 
b) Focal motor with march (Jacksonian) 
c) Versive 
d) Postural 
e) Phonatory (vocalization or arrest of speech) 
2. With somatosensory or special sensory symptoms (simple hallucinations, eg, 
 
tingling, light flashes, buzzing) 
a) Somatosensory 
b) Visual 
c) Auditory 
d) Olfactory 
e) Gustatory 
f) Vertiginous 
3. With autonomic symptoms or signs (including epigastric sensation, pallor, 
 
sweating, flushing, piloerection, and pupillary dilatation) 
4. With psychic symptoms (disturbance of higher cerebral function). These  symptoms 
rarely occur without impairment of consciousness and are much more  commonly 
experienced as complex partial seizures. 
a) Dysphasic 
b) Dysmnesic (eg, déjà-vu) 
c) Cognitive (eg, dreamy states, distortions of time sense) 
d) Affective (fear, anger, etc.) 
e) Illusions (eg, macropsia) 
f) Structured hallucinations (eg, music, scenes) 
B. Complex partial seizures (with impairment of consciousness: may sometimes begin 
 
with simple symptomatology) 
1. Simple partial onset followed by impairment of consciousness 
a) With simple partial features followed by impaired consciousness (A.1. - A.4.) 
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b) With automatisms 
2. With impairment of consciousness at onset 
a) With impairment of consciousness only 
b) With automatisms 
C. Partial seizures evolving to secondarily generalized seizures (this may be  
generalized 
tonic-clonic, tonic, or clonic) 
1. Simple partial seizures (A) evolving to generalized seizures 
2. Complex partial seizures (B) evolving to generalized seizures 
3. Simple partial seizures evolving to complex partial seizures evolving to  generalized 
seizures 
II. Generalized seizures (convulsive or non-convulsive) 
A. 1. Absence seizures 
a) Impairment of consciousness only 
b) With mild clonic components 
c) With atonic components 
d) With tonic components 
e) With automatisms 
f) With autonomic components 
(b through f may be used alone or in combination) 
2. Atypical absence 
May have: 
a) Changes in tone that are more pronounced than in A.1 
b) Onset and/or cessation that is not abrupt 
B. Myoclonic seizures - Myoclonic jerks (single or multiple) 
C. Clonic seizures 
D. Tonic seizures 
E. Tonic-clonic seizures 
F. Atonic seizures - (Astatic) 
(combinations of the above may occur, eg, B and F, B and D) 
Ш. Unclassified epileptic seizures 
Includes all seizures that cannot be classified because of inadequate or incomplete data and some 
that defy classification in hitherto described categories. This includes some neonatal seizures, eg, 
rhythmic eye movements, chewing, and swimming movements. 
 
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Status epilepticus (prolonged partial or generalized seizures without recovery between attacks) 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. 
Epilepsia. 1981;22:489-501. 
 
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17.2 
Appendix 2 - International Classification of Epilepsies and 
Epileptic Syndromes 
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 
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 Epilepsy with myoclonic absences 
2.3 Symptomatic 
2.3.1 Non-specific etiology 
 Early myoclonic encephalopathy 
 Early infantile epileptic encephalopathy with suppression-burst 
 Other symptomatic generalized epilepsies not defined above 
2.3.2 Specific syndromes 
3. Epilepsies and syndromes undetermined whether focal or generalized 
3.1 With both generalized and focal seizures 
 Neonatal seizures 
 Severe myoclonic epilepsy in infancy 
 Epilepsy with continuous spikes-waves during slow wave sleep 
 Acquired epileptic aphasia (Landau-Kleffner-syndrome) 
 Other undetermined epilepsies not defined above 
3.2 Without unequivocal generalized or focal features 
4. Special syndromes 
4.1 Situation-related seizures (Gelegenheitsanfälle, Occasional seizures) 
 Febrile convulsions 
 Isolated seizures or isolated status epilepticus 
 Seizures occurring only when there is an acute metabolic or toxic event due to factors 
such as alcohol, drugs, eclampsia, nonketotic hyperglycemia 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 
1989;30:389-99. 
 
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17.3 
Appendix 3 - 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 
• Perampanel 
• Phenacemide 
• Pheneturide 
• Phenobarbital 
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• Phensuximide 
• Phenytoin 
• Pregabalin 
• Primidone 
• Progabide 
• Retigabine 
• Rufinamide 
• Stiripentol 
• Sultiame 
• Tiagabine 
• Topiramate 
• Trimethadione 
• Valproic acid 
• Valpromide 
• Vigabatrin 
• Zonisamide 
 
Note: An AED that contains more than one compound in this list is not counted as 1 AED. 
The number of compounds contained in 1 AED is counted as the number of AED 
administered. 
It is prohibited that subjects take Levetiracetam, or Brivaracetam other than IMP, during the 
study. 
 
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17.4 
Appendix 4 - Protocol Amendment 1 
This protocol has been amended to incorporate the following:  
 New study details of allowing temporary BRV to act as rescue for patients entering MAP.   
 Amended details for including at least one planned interim report for the purpose of 
supporting regulatory submissions. 
In addition, minor administrative edits including typographical changes for formatting and/or 
spelling errors have been made.  
The following shows the changes made in Amendment 1 compared to the original protocol, 
dated 17 Oct 2016. 
Modifications and changes 
Global changes 
There were no global changes to the protocol during this amendment.   
Specific changes 
Change #1 
STUDY CONTACT INFORMATION 
Sponsor/Local Legal Representative 
Has been changed to: 
Sponsor/Local Legal Representative in Japan 
Change #2 
LIST OF ABBREVIATIONS 
The following was removed from the list of abbreviations: 
ECD 
electronic data capture 
Change #3  
1  
SUMMARY 
Additional study information:  
If BRV is commercially available upon subject completion of the Treatment and Transition 
Period, subjects will receive BRV directly without entering the LTFU study or MAP. 
Change #4  
5.1  
Study Description 
Additional study information:  
If BRV is commercially available upon subject completion of the Treatment and Transition 
Period, subjects will receive BRV directly without entering the LTFU study or MAP. 
Change #5  
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5.1.1  
Study duration per subjects 
Additional study information:  
As a procedure of MAP, the import license of medication for MAP is necessary. The process to 
obtain the import license starts after patient enrollment and can on occasions take a long time. To 
avoid a scenario where a subject cannot enter MAP due to the delayed importation of 
medication, a temporary period for providing BRV will be prepared as the rescue. Once 
medication for MAP is ready, a subject can start MAP. 
 
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Change #6 
Table 5-1: Schedule of study assessments 
 
Assessments 
 
Prospective Baseline 
Period 
(8 weeks) 
Treatment Period 
(12 weeks) 
Early 
discontinuation 
Transition 
Period 
(2 weeks)/ 
Down 
Titration 
Period 
(4 weeks) 
Study 
Drug-Free 
Period  
(2 weeks)a 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
EDV 
V8 
Safety Visit 
W -8 
W -4 
W 0 
W 2 
W 4 
W 8 
W 12 
 
W 14/W 16 
W 18 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Subject ID Card dispense 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
Xb 
Xb 
Xb 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical/procedures history 
X 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
Lifetime AED history 
X 
 
 
 
 
 
 
 
 
 
Birth control 
X 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
X 
Body weight and heighte 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
X 
 
 
 
X 
Xd 
X 
X 
Neurological examination 
X 
 
X 
 
 
 
X 
Xd 
X 
X 
Psychiatric and mental status 
X 
 
X 
 
 
 
X 
Xd 
X 
X 
ECG 
Xf 
 
 
X 
X 
 
X 
Xd 
Xk 
X 
EEG 
Xg 
 
 
 
 
 
 
 
 
 
CT scan/MRI 
Xh 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Subject DRC dispensed 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
 
 
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Has been changed to: 
 
Assessments 
 
Prospective Baseline 
Period 
(8 weeks) 
Treatment Period 
(12 weeks) 
Early 
discontinuation 
Transition 
Period 
(2 weeks)/ 
Down 
Titration 
Period 
(4 weeks) 
Study 
Drug-Free 
Period  
(2 weeks)a 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
EDV 
V8 
Safety Visit 
W -8 
W -4 
W 0 
W 2 
W 4 
W 8 
W 12 
 
W 14/W 16 
W 18 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Subject ID Card dispense 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
Xb 
Xb 
Xb 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical/procedures history 
X 
 
 
 
 
 
 
 
 
 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 
Lifetime AED history 
X 
 
 
 
 
 
 
 
 
 
Birth control 
X 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight and heighte 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination  
X 
 
X 
 
 
 
X 
Xd 
X 
X 
Neurological examination 
X 
 
X 
 
 
 
X 
Xd 
X 
X 
Psychiatric and mental status 
X 
 
X 
 
 
 
X 
Xd 
X 
X 
ECG 
Xf 
 
 
X 
X 
 
X 
Xd 
Xk 
X 
EEG 
Xg 
 
 
 
 
 
 
 
 
 
CT scan/MRI 
Xh 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Subject DRC dispensed 
X 
X 
X 
X 
X 
X 
X 
Xd 
Xo 
 
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Change #7 
7.8.1  
Permitted concomitant treatments (medication and therapies) 
All subjects will take a minimum of 1 or 2 concomitant AEDs (Appendix 3 [Section 17.3]). Only 
daily use is permitted. 
Has been changed to: 
All subjects will take 1 or 2 concomitant AEDs (Appendix 3 [Section 17.3]). Only oral-daily use 
is permitted (any other use or route of administration is prohibited, except when it is used as 
rescue medication). 
Change #8 
7.8.3  
Restricted concomitant treatments (medications and therapies) 
Additional restriction: 
Any drug where the route of administration is not oral, except when it used as rescue medication. 
Change #9 
7.8.3  
Rescue medication 
Additional criteria: 
In addition, the use of anticonvulsants are permitted as rescue medication. 
Change #10 
8.8 Early Discontinuation Visit (after randomization) 
Bullet 7: 
 IVRT/IWRT 
Has been changed to: 
 IVRS/IWRS 
Change #11 
8.9 Visit 8 (Transition Period) 
Additional assessment added to Visit 8: 
 IVRS/IWRS 
Change #12 
8.9.1 Visit 8 (Down-Titration Period) 
Additional assessment added to Visit 8: 
 IVRS/IWRS 
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Change #13 
11.2 Laboratory measurements 
Table 11-1: 
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; FSH=follicle stimulating hormone; GGT=gamma-glutamyltransferase; 
LH=luteinizing hormone; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin 
concentration; MCV=mean corpuscular volume; RBC=red blood cell; SerV=Screening Visit; SGOT=serum 
glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; T3=triiodothyronine; 
T4=tetraiodothyronine; TSH=thyroid stimulating hormone; TV=titration visit; WBC=white blood cell 
a This assessment is used for hepatic monitoring. 
b Includes bacteria, cells, casts, and crystals for all samples. 
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Has been changed to: 
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; 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. 
b Includes bacteria, cells, casts, and crystals for all samples. 
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Change #14 
11.2.1 Evaluation of PDILI 
Table 11-2: 
Required Investigators and follow-up for PDILI, fourth row:  
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 
12.2.1.2). 
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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Has been changed to: 
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 
11.2.1.2). 
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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Change #15 
11.3.6 Body weight and height 
At all visits, body weight (subject wearing light clothing without shoes) will be measured. 
Subjects with a body weight ≥40kg during Baseline Period will not be eligible. Height will be 
recorded at Baseline (Visit 1) only. 
Has been changed to: 
At all visits, body weight (subject wearing light clothing without shoes) will be measured. 
Subjects with a body weight ≥40kg during Baseline Period will be eligible. Height will be 
recorded at Baseline (Visit 1) only. 
Change #16 
11.3.8 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 schedule of study 
assessments (Table 5‒1). 
Has been changed to: 
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 schedule of study 
assessments (Table 5‒1). 
Change #17 
13.7 Planned interim analysis and data monitoring 
No interim analyses are planned for this study. 
Has been changed to: 
No formal interim analysis is planned. However, an informal analysis is planned post data 
collection during the double-blind period of the study to support regulatory submissions. Prior to 
the analysis, an official unblinding will be completed. At a minimum, one interim report is 
planned. Regular monitoring of safety data collected during clinical studies will be performed by 
medically qualified Sponsor personnel or equivalent designee(s). 
Change #18 
17.1 
Appendix 1 
Has been changed to: 
17.1 
Appendix 1 - International Classification of Epileptic Seizures  
Change #19 
17.2 
Appendix 2 
Has been changed to: 
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17.2 
Appendix 2 - International Classification of Epilepsies and Epileptic Syndromes 
Change #20 
17.3 
Appendix 3 
Has been changed to: 
17.3 
Appendix  - List of Antiepileptic Drugs 
Change #21 
Additional appendix: 
17.4 
Appendix 4 –Protocol Amendment 1 
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17.5 
Appendix 5 – Protocol Amendment 2 
This protocol has been amended to incorporate the following:  
 A change described in Appendix 4 of Protocol Amendment 1 (dated 12 May 2017) was not 
incorporated in the relevant section of the protocol amendment. This change has been made 
to reflect that amendment.  
In addition, minor formatting corrections have been made to a sub-section.  
The following shows the changes made in Protocol Amendment 2 compared to Protocol 
Amendment 1, dated 12 May 2017. 
Modifications and changes 
Global changes 
There were no global changes to the protocol during this amendment.   
Specific changes 
Change #1 
Additional term to the abbreviation list: 
EDV  
Early Discontinuation 
Change #2 
7.8.2 Prohibited concomitant treatments (medication and therapies) 
 - LEV 
 - BRV (other than IMP) 
 - 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). 
Has been changed to: 
The following concomitant medications/treatments are prohibited during the study: 
 LEV 
 BRV (other than IMP) 
 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). 
Change #3 
7.8.3 Restricted concomitant treatments (medication and therapies)  
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The following concomitant medications/treatments are restricted during the study: 
Drugs with possible CNS effects (anxiolytics, hypnotic, and neuropsychiatric agents) including 
benzodiazepines are allowed if at stable dose from at least 4 weeks prior to Visit 1 and during the 
entire study period. In case of as-needed use, it is allowed the frequency is up to once a week in 
this study. However, it is prohibited to take more than once a week in this study. Any drug where 
the route of administration is oral, except when it used as rescue. 
Has been changed to: 
The following concomitant medications/treatments are restricted during the study: 
Drugs with possible CNS effects (anxiolytics, hypnotic, and neuropsychiatric agents) including 
benzodiazepines are allowed if at stable dose from at least 4 weeks prior to Visit 1 and during the 
entire study period. In case of as-needed use, it is allowed the frequency is up to once a week in 
this study. However, it is prohibited to take more than once a week in this study. Any drug where 
the route of administration is not oral, except when it used as rescue medication. 
 
 
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17.6 
Appendix 6 – Protocol Amendment 3 
This protocol has been amended to incorporate the following:  
 To include Non-Asian patients  
 To include EU countries 
 To raise the prior LEV limitation from 20% to 30%  
 To ensure consistency between the protocol and CRF Completion Guidelines.  
In addition, minor formatting and corrections have been made.  
Modifications and changes 
Global changes 
The deletion of exclusive Asian population to include Non-Asian subjects. 
Prior LEV limitation has been increased from 20% to 30%. 
Specific changes 
Section 
Description of change 
Rationale 
Section 4.3 Safety variables 
Added Section 4.3.1 Primary 
variable and Section 4.3.2 
Exploratory variables 
To define safety variables 
Section 8.7 Early 
Discontinuation Visit (before 
randomization) 
Updated section 
For alignment with CRF 
Completion Guidelines 
Throughout 
Removed references to Asian 
subjects  
Prior LEV limitations have 
been increased from 20% to 
30% 
Based on global  
 
 
 
 
 
 
 
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17.7 
Appendix 7 – Protocol Amendment 4  
This protocol has been amended to incorporate the following: 
 To reduce the total sample size from 504 to 444 study participants  
 To reduce the minimum required number of Japanese study participants  
 To add China Mainland to the list of participating countries and regions 
 To update exclusion criteria 20 and 27 
 To provide clarifications around the LEV use and LEV cap  
 To update the study contact information 
 To update the company name from SPRL to SRL 
In addition, minor administrative edits including typographical changes for formatting and/or 
spelling errors have been made.  
Modifications and changes 
Global changes 
The “exploratory safety variable” language was changed to “other safety variable” throughout 
the protocol. The pharmacodynamic variables were also removed.  
Specific changes 
Change #1 
STUDY CONTACT INFORMATION, Sponsor/Local Legal Representative in Japan 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
JAPAN 
Has been changed to: 
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  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
317 Room No.439, 
Futexi Yi road, China 
(Shanghai) 
Pilot Free Trade Zone 
1070 Brussels 
Tokyo 160-0023 
Shanghai 200131 
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BELGIUM 
JAPAN 
PRC 
Change #2 
STUDY CONTACT INFORMATION, Sponsor Study Physician 
Address: 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Has been changed to: 
Address: 
 Raffles City, Shanghai Office Tower, 
268 Tibet Road Central, Shanghai 200001 PRC 
Change #3 
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 #4 
SERIOUS ADVERSE EVENT REPORTING 
The following SAE reporting was added: 
Serious adverse event reporting (24 hours) for China only 
Fax 
UCB China: +86-21-23210206 
Email 
UCB China: ds.China@ucb.com 
Change #5 
Section 1, Summary, last 2 paragraphs 
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Pharmacokinetic variables include BRV (parent compound only) plasma levels. 
Safety variables include adverse events (AEs), laboratory tests (blood chemistry, hematology, 
urinalysis), electrocardiogram (ECG), vital signs, body weight, physical and neurological 
examinations, and mental and psychiatric status. 
The planned number of evaluable subjects will be a total of 504 (168 subjects per treatment 
group) for the primary efficacy analysis. The number of prior LEV use subjects will be limited to 
30% of the total study population. It is planned to have those subjects recruited in approximately 
100 centers. 
Has been changed to: 
Pharmacokinetic variable is BRV (parent compound only) plasma levels. 
Safety variables include incidence of treatment-emergent adverse events (TEAEs), incidence 
of TEAEs leading to study withdrawal, incidence of treatment-emergent serious adverse 
events (SAEs), changes in clinical laboratory test parameters (blood chemistry, hematology, 
urinalysis), electrocardiogram (ECG) parameters and findings, changes in vital signs (SBP, 
DBP, and pulse rate), changes in body weight, physical and neurological examinations, and 
mental and psychiatric status. 
The planned number of evaluable subjects will be a total of 444 (148 subjects per treatment 
group) for the primary efficacy analysis. The number of prior LEV use subjects will be limited to 
30% of the total study population. It is planned to have those subjects recruited in approximately 
95 centers. 
Change #6 
Section 2.4, Safety with BRV, first and third paragraphs 
In the BRV clinical development program, 3822 subjects were exposed to BRV (unique 
exposures) as of 14 Jul 2016.  
In addition, the safety of BRV as long-term adjunctive treatment is being evaluated in 2 ongoing 
LTFU studies (N01125 and N01379) and 3 completed LTFU studies (N01199, N01315, and 
N01372). The safety profile in the open-label extension studies (up to 8 years) was consistent to 
that observed in the short-term, PBO-controlled studies. 
Has been changed to: 
In the BRV clinical development program, 3970 subjects have been exposed to BRV (unique 
exposures) as of 14 Jan 2019.  
In addition, the safety of BRV as long-term adjunctive treatment has been evaluated in 5 LTFU 
studies (N01125, N01379, N01199, N01315, and N01372). The safety profile in the open-label 
extension studies (up to 8 years) was consistent to that observed in the short-term, PBO-
controlled studies. 
Change #7 
Section 2.5, Study rationale, first paragraph 
This adequate and well-controlled study will be performed to provide data confirming the 
efficacy and safety of BRV as an AED and to support a marketing authorization application / 
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new drug application in Japan for BRV in the indication of adjunctive treatment in subjects 
(≥16 to 80 years of age) with partial seizures with or without secondary generalization.  
Has been changed to: 
This adequate and well-controlled study will be performed to provide data confirming the 
efficacy and safety of BRV as an AED and to support a new drug application in Japan and 
China for BRV in the indication of adjunctive treatment in subjects (≥16 to 80 years of age) with 
partial seizures with or without secondary generalization. 
Change # 8 
Section 4.1.1, Primary efficacy variable 
The following sentence was removed 
The primary efficacy outcome is the percent reduction in partial seizure frequency over PBO 
based on ANCOVA. 
Change # 8 
Section 4.3.1, Primary safety variable 
The primary safety variable is AEs.  
Has been changed to: 
 Incidence of TEAEs  
 Incidence of TEAEs leading to study withdrawal 
 Incidence of treatment-emergent serious adverse events (SAEs) 
Change # 9 
Section 4.3.2 Exploratory safety variables 
The exploratory safety variables are as follows: 
 Laboratory tests (blood chemistry, hematology, urinalysis)  
 ECG 
 Vital signs 
 Body weight 
 Physical examination  
 Neurological examination  
 Mental status  
 Psychiatric status  
Has been changed to: 
Section 4.3.2 Other safety variables 
The other safety variables are as follows: 
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 Changes in clinical laboratory test parameters (blood chemistry, hematology, urinalysis)  
 ECG parameters and findings 
 Changes in vital signs (SBP, DBP, and pulse rate) 
 Changes in body weight 
 Physical examination  
 Neurological examination  
 Mental status  
 Psychiatric status  
Change #10 
Section 5.1.1, Study duration per subject, second paragraph, second bullet 
Prior to entry into LTFU study or MAP, the informed consent should be obtained from the 
subject at the end of Treatment Period (Visit 7). 
Has been changed to: 
Prior to entry into LTFU study or MAP, the informed consent, where applicable, should be 
obtained from the subject at the end of Treatment Period (Visit 7). 
Change #11 
Section 5.1.2, Planned number of subjects and sites 
The planned number of evaluable subjects will be a total of 504 (168 subjects per treatment 
group) for the primary efficacy analysis. Of the 504 subjects, approximately 129 Japanese 
subjects and approximately 375 subjects from other countries will be randomized. The number of 
prior LEV use subjects will be limited to 30% of the total study population. Considering an 
anticipated screen failure rate of approximately 20%, approximately 630 subjects (162 Japanese 
subjects and 468 subjects from other countries) will be screened. It is planned to have those 
subjects recruited in approximately 100 sites. 
Has been changed to: 
The planned number of evaluable subjects for the primary efficacy analysis will be a total of 444 
(148 subjects per treatment group). The number of prior LEV use subjects will be limited to 30% 
of the total study population as referenced in Section 13.9.  
Considering an anticipated screen failure rate of approximately 20%, approximately 555 subjects 
will be screened. It is planned to have those subjects recruited in approximately 95 sites (50 
Japan sites, 20 Southeast Asia sites in countries and regions specified in Section 5.1.3, and 
25 China Mainland sites).  
Change #12 
Section 5.1.3, Anticipated regions and countries 
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The study is planned to be conducted in Japan, Taiwan, Philippines, Thailand, Singapore, 
Malaysia, Hong Kong, Korea, Bulgaria, and Poland with possible extension to other countries or 
regions. 
Has been changed to: 
The study is being conducted in Japan, Taiwan, China Mainland, Philippines, Thailand, 
Singapore, and Malaysia.  
Change #13 
Section 6.2, Exclusion criteria, criterion #20 
20. Subject has any clinical conditions (eg, bone marrow depression, severe renal impairment)   
which impair reliable participation in the study or necessitate the use of medication not 
allowed by protocol.  
Has been changed to: 
20a. Subject has any clinical conditions (eg, bone marrow suppression, severe renal impairment 
with creatinine clearance [CLcr] <30 ml/min/1.73 m2) which impair reliable participation in 
the study or necessitate the use of medication not allowed by protocol.  
Change #14 
Section 6.2, Exclusion criteria, criterion #27 
27. Subject has clinically significant deviations from reference range values for laboratory 
parameters: creatinine clearance (CLcr) calculated <50mL/min, platelets <100,000/μL, 
neutrophil cells <1,800/μL. 
Has been changed to: 
27a. 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 judgment of the Investigator.   
Change #15 
The section below was added and following section numbers were adjusted accordingly:  
7.9, Prior LEV use 
Levetiracetam use within 90 days prior to Visit 1 [(Week -8) Baseline] is prohibited. If a 
subject has been treated with LEV in the past, in order to participate in the study: 
 oral LEV must be discontinued ≥91 days prior to Visit 1, or 
 intravenous (iv) LEV must have been administered ≥91 days prior to Visit 1. 
The management of LEV cap is specified in Section 13.9. 
Change #16  
Section 13.3.1, Analysis of the primary efficacy variable, last paragraph 
Statistical testing will be based on the comparison of each BRV treatment groups (BRV 
50mg/day and 200mg/day) to PBO with control of overall Type I error rate based on the 
Hochberg procedure. The Hochberg procedure does not require a pre-specified order of testing 
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for BRV dose groups vs PBO. In a setting with a comparison of 2 active groups to PBO, the 
Hochberg procedure is applied by first testing the BRV group with the larger p-values with 
testing at the 0.05 level. If statistical significance is achieved at this step then the study is 
positive and both BRV dose groups are declared statistically different from PBO. If the largest 
p-values is not significant at the 0.05 level, then the Hochberg procedure steps to the smaller 
p-values with testing at the 0.025 level. If statistical significance is achieved at this step then the 
study is positive and the BRV dose group associated with the smaller p-values is declared 
statistically different from PBO. If the smaller p-values is not significant at the 0.025 level, then 
neither BRV group is statistically different from PBO and the study is not positive. 
Has been changed to: 
Statistical testing will be based on the comparison of each BRV treatment group (BRV 
50mg/day and 200mg/day) to PBO with control of overall Type I error rate based on the 
Hochberg procedure. The Hochberg procedure does not require a pre-specified order of testing 
for BRV dose groups vs PBO. In a setting with a comparison of 2 active groups to PBO, the 
Hochberg procedure is applied by first testing the BRV group with the larger p-value at the 0.05 
level. If statistical significance is achieved at this step, then the study is positive and both BRV 
dose groups are declared statistically different from PBO. If the largest p-value is not significant 
at the 0.05 level, then the Hochberg procedure steps to the smaller p-value and tests at the 0.025 
level. If statistical significance is achieved at this step, then the study is positive and the BRV 
dose group associated with the smaller p-value is declared statistically different from PBO. If the 
smaller p-value is not significant at the 0.025 level, then neither BRV group is statistically 
different from PBO and the study is not positive. 
Change #17  
Section 13.3.2, Analysis of secondary efficacy variable, fourth paragraph 
Median percent change in partial seizure frequency per 28 days from Baseline to the Treatment 
Period will be compared between each BRV group and PBO using a Wilcoxon-Mann-Whitney 
test. Hodges Lehmann non-parametric effect estimates and corresponding 95% confidence 
intervals will be provided. Categorized percent change in partial seizure frequency from Baseline 
to the Treatment Period will be summarized descriptively with comparisons between each BRV 
group and PBO carried out using a Mantel-Haenszel test for comparison of row mean scores. 
Seizure freedom rates will be compared between each BRV group and PBO using Fisher’s Exact 
Test. To be considered seizure-free, a subject must not report seizures of any type and must 
complete the Treatment Period without any missing seizure DRC days.  
Has been changed to: 
Median percent reduction in partial seizure frequency per 28 days from Baseline to the 
Treatment Period will be compared between each BRV group and PBO using a Wilcoxon-Mann-
Whitney test. Hodges Lehmann non-parametric effect estimates and corresponding 95% 
confidence intervals will be provided. Categorized percent reduction (<-25%, -25% to <25%, 
25% to <50%, 50% to <75%, 75% to <100%, and 100%) in partial seizure frequency from 
Baseline to the Treatment Period will be summarized descriptively with comparisons between 
each BRV group and PBO carried out using a Mantel-Haenszel test for comparison of row mean 
scores. Seizure freedom rates will be compared between each BRV group and PBO using 
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Fisher’s Exact Test. To be considered seizure-free, a subject must not report seizures of any type 
and must complete the Treatment Period without any missing seizure DRC days.  
Change #18  
Section 13.8, Determination of sample size 
A total of 168 analyzable subjects per treatment group will provide 80% power to simultaneously 
detect differences between BRV treatment groups (BRV 50mg/day group and BRV 200mg/day 
group) and PBO group at the 1-sided 0.025 significance level assuming treatment differences of 
0.217 and 0.264 in means on the log-transformed scale and a common SD of 0.66. The estimates 
of 0.217 and 0.264 correspond to reductions of 19.5% and 23.2% of BRV over PBO after back-
transformation, respectively. The percent reduction of 23.2% is obtained from BRV 200mg/day 
in the N01358 study. Based on a similar result from the Integrated Summary of Efficacy, a 
19.5% reduction of BRV 50mg/day over PBO can be estimated. The SD of 0.66 is based on the 
observed SD from all treatment groups in N01358. The number of 168 subjects per treatment 
group will provide powers of 95% and 85% to detect the differences of BRV 200mg/day and 
BRV 50mg/day for PBO, respectively. Accordingly, a power to simultaneously detect 
differences of both BRV 200mg/day and BRV 50mg/day vs PBO will attain 81% (0.95×0.85). A 
total of 504 (168×3) analyzable subjects in the study is calculated as a target number. 
Has been changed to: 
A total of 148 analyzable subjects per treatment group will provide at least 80% power to 
simultaneously detect differences between each BRV treatment group (BRV 50mg/day group 
and BRV 200mg/day group) and the PBO group at the 1-sided 0.025 significance level. This 
sample size assumes treatment differences of 0.221 and 0.285 in means on the log-transformed 
scale and a common SD of 0.66. The estimates of 0.221 and 0.285 correspond to reductions of 
19.8% and 24.8% of BRV over PBO after back-transformation, respectively. The percent 
reduction of 24.8% is obtained from BRV 200mg/day in the N01358 study and assuming the 
LEV cap of 30% is reached overall. Based on a similar result from the Integrated Summary of 
Efficacy and again assuming the LEV cap of 30% is reached overall, a 19.8% reduction of 
BRV 50mg/day over PBO can be estimated. The SD of 0.66 is based on the observed SD from 
all treatment groups in N01358. The sample size calculation accounts for the correlation of 
the test statistics (same placebo group is compared to each BRV dose) as well as the 
planned Hochberg procedure.  A total of 444 (148×3) analyzable subjects in the study is 
calculated as a target number. 
Change #19  
The following section was added: 
13.9 Management of LEV cap 
The number of prior LEV users will be limited to 30% of the total study population.  The 
system cap will be managed in IWRS.  Operational aspects of the LEV cap will be specified 
in the Monitoring Plan.   
 
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18 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract. 
Investigator: 
 
 
 
 
Printed name  
 
Date/Signature 
 
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19 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
 
 
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Approval Signatures
Name:
EP0083-protocol-amend-4
Version:
4. 0
Document Number:
CLIN-000138362
Title:
EP0083 Protocol Amendment 4
Approved Date:
13 Jan 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 10-Jan-2020 14:13:27 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 10-Jan-2020 23:27:19 GMT+0000
Approval
Verdict: Approved
Name:
Capacity: Clinical
Date of Signature: 13-Jan-2020 02:52:51 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN  
Study: EP0083 
Product: Brivaracetam 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER, 
PARALLEL-GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
ADJUNCTIVE BRIVARACETAM IN SUBJECTS (≥16 TO 80 YEARS OF AGE) WITH 
PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALIZATION 
 
SAP/Amendment Number Date 
Final SAP 
24 Nov 2017 
SAP Amendment 1 
03 Oct 2019 
SAP Amendment 2 
09 Jun 2022 
SAP Amendment 3 
17 Aug 2022 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................. 8 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 
Study objectives ............................................................................................................. 8 
2.1.1 
Primary objective ................................................................................................... 8 
2.1.2 
Secondary objectives ............................................................................................. 8 
2.2 
Study variables ............................................................................................................... 8 
2.2.1 
Efficacy variables .................................................................................................. 8 
2.2.1.1 
Primary efficacy variable ............................................................................ 8 
2.2.1.2 
Secondary efficacy variables ....................................................................... 8 
2.2.2 
Pharmacokinetic variable ....................................................................................... 8 
2.2.3 
Primary safety variables ........................................................................................ 9 
2.2.4 
Other safety variables ............................................................................................ 9 
2.3 
Study design and conduct .............................................................................................. 9 
2.3.1 
Study duration per subject ................................................................................... 10 
2.3.2 
Planned number of subjects and sites .................................................................. 10 
2.3.3 
Anticipated regions and countries ....................................................................... 11 
2.4 
Determination of sample size ....................................................................................... 11 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 11 
3.1 
General presentation of summaries and analyses ........................................................ 11 
3.1.1 
Statistics for BRV plasma concentrations ........................................................... 12 
3.2 
General study level definitions .................................................................................... 13 
3.2.1 
Analysis time points ............................................................................................ 13 
3.2.1.1 
Relative day ............................................................................................... 13 
3.2.2 
Study periods ....................................................................................................... 13 
3.2.3 
End of treatment value ......................................................................................... 14 
3.2.4 
Actual stratification level per CRF ...................................................................... 14 
3.3 
Definition of Baseline values ....................................................................................... 15 
3.4 
Important protocol deviations ...................................................................................... 15 
3.5 
Analysis sets................................................................................................................. 15 
3.5.1 
Enrolled Set ......................................................................................................... 15 
3.5.2 
Randomized Set ................................................................................................... 15 
3.5.3 
Safety Set ............................................................................................................. 15 
3.5.4 
Full Analysis Set .................................................................................................. 15 
3.5.5 
Per Protocol Set ................................................................................................... 16 
3.5.6 
Pharmacokinetic Per Protocol Set ....................................................................... 16 
3.6 
Treatment assignment and treatment groups ............................................................... 16 
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3.7 
Site pooling strategy .................................................................................................... 16 
3.8 
Coding dictionaries ...................................................................................................... 16 
3.9 
Definitions of study-specific derived variables ........................................................... 16 
3.9.1 
Lengths of study periods ...................................................................................... 16 
3.9.2 
Seizure frequency ................................................................................................ 17 
3.9.3 
28-day adjusted seizure frequency and log-transformed seizure frequency ........ 17 
3.9.4 
Seizure freedom during the Treatment Period ..................................................... 17 
3.9.4.1 
All epileptic seizures freedom ................................................................... 17 
3.9.4.2 
Partial seizures freedom ............................................................................ 18 
3.9.5 
Time to nth partial seizure .................................................................................... 18 
3.9.6 
Dose mapping for total daily BRV dose .............................................................. 18 
3.10 
Changes to protocol-defined analyses ......................................................................... 20 
3.11 
Consideration for COVID-19 ...................................................................................... 20 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 21 
4.1 
Adjustments for covariates .......................................................................................... 21 
4.2 
Handling of dropouts or missing data .......................................................................... 21 
4.3 
Interim analyses and data monitoring .......................................................................... 22 
4.4 
Multicenter studies ....................................................................................................... 22 
4.5 
Multiple comparisons/multiplicity ............................................................................... 22 
4.6 
Active-control studies intended to show equivalence .................................................. 22 
4.7 
Examination of subgroups ........................................................................................... 22 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 23 
5.1 
Subject disposition ....................................................................................................... 23 
5.1.1 
Overall subject disposition .................................................................................. 23 
5.1.2 
Disposition by investigator site ........................................................................... 25 
5.1.3 
Number of subjects completing each visit ........................................................... 25 
5.1.4 
Number of subjects by stratification levels ......................................................... 25 
5.2 
Important protocol deviations ...................................................................................... 26 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 26 
6.1 
Demographics .............................................................................................................. 26 
6.2 
Other Baseline characteristics ...................................................................................... 26 
6.2.1 
Epileptic seizure profile ....................................................................................... 26 
6.2.2 
Classification of epileptic syndrome ................................................................... 27 
6.2.3 
History of epileptic seizures ................................................................................ 27 
6.2.4 
Seizure types and frequency experienced during Baseline .................................. 27 
6.3 
Medical history and procedures ................................................................................... 28 
6.3.1 
Previous and ongoing medical history ................................................................. 28 
6.3.2 
Procedure history and concomitant medical procedures ..................................... 28 
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6.4 
History of previous AED use ....................................................................................... 28 
6.4.1 
Number of previous AEDs .................................................................................. 28 
6.4.2 
History of previous AEDs ................................................................................... 29 
6.4.3 
Previous AEDs by reason for AED discontinuation ............................................ 29 
6.4.4 
LEV status ........................................................................................................... 29 
6.5 
Concomitant medications............................................................................................. 29 
6.5.1 
Non-AEDs taken at study entry ........................................................................... 29 
6.5.2 
Number of AEDs taken at study entry ................................................................. 29 
6.5.3 
AEDs taken at study entry ................................................................................... 29 
6.5.4 
Concomitant AEDs .............................................................................................. 30 
6.5.5 
Use of vagal nerve stimulation at study entry ..................................................... 30 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 30 
8 
EFFICACY ANALYSES ................................................................................................ 31 
8.1 
Statistical analysis of the primary efficacy variable .................................................... 31 
8.1.1 
Primary efficacy variable ..................................................................................... 31 
8.1.2 
Primary analysis of the primary efficacy variable ............................................... 31 
8.1.3 
Supportive analyses of the primary efficacy variable .......................................... 32 
8.1.3.1 
Non-parametric analysis ............................................................................ 32 
8.1.3.2 
Per-protocol analysis ................................................................................. 33 
8.2 
Statistical analysis of the secondary efficacy variable(s) ............................................ 33 
8.2.1 
Percent reduction in partial seizure frequency ..................................................... 33 
8.2.2 
50% responder rate in partial seizure frequency .................................................. 33 
8.2.3 
Categorized percent reduction in partial seizure frequency................................. 33 
8.2.4 
Seizure freedom (partial, all epileptic seizure) .................................................... 34 
8.2.5 
Seizure frequency for all seizure types ................................................................ 34 
8.2.6 
Time to nth partial seizure .................................................................................... 34 
9 
PHARMACOKINETICS ................................................................................................. 35 
9.1 
BRV plasma concentrations ......................................................................................... 35 
10 SAFETY ANALYSES ..................................................................................................... 36 
10.1 
Extent of exposure ....................................................................................................... 36 
10.2 
Adverse events ............................................................................................................. 36 
10.2.1 
General summaries of AEs .................................................................................. 36 
10.2.2 
TEAEs of special interest .................................................................................... 38 
10.3 
Clinical laboratory evaluations .................................................................................... 38 
10.3.1 
Hematology, Biochemistry and Urinalysis parameters ....................................... 38 
10.3.2 
PDILI laboratory measurements .......................................................................... 38 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 39 
10.4.1 
Vital signs ............................................................................................................ 39 
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10.4.2 
Electrocardiograms .............................................................................................. 39 
10.4.3 
Electroencephalography ...................................................................................... 39 
10.4.4 
Computed tomography/ Magnetic resonance imaging ........................................ 39 
10.4.5 
Physical examination ........................................................................................... 40 
10.4.6 
Neurological examination .................................................................................... 40 
10.4.7 
Psychiatric and mental status ............................................................................... 40 
10.4.8 
Columbia-Suicide Severity Rating Scale ............................................................. 40 
11 REFERENCES ................................................................................................................ 41 
12 APPENDICES ................................................................................................................. 42 
12.1 
Actual BRV dose conversion table .............................................................................. 42 
12.2 
PCST criteria ................................................................................................................ 43 
12.2.1 
Laboratory assessments - PCST .......................................................................... 43 
12.2.1.1 
Hematology ............................................................................................... 43 
12.2.1.2 
Blood chemistry ........................................................................................ 43 
12.2.1.3 
Urinalysis ................................................................................................... 45 
12.2.2 
Vital sign assessments – abnormal ...................................................................... 46 
13 AMENDMENT TO THE STATISTICAL ANALYSIS PLAN (SAP) ........................... 49 
13.1 
Amendment 1 ............................................................................................................... 49 
13.2 
Amendment 2 ............................................................................................................... 49 
13.3 
Amendment 3 ............................................................................................................... 60 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 72 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
AED 
antiepileptic drug 
ANCOVA 
analysis of covariance 
BMI 
body mass index 
BRV 
brivaracetam 
CI 
confidence interval 
Concnorm 
Dose-normalized plasma concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DEM 
Data Evaluation Meeting 
ECG 
electrocardiogram 
EEG 
electroencephalography 
CRF 
case report form 
EDV 
Early Discontinuation Visit 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
IPD 
important protocol deviation 
KM 
Kaplan–Meier 
LEV 
levetiracetam 
LLOQ 
lower limit of quantification 
LTFU 
long-term follow-up 
MAP 
managed access program 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PBO 
placebo 
PCST 
possibly clinically significant treatment-emergent 
PDILI 
potential drug-induced liver injury 
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PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PPS 
Per-Protocol Set 
PT 
preferred term 
RS 
Randomized Set 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
VNS 
vagal nerve stimulation 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report (CSR). The SAP is based on the following study document: Protocol 
Amendment 4 (10 Jan 2020) and Protocol Amendment 4.1 (07 Feb 2020). 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
To evaluate the efficacy of brivaracetam (BRV) compared to placebo (PBO) as adjunctive 
treatment in subjects (≥16 to 80 years of age) with partial seizures with or without secondary 
generalization despite current treatment with 1 or 2 concomitant antiepileptic drugs (AEDs). 
2.1.2 
Secondary objectives 
The secondary objectives are to assess the safety and tolerability of BRV in subjects ≥16 years to 
80 years of age. 
2.2 
Study variables 
2.2.1 
Efficacy variables 
2.2.1.1 
Primary efficacy variable 
The primary efficacy variable is the partial seizure frequency per 28 days during the 12-week 
Treatment Period.  
2.2.1.2 
Secondary efficacy variables 
Secondary efficacy variables are as follows: 
• The 50% responder rate based on percent reduction in partial seizure frequency per  
28 days from Baseline to the 12-week Treatment Period 
• Percent reduction in partial seizure frequency per 28 days from Baseline to the 12-week 
Treatment Period 
• Categorized percent reduction in partial seizures frequency per 28 days from Baseline to the 
12-week Treatment Period 
• All seizure frequency (partial, generalized, and unclassified epileptic seizures) per  
28 days during the 12-week Treatment Period 
• Seizure freedom (partial, all epileptic seizures) during the 12-week Treatment Period 
• Time to nth (n=1, 5, 10) partial seizure during the 12-week Treatment Period  
2.2.2 
Pharmacokinetic variable 
The pharmacokinetic (PK) variable is BRV (parent compound only) plasma levels. 
 
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2.2.3 
Primary safety variables 
The primary safety variables are as follows: 
• Incidence of treatment-emergent adverse events (TEAE) 
• Incidence of TEAEs leading to study withdrawal 
• Incidence of treatment-emergent serious adverse events (SAEs) 
2.2.4 
Other safety variables 
The other safety variables are as follows: 
• Changes in clinical laboratory test parameters (blood chemistry, hematology, urinalysis) 
• Change in electrocardiogram (ECG) parameters and findings 
• Changes in vital signs [systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse 
rate] 
• Changes in body weight 
• Physical examination 
• Neurological examination 
• Mental status 
• Psychiatric status 
2.3 
Study design and conduct 
This is a randomized, double-blind, PBO-controlled, multicenter, therapeutic confirmatory study 
evaluating 2 doses of BRV. The subject population will be subjects (≥16 to 80 years of age) with 
partial seizures with or without secondary generalization. Subjects who are not legal adults will 
be included only where legally permitted and ethically accepted. 
Subjects will complete an 8-week prospective Baseline Period, followed by a 12-week Treatment 
Period. Subjects may be eligible for conversion to a long-term follow-up (LTFU) study or 
managed access program (MAP) upon completion of the Treatment and Transition Period. 
Subjects who are assigned to enter MAP but who cannot directly convert to MAP will be 
assigned to an Open-Label Temporary Period until the date when the subjects can convert to 
MAP.  There is a 4-week Down-Titration Period followed by a 2-week Study Drug-Free Period 
for subjects not entering the LTFU study or MAP. If BRV is commercially available upon 
subject completion of the Treatment and Transition Periods, subjects will receive BRV directly 
without entering the LTFU study or MAP.  
A 1:1:1 central randomization (random permuted blocks) stratified for country, levetiracetam 
(LEV) use (LEV naïve versus prior LEV use), and number of AEDs previously used but 
discontinued prior to study entry (≤2 versus >2 AEDs) will be used to ensure the balance across 
treatment groups (PBO, BRV 50mg/day, BRV 200mg/day) within each combination of 
stratification levels. Randomization will not be stratified by study center due to the expected 
small number of randomized subjects per study center.  
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No restrictions are placed on the proportion of randomized subjects within each stratification 
level, either overall or on a regional basis. 
2.3.1 
Study duration per subject 
Aside from the Open-Label Temporary Period, the total duration of the study will be up to 
approximately 26 weeks with a maximum 16-weeks exposure to BRV consisting of the 
following study periods: 
• Baseline Period (8 weeks) 
• Treatment Period (12 weeks) 
• Down-Titration Period (4 weeks) 
• Study Drug-Free Period (2 weeks) 
• Transition Period (2 weeks) (required for subjects participating in the LTFU study or MAP) 
• Open-Label Temporary Period (for subjects who are assigned to enter MAP but who cannot 
directly convert to MAP; starts after the end date of the Transition Period and continues until 
date when subject can convert to MAP, BRV is commercially available or until UCB decides 
to close the study) 
A schematic diagram of study periods is shown in Figure 2-1. 
Figure 2-1 Schematic diagram of study periods 
 
 
Ideally, visits should occur on the specified Visit/Week. A ±3 days 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. 
2.3.2 
Planned number of subjects and sites 
The planned number of evaluable subjects for the primary efficacy analysis is 444 (148 subjects 
per treatment group). The number of prior LEV use subjects will be limited to 30% of the total 
study population. Considering an anticipated screen failure rate of approximately 20%, 
approximately 555 subjects were to be screened. It is planned to have subjects recruited in 
approximately 95 sites. 
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2.3.3 
Anticipated regions and countries 
The study is being conducted in Japan, Taiwan, China Mainland, Philippines, Thailand, 
Singapore, and Malaysia.   
2.4 
Determination of sample size 
A total of 148 analyzable subjects per treatment group will provide 80% power to simultaneously 
detect differences between BRV treatment groups (BRV 50mg/day group and BRV 200mg/day 
group) and the PBO group at the 1-sided 0.025 significance level. The sample size assumes 
treatment differences of 0.221 and 0.285 in means on the log-transformed scale and a common 
SD of 0.66. The estimates of 0.221 and 0.285 correspond to reductions of 19.8% and 24.8% of 
BRV over PBO after back-transformation, respectively. The percent reduction of 24.8% is 
obtained from BRV 200mg/day in the N01358 study and assuming the LEV cap of 30% is 
reached overall. Based on a similar result from the Integrated Summary of Efficacy and again 
assuming the LEV cap of 30% is reached overall, a 19.8% reduction of BRV 50mg/day over 
PBO can be estimated. The SD of 0.66 is based on the observed SD from all treatment groups in 
N01358. The sample size calculation accounts for the correlation of the test statistics (same 
placebo group is compared to each BRV dose) as well as the planned Hochberg procedure. A 
total of 444 (148×3) analyzable subjects in the study is calculated as a target number. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be carried out using SAS® Version 9.3 or higher. Descriptive statistics, such as the number 
of subjects with available measurement (n), mean, SD, median, 25th percentile, 75th percentile, 
minimum value, and maximum value for quantitative variables, and counts and percentages for 
categorical variables, will be provided. Unless otherwise noted, denominator for percentages will 
generally be based on the set of subjects with at least 1 assessment at the time point or at least 1 
assessment during the time interval being summarized. 
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer 
• Mean, SD, median, 25th percentile and 75th percentile 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. 
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%. All 
statistical testing will be carried out at a two-sided 0.05 significance level unless otherwise 
indicated. P-values less than 0.0001 will be presented as “<0.0001” and p-values greater than 
0.9999 will be presented as “>0.9999”. The rounded value of p-values ≥0.0001 and ≤0.9999 will 
be displayed. P-values exactly equal to 1 should be shown as 1.0000. 
Summaries for disposition, important protocol deviations, demographics and other baseline 
characteristics, medical history, and prior and concomitant medications (AEDs and non-AEDs) 
will present results for individual treatment groups, for both BRV groups combined, and all 
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treatment groups combined. Summaries of seizure outcomes will present results for individual 
treatment groups only. Summaries of safety outcomes will present results for individual 
treatment groups and for both BRV groups combined. Summaries of IMP (including study 
medication duration, cumulative duration, and compliance) will present results for individual 
treatment groups and for both BRV groups combined.  Summaries of PK will present results for 
individual BRV treatment group only.   
Statistical outliers are defined as values that are discordant with other values and are clinically 
implausible. Exclusion of outliers from an analysis requires thorough justification based on 
statistical and clinical grounds. Any outliers will be reviewed during the data evaluation meeting 
(DEM) prior to database lock. Subject data listings will be provided and will present source data 
and key derived variables for statistical analyses. 
Generally, the Down-Titration Period follows the Treatment Period, but it is also possible that 
down-titration is carried out during the Transition Period or the Open-Label Temporary Period. 
In the cases of the down-titration during the Transition Period, it will be handled as same as that 
after the Treatment 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 (morning dose only) for one 
week should be included.  
Tables for the Open-Label Temporary Period will be created separately from those for other 
periods unless stated otherwise. 
All summary tables and figures will be presented overall and by Japan, unless stated otherwise. 
In addition, by-region subgroup analysis will be performed overall, by Japan, and by Non-Japan 
to the selected efficacy endpoints (see Section 4.7). 
3.1.1 
Statistics for BRV plasma concentrations 
For BRV plasma concentration (μg/mL) and daily dose-normalized (to 50mg) BRV plasma 
concentrations (Concnorm, in μg/mL), descriptive statistics include number of values, number of 
values above or equal to the lower limit of quantification (LLOQ), geometric mean, geometric 
95% confidence interval (CI), geometric coefficient of variation (CV), arithmetic mean, SD, 
median, minimum, and maximum. For the calculation of descriptive statistics, a BRV plasma 
concentration below LLOQ is substituted by LLOQ/2. 
• Concnorm is derived as follows; 
Concnorm =
Concentration × 25
Actual dose/administration (mg). 
• Geometric 100×(1- α/2)% CI is constructed using the following formula; 
[𝑒(𝑚−t(1−α/2,𝑛−1)×SD √𝑛,
⁄
), 𝑒(𝑚+t(1−α/2,𝑛−1)×SD √𝑛
⁄
)], 
where m and SD are the arithmetic mean and standard deviation of the log transformed BRV 
plasma concentrations for a time point, respectively. Furthermore t(1-α/2, n-1) is the 100×(1-
α/2) percentile of the t-distribution with n-1 degrees of freedom. 
Lower and upper limits of CI are presented using significant digits same as the corresponding 
geometric mean. 
• Geometric CV (%) is calculated using the following formula; 
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geometric CV(%) = √𝑒SD2 −1 × 100, 
where SD is the standard deviation from the log-transformed data. 
Geometric CV (%) is presented to one decimal place.  
 
3.2 
General study level definitions 
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 for 
days prior to the date of first dose of study drug, and the current date minus the date of first dose 
of study drug plus 1 for days on or after the date of first dose of study drug and prior to or on the 
day of last study drug dose (eg, the day of first dose will be Day 1 and the day prior to first dose 
will be Day -1). For days after the last dose of study drug (including Open-Label Temporary 
Period), relative day will be calculated as the current date minus the date of last dose of study 
drug and 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 dates. 
3.2.2 
Study periods 
All measurements will be classified into study periods as follows: 
Baseline Period 
From the date of Visit 1 prior to the date of Visit 3.  
Treatment Period 
From the date of Visit 3 until the day of Visit 7 in subjects who 
complete the Treatment Period; or EDV in subjects who 
discontinue treatment early prior to Visit 7. 
A subject is considered starting Treatment Period if the subject 
enters Visit 3 and is randomized.  If a subject does not have a 
Visit 7 or EDV date, then either the date of the last scheduled or 
unscheduled visit during the Treatment Period or the date of last 
known dose of IMP during the Treatment Period, whichever is 
later, will define the end date of the Treatment Period. 
Down-Titration Period 
From immediately after the last visit of the Treatment Period 
(Visit 7 or EDV) until Visit 8 for subjects who take any IMP 
during the Down-Titration Period. 
For subjects who enter the Down-Titration Period after the 
Transition Period without entering either LTFU study, MAP, or 
the Open-Label Temporary Period, it starts from immediately 
after the last visit of the Transition Period (Visit 8 Week 14).  
Study Drug-Free Period From immediately after the last visit of the Down-Titration 
Period until date of Safety Visit for subjects who enter the 
Down-Titration Period. 
Transition Period 
From immediately after the last visit of the Treatment Period 
(Visit 7 or EDV) until Visit 8 for subjects who take any IMP 
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during the Transition Period and who are scheduled to enter 
LTFU study, MAP or Open-Label Temporary Period. 
Open-Label Temporary 
Period 
This period is only applicable for subjects who cannot convert to 
MAP due to delayed importation of medication.  The period is 
defined from immediately after the last visit of the Transition 
Period (Visit 8) and until a visit when the subject can convert to 
MAP.   
3.2.3 
End of treatment value 
The “End of treatment” value for laboratory tests, vital signs and ECG is a value collected in the 
last visit including unscheduled visits during the treatment period.   
3.2.4 
Actual stratification level per CRF 
During the conduct of the randomization, some subjects with the stratification levels of LEV 
status or number of previous AEDs mistakenly entered to the IVRS system.  The actual 
stratification level will be derived according to the CRF data: 
The LEV status per CRF (LEV naïve vs prior LEV use) will be captured from the CRF form 
“History of Previous Antiepileptic Drug Treatment”. Subjects will be considered with prior LEV 
use if levetiracetam is captured in any preferred drug name in this CRF form. Otherwise, the 
subjects will be considered LEV naïve. 
The number of AEDs previously used but discontinued prior to study entry per CRF (≤2 vs >2 
AEDs) will also be captured from the CRF form “History of Previous Antiepileptic Drug 
Treatment” by counting the number of unique AED entered in this form.  However, if the same 
compound name is also entered in the CRF form “Prior and Concomitant Medications”, the drug 
is not counted as a previous AED because it is considered that the subject has taken the same 
AED concomitantly during the study.  This was instructed in the CRF completion instruction 
regarding how to count the number of previous AED at the randomization.   
The following AEDs will be considered the same AED at the group level while counting the 
number of previous AEDs:  
• Valproate includes valproate sodium, valproate semisodium, valproate bismuth, valproate 
magnesium, valpromide, ergenyl chrono, valproic acid.  
• Phenytoin includes phenytoin sodium, phenytoin calcium, mephenytoin, zentronal, 
metetoin, ethotoin, albutoin, hydantal, phelantin, hydantol D, anirrit, dintoinale, 
fosphenytoin sodium, phenytoin, fosphenytoin, hydantoin derivatives, hydantoin.  
• Phenobarbital includes phenobarbital sodium, methylphenobarbital, metharbital, alepsal, 
phenobarbital, kaneuron, epanal.  
• Benzodiazepine AEDs are grouped separately by bromazepam, alprazolam, cloxazolam, 
diazepam group, chlordiazepoxide, clonazepam, clobazam, lorazepam, clotiazepam, 
temazepam, and clorazepate.  
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3.3 
Definition of Baseline values 
Baseline values will be determined from the last non-missing data collected prior to the first dose 
of IMP, unless otherwise noted for a specific type of data. 
Baseline value for seizure frequency will be based on the 28-day adjusted seizure frequency 
calculated from daily record card (DRC) days over the Baseline Period.  For seizures occurred on 
the date of Visit 3 will be entered to Visit 3 or Visit 4 CRF form “Seizure Count” depending on 
whether the seizure occurred before or after the randomization time.  If the seizure occurred 
before the randomization, it would be entered to Visit 3 and counted as seizure at Baseline 
Period; if the seizure occurred after the randomization, it would be entered to Visit 4 and counted 
as seizure at Treatment Period.  The calculation of 28-day adjusted frequency is described in 
detail in Section 3.9.3.   
Baseline values for laboratory parameters, vital signs, body weight, and ECGs will be based on 
the latest scheduled or unscheduled assessment prior to or on the date of first administration of 
IMP. Baseline value will be determined separately for each individual clinical laboratory 
parameter for hematology, blood chemistry, and urinalysis assessments. 
3.4 
Important protocol deviations 
Important protocol deviations (IPDs) are deviations from the protocol that could potentially 
impact the interpretation of the study data. The criteria for identifying IPDs and the classification 
of IPDs will be defined separately in the Specifications for IPDs document. To the extent 
feasible, rules for identifying IPDs will be defined without review of the data and without 
consideration of the frequency of occurrence of such deviations. Whenever possible, criteria for 
identifying IPDs will be implemented algorithmically to ensure consistency in the classification 
of IPDs across all subjects. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) consists of all screened subjects who gave informed consent (and 
informed assent where required). Subjects who discontinued due to screen failure are included in 
the ES. This analysis set is referred to as “All Subjects Screened”. 
3.5.2 
Randomized Set 
The Randomized Set (RS) consists of all subjects who were randomized to treatment.  
3.5.3 
Safety Set 
The Safety Set (SS) will include all randomized subjects who received at least 1 dose of study 
medication. Safety analyses will be carried out using the SS. 
3.5.4 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least 1 dose 
of study drug and have at least 1 post-Baseline seizure daily record card (DRC) data during the 
Treatment Period. Both primary and secondary efficacy analyses will primarily be carried out 
using the FAS. 
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3.5.5 
Per Protocol Set 
The Per-Protocol Set (PPS) will consist of all subjects in the FAS who do not have any IPDs 
potentially impacting the primary efficacy variable. In order to verify the robustness of the 
efficacy results, the primary efficacy variable will also be analyzed using the PPS. 
3.5.6 
Pharmacokinetic Per Protocol Set 
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects who took at least  
1 dose of BRV and for whom at least 1 valid BRV plasma concentration-time record and dosing 
information are available. 
3.6 
Treatment assignment and treatment groups 
All analyses will be based on randomized treatment group. Incorrectly treated subjects will be 
evaluated during the blinded DEM to assess the potential impact of such cases and any special 
considerations for statistical analyses. In general, subjects will be analyzed according to the 
planned treatment dose for efficacy analyses and according to the actual treatment dose for safety 
and PK analyses. 
The labels used in presentations will be: 
• BRV 200mg/day 
• BRV 50mg/day 
• Placebo (or PBO) 
• All Subjects 
• Not randomized 
• All BRV (BRV 200mg/day + BRV 50mg/day) 
3.7 
Site pooling strategy 
The number of randomized subjects for most investigator sites is expected to be low. In general, 
it will not be feasible to adjust statistical analyses for site effect and there are no plans to present 
any study outcomes by site. No site pooling strategy is defined for this study.  
3.8 
Coding dictionaries 
Medical history and adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 18.1. Medications will be coded using the World 
Health Organization Drug Reference List (WHO-DRL) version SEP 2017. Medical procedures 
will not be coded. 
3.9 
Definitions of study-specific derived variables 
3.9.1 
Lengths of study periods 
Number of days in Baseline Period = date of day before Visit 3 – date of Visit 1.  
Note that the 0.5 day is attributed from the day of Visit 3 which is considered part of the 
Baseline Period, and 0.5 days from the day of Visit 1 which is also considered part of the 
Baseline Period 
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Number of days in Treatment Period = date of Visit 7 (or EDV) – date of Visit 3.  
Note that the first and last day of treatment period are considered as half days.  
A similar calculation formula to the Treatment Period is applied to other post-treatment periods.    
3.9.2 
Seizure frequency 
Each seizure code in the clinical database will be mapped to exactly 1 of the following codes 
based on the International League Against Epilepsy (ILAE) classification (1981): IA (IA1, IA2, 
IA3, and IA4), IB, IC, II (IIA, IIB, IIC, IID, IIE, and IIF) or III. 
With regard to cluster seizures, investigator sites are to report the number of cluster episodes 
rather than reporting the estimated number of individual seizures. Therefore, no imputation will 
be applied for the seizure counts corresponding to reports of cluster seizures. Namely, in all the 
efficacy analyses, each cluster episode will be counted as one seizure of reported seizure type. 
The total number of seizures for seizure type I (IA+IB+IC) and the total number of seizures for 
all seizure types (I+II+III) will be calculated across all DRC data over the study period being 
summarized. 
3.9.3 
28-day adjusted seizure frequency and log-transformed seizure 
frequency 
Twenty-eight day adjusted seizure frequency for partial seizures (seizure types IA+IB+IC), and 
for all seizure types (I+II+III) will be calculated for each study period by dividing the number of 
targeted seizures (partial seizures or all seizure types) by the number of days for which the DRC 
was completed for each study period, and multiplying the resulting value by 28. 
The above values for each study period will be transformed using the function log(x+1), where 
log represents the natural logarithm function.  
3.9.4 
Seizure freedom during the Treatment Period 
Seizure freedom is assessed for partial seizures and all epileptic seizures. 
3.9.4.1 
All epileptic seizures freedom 
Subjects are defined as all epileptic seizure-free during the Treatment Period if they meet all of 
the following criteria. 
1. The subject completed the Treatment Period, and  
2. The subject did not have any missing days in the DRC over the Treatment Period, and 
3. The subject did not report any seizures over the Treatment Period 
Specific algorithmic rules for each of the above are defined as follows: 
Criterion 1: A subject is defined as completing the Treatment Period if the subject completed all 
scheduled visits of Treatment Period (ie, Visit 4 to Visit 7). 
Criterion 2: A subject meets criterion 2 if no "Not Done" dates were reported from Visit 4 up to 
Visit 7 in the Seizure Counts CRF module.  
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Note that the CRF module for Visit 4 covers seizure records from the afternoon at the date of 
Visit 3 up to the morning at the date of Visit 4, and that the module for Visit 7 covers seizure 
records from the afternoon at the date of Visit 6 up to the morning at the date of Visit 7. 
Criterion 3: A subject meets criterion 3 if there are no records of seizures from Visit 4 up to Visit 
7 in the Seizure Counts CRF module with either a count >0 or a reported seizure code with an 
unknown or missing seizure count. 
3.9.4.2 
Partial seizures freedom 
Criteria 1 and 2 (see Section 3.9.4.1) are the same as for all epileptic seizure freedom. However, 
criterion 3 is modified to only include partial seizures.  
3. The subject did not report any partial seizures over the Treatment Period 
Criterion 3: A subject meets criterion 3 if there are no records of partial seizures from Visit 4 up 
to Visit 7 in the Seizure Counts CRF module with either a partial seizure frequency count >0 or a 
reported partial seizure code with an unknown or missing seizure count. 
3.9.5 
Time to nth partial seizure 
The evaluation of time to nth partial seizure is based on the relative day of occurrence of the nth 
partial seizure (n=1, 5, and 10) during the Treatment Period. Only seizure DRC data from the 
randomization up to and including the last visit of the Treatment Period will be considered. The 
algorithms described in Section 3.9.2 also apply to this analysis. 
The time to nth seizure will be calculated as the date of the nth partial seizure minus the date of 
randomization plus 1 day for subjects who have at least n partial seizures in the Treatment 
Period. Subjects with fewer than n partial seizures during this period will be addressed as 
follows: 
• Subjects who complete the Treatment Period will be analyzed as censored cases with date of 
censoring (ie, analyzed as non-events) based on the date of last dose of IMP during the 
Treatment Period. 
• Subjects who discontinue due to lack of efficacy during the Treatment Period will be 
analyzed as having the nth seizure (i.e. as an event) on the date of last dose of IMP during the 
Treatment Period. 
• Subjects who discontinue for reasons other than lack of efficacy during the Treatment Period 
will be analyzed as censored cases with date of censoring based on the date of last dose of 
IMP during the Treatment Period. 
For those cases, time to censoring or time to event will be calculated as the date of last dose of 
IMP during the Treatment Period minus the date of randomization plus 1 day. 
3.9.6 
Dose mapping for total daily BRV dose  
During the Treatment Period, subjects are to take 3 tablets twice per day (morning and evening) 
except for the first day where they will only take the evening dose, and the last day where they 
will only take the morning dose.  
The 3 tablets will consist of: 2 × 50mg BRV tablets and 1 × 25mg PBO tablet for subjects 
randomized to the BRV 200mg treatment group; 1 × 25mg BRV tablet and 2 × 50mg PBO 
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tablets for subjects randomized to the BRV 50mg treatment group; 2 × 50mg PBO tablets and 1 
× 25mg PBO tablet for subjects randomized to the PBO group, as shown in Table 3.1.  
Table 3.1: 
Doses of individual BRV and PBO tablets during the Treatment 
Period 
 
Individual tablet contents and dose (mg) 
Treatment group 
Morning 
Evening 
BRV 200mg/day 
BRV 50 BRV 50 PBO 25 BRV 50 BRV 50 PBO 25 
BRV 50mg/day 
PBO 50 
PBO 50 BRV 25 PBO 50 
PBO 50 BRV 25 
PBO 
PBO 50 
PBO 50 
PBO 25 
PBO 50 
PBO 50 
PBO 25 
During the Transition Period subjects are to take 2 tablets twice per day (morning and evening) 
except for the first day where they will only take the evening dose, and the last day where they 
will only take the morning dose. The 2 tablets will consist of: 1 × 50mg BRV tablet and 1 × 
25mg BRV tablet for subjects randomized to the BRV 200mg treatment group; 1 × 25mg BRV 
tablet and 1 × 50mg PBO tablet for subjects randomized to the BRV 50mg treatment group; 1 × 
50mg PBO tablet and 1 × 25mg PBO tablet for subjects randomized to the PBO group, as shown 
in Table 3.2.  
Table 3.2: 
Doses of individual BRV and PBO tablets during the Transition 
Period 
 
Individual tablet contents and dose (mg) 
Treatment group 
Morning 
Evening 
BRV 200mg/day 
BRV 50 
BRV 25 
BRV 50 
BRV 25 
BRV 50mg/day 
PBO 50 
BRV 25 
PBO 50 
BRV 25 
PBO 
PBO 50 
PBO 25 
PBO 50 
PBO 25 
During the Down-Titration Period in weeks 1 to 3 subjects are to take 2 tablets twice per day 
(morning and evening) except for the first day where they will only take the evening dose, and 
the last day where they will only take the morning dose.  In week 4 subjects will take 2 tablets in 
the morning only. The total dose of BRV will decrease each week, as shown in Table 3.3.  
Table 3.3: 
Doses of individual BRV and PBO tablets during the Down-Titration 
Period 
 
Individual tablet contents and dose (mg) 
Treatment group 
Morning 
Evening 
BRV 200mg/day 
 
 
 
 
BRV 150mg/day (Week1) 
BRV 50 
BRV 25 
BRV 50 
BRV 25 
BRV 100mg/day (Week 2) 
BRV 50 
PBO 25 
BRV 50 
PBO 25 
BRV 50mg/day (Week 3) 
PBO 50 
BRV 25 
PBO 50 
BRV 25 
BRV 25mg/day (Week4) 
PBO 50 
BRV 25 
- 
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Individual tablet contents and dose (mg) 
Treatment group 
Morning 
Evening 
BRV 50mg/day  
 
 
 
 
BRV 25mg/day (Week1) 
PBO 50 
BRV 25 
PBO 50 
PBO 25 
PBO (Week 2 & 3) 
PBO 50 
PBO 25 
PBO 50 
PBO 25 
PBO (Week 4) 
PBO 50 
PBO 25 
- 
PBO 
 
 
 
 
PBO (Week 1, 2 & 3)  
PBO 50 
BRV 25 
PBO 50 
PBO 25 
PBO (Week 4) 
PBO 50 
PBO 25 
- 
In the drug dosing log CRF the daily total blinded dose (BRV + PBO) is recorded. The appendix 
Section 12.1  describes how to determine the daily BRV dose and number of tablets taken using 
the total blinded dose for each treatment group. It should be noted that when a subject is on 
200mg BRV or 50mg BRV treatment and if subject takes less than the number of tablets per day 
they are supposed to take, it is unknown whether they missed an active or placebo treatment. It is 
assumed that the subject took the active treatment before PBO. For example, suppose a BRV 
200mg subject used 3 tablets on a study day during the Treatment Period, and this day was not 
their first or last day during the Treatment Period, it would be assumed that the subject used the 3 
× 50mg BRV tablets so would have a BRV quantity of 150mg BRV tablets.  
If a subject on 200mg BRV or 50mg BRV treatment exceeds the number of tablets per day they 
are supposed to take, it is assumed they begin retaking the tablets for the same study day, and it 
is assumed that the subject took active treatment before PBO for the additional tablets. For 
example, suppose a BRV 200mg subject used 7 tablets on a study day during the Treatment 
Period, and this day was not their first or last day during the treatment period, it would be 
assumed that the subject used the 4 × 50mg BRV tablets and 2 PBO tablets they were supposed 
to take on the study day, and an additional active treatment of 50mg so they would have a BRV 
quantity of 250mg BRV tablets. 
In the circumstance the daily total blinded dose as recorded on the CRF exceeds the maximum 
nominal dose as described in the appendix Section 12.1, it is assumed the subject took the active 
treatment for all additional dosage.  For example, suppose a BRV 200mg subject was recorded 
275 mg/day total daily dose during the treatment period on the CRF (exceeding the maximum 
dose of 200 mg/day during the treatment period), it would be assumed the subject took active 
200mg + 75 mg =275 mg/day.  
3.10 
Changes to protocol-defined analyses 
Not applicable 
3.11 
Consideration for COVID-19 
A new 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 in CRF form 
COVID-19 Impact: “Relationship to COVID-19” as: confirmed COVID-19 infection, suspected 
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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 5.1.3) to describe the impact due to COVID-19 will be 
performed.  
Summary and listing to describe the AE related to COVID-19 vaccination will be provided (see 
Section 10.2.1) 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
The subject randomization for this study is stratified by  
• country, and 
• LEV use (LEV naïve versus prior LEV use), and  
• number of prior AEDs (≤2 versus >2) based on AEDs previously used and discontinued 
prior to Visit 1.  
In this regard, the primary analyses based on ANCOVA will include an effect for treatment, an 
effect for country, and an effect for the 4 combinations of levels for LEV status and number of 
previous AEDs.  The actual stratification level (see Section 3.2.4) will be used for the primary 
analyses. Lower-enrolling countries will be pooled as described below.  
The primary analyses will also adjust for log-transformed 28-day adjusted Baseline partial 
seizure frequency as a continuous covariate. The adjustment for this covariate will account for 
any imbalance across treatment groups with respect to Baseline partial seizure frequency. 
To minimize the risk of issues due to data sparsity, any country with fewer than 20 subjects in 
the FAS population will be pooled with an appropriately selected country. Based on the number 
of enrolled subjects, it is concluded Taiwan, Singapore, and Malaysia will be combined together 
due to small number of participants in each country. 
4.2 
Handling of dropouts or missing data 
Seizure frequency will be computed over non-missing days in the DRC as described in Section 
3.9.3; missing seizure days in the DRC will not be considered in the calculation of seizure 
frequency. Generally, compliance with the DRC is expected to be high in a refractory population 
and, therefore, the impact of missing data in the DRC is expected to be minimal. However, the 
impact of missing data of DRC cannot be ruled out, and missing data will be assessed as part of 
the DEM prior to database lock to ensure an acceptable level of compliance with the seizure data 
in the DRC across the study population. 
For subjects who prematurely discontinue during the Treatment Period, the calculation of 28-day 
adjusted partial seizure frequency over the Treatment Period will be based on available seizure 
data in the DRC up to the time of last visit during the Treatment Period. This effectively imputes 
the unobserved seizure frequency after discontinuation with the seizure frequency observed prior 
to discontinuation. The potential impact of dropouts cannot be ignored; however, a low 
percentage of dropouts has generally been observed across BRV treatment groups in prior 
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studies of similar design for BRV with no clear dose-response with regard to either overall 
dropout rate or rate of dropout due to AEs.  
4.3 
Interim analyses and data monitoring 
No formal interim analyses are planned for this study.  Regular monitoring of safety data 
collected during clinical studies will be performed by medically qualified Sponsor personnel or 
equivalent designee(s).  
4.4 
Multicenter studies 
Study outcomes will not be assessed for individual investigator sites due to the expected low 
enrollment within each investigator site and because the subject randomization is not stratified 
by investigator site. Treatment by investigator site interactions will not be assessed. 
4.5 
Multiple comparisons/multiplicity 
This study can be considered positive if superiority of at least 1 of 2 active treatment groups to a 
control treatment group is demonstrated for a primary efficacy variable. It indicates that 
multiplicity of multiple comparisons of treatment groups should be controlled critically. 
Statistical testing will be based on the comparison of each BRV treatment group (BRV 50mg/day 
and 200mg/day) to PBO with control of overall type I error rate based on the Hochberg 
procedure. The Hochberg procedure does not require a pre-specified order of testing for BRV 
treatment groups versus PBO. In a setting with a comparison of 2 active treatment groups to 
PBO, the Hochberg procedure is applied by first testing the BRV treatment group with the larger 
2-sided p-value at 0.05 level. If statistical significance is achieved at this step, then the study is 
positive and both BRV treatment groups are declared statistically different from PBO. If the 
largest p-value is not significant at the 0.05 level, then the Hochberg procedure steps to the 
smaller p-value and tests at 0.025 level. If statistical significance is achieved at this step, then the 
study is positive and the BRV treatment group associated with the smaller p-value is declared 
statistically different from PBO. If the smaller p-value is not significant at the 0.025 level, then 
neither BRV treatment group is statistically different from PBO nor is the study positive.  
 
Significant level 
Unadjusted p-value 
Adjusted p-value 
Step 1 
0.05 
p1 (larger one) 
p1 
Step 2 
0.025 (=0.05/2) 
p2 (<p1) 
min (p1, p2×2) 
 
4.6 
Active-control studies intended to show equivalence 
Efficacy outcomes are based on superiority comparisons of each BRV treatment group to PBO; 
this section is therefore not applicable for this study. 
4.7 
Examination of subgroups 
Subgroup analysis will be conducted for the following efficacy outcomes: 
• Percent reduction in partial seizure frequency (per 28 days during the 12-week Treatment 
Period) over PBO based on ANCOVA 
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• 50% responder rate based on percent reduction in partial seizure frequency per  
28 days from Baseline to the 12-week Treatment Period 
• Percent reduction in partial seizure frequency per 28 days from Baseline to the 12-week 
Treatment Period 
The above selected efficacy outcomes will be evaluated for the following subgroup variables:  
• Gender 
• Categorized age (<17 years, 17 to <65 years, 65 years and older) 
• Country (Japan, China Mainland, Philippines, Thailand, Taiwan, Singapore, and Malaysia, 
where Taiwan, Singapore, and Malaysia will be combined together due to small number of 
participants in each country, see Section 4.1) 
• Region (Japan, non-Japan) 
• LEV use (LEV naive, prior LEV use) according to actual stratification level as per the CRF 
• Number of AEDs previously used but discontinued prior to study entry (≤2 versus >2) 
according to actual stratification level as per the CRF 
• AED inducer status (use of an inducer at study entry versus no inducer at study entry) 
The AED inducer will be captured according to the drug list provided by UCB.  
• Seizure type at Baseline (types IA, IB, and IC)  
Subjects who experience at least one type of IA, IB, and IC seizure, respectively, during the 
Baseline Period will be included in the analysis for that seizure type. Subjects may be 
classified into more than 1 subgroup based on their baseline seizure profile. 
All evaluations will be descriptive; neither statistical testing of treatment by subgroup 
interactions nor statistical testing of treatment effects within subgroups will be carried out. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
5.1.1 
Overall subject disposition 
Subjects will be allowed for rescreening if he or she failed the eligibility criteria at his/her first 
screening attempt. The number of screening events, screened subjects, number of screen failures 
and the primary reason for screen failure, number of rescreened and failed again and the primary 
reason for rescreening failure, and overall successfully screened subjects will be summarized for 
the ES.  
The overall summary of disposition for the RS will present the number and percentage of 
subjects for the categories described below. A patient will be regarded as completing a study 
period if he or she completed the last scheduled visit within the study period. All percentages 
will be relative to the number of subjects in the RS. 
Overall Disposition 
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• The number of subjects completing the double-blind part of the study (ie, the Treatment 
Period, the Down-Titration Period, Study Drug Free Period and the Transition Period) 
• The number of subjects discontinuing double-blind part of the study and the primary reason 
for discontinuation 
Treatment Period Disposition 
• The number of subjects completing the Treatment Period 
− The number of subjects completing the Treatment Period and entering the Down-
Titration Period 
− The number of subjects completing the Treatment Period and entering the Transition 
Period 
• The number of subjects discontinuing during the Treatment Period and the primary reason 
for discontinuation 
− The number of subjects discontinuing during the Treatment Period and entering the 
Down-Titration Period 
− The number of subjects discontinuing during the Treatment Period and not entering the 
Down-Titration Period 
Down-Titration Period Disposition 
• The number of subjects entering the Down-Titration Period 
• The number of subjects completing the Down-Titration Period  
A subject is considered completing the Down-Titration Period if this subject also completes the 
Study Drug Free Period.  
• The number of subjects discontinuing the Down-Titration Period and the primary reason for 
discontinuation  
Transition Period Disposition 
• The number of subjects entering the Transition Period 
• The number of subjects completed the Transition Period and transited to LTFU or MAP 
• The number of subjects discontinuing during the Transition Period and not entering the 
LTFU or MAP and the primary reason for discontinuation 
Open-Label Temporary Period Disposition 
• The number of subjects entering the Open-Label Temporary Period 
• The number of subjects discontinuing during the Open-Label Temporary Period and the 
primary reason for discontinuation 
Open-Label Temporary Period and MAP are not applicable to subjects enrolled in Japan and 
China. Percentages for Open-Label Temporary Period will be relative to the number of subjects 
entering the Open-Label Period in the RS. 
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In addition to the overall summary of disposition, the above will also be summarized by LEV 
status, and number of previous AEDs (≤2 versus >2) according to the actual stratification level as 
per the CRF.  
In order to meet the EudraCT reporting requirement, a summary table of discontinuation due to 
AEs will be provided.  
Subject disposition will be listed for all subjects screened and will include the following 
information: subject status (screen failure, completed or dropout), date of informed consent, date 
of randomization, dates of first and last dose of study medication, total days on study medication, 
and the date of final contact for the subject. Further discontinuation information will be listed for 
all subjects discontinued from the study including primary reason for discontinuation, period in 
which subjects discontinued, and dose as well as days on dose from which the subject 
discontinued. The listing will also include the date and reason for breaking the randomization 
code (if applicable). For screen failures the date and reason for screen failure will be listed 
instead of the last dose of study medication and the primary reason for discontinuation, 
respectively, for discontinued subjects.   
A subject data listing for rescreened subjects will also be prepared including previously assigned 
subject number, final subject number, screening status, date of informed consent, date of screen 
failure and reason for screen failure.   
5.1.2 
Disposition by investigator site 
An overview of the date of first subject in (earliest Visit 1), date of last subject out (latest 
scheduled or unscheduled visit), and the number of screened subjects will be summarized for all 
study sites, individual study site and country. Additionally, the number of randomized subjects 
and the number of subjects in each of the SS, FAS, PK-PPS and PPS will be summarized for all 
treatment groups combined and by treatment group for all study sites, study site and for country. 
5.1.3 
Number of subjects completing each visit 
The number and percentage of randomized subjects completing each scheduled visit will be 
summarized for the RS. EDVs that correspond to scheduled visits will be included in the counts 
for the scheduled visits to which they correspond. EDVs occurred before Visit 7 will be re-
mapped to the next scheduled visit.   
A subject data listing including treatment group, study period, visit number, visit label, visit date, 
and relative day will be prepared for the RS.   
A separate table presenting the impact of COVID-19 for any reason will be summarized by 
impact category and timepoint (visits and non-visit events) for all randomized subjects. Subject 
will be counted more than once if the subject has multiple impact categories at each timepoint. 
A subject data listing including visit, date, relationship to COVID-19, impact category and 
narrative of event will be presented for the RS.   
5.1.4 
Number of subjects by stratification levels  
The number and percentage of randomized subjects for each level of LEV status (never used 
LEV versus prior LEV use only), and number of AEDs previously used but discontinued prior to 
study entry (≤2 versus >2) will be summarized overall per the data entered in IVRS system and 
per the actual levels according to the CRF data, separately. 
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The number and percentage of randomized subjects with discrepancies between the IVRS 
stratification and the actual stratification levels identified on the CRF will be summarized for 
LEV status and number of previous AEDs. 
Additionally, the number and percentage of randomized subjects by country will be summarized. 
5.2 
Important protocol deviations 
The number and percentage of randomized subjects with at least 1 IPD will be summarized 
overall and by main category of protocol deviation for randomized subjects. Specific categories 
of protocol deviations will be defined within the IPD. 
The assignment of subjects to each of the analysis sets will be listed for the ES. In addition, IPDs 
will be listed as well as whether it excluded the subject from the per-protocol analysis based on 
the RS. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized by treatment group, over all 
subjects on BRV treatment and over all subjects. Unless otherwise specified, tables will be 
provided for the FAS and listings will be done for the ES.  
6.1 
Demographics 
Age in years will be calculated based on date of informed consent and an incomplete birth date 
assuming birth on the first day of the month (yyyy-mm-01). Weight will be summarized at Visit 
1 and body mass index (BMI) will be calculated using the following formula with the subject 
weight recorded at Visit 1. 
BMI ( kg m2
⁄
)= weight (kg) height2
⁄
(m) 
Tables with descriptive statistics for the FAS as well as the SS and listings for the ES will be 
given for the demographic variables: age, categorized age [(the 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) and 
(clinicaltrials.gov; ≤18, 19 to <65 and ≥65 years)], gender, race (ie, racial group) , ethnicity, 
ethnic subgroup, countries, height, weight, BMI, categorized BMI (<18.5, 18.5 to <25, 25 to 
<30, 30 to <40, ≥40), and AED inducer status. 
No tables will be presented for childbearing potential/birth control. A subject data listing will 
cover gender, subject of childbearing potential/fertile (yes/no), method of birth control, and 
reason not of child-bearing potential/fertile. 
6.2 
Other Baseline characteristics 
6.2.1 
Epileptic seizure profile 
The number and percentage of subjects experiencing each seizure type at any time prior to study 
entry will be summarized based on the ILAE classification (1981) (see protocol Appendix). 
The overall number and percentage of subjects with a history of type I, II and III seizures will be 
summarized with their subclasses. A subject will be classified as having a history of type I 
seizures if the subject has a history of IA, IA1, IA2, IA3, IA4, IB, IB1, IB2, or IC seizures. A 
subject will be classified as having a history of type II seizures if the subject has a history of IIA, 
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IIB, IIC, IID, IIE, or IIF seizures. A listing will include the historical seizure types based on the 
ILAE classification. 
6.2.2 
Classification of epileptic syndrome 
Classification of epileptic syndrome will be summarized based on the classifications of epilepsy 
and epileptic syndrome (ILAE, 1989) (see protocol Appendix). An appropriate listing will be 
done. 
6.2.3 
History of epileptic seizures 
History of epileptic seizures will summarize whether history or presence of status epilepticus 
during the year preceding Visit 1 or during Baseline Period, whether at least 2 partial seizures 
per month were experienced during the 3 months before Visit 1, epilepsy duration in years, age 
at time of first seizure in years, and percent of life with epilepsy. A listing reflecting epilepsy 
duration in years, age at time of first seizure in years, and percent of life with epilepsy will be 
provided in addition. 
Epilepsy Duration 
Epilepsy duration is the number of years from the first date of diagnosis of epilepsy to the date of 
informed consent.  
The epilepsy duration (years) will be derived as the date of informed consent minus the date of 
the first diagnosis (yyyy-mm-01), which is similar to the derivation of age. For subjects who 
only have a year of the diagnosis date, the date of January 1 will be assumed. If an imputed date 
of the diagnosis is less than the date of birth due to the application of imputation rules, then set 
epilepsy duration equal to the subject’s age. No imputation will be done for completely missing 
diagnosis date and epilepsy duration will not be calculated for subjects with completely missing 
diagnosis date. 
Age at Time of First Seizure 
Calculated in the same manner as age, but using the date of first diagnosis of epilepsy in place of 
the date of informed consent.  
For partial dates of birth and first diagnosis of epilepsy, imputation rules are applied. If an 
imputed date of first diagnosis of epilepsy is less than the date of birth due to the application of 
imputation rules, then set the date of first diagnosis of epilepsy to the date of birth. For 
completely missing dates of first diagnosis of epilepsy, no imputation will be done and age at 
time of first seizure will not be calculated. 
Percent of Life with Epilepsy 
Percent of life with epilepsy will be calculated as 100 times epilepsy duration divided by the 
subject’s age which is calculated based on date of informed consent. Based on defined rules it 
should not be possible to have a calculated percent of life with epilepsy that is either <0% or 
>100%. 
6.2.4 
Seizure types and frequency experienced during Baseline 
The number and percentage of subjects who experienced each seizure type during the Baseline 
Period will be presented for FAS in the same way as epileptic seizure profile in the Section 6.2.1. 
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In addition, 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 using FAS. 
Summaries will be presented for separate types IA, IB, IC and for overall type I. 
6.3 
Medical history and procedures 
6.3.1 
Previous and ongoing medical history 
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 overall and by MedDRA 
primary system organ class (SOC) and preferred term (PT) according to the SS. A listing of 
subjects with previous and ongoing medical history will be provided. A separate listing of 
medical history glossary which represent mapping of reported terms to PTs and SOCs based on 
the MedDRA coding dictionary will also be provided. 
6.3.2 
Procedure history and concomitant medical procedures 
Listings of subjects with procedure history for the ES and concomitant medical procedures in the 
RS will be provided, separately. 
6.4 
History of previous AED use 
Previous AEDs are AEDs taken and discontinued prior to study entry.  The history of previous 
AED will be recorded in accordance with the list of AEDs as indicated in Appendix 3 of the 
study protocol.  However, investigator’s judgement will be prioritized and taken into 
consideration.  Summaries in this section will be based on the History of Previous AED 
Treatment CRF which includes only AEDs stopped prior to study entry.  
For summaries by preferred drug name, some AEDs will be grouped as follows (same grouping 
rules in Section 3.2.4): 
Valproate includes valproate sodium, valproate semisodium, valproate bismuth, valproate 
magnesium, valpromide, ergenyl chrono, valproic acid.  
Phenytoin includes phenytoin sodium, phenytoin calcium, mephenytoin, zentronal, metetoin, 
ethotoin, albutoin, hydantal, phelantin, hydantol D, anirrit, dintoinale, fosphenytoin sodium, 
phenytoin, fosphenytoin, hydantoin derivatives, hydantoin.  
Phenobarbital includes phenobarbital sodium, methylphenobarbital, metharbital, alepsal, 
phenobarbital, kaneuron, epanal.  
Benzodiazepine AEDs are grouped separately by bromazepam, alprazolam, cloxazolam, 
diazepam group, chlordiazepoxide, clonazepam, clobazam, lorazepam, clotiazepam, temazepam, 
and clorazepate.  
Other combination AEDs are not considered for grouping. 
In addition to the following summary tables, a corresponding subject data listing will be 
provided. 
6.4.1 
Number of previous AEDs 
The number of previous AEDs will be summarized based on the following categorization: 0-1, 2-
4, and ≥5 AEDs. When counting the number of previous AED from the CRF form “History of 
Previous Antiepileptic Drug Treatment”, if the same compound name is also entered in the CRF 
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form “Prior and Concomitant Medications”, the drug is not counted as a previous AED (see 
Section 3.2.4). 
6.4.2 
History of previous AEDs 
The number and percentage of subjects who had taken at least 1 AED prior to study entry will be 
summarized overall and by preferred drug name.  
6.4.3 
Previous AEDs by reason for AED discontinuation 
The number and percentage of subjects by reason for discontinuation of previous AEDs 
(insufficient efficacy, adverse drug reaction, tachyphylaxis, remission, other, unknown) will be 
summarized. Percentages for each reason for discontinuation will be relative to the number of 
subjects taking each AED.  
6.4.4 
LEV status 
LEV status (LEV naïve or prior LEV use) will be summarized. Subject is considered LEV naïve 
if he/she has never taken LEV.  Prior LEV use means the subject has taken LEV at any time 
prior to Visit 1 and discontinued prior to Visit 1. 
6.5 
Concomitant medications 
Summaries in this section will be based on the CRF form “Prior and Concomitant Medications 
(including AEDs)”. In addition to the following summary tables, a corresponding subject data 
listing will be provided with a glossary of medications which represents mapping of reported 
terms to WHO DRL pharmacological group and preferred drug name. The glossary list will 
cover medications found not only in prior and concomitant medications but also in previous 
AEDs. 
Prior medication is defined as any medication (including AEDs) with end date prior to the first 
administration of study medication. 
Concomitant AEDs (including AEDs taken at study entry) 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.   
Medications taken at study entry are the ongoing medications at the study entry (Visit 1).   
6.5.1 
Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AED medications at the time of study entry 
will be summarized by WHO-DRL pharmacological group and preferred drug name according to 
the SS. 
6.5.2 
Number of AEDs taken at study entry 
The number and percentage of subjects taking 1, 2, and ≥3 AEDs at the time of study entry will 
be summarized overall and separately by VNS status at study entry (no VNS or VNS not active 
versus currently active VNS). 
6.5.3 
AEDs taken at study entry 
AEDs taken at the time of study entry will be summarized by WHO-DRL preferred drug name.  
The AEDs will be grouped in the same way as indicated in Section 6.4. 
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6.5.4 
Concomitant AEDs 
Concomitant AEDs are AEDs that were taken during the study on/after the first dose of IMP, 
regardless of the start and stop date of the AED. The number and percentage of subjects taking 
concomitant AEDs will be summarized by WHO-DRL preferred drug name.  
6.5.5 
Use of vagal nerve stimulation at study entry 
Use of vagal nerve stimulation (VNS) will be identified from the VNS Status at Baseline CRF 
module. The number and percentage of subjects with an active VNS and the number and 
percentage of subjects with no VNS implant or a non-active VNS implant will be summarized. 
All other VNS data at study entry (eg, VNS settings) will be provided in subject data listings. 
 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
IMP compliance (%) will be calculated according to the definition shown in the formula below;  
Compliance(%) = 100 ×
Number of tablets taken
Number of tablets that should have been taken 
In general, for a duration where the number of tablets which should be taken per day is constant, 
the compliance is represented as follows; 
Compliance(%) = 100 ×
(Number of tablets dispensed) −(Number of tablets returned)
(Number of tablets per day) × (Number of days in the duration) 
If a period where the number of tablets which should be taken per day may not be constant, the 
compliance will be calculated as a weighted sum of compliance of each duration weighted by 
length of the duration.  
Compliance(%) = 100 × ∑(𝐶𝑖× 𝑊𝑖)
𝑖
, 
where i represents a duration with a constant number of tablets per day, 
𝐶𝑖=
(Number of tablets dispensed for 𝑖)-(Number of tablets returned for 𝑖)
(Number of tablets per day for 𝑖) × [(End date of 𝑖) −(Start date of 𝑖)],  
𝑊𝑖=
(End date of 𝑖) −(Start date of 𝑖)
(End date of Period) −(Start date of Period). 
Note that the first and last day of treatment are considered as half days because the start day of 
each duration will contribute evening only and the last day of it will contribute morning only.  
For a period where treatment is double-blind, the number of tablets which should been taken per 
day is defined in Table 3.1, Table 3.2 and Table 3.3.  
For instance, total planned tablet number during the Treatment Period will be calculated as 6 
times the number of days from the first dose of IMP (Visit 3) up to the last visit in the period 
(EDV for early discontinuers, Visit 7 otherwise).  
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Compliance for Treatment Period (%)
= 100 × (Number of tablets dispensed)-(Number of tablets returned)
6 × [(Date of EDV or Visit 7) −(Date of Visit 3)]
 
For the overall compliance which consists of the Treatment Period and either the Transition 
Period or the Down-Titration Period, the denominator of the formula for Wi is represented as 
[(the latest date of EDV, Visit 7 and Visit 8) − (Date of Visit 3)]. 
For the Open-Label Temporary Period, Ci can be applied for the above formula as only BRV 
25mg tablet will be used. 
𝐶𝑖=
(Number of tablets dispensed)-(Number of tablets returned)
(Daily Dose)
25
× [(End date of Visit 𝑖) −(Start date of Visit 𝑖)]
  
Note that end date of visit i is the same as the start date of visit i+1.  
Compliance will be summarized for the SS with quantitative descriptive statistics by treatment 
group and overall for the Treatment, Transition, Down-titration Periods and overall periods 
except Open-Label Temporary Period, which will be summarized separately only for the entire 
population. Additionally, the number and percentage of subjects with compliance levels <80%, 
80% to 120%, and >120% will be summarized as well. 
Compliance for each period will be listed for each subject. 
8 
EFFICACY ANALYSES 
Unless otherwise indicated, all efficacy analyses will be carried out for the FAS. 
Unless otherwise specified, statistical testing for supportive and secondary analyses will be 
carried out at a nominal two-sided 0.05 significance level without multiplicity adjustment. 
8.1 
Statistical analysis of the primary efficacy variable 
8.1.1 
Primary efficacy variable  
The primary efficacy variable is the partial seizure frequency per 28 days during the 12-week 
Treatment Period. The details regarding the calculation of standardized seizure frequencies are 
provided in Sections 3.9.1, 3.9.2, and 3.9.3. 
8.1.2 
Primary analysis of the primary efficacy variable 
The primary efficacy outcome will be the percent reduction in partial seizure frequency per 28 
days during the Treatment Period of each BRV treatment individually over PBO. 
The primary analysis will be based on ANCOVA with log-transformed [log(x+1)] Treatment 
Period 28-day adjusted partial seizure frequency as the outcome and an effect for treatment, an 
effect for country, and an effect for the 4 combinations of actual stratification levels for LEV 
status and number of previous AEDs (≤2 versus >2) according to the CRF data (see Section 
3.2.4), and log-transformed 28-day adjusted Baseline partial seizure frequency as a continuous 
covariate. Lower enrolling countries will be pooled for this analysis as described in Section 4.1. 
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Statistical treatment group comparisons will be based on the comparison of each BRV treatment 
group to PBO on the log-transformed scale using the above ANCOVA model. The evaluation of 
statistical significance will be based on the Hochberg multiple comparison procedure as 
described in Section 4.5. Both multiplicity-adjusted and unadjusted p-values will be presented. 
Treatment effects will be characterized using percent reduction over PBO based on back 
transformation of least squares (LS) means obtained for each treatment group from the above 
ANCOVA model. Percent reduction will be calculated using the following formula, where LS 
Mean (PBO) is the LS mean for the PBO treatment group and LS Mean (BRV) is the LS mean 
for either the BRV 50mg/day or BRV 200mg/day treatment group:  
 
 
The following formula is equivalent to the above: 
 
Two-sided 95% CIs for the comparison of each BRV treatment group to PBO will also be 
obtained using the above ANCOVA model. Confidence limits will be back-transformed using 
the above formula to obtain confidence limits for percent reduction over PBO. Confidence limits 
will not be adjusted for multiplicity and will correspond to a nominal two-sided 0.05 significance 
level. 
During the conduct of the randomization, some subjects with the stratification levels mistakenly 
entered to the IVRS system and a sensitivity analysis will be performed to assess the impact due 
to this error.  The sensitivity analysis will be conducted to the primary efficacy variable using the 
similar ANCOVA model with log-transformed [log(x+1)] Treatment Period 28-day adjusted 
partial seizure frequency as the outcome and an effect for treatment, an effect for country, and an 
effect for the 4 combinations of stratification levels for LEV status and number of previous 
AEDs (≤2 versus >2) according to the IVRS data, and log-transformed 28-day adjusted Baseline 
partial seizure frequency as a continuous covariate.    
8.1.3 
Supportive analyses of the primary efficacy variable 
8.1.3.1 
Non-parametric analysis 
A non-parametric ANCOVA will be carried out to assess the robustness of the parametric 
ANCOVA results. The following steps will be applied to perform this analysis: 
1. Baseline and Treatment Period 28-day adjusted partial seizure frequency will each be ranked 
across subjects in the PBO and BRV 50mg/day treatment groups 
2. A regression of ranked Treatment Period partial seizure frequency versus ranked Baseline 
partial seizure frequencies will be performed using the ranked values from Step 1 
3. A Mantel-Haenszel test to assess difference in row-mean scores will be applied to the 
residuals from Step 2 
4. The above steps will be repeated for the comparison of BRV 200mg/day versus PBO. 
Mean(PBO)]
 
exp[LS
Mean(BRV)]
 
exp[LS
Mean(PBO)]
 
exp[LS
100
 
PBO
/ 
Reduction 
 
%
−

=


Mean(PBO)]
 
LS
Mean(BRV)
 
exp[LS
1
100
 
PBO
/ 
Reduction 
 
%
−
−

=
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8.1.3.2 
Per-protocol analysis 
The primary efficacy variable will be analyzed for the PPS for the percent reduction over PBO 
based on ANCOVA as described in Section 8.1.2. 
8.2 
Statistical analysis of the secondary efficacy variable(s) 
8.2.1 
Percent reduction in partial seizure frequency 
Percent reduction from Baseline to the Treatment Period in partial seizure frequency will be 
calculated by subtracting 28-day adjusted Treatment Period partial seizure frequency [A] from 
28-day adjusted Baseline Period partial seizure frequency [B], and multiplying the resulting 
quantity by 100 and dividing by the Baseline Period 28-day adjusted partial seizure frequency. 
%Reduction = 100 ×
[B] −[A] 
[B]
 
Percent reduction in partial seizure frequency from Baseline to the Treatment Period as well as 
[A], [B] and [B]-[A] will be summarized with quantitative descriptive statistics. Statistical 
comparisons between each BRV treatment group and PBO will be based on a Wilcoxon-Mann-
Whitney test. Hodges-Lehmann non-parametric effect estimates and corresponding two-sided 
95% CIs will be provided for the effect difference between each BRV treatment group versus 
PBO. 
Plots displaying the complementary cumulative distribution function for percent reduction from 
Baseline to the Treatment Period will be provided. 
8.2.2 
50% responder rate in partial seizure frequency 
The 50% responder outcome will be evaluated based on percent reduction in partial seizure 
frequency per 28 days from Baseline to the Treatment Period. A subject with at least a 50% 
reduction in 28-day adjusted partial seizure frequency is classified as a responder.  
50% Responder Rate (%) =
Number of 50% responders
Number of subjects in the analysis set × 100 
The number and rate (%) of the responders for each treatment group will be summarized with the 
corresponding 95% CI for the rate. The CIs will be calculated by an exact method for the 
binomial distribution (ie, Clopper-Pearson interval). 
Statistical comparisons between each BRV treatment group and PBO will be conducted with 
logistic regression (based on Firth's penalized maximum likelihood inferences). The logistic 
regression analysis will be done for the event (50% reduction or more) with the predictors 
described in Section 8.1.2. If the model does not converge or does not produce the estimates, the 
covariates may be modified. An odds ratio of BRV/PBO for each BRV treatment group will be 
estimated with its profile-likelihood 95% CI. Both multiplicity-adjusted and unadjusted p-values 
for the Wald chi-square test for treatment effect will be given. 
In addition, 50% responder outcome will be evaluated for the PPS as described above.  
8.2.3 
Categorized percent reduction in partial seizure frequency 
The number and percentage of subjects within each of the following categories of percent 
reduction in partial seizure frequency from Baseline to the Treatment Period will be summarized 
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for each treatment group: <-25%, -25% to <25%, 25% to <50%, 50% to <75%, 75% to <100%, 
and 100%. Statistical comparisons between each BRV treatment group and PBO will be based 
on a Mantel-Haenszel test for the comparison of row mean scores. 
8.2.4 
Seizure freedom (partial, all epileptic seizure) 
Seizure freedom will be assessed separately for partial seizure and for all epileptic seizure. 
A subject is defined as all epileptic seizure free over the Treatment Period if they meet all of the 
following criteria. 
1. The subject completed the Treatment Period 
2. The subject did not have any missing days in the DRC during the Treatment Period, and  
3. The subject did not report any seizures during the Treatment Period 
The algorithm rules for all epileptic seizure freedom are described in Section 3.9.4.1. 
The number and percentage of subjects who are seizure free for partial seizure and for all seizure 
types over the Treatment Period will be summarized.  
Additionally, the number and percentage of subjects who met each individual criterion will be 
summarized, irrespective of whether the other criteria were met. Furthermore, the number and 
percentage of subjects meeting criteria 2 and 3 but not meeting criterion 1 (ie, subjects without 
seizures and without missing days in the DRC but discontinued) will be summarized.  
Seizure freedom rates for all seizure types will be compared between each BRV treatment group 
and PBO using Fisher’s Exact Test. 
The analysis above will be repeated for partial seizure instead of all epileptic seizure (also refer 
to Section 3.9.4.2). 
8.2.5 
Seizure frequency for all seizure types 
Estimates of percent reduction over PBO and odds ratios for 50% responder rates and 
corresponding two-sided 95% CIs for seizure frequency for all seizure types (I+II+III) will be 
provided based on the statistical methodology described in Section 8.1.1, Section 8.1.2 and 
Section 8.2.2. Additionally, percent reduction from Baseline in seizure frequency for all seizure 
types will be analyzed as described in Section 8.2.1. Statistical treatment group comparisons will 
also be provided as described in these sections. In addition, seizure frequency will be listed by 
subject, study period and seizure type. The data from the DRC will also be listed by subject and 
study period. 
8.2.6 
Time to nth partial seizure 
The algorithm rules for time to nth partial seizure are described in Section 3.9.5. 
Median time to nth seizure and corresponding 95% CIs will be provided based on Kaplan–Meier 
(KM) estimation. KM plots will be provided for time to nth partial seizure (n=1, 5, 10). 
Time to nth partial seizure will be compared between each BRV treatment group and PBO using 
a semi-parametric proportional hazards regression model with an effect for country, an effect for 
the 4 combinations of actual stratification levels for LEV status and number of previous AEDs 
(≤2 versus >2) per the CRF data, and log-transformed Baseline partial seizure frequency as a 
continuous covariate. Significance probabilities (ie, p-values) and hazard ratios and 
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corresponding two-sided 95% CIs will be presented for the comparison of each BRV treatment 
group to PBO. Lower enrolling countries will be pooled for this analysis as described in Section 
4.1.  
9 
PHARMACOKINETICS  
In addition to the following analyses for PK, population PK and/or PK/PD analyses will be 
considered as needed and described in a separate data analysis plan. 
9.1 
BRV plasma concentrations 
The daily dose information for PK analysis will be calculated according to the “Last Dosage 
Amount” from the CRF form: “BRV Plasma Level Monitoring”: 
• If the last dosage amount is 25mg/dose, the total daily dose will be 50mg/day 
• If the last dosage amount is 100mg/dose, the total daily dose will be 200mg/day 
• In case the subjects enter the Transition Period (Visit 8), the last dosage amount can be 
75mg/day and the total daily dose will be 150mg/day.  
Descriptive statistics in Section 3.1.1 for BRV observed plasma concentrations are computed per 
defined time window post-dose (>0-4 hours, >4-8 hours, and >8 hours, based on the date and 
time of last intake of IMP prior to blood sampling) for all PK-PPS by actual dose given before 
each blood sampling for PK and dose normalized BRV plasma concentrations are computed for 
all doses with the same manner. The statistics are calculated only if at least 2/3 of the individual 
data at a specific sampling point are above or equal to the LLOQ. 
Figures of the geometric means of BRV observed concentrations versus median time are 
presented by actual dose given before each blood sampling for PK and by visit.  Median time 
will be calculated separately by each time window post-dose (>0-4 hours, >4-8 hours, and >8 
hours). Daily dose normalized (to 50mg) BRV plasma concentrations will be presented with the 
same manner. 
Figures of individual observed BRV plasma concentrations versus time after the last intake of 
IMP prior to blood sampling will be presented by actual dose given before each blood sampling 
for PK and by visit. Dose normalized (to 50mg) BRV plasma concentrations will be presented 
with the same manner. 
Furthermore, above analyses are repeated for Japanese and Non-Japanese.  
A subject data listing of BRV Plasma Concentration Monitoring covers 
• Treatment Group  
• Site-Subject Number 
• Gender/Age(years)/Race/Weight(kg) 
• Visit 
• Not Done (with a flag ‘ND’) 
• Last dose of study medication prior to Blood Sampling: (Datetime) (yyyy-mm-
ddThh:mm)/Relative Day 
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• Blood Sampling Datetime (yyyy-mm-ddThh:mm:ss)/Relative Hours to Last Medication 
• Last Dose (mg/day) 
• Plasma BRV Concentration (μg/mL) 
• Time Window [>0-4 hours, >4-8 hours, and >8 hours post dosing] 
• Dose Normalized Plasma Level (μg/mL/50mg): equivalent to 50mg/day  
10 
SAFETY ANALYSES 
Safety is assessed with AEs, laboratory tests (blood chemistry, hematology, urinalysis, and 
pregnancy test), vital signs, body weight, ECGs, physical examination, neurological 
examination, mental status, and psychiatric status. Summary tables will be provided for AEs; 
blood chemistry, hematology, and urinalysis; vital signs; body weight; and ECGs. No summary 
tables will be provided for pregnancy testing, physical examination, neurological examination, 
mental status, or psychiatric status. 
All safety summaries will be based on the SS. 
Regarding safety for the Open-Label Temporary Period, it will be summarized separately from 
other preceding study periods as described in Section 3.2.2. 
10.1 
Extent of exposure 
The duration of study medication exposure for the Treatment Period will be calculated as the 
date of last dose of IMP during the Treatment Period minus the date of first dose of IMP plus 1 
day. The overall duration of study medication exposure for the entire study will be calculated as 
the date of last dose of IMP minus the date of first dose of IMP plus 1 day. 
The duration of study medication exposure and the overall duration of IMP exposure will be 
summarized with quantitative descriptive statistics for the Treatment Period and for the entire 
study (except the Open-Label Temporary Period), respectively, for the SS. The number and 
percentage of subjects with the following categories of durations of study medication exposure 
for the Treatment Period and the entire study will also be summarized:>0 weeks, >=2 weeks, 
>=4 weeks, >=6 weeks, >=8 weeks, >=10 weeks, and >=12 weeks.  
10.2 
Adverse events 
TEAEs are defined as AEs which had onset on or after the first dose of IMP. 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 or after the month and year of the first dose of IMP 
or the year of onset (when only year is specified) is the same as or after the year of first dose of 
IMP. 
AEs are classified by study period as described in Section 3.2.2.  
10.2.1 
General summaries of AEs 
An overall summary of TEAEs will provide the overall number of TEAEs and the numbers and 
percentages of subjects with at least 1 TEAE, with a TEAE that led to permanent discontinuation 
of study drug, with a TEAE leading to withdrawal from study, with a TEAE requiring dose 
change, with a drug-related TEAE, with a severe TEAE, and with a treatment-emergent serious 
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AE (SAE). The number and percentage of subjects who died due to AE as well as TEAE will 
also be summarized. 
The following summaries of TEAEs will be provided by primary SOC and PT. All summaries 
are for all study periods combined excluding Open-Label Temporary period (Treatment, Down-
Titration, Study Drug-Free Period, and Transition) unless otherwise indicated. Summaries for 
Open-Label Temporary will be presented separately.  The number of individual occurrences will 
be included with the numbers and percentages if applicable. 
• Incidence of TEAEs 
• Incidence of TEAEs by study period (Treatment, Down-Titration, Study Drug-Free, and 
Transition Periods) 
• Incidence of drug-related TEAEs by study period (Treatment, Down-Titration, Study Drug-
Free, and Transition Periods) 
• Incidence of TEAEs occurring in at least 2% of subjects in any treatment group 
• Incidence of TEAEs occurring in at least 2% of subjects by relationship to study drug in any 
treatment group 
• Incidence of non-serious TEAEs occurring in at least 5% of subjects in any treatment group 
• Incidence of non-serious TEAEs occurring in at least 5% of subjects by relationship to study 
drug in any treatment group 
• Incidence of TEAEs by intensity 
•  Incidence of TEAEs by maximum intensity 
• Incidence of TEAEs by relationship to study drug 
• Incidence of TEAEs by maximum relationship to study drug 
• Incidence of treatment-emergent SAEs 
• Incidence of non-serious TEAEs 
• Incidence of TEAEs leading to permanent discontinuation of study drug 
• Incidence of TEAEs leading to discontinuation of study 
• Incidence of TEAEs related to COVID-19 vaccination by study period  
For the summary by maximum intensity and by maximum relationship, each subject will be 
counted at most once per primary SOC or PT according to the maximum intensity and the 
maximum relationship of all AEs within that SOC or PT. For the summary by intensity and by 
relationship, a subject may be counted more than once according to the intensity of the TEAEs 
and the relationship assessments. 
Severe intensity will be assumed for AEs for which intensity is not specified. 
Drug-related TEAEs are TEAEs for which the relationship to IMP is specified as Related or AEs 
for which relationship is not specified. 
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In addition, AEs including Pre-treatment AEs will be listed with respect to general information, 
relationship, seriousness, withdrawal of study drug and study discontinuation.  
10.2.2 
TEAEs of special interest 
The following TEAEs are considered as TEAEs of special interest: 
• autoimmune nephritis 
• nephritis 
• nephritis allergic 
• tubulointerstitial nephritis 
• uveitis syndrome 
• potential Hy’s law 
The TEAEs of special interest, which are captured on the CRF page, will be categorized and 
presented by SOC, PT and relationship similar to appropriate description in Section 10.2.1. 
10.3 
Clinical laboratory evaluations 
End of Treatment is defined as the last assessment point at which a measured value of the 
parameter is available during the Treatment Period regardless of scheduled visit or unscheduled 
visit. The same definition applies hereafter. 
10.3.1 
Hematology, Biochemistry and Urinalysis parameters 
Hematology, biochemistry, and urinalysis parameters are assessed at Visits 1, 3 through 7, EDV, 
Visit 8, and the Safety Visit and may also be assessed at unscheduled visits.  
Observed results as well as change from baseline will be analyzed descriptively for all laboratory 
parameters by visit and End of Treatment. Incidence of possibly clinically significant treatment-
emergent (PCST) results, PCST low value, and PCST high value will be summarized for 
hematology, blood chemistry and urinalysis parameters, if applicable. The PCST criteria are 
defined in Section 12.2.1. 
A serum pregnancy test is performed at Visit 1 and a urine pregnancy test is performed at Visit 2 
and Visit 7/EDV. A urine pregnancy test may also be performed at unscheduled visits. 
Pregnancy test results will not be summarized but will be provided in a subject data listing. 
All summaries of laboratory parameters will only summarize parameters planned based on the 
protocol; however, both planned and unplanned laboratory parameters will be provided in 
subject data listings. 
10.3.2 
PDILI laboratory measurements 
The number and percentage of subjects with PDILI will be summarized by treatment group.  The 
number and percentage of subjects meeting ALT or AST or both, total bilirubin, alkaline 
phosphatase criteria and presence of symptoms will be summarized in table. 
Listings of subjects with PDILI include alcohol and illicit drug use within past 6 months, the 
laboratory results for ALT, AST and Total bilirubin, symptoms of hepatitis or hypersensitivity 
will be provided. 
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10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate are assessed for 
Visits 1 through 7, EDV, Visit 8, and the Safety Visit and may also be assessed at unscheduled 
visits. Body weight is assessed at all of the same time points except for Visit 2. 
Observed values for SBP, DBP, and pulse rate will be summarized for Visits 1 through 7, End of 
Treatment, Visit 8, and the Safety Visit. Changes from Baseline for SBP, DBP, and pulse rate 
will be summarized for Visits 4 through 7, End of Treatment, the Visit 8, and the Safety Visit. 
Same summaries will be provided for body weight. 
The number and percentage of subjects with at least one PCST low values, and subjects with at 
least one PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. 
Percentages will be relative to the number of subjects with an assessment within each study 
period. PCST criteria are defined in Section 12.2.2. 
Vital signs measurements (absolute values and changes from Baseline) will be listed by visit and 
timing relative to dosing including changes from Baseline. 
10.4.2 
Electrocardiograms 
ECGs are performed at Visits 1, 4, 5, 7/EDV and Visit 8, and may also be performed at 
unscheduled visits. An ECG is also performed at the Safety Visit if there is an abnormal finding 
at Visit 7/EDV.  
As for the reported ECG parameters, the observed values and change from baseline will be 
presented descriptively by treatment group for each scheduled visit and End of Treatment. 
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 Visits 1, 4, 5, and 
7; End of Treatment; Visit 8 (by Period) and the Safety Visit. Percentages will be relative to the 
number of subjects with an ECG at each analytical time point. Subjects will be counted at most 
once within each time point based on the worst observed outcome across all abnormalities at that 
time point. 
Summaries of shift from Baseline to Visits 4, 5, and 7 and End of Treatment will also be 
provided based on the categories normal and abnormal. 
Abnormal ECGs will be listed by subject, visit, and timing relative to dosing. 
10.4.3 
Electroencephalography 
Electroencephalography (EEG) is performed at Visit 1 and appropriate data will only be listed by 
subject.  
10.4.4 
Computed tomography/ Magnetic resonance imaging 
Computed tomography (CT) scan/ magnetic resonance imaging (MRI) is performed at Visit 1 
and will be listed by subject and type of image.  
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10.4.5 
Physical examination 
A physical examination is performed at Visits 1, 3, and 7/EDV, Visit 8 and the Safety Visit and 
may also be performed at unscheduled visits, although findings are only recorded on the CRF at 
Visit 1. A listing of abnormal physical examination findings at Visit 1 will be provided; no 
summaries of physical examination findings are planned. 
10.4.6 
Neurological examination 
A neurological examination is performed at Visits 1, 3, and 7/EDV, Visit 8 and at the Safety 
Visit and may also be performed at unscheduled visits. A listing of neurological examination 
results will be provided; no summaries of neurological examination findings are planned. 
10.4.7 
Psychiatric and mental status 
An evaluation of Psychiatric and Mental Status is performed at Visits 1, 3, and 7/EDV, Visit 8 
and at the Safety Visit and may also be performed at unscheduled visits. A listing of Psychiatric 
and Mental Status results will be provided; no summaries of Psychiatric and Mental Status 
findings are planned. 
10.4.8 
Columbia-Suicide Severity Rating Scale 
With global amendment 1 to the protocol, the Columbia-Suicide Severity Rating Scale (C-SSRS) 
has been added as an assessment at all study visits to assess suicidality. Specific rules are 
provided to the study sites with regard to the identification of AEs or SAEs based on the 
outcome of this assessment. Because clinical events of interest will be recorded as AEs or SAEs, 
no study variable is defined for this assessment and no 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. 
 
 
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11 
REFERENCES 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988, 
75: 800-2. 
 
 
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12 
APPENDICES 
12.1 
Actual BRV dose conversion table 
Table 12.1: Conversion from blinded daily dose to unblinded BRV daily dose 
 
 
Blinded Nominal Dose (mg/day) from Dosing Log CRF 
Treatment group 
Period or Visit 
0 
25 
50 
75 
100 
125 
150 
175 
200 
225 
250 
200mg/day 
Start day of Treatment Period 
0 
0 
50 
50 
100 
100 
 
 
 
 
 
 
Treatment Period (except first and last dates) 
0 
0 
50 
50 
100 
100 
150 
150 
200 
200 
200 
 
Day of end Treatment and start Transition 
0 
25 
50 
75 
100 
125 
150 
175 
175 
 
 
 
Transition Period (except first and last dates) 
0 
25 
50 
75 
100 
125 
150 
 
 
 
 
 
Last day of Transition Period 
0 
25 
50 
75 
 
 
 
 
 
 
 
50mg/day 
Start day of Treatment Period 
0 
25 
0 
25 
0 
25 
 
 
 
 
 
 
Treatment Period (except first and last dates) 
0 
25 
50 
25 
50 
25 
50 
25 
50 
25 
50 
 
Day of end Treatment and start Transition 
0 
25 
50 
25 
50 
25 
50 
25 
50 
 
 
 
Transition Period 
0 
25 
50 
25 
50 
25 
50 
 
 
 
 
 
Last day of Transition Period 
0 
25 
0 
25 
 
 
 
 
 
 
 
PBO 
Start day of Treatment Period 
0 
0 
0 
0 
0 
0 
 
 
 
 
 
 
Treatment Period (except first and last dates) 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
 
Day of end Treatment and start Transition 
0 
0 
0 
0 
0 
0 
0 
0 
0 
 
 
 
Transition Period (except first and last dates) 
0 
0 
0 
0 
0 
0 
0 
 
 
 
 
 
Last day of Transition Period 
0 
0 
0 
0 
 
 
 
 
 
 
 
Note: Figures in italics indicate that there are two theoretically possible doses, of which the higher one is selected. 
 
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12.2 
PCST criteria 
12.2.1 
Laboratory assessments - PCST  
The following criteria will be applied in the determination of PCST laboratory assessment 
values. 
12.2.1.1 
Hematology 
Table 12‒2: 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 
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; y= year. A month is defined as 30 days; a year is defined as 365.25 
days. 
12.2.1.2 
Blood chemistry  
Table 12‒3: Chemistry PCST criteria 
PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
AST (SGOT) 
<14y 
U/L 
>180 
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PARAMETER 
AGE RANGE 
UNIT 
(standard) 
ABNORMALITY CRITERIA 
(standard) 
 
≥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 
 
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; 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 as 30 days) mg = milligram; mmol = millimoles; μg 
= microgram; 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 
 
12.2.1.3 
Urinalysis 
[Instruction] 
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 
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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 
[Application] 
Table 12‒4: 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) 
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 
 
12.2.2 
Vital sign assessments – abnormal 
Abnormality criteria to be applied in the assessment of vital signs parameter values are given 
below. 
Table 12‒5: 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 
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PARAMETER 
AGE RANGE ABNORMALITY CRITERIA 
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 
 
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 TO THE STATISTICAL ANALYSIS PLAN 
(SAP)  
13.1 
Amendment 1 
The main purpose for the SAP amendment 1 is to apply the modifications introduced up to 
Protocol Amendment 3 and 3.1. Moreover, many technical and detailed descriptions for 
executing the statistical analysis have been added in existing or new sections. 
13.2 
Amendment 2 
Rationale for the amendment 
The SAP is amended to reflect following changes adopted in Protocol Amendment 4 and 
Protocol Amendment 4.1. 
• To reduce the total sample size from 504 to 444 study participants 
• To reduce the minimum required number of Japanese study participants 
• To add China Mainland to the list of participating countries and regions 
• To update exclusion criteria 20 and 27 
• To provide clarifications around the LEV use and LEV cap 
• To update the study contact information 
• To update the company name from SPRL to SRL 
 
Modifications and changes 
Global changes 
There are no global changes to the SAP during this amendment. 
Specific changes 
Change #1 
1 INTRODUCTION (last sentence) 
… The SAP is based on the following study document: Protocol Amendment 3.0 and 3.1 (01 
Feb 2019). 
Has been changed to: 
… The SAP is based on the following study document: Protocol Amendment 4 (10 Jan 
2020). 
 
Change #2 
2.2.1.1 Primary efficacy variable 
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The primary efficacy variable is the partial seizure frequency per 28 days during the 12-week 
Treatment Period. The primary efficacy outcome is the percent reduction in partial seizure 
frequency over PBO based on analysis of covariance (ANCOVA). 
Has been changed to: 
2.2.1.1 Primary efficacy variable 
The primary efficacy variable is the partial seizure frequency per 28 days during the 12-week 
Treatment Period. The primary efficacy outcome is the percent reduction in partial seizure 
frequency over PBO based on analysis of covariance (ANCOVA). 
 
Change #3 
2.2.3 Primary Safety variable 
The primary safety variable is adverse events (AEs). 
Has been changed to: 
2.2.3 Primary Safety variables 
The primary safety variables are as follows:  
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of TEAEs leading to study withdrawal 
• Incidence of treatment-emergent serious adverse events (SAEs) 
 
Change #4 
2.2.4 Exploratory Safety Variables 
The exploratory safety variables are as follows: 
• Laboratory tests (blood chemistry, hematology, urinalysis) 
• Electrocardiogram (ECG) 
• Vital signs 
• Body weight 
• … 
Has been changed to: 
2.2.4 Other Safety Variables 
Other safety variables are as follows: 
• Changes in clinical laboratory test parameters (blood chemistry, hematology, urinalysis) 
• Electrocardiogram (ECG) parameters and findings 
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• Changes in vital signs [systolic blood pressure (SBP), diastolic blood pressure (DBP), 
pulse rate] 
• Changes in body weight 
• … 
 
Change #5 
2.3.1 Study duration per subject (second paragraph) 
• 
Prior to entry into LTFU study or MAP, the informed consent should be obtained from 
the subject at the end of Treatment Period (Visit 7). …  
Has been changed to: 
• 
Prior to entry into LTFU study or MAP, the informed consent, where applicable, should 
be obtained from the subject at the end of Treatment Period (Visit 7). … 
 
Change #6 
2.3.2 Planned number of subjects and sites 
The planned number of subjects who are evaluable for the primary efficacy analysis is 504 
(168 subjects per treatment group). Of the 504 subjects, approximately 129 Japanese subjects 
and approximately 375 subjects from other countries will be randomized.  
The number of prior LEV use subjects will be limited to 30% of the total study population. 
Considering an anticipated screen failure rate of approximately 20%, approximately 630 
subjects (162 Japanese subjects and 468 subjects from other countries) will be screened. It is 
planned to have those subjects recruited in approximately 100 sites. 
Has been changed to: 
2.3.2 Planned number of subjects and sites 
The planned number of evaluable subjects for the primary efficacy analysis is 444 (148 
subjects per treatment group). The number of prior LEV use subjects will be limited to 30% 
of the total study population. Considering an anticipated screen failure rate of approximately 
20%, approximately 555 subjects were to be screened. It is planned to have subjects recruited 
in approximately 95 sites. 
 
Change #7 
2.3.3 Anticipated regions and countries 
The study is planned to be conducted in Japan, Taiwan, Philippines, Thailand, Singapore, and 
Malaysia, Hong Kong, Korea, Bulgaria, and Poland with possible extension to other 
countries or regions. 
Has been changed to: 
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2.3.3 Anticipated regions and countries 
The study is being conducted in Japan, Taiwan, China Mainland, Philippines, Thailand, 
Singapore, and Malaysia.   
 
Change #8 
2.4 Determination of sample size 
A total of 168 analyzable subjects per treatment group will provide 80% power to 
simultaneously detect differences between BRV treatment groups (BRV 50mg/day group and 
BRV 200mg/day group) and PBO group at the 1-sided 0.025 significance level assuming 
treatment differences of 0.217 and 0.264 in means on the log-transformed scale and a 
common SD of 0.66. The estimates of 0.217 and 0.264 correspond to reductions of 19.5% 
and 23.2% of BRV over PBO after back-transformation, respectively. The percent reduction 
of 23.2% is obtained from BRV 200mg/day in the N01358 study. Based on a similar result 
from the Integrated Summary of Efficacy, a 19.5% reduction of BRV 50mg/day over PBO 
can be estimated. The SD of 0.66 is based on the observed SD from all treatment groups in 
N01358. The number of 168 subjects per treatment group will provide powers of 95% and 
85% to detect the differences of BRV 200mg/day and BRV 50mg/day for PBO, respectively. 
Accordingly, a power to simultaneously detect differences of both BRV 200mg/day and 
BRV 50mg/day vs PBO will attain 81% (0.95×0.85). A total of 504 (168×3) analyzable 
subjects in the study is calculated as a target number. 
Has been changed to: 
A total of 148 analyzable subjects per treatment group will provide 80% power to 
simultaneously detect differences between BRV treatment groups (BRV 50mg/day group and 
BRV 200mg/day group) and the PBO group at the 1-sided 0.025 significance level.   The 
sample size assumes treatment differences of 0.221 and 0.285 in means on the log-
transformed scale and a common SD of 0.66. The estimates of 0.221 and 0.285 correspond to 
reductions of 19.8% and 24.8% of BRV over PBO after back-transformation, respectively. 
The percent reduction of 24.8% is obtained from BRV 200mg/day in the N01358 study and 
assuming the LEV cap of 30% is reached overall. Based on a similar result from the 
Integrated Summary of Efficacy and again assuming the LEV cap of 30% is reached overall, 
a 19.8% reduction of BRV 50mg/day over PBO can be estimated. The SD of 0.66 is based on 
the observed SD from all treatment groups in N01358. The sample size calculation accounts 
for the correlation of the test statistics (same placebo group is compared to each BRV dose) 
as well as the planned Hochberg procedure. A total of 444 (148×3) analyzable subjects in the 
study is calculated as a target number. 
 
Change #9 
3.1 General presentation of summaries and analyses (last paragraph) 
All summary tables and figures will be presented overall and by racial subgroup, ie, for 
group “All”, “Japanese” and “Non-Japanese” unless stated otherwise. 
Has been changed to: 
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All summary tables and figures will be presented overall and by Japan, unless stated 
otherwise. In addition, by-region subgroup analysis will be performed overall, by Japan, and 
by Non-Japan to the selected efficacy endpoints (see Section 4.7). 
 
Change #10 
3.2.1.2 End date of the Treatment Period 
The end date of the Treatment Period will be either the date of Visit 7 for subjects 
completing the Treatment Period, or the date of the Early Discontinuation Visit (EDV) for 
subjects who discontinued during the Treatment Period. If a subject does not have a Visit 
7/EDV, then either the date of the last scheduled or unscheduled visit during the Treatment 
Period or the date of last known dose of study drug during the Treatment Period, whichever 
is later, will define the end date of the Treatment Period. 
Has been changed to: 
This section is removed.  
 
Change #11 
3.2.3 Last value 
The Last value for laboratory tests, vital signs and ECG is a value collected in the last visit 
including unscheduled visits during a given period.   
Has been changed to: 
3.2.3 End of treatment value 
The “End of treatment” value for laboratory tests, vital signs and ECG is a value collected in 
the last visit including unscheduled visits during the treatment period.   
 
Change #12 
3.4 Protocol deviations 
Has been changed to: 
3.4 Important Protocol deviations 
 
Change #13 
…Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1. Medications will be coded using the World Health 
Organization Drug Reference List (WHO-DRL) version SEP 2017. Medical procedures will 
not be coded. 
Has been changed to: 
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3.8 Coding dictionaries 
Medical history and  adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 18.1. Medications will be coded using the World 
Health Organization Drug Reference List (WHO-DRL) version SEP 2017. Medical 
procedures will not be coded. 
 
Change #14 
3.8.6 Dose mapping for total daily BRV dose 
Has been changed to: 
 
3.9.6 Dose mapping for total daily BRV dose 
 
(last paragraph is newly added) 
In the circumstance the daily total blinded dose as recorded on the CRF exceeds the 
maximum nominal dose as described in the appendix Section 12.1, it is assumed the subject 
took the active treatment for all additional dosage.  For example, suppose a BRV 200mg 
subject was recorded 275 mg/day total daily dose during the treatment period on the CRF 
(exceeding the maximum dose of 200 mg/day during the treatment period), it would be 
assumed the subject took active 200mg + 75 mg =275 mg/day. 
 
 
Change #15 
Section 3.11 is newly added: 
3.11 
Consideration for COVID-19 
A new 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 5.1.3) to describe the impact on the interpretability of 
efficacy and safety endpoint due to COVID-19 will be performed.  
Summary and listing to describe the AE related to COVID-19 vaccination will be provided 
(see Section 10.2.1) 
 
Change #16 
4.3 Interim analyses and data monitoring 
No formal interim analyses are planned for this study.  
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However, an informal analysis is planned post data collection during the double-blind period 
of the study to support regulatory submissions. Prior to the analysis, an official unblinding 
will be completed.  
At a minimum, one interim report is planned. Regular monitoring of safety data collected 
during clinical studies will be performed by medically qualified Sponsor personnel or 
equivalent designee(s). Multicenter studies 
Study outcomes will not be assessed for individual investigator sites due to the expected low 
enrollment within each investigator site and because the subject randomization is not 
stratified by investigator site. Treatment by investigator site interactions will not be assessed. 
Has been changed to: 
4.3 Interim analyses and data monitoring 
No formal interim analyses are planned for this study. 
 
Change #17 
Multicenter studies 
Study outcomes will not be assessed for individual investigator sites due to the expected low 
enrollment within each investigator site and because the subject randomization is not 
stratified by investigator site. Treatment by investigator site interactions will not be assessed. 
Has been changed to: 
4.4 Multicenter studies 
Study outcomes will not be assessed for individual investigator sites due to the expected low 
enrollment within each investigator site and because the subject randomization is not 
stratified by investigator site. Treatment by investigator site interactions will not be assessed. 
 
Change #18 
4.6 Examination of subgroups 
Selected efficacy outcomes will be evaluated for the following subgroup variables:  
• 
Gender 
• 
Categorized age (<17 years, 17 to <65 years, 65 years and older) 
• 
Country (Japan, Taiwan, Philippines, Thailand, Singapore, Malaysia, Hong Kong, Korea, 
Bulgaria, and Poland) 
• 
Region (Japan and Non-Japan) 
• 
LEV use (LEV naive versus prior LEV use) 
• 
Number of AEDs previously used but discontinued prior to study entry (≤2 versus >2) 
• 
AED inducer status (use of an inducer at study entry versus no inducer at study entry) 
• 
Seizure frequency by seizure type for seizure types IA, IB, and IC 
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All evaluations will be descriptive; neither statistical testing of treatment by subgroup 
interactions nor statistical testing of treatment effects within subgroups will be carried out. 
Has been changed to: 
4.7 Examination of subgroups 
Subgroup analysis will be conducted for the following efficacy outcomes: 
• 
Percent reduction in partial seizure frequency (per 28 days during the 12-week Treatment 
Period) over PBO based on ANCOVA 
• 
50% responder rate based on percent reduction in partial seizure frequency per  
28 days from Baseline to the 12-week Treatment Period 
• 
Percent reduction in partial seizure frequency per 28 days from Baseline to the 12-week 
Treatment Period 
The above selected efficacy outcomes will be evaluated for the following subgroup variables:  
• 
Gender 
• 
Categorized age (<17 years, 17 to <65 years, 65 years and older) 
• 
Country (Japan, China Mainland, Philippines, Thailand, Taiwan, Singapore, and 
Malaysia, in which Taiwan and Singapore will be combined with Malaysia due to small 
number of enrolments) 
• 
Region (Japan, non-Japan) 
• 
LEV use (LEV naive, prior LEV use) 
• 
Number of AEDs previously used but discontinued prior to study entry (≤2 versus >2) 
• 
AED inducer status (use of an inducer at study entry versus no inducer at study entry) 
The AED inducer will be captured according to the drug list provided by UCB.  
• 
Seizure frequency by seizure type for seizure types IA, IB, and IC 
All evaluations will be descriptive; neither statistical testing of treatment by subgroup 
interactions nor statistical testing of treatment effects within subgroups will be carried out. 
 
Change #19 
New section 5.1.4 is added: 
5.1.4 Stratification levels per CRF 
During the conduct of the randomization, some subjects with the stratification levels of LEV 
status or number of previous AEDs mistakenly entered to the IVRS system.  A sensitivity 
analysis using the actual stratification levels for LEV status and number of previous AEDs 
will be performed (see Section 8.1.2).   
The actual LEV status will be captured from CRF form “History of Previous Antiepileptic 
Drug Treatment”.  Subjects will be considered with prior LEV use if levetiracetam is 
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captured in any preferred drug name in this CRF form.  Otherwise, the subjects will be 
considered LEV naïve. 
The number of AEDs previously used but discontinued prior to study entry will also be 
captured from CRF form “History of Previous Antiepileptic Drug Treatment” by counting 
the number of unique preferred drug name (≤2 vs >2 AEDs). 
 
Change #20 
6.1 Demographics 
Age in years will be calculated based on date of Visit 1 and an incomplete birth date 
assuming birth of first day of the month (yyyy-mm-01) in the interactive voice/WEB 
response system. 
Has been changed to: 
6.1 Demographics 
Age in years will be calculated based on date of informed consent and an incomplete birth 
date assuming birth on the first day of the month (yyyy-mm-01) in the interactive voice/WEB 
response system. 
 
Change #21 
6.4 History of previous AED use 
Summaries in this section will be based on the History of Previous AED Treatment CRF 
which includes only AEDs stopped prior to study entry. In addition to the following 
summary tables, a corresponding subject data listing will be provided. 
Has been changed to: 
6.4 History of previous AED use 
Previous AEDs are AEDs taken and discontinued prior to study entry.  The history of 
previous AED will be recorded in accordance with the list of AEDs as indicated in Appendix 
3 of the study protocol.  However, investigator’s judgement will be prioritized and taken into 
consideration.  Summaries in this section will be based on the History of Previous AED 
Treatment CRF which includes only AEDs stopped prior to study entry.  
For summaries by preferred drug name, some AEDs will be grouped as follows: 
Valproate includes valproate sodium, valproate semisodium, valproate bismuth, valproate 
magnesium, valpromide, ergenyl chrono, valproic acid.  
Phenytoin includes phenytoin sodium, phenytoin calcium, mephenytoin, zentronal, metetoin, 
ethotoin, albutoin, hydantal, phelantin, hydantol D, anirrit, dintoinale, fosphenytoin sodium, 
phenytoin, fosphenytoin, hydantoin derivatives, hydantoin.  
Phenobarbital includes phenobarbital sodium, methylphenobarbital, metharbital, alepsal, 
phenobarbital, kaneuron, epanal.  
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Benzodiazepine AEDs that can be grouped by bromazepam, alprazolam, cloxazolam, 
diazepam group, chlordiazepoxide, clonazepam, clobazam, lorazepam, clotiazepam, 
temazepam, and clorazepate are considered the same AED at the group level.  
Combination AEDs are not considered for grouping. 
In addition to the following summary tables, a corresponding subject data listing will be 
provided. 
 
Change #22 
8.1.2 Primary analysis of the primary efficacy variable 
Has been changed to: 
8.1.2 Primary analysis of the primary efficacy variable 
(last paragraph is newly added) 
During the conduct of the randomization, some subjects with the stratification levels 
mistakenly entered to the IVRS system and a sensitivity analysis will be performed to assess 
the impact due to this error.  The sensitivity analysis will be conducted to the primary 
efficacy variable using the similar ANCOVA model with log-transformed [log(x+1)] 
Treatment Period 28-day adjusted partial seizure frequency as the outcome and an effect for 
treatment, an effect for country, and an effect for the 4 combinations of stratification levels 
for LEV status and number of previous AEDs (≤2 versus >2) according to the actual 
stratification levels for LEV status and number of previous AEDs as entered in the CRF (see 
Section 5.1.4), and log-transformed 28-day adjusted Baseline partial seizure frequency as a 
continuous covariate.    
 
Change #23 
8.2.1 Percent reduction in partial seizure frequency 
Percent reduction from Baseline to the Treatment Period in partial seizure frequency will be 
calculated by subtracting 28 day adjusted Treatment Period partial seizure frequency [A] 
from 28 day adjusted Baseline Period partial seizure frequency [B], and multiplying the 
resulting quantity by 100 and dividing by the Baseline Period 28 day adjusted partial seizure 
frequency. 
%Reduction = 100 ×
[A] −[B]
[B]
 
Has been changed to: 
Percent reduction from Baseline to the Treatment Period in partial seizure frequency will be 
calculated by subtracting 28 day adjusted Treatment Period partial seizure frequency [A] 
from 28 day adjusted Baseline Period partial seizure frequency [B], and multiplying the 
resulting quantity by 100 and dividing by the Baseline Period 28 day adjusted partial seizure 
frequency. 
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%Reduction = 100 × [B] −[A] 
[B]
 
Change #24 
9.1 BRV plasma concentrations 
Descriptive and inferential statistics in Section 3.1.1 for BRV observed plasma 
concentrations are computed per defined time window post-dose for all PK-PPS by actual 
dose given before each blood sampling for PK and dose normalized BRV plasma 
concentrations are computed for all doses with the same manner. The statistics are calculated 
only if at least 2/3 of the individual data at a specific sampling point are above or equal to the 
LLOQ. 
… 
• 
Time Window [-0 (Just before dosing), >0-1, >1-2, >2-4, >4-8, >8-10, >10-12, >12 hours 
post dosing] 
Has been changed to: 
9.1 BRV plasma concentrations 
Descriptive and inferential statistics in Section 3.1.1 for BRV observed plasma 
concentrations are computed per defined time window post-dose (>0-4 hours, >4-8 hours, 
and >8 hours) for all PK-PPS by actual dose given before each blood sampling for PK and 
dose normalized BRV plasma concentrations are computed for all doses with the same 
manner. The statistics are calculated only if at least 2/3 of the individual data at a specific 
sampling point are above or equal to the LLOQ. 
… 
• 
Time Window [>0-4 hours, >4-8 hours, and >8 hours post dosing] 
 
Change #25 
10.1 
Extent of exposure 
(last paragraph) 
… The number and percentage of subjects with the following categories of durations of study 
drug exposure for the Treatment Period and the entire study will also be summarized: ≤2 
weeks, >2 weeks and ≤4 weeks, >4 weeks and ≤8 weeks, >8 weeks and ≤12 weeks, >12 
weeks. 
Has been changed to: 
10.1 
Extent of exposure 
(last paragraph) 
… The number and percentage of subjects with the following categories of durations of study 
medication exposure for the Treatment Period and the entire study will also be 
summarized:>0 weeks, >=2 weeks, >=4 weeks, >=6 weeks, >=8 weeks, >=10 weeks, and 
>=12 weeks. 
 
Change #26 
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10.2.1 General summaries of AEs 
A new summary table is added: 
• 
Incidence of TEAEs related to COVID-19 vaccination 
13.3 
Amendment 3 
Rationale for the amendment 
The SAP is amended to change the stratification level used to the efficacy analyses from IVRS 
data to the actual stratification level according to the CRF data. 
Modifications and changes 
Change #1 
Section 3.2.2 Study periods 
Treatment Period 
From the date of Visit 3 until the day of Visit 7 in subjects who 
complete the Treatment Period; or EDV in subjects who discontinue 
treatment early prior to Visit 7. 
If a subject does not have a Visit 7 or EDV date, then either the date 
of the last scheduled or unscheduled visit during the Treatment 
Period or the date of last known dose of IMP during the Treatment 
Period, whichever is later, will define the end date of the Treatment 
Period. 
Has been changed to: 
Section 3.2.2 Study periods 
Treatment Period 
From the date of Visit 3 until the day of Visit 7 in subjects who 
complete the Treatment Period; or EDV in subjects who discontinue 
treatment early prior to Visit 7. 
A subject is considered starting Treatment Period if the subject 
enters Visit 3 and is randomized.  If a subject does not have a Visit 7 
or EDV date, then either the date of the last scheduled or 
unscheduled visit during the Treatment Period or the date of last 
known dose of IMP during the Treatment Period, whichever is later, 
will define the end date of the Treatment Period. 
 
Change #2 
New section 3.2.4 is added: 
3.2.4 Actual stratification level per CRF 
During the conduct of the randomization, some subjects with the stratification levels of LEV 
status or number of previous AEDs mistakenly entered to the IVRS system.  The actual 
stratification level will be derived according to the CRF data: 
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The LEV status per CRF (LEV naïve vs prior LEV use) will be captured from the CRF form 
“History of Previous Antiepileptic Drug Treatment”. Subjects will be considered with prior 
LEV use if levetiracetam is captured in any preferred drug name in this CRF form. 
Otherwise, the subjects will be considered LEV naïve. 
The number of AEDs previously used but discontinued prior to study entry per CRF (≤2 vs 
>2 AEDs) will also be captured from the CRF form “History of Previous Antiepileptic Drug 
Treatment” by counting the number of unique AED entered in this form.  However, if the 
same compound name is also entered in the CRF form “Prior and Concomitant Medications”, 
the drug is not counted as a previous AED because it is considered that the subject has taken 
the same AED concomitantly during the study.  This was instructed in the CRF completion 
instruction regarding how to count the number of previous AED at the randomization.   
The following AEDs will be considered the same AED at the group level while counting the 
number of previous AEDs:  
• 
Valproate includes valproate sodium, valproate semisodium, valproate bismuth, valproate 
magnesium, valpromide, ergenyl chrono, valproic acid.  
• 
Phenytoin includes phenytoin sodium, phenytoin calcium, mephenytoin, zentronal, 
metetoin, ethotoin, albutoin, hydantal, phelantin, hydantol D, anirrit, dintoinale, fosphenytoin 
sodium, phenytoin, fosphenytoin, hydantoin derivatives, hydantoin.  
• 
Phenobarbital includes phenobarbital sodium, methylphenobarbital, metharbital, alepsal, 
phenobarbital, kaneuron, epanal.  
• 
Benzodiazepine AEDs are grouped separately by bromazepam, alprazolam, cloxazolam, 
diazepam group, chlordiazepoxide, clonazepam, clobazam, lorazepam, clotiazepam, 
temazepam, and clorazepate. 
 
Change 3 
 
3.5.4 Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least 1 
dose of study drug and have at least 1 post-Baseline seizure daily record card (DRC) data. 
Both primary and secondary efficacy analyses will primarily be carried out using the FAS. 
Has been changed to: 
3.5.4 Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least 1 
dose of study drug and have at least 1 post-Baseline seizure daily record card (DRC) data 
during the Treatment Period. Both primary and secondary efficacy analyses will primarily be 
carried out using the FAS. 
 
Change 4 
4.1 Adjustments for covariates 
... 
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In this regard, the primary analyses based on ANCOVA will include an effect for treatment, 
an effect for country, and an effect for the 4 combinations of levels for LEV status and 
number of previous AEDs.  Lower-enrolling countries will be pooled as described below. 
Has been changed to: 
4.1 Adjustments for covariates 
… 
In this regard, the primary analyses based on ANCOVA will include an effect for treatment, 
an effect for country, and an effect for the 4 combinations of levels for LEV status and 
number of previous AEDs.  The actual stratification level (see Section 3.2.4) will be used for 
the primary analyses. Lower-enrolling countries will be pooled as described below. 
 
Change 5 
4.7 Examination of subgroups 
… 
• 
LEV use (LEV naive, prior LEV use)  
• 
Number of AEDs previously used but discontinued prior to study entry (≤2 versus >2)  
• 
AED inducer status (use of an inducer at study entry versus no inducer at study entry) 
The AED inducer will be captured according to the drug list provided by UCB.  
• 
Seizure frequency by seizure type for seizure 
Has been changed to: 
4.7 Examination of subgroups 
… 
• 
LEV use (LEV naive, prior LEV use) according to actual stratification level as per the 
CRF 
• 
Number of AEDs previously used but discontinued prior to study entry (≤2 versus >2) 
according to actual stratification level as per the CRF 
• 
AED inducer status (use of an inducer at study entry versus no inducer at study entry) 
The AED inducer will be captured according to the drug list provided by UCB.  
• 
Seizure frequency by Seizure type for seizure at Baseline (types IA, IB, and IC)  
Subjects who experience at least one type of IA, IB, and IC seizure, respectively, during 
the Baseline Period will be included in the analysis for that seizure type. Subjects may be 
classified into more than 1 subgroup based on their baseline seizure profile. 
 
Change #6 
5.1.1 Overall subject disposition 
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… 
Down-Titration Period Disposition 
• 
The number of subjects entering the Down-Titration Period 
• 
The number of subjects completing the Down-Titration Period  
The number of subjects completing the Study Drug -Free Period (ie, subjects with Safety 
Visit). 
Has been changed to: 
5.1.1 Overall subject disposition 
… 
Down-Titration Period Disposition 
• 
The number of subjects entering the Down-Titration Period 
• 
The number of subjects completing the Down-Titration Period  
A subject is considered completing the Down-Titration Period if this subject also 
completes the Study Drug -Free Period (ie, subjects with Safety Visit). 
 
Change #7 
5.1.1 Overall subject disposition 
… 
Open-Label Temporary Period and MAP are not applicable to subjects enrolled in Japan and 
China.  
In addition to the overall summary of disposition, the above will also be summarized by LEV 
status, and number of previous AEDs (≤2 versus >2). 
Has been changed to: 
5.1.1 Overall subject disposition 
… 
Open-Label Temporary Period and MAP are not applicable to subjects enrolled in Japan and 
China. Percentages for Open-Label Temporary Period will be relative to the number of 
subjects entering the Open-Label Period in the RS. 
In addition to the overall summary of disposition, the above will also be summarized by LEV 
status, and number of previous AEDs (≤2 versus >2) according to the actual stratification 
level as per the CRF. 
 
Change #8 
5.1.4 Stratification levels per CRF 
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During the conduct of the randomization, some subjects with the stratification levels of LEV 
status or number of previous AEDs mistakenly entered to the IVRS system. A sensitivity 
analysis using the actual stratification levels for LEV status and number of previous AEDs 
will be performed (see Section 8.1.2).   
The actual LEV status will be captured from CRF form “History of Previous Antiepileptic 
Drug Treatment”. Subjects will be considered with prior LEV use if levetiracetam is captured 
in any preferred drug name in this CRF form. Otherwise, the subjects will be considered 
LEV naïve. 
The number of AEDs previously used but discontinued prior to study entry will also be 
captured from CRF form “History of Previous Antiepileptic Drug Treatment” by counting 
the number of unique preferred drug name (≤2 vs >2 AEDs). 
Has been changed to: 
5.1.4 Number of subjects by stratification levels  
The number and percentage of randomized subjects for each level of LEV status (never used 
LEV versus prior LEV use only), and number of AEDs previously used but discontinued 
prior to study entry (≤2 versus >2) will be summarized overall per the data entered in IVRS 
system and per the actual levels according to the CRF data, separately. 
The number and percentage of randomized subjects with discrepancies between the IVRS 
stratification and the actual stratification levels identified on the CRF will be summarized for 
LEV status and number of previous AEDs. 
Additionally, the number and percentage of randomized subjects by country will be 
summarized. 
 
Change #9 
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized by treatment group, over 
all subjects on BRV treatment and over all subjects. Unless otherwise specified, tables will 
be provided for the SS and listings will be done for the ES. 
Has been changed to: 
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized by treatment group, over 
all subjects on BRV treatment and over all subjects. Unless otherwise specified, tables will 
be provided for the SS FAS and listings will be done for the ES. 
 
Change #10 
6.2.3 History of epileptic seizures 
… 
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The epilepsy duration (years) will be derived as the date of informed consent minus the date 
of the first diagnosis (yyyy-mm-01), which is similar to the derivation of age. For subjects 
who only have a year of the diagnosis date, the date of January 1 will be assumed. If an 
imputed date of the diagnosis is less than the date of birth due to the application of 
imputation rules, then set epilepsy duration equal to the subject’s age.  
Has been changed to: 
6.2.3 History of epileptic seizures 
… 
The epilepsy duration (years) will be derived as the date of informed consent minus the date 
of the first diagnosis (yyyy-mm-01), which is similar to the derivation of age. For subjects 
who only have a year of the diagnosis date, the date of January 1 will be assumed. If an 
imputed date of the diagnosis is less than the date of birth due to the application of 
imputation rules, then set epilepsy duration equal to the subject’s age. No imputation will be 
done for completely missing diagnosis date and epilepsy duration will not be calculated for 
subjects with completely missing diagnosis date. 
 
Change #11 
6.2.3 History of epileptic seizures 
… 
For partial dates of birth and first diagnosis of epilepsy, imputation rules are applied. If an 
imputed date of first diagnosis of epilepsy is less than the date of birth due to the application 
of imputation rules, then set the date of first diagnosis of epilepsy to the date of birth.  
Has been changed to: 
6.2.3 History of epileptic seizures 
… 
For partial dates of birth and first diagnosis of epilepsy, imputation rules are applied. If an 
imputed date of first diagnosis of epilepsy is less than the date of birth due to the application 
of imputation rules, then set the date of first diagnosis of epilepsy to the date of birth. For 
completely missing dates of first diagnosis of epilepsy, no imputation will be done and age at 
time of first seizure will not be calculated. 
 
Change #12 
6.3.1 Previous and ongoing medical history 
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 overall and 
by MedDRA primary system organ class (SOC) and preferred term (PT). 
Has been changed to: 
6.3.1 Previous and ongoing medical history 
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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 overall and 
by MedDRA primary system organ class (SOC) and preferred term (PT) according to the SS. 
 
Change #13 
6.4 History of previous AED use 
Previous AEDs are AEDs taken and discontinued prior to study entry.  The history of 
previous AED will be recorded in accordance with the list of AEDs as indicated in Appendix 
3 of the study protocol.  However, investigator’s judgement will be prioritized and taken into 
consideration.  Summaries in this section will be based on the History of Previous AED 
Treatment CRF which includes only AEDs stopped prior to study entry.  
For summaries by preferred drug name, some AEDs will be grouped as follows: 
… 
Has been changed to: 
6.4 History of previous AED use 
Previous AEDs are AEDs taken and discontinued prior to study entry.  The history of 
previous AED will be recorded in accordance with the list of AEDs as indicated in Appendix 
3 of the study protocol.  However, investigator’s judgement will be prioritized and taken into 
consideration.  Summaries in this section will be based on the History of Previous AED 
Treatment CRF which includes only AEDs stopped prior to study entry.  
For summaries by preferred drug name, some AEDs will be grouped as follows (same 
grouping rules in Section 3.2.4:): 
… 
 
Change #14 
6.4.1 Number of previous AEDs 
The number of previous AEDs will be summarized based on the following categorization: 0-
1, 2-4, and ≥5 AEDs.  
Has been changed to: 
6.4.1 Number of previous AEDs 
The number of previous AEDs will be summarized based on the following categorization: 0-
1, 2-4, and ≥5 AEDs. When counting the number of previous AED from the CRF form 
“History of Previous Antiepileptic Drug Treatment”, if the same compound name is also 
entered in the CRF form “Prior and Concomitant Medications”, the drug is not counted as a 
previous AED (see Section 3.2.4). 
 
Change #15 
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6.5 Concomitant medications 
… 
Concomitant AEDs (including AEDs taken at study entry) will be recorded in accordance 
with the list of AEDs as indicated in Appendix 3 of the study protocol.  
Has been changed to: 
6.5 Concomitant medications 
… 
Concomitant AEDs (including AEDs taken at study entry) 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.   
 
Change #16 
6.5.1 Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AED medications at the time of study 
entry will be summarized by WHO DRL pharmacological group and preferred drug name. 
Has been changed to: 
6.5.1 Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AED medications at the time of study 
entry will be summarized by WHO DRL pharmacological group and preferred drug name 
according to the SS. 
 
Change #17 
8.1.2 Primary analysis of the primary efficacy variable 
The primary efficacy outcome will be the percent reduction in partial seizure frequency per 
28 days during the Treatment Period of each BRV treatment individually over PBO. 
The primary analysis will be based on ANCOVA with log-transformed [log(x+1)] Treatment 
Period 28-day adjusted partial seizure frequency as the outcome and an effect for treatment, 
an effect for country, and an effect for the 4 combinations of stratification levels for LEV 
status and number of previous AEDs (≤2 versus >2) according to the IVRS data, and log-
transformed 28-day adjusted Baseline partial seizure frequency as a continuous covariate. 
Lower enrolling countries will be pooled for this analysis as described in Section 4.1. 
… 
During the conduct of the randomization, some subjects with the stratification levels 
mistakenly entered to the IVRS system and a sensitivity analysis will be performed to assess 
the impact due to this error.  The sensitivity analysis will be conducted to the primary 
efficacy variable using the similar ANCOVA model with log-transformed [log(x+1)] 
Treatment Period 28-day adjusted partial seizure frequency as the outcome and an effect for 
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treatment, an effect for country, and an effect for the 4 combinations of stratification levels 
for LEV status and number of previous AEDs (≤2 versus >2) according to the actual 
stratification levels for LEV status and number of previous AEDs as entered in the CRF (see 
Section 5.1.4), and log-transformed 28-day adjusted Baseline partial seizure frequency as a 
continuous covariate.    
Has been changed to: 
8.1.2 Primary analysis of the primary efficacy variable 
The primary efficacy outcome will be the percent reduction in partial seizure frequency per 
28 days during the Treatment Period of each BRV treatment individually over PBO. 
The primary analysis will be based on ANCOVA with log-transformed [log(x+1)] Treatment 
Period 28-day adjusted partial seizure frequency as the outcome and an effect for treatment, 
an effect for country, and an effect for the 4 combinations of actual stratification levels for 
LEV status and number of previous AEDs (≤2 versus >2) according to the IVRS CRF data 
(see Section 3.2.4), and log-transformed 28-day adjusted Baseline partial seizure frequency 
as a continuous covariate. Lower enrolling countries will be pooled for this analysis as 
described in Section 4.1. 
… 
During the conduct of the randomization, some subjects with the stratification levels 
mistakenly entered to the IVRS system and a sensitivity analysis will be performed to assess 
the impact due to this error.  The sensitivity analysis will be conducted to the primary 
efficacy variable using the similar ANCOVA model with log-transformed [log(x+1)] 
Treatment Period 28-day adjusted partial seizure frequency as the outcome and an effect for 
treatment, an effect for country, and an effect for the 4 combinations of stratification levels 
for LEV status and number of previous AEDs (≤2 versus >2) according to the actual 
stratification levels for LEV status and number of previous AEDs as entered in the CRF 
IVRS data, and log-transformed 28-day adjusted Baseline partial seizure frequency as a 
continuous covariate.    
 
Change #18 
8.2.6 Time to nth partial seizure 
… 
Time to nth partial seizure will be compared between each BRV treatment group and PBO 
using a semi-parametric proportional hazards regression model with an effect for country, an 
effect for the 4 combinations of levels for LEV status and number of previous AEDs (≤2 
versus >2) and log transformed Baseline partial seizure frequency as a continuous covariate. 
Significance probabilities (ie, p values) and hazard ratios and corresponding two-sided 95% 
CIs will be presented for the comparison of each BRV treatment group to PBO. Lower 
enrolling countries will be pooled for this analysis as described in Section 4.1. 
Has been changed to: 
8.2.6 Time to nth partial seizure 
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… 
Time to nth partial seizure will be compared between each BRV treatment group and PBO 
using a semi-parametric proportional hazards regression model with an effect for country, an 
effect for the 4 combinations of actual stratification levels for LEV status and number of 
previous AEDs (≤2 versus >2) per the CRF data, and log transformed Baseline partial seizure 
frequency as a continuous covariate. Significance probabilities (ie, p values) and hazard 
ratios and corresponding two-sided 95% CIs will be presented for the comparison of each 
BRV treatment group to PBO. Lower enrolling countries will be pooled for this analysis as 
described in Section 4.1. 
 
Change #19 
10.2.1 General summaries of AEs 
… 
New summary tables are added: 
• 
Incidence of drug-related TEAEs by study period (Treatment, Down-Titration, Study 
Drug-Free, and Transition Periods) 
• 
Incidence of TEAEs leading to discontinuation of study 
 
Change #20 
10.2.1 General summaries of AEs 
… 
For the summary by maximum intensity, each subject will be counted at most once per 
primary SOC or PT according to the maximum intensity of all AEs within that SOC or PT. 
Severe intensity will be assumed for AEs for which intensity is not specified. 
Has been changed to: 
10.2.1 General summaries of AEs 
… 
For the summary by maximum intensity and by maximum relationship, each subject will be 
counted at most once per primary SOC or PT according to the maximum intensity and the 
maximum relationship of all AEs within that SOC or PT. For the summary by intensity and 
by relationship, a subject may be counted more than once according to the intensity of the 
TEAEs and the relationship assessments. 
 
Change #21 
10.3.1 Hematology, Biochemistry and Urinalysis parameters 
Hematology, biochemistry, and urinalysis parameters are assessed at Visits 1, 3 through 7, 
EDV, Visit 8, and the Safety Visit and may also be assessed at unscheduled visits.  
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Observed results as well as change from baseline will be analyzed descriptively for all 
laboratory parameters by visit and End of Treatment. Incidence of possibly clinically 
significant treatment-emergent (PCST) results will be summarized in the form of shift tables 
(from Baseline to End of Treatment) for hematology, blood chemistry and urinalysis 
parameters, if applicable. The PCST criteria are defined in Section 12.2.1. 
… 
Has been changed to: 
10.3.1 Hematology, Biochemistry and Urinalysis parameters 
Hematology, biochemistry, and urinalysis parameters are assessed at Visits 1, 3 through 7, 
EDV, Visit 8, and the Safety Visit and may also be assessed at unscheduled visits.  
Observed results as well as change from baseline will be analyzed descriptively for all 
laboratory parameters by visit and End of Treatment. Incidence of possibly clinically 
significant treatment-emergent (PCST) results, PCST low value, and PCST high value will 
be summarized in the form of shift tables (from Baseline to End of Treatment) for 
hematology, blood chemistry and urinalysis parameters, if applicable. The PCST criteria are 
defined in Section 12.2.1. 
… 
 
Change #22 
10.4.1 Vital signs 
… 
The number and percentage of subjects with at least one PCST low values, and subjects with 
at least one PCST high value will be summarized for SBP, DBP, pulse rate, and body weight 
for the Treatment Period and overall for the combined Treatment, Transition, Down-
Titration, and Study Drug-Free Periods.. Percentages will be relative to the number of 
subjects with an assessment within each study period. PCST criteria are defined in Section 
12.2.2. 
Has been changed to: 
10.4.1 Vital signs 
… 
The number and percentage of subjects with at least one PCST low values, and subjects with 
at least one PCST high value will be summarized for SBP, DBP, pulse rate, and body weight 
for the Treatment Period and overall for the combined Treatment, Transition, Down-
Titration, and Study Drug-Free Periods.. Percentages will be relative to the number of 
subjects with an assessment within each study period. PCST criteria are defined in Section 
12.2.2. 
 
Change #23 
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10.4.6 Neurological examination 
A neurological examination is performed at Visits 1, 3, and 7/EDV, Visit 8 and at the Safety 
Visit and may also be performed at unscheduled visits. A listing of abnormal neurological 
examination findings will be provided ; no summaries of neurological examination findings 
are planned. 
Has been changed to: 
10.4.6 Neurological examination 
A neurological examination is performed at Visits 1, 3, and 7/EDV, Visit 8 and at the Safety 
Visit and may also be performed at unscheduled visits. A listing of abnormal neurological 
examination findings results will be provided ; no summaries of neurological examination 
findings are planned. 
 
Change #24 
10.4.7 Psychiatric and mental status 
An evaluation of Psychiatric and Mental Status is performed at Visits 1, 3, and 7/EDV, Visit 
8 and at the Safety Visit and may also be performed at unscheduled visits. A listing of 
abnormal Psychiatric and Mental Status findings will  be provided; no summaries of 
Psychiatric and Mental Status findings are planned. 
Has been changed to: 
10.4.7 Psychiatric and mental status 
An evaluation of Psychiatric and Mental Status is performed at Visits 1, 3, and 7/EDV, Visit 
8 and at the Safety Visit and may also be performed at unscheduled visits. A listing of 
abnormal Psychiatric and Mental Status findings results will  be provided; no summaries of 
Psychiatric and Mental Status findings are planned. 
 
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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:
ep0083-sap-amend-3
Version:
1. 0
Document Number:
CLIN-000202076
Title:
ep0083-sap-amend-3
Approved Date:
17 Aug 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 17-Aug-2022 14:07:09 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 17-Aug-2022 14:30:29 GMT+0000
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