Clinical trial NCT01364597
Conditions: Epilepsy
Keywords: Brivaracetam Epilepsy Child Infant Adolescents Partial onset seizures
Sponsor: UCB Pharma SA
Start date: 2011-08-01; Completion date: 2022-02-03
Enrollment: 257 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the safety and tolerability of brivaracetam in pediatric subjects with epilepsy.

Detailed description:
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy.

This study was initially designed for pediatric subjects who had completed a previous BRV study.

With protocol amendment 4, enrollment for "directly enrolled" subjects was modified from 'up to' an additional 100 subjects to "at least" 100 subjects, keeping the planned total enrollment of approximately 600 subjects to allow flexibility in the number of patients reaching 1 year of exposure.

With protocol amendment 5, entry criteria for subjects coming for other pediatric core studies in development were included. Additional clarity was provided for subjects enrolled in N01266 that temporary roll over to one of those studies and resume participation in N01266.

With protocol amendment 6, central EEG reading and entry visit EEG were removed. Some clarifications on study assessments (questionnaires, EEGs) was provided and inclusion criteria were aligned from an earlier local amendment.

With protocol amendment 7, the pregnancy section was updated to clarify that Pregnancy Report and Outcome Form has to be completed in all pregnancies.

With protocol amendment 8, re-categorization of study variables in compliance with reporting registries was performed. Modifications due to COVID19 pandemic were implemented and clarification provided that participants may transition to another BRV study.

The primary objective is to evaluate the long-term safety and tolerability of BRV. The secondary objective is to assess the efficacy of BRV during long-term exposure.

Arms: arm 1: None
Interventions: intervention 1: Brivaracetam (BRV)
Intervention descriptions: intervention 1: The max BRV dose will be 5.0 mg/kg/day, not to exceed a dose of 200 mg/day for subjects with body weight \>40kg. Subjects may receive oral solution or oral tablets. The LTFU subjects will start dosing in N01266 on the individualized BRV dose they were receiving at the completion of the core study. Subjects must be able to tolerate the min BRV dose specified in the core study to be eligible for entry into the Evaluation Period of N01266. Dose can be adjusted as considered necessary by the Investigator and required by the subject's medical condition. All subjects who prematurely discontinue the study should complete an EDV and have their BRV dose down titrated by a maximum of half the dose every week for a maximum of 4 weeks until a dose of 1 mg/kg/day (50 mg/day for subjects with body weights \>50kg) is reached.

Protocol documents:
Prot_000.pdf: 
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PROTOCOL N01266 AMENDMENT 8 
OPEN-LABEL, SINGLE-ARM, MULTICENTER, LONG-TERM 
STUDY TO EVALUATE SAFETY AND EFFICACY OF 
BRIVARACETAM USED AS ADJUNCTIVE TREATMENT IN 
PEDIATRIC SUBJECTS WITH EPILEPSY  
PHASE 3 
EudraCT-Number: 2011-000374-60 
IND Number: 110606 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
Protocol/Amendment Number 
Date 
Type of amendment 
Final Protocol 
10 Mar 2011 
N/A 
Protocol Amendment 1 
26 Aug 2011 
Substantial 
Protocol Amendment 2 
09 Dec 2011 
Substantial 
Protocol Amendment 3 
26 Sep 2012 
Substantial 
Protocol Amendment 4 
10 Dec 2013 
Substantial 
Protocol Amendment 5 
14 Dec 2016 
Substantial 
Protocol Amendment 6 
06 Mar 2018 
Substantial 
Protocol Amendment 7 
18 Apr 2018 
Non-substantial 
Protocol Amendment 8 
25 Jun 2020 
Substantial 
 
Confidential Material 
Confidential 
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on, reproduced, published or otherwise used without the express permission of UCB. 
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STUDY CONTACT INFORMATION 
Sponsor 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
Sponsor Study Physician 
Name: 
 
Address: 
UCB Biosciences GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim  
Germany 
Phone: 
 
Fax: 
 
 
Clinical Project Manager 
Name: 
  
Address: 
UCB Biosciences GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim  
Germany 
Phone: 
 
Fax: 
 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
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Clinical Monitoring Contract Research Organization 
Name: 
Pharma-Research Associates (UK) Ltd.  
Address: 
Green Park 
500 South Oak Way 
Reading, RG2 6AD 
United Kingdom 
Phone: 
+44 118 918 1000 
Fax: 
+44 118 918 1001 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h)  
Fax 
Europe and Rest of the World: +32 2 386 2421 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 13 
2 
INTRODUCTION ........................................................................................................... 14 
2.1 
Background regarding targeted disease ....................................................................... 14 
2.2 
Background information regarding product................................................................. 15 
2.3 
Rationale for the study ................................................................................................. 16 
3 
STUDY OBJECTIVES .................................................................................................... 16 
3.1 
Primary objective ......................................................................................................... 16 
3.2 
Secondary objective ..................................................................................................... 16 
3.3 
Other objectives ........................................................................................................... 16 
4 
STUDY VARIABLES ..................................................................................................... 17 
4.1 
Primary variables ......................................................................................................... 17 
4.2 
Secondary variables ..................................................................................................... 17 
4.3 
Other variables ............................................................................................................. 17 
5 
STUDY DESIGN ............................................................................................................. 19 
5.1 
Study description ......................................................................................................... 19 
5.1.1 
Study duration per subject ................................................................................... 20 
5.1.2 
Planned number of subjects and sites .................................................................. 20 
5.1.3 
Anticipated regions and countries ....................................................................... 20 
5.2 
Schedules of study assessments ................................................................................... 20 
5.3 
Visit sequence .............................................................................................................. 32 
5.4 
Rationale for study design and selection of dose ......................................................... 33 
5.5 
Study conduct due to coronavirus (severe acute respiratory syndrome coronavirus-
2) disease 2019 ............................................................................................................. 34 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 35 
6.1 
Inclusion criteria .......................................................................................................... 35 
6.1.1 
Inclusion criteria for all subjects .......................................................................... 35 
6.1.2 
Inclusion criteria for LTFU subjects only ........................................................... 36 
6.1.3 
Inclusion criteria for directly enrolled subjects only ........................................... 36 
6.2 
Exclusion criteria ......................................................................................................... 36 
6.2.1 
Exclusion criteria for all subjects ........................................................................ 37 
6.2.2 
Exclusion criteria for LTFU subjects only .......................................................... 37 
6.2.3 
Exclusion criteria for directly enrolled subjects only .......................................... 38 
6.3 
Withdrawal criteria ...................................................................................................... 39 
7 
STUDY TREATMENTS ................................................................................................. 41 
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7.1 
Description of investigational medicinal products ...................................................... 41 
7.2 
Treatments to be administered ..................................................................................... 41 
7.2.1 
Up-Titration Period for directly enrolled subjects ............................................... 41 
7.2.2 
Evaluation Period for all subjects ........................................................................ 42 
7.2.3 
Down-Titration Period ......................................................................................... 42 
7.2.4 
Alternative study treatment supply due to COVID-19 ........................................ 42 
7.3 
Packaging ..................................................................................................................... 43 
7.4 
Labeling ....................................................................................................................... 43 
7.5 
Handling and storage requirements ............................................................................. 43 
7.6 
Drug accountability ...................................................................................................... 43 
7.7 
Procedures for monitoring subject compliance ............................................................ 44 
7.8 
Concomitant medications/treatments ........................................................................... 44 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 45 
7.8.1.1 
Permitted concomitant medications .......................................................... 45 
7.8.1.2 
Permitted concomitant therapy .................................................................. 45 
7.8.2 
Prohibited concomitant medications .................................................................... 45 
7.8.3 
Rescue medication ............................................................................................... 45 
7.9 
Blinding........................................................................................................................ 45 
7.10 
Randomization and numbering of subjects .................................................................. 46 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 46 
8.1 
Screening Visit for directly enrolled subjects only ...................................................... 46 
8.2 
Titration Visit(s) (TV1, TV2, and TV3) for directly enrolled subjects only ............... 48 
8.3 
Entry Visit .................................................................................................................... 49 
8.3.1 
LTFU subjects ..................................................................................................... 49 
8.3.1.1 
Core study: N01349 ................................................................................... 49 
8.3.1.2 
Core study: EP0065 ................................................................................... 50 
8.3.1.3 
Core study: Other (not N01349 or EP0065) .............................................. 51 
8.3.2 
Directly enrolled subjects .................................................................................... 51 
8.4 
Minimal Evaluation Visit (all subjects) ....................................................................... 52 
8.5 
Full Evaluation Visit (all subjects) .............................................................................. 53 
8.6 
Yearly Evaluation Visit (all subjects) .......................................................................... 54 
8.7 
Unscheduled Visit (all subjects) .................................................................................. 55 
8.8 
Early Discontinuation Visit (all subjects) .................................................................... 56 
8.9 
Down-Titration Visit (all subjects) .............................................................................. 57 
8.10 
Safety Visit (all subjects) ............................................................................................. 58 
8.11 
Final Visit (all subjects) ............................................................................................... 58 
9 
ASSESSMENT OF SAFETY .......................................................................................... 60 
9.1 
Adverse events ............................................................................................................. 60 
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9.1.1 
Definitions ........................................................................................................... 60 
9.1.1.1 
Adverse event ............................................................................................ 60 
9.1.1.2 
Serious adverse event ................................................................................ 61 
9.1.2 
Procedures for reporting and recording adverse events ....................................... 62 
9.1.2.1 
Description of adverse events .................................................................... 63 
9.1.2.2 
Rule for repetition of an adverse event...................................................... 63 
9.1.2.3 
Additional procedures for reporting adverse events .................................. 63 
9.1.3 
Follow-up on adverse events ............................................................................... 64 
9.1.4 
Pregnancy ............................................................................................................ 64 
9.1.6 
Overdose of investigational medicinal product ................................................... 65 
9.1.7 
Safety signal detection ......................................................................................... 65 
9.2 
Laboratory measurements ............................................................................................ 66 
9.2.1 
Laboratory assessments for safety ....................................................................... 66 
9.2.2 
Evaluation of PDILI ............................................................................................ 68 
9.2.2.1 
Consultation with Medical Monitor and local hepatologist ...................... 73 
9.2.2.2 
Immediate action: determination of IMP discontinuation ......................... 73 
9.2.2.3 
Testing: identification/exclusion of alternative etiology ........................... 73 
9.2.2.4 
Follow-up evaluation ................................................................................. 75 
9.2.3 
Plasma concentration measurements ................................................................... 75 
9.2.3.1 
BRV plasma concentrations ...................................................................... 75 
9.2.3.2 
Phenytoin plasma concentrations (if applicable) ....................................... 76 
9.3 
Other safety measurements .......................................................................................... 76 
9.3.1 
ECG ..................................................................................................................... 76 
9.3.2 
Vital signs ............................................................................................................ 76 
9.3.3 
Body weight, height, and head circumference ..................................................... 76 
9.3.4 
Physical examination ........................................................................................... 76 
9.3.5 
Neurological examination .................................................................................... 76 
9.3.6 
Psychiatric and mental status ............................................................................... 77 
9.3.7 
Assessment of suicidality .................................................................................... 77 
9.3.8 
BRIEF-P and BRIEF ........................................................................................... 77 
10 ASSESSMENT OF EFFICACY ...................................................................................... 77 
10.1 
Efficacy assessments for seizure data based on DRC .................................................. 78 
10.2 
Efficacy assessments for seizure data based on EEG .................................................. 78 
10.3 
Other assessments ........................................................................................................ 78 
10.3.1 
Direct cost parameters ......................................................................................... 78 
10.3.1.1 
Concomitant medications/treatments ........................................................ 78 
10.3.1.2 
Medical procedures ................................................................................... 79 
10.3.1.3 
Health care provider consultations not foreseen by the protocol .............. 79 
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10.3.1.4 
Hospital stays ............................................................................................ 79 
10.3.2 
Bayley Scales of Infant and Toddler Development, Third Edition ..................... 79 
10.3.3 
Achenbach Child Behavior Checklist .................................................................. 80 
10.3.4 
Assessment of seizure types ................................................................................ 80 
10.3.5 
PedsQL ................................................................................................................ 80 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 81 
11.1 
Adherence to protocol .................................................................................................. 81 
11.2 
Monitoring ................................................................................................................... 81 
11.2.1 
Definition of source data ..................................................................................... 81 
11.2.2 
Source data verification ....................................................................................... 82 
11.3 
Data handling ............................................................................................................... 82 
11.3.1 
Case report form completion ............................................................................... 82 
11.3.2 
Database entry and reconciliation ........................................................................ 82 
11.3.3 
Subject Selection and Enrollment log/Subject Identification Code list ............... 83 
11.4 
Termination of the study .............................................................................................. 83 
11.5 
Archiving and data retention ........................................................................................ 83 
11.6 
Audit and inspection .................................................................................................... 83 
11.7 
Good Clinical Practice ................................................................................................. 84 
12 STATISTICS ................................................................................................................... 84 
12.1 
Definition of analysis sets ............................................................................................ 84 
12.2 
General statistical considerations ................................................................................. 84 
12.3 
Planned safety analyses................................................................................................ 84 
12.4 
Planned efficacy analyses ............................................................................................ 85 
12.5 
Other analyses .............................................................................................................. 85 
12.6 
Handling of protocol deviations................................................................................... 85 
12.7 
Handling of dropouts or missing data .......................................................................... 85 
12.8 
Planned interim analysis and data monitoring ............................................................. 85 
12.9 
Determination of sample size ....................................................................................... 86 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 86 
13.1 
Informed consent ......................................................................................................... 86 
13.2 
Subject identification cards .......................................................................................... 86 
13.3 
Institutional Review Boards and Independent Ethics Committees .............................. 87 
13.4 
Subject privacy............................................................................................................. 87 
13.5 
Protocol amendments ................................................................................................... 88 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 88 
15 REFERENCES ................................................................................................................ 88 
16 APPENDICES ................................................................................................................. 89 
16.1 
Protocol Amendment 1 ................................................................................................ 89 
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16.2 
Protocol Amendment 2 .............................................................................................. 105 
16.3 
Protocol Amendment 3 .............................................................................................. 130 
16.4 
Protocol Amendment 4 .............................................................................................. 195 
16.5 
Protocol Amendment 5 .............................................................................................. 224 
16.6 
Protocol Amendment 6 .............................................................................................. 318 
16.7 
Protocol Amendment 7 .............................................................................................. 328 
16.8 
Protocol Amendment 8 .............................................................................................. 330 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 345 
18 SPONSOR DECLARATION ........................................................................................ 346 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of assessments for the Entry Visit (EV) (all subjects) ..................... 21 
Table 5‒2: 
Schedule of all study assessments for the Evaluation, Down-Titration, 
and Safety (Drug-Free) Periods (all subjects) .................................................. 24 
Table 5‒3: 
Schedule of study assessments from the ScrV through the final TV 
(directly enrolled subjects only)....................................................................... 29 
Table 5‒4: 
Visit sequence .................................................................................................. 32 
Table 7‒1: 
Recommended BRV dosing schedule for directly enrolled subjects 
during the Up-Titration Period ......................................................................... 42 
Table 9‒1: 
Anticipated serious adverse events for the pediatric epilepsy 
population ........................................................................................................ 62 
Table 9‒2: 
Required investigations and follow up for PDILI............................................ 70 
Table 9‒3: 
PDILI laboratory measurements ...................................................................... 74 
Table 9‒4: 
PDILI information to be collected ................................................................... 75 
 
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LIST OF ABBREVIATIONS 
ADF 
average daily frequency 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
Bayley-III® 
Bayley Scales of Infant and Toddler Development®, Third Edition 
bid 
bis in die (twice daily)  
BRIEF® 
Behavior Rating Inventory of Executive Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive Function®-Preschool 
Version 
BRV 
brivaracetam 
BSID-II™ 
Bayley Scales of Infant Development™, Second Edition 
CBCL 
Child Behavior Checklist  
CPM 
Clinical Project Manager 
CDMS 
clinical data management system 
COVID-19 
coronavirus (SARS-CoV-2) disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DRC 
daily record card 
DTV 
Down-Titration Visit 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDV 
Early Discontinuation Visit 
EEG 
electroencephalogram 
EV 
Entry Visit 
FDA 
Food and Drug Administration 
FEV 
Full Evaluation Visit 
FV 
Final Visit 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
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IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
iv 
intravenous 
IVRS 
interactive voice response system 
LEV 
levetiracetam 
LFT 
liver function test 
LTFU 
long-term follow-up 
M 
Month 
MEV 
Minimal Evaluation Visit 
PDCO 
European Paediatric Committee 
PDILI 
potential drug-induced liver injury 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
PK 
pharmacokinetics 
POS 
partial-onset seizures 
PP 
polypropylene 
PPR 
photoparoxysmal response 
PS 
Patient Safety 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus-2 
ScrV 
Screening Visit 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SV 
Safety Visit 
SV2A 
synaptic vesicle protein 2A 
TEAE 
treatment-emergent adverse event 
TV 
Titration Visit 
ULN 
upper limit of normal 
UV 
Unscheduled Visit 
V 
Visit 
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YEV 
Yearly Evaluation Visit 
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1 
SUMMARY 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety 
and efficacy of brivaracetam (BRV) in children with epilepsy. This study is designed for 
pediatric subjects ≥1 month to <17 years of age who have completed other pediatric BRV 
studies (herein referred to as “long-term follow-up” [LTFU] subjects) and for at least 
100 subjects ≥4 years to <17 years of age with POS who had not previously enrolled in a 
pediatric BRV study (herein referred to as “directly enrolled subjects”), with a planned total 
enrollment of approximately 600 subjects. 
The primary objective is to document the long-term safety and tolerability of BRV. The 
secondary objective is to assess the efficacy of BRV during long-term exposure. The other 
objectives are to explore direct cost parameters and to assess the effect of BRV 1) on 
behavior and cognition using the age-appropriate Achenbach Child Behavior Checklist 
(CBCL/1½-5 or CBCL/6-18) for LTFU subjects ≥18 months of age at Baseline of their initial 
BRV study (herein referred to as their “core study”) and for all directly enrolled subjects, 
2) on cognition using the Behavior Rating Inventory of Executive Function® 
(BRIEF®)/BRIEF®-Preschool Version (BRIEF®-P), and 3) on quality of life using the 
Pediatric Quality of Life Inventory™ (PedsQL™) for LTFU subjects ≥2 years of age at the 
Baseline of the core study and for all directly enrolled subjects. The Bayley Scales of Infant 
and Toddler Development®, Third Edition (Bayley-III®) will be used to assess LTFU subjects 
enrolled in English-speaking countries and in countries where a validated translation is 
available and <18 months of age at Baseline of the core study; the Bayley-III will not be used 
to assess directly enrolled subjects since all are to be ≥4 years of age. 
The LTFU subjects will enter directly into the Evaluation Period at the Entry Visit (EV) and 
will continue BRV treatment at the individualized dose they were receiving at the completion 
of their core study. Directly enrolled subjects will enter N01266 at the Screening Visit (ScrV) 
and then participate in up to 3 weeks of an Up-Titration Period. If a directly enrolled subject 
demonstrates, in the opinion of the Investigator, acceptable tolerability and seizure control on 
the same daily dose of BRV (no lower than 1mg/kg/day) for 7±2 days during the 
Up-Titration Period, the subject will attend the EV and enter the Evaluation Period on that 
dose. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able to tolerate the minimum dose specified in the 
core study to be eligible for entry into the Evaluation Period of N01266. All directly enrolled 
subjects must be able to tolerate at least 1mg/kg/day during the Up-Titration Period prior to 
entering the Evaluation Period of N01266, as indicated in Section 7.2. 
The maximum allowable BRV dose is 5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose of 
200mg/day. Subjects will receive oral solution or tablets, as appropriate. With the exception 
of dose adjustments for BRV during the Up-Titration Period, which should be made in 
accordance with the protocol-specified guidelines, dose adjustments of BRV and any 
concomitant antiepileptic drugs (AEDs) are allowed at any time based on clinical judgment. 
Subjects will receive BRV treatment in this study for at least 3 years, until approval of BRV 
has been obtained for pediatric subjects in their age range, until a managed access program is 
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established as allowed per country-specific requirements in addition to legal and regulatory 
guidelines, until subjects transition to another BRV study, or until the investigational product 
development in the related age range of the pediatric population is stopped by the Sponsor, 
whichever comes first. 
For LTFU subjects, the EV is the first study visit. For directly enrolled subjects, the EV 
occurs after subjects have completed the ScrV and at least 1 Titration Visit (TV), and have 
maintained acceptable tolerability and seizure control on the same daily dose of BRV (no 
lower than the minimum specified dose) for 7±2 days of the Up-Titration Period. For subjects 
who continue in this study until it ends, the Evaluation Period will extend from the EV until 
the final evaluation visit (Final Visit, FV). For subjects who prematurely discontinue the 
study, the Evaluation Period will last from the EV until the Early Discontinuation Visit 
(EDV), followed by a maximum 4-week Down-Titration Period, a 2-week Safety 
(Drug-Free) Period, and a final Safety Visit (SV). Subjects already enrolled in N01266 may 
participate in EP0065 (an intravenous [iv] BRV study for pediatric subjects), if eligible, and 
then resume participation in N01266.  
During the Evaluation Period, Minimal Evaluation Visits (MEVs) and Full Evaluation Visits 
(FEVs) will be performed alternatively every month during the first 3 months and every 
3 months thereafter, with a Yearly Evaluation Visit (YEV) every 12 months. 
Safety variables include adverse events (AEs), safety laboratory assessments (hematology, 
biochemistry including hepatic monitoring of alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], total bilirubin, and 
gamma-glutamyltransferase [GGT], and endocrinology for all subjects and urinalysis for 
subjects for whom sample collection is feasible), plasma concentrations of BRV and 
phenytoin (if applicable), electrocardiograms (ECGs), vital signs, physical and neurological 
examinations, psychiatric and mental status, body weight, height, and head circumference. 
All efficacy variables will be considered exploratory in nature. Seizure counts will be based 
on the daily record card (DRC) information or electroencephalograms (EEGs) and the disease 
characteristics of each subject. 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital 
stays) and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18), BRIEF-P/BRIEF, 
and PedsQL scores, and the change in Bayley-III scales for subjects enrolled in 
English-speaking countries and countries where a validated translation is available.  
Up to 600 subjects may possibly enroll in this study. The number and location of sites will 
depend on those participating in core studies from which LTFU subjects will be enrolled, and 
those participating in direct enrollment. Sites of direct enrollment will include, but not be 
limited to, sites participating in core studies. 
2 INTRODUCTION 
2.1 
Background regarding targeted disease 
Epilepsy is the second most prevalent neurological disorder in the world. It is estimated that 
almost 70 million people suffer from epilepsy (Ngugi et al, 2011). Epilepsy affects about 4 to 
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6 out of 1,000 children aged less than 20 years old, and the overall annual incidence rates of 
epilepsy for all seizure types for all children aged less than 19 years range between 45 and 
86 out of 100,000 children. Long-term prognosis of epilepsy varies across several factors 
such as types of syndromes, etiology, and presence of co-morbidities.  
The existing treatment options for epilepsy in childhood generally follow the treatment 
options for adults, and clinical experience demonstrates that children may benefit from the 
administration of conventional AEDs for the treatment of partial-onset seizures (POS) with 
comparable results to adults. Despite the availability of new AEDs, more than 25% of 
pediatric patients have inadequate seizure control on currently available AEDs, or experience 
significant adverse drug effects (Hadjiloizou and Bourgeois, 2007). Thus, there remains a 
need for potent AEDs with a positive benefit-risk profile in this population. 
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 is 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 purposes of this study, the seizure type classification will follow the 1981 
International League Against Epilepsy (ILAE) classification of epileptic seizures, which 
classifies partial seizures as simple partial seizures (no alteration of consciousness), complex 
partial seizures (with alteration of consciousness), and secondarily generalized seizures, and, 
on the other hand, classifies 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 (Commission on Classification and Terminology of the ILAE, 
1981).  
Likewise, the classification of epilepsy syndromes will be used according to the 1989 
ILAE publication (Commission on Classification and Terminology of the ILAE, 1989). 
2.2 
Background information regarding product 
Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) displays a 
high and selective affinity for the synaptic vesicle protein 2A (SV2A) in the brain. Binding to 
SV2A is believed to be the primary mechanism for BRV anticonvulsant activity. In 2016, 
marketing authorization for the use of oral and iv BRV as adjunctive treatment of 
partial-onset seizures (POS) in patients 16 years of age and older with epilepsy was granted in 
the EU, US, Australia, and Switzerland, and in Canada for patients 18 years and older with 
epilepsy. 
More detailed information regarding the nonclinical and clinical development programs for 
BRV, including all completed and ongoing studies, is provided in the Investigator’s 
Brochure. 
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2.3 
Rationale for the study 
N01266 is designed for pediatric subjects ≥1 month to <17 years of age who have completed 
core studies (LTFU subjects) and for at least 100 subjects ≥4 years to <17 years of age with 
POS who have not participated in a core study (directly enrolled subjects). The total 
enrollment planned for N01266 is approximately 600 subjects.  
N01266 will provide long-term safety and tolerability data on BRV in pediatric subjects with 
epilepsy, while providing access to BRV for subjects who may benefit from long-term 
treatment. The enrollment of directly enrolled subjects is intended to provide both long-term 
safety and tolerably data and efficacy data for subjects 4 years to <17 years of age with POS 
to supplement data collected for subjects with POS in N01263. 
Subjects will receive BRV treatment in this study for at least 3 years, until approval of BRV 
has been obtained for pediatric subjects in their age range, until a managed access program is 
established as allowed per country-specific requirements in addition to legal and regulatory 
guidelines, until subjects transition to another BRV study, or until the investigational product 
development in the related age range of the pediatric population is stopped by the Sponsor, 
whichever comes first.  
Subjects already enrolled in N01266 may participate in EP0065, if eligible, and then resume 
participation in N01266.  
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
• To document the long-term safety and tolerability of BRV 
3.2 
Secondary objective 
• To assess the efficacy of BRV during long-term exposure 
3.3 
Other objectives 
• To explore direct cost parameters 
• To assess the effect of BRV on behavior using the Achenbach CBCL in subjects ≥18 months 
of age 
• To explore the effect of BRV on cognition using the BRIEF-P/BRIEF in subjects ≥2 years of 
age 
• To assess the effect of BRV on cognition using the Bayley-III scales in subjects <18 months 
of age (applicable only to LTFU subjects enrolled in English-speaking countries and 
countries where a validated translation is available)  
• To explore the effect of BRV on health-related quality of life (HRQoL) using the PedsQL in 
subjects ≥ 2 years of age 
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4 
STUDY VARIABLES 
4.1 
Primary variables 
• Treatment-emergent AEs 
• Treatment-emergent serious adverse events (SAEs) 
4.2 
Secondary variables 
For subjects ≥2 years of age (based on DRC data): 
• Absolute change in 28-days adjusted POS frequency from Baseline to the end of the 
Evaluation Period (subjects with POS only) 
• Percent change in 28-days adjusted POS frequency from Baseline to the end of the 
Evaluation Period (subjects with POS only) 
• 50% responder rate for total seizures (all types) 
For subjects <2 years of age (based on EEG data [recorded at least 24 hours]) or subjects with 
typical absence seizures (based on EEG data): 
• Absolute change in average daily frequency (ADF) of POS (subjects with POS only) 
• Percent change in ADF of POS (subjects with POS only) 
• 50% responder rate for total seizures (all types) 
4.3 
Other variables 
For subjects ≥2 years of age (based on DRC data): 
• Responder rate (the percentage of subjects who have a ≥50% reduction in seizure 
frequency per 28 days from Baseline for POS) 
• Absolute change in seizure frequency (total seizures) per 28 days from Baseline to the 
end of the Evaluation Period 
• Percent change in seizure frequency (total seizures) per 28 days from Baseline to the end 
of the Evaluation Period 
• Seizure freedom over the Evaluation Period 
• Proportion of seizure-free days over the Evaluation Period 
For subjects <2 years of age or subjects with absence seizures based on the DRC seizure 
counts:  
• Seizure freedom rate over the Evaluation Period (all types) by visit and by time intervals 
(6 months, 12 months, etc.)  
• Proportion of seizure-free days over the Evaluation Period (all types) and by time 
intervals (6 months, 12 months, etc.)  
• Absolute worsening in ADF of total seizures (all types)  
• Percent worsening in ADF of total seizures (all types)  
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• A descriptive summary of seizure frequency by visit based on the DRC data will be also 
provided for these subjects 
In addition for subjects <2 years of age (based on EEG data [recorded at least 24 hours]) or 
subjects with absence seizures (based on EEG data):  
• Responder rate for total POS defined as the percentage of subjects with a ≥50% reduction 
in ADF of POS recorded on EEG 
• Absolute change in ADF of total seizures (all types) 
• Percent change in ADF of total seizures (all types) 
• Seizure freedom (rate and proportion) 
• Absolute worsening of other types of seizures  
• Percent worsening of other types of seizures 
For subjects with absence seizures: 
• Number and type of nonabsence seizure 
For all subjects: 
• Physical (including Tanner staging, if applicable depending on subject’s developmental 
status) 
• Neurological examinations 
• Psychiatric and mental status 
• Laboratory tests (hematology, biochemistry including hepatic monitoring of ALT, AST, 
ALP, total bilirubin, and GGT, endocrinology [follicle-stimulating hormone, luteinizing 
hormone, thyroid-stimulating hormone, triiodothyronine, and tetraiodothyronine] for all 
subjects and urinalysis for subjects for whom sample collection is feasible) (See 
Section 9.2.1) 
• ECG 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight  
• Height and head circumference  
• Plasma concentrations of BRV and phenytoin (if applicable) 
• Direct cost parameters: concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and hospital stays 
• Change from Baseline in the Achenbach CBCL score: the Achenbach CBCL/1½-5 for 
children from 1½ to 5 years old and the Achenbach CBCL/6-18 for children 6 years and 
older (age at initiation of study drug in N01266 or core study) 
• Change from Baseline in the BRIEF-P/BRIEF score for subjects ≥2 years of age (age at 
initiation of study drug in N01266 or core study) 
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• Change from the Baseline in the Bayley-III scales for children <18 months of age at 
baseline of the core study (applicable only to LTFU subjects enrolled in English-speaking 
countries and in countries where a validated translation is available)  
• Change from Baseline in PedsQL for subjects ≥2 years of age (age at initiation of study 
drug in N01266 or core study) 
5 
STUDY DESIGN 
5.1 
Study description 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety 
and efficacy of BRV in up to 600 subjects with epilepsy. Subjects who enroll in N01266 from 
a core study (ie, LTFU subjects) must have been <16 years of age upon entry in the core 
study; eligible subjects who have POS and enroll in N01266 without having participated in a 
core study (ie, directly enrolled subjects) must be ≥4 years to <17 years of age. 
Upon enrollment, eligible LTFU subjects will enter the Evaluation Period and continue their 
BRV treatment in accordance with their individualized dose at the completion of the core 
study. Directly enrolled subjects will be screened and participate in up to 3 weeks of an 
Up-Titration Period. If a directly enrolled subject demonstrates, in the opinion of the 
Investigator, acceptable tolerability and seizure control on the same daily dose of BRV (no 
lower than the minimum specified dose) for 7±2 days during the Up-Titration Period, the 
subject will attend the EV and enter the Evaluation Period on that dose. The subjects already 
enrolled in N01266 who then participate in EP0065 will resume dosing in N01266 in 
accordance with the individualized dose they received at the completion of EP0065. 
Brivaracetam (tablet and oral solution) should be administered bid in 2 equally divided doses. 
All LTFU subjects must be able to tolerate the minimum BRV dose specified in the core 
study to be eligible for entry into the Evaluation Period of N01266. All directly enrolled 
subjects must be able to tolerate at least 1mg/kg/day during the Up-Titration Period prior to 
entering the Evaluation Period of N01266, as indicated in Section 7.2. 
For all subjects enrolled in N01266, the maximum BRV dose is 5.0mg/kg/day (2.5mg/kg 
bid), not to exceed a dose of 200mg/day. Subjects will receive oral solution or oral tablets, as 
appropriate. Dose adjustments of BRV and/or concomitant AEDs are allowed at any time 
based on clinical judgment; however, during the Up-Titration Period, dose adjustments for 
BRV should be made only as specified in Section 7.2.1. Additional information on BRV 
administration is presented in Section 7.2.  
For LTFU subjects, the EV is the first study visit. For directly enrolled subjects, the EV is the 
visit at which subjects enter the Evaluation Period and occurs after subjects have completed 
the ScrV and at least 1 Titration Visit (TV). For subjects who continue in the study until it 
ends, the Evaluation Period will extend from the EV to the FV. For subjects who prematurely 
discontinue the study, the Evaluation Period will last from the EV until the EDV. Following 
the EDV, or following the FV for subjects who complete the study but do not continue BRV 
treatment, subjects will have their BRV dose reduced by a maximum of half the dose every 
week for a maximum of 4 weeks until a dose of 1mg/kg/day (50mg/day for subjects with 
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body weights >50kg) is reached. After 2 weeks free of study drug (Safety Period), subjects 
will complete the SV.  
During the Evaluation Period, MEVs and FEVs will be performed alternatively every month 
during the first 3 months and every 3 months thereafter, with a YEV every 12 months. The 
sequence of these visits is presented in Section 5.3. Enrolled subjects who participate in 
EP0065 and then resume participation N01266 will maintain the visit schedule established for 
them in N01266 before participation in EP0065.  
Both safety data and efficacy data (seizure data) will be collected during the study. Lists of 
the study assessments performed at each of the visits are presented in Section 5.2.  
No formal interim analysis is planned; however, data may be reported prior to the completion 
of this study (see Section 12.8).  
5.1.1 
Study duration per subject 
Subject participation will extend from study entry for at least 3 years until approval of BRV 
has been obtained for pediatric subjects in their age range, until a managed access program is 
established as allowed per country-specific requirements in addition to legal and regulatory 
guidelines, until subjects transition to another BRV study, or until the investigational product 
development in the related age range of the pediatric population is stopped by the Sponsor, 
whichever comes first.  
Study entry is defined as the EV for LTFU subjects and the ScrV for directly enrolled 
subjects. 
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  
N01266 is planned for a total enrollment of approximately 600 subjects, including at least 
100 eligible directly enrolled subjects ≥4 years to <17 years of age with POS. 
5.1.3 
Anticipated regions and countries 
The LTFU subjects will be enrolled in regions and countries participating in the core studies. 
Enrollment is planned for Europe, US, and Mexico, with the possibility to extend to other 
countries and regions if deemed necessary.  
Directly enrolled subjects may be enrolled from sites participating in core studies and 
possibly other sites. 
5.2 
Schedules of study assessments 
Table 5‒1 provides a schedule of assessments for the EV (all subjects). Table 5‒2 provides a 
schedule of assessments for the Evaluation, Down-Titration, and Safety (Drug-Free) Periods 
(all subjects). Table 5‒3 provides a schedule of study assessments from the ScrV through the 
final TV (directly enrolled subjects only). 
 
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Table 5‒1: 
Schedule of assessments for the Entry Visit (EV) (all subjects)  
 
Subjects 
LTFU 
DE 
Core study: 
N01349 
EP0065 
Othera 
Not applicable 
Assessment 
 
 
 
Written informed consent 
X 
X 
X 
 
Assent form (if applicable, according to age and local 
requirements) 
 
X 
X 
 
Subject identification card dispensing 
X 
X 
X 
 
Childbearing potential  
 
X 
X 
X 
Verification inclusion/exclusion criteria 
X 
X 
X 
 
Demographic data 
X 
X 
X 
 
General medical history 
Xc 
Xc 
Xc 
 
Procedure history 
X 
Xc 
Xc 
 
Epilepsy history 
 
X 
Xc 
 
AED history 
X 
Xc 
Xc 
 
Physical and neurological examinations 
Xb 
Xb 
Xb 
X 
Psychiatric and mental status 
X 
X 
Xb 
X 
Vital signsd 
X 
Xb 
Xb 
X 
Body weight 
X 
Xb 
Xb 
X 
Height 
Xc 
X 
Xc 
X 
Head circumference 
Xc 
X 
Xb 
X 
ECG 
X 
Xb 
Xb 
X 
DRC dispensed 
X 
X 
X 
X 
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Table 5‒1: 
Schedule of assessments for the Entry Visit (EV) (all subjects)  
 
Subjects 
LTFU 
DE 
Core study: 
N01349 
EP0065 
Othera 
Not applicable 
DRC retrieved 
 
 
 
X 
Seizure count  
X 
Xc 
Xb 
X 
Recording of medicationse 
Xb 
Xb 
Xb 
X 
Recording of procedures 
X 
X 
Xb 
X 
Recording of AEsf 
Xb 
Xb 
Xb 
X 
IVRS call 
X 
X 
X 
X 
Study drug dispensed 
X 
X 
X 
X 
Study drug returnedg 
 
 
 
X 
Study drug compliance 
 
 
 
X 
Laboratory assessments for safetyh 
Xb 
Xc 
Xb 
X 
Phenytoin plasma concentrations, if applicable 
 
 
Xb 
 
C-SSRSi 
 
Xb 
Xb 
X 
Bayley-III scalesj 
Xb 
X 
Xc 
 
Achenbach CBCLk 
 
X 
Xc 
 
BRIEF-P/BRIEFl 
 
X 
Xc 
 
PedsQLm 
 
X 
Xc 
 
Health care provider consultations not foreseen by protocol 
 
 
Xb 
X 
Hospital stays 
 
 
Xb 
X 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF=Behavior Rating Inventory of Executive Function; 
BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; CBCL=Child Behavior Checklist; 
C-SSRS=Columbia-Suicide Severity Rating Scale; DE=directly enrolled; DRC=daily record card; ECG=electrocardiogram; eCRF=electronic case report 
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Table 5‒1: 
Schedule of assessments for the Entry Visit (EV) (all subjects)  
 
Subjects 
LTFU 
DE 
Core study: 
N01349 
EP0065 
Othera 
Not applicable 
form; EDV=Early Discontinuation Visit; EEG=electroencephalogram; EV=Entry Visit; GGT=gamma-glutamyltransferase; IVRS=interactive voice 
response system; LTFU=long-term follow-up; PedsQL=Pediatric Quality of Life Inventory; SAE=serious adverse event 
a Other” core studies include those other than EP0065 and N01349. 
b To be obtained from the final visit of the core study and not recorded in the N01266 eCRF.   
c To be obtained from baseline of the core study and not recorded in the N01266 eCRF. 
d Vital sign measurements include blood pressure, pulse rate, and body temperature.  
e Any ongoing concomitant medication at the time the subject completed the core study should not be recorded in the N01266 eCRF. Changes in ongoing 
concomitant medications should be recorded in the N01266 eCRF. 
f Any ongoing AEs at the time the subject completed the core study should not be recorded in the N01266 eCRF. Worsening of the AE should be recorded in 
the N01266 eCRF as a new AE. A pharmacokinetic sample for determination of BRV plasma concentration should be taken whenever a subject experiences 
an SAE. 
g Drug return includes study medication intake recording and accountability. 
h Full laboratory assessments for safety include hematology and biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT) 
for all subjects, endocrinology for LTFU subjects, and urinalysis for all subjects for whom sample collection is feasible as described in Section 9.2.1. 
Female subjects of childbearing potential will have a urine pregnancy test done at the site.  
i The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” version of the C-SSRS will be used. If a subject turns 6 years of age 
during the study, the “Already Enrolled” version of the C SSRS should be completed at the first visit after the sixth birthday. 
j The Bayley-III is applicable to subjects enrolled in English-speaking countries and in countries where a validated translation is available only and as follows: 
• 
Core study N01349: all subjects  
• 
Core study EP0065: subjects <18 months of age at baseline (Screening)  
• 
Other core studies: subjects <18 months of age at baseline for the core study (as indicated in footnote c)  
k The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) should be in accordance with the subject’s age. 
l The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF should be used for subjects ≥5 years of age. 
m The version of the PedsQL used should be consistent with the subject’s age.  
 
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Table 5‒2: 
Schedule of all study assessments for the Evaluation, Down-Titration, and Safety (Drug-Free) 
Periods (all subjects) 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
Free) 
Visit 
Minimal 
Evaluation Visit 
(MEV) 
Full Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(FEV) 
(YEV/FVa) 
(UV) 
(EDV) 
(DTV)b 
(SV) 
Assessment 
 
Childbearing potential  
X 
X 
X 
 
X 
 
 
Physical and 
neurological 
examinations 
 
X 
X 
 
X 
 
X 
Psychiatric and mental 
status 
 
X 
X 
 
X 
 
X 
Vital signsc 
X 
X 
X 
 
X 
X 
X 
Body weight, height, 
and head 
circumference 
X 
X 
X 
 
X 
 
X 
ECGd 
 
 
X 
 
X 
 
Xe 
EEGf 
 
X 
X 
 
X 
 
 
DRC dispensed 
X 
X 
Xg 
 
X 
X 
 
DRC retrieved 
X 
X 
X 
 
X 
X 
X 
Seizure count  
X 
X 
X 
 
X 
X 
X 
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Table 5‒2: 
Schedule of all study assessments for the Evaluation, Down-Titration, and Safety (Drug-Free) 
Periods (all subjects) 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
Free) 
Visit 
Minimal 
Evaluation Visit 
(MEV) 
Full Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(FEV) 
(YEV/FVa) 
(UV) 
(EDV) 
(DTV)b 
(SV) 
Assessment 
 
Assessment of seizure 
typesh 
 
X 
X 
 
 
 
 
Recording of 
medicationsi 
X 
X 
X 
X 
X 
X 
X 
Recording of 
procedures 
X 
X 
X 
X 
X 
X 
X 
Recording of AEsj 
X 
X 
X 
X 
X 
X 
X 
IVRS 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensed 
X 
X 
Xg 
 
X 
 
 
Study drug returnedk 
X 
X 
X 
 
X 
X 
 
Study drug compliance 
X 
X 
X 
 
X 
X 
 
Laboratory 
assessments for safetyl 
Xm 
X 
X 
 
X 
 
Xe 
BRV plasma 
concentrationsn 
 
X 
X 
 
X 
 
 
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Table 5‒2: 
Schedule of all study assessments for the Evaluation, Down-Titration, and Safety (Drug-Free) 
Periods (all subjects) 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
Free) 
Visit 
Minimal 
Evaluation Visit 
(MEV) 
Full Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(FEV) 
(YEV/FVa) 
(UV) 
(EDV) 
(DTV)b 
(SV) 
Assessment 
 
Phenytoin plasma 
concentrations, if 
applicable 
 
X 
X 
 
X 
 
Xe 
C-SSRSo 
X 
X 
X 
Xp 
X 
X 
X 
Bayley-III scalesq 
 
X 
X 
 
X 
 
 
Achenbach CBCLr 
 
X 
X 
 
X 
 
 
BRIEF-P/BRIEFs 
 
X 
X 
 
X 
 
 
PedsQLt 
 
X 
X 
 
X 
 
 
Health care provider 
consultations not 
foreseen by protocol 
X 
X 
X 
X 
X 
X 
X 
Hospital staysu 
X 
X 
X 
X 
X 
X 
X 
End of study status 
 
 
Xv 
 
 
 
X 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF=Behavior Rating Inventory of Executive Function; 
BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; CBCL=Child Behavior Checklist; 
C-SSRS=Columbia-Suicide Severity Rating Scale; DE=directly enrolled; DRC=daily record card; DTV=Down-Titration Visit; ECG=electrocardiogram; 
eCRF=electronic case report form; EDV=Early Discontinuation Visit; EEG=electroencephalogram; EV=Entry Visit; FEV= Full Evaluation Visit; FV=Final 
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Table 5‒2: 
Schedule of all study assessments for the Evaluation, Down-Titration, and Safety (Drug-Free) 
Periods (all subjects) 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
Free) 
Visit 
Minimal 
Evaluation Visit 
(MEV) 
Full Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(FEV) 
(YEV/FVa) 
(UV) 
(EDV) 
(DTV)b 
(SV) 
Assessment 
 
Visit; GGT=gamma-glutamyltransferase; IVRS=interactive voice response system; LTFU=long-term follow-up; M=Month; MEV=Minimal Evaluation 
Visit; PedsQL=Pediatric Quality of Life Inventory; SAE=serious adverse event; SV=Safety Visit; TV=Titration Visit; UV=Unscheduled Visit; V=Visit; 
YEV=Yearly Evaluation Visit 
a For subjects staying in the study until it ends, the same procedures as for a YEV should be performed at the subject’s FV. 
b Visit should be scheduled at the end of the Down-Titration Period. The duration of the Down-Titration Period will depend on when the final dose of the 
study drug was taken during the Evaluation Period, with a maximum duration of 4 weeks. 
c Vital sign measurements include blood pressure, pulse rate, and body temperature.  
d An ECG has to be scheduled once a year at the YEV and at the EDV in the case of early discontinuation. 
e At the SV, ECGs, laboratory assessments for safety, and determination of phenytoin plasma concentration will be performed only if abnormal at the EDV. 
f EEG (for LTFU subjects only) 
• 
For subjects ≥2 years of age at V5 who have typical absence seizures, an EEG of at least 1 hour that includes hyperventilation and intermittent 
photic stimulation must be performed at V5 and yearly thereafter. For subjects prematurely discontinuing from the study, an at least 1-hour EEG 
may be performed at the EDV at the Investigator’s discretion. 
• 
For subjects <2 years of age at V5, an EEG of at least 24 hours must be performed for efficacy assessment at V5 and yearly thereafter until subjects 
reach 2 years of age. For subjects prematurely discontinuing from the study, an at least 24-hour EEG may be performed at the EDV at the 
Investigator’s discretion. 
g No DRC or study drug will typically be dispensed at the FV. However, for subjects who complete the study but do not continue BRV treatment, study drug 
for down-titration will be dispensed. 
h The assessment of seizure types will be done at 6-monthly intervals (at the FEV and the YEV) for subjects <2 years of age. 
i For subjects enrolled in N01266 who volunteered to participate in EP0065 and then returned to N01266, changes to ongoing concomitant medications 
during EP0065 will be recorded in the N01266 eCRF. 
j For subjects enrolled in N01266 who volunteered to participate in EP0065 and then returned to N01266, ongoing AEs that stop during EP0065 will be 
recorded in the N01266 eCRF. 
k Drug return includes study medication intake recording and accountability. 
l Full laboratory assessments for safety include hematology, biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), and 
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Table 5‒2: 
Schedule of all study assessments for the Evaluation, Down-Titration, and Safety (Drug-Free) 
Periods (all subjects) 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
Free) 
Visit 
Minimal 
Evaluation Visit 
(MEV) 
Full Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(FEV) 
(YEV/FVa) 
(UV) 
(EDV) 
(DTV)b 
(SV) 
Assessment 
 
endocrinology for all subjects and urinalysis for subjects for whom sample collection is feasible as described in Section 9.2.1. Female subjects of 
childbearing potential should have a urine pregnancy test done at the site at all laboratory assessment visits. Endocrinology testing will be performed at the 
YEV/FV.  
m Additional hepatic monitoring laboratory assessments (ALT, AST, ALP, total bilirubin, and GGT only) are to be done only at the MEV at V4 (M3) and V6 
(M9). Urine pregnancy tests are to be done at the site for female subjects of childbearing potential at all visits. 
n In addition to the scheduled assessments, a pharmacokinetic sample for determination of BRV plasma concentration should be taken whenever a subject 
experiences an SAE. 
o The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” version of the C-SSRS will be used, with the following exception: If a 
subject turns 6 years of age during N01266, the “Already Enrolled” version of the C-SSRS should be completed at the first visit after the sixth birthday, and 
the “Since Last Visit” version of the C-SSRS should be completed at subsequent visits.  
p If an unscheduled visit is conducted due to safety or efficacy reasons, the C-SSRS will be performed for subjects ≥6 year of age. 
q The Bayley-III is applicable to subjects who meet all of the following criteria: are enrolled in English-speaking countries and in countries where a validated 
translation is available, were <18 months of age at baseline of the core study, and are <42 months of age.  
r The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) should be in accordance with the subject’s age, with the following exception: If a 
subject completed the Achenbach CBCL/1½-5 at the Baseline assessment and turns 6 years of age between that assessment and the initial YEV, the 
CBCL/1½-5 should be completed through and including the initial YEV, and subsequently the CBCL/6-18 should be completed.  
s The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF should be used for subjects ≥5 years of age, with the following 
exception: For subjects who completed the BRIEF-P at the Baseline assessment and turns 5 years of age between that assessment and the initial YEV, the 
BRIEF-P should be completed through and including the initial YEV, and subsequently the BRIEF should be completed. 
t The version of the PedsQL used should be consistent with the subject’s age at each visit when it is administered with the following exception: If a subject 
ages up to the next PedsQL between the Baseline assessment and the initial YEV, the PedsQL that was used at the Baseline assessment should be 
completed through and including the initial YEV, and subsequently the PedsQL consistent with the age at the time of assessment should be completed. 
u This refers to any hospital stay that occurs during the study. Data recorded in the eCRF include the reason for the hospitalization, the admission ward, 
transfers, and length of stay. 
v End of study status only for subjects who continue in the study until it ends and for whom the visit corresponds to the final evaluation visit or FV.  
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Table 5‒3: 
Schedule of study assessments from the ScrV through the final TV (directly enrolled subjects only) 
Period 
Screeninga 
Up-Titration 
Visit 
Screening 
Titration Visit 1 
Titration Visit 2 
Titration Visit 3 
(ScrV) 
(TV1) 
(TV2) 
(TV3) 
Assessment 
 
Written informed consent/assent 
X 
 
 
 
Subject identification card dispensing 
X 
 
 
 
Demographic data 
X 
 
 
 
Childbearing potential 
X 
 
 
 
Verification inclusion/exclusion criteria 
X 
X 
 
 
Physical and neurological examinations 
X 
 
 
 
Psychiatric and mental status 
X 
 
 
 
General medical and procedures history 
X 
 
 
 
Epilepsy and AED history 
X 
 
 
 
Vital signsb 
X 
X 
X 
X 
Body weight, height, and head circumferencec 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
EEGd 
X 
 
 
 
Neuro-imaging proceduree 
X 
 
 
 
DRC dispensedf 
X 
X 
X 
X 
DRC retrieved 
 
X 
X 
X 
Seizure count 
 
X 
X 
X 
Recording of medications 
X 
X 
X 
X 
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Table 5‒3: 
Schedule of study assessments from the ScrV through the final TV (directly enrolled subjects only) 
Period 
Screeninga 
Up-Titration 
Visit 
Screening 
Titration Visit 1 
Titration Visit 2 
Titration Visit 3 
(ScrV) 
(TV1) 
(TV2) 
(TV3) 
Assessment 
 
Recording of procedures 
X 
X 
X 
X 
Recording of AEsg 
X 
X 
X 
X 
IVRS call 
X 
X 
X 
X 
Study drug dispensed 
 
X 
X 
X 
Study drug returnedh 
 
 
X 
X 
Study drug compliance 
 
 
X 
X 
Laboratory assessments for safetyi 
X 
 
X 
X 
Phenytoin plasma concentrations 
X 
 
 
 
C-SSRSj 
X 
X 
X 
X 
Achenbach CBCLk 
X 
 
 
 
BRIEF-P/BRIEFl 
X 
 
 
 
PedsQLm 
X 
 
 
 
Health care provider consultations not foreseen 
by protocol 
 
X 
X 
X 
Hospital staysn 
 
X 
X 
X 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BRIEF=Behavior 
Rating Inventory of Executive Function; BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; CBCL=Child 
Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; DRC=daily record card; ECG=electrocardiogram; eCRF=electronic case report form; 
EEG=electroencephalogram; EV=Entry Visit; GGT=gamma-glutamyltransferase; IVRS=interactive voice response system; PedsQL=Pediatric Quality of 
Life Inventory; POS=partial-onset seizure; SAE=serious adverse event; ScrV=Screening Visit; TV=Titration Visit 
a The Screening Period will serve as the Baseline Period for directly enrolled subjects. Directly enrolled subjects will begin receiving BRV at TV1 after all 
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Table 5‒3: 
Schedule of study assessments from the ScrV through the final TV (directly enrolled subjects only) 
Period 
Screeninga 
Up-Titration 
Visit 
Screening 
Titration Visit 1 
Titration Visit 2 
Titration Visit 3 
(ScrV) 
(TV1) 
(TV2) 
(TV3) 
Assessment 
 
inclusion and exclusion criteria are met. 
b Vital sign measurements include blood pressure, pulse rate, and body temperature.  
c Height and head circumference will be recorded only at the ScrV. 
d A previous EEG documenting the diagnosis of POS must be available at the ScrV. If an EEG is not available at the ScrV, it must be scheduled during the 
Screening Period. 
e A neuro-imaging procedure (brain magnetic resonance imaging/brain computerized tomography scan [except in Germany]/ultrasounds or any other imaging 
test) should be performed if no report is available within the previous 2 years. 
f Seizure counts are collected in the subject’s DRC on a daily basis. 
g A pharmacokinetic sample for determination of BRV plasma concentration should be obtained whenever a subject experiences an SAE. 
h Drug return includes study medication intake recording and accountability. 
i The ScrV laboratory assessments for safety will include hematology, biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT), urinalysis (for subjects for whom sample collection is feasible), endocrinology, and a urine pregnancy test at the site (for female subjects of 
childbearing potential). The TV laboratory assessments for safety will include only hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT. 
Laboratory samples should be collected at TV2 only if the Investigator anticipates that it will be the final TV before the subject advances to the EV. The 
decision for treatment at TV1 will include the results of the laboratory sample collected at the ScrV. 
j The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” version of the C-SSRS is to be used with the following exceptions: 1) 
the “Baseline/Screening” version of the C-SSRS should be used at the ScrV, and 2) if a subject turns 6 years of age during N01266, the “Already Enrolled” 
version of the C-SSRS should be completed at the first visit after the sixth birthday, and the “Since Last Visit” version of the C-SSRS should be completed at 
subsequent visits. 
k The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) used at the ScrV should be in accordance with the subject’s age at this visit.  
l The BRIEF-P should be used for subjects <5 years of age at the ScrV. The BRIEF should be used for subjects ≥5 years of age at the ScrV. 
m The version of the PedsQL used should be consistent with the subject’s age at the ScrV.  
n This refers to any hospital stay that occurs during the study. Data recorded in the eCRF include the reason for the hospitalization, the admission ward, 
transfers, and length of stay. 
 
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5.3 
Visit sequence 
Study visits are to be scheduled in the order presented in the following table: 
Table 5‒4: 
Visit sequence 
Directly enrolled subjects 
 
Visit 
Type of visit 
 
ScrV 
Screening 
W1  
TV1 a  
TV 
W2 
TV2 a 
TV 
W3 
TV3 a 
TV 
All subjects 
First year follow-up 
M0 
V1 
EVb 
M1 
V2 
MEV 
M2 
V3 
FEV 
M3 
V4 
MEVc 
M4 
- 
- 
M5 
- 
- 
M6 
V5 
FEV 
M7 
- 
- 
M8 
- 
- 
M9 
V6 
MEVc 
M10 
- 
- 
M11 
- 
- 
Second and subsequent years follow-upd 
M12 
V7 
YEV 
M15 
V8 
MEV 
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Table 5‒4: 
Visit sequence 
M18 
V9 
FEV 
M21 
V10 
MEV 
and every 3 months thereafter 
V11, V12, etc 
YEV, MEV, etc 
BRV=brivaracetam; EV=Entry Visit; FEV=Full Evaluation Visit; LTFU=long-term follow-up; M=Month; 
MEV=Minimal Evaluation Visit; ScrV=Screening Visit; TV=Titration Visit; V=Visit; W=Week; YEV=Yearly 
Evaluation Visit 
Note: Visits at W1, W2, W3, and M0 will occur 7±2 days after the previous visit; visits at M1, M2, and M3 will 
occur 30±7 days after the previous visit; visits at M6, M9, M12, M15, M18, M21, and every 3 months 
thereafter will occur 90±15 days after the previous visit. 
“-” denotes that no visit is scheduled in that month. 
a All directly enrolled subjects must participate in at least TV1, but may participate in fewer than 3 TVs as 
described in Section 7.2.1. 
b For directly enrolled subjects, the EV represents the point of entry into the Evaluation Period. 
c Hepatic monitoring tests only will be performed as described in Section 9.2.1. 
d Subsequent years will follow the same visit schedule. 
5.4 
Rationale for study design and selection of dose 
N01266 will allow BRV long-term safety and tolerability data to be collected from pediatric 
subjects with epilepsy who will have participated in core studies and now have the opportunity to 
continue BRV treatment, and from directly enrolled subjects with POS. The safety and efficacy 
data collected in this study will support the applications for BRV indications in pediatric 
patients. 
Each LTFU subject will begin treatment in N01266 at the individualized BRV dose he/she was 
receiving at the completion of the core study. Enrolled subjects who volunteer to participate in 
EP0065 will resume dosing in N01266 in accordance with the individualized dose they received 
at the completion of EP0065. Directly enrolled subjects will participate in up to 3 weeks of an 
Up-Titration Period. If a subject demonstrates, in the opinion of the Investigator, acceptable 
tolerability and seizure control on the same daily dose of BRV for 7±2 days during the 
Up-Titration Period, the subject will be allowed to enter the Evaluation Period (subject must be 
able to tolerate the minimum dose of 1mg/kg/day; see Section 7.2). 
A physiologically-based PK model (N01313) was developed to predict the doses to be tested in 
N01263. The same doses that were used for up-titration in N01263 will be used for the 
3 consecutive weeks that comprise the Up-Titration Period of N01266. Based on the PK analyses 
performed on the plasma samples collected in N01263, the plasma concentrations approximating 
the concentrations for adults receiving BRV 200mg/day were not achieved by the dosing scheme 
initially included in N01266; as a result, it was recommended that the same doses are to be 
administered in all pediatric subgroups, ≥1 month to ≤16 years of age. For all subjects, the 
approximate doses to be administered are 0.5, 1, and 2mg/kg bid (1, 2, and 4mg/kg/day, 
respectively), with the daily doses not exceeding the maximums of 50mg/day, 100mg/day, and 
200mg/day for Weeks 1, 2, and 3 of up-titration, respectively. The dose selection was based on 
the following observations: 
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• The PK of BRV is linear and of low variability in adults up to 1 order of magnitude above 
the therapeutic dose range. 
• Efficacious doses in adults are expected to be from 50mg/day up to 200mg/day. 
• In N01263, BRV was eliminated more rapidly in pediatric subjects than in adult subjects, 
resulting in a lower plasma concentration. Therefore, clearance of BRV was shown to be 
higher in pediatric subjects than in adult subjects. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able to tolerate the minimum dose specified in the 
core study to be eligible for entry into the Evaluation Period of N01266. All directly enrolled 
subjects must be able to tolerate at least 1mg/kg/day during the Up-Titration Period prior to 
entering the Evaluation Period of N01266, as indicated in Section 7.2.  
The maximum allowable BRV dose in N01266 is 5.0mg/kg/day (2.5mg/kg bid), not to exceed a 
dose of 200mg/day. Subjects will receive oral solution or tablets, as appropriate. 
The maximum BRV dose allowed in this study will be 200mg/day (100mg bid), which is the 
maximum allowed dose for those subjects dosed as adults. 
5.5 
Study conduct due to coronavirus (severe acute respiratory 
syndrome coronavirus-2) disease 2019 
The following applies where normal study conduct is impacted by coronavirus (severe acute 
respiratory syndrome coronavirus-2 [SARS-CoV-2]) disease 2019 (COVID-19). The protocol 
visit schedule should be followed to the extent possible, considering the individual benefit-risk 
assessment by the Investigator. If necessary, remote visits may be conducted and the subjects or 
caregivers will be contacted by telephone or videoconference. Remote follow-up, at minimum 
with a telephone call after 3 months, must be done (preferably more frequently and as needed to 
follow-up on subject safety assessments). 
If a subject needs to be discontinued and cannot come into the study site, then appropriate 
down-titration instructions will be provided, and a visit will be scheduled to perform safety 
assessments as soon as possible (see Section 7.2.3 for down-titration instructions). 
In situations where a subject is unable to return to the study site, Investigators will assess and 
document the subject’s safety via telephone contact. Based on information gathered from the 
telephone contact, Investigators will confirm whether the subject could continue the current 
study treatment based upon the outcome of the safety assessment. Subjects’ agreement to 
implement this procedure should be obtained and documented prior to implementing any 
changes. Changes in the study treatment supply in this situation are described in Section 7.2.4. 
Ad hoc subject contact may be warranted  to understand the current health status of the subjects, 
follow up on AEs and inform them of any protective measures taken by the study site as a result 
of the COVID-19 pandemic (eg, any measures which may limit access to the site or may 
require additional actions by the subject prior to entry to the site).   
Investigators and study coordinators may use discretion when determining the need to perform a 
home visit (eg, for safety laboratory parameters or PK samples). 
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If subjects are unable to return to the study site, protocol deviations will occur (even if the study 
visit is replaced by a home visit or remote visit) (Section 12.6). Investigators must carefully 
document the occurrence of these and any other deviations, clearly noting deviations which 
occurred during and in accordance to the COVID-19 pandemic. 
If a subject visits another facility for a medical issue (or has to switch sites for some 
COVID-19-related reason), the Investigator should request contact with the physician providing 
care to provide a detailed explanation of the subject’s condition and his/her participation in the 
study. Subjects or caregivers shall be reminded to completely collect and keep records of this 
visit. 
In case laboratory assessments cannot be conducted via central laboratory vendor due to 
restricted site access or home visits by Investigators are not an option, local laboratory safety 
assessment may need to be conducted, in a format that allows the Investigator to receive and 
review these results and include as source documentation. 
Deviations to data collection including inability to perform some assessments such as EEG, ECG 
or blood collection for safety laboratory assessments and PK, or alternative methods of 
assessment such as phone calls should be recorded in the source documentation and notated as 
“not done” in the electronic case report form (eCRF). 
In cases where subjects cannot return to the study site, and it will not be possible to dispense a 
new DRC, subjects will be instructed to continue recording of seizures in a manner that is 
mutually agreed with the Investigator (eg, hand-written notes, taking notes on a smart device). 
Any recording of seizures in a manner outside of the study DRC must be carefully documented 
in the source medical records (copies or printouts of these recordings will be brought to and 
retained at site). 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The nonconsecutive numbering and application of letters to some numbers in this section reflect 
changes that have occurred with protocol amendments. 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met as specified.  
6.1.1 
Inclusion criteria for all subjects 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the parent(s) or legal representative(s). The 
Consent form or a specific Assent form, where required, will be signed and dated by minors. 
2a. 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 (including 
BRV oral solution or tablets) according to the judgment of the Investigator. 
14. For female subjects, the subject is 
• Not of childbearing potential  
-OR- 
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• Of childbearing potential, and 
− Is not sexually active 
− Has a negative pregnancy test  
-OR- 
• Of childbearing potential, and  
− Is sexually active 
− Has a negative pregnancy test 
− Understands the consequences and potential risks of inadequately protected sexual 
activity, understands and properly uses contraceptive methods, and is willing to 
inform the Investigator of any contraception changes. Medically acceptable 
contraceptive methods for the study include, but are not limited to: 
− Oral or depot contraceptive treatment with at least ethinylestradiol 30µg per 
intake or ethinylestradiol 50µg per intake if also taking one of the following: 
carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. John's 
Wort, or rifampicin  
− Barrier contraception: intrauterine device, diaphragm with spermicide, male or 
female condom with spermicide  
6.1.2 
Inclusion criteria for LTFU subjects only 
3a. Male or female subjects having participated in a core study with a confirmed diagnosis of 
epilepsy and for whom a reasonable benefit from long-term administration of BRV is 
expected. 
6.1.3 
Inclusion criteria for directly enrolled subjects only 
8. Subject is a male or female ≥4 years to <17 years of age. 
9. Subject has a clinical diagnosis of POS according to the ILAE classification. 
10. Subject has an EEG compatible with the clinical diagnosis of POS.  
11. Subject has been observed to have uncontrolled POS after an adequate course of treatment 
(in the opinion of the Investigator) with at least 1 AED (concurrently or sequentially). 
12. Subject had at least 1 seizure (POS) during the 3 weeks before the ScrV. 
13. Subject is taking at least 1 AED. All AEDs need to be at a stable dose for at least 7 days 
before the ScrV. Vagal nerve stimulator-stable for at least 2 weeks before the ScrV is 
allowed and will be counted as a concomitant AED. Benzodiazepines taken more than once a 
week (for any indication) will be considered as a concomitant AED. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria are met as 
specified. Criteria that were in place before Protocol Amendment 3 have retained the previous 
numbering. 
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6.2.1 
Exclusion criteria for all subjects 
1. Subject is a pregnant or nursing female. 
3. Subject has severe medical, neurological, or psychiatric disorders or laboratory values, which 
may have an impact on the safety of the subject. 
5. Subject has planned participation in any clinical study of another investigational drug or 
device. 
6. Subject has any medical condition, which in the Investigator’s opinion, warrants exclusion. 
29. Subject has >1.5x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>1.0xULN 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%). 
N01349 subjects with a total bilirubin > ULN may be considered for the study if benign 
unconjugated hyperbilirubinemia is suspected in the context of prolonged neonatal jaundice, 
after discussion with the medical monitor. 
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 eCRF. 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at the baseline 
referenced in Table 5‒1 for LTFU subjects and at the Screening Visit for directly enrolled 
subjects, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing 
clinically relevant increase. In case of a clinically relevant increase, inclusion of the subject 
must be discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening.  
30. Subject has chronic liver disease. 
6.2.2 
Exclusion criteria for LTFU subjects only 
2a. Subject had hypersensitivity to BRV or excipients or comparative drugs as stated in this 
protocol during the course of the core study. 
4a. Subject had poor compliance with the visit schedule or medication intake in the core study. 
7a. Subject ≥6 years of age has a lifetime history of suicide attempt (including actual attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to Question 5 of the Columbia-Suicide Severity 
Rating Scale (C-SSRS) at the EV. If a subject has active suicidal ideation without a specific 
plan as indicated by a positive response (“Yes”) to Question 4 of Columbia-Suicide Severity 
Rating Scale (C-SSRS) at the EV, the subject should be referred immediately to a Mental 
Healthcare Professional and may be excluded 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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6.2.3 
Exclusion criteria for directly enrolled subjects only 
8. Subject has previously received BRV. 
9. Subject had concomitant use of LEV at the ScrV. In addition, the use of LEV is prohibited 
for at least 4 weeks prior to the ScrV. 
10. Subject has epilepsy secondary to a progressive cerebral disease or tumor, or any other 
progressively neurodegenerative disease. Stable arteriovenous malformations, meningiomas 
or other benign tumors may be acceptable according to Investigator’s opinion. 
11. Subject has a history of primary generalized epilepsy. 
12. Subject has a history of status epilepticus in the month immediately prior to the ScrV or 
during the Up-Titration Period. 
13. Subject has a history or presence of pseudoseizures. 
14. Subject is suffering only from febrile seizures. 
15. Subject is on felbamate with less than 18 months continuous exposure. Subject who has 
taken felbamate for a combined duration of treatment and wash out of <18 months before the 
ScrV. 
16. Subjects treated with vigabatrin who have visual field defects. 
17. Subject has an allergy to pyrrolidone derivatives or investigational product excipients or a 
history of multiple drug allergies. 
18. Subject has any clinically significant acute or chronic illness as determined during the 
physical examination or from other information available to the Investigator (eg, bone 
marrow depression, chronic hepatic disease, severe renal impairment, psychiatric disorder). 
19. Subject has an underlying disease or is receiving a treatment that may interfere with the 
absorption, distribution, metabolism, and elimination of the study drug.  
20. Subject has any medical condition that might interfere with his/her study participation (eg, 
serious infection or scheduled elective surgery). 
21. Subject has a terminal illness. 
22. Subject has any clinically significant deviations from reference range values for laboratory 
parameters as determined by the Investigator. 
23. Subject has a clinically relevant ECG abnormality according to the Investigator. 
24. Subject had major surgery within 6 months prior to the ScrV. 
25. Subject received any investigational drug or device within the 30 days prior to the ScrV. The 
use of AEDs marketed for adults but not approved for pediatric use is not considered to be 
“investigational” for the purposes of this study. 
26. Investigators’ and co-Investigators’ children may not be included as subjects in the study. 
28. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
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positive response (“Yes”) to either Question 4 or Question 5 of the 
C-SSRS-Baseline/Screening at the ScrV. 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Withdrawal criteria are provided as follows, with criteria for potential drug-induced liver 
injury provided in Section 6.3.1.  
Subjects must be withdrawn from the study if any of the following events occurs: 
1. Subject develops an illness that, in the opinion of the Investigator, would interfere with 
his/her continued participation or would potentially be detrimental to his/her physical/mental 
health.  
4. Subject takes prohibited concomitant medications as defined in the protocol. 
5. Subject/parent(s)/legal representative(s) withdraws his/her/their consent. 
6. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
7. The Sponsor or a regulatory agency requests withdrawal of the subject. 
8a. Subject has an episode of convulsive status epilepticus, a prolongation of seizure duration, a 
worsening of seizure frequency, or emergence of a new type, that is considered by the 
Investigator to require intervention. 
12. Investigator decides that withdrawal from further participation would be in the subject’s best 
interest. 
13. Subject is unwilling or unable to continue, or the parent/legal guardian is unwilling or unable 
to allow the subject to continue in this study. 
14. If subject is ≥6 years of age, subject has active suicidal ideation with a specific plan as 
indicated by a positive response (“Yes”) to Question 5 of the “Since Last Visit” or “Already 
Enrolled Subjects” (as applicable) version of the C-SSRS. The subject should be referred 
immediately to a Mental Healthcare Professional and must be withdrawn from the study. 
Subjects may be withdrawn from the study if any of the following events occurs: 
15. If subject is ≥6 years of age, subject has active suicidal ideation without a specific plan as 
indicated by a positive response (“Yes”) to Question 4 of the “Since Last Visit” or “Already 
Enrolled Subjects” version of C-SSRS. The subject should be referred immediately to a 
Mental Healthcare Professional and may be withdrawn from the study based on the 
Investigator’s judgment of benefit/risk of continuing with the subject in the study/on study 
medication. 
If a subject from N01266 enrolls in EP0065 and either withdraws consent solely due to route of 
BRV administration (iv) or if the subject requires more than 10 iv doses of BRV, the subject may 
be allowed to return to N01266 after discussion with and agreement from the Medical Monitor. 
If a subject from N01266 is advised to withdraw from N01266 after participation in EP0065, the 
subject will be required to return to the N01266 to complete the required EDV, DTV, and SV 
assessments. 
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Investigators should attempt to obtain information on subjects, in the case of withdrawal or 
discontinuation. In case of discontinuation, the Investigator will complete a full evaluation 
documented as an EDV. 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/parent[s]/legal 
representative[s]), 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 reasons for 
removing or discontinuing the subject, must be recorded in the source documents. The main 
reason for terminating the study will be reported in the eCRF. 
Subjects who are withdrawn from the study should have their BRV dose down titrated weekly as 
described in Section 7.2. Refer to Table 5‒2 for procedures to be performed at the time of 
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 investigational medicinal product 
discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if the 
investigational medicinal product (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 9.2.2. 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 
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observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal products 
Immediate-release BRV oral solution and immediate-release, film-coated BRV oral tablets will 
be provided during the study.  
Brivaracetam oral solution at a concentration of 10mg/mL will be supplied in 300mL glass 
bottles. 
Brivaracetam oral tablets will be provided in the following strengths; 10mg, 25mg, and 50mg. 
There is no placebo or reference product. 
7.2 
Treatments to be administered 
Brivaracetam (tablet and oral solution) should be administered bid approximately 12 hours apart 
in 2 equally divided doses. Subjects should be dosed with either oral tablets or oral solution and 
not a combination of both. The mg dosage for the oral tablet treatment should be calculated to 
match as closely as possible the mg/kg based dosage and should be a combination of the BRV 
10mg, 25mg, and 50mg tablets. Only the following exact dosages are allowed for the oral tablet 
administration: BRV 20, 40, 50, 70, 100, 150, and 200mg/day.  
The dose of oral solution will be measured using the appropriate syringes (1mL, 3mL, and/or 
10mL) with an adaptor able to fit both bottle sizes. Oral solution should not be mixed with other 
liquids prior to administration.  
Subjects should take their BRV treatment according to instructions provided by the Investigator. 
Dose adjustments for concomitant AEDs are allowed at any time based on clinical judgment. 
Dispensation of IMP will be done by an interactive voice response system (IVRS). 
7.2.1 
Up-Titration Period for directly enrolled subjects 
Beginning with Protocol Amendment 3, at TV1, eligible directly enrolled subjects will initiate 
treatment with BRV (oral solution or tablet, as appropriate). 
The BRV dose will be titrated to optimize tolerability and seizure control. Table 7‒1 provides the 
recommended titration steps for the oral solution and tablet formulations. Subjects must be on 
the same daily dose for 7±2 days before the dose is titrated to the next dosing level. Subjects may 
enter the Evaluation Period after they have remained on the same daily dose (no lower than the 
minimum specified dose) for 7±2 days that, in the opinion of the Investigator, has demonstrated 
acceptable tolerability and seizure control. Fewer than 3 TVs may be needed before entry into 
the Evaluation Period, depending on the BRV dose at which acceptable tolerability and seizure 
control is demonstrated. 
Based on tolerability and seizure control, a subject’s BRV dose may be reduced to no lower than 
the designated minimum dose indicated in Table 7‒1. If a subject had previously received the 
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reduced BRV dose for 7±2 days with acceptable tolerability and seizure control, then the subject 
may enter directly into the Evaluation Period. 
Table 7‒1: 
Recommended BRV dosing schedule for directly enrolled subjects 
during the Up-Titration Period  
Visit (Week) 
BRV dose per dosing occasion (mg/kg) 
BRV dose per day 
(mg/kg/day) 
TV1 (1) 
~0.5 
~1.0 
TV2 (2) 
~1.0 
~2.0 
TV3 (3) 
~2.0 
~4.0 
BRV=brivaracetam; TV=Titration Visit; “~”=approximately 
Daily doses will not exceed the maximums of 50mg/day, 100mg/day, and 200mg/day for Weeks 
1, 2, and 3 of up-titration, respectively. 
7.2.2 
Evaluation Period for all subjects 
The maximum BRV dose will be 5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose of 
200mg/day. Subjects may receive oral solution or oral tablets, as appropriate.  
The LTFU subjects will ordinarily start dosing in N01266 on the individualized BRV dose they 
were receiving at the completion of the core study; enrolled subjects who volunteer to participate 
in EP0065 should resume dosing in N01266 on the individualized BRV dose they were receiving 
at the completion of EP0065. Subjects must be able to tolerate the minimum BRV dose specified 
in the core study to be eligible for entry into the Evaluation Period of N01266.  
Dose can be adjusted at any time as considered necessary by the Investigator and required by the 
subject’s medical condition. The newly adjusted dose must not exceed the maximum allowed 
dose (5mg/kg/day [2.5mg/kg bid], not to exceed a dose of 200mg/day). 
7.2.3 
Down-Titration Period 
All subjects who prematurely discontinue the study should complete an EDV and have their 
BRV dose down titrated by a maximum of half the dose every week for a maximum of 4 weeks 
until a dose of 1mg/kg/day (50mg/day for subjects with body weights >50kg) is reached. 
Equally, all subjects completing the study but switching to treatment other than BRV should 
have their BRV dose down titrated. 
7.2.4 
Alternative study treatment supply due to COVID-19 
When a subject can no longer return to the study site but will continue in the study, the following 
methods may be used to provide study treatment: 
• Site to subject: In instances where site staff can ship study treatment dispensed from the site 
or pharmacy supply directly to the subject, or 
• Depot to subject: In instances where it is not possible for the site staff to access study 
treatment and/or ship study treatment dispensed from the site or pharmacy supply directly to 
the subject. 
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7.3 
Packaging 
Oral solution (10mg/mL) will be packaged in 300mL type III amber glass bottles with 
child-resistant tamper evident polypropylene (PP) screw closures. Measuring devices, 1mL, 
3mL, and 10mL syringes, will be provided as necessary with an adaptor able to fit all the bottle 
sizes. 
Oral tablets of BRV 10mg, 25mg, and 50mg will be packaged in high-density PP bottles with 
child-resistant PP screw closures. 
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. 
The labels will be adapted to the size of the IMP bottles. 
7.5 
Handling and storage requirements 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the Investigator is to be kept in a secured area with 
limited access, according to the storage conditions mentioned in the label.  
Appropriate storage conditions must be ensured either by 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 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. 
Investigational medicinal product intended for the study cannot be used for any other purpose 
than that described in this protocol. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
bottles of IMP until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
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The Investigator must ensure that the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee). 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 solution or oral tablets) will be supplied to the subject/parent(s)/legal 
representative(s) at the TV(s) (directly enrolled subjects only), EV, MEV, FEV, YEV, and at the 
EDV in the case of early discontinuation. The IMP for down-titration will be dispensed at the FV 
for subjects who complete the study but do not continue BRV treatment. 
The Investigator will instruct the subject/parent(s)/legal representative(s) to bring back at each 
visit the bottles (even empty) dispensed at the previous visit and containing all the remaining 
tablets or oral solution.  
Drug accountability must be done in the parent(s)/legal representative(s), and when possible, the 
subject’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. 
If a subject is found to be persistently noncompliant in the Investigator’s opinion, the Sponsor in 
conjunction with the Investigator will make a decision as to whether the subject should be 
withdrawn from the study. 
Study drug compliance will be assessed at the TV(s) and EV (directly enrolled subjects only), 
MEV, FEV, YEV, FV, and at the EDV and the Down-Titration Visit (DTV) in the case of early 
discontinuation. 
The number of tablets and the quantity of the oral solution dispensed and returned must be 
recorded in the source documents. 
7.8 
Concomitant medications/treatments 
For any treatment other than the IMP, including over-the-counter products, an accurate record 
must be kept in the clinic chart (source documentation) and in the eCRF. 
For LTFU subjects, ongoing medications at the time the subject completed the core study should 
not be recorded in the eCRF at the EV, or any subsequent visit. Changes in ongoing concomitant 
medications should be recorded in the N01266 eCRF. For directly enrolled subjects, all 
concomitant medications should be recorded in the eCRF at the ScrV 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, and the 
indication for use. 
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Please contact the study physician or designee before initiating or stopping any medication 
during the study unless it is a medical emergency. 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
All concomitant AEDs, except the ones specified in Section 7.8.2, are permitted during the 
study. 
7.8.1.1 
Permitted concomitant medications 
Benzodiazepines are allowed. If taken more than once a week, for any indication, a 
benzodiazepine will be considered as an AED. Each intake for as needed use must be listed 
individually in the eCRF, either on the concomitant AED medication page or on the concomitant 
non-AED medication page, according to the indication. 
Levetiracetam is allowed after the EV. 
Felbamate is allowed as follows: 
• LTFU subjects: 
− At the established dose if a stable dose was maintained during the core study 
• Directly enrolled subjects: 
− At a stable dose during the Screening and Up-Titration Periods 
− At the established dose from the EV onwards if a stable dose was maintained during the 
Screening and Up-Titration Periods  
7.8.1.2 
Permitted concomitant therapy 
Vagal nerve stimulation is allowed and will be counted as a concomitant AED. Ketogenic diet is 
allowed.  
7.8.2 
Prohibited concomitant medications 
The following concomitant AED medication is prohibited during the study: 
• LTFU subjects: 
− Felbamate (except if on a stable dose during the core study) 
• Directly enrolled subjects: 
− Felbamate (except if on a stable dose during the Screening and Up-Titration Periods) 
− LEV (from the ScrV until the EV) 
7.8.3 
Rescue medication 
No rescue medication will be provided. 
7.9 
Blinding 
This is an open-label study and therefore, no blinding is required. 
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7.10 
Randomization and numbering of subjects 
Subjects will not be randomized in this study, as each LTFU subject will start on the 
individualized BRV dose that he/she was receiving at the completion of the core study, and 
directly enrolled subjects will start the Evaluation Period on the dose established during the 
Up-Titration Period. 
To enroll a LTFU subject (EV, V1), the Investigator will call the IVRS and provide brief details 
about the subject to be enrolled. Subjects will continue with the 5-digit subject number assigned 
by the IVRS in the core study.  
Directly enrolled subjects will be assigned unique numbers for the purpose of study and subject 
identification, as well as for subject confidentiality. To enroll these subjects, at the ScrV, the 
Investigator will call the IVRS and provide information about the subject to be enrolled. Subjects 
will then be assigned a 5-digit subject number by the IVRS.  
For all subjects, the subject number will be required in all communication between the 
Investigator (or designee) and the IVRS regarding a particular subject. Subjects’ status and the 
dispensing of IMP (bottle numbers) will be tracked via the IVRS. 
8 
STUDY PROCEDURES BY VISIT 
Prior to any study activities, the parent(s)/legal representative(s) will be asked to read and sign an 
Informed Consent form that has been approved by an IRB/IEC and which complies with 
regulatory requirements. The parent(s)/legal representative(s) will be given adequate time to 
consider any information concerning the study, given to them by the Investigator or designee. As 
part of the informed consent procedure, the subject/parent(s) or legal representative(s) will be 
given the opportunity to ask the Investigator any questions regarding potential risks and benefits 
of participation in the study. Additionally, if applicable (according to subject’s age and local 
requirements), the subject will sign an IRB/IEC-approved Assent form. 
8.1 
Screening Visit for directly enrolled subjects only 
The ScrV is applicable only to directly enrolled subjects (ie, subjects ≥4 years to <17 years of 
age with POS who have not participated in a core study). The Screening Period will serve as the 
Baseline Period for directly enrolled subjects. The ScrV is not applicable for LTFU subjects; the 
first N01266 visit for LTFU subjects is the Entry Visit (Section 8.3.1). 
The ScrV assessments will be conducted 7±2 days prior to the first administration of BRV. It is 
acceptable for the ScrV assessments to be conducted on more than 1 day. 
The ScrV assessments are as follows: 
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and local 
requirements) 
• Subject identification card dispensing  
• Demographic data  
• Childbearing potential  
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• Verification of inclusion/exclusion criteria 
• Physical (including Tanner Scale, as applicable) and neurological examinations 
• Psychiatric and mental status 
• General medical and procedures history 
• Epilepsy and AED history 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• ECG 
• EEG (A previous EEG documenting the POS diagnosis must be available at the ScrV for 
directly enrolled subjects. If an EEG is not available at the ScrV, it must be scheduled during 
the Screening Period.) 
• Neuro-imaging procedure (brain magnetic resonance imaging/brain computerized 
tomography scan [except in Germany]/ultrasounds or any other imaging test) should be 
performed if no report is available within the previous 2 years  
• DRC dispensed 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• IVRS call 
• Laboratory assessments for safety including: 
− Hematology 
− Biochemistry including hepatic monitoring 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Endocrinology 
− Urine pregnancy test (see Section 9.2.1) 
• Phenytoin plasma concentrations (if applicable) 
• Suicidality assessment (C-SSRS-Baseline/Screening) (for subjects ≥6 years of age) 
• Achenbach CBCL (version consistent with age at the visit)  
• BRIEF-P (<5 years of age)/BRIEF (≥5 years of age) (version consistent with age at the visit) 
• PedsQL (version consistent with age at the visit) 
• Appointment for the next visit (TV1) 7±2 days later 
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8.2 
Titration Visit(s) (TV1, TV2, and TV3) for directly enrolled 
subjects only 
Directly enrolled subjects will initiate treatment with BRV at TV1 (see Section 7.2.1 for dosing 
information). The TVs are not applicable for LTFU subjects; the first visit in N01266 for these 
subjects is the EV (Section 8.3.1). 
The first dose of BRV at each titration level will be administered at the clinic during the TV. 
Subjects will remain on the BRV dose administered at the clinic for 7±2 days before titrating up 
to the next dose. The BRV up-titration schedule is provided in Section 7.2.1. 
A total of up to 3 TVs may be required; however, based on tolerability and seizure control, a 
subject’s BRV dose may be titrated to a lower dose level and 3 TVs would not be needed.  
The following assessments are required at each TV: 
• Verification of inclusion/exclusion criteria (TV1 only) 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight  
• ECG 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• IVRS call 
• Hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT (TV3 only unless the 
Investigator anticipates that TV2 will be the final TV, in which case hepatic monitoring 
assessments are to be done at TV2) 
• Study drug dispensed 
• Study drug returned (TV2 and TV3 only) 
• Study drug compliance (TV2 and TV3 only) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Healthcare provider consultation not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit 7±2 days later 
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8.3 
Entry Visit 
At the EV, the progress of directly enrolled subjects will become aligned with LTFU subjects; 
for all subjects, the EV is the time of entry into the Evaluation Period. For LTFU subjects, the 
EV is the first visit in N01266. For directly enrolled subjects, the EV will occur after subjects 
have attended the ScrV and at least 1 TV and achieved, in the opinion of the Investigator, 
acceptable tolerability and seizure control on the same daily dose of BRV (no lower than the 
minimum specified dose) for 7±2 days. 
8.3.1 
LTFU subjects 
8.3.1.1 
Core study: N01349 
The following assessments will be performed at this visit:  
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Subject identification card dispensing  
• Verification of inclusion/exclusion criteria 
• Demographic data  
• Procedure history 
• AED history 
• Psychiatric and mental status examination 
• Vital signs 
• Body weight 
• ECG 
• DRC dispensed 
• Seizure count 
• Recording of medications (Any ongoing medications [including AEDs and non-AEDs] at the 
time the subject completed N01349 should not be recorded in the N01266 eCRF. Changes in 
ongoing concomitant medications should be recorded in the N01266 eCRF). 
• Recording of procedures 
• Recording of AEs (Any ongoing AEs at the time the subject completed N01349 should not 
be recorded in the N01266 eCRF. Worsening of the AE should be recorded as a new AE.) 
• IVRS call 
• Study drug dispensed 
• Bayley-III scales (subjects enrolled in English-speaking countries and in countries where a 
validated translation is available) 
Other assessments listed in Table 5‒1 will be obtained from N01349 (as footnoted in Table 5‒1) 
and are not to be recorded in the N01266 eCRF. 
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8.3.1.2 
Core study: EP0065 
The following assessments will be performed at this visit:  
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of the Assent form by the subject (if applicable, according to age and 
local requirements) 
• Subject identification card dispensing  
• Childbearing potential 
• Verification of inclusion/exclusion criteria 
• Demographic data  
• Epilepsy history 
• Psychiatric and mental status examination  
• Height 
• Head circumference 
• DRC dispensed 
• Recording of medications (Any ongoing medications [including AEDs and non-AEDs] at the 
time the subject completed EP0065 should not be recorded in the N01266 eCRF. Changes in 
ongoing concomitant medications should be recorded in the N01266 eCRF.)  
• Recording of procedures 
• Recording of AEs (Any ongoing AEs at the time the subject completed EP0065 should not 
be recorded in the N01266 eCRF. Worsening of the AE should be recorded as a new AE.) 
• IVRS call 
• Study drug dispensed 
• Bayley-III scales (subjects enrolled in English-speaking countries and in countries where a 
validated translation is available, and <18 months of age) 
• Achenbach CBCL (see Section 10.3.3)  
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (see Section 9.3.8) 
• PedsQL (see Section 10.3.5) 
Other assessments listed in Table 5‒1 will be obtained from EP0065 (as footnoted in Table 5‒1) 
and are not to be recorded in the N01266 eCRF. 
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8.3.1.3 
Core study: Other (not N01349 or EP0065) 
The following assessments will be performed at this visit:  
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and local 
requirements) 
• Subject identification card dispensing  
• Childbearing potential 
• Verification of inclusion/exclusion criteria 
• Demographic data  
• DRC dispensed 
• Recording of medications (Any ongoing medications [including AEDs and non-AEDs] at the 
time the subject completed the core study should not be recorded in the N01266 eCRF. 
Changes in ongoing concomitant medications should be recorded in the N01266 eCRF.) 
• Recording of AEs (Any ongoing AEs at the time the subject completed the core study should 
not be recorded in the N01266 eCRF. Worsening of the AE should be recorded as a new 
AE.) 
• IVRS call 
• Study drug dispensed 
Other assessments listed in Table 5‒1 will be obtained from the core study (as footnoted in 
Table 5‒1) and are not to be recorded in the N01266 eCRF.  
8.3.2 
Directly enrolled subjects 
Directly enrolled subjects will finish the Up-Titration Period and attend the EV when the same 
BRV dose (no lower than the minimum specified dose) has been maintained for 7±2 days at a 
level that, in the opinion of the Investigator, achieves acceptable tolerability and seizure control. 
• Childbearing potential 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• DRC dispensed 
• DRC retrieved 
• Recording of medications 
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• Recording of procedures 
• Recording of AEs 
• ECG 
• Seizure count 
• IVRS call 
• Study drug dispensed 
• Study drug returned 
• Study drug compliance 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Urine pregnancy test (see Section 9.2.1) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit according to the schedule described in Section 5.3  
8.4 
Minimal Evaluation Visit (all subjects) 
• Childbearing potential  
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• Hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT (performed only at V4 
[M3] and V6 [M9]) 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
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• IVRS call  
• Study drug dispensed 
• Study drug returned 
• Study drug compliance 
• Urine pregnancy test (see Section 9.2.1) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit according to the schedule described in Section 5.3  
8.5 
Full Evaluation Visit (all subjects) 
• Childbearing potential  
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference  
• EEG (for LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have typical absence seizures, an EEG of at least 
1 hour that includes hyperventilation and intermittent photic stimulation must be 
performed only at V5 and yearly thereafter. 
− For subjects <2 years of age at V5, an EEG of at least 24 hours of recording must be 
performed at V5 and yearly thereafter. 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Assessment of seizure types for subjects <2 years of age 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• IVRS call 
• Study drug dispensed 
• Study drug returned 
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• Study drug compliance 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Urine pregnancy test (see Section 9.2.1) 
• BRV plasma concentrations 
• Phenytoin plasma concentrations (if applicable) 
• Bayley-III scales (for LTFU subjects enrolled in English-speaking countries and in countries 
where a validated translation is available, <18 months of age at baseline of the core study, 
and <42 months of age) 
• Achenbach CBCL (see Section 10.3.3)  
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (see Section 9.3.8) 
• PedsQL (see Section10.3.5) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit according to the schedule described in Section 5.3 
8.6 
Yearly Evaluation Visit (all subjects) 
• Childbearing potential  
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• ECG 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Assessment of seizure types for subjects <2 years of age 
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• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• IVRS call 
• Study drug dispensed 
• Study drug returned 
• Study drug compliance 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Urine pregnancy test (see Section 9.2.1) 
− Endocrinology 
• BRV plasma concentrations 
• Phenytoin plasma concentrations (if applicable) 
• Bayley-III scales (for LTFU subjects enrolled in English-speaking countries and in countries 
where a validated translation is available, <18 months of age at baseline of the core study, 
and <42 months of age) 
• Achenbach CBCL (see Section 10.3.3) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (see Section 9.3.8) 
• Peds QL (see Section 10.3.5) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit according to the schedule described in Section 5.3. 
8.7 
Unscheduled Visit (all subjects) 
At any time, the subject may have an Unscheduled Visit (UV) if the Investigator or the subject 
and/or parent(s)/legal representative(s) consider it necessary. 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• IVRS call (if applicable) 
• Health care provider consultations not foreseen by the protocol 
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• Hospital stays 
If an Unscheduled Visit is conducted due to safety or efficacy reasons, a suicidality assessment 
(C-SSRS) will be performed with subjects ≥6 years of age 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. 
8.8 
Early Discontinuation Visit (all subjects) 
• Childbearing potential 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• ECG 
• EEG (LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have typical absence seizures, a 1-hour EEG may 
be performed at the Investigator’s discretion. 
− For subjects <2 years of age at V5, a 24-hour EEG may be performed at the 
Investigator’s discretion. 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• IVRS call 
• Study drug dispensed 
• Study drug returned 
• Study drug compliance 
• Laboratory assessments for safety  
− Hematology 
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− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Urine pregnancy test (see Section 9.2.1) 
• BRV plasma concentrations 
• Phenytoin plasma concentrations (if applicable) 
• Bayley-III scales (for LTFU subjects enrolled in English-speaking countries and in countries 
where a validated translation is available, <18 months of age at baseline of the core study, 
and <42 months of age) 
• Achenbach CBCL (see Section 10.3.3) 
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (see Section 9.3.8) 
• PedsQL (see Section 10.3.5) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit should be scheduled for the end of the 4-week Down-Titration 
Period (maximum) 
8.9 
Down-Titration Visit (all subjects) 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• IVRS call 
• Study drug returned 
• Study drug compliance 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit according to the schedule described in Section 5.2. 
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8.10 
Safety Visit (all subjects) 
The SV will be performed after the subject has been free of study drug for 2 weeks 
(Safety Period). 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• ECG performed only if abnormal at the EDV 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• IVRS call 
• Laboratory assessments for safety (to be performed only if abnormal at the EDV)  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Urine pregnancy test (see Section 9.2.1) 
• Phenytoin plasma concentrations (if applicable) only if abnormal at the EDV 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• End of study status 
8.11 
Final Visit (all subjects) 
Subjects who continue in the study until it ends should complete a FV. 
• Childbearing potential  
• Physical examination 
• Neurological examination 
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• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight, height, and head circumference 
• ECG 
• EEG (for LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have typical absence seizures, an EEG of at least 
1 hour that includes hyperventilation and intermittent photic stimulation must be 
performed 
− For subjects <2 years of age at V5, an EEG of at least 24 hours must be performed 
• DRC retrieved  
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• IVRS call 
• Study drug returned 
• Study drug compliance 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects for whom sample collection is feasible) 
− Urine pregnancy test (see Section 9.2.1) 
− Endocrinology 
• BRV plasma concentrations 
• Phenytoin plasma concentrations (if applicable) 
• Bayley-III scales (for LTFU subjects enrolled in English-speaking countries and in countries 
where a validated translation is available, <18 months of age at baseline of the core study, 
and <42 months of age) 
• Achenbach CBCL (see Section 10.3.3)  
• BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (see Section 9.3.8) 
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• PedsQL (see Section 10.3.5) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• End of study status 
• Appointment for the next visit should be scheduled for the end of the 4-week Down-Titration 
Period (maximum) if BRV treatment is not continued after study completion (FV), and study 
drug for down-titration should be dispensed 
9 
ASSESSMENT OF SAFETY 
The safety variables will be evaluated during the Up-Titration Period (directly enrolled subjects 
only) and the Evaluation Period. For subjects who continue in the study until it ends, the 
Evaluation Period will include the EV through the FV. For subjects who prematurely discontinue 
the study, the Evaluation Period will include the EV through the EDV, followed by a 4-week 
Down-Titration Period (maximum), and a 2-week Safety (Drug-Free) Period.  
9.1 
Adverse events 
9.1.1 
Definitions 
9.1.1.1 
Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which 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 
signing the Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no investigational product was 
taken but specific study procedures were conducted. This includes all AEs not present prior to 
the initial visit and all AEs, which recurred or worsened after the initial visit. 
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Signs or symptoms of the condition/disease for which the investigational product 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. 
9.1.1.2 
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 one of the other 
outcomes listed in the definition of serious 
(Important medical events may include 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 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 criterion. 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.) 
9.1.1.2.1 
Anticipated serious adverse events  
The following Anticipated SAEs are anticipated to occur in the population studied in this 
protocol at some frequency that is independent of drug exposure.  
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This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 9.1.2.3. 
Table 9‒1: 
Anticipated serious adverse events for the pediatric epilepsy 
population 
MedDRA SOC 
MedDRA PT 
Congenital, familial and genetic disorders 
Teratogenicity 
General disorders and administration site conditions 
Sudden unexpected death in epilepsy 
Nervous system disorders 
Convulsiona 
Status epilepticus 
Pregnancy, puerperium and perinatal disorders 
Abortion spontaneous 
Psychiatric disorders 
Psychotic behavior 
Abnormal behavior 
Anxiety 
Sleep disorder 
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SOC=system organ class 
a Convulsion if consistent with the seizure type known for the subject. 
9.1.1.3 
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. For this study, the AEs of special interest include:  
• Autoimmune nephritis 
• Nephritis 
• Nephritis allergic 
• Tubulointerstitial nephritis 
• Tubulointerstitial nephritis and 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. 
9.1.2 
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)?” 
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In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
For LTFU subjects, AEs ongoing at the time the subject completed the core study should not be 
recorded in the eCRF at the EV, or any subsequent visit. Worsening of the AE should be 
recorded as a new AE. For all subjects, new AEs should be recorded in the eCRF at only the first 
visit at which they are reported and subsequently only if there is a change.  
9.1.2.1 
Description of adverse events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the Adverse Event in the eCRF (including judgment of relationship to 
study medication) are described in the eCRF Completion Guidelines. 
Occurrence of COVID-19 in subjects should be reported as either “suspected COVID-19” or 
“confirmed COVID-19.” For subjects where COVID-19 is still suspected despite a negative viral 
test, please report as “suspected COVID-19.” 
9.1.2.2 
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.  
9.1.2.3 
Additional procedures for reporting adverse events 
A blood sample for determination of BRV plasma concentration should be obtained for any 
subject who has an SAE. 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact numbers 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 provided by UCB, even if the data are 
incomplete, or if it is obvious that more data will be needed in order to draw any conclusions. 
Information recorded on this form will be entered into the global safety database. 
An Investigator SAE Report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English. 
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. 
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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 
investigational product), 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. Any SAEs that the Investigator thinks may be associated with the investigational product 
must be reported to UCB regardless of the time between the event and the end of the study. 
Upon receipt of the SAE form, UCB will perform an assessment of expectedness of the reported 
SAE. The assessment of the expectedness of the SAE is based on the Investigator’s Brochure. 
9.1.3 
Follow-up on 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.  
If an AE is still ongoing at the end of the study for a subject, follow-up should be provided until 
resolution/stable level of sequelae, 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 their IMP. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
9.1.4 
Pregnancy 
Should a subject become pregnant after the first intake of any IMP, UCB’s PS department should 
be informed immediately. The subject should be withdrawn from the study as soon as the 
pregnancy is known 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. 
• A SV should be scheduled 2 weeks after the subject has discontinued their IMP. 
The Investigator must inform the subject/parent(s)/legal representative(s) of information 
currently known about potential risks and about available treatment alternatives. 
The Investigator will complete the Pregnancy Report and Outcome form for any pregnancy and 
send it to UCB’s PS department (for contact details see SAE reporting information at the 
beginning of this protocol).  
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or 
anomaly/birth defect of the child. Those SAEs must be additionally reported using the 
Investigator SAE Report form. 
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
be available in the Investigator site file. In case of questions about the consent process, the 
Investigator may contact the UCB/contract research organization contract monitor for the study. 
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If the partner has agreed that additional information can be captured and has provided the signed 
Partner Pregnancy Consent form, the Pregnancy Report and Outcome form will be completed. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the partner pregnancy, eventual birth, and follow-up. 
9.1.5 
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. 
9.1.6 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded on the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other serious or nonserious AE. These events may be symptomatic, in that the 
excessive dosing results in clinical signs and symptoms, or the excessive intake may itself be a 
symptom. 
9.1.7 
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 Patient Safety 
representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (examples: AEs, 
vital signs, laboratory, or ECG results) for which data will be periodically reviewed during the 
course of the study. 
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9.2 
Laboratory measurements 
9.2.1 
Laboratory assessments for safety 
Laboratory assessments for safety (including hematology, biochemistry, and endocrinology for 
all subjects, and urinalysis for subjects for whom sample collection is feasible) will be conducted 
using standard methods at a central laboratory. 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.  
For blood samplings, methods to minimize pain are recommended (eg, topical anesthetic and 
microsamplings will be used).  
The total blood volume drawn for clinical laboratory assessments in subjects ≥2 years of age will 
be a maximum of 11mL per sampling, which includes up to 3mL for hematology and up to 8mL 
for biochemistry. For subjects <2 years of age, the blood volume drawn will be typically much 
smaller and in the range of 1mL to 2.5mL. Further details will be provided in the laboratory 
manual. 
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The following laboratory parameters will be measured: 
Hematology 
 
Biochemistry 
 
Urinalysisa 
Pregnancy 
Endocrinology 
WBC 
Glucose 
Glucose 
β-hCGd 
FSH 
RBC 
Sodium 
Ketones 
 
LH 
Hemoglobin 
Potassium 
Occult blood 
 
TSH 
Hematocrit 
Calcium 
Protein 
 
T3 
MCV 
Chloride 
Nitrites 
 
T4 
MCH 
Bicarbonate 
Leukocytes 
 
 
MCHC 
Phosphorus 
(inorganic) 
Microscopic 
examinationc 
 
 
Platelet count 
Total protein 
 
 
 
Lymphocytes (number, %) Albumin 
 
 
 
Monocytes (number, %) 
Total bilirubinb 
 
 
 
Neutrophils (number, %) 
ALPb 
 
 
 
Eosinophils (number, %) 
AST (SGOT)b 
 
 
 
Basophils (number, %) 
ALT (SGPT)b 
 
 
 
 
GGTb 
 
 
 
 
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; ScrV=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 Urinalysis will be performed for subjects for whom sample collection is feasible. 
b This assessment is used for hepatic monitoring. 
c Includes bacteria, cells, casts, and crystals for all samples. 
d Urine pregnancy tests should be conducted at the site for all female subjects of childbearing potential. 
 
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The creatinine clearance will be calculated over time by the central laboratory using their current 
methods. The subject’s age, body weight and height, and gender must be recorded on the 
laboratory requisition form. 
All female subjects of childbearing potential should have urine pregnancy tests. A serum 
pregnancy test will be performed as backup if a urine sample is not available. A urine pregnancy 
test should be performed at any time during the study if a pregnancy is suspected. All urine 
pregnancy tests should be conducted at the site. 
Results for hematology, biochemistry, urinalysis, pregnancy tests, and endocrinology 
measurements will be provided by fax to the Investigator within 72 hours after sample receipt. 
9.2.2 
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 9.1.1.3), and, if applicable, also reported as an 
SAE (see Section 9.1.2.3).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 9‒2 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 9.2.2.1). 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 9.2.2.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the Investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
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The table below summarizes the approach to investigate PDILI. 
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Table 9‒2: 
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 9.2.2.3); 
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 
≥8x ULN. 
Immediate, 
permanent 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 9.2.2.3). 
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Table 9‒2: 
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 9.2.2.2). 
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 
≥2x baseline) 
after 2 weeks of 
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 weeks.d 
Immediate IMP discontinuation 
required if : 
• Liver chemistry values 
continue to increase 
• 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 values. d 
 
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Table 9‒2: 
Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare 
practitioner; IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include 
eosinophilia (>5%), rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 9.2.2.1. 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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9.2.2.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 9.2.2.3) and SAE report (if applicable). 
9.2.2.2 
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 9‒2 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 of medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
9.2.2.3 
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 9‒3 (laboratory measurements) and Table 9‒4 (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 9‒3: 
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 ≥2xULN, 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 testb 
PK samplec 
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). 
b Determined only for female subjects of childbearing potential. 
c Blood sample for determination of plasma concentrations of BRV. 
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The following additional information is to be collected: 
Table 9‒4: 
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, if applicable 
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 
9.2.2.4 
Follow-up evaluation 
Potential drug-induced liver injury events will require follow-up monitoring as described in 
Table 9‒2. 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. 
9.2.3 
Plasma concentration measurements 
9.2.3.1 
BRV plasma concentrations 
Blood samples for the analysis of BRV concentrations will be collected at the visits designated in 
Table 5‒2. Additionally, a blood sample for determination of BRV plasma concentration should 
be taken whenever the subject experiences an SAE. 
Brivaracetam will be assayed in batch runs at the bioanalytical laboratory. Plasma levels will be 
reported to the central laboratory after the batch run is performed, according to laboratory 
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methodology. Results will be reported by the central laboratory to the Investigator as exact 
values, with a flag to those values that are outside the therapeutic range. 
9.2.3.2 
Phenytoin plasma concentrations (if applicable) 
Subjects receiving phenytoin as a concomitant AED during the study will have blood samples 
collected at the visits designated in Table 5‒1, Table 5‒2, and Table 5‒3 to monitor phenytoin 
plasma concentrations.  
Phenytoin plasma levels will be determined by the central laboratory. Further details on sample 
collection, bioanalytical method, and shipping of the samples will be provided in the central 
laboratory manual. 
9.3 
Other safety measurements 
Other safety measurements will be performed at the visits indicated in Table 5‒1, Table 5‒2, and 
Table 5‒3.  
9.3.1 
ECG 
A standard 12-lead ECG will be performed. 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 retained 
as part of the source documentation.  
9.3.2 
Vital signs 
Vital signs, including measurements of blood pressure, supine or sitting pulse rate, and body 
temperature, will be performed after 5 minutes of rest. Vital signs measurements will be repeated 
after 30 minutes if unusual values are observed at the initial reading.  
9.3.3 
Body weight, height, and head circumference 
Body weight (subject wearing light clothing without shoes), height (length may be used for this 
measure, as appropriate), and head circumference (occipital-frontal circumference) will be 
measured.  
9.3.4 
Physical examination 
A standard physical examination will be performed. Clinically significant new or worsened 
abnormalities discovered at the physical examination must be reported as AEs. 
The Investigator or qualified designee will evaluate the subject’s physical development using the 
3-item Tanner scale. The Investigator should use clinical judgment in deciding which subjects 
are selected for evaluation of Tanner Stage (ie, those subjects who are pubescent at Baseline). 
9.3.5 
Neurological examination 
A standard neurological examination will be performed. Clinically significant new or worsened 
abnormalities in the neurological examination must be reported as AEs. 
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9.3.6 
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. Clinically significant new or worsened 
abnormalities must be reported as AEs. 
9.3.7 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS for subjects ≥6 years of 
age. This scale will be used for screening as well as to assess suicidal ideation and behavior that 
may occur during the study. The C-SSRS will be completed according to the tabular schedules of 
study procedures, Section 5.2. 
The “Since Last Visit” version of the C-SSRS will be used, with the following exceptions: 
• For directly enrolled subjects, the “Baseline/Screening” version of the C-SSRS should be 
completed at the ScrV.  
If a subject turns 6 years of age during the study, the “Already Enrolled” version of the C-SSRS 
should be completed at the first visit after the sixth birthday. 
The C-SSRS is not validated for subjects <6 years of age and will not be used for this population. 
Subjects should be monitored for any changes in mood, ideas, or behavior for warning signs of 
depression. The Investigator should be aware of common warning signs that might be a signal 
for risk of depression. For common signs and symptoms of depression in children younger than 
6 years old, reference should be made to the current version of the Diagnostic and Statistical 
Manual of Mental Disorders. Parents and caregivers should also be advised accordingly and 
effort should be made at clinic visits to specifically assess potential depression. 
9.3.8 
BRIEF-P and BRIEF 
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of subjects 
≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P and BRIEF include 
rating forms used by parents to assess subjects’ executive functioning. Executive functions 
broadly encompass a set of cognitive skills that are responsible for the planning, initiation, 
sequencing, and monitoring of complex goal-directed behavior. 
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. The 
clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and Emergent 
Metacognition) and 1 composite score (Global Executive Composite).  
The BRIEF rating form contains items in nonoverlapping clinical scales. These theoretically and 
statistically derived scales form 2 broader Indexes: Behavioral Regulation (3 scales) and 
Metacognition (5 scales), as well as a Global Executive Composite score. 
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses. 
10 
ASSESSMENT OF EFFICACY 
Efficacy variables will be assessed using the seizure count information recorded on the DRC and 
EEG data. Seizure count information will be evaluated over the Evaluation Period by 3-month 
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periods based on the DRC (EV until EDV or FV). For directly enrolled subjects, seizure count 
information collected during the Up-Titration Period will be summarized separately. The EEG 
data will be reviewed at 6 months and yearly thereafter. 
10.1 
Efficacy assessments for seizure data based on DRC 
At each visit, the subject/parent(s)/legal representative(s) will receive a DRC, which has to be 
filled in daily by the parent(s)/legal representative(s) or subject, if applicable, and returned at the 
next visit. No DRC will be dispensed at the SV or the FV. 
The date and the number of epileptic seizures will be recorded on the DRC, as well as the type of 
seizure (according to individual description of seizures), occurrence of clusters, intake of 
concomitant AEDs, undesirable events with start and end dates, health care provider 
consultations not foreseen per protocol, and changes in concomitant medication, if applicable. 
The written information will be discussed with the subject/parent(s)/legal representative(s) 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 eCRF; he/she will also confirm the presence of AEs (if applicable). 
Concomitant medication changes, health care provider consultations not foreseen per protocol, 
and AEs will be reported by the Investigator on the specific pages of the eCRF. 
The DRC will be considered as source documentation. The subject/parent(s)/legal 
representative(s) should be educated to complete the DRC on a daily basis (eg, when taking 
evening dose of BRV). Substantial noncompliance with diary completion (seizures recording) 
may result in subject discontinuation from the study at any time by the Investigator or the 
Sponsor.  
10.2 
Efficacy assessments for seizure data based on EEG 
All EEGs specific to this study will be recorded in the eCRF modules specifically designed for 
this purpose.  
10.3 
Other assessments 
Other assessments will be performed at the visits indicated in Table 5‒1, Table 5‒2, and 
Table 5‒3.  
10.3.1 
Direct cost parameters 
Direct cost parameters include the following: concomitant medications, medical procedures, 
health care provider consultations not foreseen by the protocol, and hospital stays. 
10.3.1.1 
Concomitant medications/treatments 
Concomitant medication information will be collected and recorded.  
For LTFU subjects, any ongoing medications (including AEDs and non-AEDs) at the time the 
subject completed the core study should not be recorded in the N01266 eCRF. Changes in 
ongoing concomitant medications should be recorded in the N01266 eCRF. In this event, the 
medication should be recorded in the eCRF for N01266 with the start date corresponding to the 
date of change in administration.  
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Details of the concomitant medications and therapy are provided in Section 7.8. 
10.3.1.2 
Medical procedures 
Data on medical procedures (surgery, therapeutic and/or diagnostic, hospitalizations) 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. 
10.3.1.3 
Health care provider consultations not foreseen by the protocol 
Data collected for health care provider consultations not foreseen by the protocol will include the 
type of provider (general practitioner, specialist physician, nurse), the site of care (office-private, 
office-hospital, home, emergency room), and the reason leading to the consultation.  
10.3.1.4 
Hospital stays 
Data collected for hospital stays will include the reason leading to the hospitalization, the 
admission ward, transfers, and length of stay.  
10.3.2 
Bayley Scales of Infant and Toddler Development, Third Edition 
The Bayley-III scales are validated as a tool for assessment of neurological development in 
young children and recognized internationally as one of the most comprehensive developmental 
assessment instruments (Sattler and Hoge, 2006) used to examine the major facets of a young 
child’s development (Bayley, 2006). The Bayley Scales of Infant and Toddler Development, 
Third Edition (Bayley-III) are a standardized individually administered adaptive assessment that 
measures the developmental functioning of infants and young children from 1 month to 
42 months of age (Bayley, 2006). The Bayley-III scales measure cognitive, language, motor, 
social-emotional, and adaptive development and are a revision of the predecessor, the Bayley 
Scales of Infant Development, Second Edition (BSID-II) (Bayley, 1993). The Bayley-III scales 
are a technically sound instrument, with strong internal consistency, as well as test-retest 
stability. The Bayley-III scales are provided in English and in countries where a validated 
translation is available. 
The Bayley-III scales are an individually administered adaptive assessment that presents children 
with situations and tasks designed to produce an observable set of behavioral responses. They 
consist of a cognitive scale, a language composite scale with receptive and expressive language 
subscales, and a motor composite scale with fine and gross motor subscales to be completed by 
the Investigator or designee, and of a social-emotional scale, comprising social-emotional 
competence and sensory processing, and an adaptive behavior scale, which assesses the 
attainment of skills necessary for the development of independence, to be completed by the 
child’s parent or caregiver.  
The completion of the Bayley-III scales will require approximately 50 minutes for children who 
are 12 months old or younger and 90 minutes for children aged 13 months and older.  
The Bayley-III scales will be applied to subjects as described in Table 5‒1 and Table 5‒2. The 
Bayley-III scale is not applicable to directly enrolled subjects due the age of these subjects (≥4 
years of age) at entry into N01266. 
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10.3.3 
Achenbach Child Behavior Checklist 
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. Behavioral problems will be scored by the 
parent(s) or legal representative(s). Depending on the subject’s age, 2 versions of the Achenbach 
CBCL will be used. The Achenbach CBCL/1½-5 checklist is intended for use in children aged 
between 18 months and 5 years and 11 months. For subjects between 6 years and <16 years, the 
Achenbach CBCL/6-18 version will be used. The Achenbach CBCL will not be applied to 
children below 18 months of age. 
The Achenbach CBCL should be completed by the same parent(s)/legal representative(s) who 
completed the CBCL in the core study, when possible. The completion of the Achenbach CBCL 
will require approximately 45 minutes.  
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
0=not true (as far as known) 
1=somewhat or sometimes true 
2=very true or often true  
Eight syndrome scores will be calculated from these questions, which will in turn be summarized 
by 2 composite scores. Additionally, for each score on the question, syndrome, and total level, 
categorizations based on a normative sample will be used to evaluate normal, borderline, or 
clinically relevant behavior. 
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests. 
The version of the Achenbach CBCL appropriate to each subject’s age should be administered 
with the following exception: If a subject completed the Achenbach CBCL/1½-5 at the Baseline 
assessment and turns 6 years of age between that assessment and the initial YEV, the 
CBCL/1½-5 should be completed through and including the initial YEV, and subsequently the 
CBCL/6-18 should be completed. 
10.3.4 
Assessment of seizure types 
The assessment of seizure types will be done at 6-monthly intervals (at the FEV and the YEV) 
for subjects <2 years of age. 
10.3.5 
PedsQL 
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions (Varni et al, 1999). 
The PedsQL Measurement Model consists of developmentally appropriate forms for pediatric 
subjects ≥2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 
years of age. Self-report is measured for pediatric subjects ≥5 years to ≤18 years of age, and 
parent proxy report of child HRQoL is measured for pediatric subjects ≥2 years to ≤18 years of 
age.  
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The multidimensional PedsQL generic core scales encompass the essential core domains for 
pediatric HRQoL measurement: Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning. The PedsQL assessment is retrospective to the prior 
4 weeks, and individual items are scored using a 5-point Likert scale (never, almost never, 
sometimes, often, or always). A total health summary score ranging between 0 and 100 is 
calculated from the sum of the raw scores, with higher scores indicating higher HRQoL. 
The version of the PedsQL appropriate for each subject’s age should be completed, with the 
following exception: If a subject ages up to the next version of the PedsQL between the Baseline 
assessment and the initial YEV, the version that was used at the Baseline assessment should be 
completed through and including the initial YEV, and subsequently the version consistent with 
his/her age at the time of assessment should be completed.  
11 
STUDY MANAGEMENT AND ADMINISTRATION  
11.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. In medical emergencies, the Investigator 
may use his/her medical judgment and may remove a study participant from immediate hazard 
before notifying UCB (or its representative) and the IRB/IEC in writing regarding the type of 
emergency and the course of action taken. 
11.2 
Monitoring 
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a contract research organization or a contract monitor. Remote monitoring 
visits may be conducted during the COVID-19 pandemic or under other exceptional 
circumstances as deemed appropriate to ensure subjects’ safety. 
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The Investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
11.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
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(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECGs, or other printouts, or completed scales, 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 
placed and 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 authorize the monitor to compare the content of the printout and the data stored 
in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or EEG records must be saved and stored 
as instructed by UCB (or designee). 
11.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], x-
ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 11.2.1. 
11.3 
Data handling 
11.3.1 
Case report form completion 
This study will be performed using electronic data capture.  
The Investigator is responsible for prompt reporting of accurate and complete data in the eCRFs 
and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
11.3.2 
Database entry and reconciliation 
External electronic data will be loaded in 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. Data are entered 
into the eCRFs once and are subsequently verified. 
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An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data has been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
11.3.3 
Subject Selection and Enrollment log/Subject Identification Code list 
The subject’s selection and enrollment will be recorded in the Subject Selection 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. 
11.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused investigational products and other material in accordance with UCB procedures for the 
study. 
11.5 
Archiving and data retention 
The Investigator will maintain adequate records for the study including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with UCB (CPMP/ICH/135/95, 2002, [Section 4.9.5]). The 
Investigator will contact UCB for authorization prior to the destruction of any study records or in 
the event of accidental loss or destruction of any study records. The Investigator will also notify 
UCB should he/she relocate or move the study-related files to a location other than that specified 
in the Sponsor’s trial master file. 
11.6 
Audit and inspection 
The Investigator will permit study-related audits mandated by UCB and inspections by domestic 
or foreign regulatory authorities, after reasonable notice. 
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The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH/GCP, and applicable regulatory 
requirements. 
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee).  
11.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH/GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
12 
STATISTICS 
A description of statistical methods is presented below and will be described in more detail in the 
statistical analysis plan (SAP).  
12.1 
Definition of analysis sets 
Analysis sets will be defined as follows: 
• The Safety Set (SS) will consist of all enrolled subjects who took at least 1 dose of study 
medication in this long-term study. All safety analyses will be performed on the SS. 
• The Full Analysis Set will be used for the analysis of seizure data and will consist of all 
subjects in the SS, who have at least 1 completed post-Baseline DRC or EEG. 
12.2 
General statistical considerations 
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 
75th percentile, minimum value, and maximum value for quantitative variables, and counts and 
percentages for categorical variables, will be provided. Key supporting data will be provided in 
data listings. Data collected during the Up-Titration Period for directly enrolled subjects will be 
summarized separately. 
Analyses may also be summarized for direct enrollers, as well as by core study (eg, EP0065 and 
N01349). 
12.3 
Planned safety analyses 
The long-term safety of BRV at individualized doses will be evaluated by means of the safety 
analyses. Summary tables will be presented over the Evaluation Period by 3-month periods and 
by categories of total duration of exposure. 
All safety variables will be analyzed by descriptive methods on the Safety Set. 
Treatment-emergent adverse events will be summarized by categories of total duration of 
exposure, 3-month period, Medical Dictionary for Regulatory Activities (MedDRA®) Primary 
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System Organ Class and Preferred Term in incidence tables. Separate tables will be provided by 
categories of total duration of exposure for AEs leading to withdrawal from the study and SAEs.  
Laboratory values, vital signs, and weight will be summarized by 3-month period and visit. 
Possibly clinically significant treatment-emergent abnormalities for laboratory values, vital 
signs, and weight will be listed and summarized by 3-month period and visit. ECG 
abnormalities, as well as physical and neurological abnormalities, will also be listed by 3-month 
periods and visit. 
12.4 
Planned efficacy analyses 
Efficacy parameters related to seizures will be summarized descriptively and will be reported 
individually using data listings. Subgroup analyses based on seizure types and other 
characteristics may be conducted, depending on the number of subjects enrolled per seizure type 
and epilepsy syndrome. Additional details will be provided in the SAP. 
12.5 
Other analyses 
Descriptive statistics will be also presented for the number of medical resources used 
(medications, consultations, procedures, hospitalizations, and length of hospital stays). 
The Achenbach CBCL, the Bayley-III scores (LTFU subjects only), BRIEF-P/BRIEF, PedsQL, 
and change from Baseline scores (core study for LTFU subjects and ScrV for directly enrolled 
subjects) will be analyzed in a descriptive manner. 
12.6 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol, which potentially could have a 
meaningful impact on either the primary efficacy outcome or key safety outcomes for an 
individual subject. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the project Data Cleaning 
Plan. To the extent feasible, the rules for identifying protocol deviations will be defined without 
review of the data and without the consideration of the frequency of occurrence of such 
deviations. Whenever possible, criteria for identifying important protocol deviations will be 
implemented algorithmically to ensure consistency in the classification of important protocol 
deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning meetings 
prior to database lock to confirm exclusion from analysis sets. 
Protocol deviations (eg, missing assessments or visits) related to COVID-19 will be documented. 
12.7 
Handling of dropouts or missing data 
No specific procedure is foreseen for handling dropouts or missing data. 
12.8 
Planned interim analysis and data monitoring 
No formal interim analysis is planned; however, data may be reported prior to the completion of 
this study to support ongoing data cleaning, annual reports, regulatory submissions, and 
publications.  
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12.9 
Determination of sample size 
No formal sample size calculation was performed for this study. Originally, up to 500 subjects 
might have possibly enrolled in this study. The original number was based upon the assumption 
that 90% of the subjects having completed a core study will rollover into the present study. 
Planned enrollment now includes approximately 600 subjects, including at least 100 directly 
enrolled subjects, with no change in the assumption regarding core study completion.  
13 
ETHICS AND REGULATORY REQUIREMENTS 
13.1 
Informed consent 
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 in both oral and written form by the Investigator (or designee). 
Parent(s), legal representative(s), and subject if applicable 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’s parent(s)/legal representative(s), and by the person who conducted the 
informed consent discussion (Investigator [or designee]). The subject/parent(s)/legal 
representative(s) must receive a copy of the signed and dated Informed Consent form. As part of 
the consent process, each subject/parent(s)/legal representative(s) must consent to direct access 
to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and 
regulatory inspection. In addition, a Consent form or a specific Assent form, where required, will 
be signed and dated by minors. Any subject who is over 16 years of age during N01266 must 
sign and date the Informed Consent form according to local regulations. 
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. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act (ie, HIPAA) Authorization form. 
The subject/parent(s)/legal representative(s) may withdraw his/her/their consent to participate in 
the study at any time. A subject is considered as enrolled in the study when he/she or 
parent(s)/legal representative(s) has signed the Informed Consent form. An eCRF must not be 
started nor may any study specific procedure be performed for a given subject without having 
obtained his/her written consent to participate in the study. 
13.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject’s parent(s) or 
legal representative(s) will be provided with a subject identification card in the language of the 
subject. The Investigator will fill in the name of the study and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with them at all times. 
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13.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
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 the 
Committee’s requirements), at intervals appropriate to the degree of subject risk involved but no 
less than once per year. The Investigator should provide a final report to the IRB/IEC following 
study completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
13.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at selection. 
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 
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admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
13.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
14 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements as applicable. 
15 
REFERENCES 
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006. 
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: The Psychological 
Corporation; 1993. 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-
99. 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. 
Epilepsia. 1981;22:489-501. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Hadjiloizou SM, Bourgeois BF. Antiepileptic drug treatment in children. Expert Rev Neurother. 
2007;7:179-93. 
Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Incidence of 
epilepsy: a systematic review and meta-analysis. Neurology. 2011; 77(10): 1005–12. 
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. 5th 
ed. La Mesa: Jerome M Sattler; 2006. 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999;37:126-39. 
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16 
APPENDICES 
16.1 
Protocol Amendment 1 
Rationale for the amendment 
The BSID-II was included in order to assess the cognitive development of children <18 months 
at Baseline in response to the PDCO request. Withdrawal criteria have been extended to include 
the consequences of any findings related to the results of LFTs. Procedures for reporting SAEs 
were updated to implement the Food and Drug Administration (FDA) Final Rule requirements. 
The C-SSRS was added to address the request of the FDA that prospective assessments for 
suicidality should be included in clinical studies involving all drugs for neurological indications. 
Some operational updates are also considered.  
Administrative changes include the update of the SAE reporting and CRO contact details. A few 
changes of editorial nature are not listed in the specific changes section. 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• Addition of a new Section 9.6.7 (Assessment of suicidality) to introduce the C-SSRS for 
subjects ≥6 years of age. Respective exclusion and withdrawal criteria possibly resulting 
from the individual C-SSRS assessment were added to the list of withdrawal criteria. 
• Addition of a new Section 9.4 (Anticipated SAEs) to account for the FDA Final Rule 
implementation. 
• Addition of a cognition scale (Section 10.3.2; BSID-II) for subjects <18 months of age at 
Baseline of N01263. 
• Addition of an assessment of seizure types at 6-monthly intervals for subjects <2 years of 
age.  
• Update of the withdrawal criteria in order to clarify the withdrawal of subjects with findings 
in LFT results above the references ranges.  
• Clarification of the age limit (subjects >2 years) for the 1-hour EEG including 
hyperventilation and intermittent photic stimulation for subjects with typical absence 
seizures. 
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Specific changes 
Change #1, TITLE PAGE 
The title page was updated to reflect the current amendment. 
Change #2, SPONSOR DECLARATION 
The following signature was added to the list of signatures: 
Exploratory Development Director 
 
 
_____________________________ 
Date/Signature 
 
Change #3, Clinical Monitoring Contract Research Organization 
The empty table was updated as follows: 
Name: 
Pharma-Research Associates (UK) Ltd. 
Address: 
Imperial Way 
Reading, Berkshire 
RG2 OTD 
United Kingdom 
Phone: 
+44 118 918 1000 
Fax: 
+44 118 918 1001 
 
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Change #4, SERIOUS ADVERSE EVENT REPORTING 
The original table: 
Serious adverse event reporting (24h), safety related issues 
 
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
USA and Canada: +1 800 880 6949 or +1 866 890 3175 
Phone 
During business hours: 
Outside business hours: 
Europe and Rest of the World 
(except Japan):  
+32 2 386 2468 
USA and Canada: 
+1 919 767 2627 
Europe and Rest of the World 
(except Japan): 
+32 2 386 2468 
USA and Canada: 
+1 404 895 0794 
 
Has been changed to: 
Serious adverse event reporting (24h), safety related issues, and emergency unblinding  
 
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
Phone 
During business hours: 
Outside business hours: 
Europe and Rest of the World 
(except Japan):  
+32 2 386 2468 
USA and Canada: 
+1 404 895 0794 
Europe and Rest of the World 
(except Japan): 
+32 2 386 2468 
USA and Canada: 
+1 404 895 0794 
 
Change #5, LIST OF ABBREVIATIONS 
The following abbreviations were added to the list: 
ADF 
average daily frequency 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BSID-II™ 
Bayley Scales of Infant Development-II 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
FDA 
Food and Drug Administration 
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ADF 
average daily frequency 
LFT 
liver function test 
PDCO 
European Pediatric Committee 
ULN 
upper limit of normal 
Change #6, Section 1, SUMMARY, paragraph 1 
The original text: 
This is a Phase 3, open-label, single-arm, multicenter, long-term follow-up (LTFU) study to 
evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy. The primary 
objective is to document the long-term safety and tolerability of BRV. The secondary objective 
is to assess the efficacy of BRV during long-term exposure and the other objectives are to 
explore direct cost parameters and to assess the effect of BRV on behavior using the age-
appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 or CBCL/6-18). 
Has been changed to: 
This is a Phase 3, open-label, single-arm, multicenter, long-term follow-up (LTFU) study to 
evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy. The primary 
objective is to document the long-term safety and tolerability of BRV. The secondary objective 
is to assess the efficacy of BRV during long-term exposure and the other objectives are to 
explore direct cost parameters and to assess the effect of BRV on behavior and cognition using 
the age-appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 or CBCL/6-18) for 
subjects ≥18 months of age at Baseline of the previous study N01263 or the Bayley Scales of 
Infant Development-II (BSID-II™) for subjects <18 months of age at Baseline of the 
previous study N01263. 
Change #7, Section 1, SUMMARY, paragraph 8 
The original text: 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital stays) 
and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) scores over time.   
Has been changed to: 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital stays) 
and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) and BSID-II scores over 
time.   
Change #8, Section 2.4, Safety with BRV, paragraph 2 
The original text: 
In addition, there are 3 ongoing open-label LTFU studies (N01125, N01199, and N01315) that 
include subjects with POS, primary generalized seizures, or ULD who completed 1 of the above 
Phase 2/3 well-controlled studies. As of 20 Sep 2010, 1628 subjects have been enrolled in these 
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studies. The most frequently reported TEAEs based on interim safety monitoring review include 
headache, dizziness, nasopharyngitis, convulsion, somnolence, and fatigue. Overall, 227 subjects 
(14.0%) reported SAEs. The only SAE occurring at a frequency >1% was convulsion (2.3%). 
Overall, 130 subjects (8.0%) discontinued due to TEAEs. 
Has been changed to: 
In addition, there are 3 ongoing open-label LTFU studies (N01125, N01199, and N01315) that 
include subjects with POS, primary generalized seizures, or ULD who completed 1 of the 
Phase 2/3 well-controlled studies. As of 04 Jan 2011, 1629 subjects have been enrolled into 
these studies and 1624 subjects have received study medication. The median duration of 
BRV exposure in LTFU studies was 91 weeks. The most common TEAEs based on interim 
safety monitoring review include headache, dizziness, nasopharyngitis, convulsion, somnolence, 
and fatigue. Overall, 234 subjects reported SAEs. The only SAE occurring at a frequency >1% 
was convulsion (2.4%). Overall, 132 subjects discontinued due to TEAEs. The most common 
TEAEs leading to premature discontinuation were convulsion and depression.  
Change #9, Section 3.3, Other objectives 
The original text: 
• To explore direct cost parameters 
• To assess the effect of BRV on behavior using the Achenbach CBCL  
Has been changed to: 
• To explore direct cost parameters 
• To assess the effect of BRV on behavior using the Achenbach CBCL in subjects 
≥18 months of age 
• To assess the effect of BRV on cognition using the BSID-II in subjects <18 months of 
age 
Change #10, Section 4.1, Safety variables 
The original text displayed below has been removed. 
At a later stage in the study, new variables (such as tests to assess cognitive functions) may be 
added in order to continue to gather additional information from the subjects who will enter this 
LTFU study from future pediatric studies. 
Change #11, Section 4.2, Efficacy variables 
The original text: 
Due to the wide range in age, epilepsy syndromes and conditions of subjects who will be eligible 
to enroll in this LTFU study, all efficacy variables will be considered exploratory in nature. 
Seizure count information will be measured using appropriate methods based on the subject’s 
age and type of epilepsy, taking into account the potential evolution of the disease as the subject 
ages over the course of the study. Appropriate descriptive statistics will be presented for 
variables related to seizure counts based on the types of measurements obtained (DRCs or EEGs) 
and disease characteristics of each subject. 
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Has been changed to: 
The efficacy variables planned for analysis of subjects ≤2 years of age or subjects with 
absence seizures will be based on EEG data and will include the following:  
• Responder rate for total POS defined as the percentage of subjects with a ≥50% 
reduction in ADF (average daily frequency) of POS recorded on EEG  
• Absolute and percent reduction in ADF of POS 
• 50% responder rate for total seizures (all types) 
• Absolute and percent reduction in ADF of total seizures (all types) 
The efficacy variables planned for analysis of subjects ≥2 years of age will be based on 
DRC data and will include the following: 
• Responder rate (the percentage of subjects who have a ≥50% reduction in seizure 
frequency per 28 days from Baseline for POS)  
• Absolute and percent reduction in seizure frequency (POS) per 28 days from Baseline 
to the end of the Evaluation Period 
• 50% responder rate for total seizures (all types) 
• Absolute and percent reduction in seizure frequency (total seizures) per 28 days from 
Baseline to the end of the Evaluation Period  
• Seizure freedom rate over the Evaluation Period 
• Proportion of seizure-free days over the Evaluation Period 
Change #12, Section 4.3, Other variables 
The original text: 
The other variables include the following: 
• Direct cost parameters: concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays 
• Change over time from previous study Baseline in the Achenbach CBCL score: the 
Achenbach CBCL/1½-5 for children from 1½ to 5 years old and the Achenbach CBCL/6-18 
for children 6 years and older. 
Has been changed to: 
The other variables include the following: 
• Direct cost parameters: concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays 
• Change over time from previous study Baseline in the Achenbach CBCL score: the 
Achenbach CBCL/1½-5 for children from 1½ to 5 years old and the Achenbach CBCL/6-18 
for children 6 years and older. 
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• Change over time from previous study Baseline in the BSID-II score for children 
<18 months of age 
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Change #13, Section 5.2, Schedule of study assessments 
The following assessments have been added: 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-free) 
Visit 
Entry 
Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety Visit 
(EV)a 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Assessment 
 
Assessment of seizure typesi 
 
 
X 
X 
 
 
 
 
C-SSRSo 
X 
X 
X 
X 
 
X 
X 
X 
BSID-II scorep 
 
 
X 
X 
 
X 
 
 
 
All subsequent footnote indices have been updated accordingly and the following abbreviations have been added below the table: 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BSID-II=Bayley Scales of Infant Development-II; 
C-SSRS=Columbia-Suicide Severity Rating Scale; LFT=liver function test;  
 
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Change #14, Section 5.2, Schedule of study assessments, footnotes 
The original text: 
a. The following data will be obtained from the previous pediatric study and should not be 
recorded on the eCRF for N01266: general medical and procedure history, epilepsy 
history, AED history, seizure count, absence seizure count (1-hour EEG for subjects 
suffering from absences), ECG, laboratory assessments for safety, including phenytoin 
plasma concentrations (if applicable), the Achenbach CBCL score, vital signs, body 
weight and height, physical and neurological examinations, psychiatric and mental status, 
recording of epileptic seizures, and data on health care provider consultations not 
foreseen by the protocol and hospital stays. The EV is also the final evaluation visit of the 
previous pediatric study. 
Has been changed to: 
a. The following data will be obtained from the previous pediatric study and should not be 
recorded on the eCRF for N01266: general medical and procedure history, epilepsy 
history, AED history, seizure count, EEG, ECG, laboratory assessments for safety, 
including phenytoin plasma concentrations (if applicable), the Achenbach CBCL score, 
BSID-II score, vital signs, body weight and height, physical and neurological 
examinations, psychiatric and mental status, recording of epileptic seizures, and data on 
health care provider consultations not foreseen by the protocol and hospital stays. The EV 
is also the final evaluation visit of the previous pediatric study. 
The original text: 
g. EEG 
− For subjects with typical absence seizures: every 3 months during the first 6 months 
(starting at V4), and then yearly thereafter: a 1-hour EEG including hyperventilation 
and intermittent photic stimulation must be performed for efficacy assessment. For 
subjects prematurely discontinuing from the study, a 1-hour EEG should also be 
performed at the EDV. 
− For subjects ≥1 month to ≤2 years: every 3 months during the first 6 months (starting 
at V4), then yearly thereafter: a 24-hour EEG including sleeping and awakening 
periods must be performed for efficacy assessment. For subjects prematurely 
discontinuing from the study, a 24-hour EEG should also be performed at the EDV. 
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Has been changed to: 
g. EEG 
− For subjects >2 years with typical absence seizures: every 3 months during the first 6 
months (starting at V4), and then yearly thereafter: a 1-hour EEG including 
hyperventilation and intermittent photic stimulation must be performed for efficacy 
assessment. For subjects prematurely discontinuing from the study, a 1-hour EEG 
should also be performed at the EDV. 
− For subjects ≥1 month to ≤2 years: every 3 months during the first 6 months (starting 
at V4), then yearly thereafter: a 24-hour EEG including sleeping and awakening 
periods must be performed for efficacy assessment. For subjects prematurely 
discontinuing from the study, a 24-hour EEG should also be performed at the EDV. 
Change #15, Section 5.2, Schedule of study assessments, footnotes 
The following footnotes have been added: 
i. 
The assessment of seizure types will be done at 6-monthly intervals (at the FEV and 
the YEV) for subjects <2 years of age. 
o. The C-SSRS will be administered to subjects ≥6 years of age. 
p. The cognition scale (BSID-II) to be used in this study for subjects <18 months of age 
will be the same as the one used in the previous pediatric study. If the subject 
reaches 18 months of age in this LTFU study, the subject will still be assessed using 
the BSID-II to allow for an evaluation of the change from Baseline even if their age 
increases to ≥18 months. 
Change #16, Section 6.2, Exclusion criteria 
The following exclusion criterion has been added to the list:  
7. Subject has a lifetime history of suicide attempt (including an active attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 
6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at the EV. 
Change #17, Section 6.3, Withdrawal criteria 
The following withdrawal criteria have been added to the list: 
9. Subject has the following findings based on liver function tests (LFT): 
• If the subject has LFT results of transaminases (aspartate aminotransferase 
[AST] and/or alanine aminotransferase [ALT]) ≥3x the upper limit of normal 
(ULN) to <5xULN or total bilirubin ≥2xULN, the measurements will be repeated 
within a few days. If the repeat testing confirms the abnormality 
(eg, transaminases are ≥3xULN to <5xULN), then monitoring of LFTs should 
continue at subsequent study visits until resolved (eg, <3xULN or stable 
condition). The Investigator is to decide whether or not to stop the study 
medication. 
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• If the subject has LFT results of transaminases (AST and/or ALT) ≥5xULN, 
study medication should be tapered off immediately and the subject must be 
withdrawn from the study. 
10. Criteria for subjects who completed a C-SSRS assessment at the EV: 
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Children’s 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. 
11. Criteria for already enrolled subjects who did not complete a C-SSRS assessment at 
the EV: 
• Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of 
the “Children’s Baseline/Screening” version of the C-SSRS. The Investigator 
must withdraw the subject from the study and immediately refer the subject to a 
Mental Healthcare Professional. 
• Subject had active suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the “Children’s 
Baseline/Screening” version of the C-SSRS. The Investigator must immediately 
refer the subject to a Mental Healthcare Professional and use clinical judgment 
as to whether to withdraw the subject from the study.  
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Children’s Since Last Visit” version of 
the C-SSRS. The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study. 
Change #18, Section 7.2, Treatments to be administered, paragraph 1 
The original text: 
At study entry (EV), subjects will start on the individualized BRV dose that they had reached 
at the completion of the previous study.  
Has been changed to: 
At study entry (EV), subjects will ordinarily start on the individualized BRV dose that they 
had reached at the completion of the previous study.  
Change #19, Section 7.2, Treatments to be administered, paragraph 4 
The original text: 
The mg dosage for the oral tablet treatment should be calculated to match as closely as 
possible the mg/kg oral solution treatment and should be a combination of the BRV 10mg, 
25mg, and 50mg tablets (given bid in 2 equally divided doses). Subjects should be dosed with 
either oral tablets or oral solution and not a combination of both. 
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Has been changed to: 
The mg dosage for the oral tablet treatment should be calculated to match as closely as 
possible the mg/kg oral solution treatment and should be a combination of the BRV 10mg, 
25mg, and 50mg tablets (given bid in 2 equally divided doses). Only the following exact 
dosages are allowed for the oral tablet administration: BRV 20, 40, 50, 70, 100, 150, and 
200mg/day. Subjects should be dosed with either oral tablets or oral solution and not a 
combination of both. 
Change #20, Section 8, STUDY PROCEDURES BY VISIT 
The C-SSRS assessment has been added to the bulleted lists for all visits except for the 
Unscheduled Visit. 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
Change #21, Section 8.1, Entry Visit 
The original text: 
The following data will be obtained from the previous pediatric study and should not be 
recorded on the eCRF for N01266: 
• General medical and procedures history 
• Epilepsy history 
• AED history  
• Seizure count 
• Absence seizure count (a 1-hour EEG for subjects suffering from absences) 
• ECG 
• Laboratory assessments for safety 
• Phenytoin plasma concentrations (if applicable) 
• Achenbach CBCL score 
• Vital signs 
• Body weight and height 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Recording of epileptic seizures 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
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Has been changed to: 
The EV is also the final evaluation visit of the previous pediatric study. The following 
data will be obtained from the previous pediatric study and should not be recorded on the 
eCRF for N01266: 
• General medical and procedures history 
• Epilepsy history 
• AED history  
• Seizure count 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and 
awakening periods) must be performed 
• ECG 
• Laboratory assessments for safety  
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Phenytoin plasma concentrations (if applicable) 
• BSID-II score for subjects <18 months of age at Baseline of N01263 
• Achenbach CBCL score for subjects ≥18 months of age at Baseline of N01263 
• Vital signs 
• Body weight and height 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Recording of epileptic seizures 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
Change #22, Section 8.2 to Section 8.4, Section 8.6, and Section 8.9, 
bullet on the 1-hour EEG 
The original text: 
• EEG 
− For subjects with typical absence seizures: a 1-hour EEG (including hyperventilation 
and intermittent photic stimulation) must be performed 
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Has been changed to: 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
Change #23, Section 8.3 and Section 8.4  
The following bullet has been added to the list.  
• Assessment of seizure types for subjects <2 years of age 
Change #24, Section 8.3, Section 8.4, Section 8.6, and Section 8.9  
The following bullet has been added to the list.  
• BSID-II score for subjects <18 months of age at Baseline of N01263 
Change #25, Section 8.5, Unscheduled Visit 
The following text was added to the section. 
• If an Unscheduled Visit is conducted due to safety or efficacy reasons, a suicidality 
assessment (C-SSRS) 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. 
Change #26, Section 9, ASSESSMENT OF SAFETY 
The following Section 9.4 has been added. The subsequent section numbers were updated 
accordingly. 
The following list of Anticipated SAEs has been identified, as these events are 
anticipated to occur in the population studied in this protocol at some frequency that is 
independent of drug exposure: convulsion. This original list will remain in effect for the 
duration of the protocol. 
This list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 9.2.3. 
Change #27, Section 9.6, Other safety measurements 
The following section has been added. The following section numbers were updated 
accordingly. 
9.6.7 Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS for subjects 
≥6 years of age. This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. The C-SSRS will be completed 
according to the tabular schedule of study procedures, Section 5.2. 
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Change #28, Section 10.2, Efficacy assessments for seizure data based 
on EEG, paragraph 1 
The original text: 
At the EV, data on absence seizure count (a 1-hour EEG for subjects suffering from 
absences) will be obtained from the previous pediatric study and should not be recorded in 
the eCRF for N01266.  
Has been changed to: 
At the EV, data on absence seizure count (a 1-hour EEG for subjects >2 years suffering from 
absences) will be obtained from the previous pediatric study and should not be recorded in 
the eCRF for N01266.  
Change #29, Section 10.2, Efficacy assessments for seizure data based 
on EEG, paragraph 3, bullet on 1-hour EEG 
The original text: 
• For subjects with typical absence seizures: a 1-hour EEG (including hyperventilation and 
intermittent photic stimulation) will be performed starting at V4 and at every 3-month 
visit for the first 6 months and then yearly thereafter. For subjects prematurely 
discontinuing from the study, a 1-hour EEG should also be performed at the EDV. 
Has been changed to: 
• For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) will be performed starting at V4 and 
at every 3-month visit for the first 6 months and then yearly thereafter. For subjects 
prematurely discontinuing from the study, a 1-hour EEG should also be performed at the 
EDV. 
Change #30, Section 10.3, Other assessments 
The following sections have been added. The following section numbers were updated 
accordingly. 
10.3.2 
Bayley Scales of Infant Development-II 
The BSID‑II™ is a widely used validated questionnaire for children from 1 month up to 
42 months of age designed to evaluate a child’s developmental function, including 
cognition, language, personal-social behavior, and motor development.  
This scale is accepted as a tool for assessment of neurological development in young 
children and is therefore considered appropriate for this study. The BSID-II will be 
used throughout the study for all subjects who were <18 months of age at Baseline (V1) 
of the previous pediatric study, N01263, by the Investigator or designee. Children 
started on the BSID-II at Baseline of N01263 will also be assessed using the BSID-II in 
N01266 even if their age increases to ≥18 months. The completion of the BSID-II will 
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require approximately 25 to 35 minutes for children below 15 months of age and up to 
60 minutes for children above 15 months of age.  
The BSID-II includes a mental scale that evaluates sensory/perceptual activities, 
discriminations, acquisition of object constancy, memory, learning and problem-solving, 
vocalization, early verbal communication, abstract thinking, habituation, mental 
mapping, complex language, and mathematical concept formation; a motor scale that 
evaluates degree of body control, coordination of large muscles, fine manipulation skills, 
dynamic movement, postural imitations, and stereognosis; and a behavior rating scale 
that measures attention and arousal, orientation and engagement, emotional regulation, 
and motor quality (Bayley, 1993).  
At the EV, the BSID-II score will be obtained from the previous pediatric study and 
should not be recorded in the eCRF in N01266. The BSID-II will be completed at the 
FEV, YEV, FV, and at the EDV in the case of early discontinuation. The BSID-II should 
be completed by the same person who completed the CBCL in the previous pediatric 
study. 
10.3.4 
Assessment of seizure types 
The assessment of seizure types will be done at 6-monthly intervals (at the FEV and the 
YEV) for subjects <2 years of age. 
Change #31, Section 10.3, Other assessments, paragraph 3 
The original text: 
The Achenbach CBCL should be completed by the same parent(s)/legal representative(s) 
who completed the CBCL in the previous pediatric study.  
Has been changed to: 
The Achenbach CBCL should be completed by the same parent(s)/legal representative(s) 
who completed the CBCL in the previous pediatric study. The completion of the 
Achenbach CBCL will require approximately 45 minutes.  
Change #32, Section 12.5, Other analyses, paragraph 2 
The original text: 
The Achenbach CBCL scores and change from previous study Baseline scores will be 
analyzed in a descriptive manner. 
Has been changed to: 
The Achenbach CBCL, the BSID-II scores, and change from previous study Baseline scores 
will be analyzed in a descriptive manner. 
Change #33, Section 15, REFERENCES 
The following reference was added to the list. 
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio. The Psychological 
Corporation; 1993. 
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16.2 
Protocol Amendment 2 
Rationale for the amendment 
The purpose of this amendment is to replace the children’s version of the C-SSRS with the 
version validated in multiple languages for subjects 6 years of age and older. The BSID-II 
score was replaced by the Bayley-III scales in order to apply the most recent version of the 
cognition scale. In addition, it was clarified that the cognition scale will be used only in 
English-speaking countries, since it is validated only in English. The efficacy variables for 
subjects <2 years of age and for subjects with absence seizures were updated and amended in 
response to the PDCO requirements. It was clarified that safety laboratory assessments 
include hepatic monitoring. Furthermore, an error in the mathematical symbols used for the 
presentation of the age limits of the EEG assessments was corrected, and the SAE reporting 
details were updated. Administrative changes include the update of the Clinical Project 
Manager contact details and typographical corrections.  
Few changes of editorial nature are additionally listed in the specific changes section. 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• The efficacy variables for subjects <2 years of age and for subjects with absence seizures 
were amended in response to the PDCO requirements. Additional efficacy variables based 
on DRC data were added. In addition, the description of the EEGs has changed from 
“24-hour EEG” and “1-hour EEG” to “an EEG of at least 24 hours of recording” and “an 
EEG of at least 1 hour of recording”. The resulting wording updates were applied to 
relevant sections for consistency reasons. 
• The children’s version of the C-SSRS was replaced with the version validated for subjects 
6 years and older, since the children’s version is validated only in English, and the 
version for subjects 6 years and older is validated in multiple languages. 
• The BSID-II score was replaced by the Bayley-III scales in order to apply the most recent 
version of the cognition scale. In addition, it was clarified that the cognition scale will be 
used only in English-speaking countries. 
• Data for some assessments at the Entry Visit (as outlined in footnote “a” of Table 5:1) 
will be obtained from the previous study. The revised footnote specifies which of these 
data will be taken from the Baseline visit and which data will be taken from the last visit 
of the previous study. All related sections have been updated accordingly. 
• The assessment “recording of epileptic seizures” has been updated to “seizure count” in 
order to align with the terminology used in N01263. 
• All sections referring to biochemistry assessments were updated in order to clarify that 
tests for hepatic monitoring (ALT, AST, ALP, total bilirubin, and GGT) will be included 
in safety laboratory assessments. 
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• An error in the mathematical symbols used for the presentation of the age limits of the 
EEG assessments was corrected in all respective sections. In addition, it was clarified that 
the age limits for the EEG assessments are based on the subject’s age on the day of the 
visit. 
• A format error in the table footnotes was corrected without any content-related changes. 
Specific changes 
Change #1, TITLE PAGE 
The title page was updated to reflect the current amendment. 
Change #2, SPONSOR DECLARATION, Clinical Project Manager and 
Clinical Program Director 
The original text: 
Clinical Project Manager 
 
 
 
_____________________________ 
Date/Signature 
 
Associate Clinical Program Director  
 
 
_____________________________ 
Date/Signature 
 
Has been changed to: 
Clinical Project Manager 
 
 
 
_____________________________ 
Date/Signature 
 
Clinical Program Director  
 
 
_____________________________ 
Date/Signature 
 
 
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Change #3, STUDY CONTACT INFORMATION 
The original text: 
Clinical Project Manager 
Name: 
 
Address: 
UCB Center Bruxelles 
Allée de la Recherche 60 
B-1070 Bruxelles 
Belgium 
Phone: 
 
Fax: 
 
 
Has been changed to: 
Clinical Project Manager 
Name: 
 
Address: 
UCB Center Bruxelles 
Allée de la Recherche 60 
B-1070 Bruxelles 
Belgium 
Phone: 
 
Fax: 
 
 
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Change #4, SERIOUS ADVERSE EVENT REPORTING 
The original text: 
Serious adverse event reporting (24h), safety related issues, and emergency 
unblinding  
 
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
USA: +1 800 880 6949 
Canada: +1 877 582 8842 
Phone 
During business hours: 
Outside business hours: 
Europe and Rest of the World 
(except Japan):  
+32 2 386 2468 
USA and Canada: 
+1 404 895 0794 
Europe and Rest of the World 
(except Japan): 
+32 2 386 2468 
USA and Canada: 
+1 404 895 0794 
 
Has been changed to: 
Serious adverse event reporting (24h), safety related issues, and emergency 
unblinding  
 
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
US: +1 800 880 6949 
Canada: +1 877 582 8842 
Phone 
Europe, US, and Rest of the World (except Japan): +32 2 386 2468 
Email 
Europe, US, and Rest of the World (except Japan): GCSP@ucb.com 
 
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Change #5, Section 1, LIST OF ABBREVIATIONS 
The following abbreviations were added to the list: 
Bayley-III® 
Bayley Scales of Infant and Toddler Development®, Third 
Edition 
GGT 
gamma-glutamyltransferase 
M 
month 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
The following abbreviation was updated: 
The original text: 
BSID-II™ 
Bayley Scales of Infant Development-II 
 
Has been changed to: 
BSID-II™ 
Bayley Scales of Infant Development™, Second Edition 
 
Change #6, SUMMARY, paragraph 1 
The original text: 
This is a Phase 3, open-label, single-arm, multicenter, long-term follow-up (LTFU) study to 
evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy. The 
primary objective is to document the long-term safety and tolerability of BRV. The secondary 
objective is to assess the efficacy of BRV during long-term exposure and the other objectives 
are to explore direct cost parameters and to assess the effect of BRV on behavior and 
cognition using the age-appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 or 
CBCL/6-18) for subjects ≥18 months of age at Baseline of the previous study N01263 or the 
Bayley Scales of Infant Development-II (BSID-II™) for subjects <18 months of age at 
Baseline of the previous study N01263. 
Has been changed to: 
This is a Phase 3, open-label, single-arm, multicenter, long-term follow-up (LTFU) study to 
evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy. The 
primary objective is to document the long-term safety and tolerability of BRV. The secondary 
objective is to assess the efficacy of BRV during long-term exposure. The other objectives 
are to explore direct cost parameters and to assess the effect of BRV on behavior and 
cognition using the age-appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 or 
CBCL/6-18) for subjects ≥18 months of age at Baseline of the previous study N01263 or 
other pediatric studies. The Bayley Scales of Infant and Toddler Development®, Third 
Edition (Bayley-III®) will be used to assess subjects enrolled in English-speaking 
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countries and <18 months of age at Baseline of the previous study N01263 or other BRV 
pediatric studies. 
Change #7, Section 1, SUMMARY, paragraph 6 
The original text: 
Safety variables include adverse events (AEs), safety laboratory assessments (hematology, 
biochemistry, and endocrinology for all subjects and urinalysis for subjects ≥4 years of age), 
plasma concentrations of BRV and phenytoin (if applicable), electrocardiograms (ECGs), 
vital signs, physical and neurological examinations, psychiatric and mental status, body 
weight, and height. 
Has been changed to: 
Safety variables include adverse events (AEs), safety laboratory assessments (hematology, 
biochemistry including hepatic monitoring of alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], total bilirubin, and 
gamma-glutamyltransferase [GGT], and endocrinology for all subjects and urinalysis for 
subjects ≥4 years of age), plasma concentrations of BRV and phenytoin (if applicable), 
electrocardiograms (ECGs), vital signs, physical and neurological examinations, psychiatric 
and mental status, body weight, and height. 
Change #8, Section 1, SUMMARY, paragraph 8 
The original text: 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital 
stays) and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) and BSID-II scores 
over time.   
Has been changed to: 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital 
stays) and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) or the change in 
Bayley-III scales over time for subjects enrolled in English-speaking countries.   
Change #9, Section 3.3, Other objectives, third bullet 
The original text: 
• To assess the effect of BRV on cognition using the BSID-II in subjects <18 months of age  
Has been changed to: 
• To assess the effect of BRV on cognition using the Bayley-III scales in subjects 
<18 months of age (applicable only to subjects enrolled in English-speaking 
countries)  
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Change #10, Section 4.1, Safety variables, bullet on laboratory 
assessments 
The original text: 
• Safety laboratory tests (hematology, biochemistry, and endocrinology for all subjects and 
urinalysis for subjects ≥4 years of age)  
Has been changed to: 
• Safety laboratory tests (hematology, biochemistry including hepatic monitoring of 
ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all subjects and 
urinalysis for subjects ≥4 years of age)  
Change #11, Section 4.2, Efficacy variables 
The original text: 
The efficacy variables planned for analysis of subjects ≤2 years of age or subjects with 
absence seizures will be based on EEG data and will include the following:  
• Responder rate for total POS defined as the percentage of subjects with a ≥50% reduction 
in ADF (average daily frequency) of POS recorded on EEG  
• Absolute and percent reduction in ADF of POS 
• 50% responder rate for total seizures (all types) 
• Absolute and percent reduction in ADF of total seizures (all types) 
The efficacy variables planned for analysis of subjects ≥2 years of age will be based on 
DRC data and will include the following: 
• Responder rate (the percentage of subjects who have a ≥50% reduction in seizure 
frequency per 28 days from Baseline for POS)  
• Absolute and percent reduction in seizure frequency (POS) per 28 days from Baseline to 
the end of the Evaluation Period 
• 50% responder rate for total seizures (all types) 
• Absolute and percent reduction in seizure frequency (total seizures) per 28 days from 
Baseline to the end of the Evaluation Period  
• Seizure freedom rate over the Evaluation Period 
• Proportion of seizure-free days over the Evaluation Period 
Has been changed to: 
For subjects <2 years of age (based on EEG data [recorded at least 24 hours]) or 
subjects with absence seizures (based on EEG data): 
• Responder rate for total POS defined as the percentage of subjects with a ≥50% reduction 
in ADF (average daily frequency) of POS recorded on EEG  
• Absolute and percent reduction in ADF of POS 
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• 50% responder rate for total seizures (all types) 
• Absolute and percent reduction in ADF of total seizures (all types) 
• Seizure freedom (rate and proportion) 
• Worsening of other types of seizures (absolute and percent) 
In addition, the following efficacy variables will be repeated for subjects <2 years of age 
or subjects with absence seizures based on the DRC seizure counts: 
• Seizure freedom rate over the Evaluation Period (all types) by visit and by time 
intervals (6 months, 12 months, etc) 
• Proportion of seizure free days over the Evaluation Period (all types) and by time 
intervals (6 months, 12 months, etc) 
• Absolute and percent worsening in ADF of total seizures (all types) 
A descriptive summary of seizure frequency by visit based on the DRC data will be also 
provided for these subjects.  
The efficacy variables planned for analysis of subjects ≥2 years of age will be based on 
DRC data and will include the following: 
• Responder rate (the percentage of subjects who have a ≥50% reduction in seizure 
frequency per 28 days from Baseline for POS)  
• Absolute and percent reduction in seizure frequency (POS) per 28 days from Baseline to 
the end of the Evaluation Period 
• 50% responder rate for total seizures (all types) 
• Absolute and percent reduction in seizure frequency (total seizures) per 28 days from 
Baseline to the end of the Evaluation Period  
• Seizure freedom rate over the Evaluation Period 
• Proportion of seizure-free days over the Evaluation Period 
Change #12, Section 4.3, Other variables, third bullet 
The original text: 
• Change over time from previous study Baseline in the BSID-II score for children 
<18 months of age. 
Has been changed to: 
• Change over time from previous study Baseline in the Bayley-III scales for children 
<18 months of age (applicable only to subjects enrolled in English-speaking 
countries) 
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Change #13, Section 5.2, Schedule of study assessments, Table 5:1 
The original text: 
Recording of epileptic seizures 
Has been changed to: 
Seizure count 
The original text: 
BSID-II scorep 
Has been changed to: 
Bayley-III scalesp 
Change #14, Section 5.2, Schedule of study assessments, Table 5:1 
The table cell for the C-SSRS at the EV has been unchecked, since the data will be 
obtained from the previous study. 
Change #15, Section 5.2, Schedule of study assessments, Table 5:1, 
footnotes 
The format and content of the original text: 
a. 
AE=adverse event; AED=antiepileptic drug; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; BRV=brivaracetam; BSID-II=Bayley Scales of Infant Development-II; CBCL=Child 
Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; DRC=daily record card; 
ECG=electrocardiogram; eCRF=electronic case report form; EEG=electroencephalogram; 
IVRS=interactive voice response system; M=Month; LFT=liver function test; SAE=serious adverse event; 
V=Visit 
Have been changed to: 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; Bayley-III=Bayley Scales of Infant and Toddler Development, Third 
Edition; BRV=brivaracetam; CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating 
Scale; DRC=daily record card; ECG=electrocardiogram; eCRF=electronic case report form; 
EEG=electroencephalogram; GGT=gamma-glutamyltransferase; IVRS=interactive voice response system; 
LFT=liver function test; M=Month; SAE=serious adverse event; V=Visit 
All subsequent footnote indices have been corrected accordingly. 
Change #16, Section 5.2, Schedule of study assessments, Table 5:1, 
footnote a 
The original text: 
b. 
The following data will be obtained from the previous pediatric study and should not be recorded on the 
eCRF for N01266: general medical and procedure history, epilepsy history, AED history, seizure count, 
EEG, ECG, laboratory assessments for safety, including phenytoin plasma concentrations (if applicable), 
the Achenbach CBCL score, the BSID-II score, vital signs, body weight and height, physical and 
neurological examinations, psychiatric and mental status, recording of epileptic seizures, and data on health 
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care provider consultations not foreseen by the protocol and hospital stays. The EV is also the final 
evaluation visit of the previous pediatric study. 
Has been changed to: 
a. 
The following data will be obtained from Baseline of the previous pediatric study and should not be 
recorded on the eCRF for N01266: general medical and procedure history, epilepsy history, AED history, 
height, Bayley-III scales, and the Achenbach CBCL score. The following data will be obtained from the 
last visit of the previous pediatric study and should not be recorded on the eCRF for N01266: seizure 
count, EEG, ECG, laboratory assessments for safety, including phenytoin plasma concentrations (if 
applicable), the C-SSRS, vital signs, body weight, physical and neurological examinations, psychiatric and 
mental status, and data on health care provider consultations not foreseen by the protocol and hospital stays. 
The EV is also the final evaluation visit of the previous pediatric study. 
Change #17, Section 5.2, Schedule of study assessments, Table 5:1, 
footnotes 
The original text and the mathematical symbols: 
h. EEG 
i. 
For subjects >2 years with typical absence seizures: every 3 months during the first 6 months (starting at 
V4), and then yearly thereafter: a 1-hour EEG including hyperventilation and intermittent photic stimulation 
must be performed for efficacy assessment. For subjects prematurely discontinuing from the study, a 1-hour 
EEG should also be performed at the EDV. 
j. 
For subjects ≥1 month to ≤2 years: every 3 months during the first 6 months (starting at V4), then yearly 
thereafter: a 24-hour EEG including sleeping and awakening periods must be performed for efficacy 
assessment. For subjects prematurely discontinuing from the study, a 24-hour EEG should also be 
performed at the EDV. 
Have been changed to: 
g. EEG 
− 
For subjects ≥2 years of age on the day of the study visit and with typical absence seizures: every 
3 months during the first 6 months (starting at V4), and then yearly thereafter: an EEG of at least 
1 hour of recording including hyperventilation and intermittent photic stimulation must be performed 
for efficacy assessment. For subjects prematurely discontinuing from the study, an EEG of at least 
1 hour of recording should also be performed at the EDV. 
− 
For subjects ≥1 month to <2 years of age on the day of the study visit: every 3 months during the first 
6 months (starting at V4), then yearly thereafter: an EEG of at least 24 hours of recording including 
sleeping and awakening periods must be performed for efficacy assessment. For subjects prematurely 
discontinuing from the study, an EEG of at least 24 hours of recording should also be performed at 
the EDV. 
All subsequent footnote indices have been corrected accordingly. 
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Change #18, Section 5.2, Schedule of study assessments, Table 5:1, 
footnotes 
The original text: 
p. 
Laboratory assessments for safety include hematology, biochemistry, and endocrinology for all subjects and 
urinalysis for subjects ≥4 years of age. Female subjects with a Tanner stage >1 should have a urine 
pregnancy test performed at all laboratory assessment visits, except for the EDV and the SV, when a serum 
pregnancy test will be performed. Endocrinology testing will be performed once a year at the YEV. Liver 
function tests as described in Section 9.5.1 will be performed at the MEVs at V4 [M3] and V6 [M9]. 
Has been changed to: 
m. 
Full laboratory assessments for safety include hematology, biochemistry (including hepatic monitoring of 
ALT, AST, ALP, total bilirubin, and GGT), and endocrinology for all subjects and urinalysis for 
subjects ≥4 years of age as described in Section 9.5.1. Female subjects with a Tanner stage >1 should have 
a urine pregnancy test performed at all laboratory assessment visits, except for the EDV and the SV, when a 
serum pregnancy test will be performed. Endocrinology testing will be performed once a year at the YEV. 
In addition, liver function tests as described in Section 9.5.1 will be performed at the MEVs at V4 (M3) 
and V6 (M9). 
Change #19, Section 5.2, Schedule of study assessments, Table 5:1, 
footnotes 
The original text: 
s. 
The cognition scale (BSID-II) to be used in this study for subjects <18 months of age will be the same as 
the one used in the previous pediatric study. If the subject reaches 18 months of age in this LTFU study, the 
subject will still be assessed using the BSID-II to allow for an evaluation of the change from Baseline even 
if their age increases to ≥18 months. 
Has been changed to: 
p. 
The cognition scale (Bayley-III) to be used in this study for subjects <18 months of age and enrolled in 
English-speaking countries will be the same as the one used in the previous pediatric study. If the subject 
reaches 18 months of age in this LTFU study, the subject will still be assessed using the Bayley-III to allow 
for an evaluation of the change from Baseline even if their age increases to ≥18 months. 
Change #20, Section 5.3, Visit sequence, Table 5:2, footnotes 
The format of the original text and footnote c: 
a. 
EV=Entry Visit; FEV=Full Evaluation Visit; LTFU=long-term follow-up; MEV=Minimal Evaluation Visit; 
YEV=Yearly Evaluation Visit 
b. 
Note: “-” denotes that no visit is scheduled in that month. 
c. 
The Entry Visit is the final evaluation visit of the previous pediatric study. 
d. 
Subsequent years will follow the same visit schedule. 
e. 
Liver function tests will be performed in addition to the assessments described in Section 9.5.1. 
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Have been changed to: 
EV=Entry Visit; FEV=Full Evaluation Visit; LTFU=long-term follow-up; MEV=Minimal Evaluation Visit; 
YEV=Yearly Evaluation Visit 
Note: “-” denotes that no visit is scheduled in that month. 
a. 
The Entry Visit is the final evaluation visit of the previous pediatric study. 
b. 
Subsequent years will follow the same visit schedule. 
c. 
Liver function tests only will be performed as described in Section 9.5.1. 
Change #21, Section 6.3, Withdrawal criteria, criterion 10 
The original text: 
10. Criteria for subjects who completed a C-SSRS assessment at the EV: 
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Children’s Since Last Visit” version of the 
C-SSRS. The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study. 
Has been changed to: 
10. Criteria for subjects who completed a C-SSRS assessment at the EV: 
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a Mental Healthcare Professional and must 
be withdrawn from the study. 
Change #22, Section 6.3, Withdrawal criteria, criterion 11 
The original text: 
11. Criteria for already enrolled subjects who did not complete a C-SSRS assessment at the 
EV: 
• Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of the 
“Children’s Baseline/Screening” version of the C-SSRS. The Investigator must 
withdraw the subject from the study and immediately refer the subject to a Mental 
Healthcare Professional. 
• Subject had active suicidal ideation in the past 6 months as indicated by a positive 
response (“Yes”) to either Question 4 or Question 5 of the “Children’s 
Baseline/Screening” version of the C-SSRS. The Investigator must immediately refer 
the subject to a Mental Healthcare Professional and use clinical judgment as to 
whether to withdraw the subject from the study.  
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Children’s Since Last Visit” version of the 
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C-SSRS. The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study. 
Has been changed to: 
11. Criteria for already enrolled subjects who did not complete a C-SSRS assessment at the 
EV: 
• Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
withdraw the subject from the study and immediately refer the subject to a Mental 
Healthcare Professional. 
• Subject had active suicidal ideation prior to study entry or since study start as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
immediately refer the subject to a Mental Healthcare Professional and use clinical 
judgment as to whether to withdraw the subject from the study.  
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a Mental Healthcare Professional and must 
be withdrawn from the study. 
Change #23, Section 8.1, Entry Visit, assessments obtained from the 
previous study 
The original text: 
The EV is also the final evaluation visit of the previous pediatric study. The following data 
will be obtained from the previous pediatric study and should not be recorded on the eCRF 
for N01266: 
• General medical and procedures history 
• Epilepsy history 
• AED history  
• Seizure count 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) must be performed 
• ECG 
• Laboratory assessments for safety  
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
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• Phenytoin plasma concentrations (if applicable) 
• BSID-II score for subjects <18 months of age at Baseline of N01263 
• Achenbach CBCL score for subjects ≥18 months of age at Baseline of N01263 
• Vital signs 
• Body weight and height 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Recording of epileptic seizures 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
Has been changed to: 
The EV is also the final evaluation visit of the previous pediatric study. The following data 
will be obtained from Baseline of the previous pediatric study and should not be recorded on 
the eCRF for N01266: 
• General medical and procedures history 
• Epilepsy history 
• AED history 
• Height 
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other 
pediatric studies and only for subjects enrolled in English-speaking countries 
• Achenbach CBCL score for subjects ≥18 months of age at Baseline of N01263 
The following data will be obtained from the last visit of the previous pediatric study 
and should not be recorded on the eCRF for N01266: 
• Seizure count 
• EEG 
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed 
• ECG 
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• Laboratory assessments for safety (including hepatic monitoring) 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Phenytoin plasma concentrations (if applicable) 
• Vital signs 
• Body weight  
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
Change #24, Section 8.2, Minimal Visit 
The original text: 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) must be performed 
• Recording of epileptic seizures 
Has been changed to: 
• EEG  
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed only at V4 (M3) as described in 
Section 10.2 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed only at V4 (M3) as described in Section 10.2  
• Seizure count 
Change #25, Section 8.3, Full Evaluation Visit 
The original text: 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
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− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) must be performed 
• Recording of epileptic seizures 
• Laboratory assessments for safety (hematology and biochemistry for all subjects, and 
urinalysis for subjects ≥4 years of age)  
• BSID-II for all subjects who were <18 months of age at Baseline of N01263 
Has been changed to: 
• EEG  
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed only at V5 (M6) as described in 
Section 10.2 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed only at V5 (M6) as described in Section 10.2 
• Seizure count 
• Laboratory assessments for safety (hematology and biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT for all subjects, and 
urinalysis for subjects ≥4 years of age)  
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
Change #26, Section 8.4, Yearly Evaluation Visit 
The original text: 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) must be performed 
• Recording of epileptic seizures 
• Laboratory assessments for safety (hematology, biochemistry, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age)  
• BSID-II for all subjects who were <18 months of age at Baseline of N01263 
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Has been changed to: 
• EEG 
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording including sleeping and awakening periods) must be 
performed 
• Seizure count 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age)  
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
Change #27, Section 8.5, Unscheduled Visit, last paragraph 
The original text: 
• If an Unscheduled Visit is conducted due to safety or efficacy reasons, a suicidality 
assessment (C-SSRS) 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. 
Has been changed to: 
• If an Unscheduled Visit is conducted due to safety or efficacy reasons, a suicidality 
assessment (C-SSRS) will be performed with subjects ≥6 years of age 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. 
Change #28, Section 8.6, Early Discontinuation Visit 
The original text: 
• EEG  
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) must be performed. 
• Recording of epileptic seizures 
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• Laboratory assessments for safety (hematology, biochemistry, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age)  
• BSID-II for all subjects who were <18 months of age at Baseline of N01263 
Has been changed to: 
• EEG  
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed. 
• Seizure count 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age)  
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
Change #29, Section 8.7, Down-Titration Visit 
The original text: 
• Recording of epileptic seizures 
Has been changed to: 
• Seizure count 
Change #30, Section 8.8, Safety Visit 
The original text: 
• Recording of epileptic seizures 
• Laboratory assessments for safety (hematology, biochemistry, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age) performed only if abnormal at the 
EDV 
Has been changed to: 
• Seizure count 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age) performed only if abnormal at the 
EDV 
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Change #31, Section 8.9, Final Visit 
The original text: 
• EEG 
− For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) must be performed 
− For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) must be performed. 
• Recording of epileptic seizures 
• Laboratory assessments for safety (hematology, biochemistry, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age).   
• BSID-II for all subjects who were <18 months of age at Baseline of N01263 
Has been changed to: 
• EEG 
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed. 
• Seizure count 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age).   
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
Change #32, Section 9.4, Anticipated SAEs 
The section reference in the original text: 
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure: convulsion. This original list will remain in effect for the duration of the protocol. 
This list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 9.2.3. 
Has been changed to: 
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure: convulsion. This original list will remain in effect for the duration of the protocol. 
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This list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 9.2.2. 
Change #33, Section 9.5.1, Laboratory assessments for safety, 
table footnotes 
The format of the original text and footnote c: 
a. 
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; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; 
T3=triiodothyronine; T4=tetraiodothyronine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
b. 
Urinalysis will be performed in subjects ≥4 years of age. 
c. 
Liver function tests will be assessed at the MEVs at V4 [M3] and V6 [M9] during the first year in addition 
to the full laboratory assessments described in Section 9.5. 
d. 
Includes bacteria, cells, casts, and crystals for all samples. 
e. 
Female subjects with a Tanner stage >1 should have a urine pregnancy test at all laboratory assessment 
visits, except the EDV and the SV, when a serum pregnancy test will be performed. 
f. 
Endocrinology testing will be performed once a year at the YEV. 
Have been changed to: 
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; 
SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; 
T3=triiodothyronine; T4=tetraiodothyronine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
a. 
Urinalysis will be performed in subjects ≥4 years of age. 
b. 
In addition, liver function tests will be assessed at the MEVs at V4 (M3) and V6 (M9), as described in 
Section 9.5.1. 
c. 
Includes bacteria, cells, casts, and crystals for all samples. 
d. 
Female subjects with a Tanner stage >1 should have a urine pregnancy test at all laboratory assessment 
visits, except the EDV and the SV, when a serum pregnancy test will be performed. 
e. 
Endocrinology testing will be performed once a year at the YEV. 
All footnote indices have been corrected accordingly. 
Change #34, Section 9.5.1, Laboratory assessments for safety, 
paragraph 6 
The original text: 
Laboratory safety assessments at the EV will be obtained from the previous pediatric study 
and should not be recorded on the eCRF for N01266. Laboratory safety assessments will be 
performed at the FEV, YEV, FV, and at the EDV in the case of early discontinuation. 
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Laboratory assessments will also be mandatory at the SV if the laboratory results at the EDV 
are abnormal. Liver function tests will be performed at the MEVs at V4 (M3) and V6 (M9) 
during the first year. Endocrinology testing will be performed once a year at the YEV.  
Has been changed to: 
Laboratory safety assessments at the EV will be obtained from the last visit of the previous 
pediatric study and should not be recorded on the eCRF for N01266. Laboratory safety 
assessments will be performed at the FEV, YEV, FV, and at the EDV in the case of early 
discontinuation. Laboratory assessments will also be mandatory at the SV if the laboratory 
results at the EDV are abnormal. In addition, liver function tests will be performed at the 
MEVs at V4 (M3) and V6 (M9) during the first year. Endocrinology testing will be 
performed once a year at the YEV.  
Change #35, Section 9.6.1 to Section 9.6.6 
It was clarified whether the assessments at the Entry Visit of N01266 are taken from 
Baseline or from the last visit of the previous study. The clarification applies to the 
following assessments: ECG, vital signs, body weight and height, physical examination, 
neurological examination, and psychiatric and mental status.  
The original text: 
At the EV, ECG data will be obtained from the previous pediatric study and should not be 
recorded in the eCRF for N01266. 
At the EV, vital sign data will be obtained from the previous pediatric study and should not 
be recorded in the eCRF for N01266. 
At the EV, body weight and height data will be obtained from the previous pediatric study 
and should not be recorded in the eCRF for N01266. 
At the EV, physical examination data will be obtained from the previous pediatric study and 
should not be recorded in the eCRF for N01266. 
At the EV, neurological examination data will be obtained from the previous pediatric study 
and should not be recorded in the eCRF for N01266. 
At the EV, psychiatric and mental status data will be obtained from the previous pediatric 
study and should not be recorded in the eCRF for N01266. 
Has been changed to: 
At the EV, ECG data will be obtained from the last visit of the previous pediatric study and 
should not be recorded in the eCRF for N01266. 
At the EV, vital sign data will be obtained from the last visit of the previous pediatric study 
and should not be recorded in the eCRF for N01266. 
At the EV, body weight data will be obtained from the last visit and height data will be 
obtained from Baseline of the previous pediatric study and should not be recorded in the 
eCRF for N01266. 
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At the EV, physical examination data will be obtained from the last visit of the previous 
pediatric study and should not be recorded in the eCRF for N01266. 
At the EV, neurological examination data will be obtained from the last visit of the previous 
pediatric study and should not be recorded in the eCRF for N01266. 
At the EV, psychiatric and mental status data will be obtained from the last visit of the 
previous pediatric study and should not be recorded in the eCRF for N01266. 
Change #36, Section 10.2, Efficacy assessments for seizure data based 
on EEG 
The original text: 
At the EV, data on absence seizure count (a 1-hour EEG for subjects >2 years suffering from 
absences) will be obtained from the previous pediatric study and should not be recorded in 
the eCRF for N01266.  
All EEGs specific to this study will be recorded in the eCRF modules specifically designed 
for this purpose.  
The EEGs will be performed according to the following specifications: 
• For subjects >2 years with typical absence seizures: a 1-hour EEG (including 
hyperventilation and intermittent photic stimulation) will be performed starting at V4 and 
at every 3-month visit for the first 6 months and then yearly thereafter. For subjects 
prematurely discontinuing from the study, a 1-hour EEG should also be performed at the 
EDV. 
• For subjects ≥1 month to ≤2 years: a 24-hour EEG (including sleeping and awakening 
periods) will be performed every 3 months during the first 6 months of the study, then 
yearly thereafter, and at the FV or the EDV in the case of early discontinuation. 
The EEGs will be recorded at the MEV, FEV, YEV, FV, and at the EDV in the case of early 
discontinuation.  
A central reader will review and assess all EEGs in a standardized manner. 
Has been changed to: 
At the EV, seizure data based on an EEG of at least 24 hours of recording (including 
sleeping and awakening periods) for subjects <2 years of age and data on absence seizure 
count (based on an EEG of at least 1 hour of recording for subjects ≥2 years of age 
suffering from absences) will be obtained from the last visit of the previous pediatric study 
and should not be recorded in the eCRF for N01266.  
All EEGs specific to this study will be recorded in the eCRF modules specifically designed 
for this purpose.  
The EEGs will be performed according to the following specifications: 
• For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) will be performed starting at V4 and at every 3-month 
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visit for the first 6 months and then yearly thereafter. For subjects prematurely 
discontinuing from the study, an EEG of at least 1 hour of recording should also be 
performed at the EDV. 
• For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) will be 
performed every 3 months during the first 6 months of the study, then yearly thereafter, 
and at the FV or the EDV in the case of early discontinuation. 
A central reader will review and assess all EEGs in a standardized manner. 
Change #37, Section 10.3.1.3, Health care provider consultations not 
foreseen by the protocol, last sentence 
The original text: 
At the EV, information on the health care provider consultations not foreseen by the protocol 
will be obtained from the previous pediatric study and should not be recorded in the eCRF for 
N01266.  
Has been changed to: 
At the EV, information on the health care provider consultations not foreseen by the protocol 
will be obtained from the last visit of the previous pediatric study and should not be recorded 
in the eCRF for N01266.  
Change #38, Section 10.3.1.4, Hospital stays, last sentence 
The original text: 
At the EV, information on hospital stays will be obtained from the previous pediatric study 
and should not be recorded in the eCRF for N01266.  
Has been changed to: 
At the EV, information on hospital stays will be obtained from the last visit of the previous 
pediatric study and should not be recorded in the eCRF for N01266.  
Change #39, Section 10.3.2 
The original text: 
10.3.2 
Bayley Scales of Infant Development-II 
The BSID‑II™ is a widely used validated questionnaire for children from 1 month up to 
42 months of age designed to evaluate a child’s developmental function, including cognition, 
language, personal social behavior, and motor development.  
This scale is accepted as a tool for assessment of neurological development in young children 
and is therefore considered appropriate for this study. The BSID-II will be used throughout 
the study for all subjects who were <18 months of age at Baseline (V1) of the previous 
pediatric study, N01263, by the Investigator or designee. Children started on the BSID-II at 
Baseline of N01263 will also be assessed using the BSID-II in N01266 even if their age 
increases to >18 months. The completion of the BSID-II will require approximately 25 to 
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35 minutes for children below 15 months of age and up to 60 minutes for children above 
15 months of age.  
The BSID-II includes a mental scale that evaluates sensory/perceptual activities, 
discriminations, acquisition of object constancy, memory, learning and problem solving, 
vocalization, early verbal communication, abstract thinking, habituation, mental mapping, 
complex language, and mathematical concept formation; a motor scale that evaluates degree 
of body control, coordination of large muscles, fine manipulation skills, dynamic movement, 
postural imitations, and stereognosis; and a behavior rating scale that measures attention and 
arousal, orientation and engagement, emotional regulation, and motor quality (Bayley, 1993).  
At the EV, the BSID-II score will be obtained from the previous pediatric study and should 
not be recorded in the eCRF in N01266. The BSID-II will be completed at the FEV, YEV, 
FV, and at the EDV in the case of early discontinuation. The BSID-II should be completed by 
the same person who completed the CBCL in the previous pediatric study. 
Has been changed to: 
10.3.2 
Bayley Scales of Infant and Toddler Development, Third 
Edition 
The Bayley-III scales are recognized internationally as one of the most comprehensive 
developmental assessment instruments (Sattler and Hoge, 2006) used to examine the 
major facets of a young child’s development (Bayley, 2006). The Bayley Scales of Infant 
and Toddler Development, Third Edition (Bayley-III) are a standardized individually 
administered adaptive assessment that measures the developmental functioning of 
infants and young children from 1 month to 42 months of age (Bayley, 2006). The 
Bayley-III scales measure cognitive, language, motor, social-emotional, and adaptive 
development and are a revision of the predecessor, the Bayley Scales of Infant 
Development, Second Edition (BSID-II) (Bayley, 1993). The Bayley-III scales are a 
technically sound instrument, with strong internal consistency, as well as test-retest 
stability. The Bayley-III scales are validated only in English. 
This scale is validated as a tool for assessment of neurological development in young 
children and is therefore considered appropriate for N01266. The same scale has been 
completed by the Investigator or designee at Baseline (V1) of N01263 for children from 
1 month to <18 months of age at Baseline enrolled in English-speaking countries. 
Children started on the Bayley-III scales at Baseline of N01263 will also be assessed 
using the Bayley-III scales in N01266 even if their age increases to ≥18 months.  
The Bayley-III scales are an individually administered adaptive assessment that 
presents children with situations and tasks designed to produce an observable set of 
behavioral responses. They consist of a cognitive scale, a language composite scale with 
receptive and expressive language subscales, and a motor composite scale with fine and 
gross motor subscales to be completed by the Investigator or designee, and of a 
social-emotional scale, comprising social-emotional competence and sensory processing, 
and an adaptive behavior scale, which assesses the attainment of skills necessary for the 
development of independence, to be completed by the child’s parent or caregiver.  
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The completion of the Bayley-III scales will require approximately 50 minutes for 
children who are 12 months old or younger and 90 minutes for children aged 13 months 
and older. 
At the EV, the Bayley-III scales will be obtained from Baseline of the previous pediatric 
study if the subject was enrolled in an English-speaking country, and data should not be 
recorded in the eCRF in N01266. The Bayley-III scales will be completed at the FEV, 
YEV, FV, and at the EDV in the case of early discontinuation. The Bayley-III scales 
should be completed by the same person who completed the Bayley-III scales in the 
previous pediatric study. 
Change #40, Section 10.3.3, Achenbach Child Behavior Checklist, last 
paragraph 
The original text: 
At the EV, the Achenbach CBCL score will be obtained from the previous pediatric study 
and should not be recorded in the eCRF in N01266. The Achenbach CBCL will be completed 
at the FEV, YEV, FV, and at the EDV in the case of early discontinuation. 
Has been changed to: 
At the EV, the Achenbach CBCL score will be obtained from Baseline of the previous 
pediatric study and should not be recorded in the eCRF in N01266. The Achenbach CBCL 
will be completed at the FEV, YEV, FV, and at the EDV in the case of early discontinuation. 
Change #41, Section 12.5, Other analyses, last paragraph 
The original text: 
The Achenbach CBCL, the BSID-II scores, and change from previous study Baseline scores 
will be analyzed in a descriptive manner. 
Has been changed to: 
The Achenbach CBCL, the Bayley-III scores, and change from previous study Baseline 
scores will be analyzed in a descriptive manner. 
Change #42, Section 15, REFERENCES 
The following references have been added: 
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: 
Pearson Education Inc; 2006. 
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical 
foundations. 5th ed. La Mesa: Jerome M Sattler; 2006. 
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16.3 
Protocol Amendment 3 
Rationale for the amendment 
The primary purpose of the protocol amendment is to allow subjects who have not previously 
participated in a clinical study of BRV to enroll directly into N01266 (ie, directly enrolled 
subjects). Up to 100 subjects who are ≥4 years to <17 years of age with POS and meet entry 
criteria are planned for direct enrollment. The purpose of direct enrollment is to obtain 
sufficient long-term safety exposure data in subjects in this age group. These data will be 
included in the planned regulatory submission for BRV as adjunctive therapy for POS in 
pediatric subjects ≥1 month to ≤16 years of age with epilepsy. 
With this amendment, the BRIEF-P/BRIEF and PedsQL were added to the assessments for 
subjects ≥2 years of age. These assessments were added to provide an additional means of 
assessing the effect of BRV on cognition and quality of life, respectively, in pediatric subjects 
≥2 years of age. 
Modifications and changes 
Global changes 
The following changes that pertain to the inclusion of directly enrolled subjects were made 
throughout the protocol: 
• The study title and protocol text have been updated to reflect that, with the inclusion of 
eligible direct enrollees, N01266 is no longer exclusively a LTFU study. 
• Information has been added throughout the protocol to indicate that up to 100 subjects 
≥4 years to <17 years of age with POS who have not previously participated in a clinical 
study of BRV (ie, directly enrolled subjects) may enroll directly into N01266 provided 
eligibility criteria are met. Information specific to these subjects was added throughout 
the protocol as shown in “specific changes.” 
• A Screening Visit, TV(s), and an EV unique to directly enrolled subjects were added. A 
schedule of assessments was added to specify the assessments to be performed at these 
visits, and the text throughout the protocol was modified accordingly. 
• The visit sequence table was revised to include visits unique to directly enrolled subjects. 
• The inclusion criteria (Section 6.1) and exclusion criteria (Section 6.2) were modified to 
provide the eligibility requirements for directly enrolled subjects, and make a distinction 
between the previously existing criteria for LTFU subjects. 
The following changes that pertain to all subjects were made: 
• Table 5-1 was revised to include directly enrolled subjects and updated to provide 
additional clarity regarding assessments. The revised table is shown below in “specific 
changes.” 
• Introductory information was updated to include background safety data included in the 
most current Investigator’s Brochure (cutoff date 08 Sep 2011).  
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• Reference to the Global Clinical Safety and Pharmacovigilance department was replaced 
by reference to Drug Safety, and SAE reporting contact information was updated. 
• BRIEF-P/BRIEF and PedsQL assessments were added and included as variables and 
objectives. Descriptions of these assessments were added. 
• The contact information in the section pertaining to serious adverse event reporting was 
updated. 
• The word “active” was replaced with “actual” as a descriptor for suicide attempts in order 
to match the language used in the C-SSRS scale. 
• Laboratory safety assessments done at each visit were clarified, but not changed. 
• For subjects who prematurely discontinue, age-based targets were specified for the final 
down-titration BRV dose. 
• Minor editorial changes were made. 
• Formatting changes (eg, reduced space between lines in tables, footnote indentation, and 
table title number formatting) were made to address new technical presentation 
requirements put in place by UCB. Due to the scope of these changes and the fact that 
they do not represent content changes, they are not included in “specific changes.” 
• Minor typographical corrections were made (eg, removal of an extra full stop at the end 
of a sentence). These changes are not included in “specific changes.” 
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Specific changes 
Change #1, TITLE PAGE 
The title page was updated to reflect the current amendment. 
Change #2, TITLE PAGE 
The original title: 
Open-label, single-arm, multicenter, long-term follow-up study to evaluate safety and 
efficacy of brivaracetam used as adjunctive treatment in pediatric subjects with epilepsy  
Has been changed to: 
Open-label, single-arm, multicenter, long-term study to evaluate safety and efficacy of 
brivaracetam used as adjunctive treatment in pediatric subjects with epilepsy 
Change #3, SPONSOR DECLARATION 
The original text: 
Clinical Project Manager 
 
_____________________________ 
Date/Signature 
Study Physician 
 
_____________________________ 
Date/Signature 
Senior Clinical Program Director 
 
____________________________ 
Date/Signature 
Has been changed to: 
Clinical Project Manager 
 
_____________________________ 
Date/Signature 
Study Physician 
 
_____________________________ 
Date/Signature 
 
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Change #4, STUDY CONTACT INFORMATION 
The original text: 
Sponsor Study Physician 
Name: 
 
Address: 
8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Center Bruxelles 
Allée de la Recherche 60 
B-1070 Bruxelles 
Belgium 
Phone: 
 
Fax: 
 
 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
 
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Clinical Project Manager 
Name: 
 
Address: 
UCB Center Bruxelles 
Allée de la Recherche 60 
B-1070 Bruxelles 
Belgium 
Phone: 
 
Fax: 
 
 
Change #5, SERIOUS ADVERSE EVENT REPORTING 
The original text: 
Serious adverse event reporting (24h), safety related issues, and emergency 
unblinding  
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
US: +1 800 880 6949 
Canada: +1 877 582 8842 
Phone 
Europe, US, and Rest of the World (except Japan): +32 2 386 2468 
Email 
Europe, US, and Rest of the World (except Japan): GCSP@ucb.com 
 
Has been changed to: 
Serious adverse event reporting (24h) and safety related issues  
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
US: +1 800 880 6949 
Canada: +1 877 582 8842 
Email 
Europe, US, and Rest of the World (except Japan): DS_ICT@ucb.com 
 
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Change #6, LIST OF ABBREVIATIONS 
The following abbreviations have been added to the list: 
ALP 
alkaline phosphatase 
BRIEF® 
Behavior Rating Inventory of Executive Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive 
Function®-Preschool Version 
HRQoL 
health-related quality of life 
PedsQL™ 
Pediatric Quality of Life Inventory™ 
ScrV 
Screening Visit 
TV 
Titration Visit 
The original text for the following abbreviations: 
bid 
twice daily  
M 
month 
PDCO 
European Pediatric Committee 
POS 
partial onset seizures 
Has been changed to:  
bid 
bis in die (twice daily)  
M 
Month 
PDCO 
European Paediatric Committee 
POS 
partial-onset seizures 
The following abbreviation has been deleted from the list: 
GCSP 
Global Clinical Safety and Pharmacovigilance 
Change #7, SUMMARY, paragraphs 1 through 4 
The original text: 
This is a Phase 3, open-label, single-arm, multicenter, long-term follow-up (LTFU) study to 
evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy. The 
primary objective is to document the long-term safety and tolerability of BRV. The secondary 
objective is to assess the efficacy of BRV during long-term exposure. The other objectives 
are to explore direct cost parameters and to assess the effect of BRV on behavior and 
cognition using the age-appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 or 
CBCL/6-18) for subjects ≥18 months of age at Baseline of the previous study N01263 or 
other pediatric studies. The Bayley Scales of Infant and Toddler Development®, Third 
Edition (Bayley-III®) will be used to assess subjects enrolled in English-speaking countries 
and <18 months of age at Baseline of the previous study N01263 or other BRV pediatric 
studies. 
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To enroll in this study, subjects must have completed N01263 or will have completed a future 
BRV pediatric study. On entering this study, subjects will continue their BRV treatment at 
the individualized dose that they had reached at the completion of their previous pediatric 
study. Subjects entering this study from N01263 must be able to tolerate at least 0.4mg/kg of 
BRV twice daily (bid) if ≥8 years of age or at least 0.5mg/kg bid if <8 years of age. The 
maximum BRV dose for subjects ≥8 years of age is 3.2mg/kg/day and 4.0mg/kg/day for 
subjects <8 years of age. Younger subjects (<7 years of age) will be administered BRV oral 
solution (given bid in 2 equally divided doses). Subjects above 50kg will be dosed as adults, 
up to a maximum total daily dose not exceeding 200mg/day, and should transition from the 
oral solution to the equivalent oral tablet dose (given bid in 2 equally divided doses). Dose 
adjustments of BRV and any concomitant antiepileptic drugs (AEDs) are allowed at any time 
based on clinical judgment.  
Subjects will continue to receive BRV treatment in this study for at least 3 years, or until 
approval of BRV has been obtained for pediatric subjects in their age range, or until the 
investigational product development is stopped by the Sponsor.  
For subjects who continue in this study until it ends, the Evaluation Period will extend from 
the Entry Visit (EV, Visit 1 [V1]) until the final evaluation visit (Final Visit, FV). For 
subjects who prematurely discontinue the study, the Evaluation Period will last from the EV 
until the Early Discontinuation Visit (EDV), followed by a maximum 4-week Down-Titration 
Period, a 2-week study drug-free Safety Period, and a final Safety Visit (SV). 
Has been changed to: 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety 
and efficacy of brivaracetam (BRV) in children with epilepsy. This study was initially 
designed for pediatric subjects who had completed N01263 or would complete other 
future pediatric BRV studies (herein referred to as “long-term follow-up” [LTFU] 
subjects). With Protocol Amendment 3, enrollment was expanded to include up to 
100 subjects ≥4 years to <17 years of age with POS who had not previously enrolled in a 
pediatric BRV study (herein referred to as “directly enrolled subjects”). 
The primary objective is to document the long-term safety and tolerability of BRV. The 
secondary objective is to assess the efficacy of BRV during long-term exposure. The other 
objectives are to explore direct cost parameters and to assess the effect of BRV on behavior 
and cognition using the age-appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 
or CBCL/6-18) for LTFU subjects ≥18 months of age at Baseline of the previous BRV study 
and for all directly enrolled subjects. With Protocol Amendment 3, the effect of BRV on 
cognition will also be assessed using the Behavior Rating Inventory of Executive 
Function® (BRIEF®)/BRIEF®-Preschool Version (BRIEF®-P) and the effect of BRV on 
quality of life will be assessed using the Pediatric Quality of Life Inventory™ 
(PedsQL™) for LTFU subjects ≥1 month of age at the Baseline of the previous BRV 
study and for all directly enrolled subjects. The Bayley Scales of Infant and Toddler 
Development®, Third Edition (Bayley-III®) will be used to assess LTFU subjects enrolled in 
English-speaking countries and <18 months of age at Baseline of the previous pediatric 
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BRV study; Bayley-III will not be used to access directly enrolled subjects since all are 
to be ≥4 years of age. 
The LTFU subjects will enter directly into the Evaluation Period at the Entry Visit (EV) 
and will continue BRV treatment at the individualized dose they were receiving at the 
completion of their previous pediatric BRV study. Directly enrolled subjects will enter 
N01266 at the Screening Visit (ScrV), and then participate in up to 3 weeks of an 
Up-Titration Period. If a directly enrolled subject demonstrates, in the opinion of the 
Investigator, acceptable tolerability and seizure control on the same daily dose of BRV 
(no lower than the minimum specified dose) for 7±2 days during the Up-Titration 
Period, the subject will attend the EV and enter the Evaluation Period on that dose.  
Brivaractam (tablet and oral solution) should be administered twice daily (bid) in 
2 equally divided doses. All LTFU subjects must be able to tolerate the minimum dose 
specified in the previous BRV study to be eligible for entry into the Evaluation Period. 
This minimum tolerated dose for LTFU subjects from N01263 is 0.8mg/kg/day if 
≥8 years of age and 1.0mg/kg/day if <8 years of age. The same minimums apply to directly 
enrolled subjects as indicated in Section 7.2. 
The maximum allowable BRV dose is 3.2mg/kg/day for subjects ≥8 years of age and 
4.0mg/kg/day for subjects <8 years of age. Younger subjects (<7 years of age) will be 
administered BRV oral solution. Subjects above 50kg will be dosed as adults, up to a 
maximum total daily dose not exceeding 200mg/day, and should transition from the oral 
solution to the equivalent oral tablet dose, if appropriate. With the exception of dose 
adjustments for BRV during the Up-Titration Period, which should be made in 
accordance with the protocol-specified guidelines, dose adjustments of BRV and any 
concomitant antiepileptic drugs (AEDs) are allowed at any time based on clinical judgment. 
Subjects will receive BRV treatment in this study for approximately 3 years, until approval 
of BRV has been obtained for pediatric subjects in their age range, or until the investigational 
product development is stopped by the Sponsor.  
For LTFU subjects, the EV is the first study visit. For directly enrolled subjects, the EV 
occurs after subjects have completed the ScrV and at least 1 Titration Visit (TV), and 
have maintained acceptable tolerability and seizure control on the same daily dose of 
BRV (no lower than the minimum specified dose) for 7±2 days of the Up-Titration 
Period. For subjects who continue in this study until it ends, the Evaluation Period will 
extend from the EV until the final evaluation visit (Final Visit, FV). For subjects who 
prematurely discontinue the study, the Evaluation Period will last from the EV until the Early 
Discontinuation Visit (EDV), followed by a maximum 4-week Down-Titration Period, a 
2-week study drug-free Safety Period, and a final Safety Visit (SV). At selected sites, 
subjects may be able to participate in a substudy without withdrawing from N01266. 
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Change #8, SUMMARY, paragraphs 8 and 9 
The original text: 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital 
stays) and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) or the change in 
Bayley-III scales over time for subjects enrolled in English-speaking countries. 
Up to 500 subjects may possibly enroll in this study, with the number and location of the sites 
dependent on those participating in N01263 and in other future pediatric studies that will 
provide access to this LTFU. 
Has been changed to: 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital 
stays) and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18), BRIEF-P/BRIEF, 
and PedsQL scores, and the change in Bayley-III scales for subjects enrolled in 
English-speaking countries.  
Up to 600 subjects may possibly enroll in this study. The number and location of the sites 
will depend on those participating in N01263 and other future pediatric BRV studies from 
which LTFU subjects will be enrolled, and those participating in direct enrollment. Sites 
of direct enrollment will include, but not be limited to, sites participating in N01263 and 
other pediatric BRV studies. 
Change #9, Section 2.3, Efficacy with BRV 
The original header text: 
Efficacy with BRV 
Has been changed to: 
Efficacy with BRV (adult studies) 
Change #10, Section 2.4, Safety with BRV 
The original header text: 
Safety with BRV 
Has been changed to: 
Safety with BRV (adult studies) 
Change #11, Section 2.4. Safety with BRV, paragraph 3 
The original text: 
In addition, there are 3 ongoing open-label LTFU studies (N01125, N01199, and N01315) 
that include subjects with POS, primary generalized seizures, or ULD who completed 1 of the 
Phase 2/3 well-controlled studies. As of 04 Jan 2011, 1629 subjects have been enrolled in 
these studies and 1624 subjects have received study medication. The median duration of 
BRV exposure in LTFU studies was 91 weeks. The most common TEAEs based on interim 
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safety monitoring review include headache, dizziness, nasopharyngitis, convulsion, 
somnolence, and fatigue. Overall, 234 subjects reported SAEs. The only SAE occurring at a 
frequency >1% was convulsion (2.4%). Overall, 132 subjects discontinued due to TEAEs. 
The most common TEAEs leading to premature discontinuation were convulsion and 
depression. 
Has been changed to: 
In addition, there are 3 ongoing open-label LTFU studies (N01125, N01199, and N01315) 
that include subjects with POS, primary generalized seizures, or ULD who completed 1 of the 
Phase 2/3 well-controlled studies. As of 08 Sep 2011, 1629 subjects have been enrolled into 
these studies and 1624 subjects have received study medication. The median duration of 
BRV exposure in LTFU studies was 119 weeks. The most common TEAEs, based on interim 
safety monitoring review, include headache, dizziness, nasopharyngitis, convulsion, 
somnolence, and fatigue. Overall, 272 subjects reported SAEs. The only SAE occurring at a 
frequency >1% was convulsion (2.5%). Overall, 142 subjects discontinued due to TEAEs. 
The most common TEAEs leading to premature discontinuation were convulsion and 
depression. 
Change #12, Section 2.5, Rationale for the study, paragraph 3 and 4 
The original text: 
UCB is developing BRV as an adjunctive treatment including in subjects <16 years of age 
suffering from epilepsy. N01263 is the first study of BRV in pediatric subjects. This is an 
open-label, fixed 3-step up-titration, PK, safety and efficacy study to evaluate BRV as 
adjunctive therapy in children (aged ≥1 month to <16 years) with epilepsy using an oral 
solution. The safety and PK data from this study will be used for BRV dose adaptation in 
pediatric subjects with epilepsy. 
This present study (N01266) will give subjects who have completed N01263 or will have 
completed other future BRV pediatric studies an opportunity to continue BRV treatment for 
at least 3 years, or until approval of BRV is granted for pediatric subjects in their age range, 
or until the investigational product development is stopped by the Sponsor. In addition, 
N01266 will gather additional long-term safety and tolerability data on BRV in pediatric 
subjects with epilepsy while providing access to BRV for subjects who may benefit from 
long-term treatment. 
Has been changed to: 
N01263 is the first study of BRV in pediatric subjects. This is an open-label, fixed 3-step 
up-titration, PK, safety and efficacy study to evaluate BRV as adjunctive therapy in children 
(aged ≥1 month to <16 years) with epilepsy using an oral solution. The safety and PK data 
from this study will be used for BRV dose adaptation in pediatric subjects with epilepsy. 
N01266 was originally designed to give subjects who complete N01263 or other future 
pediatric BRV studies (ie, LTFU subjects) an opportunity to continue BRV treatment for 
approximately 3 years, until approval of BRV is granted for pediatric subjects in their age 
range, or until the investigational product development is stopped by the Sponsor. With 
Protocol Amendment 3, enrollment is expanded to include up to 100 eligible subjects 
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≥4 years to <17 years of age with POS who have not participated in another pediatric 
BRV study (ie, directly enrolled subjects). Thus, N01266 will gather additional long-term 
safety and tolerability data on BRV in pediatric subjects with epilepsy while providing access 
to BRV for subjects who may benefit from long-term treatment. 
Change #13, Section 3.3, Other objectives 
The original text: 
• To explore direct cost parameters 
• To assess the effect of BRV on behavior using the Achenbach CBCL in subjects 
≥18 months of age 
• To assess the effect of BRV on cognition using the Bayley-III scales in subjects 
<18 months of age (applicable only to subjects enrolled in English-speaking countries)  
Has been changed to: 
• To explore direct cost parameters 
• To assess the effect of BRV on behavior using the Achenbach CBCL in subjects 
≥18 months of age 
• To explore the effect of BRV on cognition using the BRIEF-P/BRIEF in subjects 
≥2 years of age 
• To assess the effect of BRV on cognition using the Bayley-III scales in subjects 
<18 months of age (applicable only to LTFU subjects enrolled in English-speaking 
countries)  
• To explore the effect of BRV on health-related quality of life (HRQoL) using the 
PedsQL in subjects ≥1 month of age 
Change #14, Section 4.3, Other variables 
The original text: 
The other variables include the following: 
• Direct cost parameters: concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and hospital stays 
• Change over time from previous study Baseline in the Achenbach CBCL score: the 
Achenbach CBCL/1½-5 for children from 1½ to 5 years old and the Achenbach 
CBCL/6-18 for children 6 years and older 
• Change over time from previous study Baseline in the Bayley-III scales for children 
<18 months of age (applicable only to subjects enrolled in English-speaking countries) 
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Has been changed to: 
The other variables include the following: 
• Direct cost parameters: concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and hospital stays 
• Change from Baseline in the Achenbach CBCL score: the Achenbach CBCL/1½-5 for 
children from 1½ to 5 years old and the Achenbach CBCL/6-18 for children 6 years and 
older 
• Change from Baseline in the BRIEF-P/BRIEF score for subjects ≥2 years of age 
• Change from previous BRV study Baseline in the Bayley-III scales for children 
<18 months of age (applicable only to LTFU subjects enrolled in English-speaking 
countries) 
• Change from Baseline in PedsQL for subjects ≥1 month of age 
Change #15, Section 5.1, Study description, paragraphs 1 through 5 
The original text: 
This is a Phase 3, open-label, single-arm, multicenter, LTFU study to evaluate the safety and 
efficacy of BRV in up to 500 subjects with epilepsy. Subjects had to be <16 years of age 
upon entry in their previous pediatric study.  
To enroll in this LTFU study, subjects must have completed N01263 or will have completed 
a future BRV pediatric study. On entering the LTFU study, subjects will continue their BRV 
treatment at the individualized dose that they had reached at the completion of the previous 
study. Younger subjects (<7 years of age) will be administered BRV oral solution (given bid 
in 2 equally divided doses). Subjects above 50kg will be dosed as adults, up to a maximum 
total daily dose not exceeding 200mg/day, and should transition from the oral solution to the 
equivalent oral tablet dose (given bid in 2 equally divided doses). Dose adjustments of BRV 
and/or concomitant AEDs are allowed at any time based on clinical judgment. Further 
information on the treatment administered is presented in Section 7.2. 
Subjects will continue to receive BRV treatment in this study for at least 3 years, or until 
approval for BRV has been obtained for pediatric subjects in their age range, or until the 
investigational product development is stopped by the Sponsor. 
For subjects who continue in the study until it ends, the Evaluation Period will extend from 
the EV to the FV. For subjects who prematurely discontinue the study, the Evaluation Period 
will last from the EV until the EDV. Following the EDV, subjects will have their dose of 
BRV down titrated over a maximum of 4 weeks (Down-Titration Period). After 2 weeks free 
of study drug (Safety Period), subjects will complete the SV. 
During the Evaluation Period, MEVs and FEVs will be performed alternatively every month 
during the first 3 months and every 3 months thereafter, with a YEV every 12 months. The 
sequence of these visits is presented in Section 5.3. Both safety data and efficacy data 
(seizure data) will be collected during the study. A list of the study assessments performed at 
each of the visits is presented in Section 5.2.  
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Has been changed to: 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety 
and efficacy of BRV in up to 600 subjects with epilepsy. Subjects who enroll in N01266 
from N01263 or another pediatric BRV study (ie, LTFU subjects) must have been 
<16 years of age upon entry in their previous study; eligible subjects who have POS and 
enroll in N01266 without having participated in a previous pediatric BRV study (ie, 
directly enrolled subjects) must be ≥4 years to <17 years of age. 
Upon enrollment, eligible LTFU subjects will enter the Evaluation Period and continue 
their BRV treatment in accordance with their individualized dose at the completion of 
their previous pediatric BRV study. Directly enrolled subjects will be screened and 
participate in up to 3 weeks of an Up-Titration Period. If a directly enrolled subject 
demonstrates, in the opinion of the Investigator, acceptable tolerability and seizure 
control on the same daily dose of BRV (no lower than the minimum specified dose) for 
7±2 days during the Up-Titration Period, the subject will attend the EV and enter the 
Evaluation Period on that dose.  
Brivaracetam (tablet and oral solution) should be administered bid in 2 equally divided 
doses. All LTFU subjects must be able to tolerate the minimum BRV dose specified in 
the previous study to be eligible for entry into the Evaluation Period of N01266. For 
LTFU subjects from N01263, this minimum tolerated BRV dose is 0.8mg/kg/day if ≥8 
years of age and 1.0mg/kg/day if <8 years of age. The same minimums apply to directly 
enrolled subjects. 
For all subjects enrolled in N01266, the maximum BRV dose is 3.2mg/kg/day for 
subjects ≥8 years of age and 4.0mg/kg/day for subjects <8 years of age. Younger subjects 
(<7 years of age) will be administered BRV oral solution. Subjects above 50kg will be dosed 
as adults, up to a maximum total daily dose not exceeding 200mg/day, and should transition 
from the oral solution to the equivalent oral tablet dose. Dose adjustments of BRV and/or 
concomitant AEDs are allowed at any time based on clinical judgment; however, during the 
Up-Titration Period, dose adjustments for BRV should be made only as specified in 
Section 7.2.1. Additional information on BRV administration is presented in Section 7.2. 
Subjects will continue to receive BRV treatment in this study for approximately 3 years, 
until approval for BRV has been obtained for pediatric subjects in their age range, or until the 
investigational product development is stopped by the Sponsor. 
For LTFU subjects, the EV is the first study visit. For directly enrolled subjects, the EV 
is the visit at which subjects enter the Evaluation Period and occurs after subjects have 
completed the ScrV and at least 1 Titration Visit (TV). For subjects who continue in the 
study until it ends, the Evaluation Period will extend from the EV to the FV. For subjects 
who prematurely discontinue the study, the Evaluation Period will last from the EV until the 
EDV. Following the EDV, subjects will have their dose of BRV down titrated over a 
maximum of 4 weeks (Down-Titration Period). After 2 weeks free of study drug (Safety 
Period), subjects will complete the SV. 
During the Evaluation Period, MEVs and FEVs will be performed alternatively every month 
during the first 3 months and every 3 months thereafter, with a YEV every 12 months. The 
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sequence of these visits is presented in Section 5.3. Both safety data and efficacy data 
(seizure data) will be collected during the study. Lists of the study assessments performed at 
each of the visits are presented in Section 5.2.  
Change #16, Section 5.1.1, Study duration per subject, paragraph 1 
The original text: 
The maximum duration for subject participation will extend from study entry (EV, V1) for at 
least 3 years, or until approval of BRV has been obtained for pediatric subjects in their age 
range, or until the investigational product development is stopped by the Sponsor. 
Has been changed to: 
Subject participation will extend from study entry for approximately 3 years, until approval 
of BRV has been obtained for pediatric subjects in their age range, or until the investigational 
product development is stopped by the Sponsor. Study entry is defined as the EV for 
LTFU subjects and the ScrV for directly enrolled subjects. 
Change #17, Section 5.1.2, Planned number of subjects and sites 
The original text: 
Up to 500 subjects (<16 years of age upon entry in their previous pediatric study) may 
possibly enroll in this study during the pediatric development plan, based upon the 
assumption that 90% of subjects having completed a previous pediatric study with BRV as 
adjunctive treatment in epilepsy will rollover into the present study. 
Has been changed to: 
As originally designed, up to 500 subjects (<16 years of age upon entry in their previous 
pediatric BRV study) might possibly enroll in this study during the pediatric development 
plan, based upon the assumption that 90% of subjects having completed a previous pediatric 
study with BRV as adjunctive treatment in epilepsy would rollover into N01266. 
With Protocol Amendment 3, enrollment is expanded to include up to 100 eligible 
directly enrolled subjects ≥4 years to <17 years of age with POS, which will allow up to 
600 subjects to enroll in N01266 instead of the up to 500 originally planned. 
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Change #18, Section 5.1.3, Anticipated regions and countries 
The original text: 
The regions and countries participating in this study will depend on the location of the sites 
participating in the previous pediatric study/studies, as these sites should have access to this 
LTFU study. Europe, US, and Mexico are foreseen, with the possibility to extend to other 
countries and regions if deemed necessary. 
Has been changed to: 
As originally designed, the regions and countries participating in this study depended on the 
location of the sites participating in the previous pediatric BRV study/studies, as these sites 
should have had access to the originally planned LTFU study. Europe, US, and Mexico 
were foreseen, with the possibility to extend to other countries and regions if deemed 
necessary.  
With Protocol Amendment 3, directly enrolled subjects may be enrolled from sites 
participating in N01263 and possibly other sites, including, but not limited to, those 
participating in other pediatric BRV studies. 
Change #19, Section 5.2, Schedule of study assessments, header text 
The original text: 
Schedule of study assessments 
Has been changed to: 
Schedules of study assessments 
Change #20, Section 5.2, Schedule of study assessments 
The following text has been added immediately below the section header: 
Once a directly enrolled subject demonstrates, in the opinion of the Investigator, 
acceptable tolerability and seizure control on the same daily dose of BRV (no lower than 
the minimum specified dose) for 7±2 days during the Up-Titration Period, the subject 
will attend the EV, enter the Evaluation Period on that dose, and follow the study 
assessments in Table 5-1. 
Table 5-1 provides a schedule of all study assessments for LTFU subjects and for 
assessments subsequent to the final TV for directly enrolled subjects. Table 5-2 provides 
a schedule of study assessments for directly enrolled subjects from the ScrV through the 
final TV. 
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Change #21, Section 5.2, Table 5:1 
The original title: 
Schedule of study assessments 
Has been changed to:  
Schedule of all study assessments for LTFU subjects and assessments 
subsequent to the final TV for directly enrolled subjects 
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The original header: 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV)a 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
 
Has been changed to: 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFU 
DE  
 
All 
 
 
 
 
 
The following row was deleted: 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
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The following cells have been added: 
BRIEF-P/BRIEFs 
 
 
 
X 
X 
 
X 
 
 
PedsQLt 
 
 
 
X 
X 
 
X 
 
 
 
The original table has been replaced with the following (with changes in addition to those noted above [title and 
header] indicated): 
 
Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Written informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
Subject identification 
card dispensing 
X 
 
 
 
 
 
 
 
 
Childbearing 
potential  
Xa 
X 
X 
X 
X 
 
X 
 
 
Verification 
inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
criteria 
Physical and 
neurological 
examinations 
Xa 
X 
 
X 
X 
 
X 
 
X 
Psychiatric and 
mental status 
Xa 
X 
 
X 
X 
 
X 
 
X 
Vital signsd 
Xa 
X 
X 
X 
X 
 
X 
X 
X 
Body weight and 
height 
Xa 
X 
X 
X 
X 
 
X 
 
X 
ECGe 
Xa 
X 
 
 
X 
 
X 
 
Xf 
EEGg 
Xa 
 
X 
X 
X 
 
X 
 
 
DRC dispensed 
X 
X 
X 
X 
Xh 
 
X 
X 
 
DRC retrieved 
 
X 
X 
X 
X 
 
X 
X 
X 
Seizure count  
Xa 
X 
X 
X 
X 
 
X 
X 
X 
Assessment of seizure 
 
 
 
X 
X 
 
 
 
 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
typesi 
Recording of 
medicationsj 
Xa  
X 
X 
X 
X 
X 
X 
X 
X 
Recording of 
procedures 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Recording of AEsk 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
IVRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensed 
X 
X 
X 
X 
Xh 
 
X 
 
 
Study drug returnedl 
 
X 
X 
X 
X 
 
X 
X 
 
Study drug 
compliance 
 
X 
X 
X 
X 
 
X 
X 
 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Laboratory 
assessments for 
safetym 
Xa 
X 
Xn 
X 
X 
 
X 
 
Xf 
BRV plasma 
concentrationso 
 
 
 
X 
X 
 
X 
 
 
Phenytoin plasma 
concentrations, if 
applicable 
Xa 
 
 
X 
X 
 
X 
 
Xf 
C-SSRSp 
Xa 
X 
X 
X 
X 
 
X 
X 
X 
Bayley-III scalesq 
 
 
 
X 
X 
 
X 
 
 
Achenbach CBCLr 
 
 
 
X 
X 
 
X 
 
 
BRIEF-P/BRIEFs 
 
 
 
X 
X 
 
X 
 
 
PedsQLt 
 
 
 
X 
X 
 
X 
 
 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Health care provider 
consultations not 
foreseen by protocol 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Hospital staysu 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
End of study status 
 
 
 
 
Xv 
 
 
 
X 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF=Behavior Rating Inventory of Executive Function; 
BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; CBCL=Child Behavior Checklist; 
C-SSRS=Columbia-Suicide Severity Rating Scale; DE=directly enrolled; DRC=daily record card; ECG=electrocardiogram; eCRF=electronic case report 
form; EEG=electroencephalogram; GGT=gamma-glutamyltransferase; IVRS=interactive voice response system; LTFU=long-term follow-up; M=Month; 
PedsQL=Pediatric Quality of Life Inventory; SAE=serious adverse event; TV=Titration Visit; V=Visit 
a For LTFU subjects, the following data will be obtained from Baseline of the previous pediatric BRV study and should not be recorded on the eCRF for 
N01266: demographics, general medical and procedure history, epilepsy history, AED history, height, Bayley-III scales, the Achenbach CBCL, 
BRIEF-P/BRIEF, and PedsQL scores. The following data will be obtained from the final visit of the previous pediatric BRV study and should not be 
recorded in the eCRF for N01266: AEs, childbearing potential, recording of medications, recording of procedures, seizure count, EEG, ECG, 
laboratory assessments for safety, including phenytoin plasma concentrations (if applicable), the C-SSRS, vital signs, body weight, physical and 
neurological examinations, psychiatric and mental status, and data on health care provider consultations not foreseen by the protocol and hospital stays. The 
EV is also the final evaluation visit of the previous pediatric BRV study. 
b For subjects staying in the study until it ends, the same procedures as for a YEV should be performed at the subject’s FV. 
c Visit should be scheduled at the end of the Down-Titration Period. The duration of the Down-Titration Period will depend on when the final dose of the 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
study drug was taken during the Evaluation Period, with a maximum duration of 4 weeks. 
d Vital sign measurements include blood pressure, pulse rate, and body temperature.  
e An ECG has to be scheduled once a year at the YEV and at the EDV in the case of early discontinuation. 
f At the SV, ECGs, laboratory assessments for safety, and determination of phenytoin plasma concentration will be performed only if abnormal at the EDV. 
g EEG (for LTFU subjects only) 
• 
For subjects ≥2 years of age on the day of the study visit and with typical absence seizures: every 3 months during the first 6 months (starting at V4), 
and then yearly thereafter: an EEG of at least 1 hour of recording including hyperventilation and intermittent photic stimulation must be performed 
for efficacy assessment. For subjects prematurely discontinuing from the study, an EEG of at least 1 hour of recording should also be performed at 
the EDV. 
• 
For subjects ≥1 month to <2 years of age on the day of the study visit: every 3 months during the first 6 months (starting at V4), then yearly 
thereafter: an EEG of at least 24 hours of recording including sleeping and awakening periods must be performed for efficacy assessment. For 
subjects prematurely discontinuing from the study, an EEG of at least 24 hours of recording should also be performed at the EDV. 
h No DRC or study drug will be dispensed at the FV. 
i The assessment of seizure types will be done at 6-monthly intervals (at the FEV and the YEV) for subjects <2 years of age. 
j For LTFU subjects, any ongoing medications (including AEDs and non-AEDs) at the time the subject completed the previous pediatric BRV study 
should not be recorded in the eCRF for N01266, unless there is a change regarding the administration of the medication. In this event, the start date 
corresponding to the date of change in administration should be recorded in the eCRF. 
k For LTFU subjects, any ongoing AEs at the time the subject completed the previous pediatric BRV study should not be recorded on the eCRF for 
N01266, unless there is a change in intensity or seriousness. In this event, the AE should be recorded in the eCRF for N01266, with the onset date 
corresponding to the date of change in condition. 
l Drug return includes study medication intake recording and accountability. 
m Full laboratory assessments for safety include hematology, biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), and 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
endocrinology for all subjects and urinalysis for subjects ≥4 years of age as described in Section 9.5.1. Female subjects with a Tanner stage >1 should have 
a urine pregnancy test performed at all laboratory assessment visits, except for the EDV and the SV, when a serum pregnancy test will be performed. 
Endocrinology testing will be performed at the YEV/FV.  
n Laboratory assessments are to be done only at the MEV at V4 (M3) and V6 (M9) and are to include only hepatic monitoring (ALE, AST, ALP, 
total bilirubin, and GGT). 
o In addition to the scheduled assessments, a pharmacokinetic sample for determination of BRV plasma concentration should be taken whenever a 
subject experiences an SAE. 
p The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” version of the C-SSRS will be used, with the following exception: 
If a subject turns 6 years of age during N01266, the “Already Enrolled” version of the C-SSRS should be completed at the first visit after the sixth 
birthday, and the “Since Last Visit” version of the C-SSRS should be completed at subsequent visits. 
q The cognition scale (Bayley-III) to be used in N01266 for subjects <18 months of age and enrolled in English-speaking countries will be the same as the 
one used in the previous pediatric BRV study. If the subject reaches 18 months of age in this study, the subject will still be assessed using the Bayley-III to 
allow for an evaluation of the change from Baseline even if his/her age increases to ≥18 months. 
r The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) should be in accordance with the subject’s age, with the following exception: If a 
subject completed the Achenbach CBCL/1½-5 at the Baseline assessment (previous pediatric BRV study for LTFU subjects and ScrV for directly 
enrolled subjects) and turns 6 years of age between that assessment and the initial YEV, the CBCL/1½-5 should be completed through and 
including the initial YEV, and subsequently the CBCL/6-18 should be completed.   
s The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF should be used for subjects ≥5 years of age, with the following 
exception: For subjects who completed the BRIEF-P at the Baseline assessment (previous pediatric BRV study for LTFU subjects and ScrV for 
directly enrolled subjects) and turn 6 years of age between that assessment and the initial YEV, the BRIEF-P should be completed through and 
including the initial YEV, and subsequently the BRIEF should be completed. 
t The version of the PedsQL used should be consistent with the subject’s age at each visit when it is administered with the following exception: If a 
subject ages up to the next PedsQL between the Baseline assessment (previous pediatric BRV study for LTFU subjects and ScrV for directly 
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Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
enrolled subjects) and the initial YEV, the PedsQL that was used at the Baseline assessment should be completed through and including the initial 
YEV, and subsequently the PedsQL consistent with the age at the time of assessment should be completed. 
u  This refers to any hospital stay that occurs during the study. Data recorded in the eCRF include the reason for the hospitalization, the admission ward, 
transfers, and length of stay. 
  End of study status only for subjects who continue in the study until it ends and for whom the visit corresponds to the final evaluation visit or FV.  
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Change #22, Section 5.2, Schedule of study assessments 
Table 5-2 has been added. 
Change #23, Section 5.3, Visit sequence, Table 5:2 
The following cells were added: 
Directly enrolled subjects 
 
Visit 
Type of visit 
 
ScrV 
Screening 
W1 
TV1a 
TV 
W2 
TV2a 
TV 
W3 
TV3a 
TV 
All subjects 
The following cells were deleted: 
Subjects coming from any pediatric study providing access to this LTFU 
Month (M) 
Visit (V) 
Type of visit 
The following have been added to the abbreviations list: 
BRV=brivaracetam; M=Month; ScrV=Screening Visit; TV=Titration Visit; V=Visit; W=Week 
The original footnotes: 
a The Entry Visit is the final evaluation visit of the previous pediatric study.  
b Subsequent years will follow the same visit schedule. 
c Liver function tests only will be performed as described in Section 9.5.1. 
Have been changed to (and referenced in the table in accordance with the 
updated lettering, as applicable): 
a All directly enrolled subjects must participate in at least TV1, but may participate in fewer than 3 TVs 
as described in Section 7.2.1 . 
b For LTFU subjects, the EV is the final evaluation visit of the previous pediatric BRV study. For directly 
enrolled subjects, the EV represents the point of entry into the Evaluation Period. 
c Hepatic monitoring tests only will be performed as described in Section 9.5.1. 
d Subsequent years will follow the same visit schedule. 
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Change #24, Section 5.4, Rationale for study design and selection of 
dose 
The original text: 
This present study will allow additional BRV long-term safety and tolerability data to be 
collected from pediatric subjects with epilepsy who will have participated in previous BRV 
pediatric studies and now have the opportunity to continue BRV treatment. The safety and 
efficacy data collected in this LTFU study will support the applications for BRV indications 
in pediatric patients. 
A physiologically-based PK model (N01313) was developed to predict the doses to be tested 
in N01263. For subjects aged ≥8 years, the approximate doses to be administered are 0.4, 0.8, 
and 1.6mg/kg bid (0.8, 1.6, and 3.2 mg/kg/day corresponding to 50, 100, and 200mg/day in 
adults). For subjects aged <8 years, the approximate doses to be administered are 0.5, 1.0, 
and 2.0mg/kg bid (1.0, 2.0, and 4.0 mg/kg/day, respectively). Daily doses will be adjusted by 
body weight, but will not exceed maximums of 50mg/day, 100mg/day, and 200mg/day. The 
dose selection was based on the following observations in adult subjects: 
• The PK of BRV is linear and of low variability in adults up to 1 order of magnitude above 
the therapeutic dose range. 
• Efficacious doses in adults are expected to be from 50mg/day up to 200mg/day. 
• Drug clearance is expected to be higher in children than in adults because of the 
physiologically based PK simulations. 
In this LTFU study, subjects will start on the individual BRV dose that they had reached at 
the completion of the previous pediatric study (N01263 or any future pediatric study). 
Subjects entering this LTFU must be able to tolerate the minimum dose and not exceed the 
maximum dose from their previous pediatric study. The maximum dose allowed in this study 
will be 200mg/day. 
Has been changed to: 
N01266 will allow BRV long-term safety and tolerability data to be collected from pediatric 
subjects with epilepsy who will have participated in previous pediatric BRV studies and now 
have the opportunity to continue BRV treatment, and from directly enrolled subjects with 
POS. The safety and efficacy data collected in this study will support the applications for 
BRV indications in pediatric patients. 
Each LTFU subject will begin treatment in N01266 at the individualized BRV dose 
he/she was receiving at the completion of the previous pediatric study. Directly enrolled 
subjects will participate in up to 3 weeks of an Up-Titration Period. If a subject 
demonstrates, in the opinion of the Investigator, acceptable tolerability and seizure 
control on the same daily dose of BRV for 7±2 days during the Up-Titration Period, the 
subject will be allowed to enter the Evaluation Period (subject must be able to tolerate 
the minimum specified dose; see Section 7). 
A physiologically-based PK model (N01313) was developed to predict the doses to be tested 
in N01263. The same doses that were used for up titration in N01263 will be used for the 
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3 consecutive weeks that comprise the Up-Titration Period of N01266. For subjects 
≥8 years of age, the approximate doses to be administered 0.4, 0.8, and 1.6mg/kg bid (0.8, 
1.6, and 3.2mg/kg/day, respectively, corresponding to 50, 100, and 200mg/day in adults) for 
Weeks 1, 2, and 3 of up titration, respectively. For subjects <8 years of age, the 
approximate doses to be administered are 0.5, 1.0, and 2.0mg/kg bid (1.0, 2.0, and 
4.0mg/kg/day, respectively) for Weeks 1, 2, and 3 of up titration, respectively. Daily doses 
will be adjusted by body weight, but will not exceed maximums of 50mg/day, 100mg/day, 
and 200mg/day. The dose selection was based on the following observations in adult 
subjects: 
• The PK of BRV is linear and of low variability in adults up to 1 order of magnitude above 
the therapeutic dose range. 
• Efficacious doses in adults are expected to be from 50mg/day up to 200mg/day. 
• Drug clearance is expected to be higher in children than in adults because of the 
physiologically based PK simulations. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 
2 equally divided doses. All LTFU subjects must be able to tolerate the minimum dose 
specified in the previous BRV study to be eligible for entry into the Evaluation Period of 
N01266. This minimum tolerated BRV dose for LTFU subjects from N01263 is 
0.8mg/kg/day if ≥8 years of age and 1.0mg/kg/day if <8 years of age. The same 
minimums apply to directly enrolled subjects. 
The maximum allowable BRV dose in N01266 is 3.2mg/kg/day for subjects ≥8 years of 
age and 4.0mg/kg/day for subjects <8 years of age. Younger subjects (<7 years of age) 
will be administered BRV oral solution. Subjects above 50kg will be dosed as adults, up 
to a maximum total daily dose not exceeding 200mg/day, and should transition from the 
oral solution to the equivalent oral tablet dose, if appropriate. 
The maximum BRV dose allowed in this study will be 200mg/day (100mg bid), which is the 
maximum allowed dose for those subjects dosed as adults. 
Change #25, Section 6.1, Inclusion criteria  
The original text: 
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 parent(s) or legal 
representative(s). The 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. Male or female subjects having participated in a previous pediatric study in epilepsy with 
BRV, and having access to the present study, and for whom a reasonable benefit from 
long-term administration of BRV is expected. 
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4. Female subjects without childbearing potential are eligible. 
5. Female subjects with childbearing potential who are not sexually active are eligible. 
Subjects need to notify the Investigator if there is an anticipated change in status. 
6. Female subjects with childbearing potential who are sexually active are eligible if they 
use a medically accepted contraceptive method. Oral or depot contraceptive treatment 
with at least ethinylestradiol 30µg per intake or ethinylestradiol 50µg per intake if 
associated with any strong inducer (eg, carbamazepine, phenobarbital, primidone, 
phenytoin, oxcarbazepine, St. John’s Wort, rifampicin), a monogamous relationship with 
a vasectomized partner, or double-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. 
7. Female subjects with childbearing potential must have a negative pregnancy test at the 
EV. 
Has been changed to the following, which includes movement of some original 
criteria under new headers and the addition of new sections: 
To be eligible to participate in this study, all of the following criteria must be met as 
specified. Criteria that were in place before Protocol Amendment 3 have retained the 
previous numbering. 
6.1.1  
 
Inclusion criteria for all subjects 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved 
written Informed Consent form is signed and dated by the parent(s) or legal 
representative(s). The 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. 
4. Female subjects without childbearing potential are eligible. 
5. Female subjects with childbearing potential who are not sexually active are eligible. 
Subjects need to notify the Investigator if there is an anticipated change in status. 
6. Female subjects with childbearing potential who are sexually active are eligible if they 
use a medically accepted contraceptive method. Oral or depot contraceptive treatment 
with at least ethinylestradiol 30µg per intake or ethinylestradiol 50µg per intake if 
associated with any strong inducer (eg, carbamazepine, phenobarbital, primidone, 
phenytoin, oxcarbazepine, St. John’s Wort, rifampicin), a monogamous relationship with 
a vasectomized partner, or double-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. 
7. Female subjects with childbearing potential must have a negative pregnancy test. 
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6.1.2  
 
Inclusion criteria for LTFU subjects only 
3. Male or female subjects having participated in a previous pediatric study in epilepsy with 
BRV and for whom a reasonable benefit from long-term administration of BRV is 
expected. 
6.1.3  
 
Inclusion criteria for directly enrolled subjects only 
8. Subject is a male or female ≥4 years to <17 years of age. 
9. Subject has a clinical diagnosis of POS according to the ILAE classification. 
10. Subject has an EEG compatible with the clinical diagnosis of POS.  
11. Subject has been observed to have uncontrolled POS after an adequate course of 
treatment (in the opinion of the Investigator) with at least 1 AED (concurrently or 
sequentially). 
12. Subject had at least 1 seizure (POS) during the 3 weeks before the ScrV. 
13. Subject is taking at least 1 AED. All AEDs need to be at a stable dose for at least 
7 days before the ScrV. Vagal nerve stimulator-stable for at least 2 weeks before the 
ScrV is allowed and will be counted as a concomitant AED. Benzodiazepines taken 
more than once a week (for any indication) will be considered as a concomitant 
AED. 
Change #26, Section 6.2, Exclusion criteria 
The original text: 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject is a pregnant or nursing female. 
2. Subject has developed hypersensitivity to any components of the investigational 
medicinal product (IMP) or comparative drugs as stated in this protocol during the course 
of the previous study. 
3. Subject has severe medical, neurological, or psychiatric disorders or laboratory values, 
which may have an impact on the safety of the subject. 
4. Subject had poor compliance with the visit schedule or medication intake in the previous 
BRV study. 
5. Subject has planned participation in any clinical study of another investigational drug or 
device. 
6. Subject has any medical condition, which in the Investigator’s opinion, warrants 
exclusion. 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the EV. 
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Has been changed to the following, with movement of some original criteria 
under new headers and the addition of new sections: 
Subjects are not permitted to enroll in the study if any of the following criteria are met as 
specified. Criteria that were in place before Protocol Amendment 3 have retained the 
previous numbering. 
6.2.1  
 
Exclusion criteria for all subjects 
1. Subject is a pregnant or nursing female. 
3. Subject has severe medical, neurological, or psychiatric disorders or laboratory values, 
which may have an impact on the safety of the subject. 
5. Subject has planned participation in any clinical study of another investigational drug or 
device. 
6. Subject has any medical condition, which in the Investigator’s opinion, warrants 
exclusion. 
6.2.2  
Exclusion criteria for LTFU subjects only 
2. Subject has developed hypersensitivity to any components of the investigational 
medicinal product (IMP) or comparative drugs as stated in this protocol during the course 
of the previous BRV study. 
4. Subject had poor compliance with the visit schedule or medication intake in the previous 
BRV study. 
7. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the EV. 
6.2.3  
Exclusion criteria for directly enrolled subjects only 
8. Subject has previously received BRV. 
9. Subject had concomitant use of LEV at the ScrV. In addition, the use of LEV is 
prohibited for at least 4 weeks prior to the ScrV. 
10. Subject has epilepsy secondary to a progressive cerebral disease or tumor, or any 
other progressively neurodegenerative disease. Stable arteriovenous malformations, 
meningiomas or other benign tumors may be acceptable according to Investigator’s 
opinion. 
11. Subject has a history of primary generalized epilepsy. 
12. Subject has a history of status epilepticus in the month immediately prior to the 
ScrV or during the Up-Titration Period. 
13. Subject has a history or presence of pseudoseizures. 
14. Subject is suffering only from febrile seizures. 
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15. Subject is on felbamate with less than 18 months continuous exposure. Subject who 
has taken felbamate for a combined duration of treatment and wash out of <18 
months before the ScrV. 
16. Subjects treated with vigabatrin who have visual field defects. 
17. Subject has an allergy to pyrrolidone derivatives or investigational product 
excipients or a history of multiple drug allergies. 
18. Subject has any clinically significant acute or chronic illness as determined during 
the physical examination or from other information available to the Investigator (eg, 
bone marrow depression, chronic hepatic disease, severe renal impairment, 
psychiatric disorder). 
19. Subject has an underlying disease or is receiving a treatment that may interfere with 
the absorption, distribution, metabolism, and elimination of the study drug.  
20. Subject has any medical condition that might interfere with his/her study 
participation (eg, serious infection or scheduled elective surgery). 
21. Subject has a terminal illness. 
22. Subject has any clinically significant deviations from reference range values for 
laboratory parameters as determined by the Investigator. 
23. Subject has a clinically relevant ECG abnormality according to the Investigator. 
24. Subject had major surgery within 6 months prior to the ScrV. 
25. Subject received any investigational drug or device within the 30 days prior to the 
ScrV. The use of AEDs marketed for adults but not approved for pediatric use is not 
considered to be “investigational” for the purposes of this study. 
26. Investigators’ and co-Investigators’ children may not be included as subjects in the 
study. 
27. Subject has impaired hepatic function:  
• 
Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT), alkaline phosphatase of more than 2x the upper limit of normal 
(ULN), or total bilirubin of more than 2xULN. 
• 
Gamma-glutamyltransferase (GGT) values of more than 3xULN. A result of 
GGT exceeding 3xULN can be accepted only if attributable to hepatic enzyme 
induction caused by concomitant antiepileptic treatment and if other hepatic 
enzymes are below 2xULN. 
28. Subject has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has suicidal ideation in the past 
6 months as indicated by a positive response (“Yes”) to either Question 4 or 
Question 5 of the C-SSRS-Baseline/Screening at the ScrV. 
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Change #27, Section 6.3, Withdrawal criteria, criterion 9, 10, and 11 
The original text: 
9. Subject has the following findings based on liver function tests (LFT): 
• If the subject has LFT results of transaminases (aspartate aminotransferase [AST] 
and/or alanine aminotransferase [ALT]) ≥3x the upper limit of normal (ULN) to 
<5xULN or total bilirubin ≥2xULN, the measurements will be repeated within a few 
days. If the repeat testing confirms the abnormality (eg, transaminases are ≥3xULN to 
<5xULN), then monitoring of LFTs should continue at subsequent study visits until 
resolved (eg, <3xULN or stable condition). The Investigator is to decide whether or 
not to stop the study medication. 
• If the subject has LFT results of transaminases (AST and/or ALT) ≥5xULN, study 
medication should be tapered off immediately and the subject must be withdrawn 
from the study. 
10. Criteria for subjects who completed a C-SSRS assessment at the EV: 
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or 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. 
11. Criteria for already enrolled subjects who did not complete a C-SSRS assessment at the 
EV: 
• Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must withdraw 
the subject from the study and immediately refer the subject to a Mental Healthcare 
Professional. 
• Subject had active suicidal ideation prior to study entry or since study start as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
immediately refer the subject to a Mental Healthcare Professional and use clinical 
judgment as to whether to withdraw the subject from the study.  
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or 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. 
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Has been changed to: 
9. Subject has the following findings based on liver function tests (LFT): 
• If the subject has LFT results of transaminases (AST and/or ALT) ≥3x the upper limit 
of normal (ULN) to <5xULN or total bilirubin ≥2xULN, the measurements will be 
repeated within a few days. If the repeat testing confirms the abnormality (eg, 
transaminases are ≥3xULN to <5xULN), then monitoring of LFTs should continue at 
subsequent study visits until resolved (eg, <3xULN or stable condition). The 
Investigator is to decide whether or not to stop the study medication. 
• If the subject has LFT results of transaminases (AST and/or ALT) ≥5xULN, study 
medication should be tapered off immediately and the subject must be withdrawn 
from the study. 
10. Criteria for subjects who completed a C-SSRS assessment at the final visit of the 
previous BRV study (LTFU subjects) or at the ScrV (directly enrolled subjects): 
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or 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. 
11. Criteria for subjects who become 6 years of age during N01266 and for whom the 
"Already Enrolled Subjects" version of the C-SSRS was completed at the first visit 
after the sixth birthday: 
• Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an actual attempt, interrupted attempt, or aborted attempt) of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must withdraw 
the subject from the study and immediately refer the subject to a Mental Healthcare 
Professional. 
• Subject had active suicidal ideation prior to study entry or since study start as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
immediately refer the subject to a Mental Healthcare Professional and use clinical 
judgment as to whether to withdraw the subject from the study.  
• Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a Mental Healthcare Professional and must 
be withdrawn from the study. 
Change #28, Section 7.2, Treatments to be administered, paragraphs 
1 through 4 
The original text: 
At study entry (EV), subjects will ordinarily start on the individualized BRV dose that they 
had reached at the completion of the previous study. 
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Subjects entering this study from N01263 must be able to tolerate at least 0.4mg/kg of BRV 
bid if ≥8 years of age or at least 0.5mg/kg if <8 years of age. The maximum BRV dose for 
subjects ≥8 years of age is 3.2mg/kg/day and 4.0mg/kg/day for subjects <8 years of age. 
Subjects above 50kg will be dosed as adults, up to a maximum total daily dose not exceeding 
200mg/day, and should transition from the oral solution to the equivalent oral tablet dose, 
unless the subject’s condition prevents him/her from swallowing oral tablets. Subjects 
<7 years of age should not transition to oral tablet treatment. Oral solution should not be 
mixed with other liquids prior to administration. 
The maximum dose allowed in this study is 200mg/day, given bid in 2 equally divided doses. 
The mg dosage for the oral tablet treatment should be calculated to match as closely as 
possible the mg/kg oral solution treatment and should be a combination of the BRV 10mg, 
25mg, and 50mg tablets (given bid in 2 equally divided doses). Only the following exact 
dosages are allowed for the oral tablet administration: BRV 20, 40, 50, 70, 100, 150, and 
200mg/day. Subjects should be dosed with either oral tablets or oral solution and not a 
combination of both. 
Has been changed to: 
The LTFU subjects will ordinarily start dosing on the individualized BRV dose they were 
receiving at the completion of the previous pediatric BRV study. The directly enrolled 
subjects will participate in an Up-Titration Period as described in Section 7.2.1 before 
entry into the Evaluation Period. 
The LTFU subjects must be able to tolerate the minimum BRV dose specified in their 
previous study to be eligible for entry into the Evaluation Period of N01266. For subjects 
entering N01266 from N01263, the minimum BRV dose is 0.8mg/kg/day if ≥8 years of age 
or at least 1.0mg/kg/day if <8 years of age; directly enrolled subjects must also tolerate at 
least these dosages for 7±2 days during the Up-Titration Period before entry into the 
Evaluation Period. 
The maximum BRV dose for subjects ≥8 years of age is 3.2mg/kg/day and 4.0mg/kg/day for 
subjects <8 years of age. Subjects above 50kg will be dosed as adults, up to a maximum total 
daily dose not exceeding 200mg/day, and should transition from the oral solution to the 
equivalent oral tablet dose, unless the subject’s condition prevents him/her from swallowing 
oral tablets. Subjects <7 years of age should not transition to oral tablet treatment. Oral 
solution should not be mixed with other liquids prior to administration. 
The maximum dose allowed in this study is 200mg/day (100mg bid). 
Brivaracetam should be given bid approximately 12 hours apart in 2 equally divided 
doses. The mg dosage for the oral tablet treatment should be calculated to match as closely as 
possible the mg/kg-based dosage and should be a combination of the BRV 10mg, 25mg, and 
50mg tablets. Only the following exact dosages are allowed for the oral tablet administration: 
BRV 20, 40, 50, 70, 100, 150, and 200mg/day. Subjects should be dosed with either oral 
tablets or oral solution and not a combination of both.  
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Change #29, Section 7.2, Treatments to be administered, paragraph 6 
The original text: 
All subjects who prematurely discontinue the study, should complete an EDV and have their 
BRV dose down titrated by a maximum of half the dose every week until a dose of 
1.0mg/kg/day is reached. 
Has been changed to: 
All subjects who prematurely discontinue the study should complete an EDV and have their 
BRV dose down titrated by a maximum of half the dose every week until a dose of 
1.0mg/kg/day is reached for subjects <8 years of age or until a dose of 0.8mg/kg/day is 
reached for subjects ≥8 years of age. 
Change #30, Section 7.2, Treatments to be administered 
The following section has been added: 
7.2.1  
 
Up-Titration Period for directly enrolled subjects 
Beginning with Protocol Amendment 3, at TV1, eligible directly enrolled subjects will 
initiate treatment with BRV (oral solution or tablet, as chosen by the Investigator and 
subject/caregiver). 
The BRV dose will be titrated to optimize tolerability and seizure control. Table 7-1 
provides the recommended titration steps for the oral solution and tablet formulations. 
Subjects must be on the same daily dose for 7±2 days before the dose is titrated to the 
next dosing level. Subjects may enter the Evaluation Period after they have remained on 
the same daily dose (no lower than the minimum specified dose) for 7±2 days that, in the 
opinion of the Investigator, has demonstrated acceptable tolerability and seizure 
control. Fewer than 3 TVs may be needed before entry into the Evaluation Period, 
depending on the BRV dose at which acceptable tolerability and seizure control is 
demonstrated. 
Based on tolerability and seizure control, a subject’s BRV dose may be reduced to no 
lower than the age-designated minimum dose indicated in Table 7-1. If a subject had 
previously received the reduced BRV dose for 7±2 days with acceptable tolerability and 
seizure control, then the subject may enter directly into the Evaluation Period. 
Table 7-1: Recommended BRV dosing schedule for directly 
enrolled subjects during the Up-Titration Period  
Visit 
(Week) 
BRV dose per dosing occasion 
(mg/kg) 
BRV dose per day 
(mg/kg/day) 
 
≥8 years 
<8 years 
≥8 years 
<8 years 
TV1 (1) 
~0.4 
~0.5 
~0.8 
~1.0 
TV2 (2) 
~0.8 
~1.0 
~1.6 
~2.0 
TV3 (3) 
~1.6 
~2.0 
~3.2 
~4.0 
BRV=brivaracetam; TV=Titration Visit; “~”=approximately 
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Change #31, Section 7.7, Procedures for monitoring subject compliance, 
paragraph 1 
The original text: 
The IMP (oral solution or oral tablets) will be supplied to the subject/parent(s)/legal 
representative(s) at the EV, MEV, FEV, YEV, and at the EDV in the case of early 
discontinuation. 
Has been changed to: 
The IMP (oral solution or oral tablets) will be supplied to the subject/parent(s)/legal 
representative(s) at the TV(s) (directly enrolled subjects only), EV, MEV, FEV, YEV, and 
at the EDV in the case of early discontinuation. 
Change #32, Section 7.7, Procedures for monitoring subject compliance, 
paragraph 5 
The original text: 
Study drug compliance will be assessed at the MEV, FEV, YEV, FV, and at the EDV and the 
Down-Titration Visit (DTV) in the case of early discontinuation. 
Has been changed to: 
Study drug compliance will be assessed at the TV(s) and EV (directly enrolled subjects 
only), MEV, FEV, YEV, FV, and at the EDV and the Down-Titration Visit (DTV) in the 
case of early discontinuation. 
Change #33, Section 7.8, Concomitant medications/treatments, 
paragraphs 1 through 3 
The original text: 
For any treatment other than the IMP, including over-the-counter products, an accurate 
record, must be kept in the clinic chart (source documentation) and in the eCRF. 
Ongoing medications at the time the subject completed the previous pediatric study, should 
not be recorded on the eCRF at the EV, unless there is a change regarding the administration 
of the medication. In this event, the start date corresponding to the date of change in 
administration should be recorded on the eCRF. 
All changes in concomitant AEDs and nonAEDs will be recorded on the AED or nonAED 
concomitant medication page in the eCRF, respectively. This record should include the name 
of the drug (preferably the brand name), the dose, the date(s) of administration, and the 
indication for use. 
Has been changed to: 
For any treatment other than the IMP, including over-the-counter products, an accurate record 
must be kept in the clinic chart (source documentation) and in the eCRF. 
For LTFU subjects, ongoing medications at the time the subject completed the previous 
pediatric BRV study should not be recorded in the eCRF at the EV, or any subsequent visit, 
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unless there is a change regarding the administration of the medication. For directly enrolled 
subjects, all concomitant medications should be recorded in the eCRF at the ScrV 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, and the indication for use. 
Change #34, Section 7.8.1.1, Permitted concomitant medications 
The following text has been added: 
Levetiracetam is allowed after the EV. 
Felbamate is allowed as follows: 
• LTFU subjects: 
− At the established dose if a stable dose was maintained during the previous 
pediatric BRV study 
• Directly enrolled subjects: 
− At a stable dose during the Screening and Up-Titration Periods  
− At the established dose from the EV onwards if a stable dose was maintained 
during the Screening and Up-Titration Periods  
Change #35, Section 7.8.2, Prohibited concomitant medications 
The original text: 
The following concomitant AED medication is prohibited during the study: 
• Felbamate (except if on a stable dose during the previous study) 
Has been changed to: 
The following concomitant AED medication is prohibited during the study: 
• LTFU subjects: 
− Felbamate (except if on a stable dose during the previous pediatric BRV study) 
• Directly enrolled subjects: 
− Felbamate (except if on a stable dose during the Screening and Up-Titration 
Periods) 
− LEV (from the ScrV until the EV) 
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Change #36, Section 7.9, Blinding 
The original text: 
This is an open-label LTFU study and therefore, no blinding is required. 
Has been changed to: 
This is an open-label study and therefore, no blinding is required. 
Change #37, Section 7.10, Randomization and numbering of subjects 
The original text: 
Subjects will not be randomized in this study, as each subject will start on the individualized 
BRV dose that they had reached at the completion of the previous study.  
To enroll a subject (EV, V1), the Investigator will call the IVRS and provide brief details 
about the subject to be enrolled. Subjects will continue with the 5-digit subject number 
assigned by the IVRS in the previous pediatric study. The subject number will be required in 
all communication between the Investigator (or designee) and the IVRS regarding a particular 
subject. Subjects’ status and the dispensing of IMP (bottle numbers) will be tracked via the 
IVRS. 
Has been changed to: 
Subjects will not be randomized in this study, as each LTFU subject will start on the 
individualized BRV dose that he/she was receiving at the completion of the previous study, 
and directly enrolled subjects will start the Evaluation Period on the dose established 
during the Up-Titration Period. 
To enroll a LTFU subject (EV, V1), the Investigator will call the IVRS and provide brief 
details about the subject to be enrolled. Subjects will continue with the 5-digit subject number 
assigned by the IVRS in the previous pediatric BRV study.  
Directly enrolled subjects will be assigned unique numbers for the purpose of study and 
subject identification, as well as for subject confidentiality. To enroll these subjects, at 
the ScrV, the Investigator will call the IVRS and provide information about the subject 
to be enrolled. Subjects will then be assigned a 5-digit subject number by the IVRS.  
For all subjects, the subject number will be required in all communication between the 
Investigator (or designee) and the IVRS regarding a particular subject. Subjects’ status and 
the dispensing of IMP (bottle numbers) will be tracked via the IVRS. 
Change #38, Section 8, STUDY PROCEDURES BY VISIT, paragraph 1, 
final sentence 
The original text: 
Additionally, if applicable (according to subject’s age and local requirements), the subject 
will sign an IRB/IEC Assent form. 
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Has been changed to: 
Additionally, if applicable (according to subject’s age and local requirements), the subject 
will sign an IRB/IEC-approved Assent form. 
Change #39, Section 8, STUDY PROCEDURES BY VISIT 
The following sections were added and the subsequent numbering of headers 
in this section increased accordingly: 
8.1  
 
Screening Visit for directly enrolled subjects only 
The ScrV is applicable only to directly enrolled subjects (ie, subjects ≥4 years to 
<17 years of age with POS who have not previously participated in a pediatric BRV 
study). Beginning with Protocol Amendment 3, up to 100 directly enrolled subjects will 
be allowed to participate in N01266. The Screening Period will serve as the Baseline 
Period for directly enrolled subjects. 
The ScrV is not applicable for LTFU subjects; the first N01266 visit for LTFU subjects 
is the Entry Visit (Section 8.3.1). 
The ScrV assessments will be conducted 7±2 days prior to the first administration of 
BRV. It is acceptable for the ScrV assessments to be conducted on more than 1 day. 
The ScrV assessments are as follows: 
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and 
local requirements) 
• Subject identification card dispensing  
• Demographic data  
• Childbearing potential  
• Verification of inclusion/exclusion criteria 
• Physical (including Tanner Scale, as applicable) and neurological (including 
measurement of head size) examinations 
• Psychiatric and mental status 
• General medical and procedures history 
• Epilepsy and AED history 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight and height 
• ECG 
• EEG (A previous EEG documenting the POS diagnosis must be available at the 
ScrV for directly enrolled subjects. If an EEG is not available at the ScrV, it must be 
scheduled during the Screening Period.) 
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• Neuro-imaging procedure (brain magnetic resonance imaging/brain computerized 
tomography scan [except in Germany]/ultrasounds or any other imaging test) should 
be performed if no report is available within the previous 2 years  
• DRC dispensed 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• IVRS call 
• Laboratory assessments for safety including: 
− Hematology 
− Biochemistry including hepatic monitoring 
− Urinalysis 
− Endocrinology 
− Serum pregnancy test (if applicable) 
• Phenytoin plasma concentrations (if applicable) 
• Suicidality assessment (C-SSRS-Baseline/Screening) (for subjects ≥6 years of age) 
• Achenbach CBCL (version consistent with age at the visit) 
• BRIEF-P (<5 years of age)/BRIEF (≥5 years of age) (version consistent with age at 
the visit) 
• PedsQL (version consistent with age at the visit) 
• Appointment for the next visit (TV1) 7±2 days later 
8.2 
Titration Visit(s) (TV1, TV2, and TV3) for directly enrolled subjects 
only 
Directly enrolled subjects will initiate treatment with BRV at TV1 (see Section 7.2.1 for 
dosing information). The TVs are not applicable for LTFU subjects; the first visit in 
N01266 for these subjects is the EV (Section 8.3.1). 
The first dose of BRV at each titration level will be administered at the clinic during the 
TV. Subjects will remain on the BRV dose administered at the clinic for 7±2 days before 
titrating up to the next dose. The BRV up-titration schedule is provided in Section 7.2.1. 
A total of up to 3 TVs may be required; however, based on tolerability and seizure 
control, a subject’s BRV dose may be titrated to a lower dose level and 3 TVs would not 
be needed.  
The following assessments are required at each TV: 
• Verification of inclusion/exclusion criteria (TV1 only) 
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• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight  
• ECG 
• DRC dispensed 
• DRC retrieved 
• Seizure count 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• IVRS call 
• Hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT (TV3 only unless 
the Investigator anticipates that TV2 will be the final TV, in which case hepatic 
monitoring assessments are to be done at TV2) 
• Study drug dispensed 
• Study drug returned (TV2 and TV3 only) 
• Study drug compliance (TV2 and TV3 only) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Healthcare provider consultation not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit 7±2 days later 
Change #40, Section 8.1, Entry Visit 
The original section: 
8.1 
Entry Visit 
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and 
local requirements) 
• Subject identification card dispensing  
• Demographic data  
• Childbearing potential  
• Verification of inclusion/exclusion criteria 
• DRC dispensed 
• Recording of medications 
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Any ongoing medications (AEDs and nonAEDs) at the time the subject completed the 
previous pediatric study should not be recorded on the eCRF for N01266, unless there is a 
change regarding the administration of the medication. In this event, the start date 
corresponding to the date of change in administration should be recorded on the eCRF. 
• Recording of procedures 
• Recording of AEs 
Any ongoing AEs at the time the subject completed the previous pediatric study should not 
be recorded on the eCRF for N01266, unless there is a change in intensity or seriousness. In 
this event, the AE should be recorded on the eCRF for N01266, with the onset date 
corresponding to the date of change in condition. 
• IVRS call 
• Study drug dispensed 
• Appointment for the next visit according to the schedule described in Section 5.3 
The EV is also the final evaluation visit of the previous pediatric study. The following data 
will be obtained from Baseline of the previous pediatric study and should not be recorded on 
the eCRF for N01266: 
• General medical and procedures history 
• Epilepsy history 
• AED history 
• Height 
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
• Achenbach CBCL score for subjects ≥18 months of age at Baseline of N01263 
The following data will be obtained from the last visit of the previous pediatric study and 
should not be recorded on the eCRF for N01266: 
• Seizure count 
• EEG  
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed  
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed  
• ECG 
• Laboratory assessments for safety (including hepatic monitoring) 
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• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Phenytoin plasma concentrations (if applicable) 
• Vital signs 
• Body weight  
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
Has been changed to (with addition of third-level section headers and 
reorganization of the EV for LTFU subjects): 
8.3 Entry Visit 
At the EV, the progress of directly enrolled subjects will become aligned with LTFU 
subjects; for all subjects, the EV is the time of entry into the Evaluation Period. For 
LTFU subjects, the EV is the first visit in N01266. For directly enrolled subjects, the EV 
will occur after subjects have attended the ScrV and at least 1 TV and achieved, in the 
opinion of the Investigator, acceptable tolerability and seizure control on the same daily 
dose of BRV (no lower than the minimum specified dose) for 7±2 days. 
8.3.1 
LTFU subjects 
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and 
local requirements) 
• Subject identification card dispensing  
• DRC dispensed 
• Verification of inclusion/exclusion criteria 
• IVRS call 
• Study drug dispensed 
• Recording of medications (Any ongoing medications [including AEDs and 
non-AEDs] at the time the subject completed the previous pediatric BRV study 
should not be recorded in the eCRF for N01266, unless there is a change regarding 
the administration of the medication. In this event, the start date corresponding to 
the date of change in administration should be recorded in the eCRF.) 
• Recording of AEs (Any ongoing AEs at the time the subject completed the previous 
pediatric BRV study should not be recorded in the eCRF for N01266, unless there is 
a change in intensity or seriousness. In this event, the AE should be recorded in the 
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eCRF for N01266, with the onset date corresponding to the date of change in 
condition.) 
• Appointment for the next visit according to the schedule described in Section 5.3 
The following data will be obtained from Baseline of the previous pediatric BRV study 
and should not be recorded in the eCRF for N01266: 
• Demographic data  
• General medical and procedures history 
• Epilepsy history 
• AED history 
• Height 
• Bayley-III scales (for LFTU subjects <18 months of age at Baseline of N01263 or 
other pediatric BRV studies and only for subjects enrolled in English-speaking 
countries) 
• Achenbach CBCL score (see Section 10.3.3) 
• Laboratory assessments 
− Endocrinology 
The following data will be obtained from the final visit of the previous pediatric BRV 
study and should not be recorded in the eCRF for N01266: 
• Childbearing potential  
• Recording of medications 
• Recording of procedures 
• Seizure count 
• EEG  
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed  
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of 
at least 24 hours of recording (including sleeping and awakening periods) must 
be performed  
• ECG 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
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− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
• Phenytoin plasma concentrations (if applicable) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Vital signs 
• Body weight  
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
8.3.2 
Directly enrolled subjects 
Directly enrolled subjects will finish the Up-Titration Period and attend the EV when 
the same BRV dose (no lower than the minimum specified dose) has been maintained 
for 7±2 days at a level that, in the opinion of the Investigator, achieves acceptable 
tolerability and seizure control. 
• Childbearing potential 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight and height 
• DRC dispensed 
• DRC retrieved 
• Recording of medications 
• Recording of procedures 
• Recording of AEs 
• ECG 
• Seizure count 
• IVRS call 
• Study drug dispensed 
• Study drug returned 
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• Study drug compliance 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
− Urinalysis 
− Urine pregnancy test (if applicable) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
• Appointment for the next visit according to the schedule described in Section 5.3  
Change #41, Section 8.2, Minimal Evaluation Visit 
The following original bullets: 
• Liver function tests will be performed at V4 (M3) and V6 (M9) as described in 
Section 9.5.1 
• EEG 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
Have been changed to: 
• Hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT (performed only at 
V4 [M3] and V6 [M9])  
• EEG (LTFU subjects only) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
Change #42, Section 8.3, Full Evaluation Visit 
The following original bullets: 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Laboratory assessments for safety (hematology and biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT for all subjects, and urinalysis 
for subjects ≥4 years of age)  
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
• Achenbach CBCL (the version used in this study, CBCL/1½-5 or CBCL/6-18, should be 
the same as the one used in the previous study)  
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Have been changed to: 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
• Bayley-III scales (for LTFU subjects <18 months of age at Baseline of N01263 or other 
pediatric BRV studies and only for subjects enrolled in English-speaking countries) 
• Achenbach CBCL (see Section 10.3.3) 
The following bullets have been added: 
• BRIEF-P (<5 years of age)/BRIEF (≥5 years of age) (see Section 9.6.8) 
• PedsQL (see Section 10.3.5) 
Change #43, Section 8.4, Yearly Evaluation Visit 
The following original bullets: 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age)  
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
• Achenbach CBCL (the version used in this study, CBCL/1½-5 or CBCL/6-18, should be 
the same as the one used in the previous study, if age appropriate) 
Have been changed to (and now appear in Section 8.6, Yearly Evaluation Visit): 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
− Endocrinology 
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• Bayley-III scales (for LTFU subjects <18 months of age at Baseline of N01263 or other 
pediatric BRV studies and only for subjects enrolled in English-speaking countries) 
• Achenbach CBCL (see Section 10.3.3) 
The following bullets have been added (and now appear in Section 8.6, Yearly 
Evaluation Visit): 
• BRIEF-P (<5 years of age)/BRIEF (≥5 years of age) (see Section 9.6.8) 
• PedsQL (see Section 10.3.5) 
Change #44, Section 8.6, Early Discontinuation Visit 
The following original bullets: 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age)  
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
• Achenbach CBCL (the version used in this study, CBCL/1½-5 or CBCL/6-18, should be 
the same as the one used in the previous study, if age appropriate) 
Have been changed to (and now appear in Section 8.8, Early Discontinuation 
Visit) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Serum pregnancy test (if applicable) 
• Bayley-III scales (for LTFU subjects <18 months of age at Baseline of N01263 or other 
pediatric BRV studies and only for subjects enrolled in English-speaking countries) 
• Achenbach CBCL (see Section 10.3.3) 
The following bullets have been added (and now appear in Section 8.8, Early 
Discontinuation Visit): 
• BRIEF-P (<5 years of age)/BRIEF (≥5 years of age) (see Section 9.6.8) 
• PedsQL (see Section 10.3.5) 
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Change #45, Section 8.7, Down-Titration Visit 
The following original bullet: 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
Has been changed to: 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
Change #46, Section 8.8, Safety Visit 
The following original bullets: 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age) performed only if abnormal at the 
EDV 
Have been changed to (and now appear in Section 8.10, Safety Visit): 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Laboratory assessments for safety (to be performed only if abnormal at the EDV)  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Serum pregnancy test (if applicable) 
Change #47, Section 8.9, Final Visit 
The following text and original bullets: 
Subjects, who continue in the study until it ends, should complete a FV. 
• Suicidality assessment (C-SSRS) for subjects ≥6 years of age 
• Laboratory assessments for safety (hematology, biochemistry including hepatic 
monitoring of ALT, AST, ALP, total bilirubin, and GGT, and endocrinology for all 
subjects, and urinalysis for subjects ≥4 years of age). 
• Bayley-III scales for subjects <18 months of age at Baseline of N01263 or other pediatric 
studies and only for subjects enrolled in English-speaking countries 
• Achenbach CBCL (the version used in this study, CBCL/1½-5 or CBCL/6-18, should be 
the same as the one used in the previous study, if age appropriate)  
Have been changed to (and now appear in Section 8.11, Final Visit): 
Subjects who continue in the study until it ends should complete a FV. 
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• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, 
and GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
− Endocrinology 
• Bayley-III scales (for LTFU subjects <18 months of age at Baseline of N01263 or other 
pediatric BRV studies and only for subjects enrolled in English-speaking countries) 
• Achenbach CBCL (see Section 10.3.3) 
The following bullets have been added (and now appear in Section 8.11, 
Final Visit):  
• BRIEF-P (<5 years of age)/BRIEF (≥5 years of age) score (see Section 9.6.8) 
• PedsQL (see Section 10.3.5) 
Change #48, Section 9, ASSESSMENT OF SAFETY, first sentence 
The original text: 
The safety variables will be evaluated during the Evaluation Period. 
Has been changed to: 
The safety variables will be evaluated during the Up-Titration Period (directly enrolled 
subjects only) and the Evaluation Period. 
Change #49, Section 9.1.2, Procedures for reporting and recording 
adverse events 
The following paragraph has been added to the end of the section: 
For LTFU subjects, AEs ongoing at the time the subject completed the previous 
pediatric BRV study should not be recorded in the eCRF at the EV, or any subsequent 
visit, unless there is a change in intensity or seriousness. For all subjects, new AEs 
should be recorded in the eCRF at only the first visit at which they are reported and 
subsequently only if there is a change.  
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Change #50, Section 9.1.6, Pregnancy, first sentence 
The original text: 
Should a subject become pregnant after the first intake of any IMP, UCB’s Global Clinical 
Safety and Pharmacovigilance (GCSP) department should be informed immediately. 
Has been changed to: 
Should a subject become pregnant after the first intake of any IMP, UCB’s Drug Safety 
department should be informed immediately. 
Change #51, Section 9.1.8, Safety signal detection, paragraph 2 
The original text: 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing 
review of SAEs and perform ongoing SAE reconciliations in collaboration with the GCSP 
representative. 
Has been changed to: 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing 
review of SAEs and perform ongoing SAE reconciliations in collaboration with the Drug 
Safety representative. 
Change #52, Section 9.2, Serious adverse events 
The following text was added immediately under the header: 
A blood sample for determination of BRV plasma concentration should be obtained for 
any subject who has an SAE. 
Change #53, Section 9.2.3, Follow-up of serious adverse events, 
paragraph 2 
The original text: 
Information on SAEs obtained after clinical database lock will be captured through the GCSP 
database without limitation of time. 
Has been changed to: 
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time. 
Change #54, Section 9.5.1, Laboratory assessments for safety 
The following have been added to the list of abbreviations under the table: 
ScrV=Screening Visit; TV=Titration Visit 
The original footnotes: 
a Urinalysis will be performed in subjects ≥4 years of age. 
b In addition, liver function tests will be assessed at the MEVs at V4 (M3) and V6 (M9), as described in 
Section 9.5..1. 
c Includes bacteria, cells, casts, and crystals for all samples. 
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d Female subjects with a Tanner stage >1 should have a urine pregnancy test at all laboratory assessment visits, 
except the EDV and the SV, when a serum pregnancy test will be performed. 
e Endocrinology testing will be performed once a year at the YEV. 
Have been changed to: 
a Urinalysis will be performed in subjects ≥4 years of age. 
b This assessment is used for hepatic monitoring. 
c Includes bacteria, cells, casts, and crystals for all samples. 
d Female subjects with a Tanner stage >1 should have urine pregnancy tests at the EV (directly enrolled 
subjects only), YEVs/FV, and FEVs and serum pregnancy tests at the ScrV (directly enrolled subjects 
only), EDV, and SV. 
e Endocrinology testing will be performed at the ScrV (directly enrolled subjects only) and at the YEV/FV. 
Change #55, Section 9.5.1, Laboratory assessments for safety, 
paragraphs 5 and 6 
The original text: 
Laboratory safety assessments at the EV will be obtained from the last visit of the previous 
pediatric study and should not be recorded on the eCRF for N01266. Laboratory safety 
assessments will be performed at the FEV, YEV, FV, and at the EDV in the case of early 
discontinuation. Laboratory assessments will also be mandatory at the SV if the laboratory 
results at the EDV are abnormal. In addition, liver function tests will be performed at the 
MEVs at V4 (M3) and V6 (M9) during the first year. Endocrinology testing will be 
performed once a year at the YEV.  
Female subjects who have a Tanner stage >1 should have a urine pregnancy test at all 
laboratory assessment visits, except the EDV and the SV, when a serum pregnancy test (beta-
human chorionic gonadotropin [β-hCG]) will be performed. A serum pregnancy test will be 
performed as backup if a urine sample is not available. A urine pregnancy test should be 
performed at any time during the study if a pregnancy is suspected. 
Has been changed to: 
For LTFU subjects, laboratory safety assessments at the EV will be obtained from the final 
visit of the previous pediatric BRV study and should not be recorded in the eCRF for 
N01266. Laboratory safety assessments (hematology, biochemistry [including hepatic 
monitoring: total bilirubin, ALP, AST, ALT, and GGT], urinalysis [for subjects 
≥4 years of age, and pregnancy testing [as applicable]) will be performed at the ScrV and 
EV (directly enrolled subjects only), FEV, YEV, FV, and at the EDV in the case of early 
discontinuation. Laboratory assessments will also be mandatory at the SV if the laboratory 
results at the EDV are abnormal. Only hepatic monitoring assessments will be performed 
at the final TV (directly enrolled subjects only), and the MEVs at V4 (M3) and V6 (M9) 
during the first year; no laboratory safety assessments will be performed at other 
MEVs. Endocrinology testing will be performed at the ScrV (directly enrolled subjects 
only) and once a year at the YEV. For LTFU subjects, the Baseline endocrinology data 
will be taken from Baseline of the previous pediatric BRV study. 
Female subjects who have a Tanner stage >1 should have urine pregnancy tests at the EV 
(directly enrolled subjects only), YEVs/FV, and FEVs, and serum pregnancy tests at the 
ScrV (directly enrolled subjects only), EDV, and the SV. A serum pregnancy test will be 
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performed as backup if a urine sample is not available. A urine pregnancy test should be 
performed at any time during the study if a pregnancy is suspected. 
Change #56, Section 9.5.2.1, BRV plasma concentrations, paragraph 2 
The original text: 
A PK blood sample should be taken whenever the subject experiences an SAE. 
Has been changed to: 
A blood sample for determination of BRV plasma concentration should be taken 
whenever the subject experiences an SAE. 
Change #57, Section 9.5.2.2, Phenytoin plasma concentrations (if 
applicable), sentence 1 
The original text: 
Subjects receiving phenytoin as a concomitant AED during the study will have blood samples 
collected at the FEV, YEV, FV, and at the EDV in the case of early discontinuation to 
monitor phenytoin plasma concentrations. 
Has been changed to: 
Subjects receiving phenytoin as a concomitant AED during the study will have blood samples 
collected at the ScrV (directly enrolled subjects only), FEV, YEV, FV, and at the EDV in 
the case of early discontinuation to monitor phenytoin plasma concentrations. 
Change #58, Section 9.6.1, ECG, paragraph 1 
The original text: 
A standard 12-lead ECG will be performed at the YEV, FV, and at the EDV in the case of 
early discontinuation. An ECG will be performed at the SV only if the ECG results at the 
EDV are abnormal. At the EV, ECG data will be obtained from the last visit of the previous 
pediatric study and should not be recorded in the eCRF for N01266. The Investigator will 
determine whether the results of the ECG are normal or abnormal and assess the clinical 
significance of any abnormalities. 
Has been changed to: 
A standard 12-lead ECG will be performed at the ScrV, TV(s), and EV (directly enrolled 
subjects only), YEV, FV, and at the EDV in the case of early discontinuation. An ECG will 
be performed at the SV only if the ECG results at the EDV are abnormal. At the EV, for 
LTFU subjects, ECG data will be obtained from the final visit of the previous pediatric 
BRV study and should not be recorded in the eCRF for N01266. The Investigator will 
determine whether the results of the ECG are normal or abnormal and assess the clinical 
significance of any abnormalities. 
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Change #59, Section 9.6.2, Vital signs, paragraph 1 
The original text: 
Vital signs, including measurements of blood pressure, supine or sitting pulse rate, and body 
temperature, will be performed after 5 minutes of rest at the MEV, FEV, YEV, FV, and at the 
EDV, DTV, and the SV in the case of early discontinuation. At the EV, vital sign data will be 
obtained from the last visit of the previous pediatric study and should not be recorded in the 
eCRF for N01266.  
Has been changed to: 
Vital signs, including measurements of blood pressure, supine or sitting pulse rate, and body 
temperature, will be performed after 5 minutes of rest at the ScrV, TV(s), and EV (directly 
enrolled subjects only), MEV, FEV, YEV, FV, and at the EDV, DTV, and the SV in the 
case of early discontinuation. For LTFU subjects, at the EV, vital sign data will be obtained 
from the final visit of the previous pediatric BRV study and should not be recorded in the 
eCRF for N01266.  
Change #60, Section 9.6.3, Body weight and height 
The original text: 
Body weight (subject wearing light clothing without shoes) will be measured at the MEV, 
FEV, YEV, FV, and at the EDV and the SV in the case of early discontinuation. At the EV, 
body weight will be obtained from the last visit and height data will be obtained from 
Baseline of the previous pediatric study and should not be recorded in the eCRF for N01266. 
Has been changed to: 
Body weight (subject wearing light clothing without shoes) will be measured at the ScrV, 
TV(s), and EV (directly enrolled subjects only), MEV, FEV, YEV, FV, and at the EDV 
and the SV in the case of early discontinuation. For LTFU subjects, at the EV, body weight 
will be obtained from the final visit and height data will be obtained from Baseline of the 
previous pediatric BRV study and should not be recorded in the eCRF for N01266. 
Body height will be recorded at the ScrV (directly enrolled subjects only), MEV, FEV, 
YEV, FV, and at the EDV and the SV in the case of early discontinuation. 
Change #61, Section 9.6.4, Physical examination, paragraphs 1 and 2 
The original text: 
A standard physical examination will be performed at the FEV, YEV, FV, and at the EDV 
and the SV in the case of early discontinuation.  
At the EV, physical examination data will be obtained from the last visit of the previous 
pediatric study and should not be recorded in the eCRF for N01266. Clinically significant 
new or worsened abnormalities must be reported as AEs. 
Has been changed to: 
A standard physical examination will be performed at the ScrV and EV (directly enrolled 
subjects only), FEV, YEV, FV, and at the EDV and the SV in the case of early 
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discontinuation. For LTFU subjects, at the EV, physical examination data will be obtained 
from the final visit of the previous pediatric BRV study and should not be recorded in the 
eCRF for N01266.  
Clinically significant new or worsened abnormalities discovered at the physical 
examination must be reported as AEs. 
Change #62, Section 9.6.5, Neurological examination 
The original text: 
A standard neurological examination will be performed at the FEV, YEV, FV, and at the 
EDV and the SV in the case of early discontinuation. At the EV, neurological examination 
data will be obtained from the last visit of the previous pediatric study and should not be 
recorded in the eCRF for N01266.The neurological examination will include a measurement 
of the head size (occipital-frontal circumference). Clinically significant new or worsened 
abnormalities must be reported as AEs. 
Has been changed to: 
A standard neurological examination will be performed at the ScrV and EV (directly 
enrolled subjects only), FEV, YEV, FV, and at the EDV and the SV in the case of early 
discontinuation. For LTFU subjects, at the EV, neurological examination data will be 
obtained from the final visit of the previous pediatric BRV study and should not be recorded 
in the eCRF for N01266. The neurological examination will include a measurement of the 
head size (occipital-frontal circumference). Clinically significant new or worsened 
abnormalities must be reported as AEs. 
Change #63, Section 9.6.6, Psychiatric and mental status 
The original text: 
Psychiatric and mental status will be reported by recording the presence or absence of 
psychiatric symptoms, mental impairment, and behavioral problems at FEV, YEV, FV, and at 
the EDV and the SV in the case of early discontinuation. At the EV, psychiatric and mental 
status data will be obtained from the last visit of the previous pediatric study and should not 
be recorded in the eCRF for N01266. Clinically significant new or worsened abnormalities 
must be reported as AEs. 
Has been changed to: 
Psychiatric and mental status will be reported by recording the presence or absence of 
psychiatric symptoms, mental impairment, and behavioral problems at the ScrV and EV 
(directly enrolled subjects only), FEV, YEV, FV, and at the EDV and the SV in the case of 
early discontinuation. For LTFU subjects, at the EV, psychiatric and mental status data will 
be obtained from the final visit of the previous pediatric BRV study and should not be 
recorded in the eCRF for N01266. Clinically significant new or worsened abnormalities must 
be reported as AEs. 
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Change #64, Section 9.6.7, Assessment of suicidality, sentence 3 
The original text: 
The C-SSRS will be completed according to the tabular schedule of study procedures, 
Section 5.2. 
Has been changed to: 
The C-SSRS will be completed according to the tabular schedules of study procedures, 
Section 5.2. 
Change #65, Section 9.6.7, Assessment of suicidality  
The following text was added: 
The “Since Last Visit” version of the C-SSRS will be used, with the following 
exceptions: 
• For directly enrolled subjects, the “Baseline/Screening” version of the C-SSRS 
should be completed at the ScrV.  
• If a subject turns 6 years of age during the study, the “Already Enrolled” version 
of the C-SSRS should be completed at the first visit after the sixth birthday.  
Change #66, Section 9, ASSESSMENT OF SAFETY 
The following section has been added:  
9.6.8  
 
BRIEF-P and BRIEF 
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of 
subjects ≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P and 
BRIEF include rating forms used by parents to assess subjects’ executive functioning. 
Executive functions broadly encompass a set of cognitive skills that are responsible for 
the planning, initiation, sequencing, and monitoring of complex goal-directed behavior. 
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. 
The clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and 
Emergent Metacognition) and 1 composite score (Global Executive Composite).  
The BRIEF rating form contains items in nonoverlapping clinical scales. These 
theoretically and statistically derived scales form 2 broader Indexes: Behavioral 
Regulation (3 scales) and Metacognition (5 scales), as well as a Global Executive 
Composite score.  
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses. 
The BRIEF-P/BRIEF will be completed at the ScrV (directly enrolled subjects only), 
FEV, YEV, FV, and the EDV in the case of early discontinuation. For LTFU subjects, at 
the EV, the BRIEF-P/BRIEF score will be obtained from Baseline of the previous 
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pediatric BRV study and should not be recorded in the eCRF for N01266. For directly 
enrolled subjects, the Baseline BRIEF-P/BRIEF should be completed at the ScrV. 
The BRIEF-P or BRIEF appropriate for each subject’s age should be completed, with 
the following exception: For subjects who completed the BRIEF-P at the Baseline 
assessment and turn 6 years of age between that assessment and the initial YEV, the 
BRIEF-P should be completed through and including the initial YEV, and subsequently 
the BRIEF should be completed. 
Change #67, Section 10, ASSESSMENT OF EFFICACY 
The original text: 
Efficacy variables will be assessed using the seizure count information recorded on the DRC 
and EEG data. Seizure count information will be evaluated over the Evaluation Period by 
3-month periods based on the DRC (EV until EDV or FV). The EEG data will be reviewed 
by 3-month periods for the first 6 months and then yearly, thereafter. 
Has been changed to: 
Efficacy variables will be assessed using the seizure count information recorded on the DRC 
and EEG data. Seizure count information will be evaluated over the Evaluation Period by 
3-month periods based on the DRC (EV until EDV or FV). For directly enrolled subjects, 
seizure count information collected during the Up-Titration Period will be summarized 
separately. The EEG data will be reviewed by 3-month periods for the first 6 months and 
yearly thereafter. 
Change #68, Section 10.2, Efficacy assessments for seizure data based 
on EEG, paragraph 1 
The original text: 
At the EV, seizure data based on an EEG of at least 24 hours of recording (including sleeping 
and awakening periods) for subjects <2 years of age and data on absence seizure count (based 
on an EEG of at least 1 hour of recording for subjects ≥2 years of age suffering from 
absences) will be obtained from the last visit of the previous pediatric study and should not be 
recorded in the eCRF for N01266. 
All EEGs specific to this study will be recorded in the eCRF modules specifically designed 
for this purpose.  
Has been changed to: 
At the EV, seizure data based on an EEG of at least 24 hours of recording (including sleeping 
and awakening periods) for subjects <2 years of age and data on absence seizure count (based 
on an EEG of at least 1 hour of recording for subjects ≥2 years of age suffering from 
absences) will be obtained from the final visit of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266. All EEGs specific to this study will be 
recorded in the eCRF modules specifically designed for this purpose.  
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Change #69, Section 10.3.1.1, Concomitant medications/treatments, 
paragraphs 1 and 2  
The original text: 
Concomitant medications will be collected and recorded in the eCRF at the following visits: 
MEV, FEV, YEV, UV, FV, and at the EDV, DTV, and the SV in the case of early 
discontinuation. Any ongoing medications (AEDs and nonAEDs) at the time the subject 
completed the previous pediatric study should not be recorded on the eCRF for N01266 at the 
EV, unless there is a change regarding the administration of the medication. In this event, the 
medication should be recorded on the eCRF for N01266 with the start date corresponding to 
the date of change in administration. 
Has been changed to: 
Concomitant medication information will be collected and recorded in the eCRF at the 
following visits: ScrV and TV(s) (directly enrolled subjects only), EV, MEV, FEV, YEV, 
UV, FV, and at the EDV, DTV, and the SV in the case of early discontinuation.  
For LTFU subjects, any ongoing medications (including AEDs and non-AEDs) at the time 
the subject completed the previous pediatric BRV study should not be recorded in the eCRF 
for N01266, unless there is a change regarding the administration of the medication. In this 
event, the medication should be recorded in the eCRF for N01266 with the start date 
corresponding to the date of change in administration.  
Change #70, Section 10.3.1.2, Medical procedures, paragraph 2 
The original text: 
Medical procedures will be recorded at the following visits: EV, MEV, FEV, YEV, UV, FV, 
and at the EDV, DTV, and the SV in the case of early discontinuation. 
Has been changed to: 
Medical procedures will be recorded at the following visits: ScrV and TV(s) (directly 
enrolled subjects only), EV, MEV, FEV, YEV, UV, FV, and at the EDV, DTV, and the SV 
in the case of early discontinuation. 
Change #71, Section 10.3.1.3, Health care provider consultations not 
foreseen by the protocol 
The original text: 
At the MEV, FEV, YEV, UV, FV, and at the EDV, DTV, and the SV in the case of early 
discontinuation, health care provider consultations not foreseen by the protocol will be 
recorded in the eCRF. It will include the type of provider (general practitioner, specialist 
physician, nurse), the site of care (office-private, office-hospital, home, emergency room), 
and the reason leading to the consultation. At the EV, information on the health care provider 
consultations not foreseen by the protocol will be obtained from the final visit of the previous 
pediatric study and should not be recorded in the eCRF for N01266.  
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Has been changed to: 
At the TV(s) and EV (directly enrolled subjects only), MEV, FEV, YEV, UV, FV, and at 
the EDV, DTV, and the SV in the case of early discontinuation, health care provider 
consultations not foreseen by the protocol will be recorded in the eCRF. It will include the 
type of provider (general practitioner, specialist physician, nurse), the site of care 
(office-private, office-hospital, home, emergency room), and the reason leading to the 
consultation. For LTFU subjects, at the EV, information on the health care provider 
consultations not foreseen by the protocol will be obtained from the final visit of the previous 
pediatric BRV study and should not be recorded in the eCRF for N01266.  
Change #72, Section 10.3.1.4, Hospital stays 
The original text: 
At the MEV, FEV, YEV, UV, FV, and at the EDV, DTV, and the SV in the case of early 
discontinuation, data on hospital stays will be collected in the eCRF. It will include the 
reason leading to the hospitalization, the admission ward, transfers, and length of stay. At the 
EV, information on hospital stays will be obtained from the last visit of the previous pediatric 
BRV study and should not be recorded in the eCRF for N01266.  
Has been changed to: 
During the TV(s) and EV (directly enrolled subjects only), MEV, FEV, YEV, UV, FV, 
and at the EDV, DTV, and the SV in the case of early discontinuation, data on hospital stays 
will be collected in the eCRF. It will include the reason leading to the hospitalization, the 
admission ward, transfers, and length of stay. For LTFU subjects, at the EV, information on 
hospital stays will be obtained from the final visit of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266.  
Change #73, Section 10.3.2, Bayley Scales of Infant and Toddler 
Development, Third Edition, paragraph 2 
The original text: 
This scale is validated as a tool for assessment of neurological development in young children 
and is therefore considered appropriate for N01266. The same scale has been completed by 
the Investigator or designee at Baseline (V1) of N01263 for children from 1 month to 
<18 months of age at Baseline enrolled in English-speaking countries. Children started on the 
Bayley-III scales at Baseline of N01263 will also be assessed using the Bayley-III scales in 
N01266 even if their age increases to ≥18 months.  
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Has been changed to: 
This scale is validated as a tool for assessment of neurological development in young children 
and is therefore considered appropriate for N01266. The same scale has been completed by 
the Investigator or designee at Baseline (V1) of N01263 for children from 1 month to 
<18 months of age at Baseline enrolled in English-speaking countries. Children started on the 
Bayley-III scales at Baseline of N01263 will also be assessed using the Bayley-III scales in 
N01266 even if their age increases to ≥18 months. Bayley-III scale assessments are not 
applicable to directly enrolled subjects due to age-based considerations. 
Change #74, Section 10.3.2, Bayley Scales of Infant and Toddler 
Development, Third Edition, paragraph 5 
The original text: 
At the EV, the Bayley-III scales will be obtained from Baseline of the previous pediatric 
study if the subject was enrolled in an English-speaking country, and data should not be 
recorded in the eCRF in N01266. The Bayley-III scales will be completed at the FEV, YEV, 
FV, and at the EDV in the case of early discontinuation. The Bayley-III scales should be 
completed by the same person who completed the Bayley-III scales in the previous pediatric 
study. 
Has been changed to: 
At the EV, the Bayley-III scales will be obtained from Baseline of the previous pediatric 
BRV study if the subject was enrolled in an English-speaking country, and data should not be 
recorded in the eCRF in N01266. The Bayley-III scales will be completed at the FEV, YEV, 
FV, and at the EDV in the case of early discontinuation. The Bayley-III scales should be 
completed by the same person who completed the Bayley-III scales in the previous pediatric 
BRV study. 
Change #75, Section 10.3.3, Achenbach Child Behavior Checklist, 
paragraph 2 through end of section 
The original text: 
The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) used should be the same 
as the one used in the previous pediatric study. However, if the subject reaches 6 years of age 
in this LTFU study, the version of the Achenbach CLCB should not be changed until at least 
after the first assessment in N01266.  
The Achenbach CBCL should be completed by the same parent(s)/legal representative(s) 
who completed the CBCL in the previous pediatric study. The completion of the Achenbach 
CBCL will require approximately 45 minutes.  
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
0=not true (as far as known) 
1=somewhat or sometimes true 
2=very true or often true  
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Eight syndrome scores will be calculated from these questions, which will in turn be 
summarized by 2 composite scores. Additionally, for each score on the question, syndrome, 
and total level, categorizations based on a normative sample will be used to evaluate normal, 
borderline, or clinically relevant behavior. 
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests. 
At the EV, the Achenbach CBCL score will be obtained from Baseline of the previous 
pediatric study and should not be recorded in the eCRF in N01266. The Achenbach CBCL 
will be completed at the FEV, YEV, FV, and at the EDV in the case of early discontinuation. 
Has been changed to the following: 
The Achenbach CBCL should be completed by the same parent(s)/legal representative(s) 
who completed the CBCL in the previous pediatric BRV study. The completion of the 
Achenbach CBCL will require approximately 45 minutes.  
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
0=not true (as far as known) 
1=somewhat or sometimes true 
2=very true or often true  
Eight syndrome scores will be calculated from these questions, which will in turn be 
summarized by 2 composite scores. Additionally, for each score on the question, syndrome, 
and total level, categorizations based on a normative sample will be used to evaluate normal, 
borderline, or clinically relevant behavior. 
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests. 
The Achenbach CBCL will be completed at the ScrV (directly enrolled subjects only), 
FEV, YEV, FV and the EDV in the case of early discontinuation. For LTFU subjects, at the 
EV, the Achenbach score will be obtained from Baseline of the previous pediatric BRV study 
and should not be recorded in the eCRF for N01266. For directly enrolled subjects, the 
Achenbach CBCL will be completed at the ScrV will be the Baseline assessment.  
The version of the Achenbach CBCL appropriate to each subject’s age should be 
administered with the following exception: If a subject completed the Achenbach 
CBCL/1½-5 at the Baseline assessment and turns 6 years of age between that assessment 
and the initial YEV, the CBCL/1½-5 should be completed through and including the 
initial YEV, and subsequently the CBCL/6-18 should be completed. 
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Change #76, Section 10, ASSESSMENT OF EFFICACY 
The following section has been added:  
10.3.5 
 
 
PedsQL 
The PedsQL is a validated instrument that consists of generic core scales suitable for 
use with pediatric populations, including those with acute or chronic health conditions 
(Varni et al, 1999). The PedsQL Measurement Model consists of developmentally 
appropriate forms for pediatric subjects 1 month to 24 months, ≥2 years to ≤4 years, 
≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 years of age. Self-
report is measured for pediatric subjects ≥5 years to ≤18 years of age, and parent proxy 
report of child HRQoL is measured for pediatric subjects ≥2 years to ≤18 years of age.  
The multidimensional PedsQL generic core scales encompass the essential core domains 
for pediatric HRQoL measurement: Physical Functioning, Emotional Functioning, 
Social Functioning, and School Functioning. The PedsQL assessment is retrospective to 
the prior 4 weeks, and individual items are scored using a 5-point Likert scale (never, 
almost never, sometimes, often, or always). A total health summary score ranging 
between 0 and 100 is calculated from the sum of the raw scores, with higher scores 
indicating higher HRQoL. 
The PedsQL will be completed at the ScrV (directly enrolled subjects only), FEV, YEV, 
FV, and the EDV in the case of early discontinuation. For LTFU subjects, at the EV, the 
PedsQL score will be obtained from Baseline of the previous pediatric BRV study and 
will not be recorded in the eCRF in N01266. For directly enrolled subjects, the Baseline 
PedsQL will be completed at the ScrV. 
The version of the PedsQL appropriate for each subject’s age should be completed, with 
the following exception: If a subject ages up to the next version of the PedsQL between 
the Baseline assessment and the initial YEV, the version that was used at the Baseline 
assessment should be completed through and including the initial YEV, and 
subsequently the version consistent with his/her age at the time of assessment should be 
completed.  
Change #77, Section 11.2.1, Definition of source data, paragraph 5 
The following text: 
Electronic data records, such as holter monitor records or EEG records must be saved and 
stored as instructed by UCB (or designee). 
Has been changed to: 
Electronic data records, such as Holter monitor records or EEG records must be saved and 
stored as instructed by UCB (or designee). 
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Change #78, Section 12.1, Definition of analysis sets 
The following bullet: 
• The Safety Set (SS) will consist of all enrolled subjects who took at least 1 dose of study 
medication in the LTFU study. All safety analyses will be performed on the SS. 
Has been changed to: 
• The Safety Set (SS) will consist of all enrolled subjects who took at least 1 dose of study 
medication in this long-term study. All safety analyses will be performed on the SS. 
Change #79, Section 12.2, General statistical considerations  
The following sentence has been added to the end of the section: 
Data collected during the Up-Titration Period for directly enrolled subjects will be 
summarized separately. 
Change #80, Section 12.5, Other analyses  
The original text: 
The Achenbach CBCL, the Bayley-III scores, and change from previous study Baseline 
scores will be analyzed in a descriptive manner. 
Has been changed to: 
The Achenbach CBCL, the Bayley-III scores (LTFU subjects only), BRIEF-P/BRIEF, 
PedsQL, and change from Baseline scores (previous BRV study for LTFU subjects and 
ScrV for directly enrolled subjects) will be analyzed in a descriptive manner. 
Change #81, Section 12.9, Determination of sample size 
The original text: 
No formal sample size calculation was performed for this study. Up to 500 subjects may 
possibly enroll in this study, based upon the assumption that 90% of the subjects having 
completed a previous pediatric study with BRV as adjunctive treatment in epilepsy will 
rollover into the present study. 
Has been changed to: 
No formal sample size calculation was performed for this study. Originally, up to 
500 subjects might have possibly enrolled in this study. The original number was based 
upon the assumption that 90% of the subjects having completed a previous pediatric study 
with BRV as adjunctive treatment in epilepsy will rollover into the present study. With 
Protocol Amendment 3, enrollment is expanded to include up to 100 directly enrolled 
subjects (≥4 years to <17 years of age) with POS, thus increasing possible enrollment to 
up to 600 subjects. 
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Change #82, Section 13.1, Informed consent, paragraph 3, final sentence 
The original text: 
Any subject who is over 16 years of age during the LTFU study must sign and date the 
Informed Consent form according to local regulations. 
Has been changed to: 
Any subject who is over 16 years of age during N01266 must sign and date the Informed 
Consent form according to local regulations. 
Change #83, Section 15, REFERENCES 
The following reference has been added  
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric 
quality of life inventory. Med Care. 1999;37:126-39. 
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16.4 
Protocol Amendment 4 
Rationale for the amendment 
As a result of the PK analyses performed on the plasma samples collected at N01263 
completion, the plasma concentrations approximating the concentrations for adults receiving 
BRV 200mg/day were not achieved by the dosing scheme initially included in N01266. Thus, 
N01266 was amended to allow a maximum BRV dose of 5.0mg/kg/day (not to exceed a total 
dose of BRV 200mg/day). 
The number of directly enrolled subjects has been increased from “up to” to “at least” 
100 subjects with the planned total enrollment of approximately 600 subjects to allow 
flexibility in the number of patients reaching 1 year of exposure. 
Demographics and childbearing potential will be captured at the EV for LTFU subjects, 
instead of using the data recorded from either the Baseline or the final visit of the previous 
study. 
The handling of protocol deviations has been made consistent with the updated statistical 
analysis process. 
In addition, it was clarified that although no formal interim analysis will be performed, the 
data may be reported prior to the completion of this study to support the ongoing data 
cleaning, annual reports, regulatory submissions, and publications. 
Modifications and changes 
Global changes 
The following changes were made throughout the protocol: 
• For all subjects, the titration dosage for pediatric subjects has been aligned without age 
limitations. 
• The maximum allowable BRV dose has been changed from 3.2mg/kg/day for subjects 
≥8 years of age and 4.0mg/kg/day for subjects <8 years of age to 5.0mg/kg/day (2.5mg/kg 
bid) for all subjects (not to exceed a total dose of BRV 200mg/day). 
• For administrative purposes and to ensure consistency with other documents, 
demographics and childbearing potential will be assessed at the EV for LTFU subjects, 
instead of using the data captured from either the Baseline or the final visit of the 
previous study. In addition, for the same reason, the age that triggers the switch from 
BRIEF-P to BRIEF between the Baseline and the initial YEV has been changed from 6 to 
5 years of age. 
• Visit windows have been added for clarity. 
• Minor administrative and editorial changes. 
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Specific changes 
Change #1, SPONSOR DECLARATION 
The original text: 
Study Physician 
 
_____________________________ 
Date/Signature 
Clinical Program Director 
 
_____________________________ 
Date/Signature 
Exploratory Development Director 
 
_____________________________ 
Date/Signature 
Has been changed to: 
Study Physician 
 
_____________________________ 
Date/Signature 
Clinical Program Director 
 
_____________________________ 
Date/Signature 
Clinical Pharmacology Director 
 
_____________________________ 
Date/Signature 
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Change #2, STUDY CONTACT INFORMATION 
The original text: 
Sponsor Study Physician 
Name: 
 
Address: 
8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
Clinical Monitoring Contract Research Organization 
Name: 
Pharma-Research Associates (UK) Ltd.  
Address: 
Imperial Way 
Reading, Berkshire 
RG2 OTD 
United Kingdom 
Phone: 
+44 118 918 1000 
Fax: 
+44 118 918 1001 
Has been changed to: 
Sponsor Study Physician 
Name: 
 
Address: 
8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
Clinical Monitoring Contract Research Organization 
Name: 
Pharma-Research Associates (UK) Ltd.  
Address: 
Green Park 
500 South Oak Way 
Reading, RG2 6AD 
United Kingdom 
Phone: 
+44 118 918 1000 
Fax: 
+44 118 918 1001 
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Change #3, SERIOUS ADVERSE EVENT REPORTING 
The original text: 
Serious adverse event reporting (24h) and safety related issues  
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
US: +1 800 880 6949 
Canada: +1 877 582 8842 
Email 
Europe, US, and Rest of the World (except Japan): DS_ICT@ucb.com 
Has been changed to: 
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) and safety related issues  
Fax 
Europe and Rest of the World (except Japan): +32 2 386 2421 
US: +1 800 880 6949 
Canada: +1 877 582 8842 
Email 
Europe, US, and Rest of the World (except Japan): DS-ICT@ucb.com 
Change #4, LIST OF ABBREVIATIONS 
The following abbreviation has been deleted: 
DRM 
data review meeting 
The following abbreviation has been added: 
UV 
Unscheduled Visit 
Change #5, Section 1, SUMMARY, paragraph 1 
The original text: 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety 
and efficacy of brivaracetam (BRV) in children with epilepsy. This study was initially 
designed for pediatric subjects who had completed N01263 or would complete other future 
pediatric BRV studies (herein referred to as “long-term follow-up” [LTFU] subjects). With 
Protocol Amendment 3, enrollment was expanded to include up to 100 subjects ≥4 years to 
<17 years of age with POS who had not previously enrolled in a pediatric BRV study (herein 
referred to as “directly enrolled subjects”). 
Has been changed to: 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety 
and efficacy of brivaracetam (BRV) in children with epilepsy. This study was initially 
designed for pediatric subjects who had completed N01263 or would complete other future 
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pediatric BRV studies (herein referred to as “long-term follow-up” [LTFU] subjects). With 
Protocol Amendment 3, enrollment was expanded to include up to 100 subjects ≥4 years to 
<17 years of age with POS who had not previously enrolled in a pediatric BRV study (herein 
referred to as “directly enrolled subjects”). With Protocol Amendment 4, the number of 
directly enrolled subjects is increased to at least 100 subjects with the planned total 
enrollment of approximately 600 subjects. In addition, the dosing scheme was aligned so 
that it is no longer age-dependent; previously, subjects ≥8 or <8 years of age were dosed 
under different dosing schemes. 
Change #6, Section 1, SUMMARY, paragraphs 3 to 5 
The original text: 
The LTFU subjects will enter directly into the Evaluation Period at the Entry Visit (EV) and 
will continue BRV treatment at the individualized dose they were receiving at the completion 
of their previous pediatric BRV study. Directly enrolled subjects will enter N01266 at the 
Screening Visit (ScrV) and then participate in up to 3 weeks of an Up-Titration Period. If a 
directly enrolled subject demonstrates, in the opinion of the Investigator, acceptable 
tolerability and seizure control on the same daily dose of BRV (no lower than the minimum 
specified dose) for 7±2 days during the Up-Titration Period, the subject will attend the EV 
and enter the Evaluation Period on that dose. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able to tolerate the minimum dose specified in the 
previous BRV study to be eligible for entry into the Evaluation Period. This minimum 
tolerated dose for LTFU subjects from N01263 is 0.8mg/kg/day if ≥8 years of age and 
1.0mg/kg/day if <8 years of age. The same minimums apply to directly enrolled subjects as 
indicated in Section 7.2. 
The maximum allowable BRV dose is 3.2mg/kg/day for subjects ≥8 years of age and 
4.0mg/kg/day for subjects <8 years of age. Younger subjects (<7 years of age) will be 
administered BRV oral solution. Subjects above 50kg will be dosed as adults, up to a 
maximum total daily dose not exceeding 200mg/day, and should transition from the oral 
solution to the equivalent oral tablet dose, if appropriate. With the exception of dose 
adjustments for BRV during the Up-Titration Period, which should be made in accordance 
with the protocol-specified guidelines, dose adjustments of BRV and any concomitant 
antiepileptic drugs (AEDs) are allowed at any time based on clinical judgment. 
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Has been changed to: 
The LTFU subjects will enter directly into the Evaluation Period at the Entry Visit (EV) and 
will continue BRV treatment at the individualized dose they were receiving at the completion 
of their previous pediatric BRV study. Directly enrolled subjects will enter N01266 at the 
Screening Visit (ScrV) and then participate in up to 3 weeks of an Up-Titration Period. If a 
directly enrolled subject demonstrates, in the opinion of the Investigator, acceptable 
tolerability and seizure control on the same daily dose of BRV (no lower than 1.0mg/kg/day) 
for 7±2 days during the Up-Titration Period, the subject will attend the EV and enter the 
Evaluation Period on that dose. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able to tolerate the minimum dose specified in the 
previous BRV study to be eligible for entry into the Evaluation Period of N01266. All 
directly enrolled subjects must be able to tolerate at least 1.0mg/kg/day during the 
Up-Titration Period prior to entering the Evaluation Period of N01266, as indicated in 
Section 7.2. 
The maximum allowable BRV dose is 5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose 
of 200mg/day for subjects with body weight >40kg. Subjects <7 years of age will receive 
oral solution. Subjects ≥7 years of age will receive tablets, as appropriate. With the 
exception of dose adjustments for BRV during the Up-Titration Period, which should be 
made in accordance with the protocol-specified guidelines, dose adjustments of BRV and any 
concomitant antiepileptic drugs (AEDs) are allowed at any time based on clinical judgment. 
Change #7, Section 2.5, Rationale for the study, paragraphs 3 and 4 
The original text: 
N01263 is the first study of BRV in pediatric subjects. This is an open-label, fixed 3-step 
up-titration, PK, safety and efficacy study to evaluate BRV as adjunctive therapy in children 
(aged ≥1 month to <16 years) with epilepsy using an oral solution. The safety and PK data 
from this study will be used for BRV dose adaptation in pediatric subjects with epilepsy. 
N01266 was originally designed to give subjects who complete N01263 or other future 
pediatric BRV studies (ie, LTFU subjects) an opportunity to continue BRV treatment for 
approximately 3 years, until approval of BRV is granted for pediatric subjects in their age 
range, or until the investigational product development is stopped by the Sponsor. With 
Protocol Amendment 3, enrollment is expanded to include up to 100 eligible subjects 
≥4 years to <17 years of age with POS who have not participated in another pediatric BRV 
study (ie, directly enrolled subjects). Thus, N01266 will gather additional long-term safety 
and tolerability data on BRV in pediatric subjects with epilepsy while providing access to 
BRV for subjects who may benefit from long-term treatment. 
Has been changed to: 
N01263 is the first study of BRV in pediatric subjects. This was an open-label, fixed 3-step 
up-titration, PK, safety and efficacy study to evaluate BRV as adjunctive therapy in children 
(aged ≥1 month to <16 years) with epilepsy using an oral solution. The safety and PK data 
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from this study will be used for BRV dose adaptation in pediatric subjects with epilepsy. A 
total of 100 subjects were enrolled into this study. 
N01266 was originally designed to give subjects who complete N01263 or other future 
pediatric BRV studies (ie, LTFU subjects) an opportunity to continue BRV treatment for 
approximately 3 years, until approval of BRV is granted for pediatric subjects in their age 
range, or until the investigational product development is stopped by the Sponsor. With 
Protocol Amendment 3, enrollment was expanded to include up to 100 eligible subjects 
≥4 years to <17 years of age with POS who have not participated in another pediatric BRV 
study (ie, directly enrolled subjects). Thus, N01266 will gather additional long-term safety 
and tolerability data on BRV in pediatric subjects with epilepsy while providing access to 
BRV for subjects who may benefit from long-term treatment. With Protocol Amendment 4, 
the number of directly enrolled subjects is increased to at least 100 subjects with the 
planned total enrollment of approximately 600 subjects. In addition, based on the PK 
analyses performed on the plasma samples collected in N01263, the dosing scheme for 
Protocol Amendment 4 was aligned so that it is no longer age-dependent; previously, 
subjects ≥8 or <8 years of age were dosed under different dosing schemes. 
Change #8, Section 5.1, Study description, paragraphs 3 to 4 
The original text: 
Brivaracetam (tablet and oral solution) should be administered bid in 2 equally divided doses. 
All LTFU subjects must be able to tolerate the minimum BRV dose specified in the previous 
study to be eligible for entry into the Evaluation Period of N01266. For LTFU subjects from 
N01263, this minimum tolerated BRV dose is 0.8mg/kg/day if ≥8 years of age and 
1.0mg/kg/day if <8 years of age. The same minimums apply to directly enrolled subjects.  
For all subjects enrolled in N01266, the maximum BRV dose is 3.2mg/kg/day for subjects 
≥8 years of age and 4.0mg/kg/day for subjects <8 years of age. Younger subjects (<7 years of 
age) will be administered BRV oral solution. Subjects above 50kg will be dosed as adults, up 
to a maximum total daily dose not exceeding 200mg/day, and should transition from the oral 
solution to the equivalent oral tablet dose. Dose adjustments of BRV and/or concomitant 
AEDs are allowed at any time based on clinical judgment; however, during the Up-Titration 
Period, dose adjustments for BRV should be made only as specified in Section 7.2.1. 
Additional information on BRV administration is presented in Section 7.2. Subjects will 
continue to receive BRV treatment in this study for approximately 3 years, until approval for 
BRV has been obtained for pediatric subjects in their age range, or until the investigational 
product development is stopped by the Sponsor. 
Has been changed to: 
Brivaracetam (tablet and oral solution) should be administered bid in 2 equally divided doses. 
All LTFU subjects must be able to tolerate the minimum BRV dose specified in the previous 
study to be eligible for entry into the Evaluation Period of N01266. All directly enrolled 
subjects must be able to tolerate at least 1.0mg/kg/day during the Up-Titration Period 
prior to entering the Evaluation Period of N01266, as indicated in Section 7.2. 
For all subjects enrolled in N01266, the maximum BRV dose is 5.0mg/kg/day (2.5mg/kg 
bid), not to exceed a dose of 200mg/day for subjects with body weight >40kg. Subjects 
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<7 years of age will receive oral solution. Subjects ≥7 years of age will receive tablets, as 
appropriate. Dose adjustments of BRV and/or concomitant AEDs are allowed at any time 
based on clinical judgment; however, during the Up-Titration Period, dose adjustments for 
BRV should be made only as specified in Section 7.2.1. Additional information on BRV 
administration is presented in Section 7.2. Subjects will continue to receive BRV treatment in 
this study for approximately 3 years, until approval for BRV has been obtained for pediatric 
subjects in their age range, or until the investigational product development is stopped by the 
Sponsor. 
Change #9, Section 5.1, Study description, paragraph 7 
The original text: 
No formal interim analysis is planned (see Section 12.8). 
Has been changed to: 
No formal interim analysis is planned; however, data may be reported prior to the 
completion of this study (see Section 12.8). 
Change #10, Section 5.1.2, Planned number of subjects and sites, 
paragraph 2 
The original text: 
With Protocol Amendment 3, enrollment is expanded to include up to 100 eligible directly 
enrolled subjects ≥4 years to <17 years of age with POS, which will allow up to 600 subjects 
to enroll in N01266 instead of the up to 500 originally planned. 
Has been changed to: 
With Protocol Amendment 3, enrollment was expanded to include up to 100 eligible directly 
enrolled subjects ≥4 years to <17 years of age with POS, which allowed up to 600 subjects to 
enroll in N01266 instead of the up to 500 originally planned. With Protocol Amendment 4, 
the number of directly enrolled subjects is increased to at least 100 subjects with the 
planned total enrollment of approximately 600 subjects.  
 
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Change #11, Section 5.2, Schedules of study assessments 
Table 5-1: 
Schedule of all study assessments for LTFU subjects and assessments subsequent to the final TV 
for directly enrolled subjects 
Footnote a appended to childbearing potential at EV for LTFU subjects has been deleted and the following 
assessment has been added: 
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Change #12, Section 5.2, Schedules of study assessments, abbreviations 
The original text: 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF=Behavior Rating Inventory 
of Executive Function; BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; 
CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; DE=directly enrolled; DRC=daily record 
card; ECG=electrocardiogram; eCRF=electronic case report form; EEG=electroencephalogram; GGT=gamma-glutamyltransferase; 
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IVRS=interactive voice response system; LTFU=long-term follow-up; M=Month; PedsQL=Pediatric Quality of Life Inventory; 
SAE=serious adverse event; TV=Titration Visit; V=Visit 
Has been changed to: 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF=Behavior Rating Inventory of 
Executive Function; BRIEF-P=Behavior Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; 
CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity Rating Scale; DE=directly enrolled; DRC=daily record card; 
DTV=Down-Titration Visit; ECG=electrocardiogram; eCRF=electronic case report form; EDV=Early Discontinuation Visit; 
EEG=electroencephalogram; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final Visit; GGT=gamma-glutamyltransferase; 
IVRS=interactive voice response system; LTFU=long-term follow-up; M=Month; MEV=Minimal Evaluation Visit; 
PedsQL=Pediatric Quality of Life Inventory; SAE=serious adverse event; SV=Safety Visit; TV=Titration Visit; UV=Unscheduled 
Visit; V=Visit; YEV=Yearly Evaluation Visit 
Change #13, Section 5.2, Schedules of study assessments, footnote a 
The original text: 
a For LTFU subjects, the following data will be obtained from Baseline of the previous pediatric BRV study and should not be 
recorded on the eCRF for N01266: demographics, general medical and procedure history, epilepsy history, AED history, height, 
Bayley-III scales, the Achenbach CBCL, BRIEF-P/BRIEF, and PedsQL scores. The following data will be obtained from the final 
visit of the previous pediatric BRV study and should not be recorded in the eCRF for N01266: AEs, childbearing potential, 
recording of medications, recording of procedures, seizure count, EEG, ECG, laboratory assessments for safety, including 
phenytoin plasma concentrations (if applicable), the C-SSRS, vital signs, body weight, physical and neurological examinations, 
psychiatric and mental status, and data on health care provider consultations not foreseen by the protocol and hospital stays. The 
EV is also the final evaluation visit of the previous pediatric BRV study. 
Has been changed to: 
a For LTFU subjects, the following data will be obtained from Baseline of the previous pediatric BRV study and should not be 
recorded on the eCRF for N01266: general medical and procedure history, epilepsy history, AED history, height, Bayley-III 
scales, the Achenbach CBCL, BRIEF-P/BRIEF, and PedsQL scores. The following data will be obtained from the final visit of 
the previous pediatric BRV study and should not be recorded in the eCRF for N01266: AEs, recording of medications, recording 
of procedures, seizure count, EEG, ECG, laboratory assessments for safety, including phenytoin plasma concentrations (if 
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applicable), the C-SSRS, vital signs, body weight, physical and neurological examinations, psychiatric and mental status, 
and data on health care provider consultations not foreseen by the protocol and hospital stays. The EV is also the final 
evaluation visit of the previous pediatric BRV study. 
Change #14, Section 5.2, Schedules of study assessments, footnote q 
The original text: 
q The cognition scale (Bayley-III) to be used in N01266 for subjects <18 months of age and enrolled in English-speaking countries 
will be the same as the one used in the previous pediatric BRV study. If the subject reaches 18 months of age in this study, the 
subject will still be assessed using the Bayley-III to allow for an evaluation of the change from Baseline even if his/her age 
increases to ≥18 months. 
Has been changed to: 
q The cognition scale (Bayley-III) to be used in N01266 for subjects <18 months to 42 months of age and enrolled in 
English-speaking countries will be the same as the one used in the previous pediatric BRV study. If the subject reaches 18 months 
of age in this study, the subject will still be assessed using the Bayley-III to allow for an evaluation of the change from Baseline 
even if his/her age increases to ≥18 months. 
Change #15, Section 5.2, Schedules of study assessments, footnote s 
The original text: 
s The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF should be used for subjects ≥5 years of age, 
with the following exception: For subjects who completed the BRIEF-P at the Baseline assessment (previous pediatric BRV study 
for LTFU subjects and ScrV for directly enrolled subjects) and turn 6 years of age between that assessment and the initial YEV, the 
BRIEF-P should be completed through and including the initial YEV, and subsequently the BRIEF should be completed. 
Has been changed to: 
s The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF should be used for subjects ≥5 years of age, 
with the following exception: For subjects who completed the BRIEF-P at the Baseline assessment (previous pediatric BRV study 
for LTFU subjects and ScrV for directly enrolled subjects) and turn 5 years of age between that assessment and the initial YEV, the 
BRIEF-P should be completed through and including the initial YEV, and subsequently the BRIEF should be completed. 
 
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Change #16, Section 5.3, Visit sequence, Table 5-3: Visit sequence 
The original table: 
Directly enrolled subjects 
 
Visit 
Type of visit 
 
ScrV 
Screening 
W1 
TV1 a 
TV 
W2 
TV2 a 
TV 
W3 
TV3 a 
TV 
All subjects 
First year follow-up 
M0 
V1 
EVb 
M1 
V2 
MEV 
M2 
V3 
FEV 
M3 
V4 
MEVc 
M4 
- 
- 
M5 
- 
- 
M6 
V5 
FEV 
M7 
- 
- 
M8 
- 
- 
M9 
V6 
MEVc 
M10 
- 
- 
M11 
- 
- 
Second and subsequent years follow-upd 
M12 
V7 
YEV 
M15 
V8 
MEV 
M18 
V9 
FEV 
M21 
V10 
MEV 
and every 3 months 
V11, V12, etc 
YEV, MEV, etc 
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Has been changed to: 
Table 5-3: 
Visit sequence 
Directly enrolled subjects 
 
Visit 
Type of visit 
 
ScrV 
Screening 
W1  
TV1 a  
TV 
W2 
TV2 a 
TV 
W3 
TV3 a 
TV 
All subjects 
First year follow-up 
M0 
V1 
EVb 
M1 
V2 
MEV 
M2 
V3 
FEV 
M3 
V4 
MEVc 
M4 
- 
- 
M5 
- 
- 
M6 
V5 
FEV 
M7 
- 
- 
M8 
- 
- 
M9 
V6 
MEVc 
M10 
- 
- 
M11 
- 
- 
Second and subsequent years follow-upd 
M12 
V7 
YEV 
M15 
V8 
MEV 
M18 
V9 
FEV 
M21 
V10 
MEV 
and every 3 months thereafter 
V11, V12, etc 
YEV, MEV, etc 
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Change #17, Section 5.3, Visit sequence, Table 5-3: Visit sequence, note 
The original text: 
Note: “-” denotes that no visit is scheduled in that month. 
Has been changed to: 
Note: Visits at W1, W2, W3, and M0 will occur 7±2 days after the previous visit; visits at 
M1, M2, and M3 will occur 30±7 days after the previous visit; visits at M6, M9, 
M12, M15, M18, M21, and every 3 months thereafter will occur 90±15 days after 
the previous visit. 
“-” denotes that no visit is scheduled in that month. 
Change #18, Section 5.4, Rationale for study design and selection of 
dose, paragraphs 2 through 5 
The original text: 
Each LTFU subject will begin treatment in N01266 at the individualized BRV dose he/she 
was receiving at the completion of the previous pediatric study. Directly enrolled subjects 
will participate in up to 3 weeks of an Up-Titration Period. If a subject demonstrates, in the 
opinion of the Investigator, acceptable tolerability and seizure control on the same daily dose 
of BRV for 7±2 days during the Up-Titration Period, the subject will be allowed to enter the 
Evaluation Period (subject must be able to tolerate the minimum specified dose; see 
Section 7). 
A physiologically-based PK model (N01313) was developed to predict the doses to be tested 
in N01263. The same doses that were used for up titration in N01263 will be used for the 
3 consecutive weeks that comprise the Up-Titration Period of N01266. For subjects ≥8 years 
of age, the approximate doses to be administered are 0.4, 0.8, and 1.6mg/kg bid (0.8, 1.6, and 
3.2mg/kg/day, respectively, corresponding to 50, 100, and 200mg/day in adults) for Weeks 1, 
2, and 3 of up titration, respectively. For subjects <8 years of age, the approximate doses to 
be administered are 0.5, 1.0, and 2.0mg/kg bid (1.0, 2.0, and 4.0mg/kg/day, respectively) for 
Weeks 1, 2, and 3 of up titration, respectively. Daily doses will be adjusted by body weight, 
but will not exceed maximums of 50mg/day, 100mg/day, and 200mg/day. The dose selection 
was based on the following observations in adult subjects: 
• The PK of BRV is linear and of low variability in adults up to 1 order of magnitude above 
the therapeutic dose range. 
• Efficacious doses in adults are expected to be from 50mg/day up to 200mg/day. 
• Drug clearance is expected to be higher in children than in adults because of the 
physiologically based PK simulations. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able to tolerate the minimum dose specified in the 
previous BRV study to be eligible for entry into the Evaluation Period of N01266. This 
minimum tolerated BRV dose for LTFU subjects from N01263 is 0.8mg/kg/day if ≥8 years 
of age and 1.0mg/kg/day if <8 years of age. The same minimums apply to directly enrolled 
subjects. 
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The maximum allowable BRV dose in N01266 is 3.2mg/kg/day for subjects ≥8 years of age 
and 4.0mg/kg/day for subjects <8 years of age. Younger subjects (<7 years of age) will be 
administered BRV oral solution. Subjects above 50kg will be dosed as adults, up to a 
maximum total daily dose not exceeding 200mg/day, and should transition from the oral 
solution to the equivalent oral tablet dose, if appropriate. 
Has been changed to: 
Each LTFU subject will begin treatment in N01266 at the individualized BRV dose he/she 
was receiving at the completion of the previous pediatric study. Directly enrolled subjects 
will participate in up to 3 weeks of an Up-Titration Period. If a subject demonstrates, in the 
opinion of the Investigator, acceptable tolerability and seizure control on the same daily dose 
of BRV for 7±2 days during the Up-Titration Period, the subject will be allowed to enter the 
Evaluation Period (subject must be able to tolerate the minimum dose of 1.0mg/kg/day; see 
Section 7.2). 
A physiologically-based PK model (N01313) was developed to predict the doses to be tested 
in N01263. The same doses that were used for up-titration in N01263 will be used for the 
3 consecutive weeks that comprise the Up-Titration Period of N01266. Based on the PK 
analyses performed on the plasma samples collected in N01263, the plasma 
concentrations approximating the concentrations for adults receiving BRV 200mg/day 
were not achieved by the dosing scheme initially included in N01266; as a result, it was 
recommended that the same doses are to be administered in all pediatric subgroups, 
≥1 month to ≤16 years of age. For all subjects, the approximate doses to be administered are 
0.5, 1.0, and 2.0mg/kg bid (1.0, 2.0, and 4.0mg/kg/day, respectively), with the daily doses 
not exceeding the maximums of 50mg/day, 100mg/day, and 200mg/day for Weeks 1, 2, 
and 3 of up-titration, respectively. The dose selection was based on the following 
observations: 
• The PK of BRV is linear and of low variability in adults up to 1 order of magnitude above 
the therapeutic dose range. 
• Efficacious doses in adults are expected to be from 50mg/day up to 200mg/day. 
• In the recently completed N01263, BRV was eliminated more rapidly in pediatric 
subjects than in adult subjects, resulting in a lower plasma concentration. Therefore, 
clearance of BRV was shown to be higher in pediatric subjects than in adult 
subjects. 
Brivaracetam (tablet and oral solution) should be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able to tolerate the minimum dose specified in the 
previous BRV study to be eligible for entry into the Evaluation Period of N01266. All 
directly enrolled subjects must be able to tolerate at least 1.0mg/kg/day during the 
Up-Titration Period prior to entering the Evaluation Period of N01266, as indicated in 
Section 7.2.  
The maximum allowable BRV dose in N01266 is 5.0mg/kg/day (2.5mg/kg bid), not to 
exceed a dose of 200mg/day for subjects with body weight >40kg. Subjects <7 years of 
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age will receive oral solution. Subjects ≥7 years of age will receive tablets, as 
appropriate. 
Change #19, Section 7.2, Treatments to be administered 
The original text: 
The LTFU subjects will ordinarily start dosing on the individualized BRV dose they were 
receiving at the completion of the previous pediatric BRV study. The directly enrolled 
subjects will participate in an Up-Titration Period as described in Section 7.2.1 before entry 
into the Evaluation Period. 
The LTFU subjects must be able to tolerate the minimum BRV dose specified in their 
previous study to be eligible for entry into the Evaluation Period of N01266. For subjects 
entering N01266 from N01263, the minimum BRV dose is 0.8mg/kg/day if ≥8 years of age 
or at least 1.0mg/kg/day if <8 years of age; directly enrolled subjects must also tolerate at 
least these dosages for 7±2 days during the Up-Titration Period before entry into the 
Evaluation Period. 
The maximum BRV dose for subjects ≥8 years of age is 3.2mg/kg/day and 4.0mg/kg/day for 
subjects <8 years of age. Subjects above 50kg will be dosed as adults, up to a maximum total 
daily dose not exceeding 200mg/day, and should transition from the oral solution to the 
equivalent oral tablet dose, unless the subject’s condition prevents him/her from swallowing 
oral tablets. Subjects <7 years of age should not transition to oral tablet treatment. Oral 
solution should not be mixed with other liquids prior to administration. 
The maximum dose allowed in this study is 200mg/day (100mg bid). 
Brivaracetam should be given bid approximately 12 hours apart in 2 equally divided doses. 
The mg dosage for the oral tablet treatment should be calculated to match as closely as 
possible the mg/kg-based dosage and should be a combination of the BRV 10mg, 25mg, and 
50mg tablets. Only the following exact dosages are allowed for the oral tablet administration:  
BRV 20, 40, 50, 70, 100, 150, and 200mg/day. Subjects should be dosed with either oral 
tablets or oral solution and not a combination of both. 
The dose of oral solution will be measured using the appropriate syringes (1mL, 3mL, and/or 
10mL) with an adaptor able to fit both bottle sizes. Dose adjustments of IMP and/or 
concomitant AEDs are allowed at any time based on clinical judgment. 
All subjects who prematurely discontinue the study should complete an EDV and have their 
BRV dose down titrated by a maximum of half the dose every week until a dose of 
1.0mg/kg/day is reached for subjects <8 years of age or until a dose of 0.8mg/kg/day is 
reached for subjects ≥8 years of age. 
Subjects should take their BRV treatment according to instructions provided by the 
Investigator. 
Dispensation of IMP will be done by an interactive voice response system (IVRS). 
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Has been changed to: 
Brivaracetam (tablet and oral solution) should be administered bid approximately 12 hours 
apart in 2 equally divided doses. Subjects should be dosed with either oral tablets or oral 
solution and not a combination of both. The mg dosage for the oral tablet treatment should 
be calculated to match as closely as possible the mg/kg based dosage and should be a 
combination of the BRV 10mg, 25mg, and 50mg tablets. Only the following exact dosages 
are allowed for the oral tablet administration: BRV 20, 40, 50, 70, 100, 150, and 200mg/day.  
The dose of oral solution will be measured using the appropriate syringes (1mL, 3mL, and/or 
10mL) with an adaptor able to fit both bottle sizes. Oral solution should not be mixed with 
other liquids prior to administration.  
All subjects who prematurely discontinue the study should complete an EDV and have their 
BRV dose down titrated by a maximum of half the dose every week until a dose of 
1.0mg/kg/day is reached. 
Subjects should take their BRV treatment according to instructions provided by the 
Investigator. Dose adjustments for concomitant AEDs are allowed at any time based on 
clinical judgment. 
Dispensation of IMP will be done by an interactive voice response system (IVRS). 
Change #20, Section 7.2.1, Up-Titration Period for directly enrolled 
subjects, paragraph 3 and Table 7-1 
The original text: 
Based on tolerability and seizure control, a subject’s BRV dose may be reduced to no lower 
than the age-designated minimum dose indicated in Table 7‒1. If a subject had previously 
received the reduced BRV dose for 7±2 days with acceptable tolerability and seizure control, 
then the subject may enter directly into the Evaluation Period. 
Table 7‒1: Recommended BRV dosing schedule for directly enrolled subjects 
during the Up-Titration Period 
Has been changed to: 
Based on tolerability and seizure control, a subject’s BRV dose may be reduced to no lower 
than the designated minimum dose indicated in Table 7‒1. If a subject had previously 
received the reduced BRV dose for 7±2 days with acceptable tolerability and seizure control, 
then the subject may enter directly into the Evaluation Period. 
Visit (Week) 
BRV dose per dosing occasion 
(mg/kg) 
BRV dose per day 
(mg/kg/day) 
 
≥8 years 
<8 years 
≥8 years 
<8 years 
TV1 (1)  
~0.4 
~0.5 
~0.8 
~1.0 
TV2 (2)  
~0.8 
~1.0 
~1.6 
~2.0 
TV3 (3)  
~1.6 
~2.0 
~3.2 
~4.0 
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Table 7‒1: Recommended BRV dosing schedule for directly enrolled subjects 
during the Up-Titration Period 
Visit (Week) 
BRV dose per dosing occasion (mg/kg) 
BRV dose per day 
(mg/kg/day) 
TV1 (1) 
~0.5 
~1.0 
TV2 (2) 
~1.0 
~2.0 
TV3 (3) 
~2.0 
~4.0 
Change #21, Section 7.2.1, Up-Titration Period for directly enrolled 
subjects 
The following paragraph has been added: 
Daily doses will not exceed the maximums of 50mg/day, 100mg/day, and 200mg/day for 
Weeks 1, 2, and 3 of up-titration, respectively. 
Change #22, Section 7.2.2, Evaluation Period for all subjects 
The following section has been added: 
7.2.2 Evaluation Period for all subjects 
The maximum BRV dose will be 5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose of 
200mg/day for subjects with body weight >40kg. Subjects <7 years of age will receive 
oral solution. Subjects ≥7 years of age will receive tablets, as appropriate.  
The LTFU subjects will ordinarily start dosing on the individualized BRV dose they 
were receiving at the completion of the previous pediatric BRV study. They must be 
able to tolerate the minimum BRV dose specified in their previous study to be eligible 
for entry into the Evaluation Period of N01266.  
Dose can be adjusted at any time as considered necessary by the Investigator and 
required by the subject’s medical condition. The newly adjusted dose must not exceed 
the maximum allowed dose (5mg/kg/day [2.5mg/kg bid], not to exceed a dose of 
200mg/day). 
Change #23, Section 8.1, Screening Visit for directly enrolled subjects 
only, paragraph 1  
The original text: 
The ScrV is applicable only to directly enrolled subjects (ie, subjects ≥4 years to <17 years of 
age with POS who have not previously participated in a pediatric BRV study). Beginning 
with Protocol Amendment 3, up to 100 directly enrolled subjects will be allowed to 
participate in N01266. The Screening Period will serve as the Baseline Period for directly 
enrolled subjects. 
Has been changed to: 
The ScrV is applicable only to directly enrolled subjects (ie, subjects ≥4 years to <17 years of 
age with POS who have not previously participated in a pediatric BRV study). Beginning 
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with Protocol Amendment 3, up to 100 directly enrolled subjects were allowed to participate 
in N01266. The Screening Period will serve as the Baseline Period for directly enrolled 
subjects. With Protocol Amendment 4, the number of directly enrolled subjects is 
increased to at least 100 subjects with the planned total enrollment of approximately 
600 subjects. 
Change #24, Section 8.1, Screening Visit for directly enrolled subjects 
only, bullet point 21 
The original text: 
• Laboratory assessments for safety including: 
− Hematology 
− Biochemistry including hepatic monitoring 
− Urinalysis 
− Endocrinology 
− Serum pregnancy test (if applicable) 
Has been changed to: 
• Laboratory assessments for safety including: 
− Hematology 
− Biochemistry including hepatic monitoring 
− Urinalysis 
− Endocrinology 
− Serum pregnancy test (see Section 9.5.1) 
Change #25, Section 8.3.1, LTFU subjects 
The original text: 
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and 
local requirements) 
• Subject identification card dispensing  
• DRC dispensed 
• Verification of inclusion/exclusion criteria 
• IVRS call 
• Study drug dispensed 
• Recording of medications (Any ongoing medications [including AEDs and non-AEDs] at 
the time the subject completed the previous pediatric BRV study should not be recorded 
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in the eCRF for N01266, unless there is a change regarding the administration of the 
medication. In this event, the start date corresponding to the date of change in 
administration should be recorded in the eCRF.) 
• Recording of AEs (Any ongoing AEs at the time the subject completed the previous 
pediatric BRV study should not be recorded in the eCRF for N01266, unless there is a 
change in intensity or seriousness. In this event, the AE should be recorded in the eCRF 
for N01266, with the onset date corresponding to the date of change in condition.) 
• Appointment for the next visit according to the schedule described in Section 5.3 
The following data will be obtained from Baseline of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266: 
• Demographic data 
• General medical and procedures history 
• Epilepsy history 
• AED history 
• Height 
• Bayley-III scales (for LTFU subjects <18 months of age at Baseline of N01263 or other 
pediatric BRV studies and only for subjects enrolled in English-speaking countries) 
• Achenbach CBCL score (see Section 10.3.3) 
• Laboratory assessments 
− Endocrinology 
The following data will be obtained from the final visit of the previous pediatric BRV study 
and should not be recorded in the eCRF for N01266: 
• Childbearing potential Recording of medications 
• Recording of procedures 
• Seizure count 
• EEG 
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed 
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed 
• ECG 
• Laboratory assessments for safety 
− Hematology 
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− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
• Phenytoin plasma concentrations (if applicable) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Vital signs 
• Body weight 
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
Has been changed to: 
• Signing and dating of written Informed Consent by parent(s)/legal representative(s) 
• Signing and dating of Assent form by the subject (if applicable, according to age and 
local requirements) 
• Subject identification card dispensing  
• DRC dispensed 
• Verification of inclusion/exclusion criteria 
• Demographic data  
• Childbearing potential 
• IVRS call 
• Study drug dispensed 
• Recording of medications (Any ongoing medications [including AEDs and non-AEDs] at 
the time the subject completed the previous pediatric BRV study should not be recorded 
in the eCRF for N01266, unless there is a change regarding the administration of the 
medication. In this event, the start date corresponding to the date of change in 
administration should be recorded in the eCRF.) 
• Recording of AEs (Any ongoing AEs at the time the subject completed the previous 
pediatric BRV study should not be recorded in the eCRF for N01266, unless there is a 
change in intensity or seriousness. In this event, the AE should be recorded in the eCRF 
for N01266, with the onset date corresponding to the date of change in condition.) 
• Appointment for the next visit according to the schedule described in Section 5.3  
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The following data will be obtained from Baseline of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266: 
• General medical and procedures history 
• Epilepsy history 
• AED history 
• Height 
• Bayley-III scales (for LTFU subjects <18 months of age at Baseline of N01263 or other 
pediatric BRV studies and only for subjects enrolled in English-speaking countries) 
• Achenbach CBCL score (see Section 10.3.3) 
• Laboratory assessments 
− Endocrinology 
The following data will be obtained from the final visit of the previous pediatric BRV study 
and should not be recorded in the eCRF for N01266: 
• Recording of medications 
• Recording of procedures 
• Seizure count 
• EEG 
− For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: an EEG of at least 1 hour of recording (including hyperventilation and 
intermittent photic stimulation) must be performed  
− For subjects ≥1 month to <2 years of age on the day of the study visit: an EEG of at 
least 24 hours of recording (including sleeping and awakening periods) must be 
performed  
• ECG 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (see Section 9.5.1) 
• Phenytoin plasma concentrations (if applicable) 
• Suicidality assessment (C-SSRS) (for subjects ≥6 years of age) 
• Vital signs 
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• Body weight  
• Physical examination 
• Neurological examination 
• Psychiatric and mental status 
• Health care provider consultations not foreseen by the protocol 
• Hospital stays 
Change #26, Section 8.3.2, Directly enrolled subjects, bullet point 18 
The original text: 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis 
− Urine pregnancy test (if applicable) 
Has been changed to: 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis 
− Urine pregnancy test (see Section 9.5.1) 
Change #27, Section 8.4, Minimal Evaluation Visit, header 
The original text: 
8.4 
Minimal Evaluation Visit 
Has been changed to: 
8.4 
Minimal Evaluation Visit (all subjects) 
Change #28, Section 8.5, Full Evaluation Visit, header  
The original text: 
8.5 
Full Evaluation Visit 
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Has been changed to: 
8.5 
Full Evaluation Visit (all subjects) 
Change #29, Section 8.5, Full Evaluation Visit, bullet point 20 
The original text: 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
Has been changed to: 
• Laboratory assessments for safety 
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (see Section 9.5.1) 
Change #30, Section 8.6, Yearly Evaluation Visit, header  
The original text: 
8.6 
Yearly Evaluation Visit 
Has been changed to: 
8.6 
Yearly Evaluation Visit (all subjects) 
Change #31, Section 8.6, Yearly Evaluation Visit, bullet point 21 
The original text: 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
− Endocrinology 
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Has been changed to: 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (see Section 9.5.1) 
− Endocrinology 
Change #32, Section 8.7, Unscheduled Visit, header 
The original text: 
8.7 
Unscheduled Visit 
Has been changed to: 
8.7 
Unscheduled Visit (all subjects) 
Change #33, Section 8.8, Early Discontinuation Visit, header  
The original text: 
8.8 
Early Discontinuation Visit 
Has been changed to: 
8.8 
Early Discontinuation Visit (all subjects) 
Change #34, Section 8.8, Early Discontinuation Visit, bullet point 20 
The original text: 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Serum pregnancy test (if applicable) 
Has been changed to: 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
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− Serum pregnancy test (see Section 9.5.1) 
Change #35, Section 8.9, Down-Titration Visit, header 
The original text: 
8.9 
Down-Titration Visit 
Has been changed to: 
8.9 
Down-Titration Visit (all subjects) 
Change #36, Section 8.10, Safety Visit, header  
The original text: 
8.10 Safety Visit 
Has been changed to: 
8.10 Safety Visit (all subjects) 
Change #37, Section 8.10, Safety Visit, bullet point 14 
• Laboratory assessments for safety (to be performed only if abnormal at the EDV)  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Serum pregnancy test (if applicable) 
Has been changed to: 
• Laboratory assessments for safety (to be performed only if abnormal at the EDV)  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Serum pregnancy test (see Section 9.5.1) 
Change #38, Section 8.11, Final Visit, header  
The original text: 
8.11 Final Visit 
Has been changed to: 
8.11 Final Visit (all subjects) 
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Change #39, Section 8.11, Final Visit, bullet point 18 
The original text: 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (if applicable) 
− Endocrinology 
Has been changed to: 
• Laboratory assessments for safety  
− Hematology 
− Biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and 
GGT) 
− Urinalysis (for subjects ≥4 years of age) 
− Urine pregnancy test (see Section 9.5.1) 
− Endocrinology 
Change #40, Section 9.5.1, Laboratory assessments for safety, table 
footnote d  
The original text: 
d Female subjects with a Tanner stage >1 should have urine pregnancy tests at the EV 
(directly enrolled subjects only), YEVs/FV, and FEVs and serum pregnancy tests at the 
ScrV (directly enrolled subjects only), EDV, and SV. 
Has been changed to: 
d All female subjects with a Tanner stage >1 should have urine pregnancy tests at the EV, 
YEVs/FV, and FEVs and serum pregnancy tests at the ScrV (directly enrolled subjects 
only), EDV, and SV. 
Change #41, Section 9.5.1, Laboratory assessments for safety, 
paragraphs 5 and 6 
The original text: 
For LTFU subjects, laboratory safety assessments at the EV will be obtained from the final 
visit of the previous pediatric BRV study and should not be recorded in the eCRF for 
N01266. Laboratory safety assessments (hematology, biochemistry [including hepatic 
monitoring: total bilirubin, ALP, AST, ALT, and GGT], urinalysis [for subjects ≥4 years of 
age, and pregnancy testing [as applicable]) will be performed at the ScrV and EV (directly 
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enrolled subjects only), FEV, YEV, FV, and at the EDV in the case of early discontinuation. 
Laboratory assessments will also be mandatory at the SV if the laboratory results at the EDV 
are abnormal. Only hepatic monitoring assessments will be performed at the final TV 
(directly enrolled subjects only), and the MEVs at V4 (M3) and V6 (M9) during the first 
year; no laboratory safety assessments will be performed at other MEVs. Endocrinology 
testing will be performed at the ScrV (directly enrolled subjects only) and once a year at the 
YEV. For LTFU subjects, the Baseline endocrinology values will be taken from Baseline of 
the previous pediatric BRV study. 
Female subjects who have a Tanner stage >1 should have urine pregnancy tests at the EV 
(directly enrolled subjects only), YEVs/FV, and FEVs and serum pregnancy tests at the ScrV 
(directly enrolled subjects only), EDV, and the SV. A serum pregnancy test will be 
performed as backup if a urine sample is not available. A urine pregnancy test should be 
performed at any time during the study if a pregnancy is suspected. 
Has been changed to: 
For LTFU subjects, pregnancy testing (if applicable) will be performed at the EV and 
other laboratory safety assessments at the EV will be obtained from the final visit of the 
previous pediatric BRV study and should not be recorded in the eCRF for N01266. 
Laboratory safety assessments (hematology, biochemistry [including hepatic monitoring: 
total bilirubin, ALP, AST, ALT, and GGT], urinalysis [for subjects ≥4 years of age, and 
pregnancy testing [as applicable]) will be performed at the ScrV and EV (directly enrolled 
subjects only), FEV, YEV, FV, and at the EDV in the case of early discontinuation. 
Laboratory assessments will also be mandatory at the SV if the laboratory results at the EDV 
are abnormal. Only hepatic monitoring assessments will be performed at the final TV 
(directly enrolled subjects only), and the MEVs at V4 (M3) and V6 (M9) during the first 
year; no laboratory safety assessments will be performed at other MEVs. Endocrinology 
testing will be performed at the ScrV (directly enrolled subjects only) and once a year at the 
YEV. For LTFU subjects, the Baseline endocrinology values will be taken from Baseline of 
the previous pediatric BRV study. 
All female subjects who have a Tanner stage >1 should have urine pregnancy tests at the EV, 
YEVs/FV, and FEVs and serum pregnancy tests at the ScrV (directly enrolled subjects only), 
EDV, and the SV. A serum pregnancy test will be performed as backup if a urine sample is 
not available. A urine pregnancy test should be performed at any time during the study if a 
pregnancy is suspected. 
Change #42, Section 9.6.8, BRIEF-P and BRIEF, paragraph 6 
The original text: 
The BRIEF-P or BRIEF appropriate for each subject’s age should be completed, with the 
following exception: For subjects who completed the BRIEF-P at the Baseline assessment 
and turn 6 years of age between that assessment and the initial YEV, the BRIEF-P should be 
completed through and including the initial YEV, and subsequently the BRIEF should be 
completed. 
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Has been changed to: 
The BRIEF-P or BRIEF appropriate for each subject’s age should be completed, with the 
following exception: For subjects who completed the BRIEF-P at the Baseline assessment 
and turn 5 years of age between that assessment and the initial YEV, the BRIEF-P should be 
completed through and including the initial YEV, and subsequently the BRIEF should be 
completed. 
Change #43, Section 12.6, Handling of protocol deviations 
The original text: 
After all eCRFs have been entered and queries addressed, and prior to locking the clinical 
database, a data review meeting (DRM) will be held. The purpose of this DRM will be to 
assess the quality of the data for subsequent database lock, identify protocol deviations, and 
finalize analysis sets. 
Has been changed to: 
Important protocol deviations are deviations from the protocol, which potentially could 
have a meaningful impact on either the primary efficacy outcome or key safety 
outcomes for an individual subject. The criteria for identifying important protocol 
deviations and the classification of important protocol deviations will be defined within 
the project Data Cleaning Plan. To the extent feasible, the rules for identifying protocol 
deviations will be defined without review of the data and without the consideration of 
the frequency of occurrence of such deviations. Whenever possible, criteria for 
identifying important protocol deviations will be implemented algorithmically to ensure 
consistency in the classification of important protocol deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning 
meetings prior to database lock to confirm exclusion from analysis sets. 
Change #44, Section 12.8, Planned interim analysis and data monitoring 
The original text: 
Due to the single-arm open-label design of this study, no formal interim analysis as such will 
be performed. However, interim database locks will be performed to allow safety and 
efficacy analyses in support of submission activities and to allow optimization of the 
development program. 
Has been changed to: 
No formal interim analysis is planned; however, data may be reported prior to the 
completion of this study to support ongoing data cleaning, annual reports, regulatory 
submissions, and publications. 
Change #45, Section 12.9, Determination of sample size 
The original text: 
No formal sample size calculation was performed for this study. Originally, up to 
500 subjects might have possibly enrolled in this study. The original number was based upon 
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the assumption that 90% of the subjects having completed a previous pediatric study with 
BRV as adjunctive treatment in epilepsy will rollover into the present study. With Protocol 
Amendment 3, enrollment is expanded to include up to 100 directly enrolled subjects 
(≥4 years to <17 years of age) with POS, thus increasing possible enrollment up to 
600 subjects. 
Has been changed to: 
No formal sample size calculation was performed for this study. Originally, up to 
500 subjects might have possibly enrolled in this study. The original number was based upon 
the assumption that 90% of the subjects having completed a previous pediatric study with 
BRV as adjunctive treatment in epilepsy will rollover into the present study. With Protocol 
Amendment 3, enrollment was expanded to include up to 100 directly enrolled subjects 
(≥4 years to <17 years of age) with POS, thus increasing possible enrollment up to 
600 subjects. With Protocol Amendment 4, the number of directly enrolled subjects is 
increased to at least 100 subjects with the planned total enrollment of approximately 
600 subjects. 
16.5 
Protocol Amendment 5 
Rationale for the amendment 
The main purposes of this amendment are to: 
• Add an updated list of Anticipated SAEs. 
• Add a section on AEs of special interest in accordance with the Sponsor template 
requirement. 
• Update of the schema for down-titration to align with N01263 and provide uniformity 
across the BRV pediatric development program. 
• Removal of requirement that subjects <7 years of age receive oral solution and, as 
appropriate, subjects ≥7 years of age receive tablets in recognition of individual subject 
preferences to allow subjects additional flexibility in treatment options.  
• Provide Entry Visit information specific to subjects who enroll from core studies under 
development. 
• Provide additional clarity regarding enrolled subjects who participate in EP0065 and then 
resume participation in N01266. Protocol Amendment 3 had allowed for subjects to 
participate in what was called a “substudy.”  
• Clarified requirement that subjects ≥2 years of age with typical absence seizures have at 
least a 24-hour EEG, instead of a 1-hour EEG. 
• Eliminate the EEG at the 3-month visit (V4) and the requirement for subjects to have 
EEGs after they reach 2 years of age (exception: subjects with typical absence seizures) 
and allow the EDV EEGs to be done at the Investigator’s discretion. This change was 
made due to the limited clinical utility of these assessments and to unburden the 
Investigator, subject, and subject’s caregiver/family. 
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• Replace serum pregnancy tests with urine pregnancy tests and inclusion of urine 
pregnancy tests at all MEVs. 
• Update according to the current Sponsor protocol template. This includes: 
− The addition of text regarding PDILI; these changes were strictly template-driven. 
They do not reflect a change in the liver safety signal for BRV and are included only 
for alignment with updated standard Sponsor text across programs.  
− The streamlining of Introduction with reference to the availability of additional 
information in the Investigator’s Brochure. 
• Update of Introduction text to include more current literature references and to include 
information about the marketing authorization of BRV.  
• Revision of the duration of the study for an individual subject from approximately 3 years 
to at least 3 years, with the addition of the possibility of subjects entering a managed 
access program, if available. 
• Removal of the BRV 1.0mg/mL oral solution from the description of the IMP as the 
BRV 10mg/mL oral solution is adequate for dosing. 
Modifications and changes 
Global changes 
These following changes are considered administrative in nature and are not included as 
separate listings in the table of specific changes below: 
• BRV 1.0mg/kg/day, 2.0mg/kg/day, and 4.0mg/kg/day have been changed to 
1mg/kg/day, 2mg/kg/day, and 4mg/kg/day, respectively, for consistency across the 
BRV pediatric development program.  
• “Drug Safety” has been replaced with “Patient Safety” as an administrative change to 
a departmental name. 
• Stylistic changes and minor editorial changes have been made and are of no 
consequence to the meaning of content. 
Specific changes 
The following table provides a list of specific changes to the protocol. Specific changes to the 
tables in Section 5.2 (Table 5-1, Table 5-2, Table 5-3, and Table 5-4) are provided 
immediately after the table and are not included in the table itself. 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Sponsor 
Declaration 
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. 
 
Removed text and signatures/dates (not shown). 
Update per template. 
Required signatures 
are now provided as 
the final page of the 
protocol. 
Clinical Project Manager 
 
____________ 
Date/Signature 
Clinical Trial 
Biostatistician 
 
____________ 
Date/Signature  
Study Physician 
 
____________ 
Date/Signature  
Clinical Program Director 
 
____________ 
Date/Signature  
Clinical Pharmacology 
Director 
 
____________ 
Date/Signature  
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Clinical Study Protocol 
Brivaracetam 
N01266 
 
 
 
Confidential 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Study Contact 
Information 
Sponsor Study Physician: 
Name: 
 
Address: 
8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
Clinical Project Manager: 
Name: 
 
Address: UCB Center Bruxelles 
Phone: 
 
Sponsor Study Physician: 
Name: 
 
Address:  
UCB Biosciences GmbH 
Alfred Nobel Strabe 10 
40789 Monheim  
Germany 
Phone: 
 
Fax: 
 
Clinical Project Manager: 
Name:
 
Address:UCB BioPharma sprl 
Phone: 
 
Update with 
administrative 
changes. 
Serious Adverse 
Event Reporting 
Serious adverse event reporting (24h) and safety 
related issues 
Fax: 
Europe and Rest of the World (except Japan): 
+32 2 386 2421 
US: +1 800 880 6949 
Canada: +1 877 582 8842 
Email: 
Europe, US, and Rest of the World (except 
Japan): DS-ICT@ucb.com 
Serious adverse event reporting (24h) 
Fax: 
Europe and Rest of the World: +32 2 386 2421 
US and Canada: +1 800 880 6949 or +1 866 890 
3175 
Email: 
Global: DS_ICT@ucb.com 
Update to Sponsor 
template. 
List of 
Abbreviations 
ICH: International Conference on 
Harmonisation 
PND: postnatal day 
ULD: Unverricht-Lundborg disease 
ICH: International Council for Harmonization 
iv: intravenous 
PDILI: potential drug-induced liver injury 
PS: Patient Safety 
SV2A: synaptic vesicle protein 2A 
Revise abbreviation. 
Provide 
intradocument 
consistency. 
 
 
 
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Section 1 
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Section 1 
This is a Phase 3, open-label, single-arm, 
multicenter, long-term study to evaluate the 
safety and efficacy of brivaracetam (BRV) in 
children with epilepsy. This study was initially 
designed for pediatric subjects who had 
completed N01263 or would complete other 
future pediatric BRV studies (herein referred to 
as “long-term follow-up” [LTFU] subjects). 
With Protocol Amendment 3, enrollment was 
expanded to include up to 100 subjects ≥4 years 
to <17 years of age with POS who had not 
previously enrolled in a pediatric BRV study 
(herein referred to as “directly enrolled 
subjects”). With Protocol Amendment 4, the 
number of directly enrolled subjects is increased 
to at least 100 subjects with the planned total 
enrollment of approximately 600 subjects. In 
addition, the dosing scheme was aligned so that 
it is no longer age-dependent; previously, 
subjects ≥8 or <8 years of age were dosed under 
different dosing schemes. 
 
The primary objective is to document the long-
term safety and tolerability of BRV. The 
secondary objective is to assess the efficacy of 
BRV during long-term exposure. The other 
objectives are to explore direct cost parameters 
and to assess the effect of BRV on behavior and 
cognition using the age-appropriate Achenbach 
Child Behavior Checklist (CBCL/1½-5 or 
CBCL/6-18) for LTFU subjects ≥18 months of 
age at Baseline of the previous BRV study and 
This is a Phase 3, open-label, single-arm, 
multicenter, long-term study to evaluate the safety 
and efficacy of brivaracetam (BRV) in children 
with epilepsy. This study is designed for pediatric 
subjects ≥1 month to <17 years of age who have 
completed other pediatric BRV studies (herein 
referred to as “long-term follow-up” [LTFU] 
subjects) and for at least 100 subjects ≥4 years to 
<17 years of age with POS who had not 
previously enrolled in a pediatric BRV study 
(herein referred to as “directly enrolled subjects”), 
with a planned total enrollment of approximately 
600 subjects. 
 
The primary objective is to document the long-
term safety and tolerability of BRV. The 
secondary objective is to assess the efficacy of 
BRV during long-term exposure. The other 
objectives are to explore direct cost parameters 
and to assess the effect of BRV 1) on behavior 
and cognition using the age-appropriate 
Achenbach Child Behavior Checklist 
(CBCL/1½-5 or CBCL/6-18) for LTFU subjects 
≥18 months of age at Baseline of their initial BRV 
study (herein referred to as their “core study”) and 
for all directly enrolled subjects, 2) on cognition 
using the Behavior Rating Inventory of Executive 
Function® (BRIEF®)/BRIEF®-Preschool Version 
(BRIEF®-P), and 3) on quality of life using the 
Pediatric Quality of Life Inventory™ (PedsQL™) 
for LTFU subjects ≥1 month of age at the 
Baseline of the core study and for all directly 
Update to Sponsor 
template to provide 
focus on current 
study design. 
Update to provide 
clarification/ 
additional 
information for 
subjects entering 
N01266 from core 
studies (previously 
referred to as 
previous BRV 
studies) and for 
enrolled subjects 
who participate in 
EP0065 then resume 
participation in 
N01266.  
Removal of 
age-based 
requirements for use 
of oral solution and 
tablets in recognition 
of individual subject 
preferences.  
Revise duration of 
individual subject 
participation to at 
least 3 years. 
Add managed access 
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Clinical Study Protocol 
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for all directly enrolled subjects. With Protocol 
Amendment 3, the effect of BRV on cognition 
will also be assessed using the Behavior Rating 
Inventory of Executive Function® 
(BRIEF®)/BRIEF®-Preschool Version 
(BRIEF®-P) and the effect of BRV on quality of 
life will be assessed using the Pediatric Quality 
of Life Inventory™ (PedsQL™) for LTFU 
subjects ≥1 month of age at the Baseline of the 
previous BRV study and for all directly enrolled 
subjects. The Bayley Scales of Infant and 
Toddler Development®, Third Edition 
(Bayley-III®) will be used to assess LTFU 
subjects enrolled in English-speaking countries 
and <18 months of age at Baseline of the 
previous pediatric BRV study; the Bayley-III 
will not be used to access directly enrolled 
subjects since all are to be ≥4 years of age. 
 
The LTFU subjects will enter directly into the 
Evaluation Period at the Entry Visit (EV) and 
will continue BRV treatment at the 
individualized dose they were receiving at the 
completion of their previous pediatric BRV 
study. Directly enrolled subjects will enter 
N01266 at the Screening Visit (ScrV) and then 
participate in up to 3 weeks of an Up-Titration 
Period. If a directly enrolled subject 
demonstrates, in the opinion of the Investigator, 
acceptable tolerability and seizure control on the 
same daily dose of BRV (no lower than 
1.0mg/kg/day) for 7±2 days during the 
Up-Titration Period, the subject will attend the 
EV and enter the Evaluation Period on that 
enrolled subjects. The Bayley Scales of Infant and 
Toddler Development®, Third Edition 
(Bayley-III®) will be used to assess LTFU 
subjects enrolled in English-speaking countries 
and <18 months of age at Baseline of the core 
study; the Bayley-III will not be used to assess 
directly enrolled subjects since all are to be 
≥4 years of age. 
 
The LTFU subjects will enter directly into the 
Evaluation Period at the Entry Visit (EV) and will 
continue BRV treatment at the individualized dose 
they were receiving at the completion of their core 
study. Directly enrolled subjects will enter 
N01266 at the Screening Visit (ScrV) and then 
participate in up to 3 weeks of an Up-Titration 
Period. If a directly enrolled subject demonstrates, 
in the opinion of the Investigator, acceptable 
tolerability and seizure control on the same daily 
dose of BRV (no lower than 1mg/kg/day) for 
7±2 days during the Up-Titration Period, the 
subject will attend the EV and enter the 
Evaluation Period on that dose. 
 
Brivaracetam (tablet and oral solution) should be 
administered twice daily (bid) in 2 equally divided 
doses. All LTFU subjects must be able to tolerate 
the minimum dose specified in the core study to 
be eligible for entry into the Evaluation Period of 
N01266. All directly enrolled subjects must be 
able to tolerate at least 1mg/kg/day during the 
Up-Titration Period prior to entering the 
Evaluation Period of N01266, as indicated in 
as a factor for 
determining length 
of participation. 
Change urinalysis 
from age-based 
requirement to 
feasibility 
requirement in 
recognition 
individual subject 
capabilities. 
Clarify that head 
circumference is 
included as a safety 
variable (previously 
included with 
neurological 
examination 
variable).  
 
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25 Jun 2020 
Clinical Study Protocol 
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dose. 
 
Brivaracetam (tablet and oral solution) should 
be administered twice daily (bid) in 2 equally 
divided doses. All LTFU subjects must be able 
to tolerate the minimum dose specified in the 
previous BRV study to be eligible for entry into 
the Evaluation Period of N01266. All directly 
enrolled subjects must be able to tolerate at least 
1.0mg/kg/day during the Up-Titration Period 
prior to entering the Evaluation Period of 
N01266, as indicated in Section 7.2. 
 
The maximum allowable BRV dose is 
5.0mg/kg/day (2.5mg/kg bid), not to exceed a 
dose of 200mg/day for subjects with body 
weight >40kg. Subjects <7 years of age will 
receive oral solution. Subjects ≥7 years of age 
will receive tablets, as appropriate. With the 
exception of dose adjustments for BRV during 
the Up-Titration Period, which should be made 
in accordance with the protocol-specified 
guidelines, dose adjustments of BRV and any 
concomitant antiepileptic drugs (AEDs) are 
allowed at any time based on clinical judgment. 
Subjects will receive BRV treatment in this 
study for approximately 3 years, until approval 
of BRV has been obtained for pediatric subjects 
in their age range, or until the investigational 
product development is stopped by the Sponsor.  
 
For LTFU subjects, the EV is the first study 
Section 7.2. 
 
The maximum allowable BRV dose is 
5.0mg/kg/day (2.5mg/kg bid), not to exceed a 
dose of 200mg/day for subjects with body weight 
>40kg. Subjects will receive oral solution or 
tablets, as appropriate. With the exception of dose 
adjustments for BRV during the Up-Titration 
Period, which should be made in accordance with 
the protocol-specified guidelines, dose 
adjustments of BRV and any concomitant 
antiepileptic drugs (AEDs) are allowed at any 
time based on clinical judgment. 
 
Subjects will receive BRV treatment in this study 
for at least 3 years, until approval of BRV has 
been obtained for pediatric subjects in their age 
range, until a managed access program is 
established as allowed per country-specific 
requirements in addition to legal and regulatory 
guidelines, or until the investigational product 
development in the related age range of the 
pediatric population is stopped by the Sponsor, 
whichever comes first.  
 
For LTFU subjects, the EV is the first study visit. 
For directly enrolled subjects, the EV occurs after 
subjects have completed the ScrV and at least 
1 Titration Visit (TV), and have maintained 
acceptable tolerability and seizure control on the 
same daily dose of BRV (no lower than the 
minimum specified dose) for 7±2 days of the 
Up-Titration Period. For subjects who continue in 
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Clinical Study Protocol 
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visit. For directly enrolled subjects, the EV 
occurs after subjects have completed the ScrV 
and at least 1 Titration Visit (TV), and have 
maintained acceptable tolerability and seizure 
control on the same daily dose of BRV (no 
lower than the minimum specified dose) for 
7±2 days of the Up-Titration Period. For 
subjects who continue in this study until it ends, 
the Evaluation Period will extend from the EV 
until the final evaluation visit (Final Visit, FV). 
For subjects who prematurely discontinue the 
study, the Evaluation Period will last from the 
EV until the Early Discontinuation Visit (EDV), 
followed by a maximum 4-week 
Down-Titration Period, a 2-week study 
drug-free Safety Period, and a final Safety Visit 
(SV). At selected sites, subjects may be able to 
participate in a substudy without withdrawing 
from N01266. 
 
Safety variables include adverse events (AEs), 
safety laboratory assessments (hematology, 
biochemistry including hepatic monitoring of 
alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase 
[ALP], total bilirubin, and 
gamma-glutamyltransferase [GGT], and 
endocrinology for all subjects and urinalysis for 
subjects ≥4 years of age), plasma concentrations 
of BRV and phenytoin (if applicable), 
electrocardiograms (ECGs), vital signs, physical 
and neurological examinations, psychiatric and 
mental status, body weight, and height. 
this study until it ends, the Evaluation Period will 
extend from the EV until the final evaluation visit 
(Final Visit, FV). For subjects who prematurely 
discontinue the study, the Evaluation Period will 
last from the EV until the Early Discontinuation 
Visit (EDV), followed by a maximum 4-week 
Down-Titration Period, a 2-week Safety 
(Drug-Free) Period, and a final Safety Visit (SV). 
Subjects already enrolled in N01266 may 
participate in EP0065 (an intravenous [iv] BRV 
study for pediatric subjects), if eligible, and then 
resume participation in N01266.  
 
Safety variables include adverse events (AEs), 
safety laboratory assessments (hematology, 
biochemistry including hepatic monitoring of 
alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase 
[ALP], total bilirubin, and 
gamma-glutamyltransferase [GGT], and 
endocrinology for all subjects and urinalysis for 
subjects for whom sample collection is feasible), 
plasma concentrations of BRV and phenytoin (if 
applicable), electrocardiograms (ECGs), vital 
signs, physical and neurological examinations, 
psychiatric and mental status, body weight, 
height, and head circumference. 
 
Up to 600 subjects may possibly enroll in this 
study. The number and location of sites will 
depend on those participating in core studies from 
which LTFU subjects will be enrolled, and those 
participating in direct enrollment. Sites of direct 
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Clinical Study Protocol 
Brivaracetam 
N01266 
 
 
 
Confidential 
Page 232 of 346 
Section Impacted 
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Key components of amended text 
Rationale 
Up to 600 subjects may possibly enroll in this 
study. The number and location of sites will 
depend on those participating in N01263 and 
other future pediatric BRV studies from which 
LTFU subjects will be enrolled, and those 
participating in direct enrollment. Sites of direct 
enrollment will include, but not be limited to, 
sites participating in N01263 and other pediatric 
BRV studies. 
enrollment will include, but not be limited to, sites 
participating in core studies. 
 
Section 2 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 2.1 
Header: 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 
Header: Background regarding targeted disease. 
Epilepsy is the second most prevalent 
neurological disorder in the world. It is estimated 
that almost 70 million people suffer from epilepsy 
(Ngugi et al, 2011). Epilepsy affects about 4 to 6 
out of 1,000 children aged less than 20 years old, 
and the overall annual incidence rates of epilepsy 
for all seizure types for all children aged less than 
19 years range between 45 and 86 out of 
100,000 children. Long-term prognosis of 
epilepsy varies across several factors such as 
types of syndromes, etiology, and presence of 
co-morbidities. 
The existing treatment options for epilepsy in 
childhood generally follow the treatment options 
for adults, and clinical experience demonstrates 
that children may benefit from the administration 
of conventional AEDs for the treatment of 
partial-onset seizures (POS) with comparable 
Update header to 
Sponsor template. 
Update to provide 
more current and 
concise background 
information. 
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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 (up to 30%) of patients, 
seizure freedom can still not be reached with 
currently available AEDs (Nasreddine et al, 
2010; Kwan and Brodie, 2001).  
Seizures encountered in adulthood may also be 
experienced in childhood, including simple and 
complex partial seizures (Dulac, 1994). The 
existing treatment options for partial epilepsy in 
childhood generally follow the treatment 
options for adults, and clinical experience 
demonstrates that children may benefit from the 
administration of conventional AEDs for the 
treatment of partial-onset seizures (POS) with 
comparable results to adults. 
results to adults. Despite the availability of new 
AEDs, more than 25% of pediatric patients have 
inadequate seizure control on currently available 
AEDs, or experience significant adverse drug 
effects (Hadjiloizou and Bourgeois, 2007). Thus, 
there remains a need for potent AEDs with a 
positive benefit-risk profile in this population. 
 
Section 2.2 
Brivaracetam is a chemical relative of the AED 
levetiracetam (LEV, Keppra®). Like LEV, 
BRV displays a high and selective interaction 
with a novel brain-specific binding site, synaptic 
vesicle protein 2A (SV2A). However, the 
binding affinity of BRV for SV2A is 
approximately 10-fold higher. This binding site 
appears to be the major target for its 
pharmacological activity. Unlike LEV, BRV 
also reduces voltage-dependent sodium currents. 
Brivaracetam also reverses the inhibitory effects 
Brivaracetam ((2S)-2-[(4R)-2-oxo-4-
propyltetrahydro-1H-pyrrol-1-yl]butanamide) 
displays a high and selective affinity for the 
synaptic vesicle protein 2A (SV2A) in the brain. 
Binding to SV2A is believed to be the primary 
mechanism for BRV anticonvulsant activity. In 
2016, marketing authorization for the use of oral 
and iv BRV as adjunctive treatment of 
partial-onset seizures (POS) in patients 16 years 
of age and older with epilepsy was granted in the 
EU, US, Australia, and Switzerland, and in 
Update to provide 
marketing approval 
status and to remove 
information 
available in the 
Investigator’s 
Brochure. 
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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.  
The effects of long-term oral administration of 
BRV were evaluated in juvenile rats (9-week 
study; up to 600mg/kg/day) and in juvenile dogs 
(9-month study; up to 100mg/kg/day). In 
juvenile rats and dogs, and consistent with adult 
animals, the target organ was the liver with 
different sensitivity across species. In the rat, 
the highest dose tested (600mg/kg/day) was 
considered to induce developmental adverse 
effects (mortality, clinical signs, and decreased 
body weights, mainly in preweaning pups). In 
the younger age category (postnatal day 
[PND] 4 in a rat and PND 4 in a dog 
corresponds to a preterm human neonate), 
exposure at the no-observed-adverse-effect level 
was 17- to 38-fold higher in rats and 3- to 7-fold 
higher in dogs than the anticipated exposure in 
the equivalent pediatric population (29µg.h/mL 
or 63µg.h/mL, which are the area under the 
curve [AUC0-24h] in adults at the doses of 100 or 
200mg/day, respectively). At later periods, the 
exposure multiples were similar to those seen in 
adult toxicity studies (at least 3-fold in rats and 
1.2-fold in dogs). 
Brivaracetam is rapidly and completely 
absorbed throughout the gastrointestinal tract. 
The extent of BRV absorption is not affected by 
food. The pharmacokinetics (PK) are 
dose-proportional (at least from 10mg to 
Canada for patients 18 years and older with 
epilepsy. 
More detailed information regarding the 
nonclinical and clinical development programs for 
BRV, including all completed and ongoing 
studies, is provided in the Investigator’s Brochure. 
 
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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, ucb-42145, 
while a minor pathway is the ω1-hydroxylation 
into ucb-100406-1 mediated by cytochrome 
P450 (CYP)2C19. The combination of these 
2 pathways results in the hydroxyacid terminal 
metabolite ucb-107092-1. 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 
ethinylestradiol 30µg and levonorgestrel 150µg. 
Brivaracetam does not induce CYP3A4 using 
midazolam as a marker probe. Brivaracetam has 
no interaction on lamotrigine and topiramate. 
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Brivaracetam plasma concentration is not 
increased by gemfibrozil, a selective CYP2C8/9 
inhibitor, but is increased in a nonclinically 
relevant manner in 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 studies. No significant 
change from Baseline or dose-related trend was 
observed for the plasma concentrations of: 
carbamazepine, lamotrigine, LEV, 
oxcarbazepine metabolite, phenobarbital, 
phenytoin, topiramate, valproate, or zonisamide. 
Carbamazepine epoxide was increased by 
50% to 60% at BRV doses of 100 and 
150mg/day due to inhibition of epoxide 
hydrolase. There is no need for BRV dose 
adjustment in the presence of carbamazepine. 
No longer 
applicable 
(Section 2.3 of 
Amendment 4) 
Section 2.3 Efficacy with BRV (adult studies) 
Following completion of the Phase 2 studies 
(N01114 and N01193), clinical results 
supported further development of BRV for the 
adjunctive treatment of POS. Two adequate and 
well-controlled fixed-dose studies (N01252 and 
N01253) were conducted to assess BRV across 
a dose range of 5 to 100mg/day.  
N01253 assessed BRV doses of 5, 20, and 
50mg/day and provided statistically significant 
and clinically relevant evidence of the efficacy 
of BRV 50mg/day. N01252 assessed BRV 
doses of 20, 50, and 100mg/day. Although 
N01252 was not positive, it provided supporting 
evidence for the efficacy of BRV 100mg/day in 
Deleted. 
Update to remove 
information now 
available in the 
prescribing 
information and the 
Investigator’s 
Brochure. 
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subjects with epilepsy.  
Two Phase 3 studies (N01187 and N01236) 
were conducted to evaluate the efficacy and 
safety of BRV at doses of 5, 50, and 150mg/day 
used as adjunctive treatment in adult subjects 
with genetically ascertained Unverricht-
Lundborg disease (ULD). In both studies, 
primary efficacy endpoints failed to reach 
statistical significance. 
Clinical photoparoxysmal response data (PPR, 
N01069) suggested efficacy of BRV in subjects 
with photosensitive epilepsy.  
In addition, a subset of subjects (N=49) with 
generalized epilepsy in the well-controlled, 
flexible-dose, safety study (N01254) provides 
further evidence of efficacy of BRV against 
generalized seizures. 
No longer 
applicable 
(Section 2.4 of 
Amendment 4) 
Section 2.4: Safety with BRV (adult studies) 
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 
placebo for all studies. The most frequently 
reported TEAEs were headache, somnolence, 
dizziness, and fatigue. The overall incidence of 
serious adverse events (SAEs) was low and 
similar to placebo. There were no clinically 
relevant changes in laboratory values, vital 
signs, or ECG abnormalities. 
Safety results in ULD subjects indicate that 
BRV was well tolerated. The most frequently 
Deleted. 
Update to remove 
information now 
available in 
prescribing 
information and in 
the Investigator’s 
Brochure. 
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reported TEAEs were headache, somnolence, 
and dizziness in N01187 and headache, 
myoclonus, and somnolence in N01236. 
In addition, there are 3 ongoing open-label 
LTFU studies (N01125, N01199, and N01315) 
that include subjects with POS, primary 
generalized seizures, or ULD who completed 
1 of the Phase 2/3 well-controlled studies. As of 
08 Sep 2011, 1629 subjects have been enrolled 
in these studies and 1624 subjects have received 
study medication. The median duration of 
BRV exposure in LTFU studies was 119 weeks. 
The most common TEAEs, based on interim 
safety monitoring review, include headache, 
dizziness, nasopharyngitis, convulsion, 
somnolence, and fatigue. Overall, 272 subjects 
reported SAEs. The only SAE occurring at a 
frequency >1% was convulsion (2.5%). Overall, 
142 subjects discontinued due to TEAEs. The 
most common TEAEs leading to premature 
discontinuation were convulsion and depression. 
For additional details on the safety and efficacy 
of BRV, please refer to the Investigator’s 
Brochure. 
Section 2.3 
(Section 2.5 of 
Amendment 4) 
Epilepsy affects about 4 to 6 out of 1,000 
children aged less than 20 years old, and the 
overall annual incidence rates of epilepsy for all 
seizure types for all children aged less than 
19 years range between 45 and 86 out of 
100,000 children. Long-term prognosis of 
epilepsy varies across several factors such as 
types of syndromes, etiology, and presence of 
co-morbidities. Despite the availability of new 
N01266 is designed for pediatric subjects ≥1 
month to <17 years of age who have completed 
core studies (LTFU subjects) and for at least 
100 subjects ≥4 years to <17 years of age with 
POS who have not participated in a core study 
(directly enrolled subjects). The total enrollment 
planned for N01266 is approximately 600 
subjects.  
N01266 will provide long-term safety and 
Eliminate repeated 
informational 
content from 
Section 2.1. 
Update in 
accordance with 
current study design. 
 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
AEDs, more than 25% of pediatric patients have 
inadequate seizure control on currently available 
AEDs, or experience significant adverse drug 
effects (Hadjiloizou and Bourgeois, 2007). 
There remains a need for potent AEDs with a 
positive benefit:risk profile in this population. 
Generally, new treatments should be made 
available to children through clinical studies as 
soon as efficacy in adults is established. Studies 
using BRV as adjunctive therapy in adults with 
POS have shown promising results in terms of 
both efficacy (Section 2.3) and safety 
(Section 2.4). In addition, BRV has 
demonstrated efficacy in a PPR study (N01069) 
as well as in a subset of subjects with 
generalized epilepsy in N01254. 
N01263 is the first study of BRV in pediatric 
subjects. This was an open-label, fixed 3-step 
up-titration, PK, safety and efficacy study to 
evaluate BRV as adjunctive therapy in children 
(aged ≥1 month to <16 years) with epilepsy 
using an oral solution. The safety and PK data 
from this study will be used for BRV dose 
adaptation in pediatric subjects with epilepsy. A 
total of 100 subjects were enrolled into this 
study. 
N01266 was originally designed to give subjects 
who complete N01263 or other future pediatric 
BRV studies (ie, LTFU subjects) an opportunity 
to continue BRV treatment for approximately 
3 years, until approval of BRV is granted for 
pediatric subjects in their age range, or until the 
investigational product development is stopped 
tolerability data on BRV in pediatric subjects with 
epilepsy, while providing access to BRV for 
subjects who may benefit from long-term 
treatment. The enrollment of directly enrolled 
subjects is intended to provide both long-term 
safety and tolerably data and efficacy data for 
subjects 4 years to <17 years of age with POS to 
supplement data collected for subjects with POS 
in N01263. 
Subjects will receive BRV treatment in this study 
for at least 3 years, until approval of BRV has 
been obtained for pediatric subjects in their age 
range, until a managed access program is 
established as allowed per country-specific 
requirements in addition to legal and regulatory 
guidelines, or until the investigational product 
development in the related age range of the 
pediatric population is stopped by the Sponsor, 
whichever comes first.   
Subjects already enrolled in N01266 may 
participate in EP0065, if eligible, and then resume 
participation in N01266.  
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Clinical Study Protocol 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
by the Sponsor. With Protocol Amendment 3, 
enrollment was expanded to include up to 
100 eligible subjects ≥4 years to <17 years of 
age with POS who have not participated in 
another pediatric BRV study (ie, directly 
enrolled subjects). Thus, N01266 will gather 
additional long-term safety and tolerability data 
on BRV in pediatric subjects with epilepsy 
while providing access to BRV for subjects who 
may benefit from long-term treatment. With 
Protocol Amendment 4, the number of directly 
enrolled subjects is increased to at least 100 
subjects with the planned total enrollment of 
approximately 600 subjects. In addition, based 
on the PK analyses performed on the plasma 
samples collected in N01263, the dosing scheme 
for Protocol Amendment 4 was aligned so that it 
is no longer age-dependent; previously, subjects 
≥8 or <8 years of age were dosed under 
different dosing schemes. 
 
Section 3 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 3.3 
• 
To assess the effect of BRV on cognition 
using the Bayley-III scales in subjects 
<18 months of age (applicable only to 
LTFU subjects enrolled in English-speaking 
countries)  
• 
To assess the effect of BRV on cognition 
using the Bayley-III scales in subjects 
<18 months of age (applicable only to LTFU 
subjects enrolled in English-speaking 
countries)  
Clarification 
regarding age. 
 
 
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Section 4 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.1 
• 
Safety laboratory tests (hematology, 
biochemistry including hepatic monitoring 
of ALT, AST, ALP, total bilirubin, and 
GGT, and endocrinology for all subjects 
and urinalysis for subjects ≥4 years of age)  
• 
Body weight and height 
• 
Safety laboratory tests (hematology, 
biochemistry including hepatic monitoring of 
ALT, AST, ALP, total bilirubin, and GGT, 
and endocrinology for all subjects and 
urinalysis for subjects for whom sample 
collection is feasible) (see Section 9.2.1) 
• 
Body weight, height, and head circumference 
Change of urinalysis 
sampling criteria as 
described above. 
Clarify that head 
circumference is 
included as 
described above. 
 
Section 4.2 
• 
Responder rate for total POS defined as the 
percentage of subjects with a ≥50% 
reduction in ADF (average daily frequency) 
of POS recorded on EEG  
• 
Absolute and percent reduction in ADF of 
POS 
• 
Responder rate for total POS defined as the 
percentage of subjects with a ≥50% reduction 
in ADF (average daily frequency) of POS 
recorded on EEG (subjects with POS only) 
• 
Absolute and percent reduction in ADF of 
POS (subjects with POS only) 
Clarity that variables 
apply to subjects 
with POS only. 
Section 4.3 
• 
Change from Baseline in the Achenbach 
CBCL score: the Achenbach CBCL/1½-5 
for children from 1½ to 5 years old and the 
Achenbach CBCL/6-18 for children 6 years 
and older  
• 
Change from Baseline in the 
BRIEF-P/BRIEF score for subjects ≥2 years 
of age  
• 
Change from previous BRV study Baseline 
in the Bayley-III scales for children 
<18 months of age (applicable only to 
LTFU subjects enrolled in English-speaking 
• 
Change from Baseline in the Achenbach 
CBCL score: the Achenbach CBCL/1½-5 for 
children from 1½ to 5 years old and the 
Achenbach CBCL/6-18 for children 6 years 
and older (age at initiation of study drug in 
N01266 or core study) 
• 
Change from Baseline in the BRIEF-P/BRIEF 
score for subjects ≥2 years of age (age at 
initiation of study drug in N01266 or core 
study) 
• 
Change from the Baseline in the Bayley-III 
scales for children <18 months of age at 
Provide clarification 
regarding ages. 
Revise for 
intradocument 
consistency in 
terminology 
regarding core 
studies. 
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Section Impacted 
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Key components of amended text 
Rationale 
countries) 
• 
Change from Baseline in PedsQL for 
subjects ≥1 month of age 
baseline of the core study (applicable only to 
LTFU subjects enrolled in English-speaking 
countries)  
• 
Change from Baseline in PedsQL for subjects 
≥1 month of age (age at initiation of study 
drug in N01266 or core study) 
 
Section 5 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 5.1 
This is a Phase 3, open-label, single-arm, 
multicenter, long-term study to evaluate the 
safety and efficacy of BRV in up to 600 subjects 
with epilepsy. Subjects who enroll in N01266 
from N01263 or another pediatric BRV study 
(ie, LTFU subjects) must have been <16 years 
of age upon entry in their previous study; 
eligible subjects who have POS and enroll in 
N01266 without having participated in a 
previous pediatric BRV study (ie, directly 
enrolled subjects) must be ≥4 years to <17 years 
of age. 
Upon enrollment, eligible LTFU subjects will 
enter the Evaluation Period and continue their 
BRV treatment in accordance with their 
individualized dose at the completion of their 
previous pediatric BRV study.  
Brivaracetam (tablet and oral solution) should 
be administered bid in 2 equally divided doses. 
All LTFU subjects must be able to tolerate the 
minimum BRV dose specified in the previous 
This is a Phase 3, open-label, single-arm, 
multicenter, long-term study to evaluate the safety 
and efficacy of BRV in up to 600 subjects with 
epilepsy. Subjects who enroll in N01266 from a 
core study (ie, LTFU subjects) must have been 
<16 years of age upon entry in the core study; 
eligible subjects who have POS and enroll in 
N01266 without having participated in a core 
study (ie, directly enrolled subjects) must be 
≥4 years to <17 years of age. 
Upon enrollment, eligible LTFU subjects will 
enter the Evaluation Period and continue their 
BRV treatment in accordance with their 
individualized dose at the completion of the core 
study.  
The subjects already enrolled in N01266 who then 
participate in EP0065 will resume dosing in 
N01266 in accordance with the individualized 
dose they received at the completion of EP0065. 
Brivaracetam (tablet and oral solution) should be 
administered bid in 2 equally divided doses. All 
Revise for 
intradocument 
consistency in 
terminology 
regarding core 
studies. 
Update in 
accordance with 
current study design. 
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N01266 
 
 
 
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Section Impacted 
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Key components of amended text 
Rationale 
study to be eligible for entry into the Evaluation 
Period of N01266. All directly enrolled subjects 
must be able to tolerate at least 1.0mg/kg/day 
during the Up-Titration Period prior to entering 
the Evaluation Period of N01266, as indicated 
in Section 7.2. 
For all subjects enrolled in N01266, the 
maximum BRV dose is 5.0mg/kg/day 
(2.5mg/kg bid), not to exceed a dose of 
200mg/day for subjects with body weight 
>40kg. Subjects <7 years of age will receive 
oral solution. Subjects ≥7 years of age will 
receive tablets, as appropriate.  
Subjects will continue to receive BRV treatment 
in this study for approximately 3 years, until 
approval for BRV has been obtained for 
pediatric subjects in their age range, or until the 
investigational product development is stopped 
by the Sponsor. 
Following the EDV, subjects will have their 
dose of BRV down titrated over a maximum of 
4 weeks (Down-Titration Period). After 2 weeks 
free of study drug (Safety Period), subjects will 
complete the SV. 
LTFU subjects must be able to tolerate the 
minimum BRV dose specified in the core study to 
be eligible for entry into the Evaluation Period of 
N01266. All directly enrolled subjects must be 
able to tolerate at least 1mg/kg/day during the Up-
Titration Period prior to entering the Evaluation 
Period of N01266, as indicated in Section 7.2. 
For all subjects enrolled in N01266, the maximum 
BRV dose is 5.0mg/kg/day (2.5mg/kg bid), not to 
exceed a dose of 200mg/day for subjects with 
body weight >40kg. Subjects will receive oral 
solution or oral tablets, as appropriate. 
Following the EDV, subjects will have their BRV 
dose reduced by a maximum of half the dose 
every week for a maximum of 4 weeks until a 
dose of 1mg/kg/day (50mg/day for subjects with 
body weights >50kg) is reached.  
Enrolled subjects who participate in EP0065 and 
then resume participation N01266 will maintain 
the visit schedule established for them in N01266 
before participation in EP0065.  
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Section Impacted 
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Key components of amended text 
Rationale 
Section 5.1.1 
Subject participation will extend from study 
entry for approximately 3 years, until approval 
of BRV has been obtained for pediatric subjects 
in their age range, or until the investigational 
product development is stopped by the Sponsor.  
Subject participation will extend from study entry 
for at least 3 years, until approval of BRV has 
been obtained for pediatric subjects in their age 
range, until a managed access program is 
established as allowed per country-specific 
requirements in addition to legal and regulatory 
guidelines, or until the investigational product 
development in the related age range of the 
pediatric population is stopped by the Sponsor, 
whichever comes first.  
Revise duration of 
individual subject 
participation to at 
least 3 years. 
Addition of managed 
access as a factor for 
determining length 
of participation. 
Section 5.1.2 
As originally designed, up to 500 subjects (<16 
years of age upon entry in their previous 
pediatric BRV study) might possibly enroll in 
this study during the pediatric development 
plan, based upon the assumption that 90% of 
subjects having completed a previous pediatric 
study with BRV as adjunctive treatment in 
epilepsy would rollover into N01266. 
With Protocol Amendment 3, enrollment was 
expanded to include up to 100 eligible directly 
enrolled subjects ≥4 years to <17 years of age 
with POS, which allowed up to 600 subjects to 
enroll in N01266 instead of the up to 500 
originally planned. With Protocol Amendment 
4, the number of directly enrolled subjects is 
increased to at least 100 subjects with the 
planned total enrollment of approximately 600 
subjects. 
N01266 is planned for a total enrollment of 
approximately 600 subjects, including at least 100 
eligible directly enrolled subjects ≥4 years to 
<17 years of age with POS. 
 
Simplify text to 
reflect current design 
only and eliminate 
repetition of sample 
size estimates from 
the study rationale 
section. 
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Section Impacted 
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Key components of amended text 
Rationale 
Section 5.1.3 
As originally designed, the regions and 
countries participating in this study depended on 
the location of the sites participating in the 
previous pediatric BRV study/studies, as these 
sites should have had access to the originally 
planned LTFU study. Europe, US, and Mexico 
were foreseen, with the possibility to extend to 
other countries and regions if deemed necessary.  
With Protocol Amendment 3, directly enrolled 
subjects may be enrolled from sites participating 
in N01263 and possibly other sites, including, 
but not limited to, those participating in other 
pediatric BRV studies. 
The LTFU subjects will be enrolled in regions and 
countries participating in the core studies. 
Enrollment is planned for Europe, US, and 
Mexico, with the possibility to extend to other 
countries and regions if deemed necessary.  
Directly enrolled subjects may be enrolled from 
sites participating in core studies and possibly 
other sites. 
 
Simplify text to 
reflect current design 
only. 
Section 5.2 
Once a directly enrolled subject demonstrates, 
in the opinion of the Investigator, acceptable 
tolerability and seizure control on the same 
daily dose of BRV (no lower than the minimum 
specified dose) for 7±2 days during the 
Up-Titration Period, the subject will attend the 
EV, enter the Evaluation Period on that dose, 
and follow the study assessments in Table 5-1. 
Table 5-1 provides a schedule of all study 
assessments for LTFU subjects and for 
assessments subsequent to the final TV for 
directly enrolled subjects. Table 5-2 provides a 
schedule of study assessments for directly 
enrolled subjects from the ScrV through the 
final TV. 
Table 5-1 provides a schedule of assessments for 
the EV (all subjects). Table 5-2 provides a 
schedule of assessments for the Evaluation, 
Down-Titration, and Safety (Drug-Free) Periods 
(all subjects). Table 5-3 provides a schedule of 
study assessments from the ScrV through the final 
TV (directly enrolled subjects only). 
Update text to reflect 
addition of new table 
and update of 
existing tables. 
Section 5.4 
N01266 will allow BRV long-term safety and 
tolerability data to be collected from pediatric 
subjects with epilepsy who will have 
participated in previous pediatric BRV studies 
N01266 will allow BRV long-term safety and 
tolerability data to be collected from pediatric 
subjects with epilepsy who will have participated 
in core studies and now have the opportunity to 
Update for 
intradocument 
consistency in 
terminology 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
and now have the opportunity to continue BRV 
treatment, and from directly enrolled subjects 
with POS. The safety and efficacy data 
collected in this study will support the 
applications for BRV indications in pediatric 
patients. 
Each LTFU subject will begin treatment in 
N01266 at the individualized BRV dose he/she 
was receiving at the completion of the previous 
pediatric study. Directly enrolled subjects will 
participate in up to 3 weeks of an Up-Titration 
Period. If a subject demonstrates, in the opinion 
of the Investigator, acceptable tolerability and 
seizure control on the same daily dose of BRV 
for 7±2 days during the Up-Titration Period, the 
subject will be allowed to enter the Evaluation 
Period (subject must be able to tolerate the 
minimum dose of 1.0mg/kg/day; see 
Section 7.2). 
For all subjects, the approximate doses to be 
administered are 0.5, 1.0, and 2.0mg/kg bid 
(1.0, 2.0, and 4.0mg/kg/day, respectively), with 
the daily doses not exceeding the maximums of 
50mg/day, 100mg/day, and 200mg/day for 
Weeks 1, 2, and 3 of up-titration, respectively.  
 
In the recently completed N01263, BRV was 
eliminated more rapidly in pediatric subjects 
than in adult subjects, resulting in a lower 
plasma concentration. Therefore, clearance of 
BRV was shown to be higher in pediatric 
subjects than in adult subjects. 
All directly enrolled subjects must be able to 
continue BRV treatment, and from directly 
enrolled subjects with POS. The safety and 
efficacy data collected in this study will support 
the applications for BRV indications in pediatric 
patients. 
Each LTFU subject will begin treatment in 
N01266 at the individualized BRV dose he/she 
was receiving at the completion of the core study. 
Enrolled subjects who volunteer to participate in 
EP0065 will resume dosing in N01266 in 
accordance with the individualized dose they 
received at the completion of EP0065. Directly 
enrolled subjects will participate in up to 3 weeks 
of an Up-Titration Period. If a subject 
demonstrates, in the opinion of the Investigator, 
acceptable tolerability and seizure control on the 
same daily dose of BRV for 7±2 days during the 
Up-Titration Period, the subject will be allowed to 
enter the Evaluation Period (subject must be able 
to tolerate the minimum dose of 1mg/kg/day; see 
Section 7.2). 
For all subjects, the approximate doses to be 
administered are 0.5, 1, and 2mg/kg bid (1, 2, and 
4mg/kg/day, respectively), with the daily doses 
not exceeding the maximums of 50mg/day, 
100mg/day, and 200mg/day for Weeks 1, 2, and 3 
of up-titration, respectively.  
In N01263, BRV was eliminated more rapidly in 
pediatric subjects than in adult subjects, resulting 
in a lower plasma concentration. Therefore, 
clearance of BRV was shown to be higher in 
pediatric subjects than in adult subjects. 
All directly enrolled subjects must be able to 
regarding core 
studies. 
Provide dosing 
information for 
subjects who resume 
dosing in N01266 
after participation in 
EP0065.  
Remove age-based 
requirement for oral 
solution and tablet 
dosing as described 
above. 
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Section Impacted 
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Key components of amended text 
Rationale 
tolerate at least 1.0mg/kg/day during the 
Up-Titration Period prior to entering the 
Evaluation Period of N01266, as indicated in 
Section 7.2.  
Subjects <7 years of age will receive oral 
solution. Subjects ≥7 years of age will receive 
tablets, as appropriate. 
tolerate at least 1mg/kg/day during the 
Up-Titration Period prior to entering the 
Evaluation Period of N01266, as indicated in 
Section 7.2.  
Subjects will receive oral solution or tablets, as 
appropriate. 
 
 
Section 6 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 6 
Not applicable. 
The nonconsecutive numbering and application of 
letters to some numbers in this section reflect 
changes that have occurred with protocol 
amendments. 
Provide explanation 
of renumbering 
required by Sponsor 
template. 
Section 6.1 
Criteria that were in place before Protocol 
Amendment 3 have retained the previous 
numbering. 
Deleted. 
Remove explanation 
no longer needed. 
Section 6.1.1 
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. 
2a. 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 (including 
BRV oral solution or tablets) according to the 
judgment of the Investigator. 
Clarify (2a).  
Update to BRV 
pediatric 
development 
program standards 
(14). 
 
 
4. Female subjects without childbearing 
potential are eligible. 
5. Female subjects with childbearing potential 
who are not sexually active are eligible. 
14. For female subjects, the subject is 
• 
Not of childbearing potential  
-OR- 
 
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Subjects need to notify the Investigator if 
there is an anticipated change in status. 
6. Female subjects with childbearing potential 
who are sexually active are eligible if they 
use a medically accepted contraceptive 
method. Oral or depot contraceptive 
treatment with at least ethinylestradiol 30µg 
per intake or ethinylestradiol 50µg per intake 
if associated with any strong inducer (eg, 
carbamazepine, phenobarbital, primidone, 
phenytoin, oxcarbazepine, St. John’s Wort, 
rifampicin), a monogamous relationship with 
a vasectomized partner, or double-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. 
7. Female subjects with childbearing potential 
must have a negative pregnancy test. 
• 
Of childbearing potential, and 
− Is not sexually active 
− Has a negative pregnancy test  
-OR- 
 
• 
Of childbearing potential, and  
− 
Is sexually active 
− 
Has a negative pregnancy test 
− 
Understands the consequences and 
potential risks of inadequately 
protected sexual activity, understands 
and properly uses contraceptive 
methods, and is willing to inform the 
Investigator of any contraception 
changes. Medically acceptable 
contraceptive methods for the study 
include, but are not limited to: 
− 
Oral or depot contraceptive 
treatment with at least 
ethinylestradiol 30µg per intake 
or ethinylestradiol 50µg per 
intake if also taking one of the 
following: carbamazepine, 
phenobarbital, primidone, 
phenytoin, oxcarbazepine, St. 
John's Wort, or rifampicin  
− 
Barrier contraception: 
intrauterine device, diaphragm 
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Section Impacted 
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Rationale 
with spermicide, male or female 
condom with spermicide  
− 
Abstinence from sexual 
intercourse 
Section 6.1.2 
3. Male or female subjects having participated 
in a previous pediatric study in epilepsy with 
BRV and for whom a reasonable benefit 
from long-term administration of BRV is 
expected. 
3a. Male or female subjects having participated in 
a core study and for whom a reasonable 
benefit from long-term administration of BRV 
is expected. 
Provide intra-
document 
consistency with 
“core study” 
terminology. 
Revise to allow 
enrollment of 
subjects from 
N01349 (a study in 
neonates with 
electroencephalo-
grahic neonatal 
seizures). 
Section 6.2.1 
Not applicable. 
29. Subject has >1.5x upper limit of normal 
(ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase 
(ALP), or >1.0xULN 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%). 
N01349 subjects with a total bilirubin > ULN 
may be considered for the study if benign 
unconjugated hyperbilirubinemia is suspected 
Update to Sponsor 
template. 
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Section Impacted 
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Key components of amended text 
Rationale 
in the context of prolonged neonatal jaundice, 
after discussion with the medical monitor. 
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 eCRF. 
If subject has >ULN ALT, AST, or ALP that 
does not meet the exclusion limit at the 
baseline referenced in Table 5-1 for LTFU 
subjects and the Screening Visit for directly 
enrolled subjects, repeat the tests, if possible, 
prior to dosing to ensure there is no further 
ongoing clinically relevant increase. In case of 
a clinically relevant increase, inclusion of the 
subject must be discussed with the Medical 
Monitor. 
Tests that result in ALT, AST, or ALP up to 
25% above the exclusion limit may be 
repeated once for confirmation. This includes 
re-screening.  
30. Subject has chronic liver disease. 
Section 6.2.2 
2. Subject has developed hypersensitivity to 
any components of the investigational 
medicinal product (IMP) or comparative 
drugs as stated in this protocol during the 
course of the previous BRV study. 
4. Subject had poor compliance with the visit 
schedule or medication intake in the 
previous BRV study. 
2a. Subject had hypersensitivity to BRV or 
excipients or comparative drugs as stated in 
this protocol during the course of the core 
study. 
4a. Subject had poor compliance with the visit 
schedule or medication intake in the core 
study. 
7a. Subject ≥ 6 years of age has a lifetime history 
of suicide attempt (including actual attempt, 
Revise to provide 
consistency with the 
BRV Investigator’s 
Brochure and across 
BRV pediatric 
program. 
Provide intra-
document 
consistency with 
“core study” 
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7. Subject has a lifetime history of suicide 
attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or 
has suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to 
either Question 4 or Question 5 of the 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) at the EV. 
interrupted attempt, or aborted attempt), has 
suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to 
Question 5 of the Columbia-Suicide Severity 
Rating Scale (C-SSRS) at the EV. If a subject 
has active suicidal ideation without a specific 
plan as indicated by a positive response 
(“Yes”) to Question 4 of Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the EV, 
the subject should be referred immediately to 
a Mental Healthcare Professional and may be 
excluded from the study based upon the 
Investigator’s judgment of benefit/risk of 
continuing the subject in the study/on study 
medication. 
terminology. 
 
Section 6.2.3 
27. Subject has impaired hepatic function:  
• 
Alanine aminotransferase/serum 
glutamic pyruvic transaminase 
(ALT/SGPT), aspartate 
aminotransferase/serum glutamic 
oxaloacetic transaminase 
(AST/SGOT), alkaline phosphatase of 
more than 2x the upper limit of normal 
(ULN), or total bilirubin of more than 
2xULN. 
• 
Gamma-glutamyltransferase (GGT) 
values of more than 3xULN. A result 
of GGT exceeding 3xULN can be 
accepted only if attributable to hepatic 
Deleted. 
Replacement by 
template text for all 
subjects (see 
Section 6.2.3) 
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enzyme induction caused by 
concomitant antiepileptic treatment 
and if other hepatic enzymes are below 
2xULN. 
 
Section 6.3 
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 occurs: 
1. Subject develops an illness that, in the 
opinion of the Investigator, would interfere 
with his/her continued participation or would 
potentially be detrimental to his/her 
physical/mental health.  
2. Subject presents with current depressive 
symptoms, current suicidal ideation, and/or 
behavior. 
3. Subject is noncompliant with the study 
procedures or medications in the opinion of 
the Investigator. 
4. Subject takes prohibited concomitant 
medications as defined in the protocol. 
Subjects are free to withdraw from the study at 
any time, without prejudice to their continued 
care. Withdrawal criteria are provided as follows, 
with criteria for potential drug-induced liver 
injury provided in Section 6.3.1.  
Subjects must be withdrawn from the study if any 
of the following events occurs: 
1. Subject develops an illness that, in the opinion 
of the Investigator, would interfere with his/her 
continued participation or would potentially be 
detrimental to his/her physical/mental health.  
4. Subject takes prohibited concomitant 
medications as defined in the protocol. 
5. Subject/parent(s)/legal representative(s) 
withdraws his/her/their consent. 
6. There is confirmation of a pregnancy during 
the study, as evidenced by a positive pregnancy 
test. 
Update to Sponsor 
template including 
movement of PDILI 
criteria to dedicated 
section 
(Section 6.3.1). 
Add information 
specific to enrolled 
subjects who 
volunteer to 
participate in 
EP0065. 
 
 
5. Subject/parent(s)/legal representative(s) 
withdraws his/her/their consent. 
6. There is confirmation of a pregnancy during 
the study, as evidenced by a positive 
pregnancy test. 
7. The Sponsor or a regulatory agency requests 
withdrawal of the subject. 
7. The Sponsor or a regulatory agency requests 
withdrawal of the subject. 
8a. Subject has an episode of convulsive status 
epilepticus, a prolongation of seizure duration, 
a worsening of seizure frequency, or 
emergence of a new type, that is considered by 
the Investigator to require intervention. 
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8. Subject has an episode of status epilepticus, a 
prolongation of seizure duration, a worsening 
of seizure frequency, or emergence of a new 
type, that is considered by the Investigator to 
require intervention. 
9. Subject has the following findings based on 
liver function tests (LFT): 
• 
If the subject has LFT results of 
transaminases (AST and/or ALT) ≥3x 
the upper limit of normal (ULN) to 
<5xULN or total bilirubin ≥2xULN, the 
measurements will be repeated within a 
few days. If the repeat testing confirms 
the abnormality (eg, transaminases are 
≥3xULN to <5xULN), then monitoring 
of LFTs should continue at subsequent 
study visits until resolved (eg, <3xULN 
or stable condition). The Investigator is 
to decide whether or not to stop the 
study medication. 
• 
If the subject has LFT results of 
transaminases (AST and/or ALT) 
≥5xULN, study medication should be 
tapered off immediately and the subject 
must be withdrawn from the study. 
10. Criteria for subjects who completed a 
C-SSRS assessment at the final visit of the 
previous BRV study (LTFU subjects) or at 
the ScrV (directly enrolled subjects): 
• 
Subject has active suicidal ideation as 
12. Investigator decides that withdrawal from 
further participation would be in the subject’s 
best interest. 
13. Subject is unwilling or unable to continue, or 
the parent/legal guardian is unwilling or unable 
to allow the subject to continue in this study. 
14. If subject is ≥6 years of age, subject has active 
suicidal ideation with a specific plan as 
indicated by a positive response (“Yes”) to 
Question 5 of the “Since Last Visit” or 
“Already Enrolled Subjects” (as applicable) 
version of the C-SSRS. The subject should be 
referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the 
study. 
Subjects may be withdrawn from the study if any 
of the following events occurs: 
15. If subject is ≥6 years of age, subject has active 
suicidal ideation without a specific plan as 
indicated by a positive response (“Yes”) to 
Question 4 of the “Since Last Visit” or 
“Already Enrolled Subjects” version of C-
SSRS. The subject should be referred 
immediately to a Mental Healthcare 
Professional and may be withdrawn from the 
study based on the Investigator’s judgment of 
benefit/risk of continuing with the subject in 
the study/on study medication. 
If a subject from N01266 enrolls in EP0065 and 
either withdraws consent solely due to route of 
BRV administration (iv) or if the subject requires 
more than 10 iv doses of BRV, the subject may be 
allowed to return to N01266 after discussion with 
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indicated by a positive response (“Yes”) 
to either Question 4 or 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. 
11. Criteria for subjects who become 6 years of 
age during N01266 and for whom the 
"Already Enrolled Subjects" version of the 
C-SSRS was completed at the first visit after 
the sixth birthday: 
• 
Subject has a lifetime history (prior to 
study entry or since study start) of 
suicide attempt (including an actual 
attempt, interrupted attempt, or aborted 
attempt) of the “Already Enrolled 
Subjects” version of the C-SSRS. The 
Investigator must withdraw the subject 
from the study and immediately refer 
the subject to a Mental Healthcare 
Professional. 
• 
Subject had active suicidal ideation 
prior to study entry or since study start 
as indicated by a positive response 
(“Yes”) to either Question 4 or 
Question 5 of the “Already Enrolled 
Subjects” version of the C-SSRS. The 
Investigator must immediately refer the 
subject to a Mental Healthcare 
and agreement from the Medical Monitor. If a 
subject from N01266 is advised to withdraw from 
N01266 after participation in EP0065, the subject 
will be required to return to the N01266 to 
complete the required EDV, DTV, and SV 
assessments. 
Refer to Table 5-2 for procedures to be performed 
at the time of withdrawal.  
 
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Professional and use clinical judgment 
as to whether to withdraw the subject 
from the study.  
• 
Subject has active suicidal ideation as 
indicated by a positive response (“Yes”) 
to either Question 4 or 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. 
Refer to Table 5-1 for procedures to be 
performed at the time of withdrawal.  
Section 6.3.1 
(No parallel 
section in 
Amendment 4) 
Not applicable. 
Header: Potential drug-induced injury 
investigational medicinal product discontinuation 
criteria 
Subjects with potential drug-induced liver injury 
(PDILI) must be assessed to determine if the 
investigational medicinal product (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  
Update to Sponsor 
template. 
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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 9.2.2. 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 
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and subject withdrawal (if applicable), must be 
recorded in the source documents. The eCRF must 
document the primary reason for IMP 
discontinuation. 
 
Section 7 
Section Impacted 
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Key components of amended text 
Rationale 
Section 7.1 
Brivaracetam oral solution, at concentrations of 
1.0mg/mL and 10mg/mL, will be supplied in 
150mL and 300mL glass bottles, respectively. 
Brivaracetam oral solution at a concentration of 
10mg/mL will be supplied in 300mL glass bottles. 
Removal of the BRV 
1.0mg/mL oral 
solution as the BRV 
10mg/mL oral 
solution is adequate 
for dosing. 
Section 7.2 
All subjects who prematurely discontinue the 
study should complete an EDV and have their 
BRV dose down titrated by a maximum of half 
the dose every week until a dose of 
1.0mg/kg/day is reached. 
Deleted. 
Align down titration 
across BRV 
pediatric program. 
Information now 
provided in 
Section 7.2.3. 
Section 7.2.1 
Beginning with Protocol Amendment 3, at TV1, 
eligible directly enrolled subjects will initiate 
treatment with BRV (oral solution or tablet, as 
chosen by the Investigator and 
subject/caregiver). 
Beginning with Protocol Amendment 3, at TV1, 
eligible directly enrolled subjects will initiate 
treatment with BRV (oral solution or tablet, as 
appropriate). 
Provide 
intradocument 
consistency. 
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Section 7.2.2 
The maximum BRV dose will be 5.0mg/kg/day 
(2.5mg/kg bid), not to exceed a dose of 
200mg/day for subjects with body weight 
>40kg. Subjects <7 years of age will receive 
oral solution. Subjects ≥7 years of age will 
receive tablets, as appropriate.  
The LTFU subjects will ordinarily start dosing 
on the individualized BRV dose they were 
receiving at the completion of the previous 
pediatric BRV study. They must be able to 
tolerate the minimum BRV dose specified in 
their previous study to be eligible for entry into 
the Evaluation Period of N01266.  
The maximum BRV dose will be 5.0mg/kg/day 
(2.5mg/kg bid), not to exceed a dose of 
200mg/day for subjects with body weight >40kg. 
Subjects may receive oral solution or oral tablets, 
as appropriate.  
The LTFU subjects will ordinarily start dosing in 
N01266 on the individualized BRV dose they 
were receiving at the completion of the core 
study; enrolled subjects who volunteer to 
participate in EP0065 should resume dosing in 
N01266 on the individualized BRV dose they 
were receiving at the completion of EP0065. 
Subjects must be able to tolerate the minimum 
BRV dose specified in the core study to be 
eligible for entry into the Evaluation Period of 
N01266.  
Remove age-based 
formulation 
requirement. 
Provide information 
specific to enrolled 
subjects who 
participate in 
EP0065 and return 
to N01266. 
Section 7.2.3 
(No parallel 
section in 
Amendment 4) 
Not applicable. 
Header: Down-Titration Period 
All subjects who prematurely discontinue the 
study should complete an EDV and have their 
BRV dose down titrated by a maximum of half 
the dose every week for a maximum of 4 weeks 
until a dose of 1mg/kg/day (50mg/day for subjects 
with body weights >50kg) is reached.  
Provide dedicated 
section for the 
Down-Titration 
Period for ease of 
document 
navigation. 
Section 7.3 
Oral solution will be packaged in 150mL 
(1.0mg/mL) and 300mL (10mg/mL) type III 
amber glass bottles with child-resistant tamper 
evident polypropylene (PP) screw closures.  
Oral solution (10mg/mL) will be packaged in 
300mL type III amber glass bottles with child 
resistant tamper evident polypropylene (PP) screw 
closures. 
Removal of bottles 
for the BRV 
1.0mg/mL oral 
solution (no longer 
supplied). 
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Section 7.4 
Clinical drug supplies will be labeled in 
accordance with the current International 
Conference on Harmonisation (ICH) guidelines 
on Good Clinical Practice (GCP) and Good 
Manufacturing Practice and will include any 
locally required statements 
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 
Revise abbreviation. 
Section 7.5 
The Investigator (or designee) is responsible for 
the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the 
Investigator is to be kept in a secured area with 
limited access. Storage conditions will be 
specified on the labels. 
Appropriate storage conditions must be ensured 
either by controlled room temperature, or by 
completing a temperature log in accordance 
with local requirements on a regular basis (eg, 
once a week), showing minimum and maximum 
temperatures reached over the time interval. 
In case an out-of-range temperature is noted, it 
must be communicated immediately to the 
Clinical Project Manager (CPM or designee) 
before further use of the IMP. 
The CPM (or designee) will transmit the out-of-
range temperature (copy of the temperature log, 
duration of the out-of-range temperature, if 
available) to the Drug Supply Coordinator. 
Based on discussion with Quality Assurance, 
the Drug Supply Coordinator will then provide 
the CPM (or designee) with instructions for the 
site regarding use of the IMP. 
The Investigator (or designee) is responsible for 
the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the 
Investigator is to be kept in a secured area with 
limited access, according to the storage conditions 
mentioned in the label.  
Appropriate storage conditions must be ensured 
either by 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 reported as per instructions contained in 
the IMP Handling Manual. 
 
Update to Sponsor 
template. 
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Section 7.6 
A Drug Accountability form will be provided 
and kept-up-to-date to record IMP dispensing 
and return information on a by-subject basis and 
will serve as source documentation during the 
course of the study. The study medication 
disposition records, such as shipping, 
dispensing, and return records, and inventory 
logs, must be kept at the site, preferably in the 
pharmacy. Details of any IMP lost (due to 
breakage or wastage), not used, disposed of at 
the study site, or returned to the Sponsor or 
designee must also be recorded on the 
appropriate forms. 
Periodically, and/or after completion of the 
clinical phase of the study, all used (including 
empty bottles) and unused IMP bottles must be 
reconciled and returned to UCB (or designee), 
preferably in their original package.  
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.  
 
Periodically, and/or after completion of the 
clinical phase of the study, all used (including 
empty containers)/partially used, unused, 
damaged, and/or expired IMP must be reconciled 
and either destroyed at the site according to local 
laws, regulations, and UCB SOPs or returned to 
UCB (or designee). Investigational medicinal 
product intended for the study cannot be used for 
any other purpose than that described in this 
protocol. 
Update to Sponsor 
template. 
Section 7.8 
For LTFU subjects, ongoing medications at the 
time the subject completed the previous 
pediatric BRV study should not be recorded in 
the eCRF at the EV, or any subsequent visit, 
unless there is a change regarding the 
administration of the medication. 
For LTFU subjects, ongoing medications at the 
time the subject completed the core study should 
not be recorded in the eCRF at the EV, or any 
subsequent visit. Changes in ongoing concomitant 
medications should be recorded in the N01266 
eCRF.  
Provide 
intradocument 
consistency for “core 
study” terminology. 
 
Section 7.8.1.1 
− 
At the established dose if a stable dose 
was maintained during the previous 
pediatric BRV study 
− 
At the established dose if a stable dose 
was maintained during the core study 
Provide 
intradocument 
consistency for “core 
study” terminology. 
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Section 7.8.2 
− 
Felbamate (except if on a stable dose 
during the previous pediatric BRV 
study) 
− 
Felbamate (except if on a stable dose 
during the core study) 
 
Provide 
intradocument 
consistency for “core 
study” terminology. 
Section 7.10 
Subjects will not be randomized in this study, as 
each LTFU subject will start on the 
individualized BRV dose that he/she was 
receiving at the completion of the previous 
study, and directly enrolled subjects will start 
the Evaluation Period on the dose established 
during the Up-Titration Period. 
Subjects will continue with the 5-digit subject 
number assigned by the IVRS in the previous 
pediatric BRV study.  
Subjects will not be randomized in this study, as 
each LTFU subject will start on the individualized 
BRV dose that he/she was receiving at the 
completion of the core study, and directly enrolled 
subjects will start the Evaluation Period on the 
dose established during the Up-Titration Period. 
Subjects will continue with the 5-digit subject 
number assigned by the IVRS in the core study.  
Provide 
intradocument 
consistency for “core 
study” terminology. 
 
 
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Section 8 
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Section 8.1 
The ScrV is applicable only to directly enrolled 
subjects (ie, subjects ≥4 years to <17 years of 
age with POS who have not previously 
participated in a pediatric BRV study). 
Beginning with Protocol Amendment 3, up to 
100 directly enrolled subjects were allowed to 
participate in N01266. The Screening Period 
will serve as the Baseline Period for directly 
enrolled subjects. With Protocol Amendment 4, 
the number of directly enrolled subjects is 
increased to at least 100 subjects with the 
planned total enrollment of approximately 
600 subjects. 
• 
Physical (including Tanner Scale, as 
applicable) and neurological (including 
measurement of head size) examinations 
• 
Body weight and height 
 
− 
Urinalysis (for subjects ≥4 years of age) 
− 
Serum pregnancy test (see Section 
9.5.1) 
The ScrV is applicable only to directly enrolled 
subjects (ie, subjects ≥4 years to <17 years of age 
with POS who have not participated in a core 
study). The Screening Period will serve as the 
Baseline Period for directly enrolled subjects.  
• 
Physical (including Tanner Scale, as 
applicable) and neurological examinations 
• 
Body weight, height, and head circumference 
 
 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
− 
Urine pregnancy test (see Section 9.2.1) 
 
Provide 
intradocument 
consistency for “core 
study” terminology. 
Remove information 
regarding numbers 
of subjects enrolled 
as non-applicable to 
this section. 
Provide clarity 
regarding head 
circumference and 
movement to 
measurement bullet. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
collection is feasible. 
Replace serum 
pregnancy test with 
urine pregnancy test 
and update section 
number. 
Section 8.3.1.1 
Not applicable. 
Header: Core study: N01349 
The following assessments will be performed at 
this visit:  
• 
Signing and dating of written Informed 
Add EV for subjects 
with N01349 as the 
core study. 
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Consent by parent(s)/legal representative(s) 
• 
Subject identification card dispensing  
• 
Verification of inclusion/exclusion criteria 
• 
Demographic data  
• 
Procedure history 
• 
AED history 
• 
Psychiatric and mental status examination 
• 
Vital signs 
• 
Body weight 
• 
ECG 
• 
EEG 
• 
DRC dispensed 
• 
Seizure count 
• 
Recording of medications (Any ongoing 
medications [including AEDs and non-AEDs] 
at the time the subject completed N01349 
should not be recorded in the N01266 eCRF. 
Changes in ongoing concomitant medications 
should be recorded in the eCRF.) 
• 
Recording of procedures 
• 
Recording of AEs (Any ongoing AEs at the 
time the subject completed N01349 should 
not be recorded in the N01266 eCRF. 
Worsening of the AE should be recorded as a 
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new AE.) 
• 
IVRS call 
• 
Study drug dispensed 
• 
Bayley-III scales (subjects enrolled in 
English-speaking countries) 
Other assessments listed in Table 5-1 will be 
obtained from N01349 (as footnoted in Table 5-1) 
and are not to be recorded in the N01266 eCRF. 
Section 8.3.1.2 
Not applicable. 
Header: Core study: EP0065 
The following assessments will be performed at 
this visit:  
• 
Signing and dating of written Informed 
Consent by parent(s)/legal representative(s) 
• 
Signing and dating of the Assent form by the 
subject (if applicable, according to age and 
local requirements) 
• 
Subject identification card dispensing  
• 
Childbearing potential 
• 
Verification of inclusion/exclusion criteria 
• 
Demographic data  
• 
Epilepsy history 
• 
Psychiatric and mental status examination  
• 
Height 
Add EV for subjects 
with EP0065 as the 
core study. 
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Section Impacted 
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• 
Head circumference 
• 
EEG 
• 
DRC dispensed 
• 
Recording of medications (Any ongoing 
medications [including AEDs and non-AEDs] 
at the time the subject completed EP0065 
should not be recorded in the N01266 eCRF. 
Changes in ongoing concomitant medications 
should be recorded in the N01266 eCRF.) 
• 
Recording or procedures 
• 
Recording of AEs (Any ongoing AEs at the 
time the subject completed EP0065 should not 
be recorded in the N01266 eCRF. Worsening 
of the AE should be recorded as a new AE. 
• 
IVRS call 
• 
Study drug dispensed 
• 
Bayley-III scales (subjects enrolled in 
English-speaking countries and <18 months of 
age) 
• 
Achenbach CBCL (see Section 10.3.3)  
• 
BRIEF-P (≥2 years to <5 years of age)/BRIEF 
(≥5 years of age) (see Section 9.3.8) 
• 
PedsQL (see Section 10.3.5.) 
Other assessments listed in Table 5-1 will be 
obtained from EP0065 (as footnoted in Table 5-1) 
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and are not to be recorded in the N01266 eCRF. 
Section 8.3.1.3 
(Section 8.3.1 of 
Amendment 4) 
Header: LTFU subjects 
• 
Signing and dating of written Informed 
Consent by parent(s)/legal representative(s) 
• 
Signing and dating of Assent form by the 
subject (if applicable, according to age and 
local requirements) 
• 
Subject identification card dispensing  
• 
DRC dispensed 
• 
Verification of inclusion/exclusion criteria 
• 
Demographic data  
• 
Childbearing potential 
• 
IVRS call 
• 
Study drug dispensed 
• 
Recording of medications (Any ongoing 
medications [including AEDs and 
non-AEDs] at the time the subject 
completed the previous pediatric BRV study 
should not be recorded in the eCRF for 
N01266, unless there is a change regarding 
the administration of the medication. In this 
event, the start date corresponding to the 
date of change in administration should be 
recorded in the eCRF.) 
• 
Recording of AEs (Any ongoing AEs at the 
Header: Core study: Other (not N01349 or 
EP0065) 
The following assessments will be performed at 
this visit:  
• 
Signing and dating of written Informed 
Consent by parent(s)/legal representative(s) 
• 
Signing and dating of Assent form by the 
subject (if applicable, according to age and 
local requirements) 
• 
Subject identification card dispensing  
• 
Childbearing potential 
• 
Verification of inclusion/exclusion criteria 
• 
Demographic data  
• 
DRC dispensed 
• 
Recording of medications (Any ongoing 
medications [including AEDs and non-AEDs] 
at the time the subject completed the core 
study should not be recorded in the N01266 
eCRF. Changes in ongoing concomitant 
medications should be recorded in the 
N01266 eCRF). 
• 
Recording of AEs (Any ongoing AEs at the 
time the subject completed the core study 
should not be recorded in the N01266 eCRF. 
Worsening of the AE should be recorded as a 
Update to align with 
revised presentation 
strategy in 
Table 5-1. 
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Rationale 
time the subject completed the previous 
pediatric BRV study should not be recorded 
in the eCRF for N01266, unless there is a 
change in intensity or seriousness. In this 
event, the AE should be recorded in the 
eCRF for N01266, with the onset date 
corresponding to the date of change in 
condition.) 
• 
Appointment for the next visit according to 
the schedule described in Section 5.3 
• 
The following data will be obtained from 
Baseline of the previous pediatric BRV 
study and should not be recorded in the 
eCRF for N01266:General medical and 
procedures history 
• 
Epilepsy history 
• 
AED history 
• 
Height 
• 
Bayley-III scales (for LTFU subjects 
<18 months of age at Baseline of N01263 or 
other pediatric BRV studies and only for 
subjects enrolled in English-speaking 
countries) 
• 
Achenbach CBCL score (see 
Section 10.3.3) 
• 
Laboratory assessments 
new AE.) 
• 
IVRS call 
• 
Study drug dispensed 
Other assessments listed in Table 5-1 will be 
obtained from the core study (as footnoted in 
Table 5-1) and are not to be recorded in the 
N01266 eCRF.  
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
− 
Endocrinology 
The following data will be obtained from the 
final visit of the previous pediatric BRV study 
and should not be recorded in the eCRF for 
N01266: 
• 
Recording of medications 
• 
Recording of procedures 
• 
Seizure count 
• 
EEG  
− 
For subjects ≥2 years of age on the day 
of the study visit and with typical 
absence seizures: an EEG of at least 
1 hour of recording (including 
hyperventilation and intermittent photic 
stimulation) must be performed  
− 
For subjects ≥1 month to <2 years of 
age on the day of the study visit: an 
EEG of at least 24 hours of recording 
(including sleeping and awakening 
periods) must be performed  
• 
ECG 
• 
Laboratory assessments for safety 
− 
Hematology 
− 
Biochemistry (including hepatic 
monitoring of ALT, AST, ALP, total 
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Rationale 
bilirubin, and GGT) 
− 
Urinalysis (for subjects ≥4 years of age) 
− 
Urine pregnancy test (see Section 9.5.1) 
• 
Phenytoin plasma concentrations (if 
applicable) 
• 
Suicidality assessment (C-SSRS) (for 
subjects ≥6 years of age) 
• 
Vital signs 
• 
Body weight  
• 
Physical examination 
• 
Neurological examination 
• 
Psychiatric and mental status 
• 
Health care provider consultations not 
foreseen by the protocol 
• 
Hospital stays 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Sections 8.3.2 
• 
Body weight and height 
 
− 
Urinalysis  
 
− 
Urine pregnancy test (see Section 9.5.1) 
• 
Body weight, height, and head circumference 
 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
 
− 
Urine pregnancy test (see Section 9.2.1) 
Clarify that head 
circumference is 
included as 
described above. 
Clarification that 
urinalysis is for all 
subjects for whom 
sample collection is 
feasible. 
 
Update of section 
number for 
pregnancy test. 
Section 8.4 
• 
Body weight and height 
• 
EEG (LTFU subjects only) 
− 
For subjects ≥2 years of age on the day 
of the study visit and with typical 
absence seizures: an EEG of at least 
1 hour of recording (including 
hyperventilation and intermittent photic 
stimulation) must be performed only at 
V4 (M3) as described in Section 10.2  
− 
For subjects ≥1 month to <2 years of 
age on the day of the study visit: an 
EEG of at least 24 hours of recording 
(including sleeping and awakening 
periods) must be performed only at V4 
(M3) as described in Section 10.2  
• 
Body weight, height, and head circumference 
• 
Urine pregnancy test (see Section 9.2.1) 
Removal of EEG at 
MEV. 
Clarify that head 
circumference is 
included as 
described above. 
Addition of 
pregnancy test to 
match Table 5-2. 
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Section Impacted 
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Key components of amended text 
Rationale 
Section 8.5 
• 
Body weight and height 
• 
EEG  
− 
For subjects ≥2 years of age on the day 
of the study visit and with typical 
absence seizures: an EEG of at least 
1 hour of recording (including 
hyperventilation and intermittent photic 
stimulation) must be performed only at 
V5 (M6) as described in Section 10.2  
− 
For subjects ≥1 month to <2 years of 
age on the day of the study visit: an 
EEG of at least 24 hours of recording 
(including sleeping and awakening 
periods) must be performed only at V5 
(M6) as described in Section 10.2. 
 
− 
Urinalysis (for subjects ≥4 years of age) 
− 
Urine pregnancy test (see Section 9.5.1) 
 
• 
Bayley-III scales (for LTFU subjects 
<18 months of age at Baseline of N01263 or 
other pediatric BRV studies and only for 
subjects enrolled in English-speaking 
countries) 
• 
BRIEF-P (<5 years of age)/BRIEF (≥5 
years of age) (see Section 9.38) 
• 
Body weight, height, and head circumference 
• 
EEG (LTFU subjects only) 
− 
For subjects ≥2 years of age at V5 who 
have typical absence seizures, an EEG of 
at least 24 hours that includes 
hyperventilation and intermittent photic 
stimulation must be performed only at V5 
and yearly thereafter. 
− 
For subjects <2 years of age at V5, an 
EEG of at least 24 hours of recording 
must be performed at V5 and yearly 
thereafter. 
 
 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
− 
Urine pregnancy test (see Section 9.2.1) 
• 
Bayley-III scales (for LTFU subjects enrolled 
in English-speaking countries, <18 months of 
age at baseline of the core study, and 
<42 months of age) 
• 
BRIEF-P (≥2 years to <5 years of age)/BRIEF 
(≥5 years of age) (see Section 9.3.8) 
Clarify that head 
circumference is 
included as 
described above.  
Clarify EEG 
requirements. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
collection is feasible. 
Update of section 
number reference for 
pregnancy test. 
Clarification of age 
for Bayley-III. 
Clarification of age 
range for 
BRIEF-P/BRIEF. 
 
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Section Impacted 
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Key components of amended text 
Rationale 
Section 8.6 
• 
Body weight and height 
• 
EEG  
− 
For subjects ≥2 years of age on the day 
of the study visit and with typical 
absence seizures: an EEG of at least 
1 hour of recording (including 
hyperventilation and intermittent photic 
stimulation) must be performed 
− 
For subjects ≥1 month to <2 years of 
age on the day of the study visit: an 
EEG of at least 24 hours of recording 
(including sleeping and awakening 
periods) must be performed 
 
− 
Urinalysis (for subjects ≥4 years of age) 
− 
Urine pregnancy test (Section 9.5.1) 
 
• 
Bayley-III scales (for LTFU subjects 
<18 months of age at Baseline of N01263 or 
other pediatric BRV studies and only for 
subjects enrolled in English-speaking 
countries) 
 
• 
BRIEF-P (<5 years of age)/BRIEF (≥5 
years of age) (see Section 9.38) 
• 
Body weight, height, and head circumference 
EEG deleted. 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
− 
Urine pregnancy test (Section 9.2.1) 
• 
Bayley-III scales (for LTFU subjects enrolled 
in English-speaking countries, <18 months of 
age at baseline of the core study, and 
<42 months of age) 
 
• 
BRIEF-P (≥2 years to <5 years of age)/BRIEF 
(≥5 years of age) (see Section 9.3.8) 
Clarify that head 
circumference is 
included as 
described above.  
Change in 
accordance with 
EEG schedule. 
Update of section 
number reference for 
pregnancy test. 
Clarification of age 
for Bayley-III. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
collection is feasible. 
Clarification of age 
range for 
BRIEF-P/BRIEF. 
 
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Section Impacted 
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Key components of amended text 
Rationale 
Section 8.8 
• 
Body weight and height 
• 
EEG 
− 
For subjects ≥2 years of age on the day 
of the study visit and with typical 
absence seizures: an EEG of at least 
1 hour of recording (including 
hyperventilation and intermittent photic 
stimulation) must be performed 
− 
For subjects ≥1 month to <2 years of 
age on the day of the study visit: an 
EEG of at least 24 hours of recording 
(including sleeping and awakening 
periods) must be performed. 
 
− 
Urinalysis (for subjects ≥4 years of age) 
 
− 
Serum pregnancy test (see Section 
9.5.1) 
 
• 
Bayley-III scales (for LTFU subjects 
<18 months of age at Baseline of N01263 or 
other pediatric BRV studies and only for 
subjects enrolled in English-speaking 
countries) 
 
• 
BRIEF-P (<5 years of age)/BRIEF (≥5 
• 
Body weight, height, and head circumference  
• 
EEG (for LTFU subjects only) 
− 
For subjects ≥2 years of age at V5 who 
have typical absence seizures, a 24-hour 
EEG may be performed at the 
Investigator’s discretion. 
− 
For subjects <2 years of age at V5, a 
24-hour EEG may be performed at the 
Investigator’s discretion. 
 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
 
− 
Urine pregnancy test (see Section 9.2.1) 
 
• 
Bayley-III scales (for LTFU subjects enrolled 
in English-speaking countries, <18 months of 
age at baseline of the core study, and 
<42 months of age) 
 
• 
BRIEF-P (≥2 years to <5 years of age)/BRIEF 
(≥5 years of age) (see Section 9.3.8) 
Clarify that head 
circumference is 
included as 
described above.  
Clarify EEG 
requirements. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
collection is feasible. 
Replace serum 
pregnancy test with 
urine pregnancy test 
and update section 
number. 
Clarification of age 
for Bayley-III. 
Clarification of age 
range for 
BRIEF-P/BRIEF. 
 
 
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Rationale 
years of age) (see Section 9.3.8) 
Section 8.9 
Not applicable. 
Appointment for the next visit according to the 
schedule described in Section 5.2. 
Update for 
intradocument 
consistency. 
Section 8.10 
• 
Body weight and height 
 
− 
Urinalysis (for subjects ≥4 years of age) 
 
− 
Serum pregnancy test (Section 9.5.1) 
• 
Body weight, height, and head circumference 
 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
 
− 
Urine pregnancy test (Section 9.2.1) 
Clarify that head 
circumference is 
included as 
described above.  
Replace serum 
pregnancy test with 
urine pregnancy test 
and update section 
number. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
collection is 
feasible.. 
Section 8.11 
• 
Body weight and height 
• 
EEG 
− 
For subjects ≥2 years of age on the day 
of the study visit and with typical 
absence seizures: an EEG of at least 
1 hour of recording (including 
hyperventilation and intermittent photic 
stimulation) must be performed 
− 
For subjects ≥1 month to <2 years of 
• 
Body weight, height, and head circumference 
• 
EEG (for LTFU subjects only) 
− 
For subjects ≥2 years of age at V5 who 
have typical absence seizures, an EEG of 
at least 24 hours that includes 
hyperventilation and intermittent photic 
stimulation must be performed 
− 
For subjects <2 years of age at V5, an 
EEG of at least 24 hours must be 
Clarify that head 
circumference is 
included as 
described above. 
Clarify EEG 
requirements. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
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Section Impacted 
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Key components of amended text 
Rationale 
age on the day of the study visit: an 
EEG of at least 24 hours of recording 
(including sleeping and awakening 
periods) must be performed. 
 
− 
Urinalysis (for subjects ≥4 years of age) 
 
− 
Urine pregnancy test (see Section 9.5.1) 
 
• 
Bayley-III scales (for LTFU subjects 
<18 months of age at Baseline of N01263 or 
other pediatric BRV studies and only for 
subjects enrolled in English-speaking 
countries) 
 
• 
BRIEF-P <5 years of age)/BRIEF (≥5 years 
of age) (see Section 9.6.8) 
performed. 
− 
Urinalysis (for subjects for whom sample 
collection is feasible) 
− 
Urine pregnancy test (see Section 9.2.1) 
• 
Bayley-III scales (for LTFU subjects enrolled 
in English-speaking countries, <18 months of 
age at baseline of the core study, and 
<42 months of age) 
• 
BRIEF-P (≥2 years to <5 years of age)/BRIEF 
(≥5 years of age) (see Section 9.3.8) 
collection is feasible. 
Clarification of age 
for Bayley-III. 
Update of section 
number for 
pregnancy test. 
Clarification of age 
range for 
BRIEF-P/BRIEF. 
 
 
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Section 9 
Section Impacted 
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Key components of amended text 
Rationale 
Section 9 
For subjects who prematurely discontinue the 
study, the Evaluation Period will include the EV 
through the EDV, followed by a 4-week Down-
Titration Period (maximum), and a 2-week 
study drug-free Safety Period. 
For subjects who prematurely discontinue the 
study, the Evaluation Period will include the EV 
through the EDV, followed by a 4-week Down-
Titration Period (maximum), and a 2-week Safety 
(Drug-Free) Period. 
Update for 
intradocument 
consistency. 
Section 9.1.1 
Header: Definition of adverse event 
Header: Definitions 
Update to Sponsor 
template. 
Section 9.1.1.1 
Not applicable. 
Header: Adverse event 
Update to Sponsor 
template. 
Section 9.1.1.2 
(Section 9.2.1 of 
Amendment 4) 
Header: Definition of serious adverse event 
Header: Serious adverse event 
 
Update to Sponsor 
template. 
Section 9.1.1.2.1 
(Section 9.4 of 
Amendment 4) 
Header: Anticipated SAEs 
Header: Anticipated serious adverse events 
Table 9-1: Added. 
Update to Sponsor 
template. 
Update list of 
anticipated SAEs. 
Section 9.1.1.3 
Not applicable. 
Header: 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. For 
this study, the AEs of special interest include:  
• 
Autoimmune nephritis 
• 
Nephritis 
• 
Nephritis allergic 
Update to Sponsor 
template. 
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Section Impacted 
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Key components of amended text 
Rationale 
• 
Tubulointerstitial nephritis 
• 
Tubulointerstitial nephritis and 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. 
Section 9.1.2 
For LTFU subjects, AEs ongoing at the time the 
subject completed the previous pediatric BRV 
study should not be recorded in the eCRF at the 
EV, or any subsequent visit, unless there is a 
change in intensity or seriousness. 
For LTFU subjects, AEs ongoing at the time the 
subject completed the core study should not be 
recorded in the eCRF at the EV, or any 
subsequent visit. Worsening of the AE should be 
recorded as a new AE. 
Update for 
intradocument 
consistency in 
terminology 
regarding core 
studies and AE 
reporting. 
Section 9.1.2.2 
(Section 9.1.5 of 
Amendment 4) 
Not applicable. 
Not applicable. 
Update numbering. 
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Section Impacted 
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Key components of amended text 
Rationale 
Section 9.1.2.3 
(Section 9.2.2 of 
Amendment 4) 
Header: Procedures for reporting serious 
adverse events 
Header: Additional procedures for reporting 
serious adverse events 
A blood sample for determination of BRV plasma 
concentration should be obtained for any subject 
who has an SAE. 
Update to Sponsor 
template. 
Add text that 
previously appeared 
elsewhere in the 
document for 
clarification. 
Section 9.1.3 
(Section 9.1.4 of 
Amendment 4) 
Not applicable. 
Information on SAEs obtained after clinical 
database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
Update to Sponsor 
template. 
Section 9.1.4 
(Section 9.1.6 of 
Amendment 4) 
Not applicable.  
Not applicable. 
Update numbering. 
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Section Impacted 
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Key components of amended text 
Rationale 
Section 9.1.5 
Not applicable. 
Header: 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. 
Update to Sponsor 
template. 
Section 9.1.6 
(Section 9.1.7 of 
Amendment 4) 
Not applicable. 
Not applicable. 
Update section 
number. 
Section 9.2.1 
(Section 9.5.1 of 
Amendment 4) 
Laboratory assessments for safety (including 
hematology, biochemistry, and endocrinology 
for all subjects, and urinalysis for subjects 
≥4 years of age) will be conducted using 
standard methods at a central laboratory. 
For the table of laboratory paraemeters that 
appears in this section: β-HCG included in the 
urinalysis. 
a Urinalysis will be performed in subjects 
Laboratory assessments for safety (including 
hematology, biochemistry, and endocrinology for 
all subjects, and urinalysis for subjects for whom 
sample collection is feasible) will be conducted 
using standard methods at a central laboratory. 
For the table of laboratory paraemeters that 
appears in this section: β-HCG deleted from the 
urinalysis column. 
Replace urinalysis 
for subjects ≥4 years 
of age, to urinalysis 
for all subjects for 
whom sample 
collection is feasible. 
Provide consistency 
across BR pediatric 
program with 
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≥4 years of age. 
d All female subjects with a Tanner stage >1 
should have urine pregnancy tests at the EV, 
YEVs/FV, and FEVs and serum pregnancy 
tests at the ScrV (directly enrolled subjects 
only), EDV, and SV. 
e Endocrinology testing will be performed at the 
ScrV (directly enrolled subjects only) and at 
the YEV/FV. 
For LTFU subjects, pregnancy testing (if 
applicable) will be performed at the EV and 
other laboratory safety assessments at the EV 
will be obtained from the final visit of the 
previous pediatric BRV study and should not be 
recorded in the eCRF for N01266. Laboratory 
safety assessments (hematology, biochemistry 
[including hepatic monitoring: total bilirubin, 
ALP, AST, ALT, and GGT], urinalysis [for 
subjects ≥4 years of age, and pregnancy testing 
[as applicable]) will be performed at the ScrV 
and EV (directly enrolled subjects only), FEV, 
YEV, FV, and at the EDV in the case of early 
discontinuation. Laboratory assessments will 
also be mandatory at the SV if the laboratory 
results at the EDV are abnormal. Only hepatic 
monitoring assessments will be performed at the 
final TV (directly enrolled subjects only), and 
the MEVs at V4 (M3) and V6 (M9) during the 
first year; no laboratory safety assessments will 
be performed at other MEVs. Endocrinology 
testing will be performed at the ScrV (directly 
 
 
a Urinalysis will be performed for subjects for 
whom sample collection is feasible. 
d Urine pregnancy tests should be conductedat at 
the site for all female subjects of childbearing 
potential. 
All female subjects of childbearing potential 
should have urine pregnancy tests. A serum 
pregnancy test will be performed as backup if a 
urine sample is not available. A urine pregnancy 
test should be performed at any time during the 
study if a pregnancy is suspected. All urine 
pregnancy tests should be conducted at the site. 
 
wording that 
pregnancy tests 
should to be 
childbearing 
potential. 
Remove information 
provided in 
Section 5.3 to 
decrease 
redundancy. 
Replace scheduled 
serum pregnancy 
tests with urine 
pregnancy tests with 
clarification that 
tests performed at 
the site. 
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enrolled subjects only) and once a year at the 
YEV. For LTFU subjects, the Baseline 
endocrinology values will be taken from 
Baseline of the previous pediatric BRV study. 
All female subjects who have a Tanner stage >1 
should have urine pregnancy tests at the EV, 
YEVs/FV, and FEVs and serum pregnancy tests 
at the ScrV (directly enrolled subjects only), 
EDV, and the SV. A serum pregnancy test will 
be performed as backup if a urine sample is not 
available. A urine pregnancy test should be 
performed at any time during the study if a 
pregnancy is suspected. 
Section 9.2.2 
(No parallel 
section in 
Amendment 4.) 
Not applicable. 
Header: 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 
9.1.1.3), and, if applicable, also reported as an 
SAE (see Section 9.1.2.3).  
Evaluation of PDILI consists of the diagnostic 
testing and continued monitoring included in 
Table 9-2 (specific tests dependent on laboratory 
results and corresponding symptoms) and 
consultation with a local hepatologist (if 
applicable; discussed in Section 9.2.2.1). The 
local hepatologist is the expert usually consulted 
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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 
9.2.2.4).  
The results of all monitoring, including laboratory 
testing and other testing, should be made available 
to the study site and Sponsor. 
All initial tests resulting in abnormal hepatic 
laboratory values need to be repeated, but 
appropriate medical action must not be delayed 
waiting for the repeat result. 
If tests are done locally for more rapid results, a 
concurrent sample should also be sent to the 
central laboratory whenever possible. Medical 
care decisions are to be made initially using the 
most rapidly available results and a conservative 
approach must be taken if the results from the 
2 laboratory tests are significantly different. Data 
from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant 
medications and herbal supplements that are not 
medically necessary should also be discontinued. 
In these cases, the Investigator should also 
consider dose reduction for medically necessary 
concomitant medication and consider changing 
any medically required concomitant medication 
known to be hepatotoxic to a suitable alternative. 
Rechallenge with a substance potentially causing 
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drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
The table below summarizes the approach to 
investigate PDILI. 
Table 9-2: Added. 
Section 9.2.2.1 
(No parallel 
section in 
Amendment 4.) 
Not applicable. 
Header: Consultation with Medical Monitor and 
local hepatologist 
Potential drug-induced liver injury events require 
notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject 
must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also 
be discussed with the local hepatologist. The local 
hepatologist is the expert usually consulted by the 
treating physician for assessment and 
management of potential hepatic disease. This 
would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this 
discussion should be followed by a full 
hepatology assessment (see Section 9.2.2.3) and 
SAE report (if applicable). 
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Section 9.2.2.2 
(No parallel 
section in 
Amendment 4.) 
Not applicable. 
Header: 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 9-2 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 of medically necessary concomitant 
medication and consider changing any medically 
required concomitant medication known to be 
hepatotoxic to a suitable alternative. 
 
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Section 9.2.2.3 
(No parallel 
section in 
Amendment 4.) 
Not applicable. 
Header: 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 
9-3 (laboratory measurements) and Table 9-4 
(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: 
Table 9-3: Added. 
The following additional information is to be 
collected: 
Table 9-4: Added. 
 
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Section 9.2.2.4 
(No parallel 
section in 
Amendment 4) 
Not applicable. 
Header: Follow-up evaluation 
Potential drug-induced liver injury events will 
require follow-up monitoring as described in 
Table 9-2. 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. 
Update to Sponsor 
template. 
Section 9.2.3 
(Section 9.5.2 of 
Amendment 4) 
Not applicable. 
Not applicable. 
Update numbering. 
Section 9.2.3.1 
(Section 9.5.2.1 of 
Amendment 4) 
Blood samples for the analysis of BRV will be 
collected at the FEV, YEV, FV, and at the EDV 
in the case of early discontinuation.  
A blood sample for determination of BRV 
plasma concentration should be taken whenever 
the subject experiences an SAE. 
Blood samples for the analysis of BRV 
concentrations will be collected at the visits 
designated in Table 5-2.  
Additionally, a blood sample for determination of 
BRV plasma concentration should be taken 
whenever the subject experiences an SAE. 
Remove information 
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Section 5.2 to 
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redundancy. 
Section 9.2.3.2 
(Section 9.5.2.2 of 
Amendment 4) 
Subjects receiving phenytoin as a concomitant 
AED during the study will have blood samples 
collected at the ScrV (directly enrolled subjects 
only), FEV, YEV, FV, and at the EDV in the 
case of early discontinuation to monitor 
phenytoin plasma concentrations. Blood 
samples will only be collected at the SV if the 
plasma levels of phenytoin are abnormal at the 
EDV. 
Subjects receiving phenytoin as a concomitant 
AED during the study will have blood samples 
collected at the visits designated in Table 5-1, 
Table 5-2, and Table 5-3 to monitor phenytoin 
plasma concentrations.  
Remove information 
provided in 
Section 5.2 to 
decrease 
redundancy. 
Section 9.3 
(Section 9.6 of 
Amendment 4) 
Not applicable. 
Other safety measurements will be performed at 
the visits indicated in Table 5-1, Table 5-2, and 
Table 5-3.   
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text for reader. 
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Section 9.3.1 
(Section 9.6.1 of 
Amendment 4) 
A standard 12-lead ECG will be performed at 
the ScrV, TV(s), and EV (directly enrolled 
subjects only), YEV, FV, and at the EDV in the 
case of early discontinuation. An ECG will be 
performed at the SV only if the ECG results at 
the EDV are abnormal. At the EV, for LTFU 
subjects, ECG data will be obtained from the 
final visit of the previous pediatric BRV study 
and should not be recorded in the eCRF for 
N01266.  
A standard 12-lead ECG will be performed.  
Remove information 
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Section 5.2 to 
decrease 
redundancy. 
Section 9.3.2 
(Section 9.6.2 of 
Amendment 4) 
Vital signs, including measurements of blood 
pressure, supine or sitting pulse rate, and body 
temperature, will be performed after 5 minutes 
of rest at the ScrV, TV(s), and EV (directly 
enrolled subjects only), MEV, FEV, YEV, FV, 
and at the EDV, DTV, and the SV in the case of 
early discontinuation. For LTFU subjects, at the 
EV, vital sign data will be obtained from the 
final visit of the previous pediatric BRV study 
and should not be recorded in the eCRF for 
N01266.  
Vital signs, including measurements of blood 
pressure, supine or sitting pulse rate, and body 
temperature, will be performed after 5 minutes of 
rest. 
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redundancy. 
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Section 9.3.3 
(Section 9.6.3 of 
Amendment 4) 
Header: Body weight and height 
Body weight (subject wearing light clothing 
without shoes) will be measured at the ScrV, 
TV(s), and EV (directly enrolled subjects only), 
MEV, FEV, YEV, FV, and at the EDV and the 
SV in the case of early discontinuation. For 
LTFU subjects, at the EV, body weight will be 
obtained from the final visit and height data will 
be obtained from Baseline of the previous 
pediatric BRV study and should not be recorded 
in the eCRF for N01266. 
Body height will be recorded at the ScrV 
(directly enrolled subjects only), MEV, FEV, 
YEV, FV, and at the EDV and the SV in the 
case of early discontinuation. 
Header: Body weight, height, and head 
circumference 
Body weight (subject wearing light clothing 
without shoes), height (length may be used for 
this measure, as appropriate), and head 
circumference (occipital-frontal circumference) 
will be measured. 
Remove information 
provided in 
Section 5.2 to 
decrease 
redundancy. 
Add information 
pertaining to the 
measurement of 
head circumference 
(in Amendment 4 
this measurement 
was included in the 
neurological 
examination). 
Section 9.3.4 
(Section 9.6.4 in 
Amendment 4) 
A standard physical examination will be 
performed at the ScrV and EV (directly enrolled 
subjects only), FEV, YEV, FV, and at the EDV 
and the SV in the case of early discontinuation. 
For LTFU subjects, at the EV, physical 
examination data will be obtained from the final 
visit of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266.  
A standard physical examination will be 
performed.  
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provided in 
Section 5.2 to 
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redundancy. 
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Section 9.3.5 
(Section 9.6.5 of 
Amendment 4) 
A standard neurological examination will be 
performed at the ScrV and EV (directly enrolled 
subjects only), FEV, YEV, FV, and at the EDV 
and the SV in the case of early discontinuation. 
For LTFU subjects, at the EV, neurological 
examination data will be obtained from the final 
visit of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266. 
The neurological examination will include a 
measurement of the head size (occipital-frontal 
circumference). Clinically significant new or 
worsened abnormalities must be reported as 
AEs. 
A standard neurological examination will be 
performed.  Clinically significant new or 
worsened abnormalities in the neurological 
examination must be reported as AEs. 
Remove information 
provided in 
Section 5.2 to 
decrease 
redundancy. 
Remove head 
circumference from 
this section with 
inclusion in 
Section 9.3.3. 
Section 9.3.6 
(Section 9.6.6 of 
Amendment 4)  
Psychiatric and mental status will be reported by 
recording the presence or absence of psychiatric 
symptoms, mental impairment, and behavioral 
problems at the ScrV and EV (directly enrolled 
subjects only), FEV, YEV, FV, and at the EDV 
and the SV in the case of early discontinuation. 
For LTFU subjects, at the EV, psychiatric and 
mental status data will be obtained from the 
final visit of the previous pediatric BRV study 
and should not be recorded in the eCRF for 
N01266. 
Psychiatric and mental status will be reported by 
recording the presence or absence of psychiatric 
symptoms, mental impairment, and behavioral 
problems.  
 
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Section 9.3.7 
(Section 9.6.7 of 
Amendment 4) 
Not applicable. 
The C-SSRS is not validated for subjects <6 years 
of age and will not be used for this population. 
Subjects should be monitored for any changes in 
mood, ideas, or behavior for warning signs of 
depression. The Investigator should be aware of 
common warning signs that might be a signal for 
risk of depression. For common signs and 
symptoms of depression in children younger than 
6 years old, reference should be made to the 
current version of the Diagnostic and Statistical 
Manual of Mental Disorders. Parents and 
caregivers should also be advised accordingly and 
effort should be made at clinic visits to 
specifically assess potential depression. 
Update to Sponsor 
template. 
Section 9.3.8 
(Section 9.6.8 of 
Amendment 4) 
The BRIEF-P/BRIEF will be completed at the 
ScrV (directly enrolled subjects only), FEV, 
YEV, FV, and the EDV in the case of early 
discontinuation. For LTFU subjects, at the EV, 
the BRIEF-P/BRIEF score will be obtained 
from Baseline of the previous pediatric BRV 
study and should not be recorded in the eCRF 
for N01266. For directly enrolled subjects, the 
Baseline BRIEF-P/BRIEF should be completed 
at the ScrV. 
The BRIEF-P or BRIEF appropriate for each 
subject’s age should be completed, with the 
following exception: For subjects who 
completed the BRIEF-P at the Baseline 
assessment and turn 5 years of age between that 
assessment and the initial YEV, the BRIEF-P 
should be completed through and including the 
initial YEV, and subsequently the BRIEF 
should be completed. 
Deleted. 
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redundancy. 
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Section 10 
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Section 10  
The EEG data will be reviewed by 3-month 
periods for the first 6 months and yearly 
thereafter. 
The EEG data will be reviewed at 6 months and 
yearly thereafter. 
Revise in accordance 
with EEG timing. 
Section 10.2 
At the EV, seizure data based on an EEG of at 
least 24 hours of recording (including sleeping 
and awakening periods) for subjects <2 years of 
age and data on absence seizure count (based on 
an EEG of at least 1 hour of recording for 
subjects ≥2 years of age suffering from 
absences) will be obtained from the final visit of 
the previous pediatric BRVstudy and should not 
be recorded in the eCRF for N01266. 
The EEGs will be performed according to the 
following specifications: 
• 
For subjects ≥2 years of age on the day of 
the study visit and with typical absence 
seizures: an EEG of at least 1 hour of 
recording (including hyperventilation and 
intermittent photic stimulation) will be 
performed starting at V4 and at every 
3-month visit for the first 6 months and then 
yearly thereafter. For subjects prematurely 
discontinuing from the study, an EEG of at 
least 1 hour of recording should also be 
performed at the EDV. 
• 
For subjects ≥1 month to <2 years of age on 
the day of the study visit: an EEG of at least 
Deleted. 
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24 hours of recording (including sleeping 
and awakening periods) will be performed 
every 3 months during the first 6 months of 
the study, then yearly thereafter, and at the 
FV or the EDV in the case of early 
discontinuation. 
Section 10.3 
Not applicable. 
Other assessments will be performed at the visits 
indicated in Table 5-1, Table 5-2, and Table 5-3.  
Provide navigational 
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Section 10.3.1.1 
Concomitant medication information will be 
collected and recorded in the eCRF at the 
following visits: ScrV and TV(s) (directly 
enrolled subjects only), EV, MEV, FEV, YEV, 
UV, FV, and at the EDV, DTV, and the SV in 
the case of early discontinuation.  
For LTFU subjects, any ongoing medications 
(including AEDs and non-AEDs) at the time the 
subject completed the core study should not be 
recorded in the eCRF for N01266, unless there 
is a change regarding the administration of the 
medication. 
Concomitant medication information will be 
collected and recorded.  
For LTFU subjects, any ongoing medications 
(including AEDs and non-AEDs) at the time the 
subject completed the core study should not be 
recorded in the N01266 eCRF. Changes in 
ongoing concomitant medications should be 
recorded in the N01266 eCRF. 
 
Remove information 
provided in 
Section 5.2 to 
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redundancy. 
Provide 
intradocument 
consistency for “core 
study” terminology. 
 
Section 10.3.1.2 
Medical procedures will be recorded at the 
following visits: ScrV and TV(s) (directly 
enrolled subjects only), EV, MEV, FEV, YEV, 
UV, FV, and at the EDV, DTV, and the SV in 
the case of early discontinuation. 
Deleted. 
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Section 5.2 to 
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Section 10.3.1.3 
At the TV(s) and EV (directly enrolled subjects 
only), MEV, FEV, YEV, UV, FV, and at the 
EDV, DTV, and the SV in the case of early 
discontinuation, health care provider 
consultations not foreseen by the protocol will 
be recorded in the eCRF.  
For LTFU subjects, at the EV, information on 
the health care provider consultations not 
foreseen by the protocol will be obtained from 
the final visit of the previous pediatric BRV 
study and should not be recorded in the eCRF 
for N01266.  
Data collected for health care provider 
consultations not foreseen by the protocol will 
include the type of provider (general practitioner, 
specialist physician, nurse), the site of care 
(office-private, office-hospital, home, emergency 
room), and the reason leading to the consultation.  
 
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Section 5.2 to 
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Section 10.3.1.4 
During the TV(s) and EV (directly enrolled 
subjects only, MEV, FEV, YEV, UV, FV, and 
at the EDV, DTV, and the SV in the case of 
early discontinuation, data on hospital stays will 
be collected in the eCRF. It will include the 
reason leading to the hospitalization, the 
admission ward, transfers, and length of stay. 
For LTFU subjects, at the EV, information on 
hospital stays will be obtained from the final 
visit of the previous pediatric BRV study and 
should not be recorded in the eCRF for N01266.  
Data collected for hospital stays will include the 
reason leading to the hospitalization, the 
admission ward, transfers, and length of stay. 
Remove information 
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Section 5.2 to 
decrease 
redundancy. 
Section 10.3.2 
The Bayley-III scales are recognized 
internationally as one of the most 
comprehensive developmental assessment 
instruments (Sattler and Hoge, 2006) used to 
examine the major facets of a young child’s 
development (Bayley, 2006). 
This scale is validated as a tool for assessment 
of neurological development in young children 
and is therefore considered appropriate for 
The Bayley-III scales are validated as a tool for 
assessment of neurological development in young 
children and recognized internationally as one of 
the most comprehensive developmental 
assessment instruments (Sattler and Hoge, 2006) 
used to examine the major facets of a young 
child’s development (Bayley, 2006). 
Children started on the Bayley-III scales at 
Baseline of the core study will also be assessed 
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N01266. The same scale has been completed by 
the Investigator or designee at Baseline (V1) of 
N01263 for children from 1 month to 
<18 months of age at Baseline enrolled in 
English-speaking countries. Children started on 
the Bayley-III scales at Baseline of N01263 will 
also be assessed using the Bayley-III scales in 
N01266 even if their age increases to ≥18 
months. Bayley-III scale assessments are not 
applicable to directly enrolled subjects due to 
age-based considerations. 
At the EV, the Bayley-III scales will be 
obtained from Baseline of the previous pediatric 
BRV study if the subject was enrolled in an 
English-speaking country, and data should not 
be recorded in the eCRF in N01266. The 
Bayley-III scales will be completed at the FEV, 
YEV, FV, and at the EDV in the case of early 
discontinuation. The Bayley-III scales should be 
completed by the same person who completed 
the Bayley-III scales in the previous pediatric 
BRV study. 
At the EV, the Bayley-III scales will be 
obtained from Baseline of the previous pediatric 
BRV study if the subject was enrolled in an 
English-speaking country, and data should not 
be recorded in the eCRF in N01266. The 
Bayley-III scales will be completed at the FEV, 
YEV, FV, and at the EDV in the case of early 
discontinuation. The Bayley-III scales should be 
completed by the same person who completed 
the Bayley-III scales in the previous pediatric 
using the Bayley-III scales in N01266 (if possible, 
by the same person who completed the scales in 
the core study) even if their age increases to ≥18 
months. Bayley-III scale assessments are not 
applicable to directly enrolled subjects due to 
age-based considerations. 
The Bayley-III scales will be applied to subjects 
as described in Table 5-1 and Table 5-2. The 
Bayley-III scale is not applicable to directly 
enrolled subjects due the age of these subjects (≥4 
years of age) at entry into N01266. 
 
redundancy. 
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study” terminology. 
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BRV study. 
Section 10.3.3 
The Achenbach CBCL should be completed by 
the same parent(s)/legal representative(s) who 
completed the CBCL in the previous pediatric 
BRV study. The completion of the Achenbach 
CBCL will require approximately 45 minutes.  
The Achenbach CBCL will be completed at the 
ScrV (directly enrolled subjects only), FEV, 
YEV, FV, and at the EDV in the case of early 
discontinuation. For LTFU subjects, at the EV, 
the Achenbach CBCL score will be obtained 
from Baseline of the previous pediatric BRV 
study and should not be recorded in the eCRF 
for N01266.  
The Achenbach CBCL should be completed by 
the same parent(s)/legal representative(s) who 
completed the CBCL in the core study, when 
possible. The completion of the Achenbach CBCL 
will require approximately 45 minutes.  
 
Provide 
intradocument 
consistency for “core 
study” terminology. 
Remove information 
provided in 
Section 5.2 to 
decrease 
redundancy. 
Clarify that CBCL is 
to be completed by 
same person if 
possible. 
Section 10.3.5 
The PedsQL will be completed at the ScrV 
(directly enrolled subjects only), FEV, YEV, 
FV, and the EDV in the case of early 
discontinuation. For LTFU subjects, at the EV, 
the PedsQL score will be obtained from 
Baseline of the previous pediatric BRV study 
and will not be recorded in the eCRF in 
N01266. For directly enrolled subjects, the 
Baseline PedsQL will be completed at the ScrV. 
Deleted.  
Remove information 
provided in 
Section 5.2 to 
decrease 
redundancy. 
 
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Section 11 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 11.2.1 
Not applicable. 
Photocopies and/or printouts of eCRFs are not 
considered acceptable source documents. 
Update to Sponsor 
template. 
Section 11.3.1 
This study will be performed using remote data 
capture. 
This study will be performed using electronic data 
capture. 
Update to Sponsor 
template. 
Section 11.5 
The Investigator will also notify UCB should 
he/she relocate or move the study-related files to 
a location other than that specified in the 
Sponsor’s study master file. 
The Investigator will also notify UCB should 
he/she relocate or move the study-related files to a 
location other than that specified in the Sponsor’s 
trial master file. 
Update to Sponsor 
template. 
 
Section 12 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 12.2 
Not applicable. 
Analyses may also be summarized for direct 
enrollers, as well as by core study (eg, 
EP0065 and N01349). 
Provide additional 
information about 
possible data 
summaries. 
Section 12.5 
The Achenbach CBCL, the Bayley-III scores 
(LTFU subjects only), BRIEF-P/BRIEF, 
PedsQL, and change from Baseline scores 
(previous BRV study for LTFU subjects and 
ScrV for directly enrolled subjects) will be 
analyzed in a descriptive manner. 
The Achenbach CBCL, the Bayley-III scores 
(LTFU subjects only), BRIEF-P/BRIEF, PedsQL, 
and change from Baseline scores (core study for 
LTFU subjects and ScrV for directly enrolled 
subjects) will be analyzed in a descriptive manner. 
 
Provide 
intradocument 
consistency for “core 
study” terminology. 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 12.9 
The original number was based upon the 
assumption that 90% of the subjects having 
completed a previous pediatric study with BRV 
as adjunctive treatment in epilepsy will rollover 
into the present study. With Protocol 
Amendment 3, enrollment was expanded to 
include up to 100 directly enrolled subjects 
(≥4 years to <17 years of age) with POS, thus 
increasing possible enrollment up to 
600 subjects. With Protocol Amendment 4, the 
number of directly enrolled subjects is increased 
to at least 100 subjects with the planned total 
enrollment of approximately 600 subjects. 
The original number was based upon the 
assumption that 90% of the subjects having 
completed a core study will rollover into the 
present study. Planned enrollment now includes 
approximately 600 subjects, including at least 100 
directly enrolled subjects, with no change in the 
assumption regarding core study completion. 
Update to provide 
clarity regarding 
current design with 
no change to sample 
size. 
Provide clarity 
regarding definition 
of “core study.” 
 
Section 13 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 13.1 
Prior to participation in the study, the written 
Informed Consent form should be signed and 
personally dated by the subject’s parent(s)/legal 
representative(s), and by the person who 
conducted the informed consent discussion 
(Investigator [or designee]). 
Prior to participation in the study, the Informed 
Consent form should be signed and personally 
dated by the subject’s parent(s)/legal 
representative(s), and by the person who 
conducted the informed consent discussion 
(Investigator [or designee]). 
Update to Sponsor 
template. 
 
Section 15 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 15 
Dulac O. Epilepsy in children. Curr Opin 
Neurol. 1994;7:102-6. 
Engel J, Pedley TA. Epilepsy: a comprehensive 
textbook. Philadelphia: Lippincott-Raven; 1998. 
Ngugi AK, Kariuki SM, Bottomley C, 
Kleinschmidt I, Sander JW, Newton CR. 
Incidence of epilepsy: a systematic review and 
meta-analysis. Neurology. 2011; 77(10): 1005–12. 
Update of references 
cited in text. 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
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. 
Perucca E. Established antiepileptic drugs. 
Baillieres Clin Neurol. 1996;5:693-722. 
Sander JW, Shorvon SD. Epidemiology of the 
epilepsies. J Neurol Neurosurg Psychiatry. 
1996;61:433-43. 
 
 
Section 18 
Section Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 18 
Not applicable. 
Header: 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. 
Update to Sponsor 
template. 
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Specific changes to tables in Section 5: 
With Amendment 5, Amendment 4 Table 5-1 (see below) was divided into 2 tables (Table 5-1 
and Table 5-2) in order to include all Entry Visits in one table (Table 5-1) and subsequent visits 
in another table (Table 5-2). With this change, the Entry Visits in Amendment 4 Table 5-1 were 
retained in Table 5-1 and the remaining contents of Amendment 4 Table 5-1 (with exceptions 
noted below) were included in Table 5-2. The rationales for the changes are noted in the table 
above.  
Amendment 4 Table 5-1 is provided below for reference. 
 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Written informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
Subject identification 
card dispensing 
X 
 
 
 
 
 
 
 
 
Childbearing potential  
X 
X 
X 
X 
X 
 
X 
 
 
Verification 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Physical and 
neurological 
examinations 
Xa 
X 
 
X 
X 
 
X 
 
X 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Psychiatric and mental 
status 
Xa 
X 
 
X 
X 
 
X 
 
X 
Vital signsd 
Xa 
X 
X 
X 
X 
 
X 
X 
X 
Body weight and 
height 
Xa 
X 
X 
X 
X 
 
X 
 
X 
ECGe 
Xa 
X 
 
 
X 
 
X 
 
Xf 
EEGg 
Xa 
 
X 
X 
X 
 
X 
 
 
DRC dispensed 
X 
X 
X 
X 
Xh 
 
X 
X 
 
DRC retrieved 
 
X 
X 
X 
X 
 
X 
X 
X 
Seizure count  
Xa 
X 
X 
X 
X 
 
X 
X 
X 
Assessment of seizure 
typesi 
 
 
 
X 
X 
 
 
 
 
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Clinical Study Protocol 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Recording of 
medicationsj 
Xa  
X 
X 
X 
X 
X 
X 
X 
X 
Recording of 
procedures 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Recording of AEsk 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
IVRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensed 
X 
X 
X 
X 
Xh 
 
X 
 
 
Study drug returnedl 
 
X 
X 
X 
X 
 
X 
X 
 
Study drug compliance 
 
X 
X 
X 
X 
 
X 
X 
 
Laboratory 
assessments for 
safetym 
Xa 
X 
Xn 
X 
X 
 
X 
 
Xf 
BRV plasma 
concentrationso 
 
 
 
X 
X 
 
X 
 
 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
Phenytoin plasma 
concentrations, if 
applicable 
Xa 
 
 
X 
X 
 
X 
 
Xf 
C-SSRSp 
Xa 
X 
X 
X 
X 
 
X 
X 
X 
Bayley-III scalesq 
 
 
 
X 
X 
 
X 
 
 
Achenbach CBCLr 
 
 
 
X 
X 
 
X 
 
 
BRIEF-P/BRIEFs 
 
 
 
X 
X 
 
X 
 
 
PedsQLt 
 
 
 
X 
X 
 
X 
 
 
Health care provider 
consultations not 
foreseen by protocol 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Hospital staysu 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
End of study status 
 
 
 
 
Xv 
 
 
 
X 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
AE=adverse event; AED=antiepileptic drug; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
Bayley-III=Bayley Scales of Infant and Toddler Development, Third Edition; BRIEF=Behavior Rating Inventory of Executive Function; BRIEF-P=Behavior 
Rating Inventory of Executive Function-Preschool Version; BRV=brivaracetam; CBCL=Child Behavior Checklist; C-SSRS=Columbia-Suicide Severity 
Rating Scale; DE=directly enrolled; DRC=daily record card; DTV=Down-Titration Visit; ECG=electrocardiogram; eCRF=electronic case report form; 
EDV=Early Discontinuation Visit; EEG=electroencephalogram; EV=Entry Visit; FEV= Full Evaluation Visit; FV=Final Visit; 
GGT=gamma-glutamyltransferase; IVRS=interactive voice response system; LTFU=long-term follow-up; M=Month; MEV=Minimal Evaluation Visit; 
PedsQL=Pediatric Quality of Life Inventory; SAE=serious adverse event; SV=Safety Visit; TV=Titration Visit; UV=Unscheduled Visit; V=Visit; 
YEV=Yearly Evaluation Visit 
a For LTFU subjects, the following data will be obtained from Baseline of the previous pediatric BRV study and should not be recorded on the eCRF for 
N01266: general medical and procedure history, epilepsy history, AED history, height, Bayley-III scales, the Achenbach CBCL, BRIEF-P/BRIEF, and 
PedsQL scores. The following data will be obtained from the final visit of the previous pediatric BRV study and should not be recorded in the eCRF for 
N01266: AEs, recording of medications, recording of procedures, seizure count, EEG, ECG, laboratory assessments for safety, including phenytoin plasma 
concentrations (if applicable), the C-SSRS, vital signs, body weight, physical and neurological examinations, psychiatric and mental status, and data on 
health care provider consultations not foreseen by the protocol and hospital stays. The EV is also the final evaluation visit of the previous pediatric BRV 
study. 
b For subjects staying in the study until it ends, the same procedures as for a YEV should be performed at the subject’s FV. 
c Visit should be scheduled at the end of the Down-Titration Period. The duration of the Down-Titration Period will depend on when the final dose of the 
study drug was taken during the Evaluation Period, with a maximum duration of 4 weeks. 
d Vital sign measurements include blood pressure, pulse rate, and body temperature.  
e An ECG has to be scheduled once a year at the YEV and at the EDV in the case of early discontinuation. 
f At the SV, ECGs, laboratory assessments for safety, and determination of phenytoin plasma concentration will be performed only if abnormal at the EDV. 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
g EEG (for LTFU subjects only) 
• 
For subjects ≥2 years of age on the day of the study visit and with typical absence seizures: every 3 months during the first 6 months (starting at V4), 
and then yearly thereafter: an EEG of at least 1 hour of recording including hyperventilation and intermittent photic stimulation must be performed 
for efficacy assessment. For subjects prematurely discontinuing from the study, an EEG of at least 1 hour of recording should also be performed at 
the EDV. 
• 
For subjects ≥1 month to <2 years of age on the day of the study visit: every 3 months during the first 6 months (starting at V4), then yearly 
thereafter: an EEG of at least 24 hours of recording including sleeping and awakening periods must be performed for efficacy assessment. For 
subjects prematurely discontinuing from the study, an EEG of at least 24 hours of recording should also be performed at the EDV. 
h No DRC or study drug will be dispensed at the FV. 
i The assessment of seizure types will be done at 6-monthly intervals (at the FEV and the YEV) for subjects <2 years of age. 
j For LTFU subjects, any ongoing medications (including AEDs and non-AEDs) at the time the subject completed the previous pediatric BRV study should 
not be recorded in the eCRF for N01266, unless there is a change regarding the administration of the medication. In this event, the start date corresponding 
to the date of change in administration should be recorded in the eCRF. 
k For LTFU subjects, any ongoing AEs at the time the subject completed the previous pediatric BRV study should not be recorded on the eCRF for N01266, 
unless there is a change in intensity or seriousness. In this event, the AE should be recorded in the eCRF for N01266, with the onset date corresponding to 
the date of change in condition. 
l Drug return includes study medication intake recording and accountability. 
m Full laboratory assessments for safety include hematology, biochemistry (including hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), and 
endocrinology for all subjects and urinalysis for subjects ≥4 years of age as described in Section 9.5.1. Female subjects with a Tanner stage >1 should have 
a urine pregnancy test performed at all laboratory assessment visits, except for the EDV and the SV, when a serum pregnancy test will be performed. 
Endocrinology testing will be performed at the YEV/FV.  
n Laboratory assessments are to be done only at the MEV at V4 (M3) and V6 (M9) and are to include only hepatic monitoring (ALT, AST, ALP, total 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
bilirubin, and GGT). 
o In addition to the scheduled assessments, a pharmacokinetic sample for determination of BRV plasma concentration should be taken whenever a subject 
experiences an SAE. 
p The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” version of the C-SSRS will be used, with the following exception: If a 
subject turns 6 years of age during N01266, the “Already Enrolled” version of the C-SSRS should be completed at the first visit after the sixth birthday, and 
the “Since Last Visit” version of the C-SSRS should be completed at subsequent visits.  
q The cognition scale (Bayley-III) to be used in N01266 for subjects <18 months to 42 months of age and enrolled in English-speaking countries will be the 
same as the one used in the previous pediatric BRV study. If the subject reaches 18 months of age in this study, the subject will still be assessed using the 
Bayley-III to allow for an evaluation of the change from Baseline even if his/her age increases to ≥18 months. 
r The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) should be in accordance with the subject’s age, with the following exception: If a 
subject completed the Achenbach CBCL/1½-5 at the Baseline assessment (previous pediatric BRV study for LTFU subjects and ScrV for directly enrolled 
subjects) and turns 6 years of age between that assessment and the initial YEV, the CBCL/1½-5 should be completed through and including the initial 
YEV, and subsequently the CBCL/6-18 should be completed.  
s The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF should be used for subjects ≥5 years of age, with the following 
exception: For subjects who completed the BRIEF-P at the Baseline assessment (previous pediatric BRV study for LTFU subjects and ScrV for directly 
enrolled subjects) and turn 5 years of age between that assessment and the initial YEV, the BRIEF-P should be completed through and including the initial 
YEV, and subsequently the BRIEF should be completed. 
t The version of the PedsQL used should be consistent with the subject’s age at each visit when it is administered with the following exception: If a subject 
ages up to the next PedsQL between the Baseline assessment (previous pediatric BRV study for LTFU subjects and ScrV for directly enrolled subjects) and 
the initial YEV, the PedsQL that was used at the Baseline assessment should be completed through and including the initial YEV, and subsequently the 
PedsQL consistent with the age at the time of assessment should be completed. 
u This refers to any hospital stay that occurs during the study. Data recorded in the eCRF include the reason for the hospitalization, the admission ward, 
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Amendment 4 Table 5-1: Schedule of all study assessments for LTFU subjects and assessments subsequent 
to the final TV for directly enrolled subjects  
Period 
Evaluation 
Down-
Titration 
Safety 
 (Drug-
free) 
Visit 
Entry Visit 
Minimal 
Evaluation 
Visit 
Full 
Evaluation 
Visit 
Yearly 
Evaluation 
Visit/Final 
Visit 
Unscheduled 
Visit 
Early 
Discontinuation 
Visit 
Down-
Titration 
Visit 
Safety 
Visit 
(EV) 
(MEV) 
(FEV) 
(YEV/FVb) 
(UV) 
(EDV) 
(DTV)c 
(SV) 
Subjects 
LTFUa 
DE 
 
 
All 
 
 
 
 
Assessment 
 
transfers, and length of stay. 
v End of study status only for subjects who continue in the study until it ends and for whom the visit corresponds to the final evaluation visit or FV.  
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Table 5-1: 
Change 1: 
The title: 
Schedule of all study assessments for LTFU subjects and assessments subsequent to the 
final TV for directly enrolled subjects 
Was changed to: 
Schedule of assessments for the Entry Visit (EV) (all subjects) 
Change 2: 
Entry Visit assessments for subjects from core studies EP0065 and N01349 were added (see 
Table 5-1 for display of assessments added).  
Change 3: 
The following rows were added: 
• General medical history 
• Procedure history 
• Epilepsy history 
• AED history 
• Head circumference 
Change 4: 
The following rows were deleted: 
• Assessment of seizure types 
• BRV plasma concentrations 
• End of study status 
Change 5:  
The following row entries were split into separate rows as follows: 
• Written informed consent/assent 
Split and revised to: 
− Written informed consent 
− Assent form (if applicable, according to age and local requirements) 
• Body weight and height 
Split into: 
− Body weight 
− Height  
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Change 6:  
The following footnote was deleted: 
a For LTFU subjects, the following data will be obtained from Baseline of the previous 
pediatric BRV study and should not be recorded on the eCRF for N01266: general 
medical and procedure history, epilepsy history, AED history, height, Bayley-III scales, 
the Achenbach CBCL, BRIEF-P/BRIEF, and PedsQL scores. The following data will be 
obtained from the final visit of the previous pediatric BRV study and should not be 
recorded in the eCRF for N01266: AEs, recording of medications, recording of 
procedures, seizure count, EEG, ECG, laboratory assessments for safety, including 
phenytoin plasma concentrations (if applicable), the C-SSRS, vital signs, body weight, 
physical and neurological examinations, psychiatric and mental status, and data on health 
care provider consultations not foreseen by the protocol and hospital stays. The EV is also 
the final evaluation visit of the previous pediatric BRV study. 
And replaced with the following: 
a “Other” core studies include those other than EP0065 and N01349. 
b To be obtained from the final visit of the core study and not recorded in the N01266 
eCRF.   
c To be obtained from baseline of the core study and not recorded in the N01266 eCRF. 
Change 7:  
The following footnotes were deleted: 
e An ECG has to be scheduled once a year at the YEV and at the EDV in the case of early 
discontinuation. 
f At the SV, ECGs, laboratory assessments for safety, and determination of phenytoin 
plasma concentration will be performed only if abnormal at the EDV. 
g EEG (for LTFU subjects only) 
• For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: every 3 months during the first 6 months (starting at V4), and then yearly 
thereafter: an EEG of at least 1 hour of recording including hyperventilation and 
intermittent photic stimulation must be performed for efficacy assessment. For subjects 
prematurely discontinuing from the study, an EEG of at least 1 hour of recording should 
also be performed at the EDV. 
• For subjects ≥1 month to <2 years of age on the day of the study visit: every 3 months 
during the first 6 months (starting at V4), then yearly thereafter: an EEG of at least 
24 hours of recording including sleeping and awakening periods must be performed for 
efficacy assessment. For subjects prematurely discontinuing from the study, an EEG of 
at least 24 hours of recording should also be performed at the EDV. 
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And replaced with the following: 
f Any ongoing AEs at the time the subject completed the core study should not be recorded 
in the N01266 eCRF. Worsening of the AE should be recorded in the N01266 eCRF as a 
new AE. A pharmacokinetic sample for determination of BRV plasma concentration 
should be taken whenever a subject experiences an SAE. 
g Drug return includes study medication intake recording and accountability. 
Change 8:  
The following footnotes were deleted: 
h No DRC or study drug will be dispensed at the FV. 
i The assessment of seizure types will be done at 6-monthly intervals (at the FEV and the 
YEV) for subjects <2 years of age. 
Change 9:  
The following footnotes: 
j For LTFU subjects, any ongoing medications (including AEDs and non-AEDs) at the 
time the subject completed the previous pediatric BRV study should not be recorded in 
the eCRF for N01266, unless there is a change regarding the administration of the 
medication. In this event, the start date corresponding to the date of change in 
administration should be recorded in the eCRF. 
k For LTFU subjects, any ongoing AEs at the time the subject completed the previous 
pediatric BRV study should not be recorded on the eCRF for N01266, unless there is a 
change in intensity or seriousness. In this event, the AE should be recorded in the eCRF 
for N01266, with the onset date corresponding to the date of change in condition. 
Were replaced with the following as shown in Change #7): 
e Any ongoing concomitant medications at the time the subject completed the core study 
should not be recorded in the N01266 eCRF. Changes in ongoing concomitant 
medications should be recorded in the N01266 eCRF. 
f Any ongoing AEs at the time the subject completed the core study should not be recorded 
on the N01266 eCRF. Worsening of the AE should be recorded in the N01266 eCRF as a 
new AE. A pharmacokinetic sample for determination of BRV plasma concentration 
should be taken whenever a subject experiences an SAE. 
Change 10:  
The following footnote was relettered to “g”: 
l Drug return includes study medication intake recording and accountability. 
Change 11: 
The following footnote: 
m Full laboratory assessments for safety include hematology, biochemistry (including 
hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), and endocrinology for 
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all subjects and urinalysis for subjects ≥4 years of age as described in Section 9.5.1. 
Female subjects with a Tanner stage >1 should have a urine pregnancy test performed at 
all laboratory assessment visits, except for the EDV and the SV, when a serum pregnancy 
test will be performed. Endocrinology testing will be performed at the YEV/FV.  
Was replaced with: 
h Full laboratory assessments for safety include hematology and biochemistry (including 
hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT) for all subjects, 
endocrinology for LTFU subjects, and urinalysis for all subjects for whom sample 
collection is feasible as described in Section 9.2.1. Female subjects of childbearing 
potential will have a urine pregnancy test done at the site.  
Change 12: 
The following footnotes were deleted: 
n Laboratory assessments are to be done only at the MEV at V4 (M3) and V6 (M9) and are 
to include only hepatic monitoring (ALT, AST, ALP, total bilirubin, and GGT). 
o In addition to the scheduled assessments, a pharmacokinetic sample for determination of 
BRV plasma concentration should be taken whenever a subject experiences an SAE. 
Change 13: 
The following footnotes: 
p The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” 
version of the C-SSRS will be used, with the following exception: If a subject turns 
6 years of age during N01266, the “Already Enrolled” version of the C-SSRS should be 
completed at the first visit after the sixth birthday, and the “Since Last Visit” version of 
the C-SSRS should be completed at subsequent visits.  
q The cognition scale (Bayley-III) to be used in N01266 for subjects <18 months to 42 
months of age and enrolled in English-speaking countries will be the same as the one 
used in the previous pediatric BRV study. If the subject reaches 18 months of age in this 
study, the subject will still be assessed using the Bayley-III to allow for an evaluation of 
the change from Baseline even if his/her age increases to ≥18 months. 
r The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) should be in 
accordance with the subject’s age, with the following exception: If a subject completed 
the Achenbach CBCL/1½-5 at the Baseline assessment (previous pediatric BRV study for 
LTFU subjects and ScrV for directly enrolled subjects) and turns 6 years of age between 
that assessment and the initial YEV, the CBCL/1½-5 should be completed through and 
including the initial YEV, and subsequently the CBCL/6-18 should be completed.  
s The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF 
should be used for subjects ≥5 years of age, with the following exception: For subjects 
who completed the BRIEF-P at the Baseline assessment (previous pediatric BRV study 
for LTFU subjects and ScrV for directly enrolled subjects) and turn 5 years of age 
between that assessment and the initial YEV, the BRIEF-P should be completed through 
and including the initial YEV, and subsequently the BRIEF should be completed. 
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t The version of the PedsQL used should be consistent with the subject’s age at each visit 
when it is administered with the following exception: If a subject ages up to the next 
PedsQL between the Baseline assessment (previous pediatric BRV study for LTFU 
subjects and ScrV for directly enrolled subjects) and the initial YEV, the PedsQL that was 
used at the Baseline assessment should be completed through and including the initial 
YEV, and subsequently the PedsQL consistent with the age at the time of assessment 
should be completed. 
Were revised as follows: 
i The C-SSRS will be administered to subjects ≥6 years of age. The “Since Last Visit” 
version of the C-SSRS will be used. If a subject turns 6 years of age during the study, the 
“Already Enrolled” version of the C SSRS should be completed at the first visit after the 
sixth birthday. 
j The Bayley-III is applicable to subjects enrolled in English-speaking countries only and 
as follows: 
• Core study N01349: all subjects  
• Core study EP0065: subjects <18 months of age at baseline (Screening)  
• Other core studies: subjects <18 months of age at baseline for the core study (as 
indicated in footnote c).  
k The version of the Achenbach CBCL (CBCL/1½-5 or CBCL/6-18) should be in 
accordance with the subject’s age. 
l The BRIEF-P should be used for subjects ≥2 years to <5 years of age and the BRIEF 
should be used for subjects ≥5 years of age. 
m The version of the PedsQL used should be consistent with the subject’s age. 
Change 14: 
The following footnotes were deleted: 
u This refers to any hospital stay that occurs during the study. Data recorded in the eCRF 
include the reason for the hospitalization, the admission ward, transfers, and length of 
stay. 
v End of study status only for subjects who continue in the study until it ends and for whom 
the visit corresponds to the final evaluation visit or FV. 
Table 5-2:  
Change 1: 
The title was updated to: 
Schedule of all study assessments for the Evaluation, Down-Titration, and Safety 
(Drug-Free) Periods (all subjects) 
Change 2: 
The row containing “Subjects” and “All” was removed.  
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Change 3: 
The following entries and associated assessment times were removed (with retention of 
information in Table 5-1): 
• Written informed consent/assent 
• Subject identification card dispensing 
• Verification inclusion/exclusion criteria 
• Demographic data 
Change 4: 
The Entry Visit columns were removed (with retention of information to Table 5-1) 
Change 5: 
The following entry: 
Body weight and height 
Was changed to: 
Body weight, height, and head circumference 
Change 6: 
The X for the EEG assessment was removed from the MEV column. 
Change 7: 
An Xp was added for the Unscheduled Visit for the C-SSRS. 
Change 8: 
The following footnote was removed and subsequent footnotes relettered accordingly (both 
below and within the table):  
a For LTFU subjects, the following data will be obtained from Baseline of the previous 
pediatric BRV study and should not be recorded on the eCRF for N01266: general 
medical and procedure history, epilepsy history, AED history, height, Bayley-III scales, 
the Achenbach CBCL, BRIEF-P/BRIEF, and PedsQL scores. The following data will be 
obtained from the final visit of the previous pediatric BRV study and should not be 
recorded in the eCRF for N01266: AEs, recording of medications, recording of 
procedures, seizure count, EEG, ECG, laboratory assessments for safety, including 
phenytoin plasma concentrations (if applicable), the C-SSRS, vital signs, body weight, 
physical and neurological examinations, psychiatric and mental status, and data on health 
care provider consultations not foreseen by the protocol and hospital stays. The EV is also 
the final evaluation visit of the previous pediatric BRV study. 
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Change 9: 
The following footnote: 
g EEG (for LTFU subjects only) 
• For subjects ≥2 years of age on the day of the study visit and with typical absence 
seizures: every 3 months during the first 6 months (starting at V4), and then yearly 
thereafter: an EEG of at least 1 hour of recording including hyperventilation and 
intermittent photic stimulation must be performed for efficacy assessment. For subjects 
prematurely discontinuing from the study, an EEG of at least 1 hour of recording should 
also be performed at the EDV. 
• For subjects ≥1 month to <2 years of age on the day of the study visit: every 3 months 
during the first 6 months (starting at V4), then yearly thereafter: an EEG of at least 
24 hours of recording including sleeping and awakening periods must be performed for 
efficacy assessment. For subjects prematurely discontinuing from the study, an EEG of 
at least 24 hours of recording should also be performed at the EDV. 
Was changed to: 
f EEG (for LTFU subjects only) 
• For subjects ≥2 years of age at V5 who have typical absence seizures, an EEG of at 
least 24 hours that includes hyperventilation and intermittent photic stimulation must be 
performed at V5 and yearly threafter. For subjects prematurely discontinuing from the 
study, a 24-hour EEG may be performed at the EDV at the Investigator’s discretion. 
• For subjects <2 years of age at V5, an EEG of at least 24 hours must be performed for 
efficacy assessment at V5 and yearly thereafter until subjects reach 2 years of age. For 
subjects prematurely discontinuing from the study, a 24-hour EEG may be performed at 
the EDV at the Investigator’s discretion. 
Change 10:  
The following footnote:  
j For LTFU subjects, any ongoing medications (including AEDs and non-AEDs) at the 
time the subject completed the previous pediatric BRV study should not be recorded in 
the eCRF for N01266, unless there is a change regarding the administration of the 
medication. In this event, the start date corresponding to the date of change in 
administration should be recorded in the eCRF. 
Was changed to: 
i For subjects enrolled in N01266 who volunteered to participate in EP0065 and then 
returned to N01266, changes to ongoing concomitant medications during EP0065 will be 
recorded in the N01266 eCRF. 
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Change 11: 
The following footnote: 
m Full laboratory assessments for safety include hematology, biochemistry (including 
hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), and endocrinology for 
all subjects and urinalysis for subjects ≥4 years of age as described in Section 9.5.1. 
Female subjects with a Tanner stage >1 should have a urine pregnancy test performed at 
all laboratory assessment visits, except for the EDV and the SV, when a serum pregnancy 
test will be performed. Endocrinology testing will be performed at the YEV/FV.  
Was changed to: 
l Full laboratory assessments for safety include hematology, biochemistry (including 
hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), and endocrinology for 
all subjects and urinalysis for subjects for whom sample collection is feasible as described 
in Section 9.2.1. Female subjects of childbearing potential should have a urine pregnancy 
test done at the site at all laboratory assessment visits. Endocrinology testing will be 
performed at the YEV/FV.  
Change 12: 
The following footnote: 
n Laboratory assessments are to be done only at the MEV at V4 (M3) and V6 (M9) and are 
to include only hepatic monitoring (ALT, AST, ALP, total bilirubin, and GGT). 
Was changed to: 
m Laboratory assessments (hepatic monitoring [ALT, AST, ALP, total bilirubin, and GGT 
only] are to be done only at the MEV at V4 (M3) and V6 (M9). Urine pregnancy tests are 
to be done at the site for female subjects of childbearing potential at all visits. 
Change 13: 
The following footnote was added: 
p If an unscheduled visit is conducted due to safety or efficacy reasons, the C-SSRS will be 
performed for subjects ≥6 year of age. 
Change 14: 
The following footnote: 
q The cognition scale (Bayley-III) to be used in N01266 for subjects <18 months to 42 
months of age and enrolled in English-speaking countries will be the same as the one 
used in the previous pediatric BRV study. If the subject reaches 18 months of age in this 
study, the subject will still be assessed using the Bayley-III to allow for an evaluation of 
the change from Baseline even if his/her age increases to ≥18 months. 
Was changed to: 
q The Bayley-III is applicable to subjects who meet all of the following criteria: are 
enrolled English-speaking countries, were <18 months of age at baseline of the core 
study, and are <42 months of age. 
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Table 5-3:  
With Amendment 5, the Amendment 4 Table 5-2 was renumbered to Table 5-3 and the 
following changes were made: 
Change 1: 
The title:  
Schedule of study assessments for directly enrolled subjects only from the ScrV through the 
final TV  
Was changed to:  
Schedule of study assessments from the ScrV through the final TV (directly enrolled 
subjects only) 
Change 2: 
The entry:  
body weight and height  
Was changed to:  
body weight, height, and head circumference 
Change 3: 
The entry: 
IVRS 
Was changed to: 
IVRS call 
Change 4: 
The footnote: 
c Height will be recorded only at the ScrV. 
Was changed to:  
c Height and head circumference will be recorded only at the ScrV. 
Change 5: 
The following sentence in footnote i: 
i The ScrV laboratory assessments for safety will include hematology, biochemistry 
(including hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), urinalysis, 
endocrinology, and a serum pregnancy test (for female subjects with a Tanner stage >1). 
Was changed to:  
i The ScrV laboratory assessments for safety will include hematology, biochemistry 
(including hepatic monitoring of ALT, AST, ALP, total bilirubin, and GGT), urinalysis 
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(for subjects for whom sample collection is feasible), endocrinology, and a urine 
pregnancy test at the site (for female subjects of childbearing potential). 
Table 5-4:  
The following footnote: 
b For LTFU subjects, the EV is the final evaluation visit of the previous pediatric study. For 
directly enrolled subjects, the EV represents the point of entry into the Evaluation Period. 
Was changed to: 
b For directly enrolled subjects, the EV represents the point of entry into the Evaluation 
Period. 
 
 
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16.6 
Protocol Amendment 6 
Rationale for the amendment 
The main purposes of this substantial protocol amendment are to: 
• Update language for Bayley-III scales to include countries where a validated 
translation is available 
• Remove reference to central reading of EEGs to provide flexibility 
• Remove EEG assessment for the EV (all subjects) 
• Update inclusion criteria to align language enhancements provided in 
country-specific amendment (Czech Republic) (ie, diagnosis of epilepsy and 
contraceptive language) 
• Update language in regards to partner pregnancy to align with Sponsor’s SOP and 
protocol templates 
• Add blood draw volumes for children <2 years of age 
• Clarify PedsQL age range (≥2 years of age ) as this assessment will not be used in 
children <2 years of age 
• Clarify for all other EEGs (ie, V5 and yearly thereafter) the duration in subjects 
>2 years of age 
Modifications and changes 
Global changes 
These following changes are considered administrative in nature and are not included as 
separate listings in the table of specific changes below: 
• Stylistic changes and minor editorial changes have been made and are of no 
consequence to the meaning of content. 
Specific changes 
The following table provides a list of specific changes to the protocol. Specific changes to the 
tables in Section 5.2 (Table 5-1, Table 5-2, and Table 5-3) are provided immediately after the 
table and are not included in the table itself. 
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Section Impacted 
Key components of previous text 
Key components of amended text 
Study contact 
information 
Sponsor Study Physician 
Address: UCB Biosciences GmbH 
Alfred Nobel Strabe 10 
40789 Monheim  
Germany 
Phone: 
 
FAX: 
 
Sponsor Study Physician 
Address: UCB Biosciences GmbH 
Alfred Nobel Strabe 10 
40789 Monheim am Rhein 
Germany 
Phone: 
 
FAX: 
 
Clinical Project Manager 
Name: 
 
Address: UCB BioPharma sprl 
Allée de la Recherche 60 
B-1070 Bruxelles 
Belgium 
Phone: 
 
Fax: 
 
Clinical Project Manager 
Name: 
 
Address: UCB Biosciences GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim  
Germany 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician: 
Name: 
 
Phone: 
 
Clinical Trial Biostatistician: 
Name: 
 
Phone: 
 
 
 
 
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Section 1 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The other objectives are to explore direct cost 
parameters and to assess the effect of BRV 1) on 
behavior and cognition using the age-appropriate 
Achenbach Child Behavior Checklist (CBCL/1½-5 or 
CBCL/6-18) for LTFU subjects ≥18 months of age at 
Baseline of their initial BRV study (herein referred to 
as their “core study”) and for all directly enrolled 
subjects, 2) on cognition using the Behavior Rating 
Inventory of Executive Function® 
(BRIEF®)/BRIEF®-Preschool Version (BRIEF®-P), 
and 3) on quality of life using the Pediatric Quality of 
Life Inventory™ (PedsQL™) for LTFU subjects 
≥1 month of age at the Baseline of the core study and 
for all directly enrolled subjects. The Bayley Scales of 
Infant and Toddler Development®, Third Edition 
(Bayley-III®) will be used to assess LTFU subjects 
enrolled in English-speaking countries and 
<18 months of age at Baseline of the core study; the 
Bayley-III will not be used to assess directly enrolled 
subjects since all are to be ≥4 years of age. 
Other variables include direct cost parameters (such as 
concomitant medications, medical procedures, health 
care provider consultations not foreseen by the 
protocol, and hospital stays) and the change in 
Achenbach CBCL (CBCL/1½-5 or CBCL/6-18), 
BRIEF-P/BRIEF, and PedsQL scores, and the change 
in Bayley-III scales for subjects enrolled in 
English-speaking countries.  
The other objectives are to explore direct cost parameters 
and to assess the effect of BRV 1) on behavior and 
cognition using the age-appropriate Achenbach Child 
Behavior Checklist (CBCL/1½-5 or CBCL/6-18) for LTFU 
subjects ≥18 months of age at Baseline of their initial BRV 
study (herein referred to as their “core study”) and for all 
directly enrolled subjects, 2) on cognition using the 
Behavior Rating Inventory of Executive Function® 
(BRIEF®)/BRIEF®-Preschool Version (BRIEF®-P), and 3) 
on quality of life using the Pediatric Quality of Life 
Inventory™ (PedsQL™) for LTFU subjects ≥2 years of age 
at the Baseline of the core study and for all directly 
enrolled subjects. The Bayley Scales of Infant and Toddler 
Development®, Third Edition (Bayley-III®) will be used to 
assess LTFU subjects enrolled in English-speaking 
countries and in countries where a validated translation is 
available, and <18 months of age at Baseline of the core 
study; the Bayley-III will not be used to assess directly 
enrolled subjects since all are to be ≥4 years of age. 
Other variables include direct cost parameters (such as 
concomitant medications, medical procedures, health care 
provider consultations not foreseen by the protocol, and 
hospital stays) and the change in Achenbach CBCL 
(CBCL/1½-5 or CBCL/6-18), BRIEF-P/BRIEF, and 
PedsQL scores, and the change in Bayley-III scales for 
subjects enrolled in countries where a validated translation 
is available.  
 
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Section 3 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 3.3 
• To assess the effect of BRV on cognition using 
the Bayley-III scales in subjects <18 months of 
age (applicable only to LTFU subjects enrolled 
in English-speaking countries)  
• To assess the effect of BRV on cognition using the 
Bayley-III scales in subjects <18 months of age 
(applicable only to LTFU subjects enrolled in 
English-speaking countries and in countries where a 
validated translation is available)  
• To explore the effect of BRV on health-related 
quality of life (HRQoL) using the PedsQL in 
subjects ≥1 month of age 
• To explore the effect of BRV on health-related quality 
of life (HRQoL) using the PedsQL in subjects ≥2 years 
of age  
 
Section 4 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 4.3 
• Change from the Baseline in the Bayley-III scales 
for children <18 months of age at baseline of the 
core study (applicable only to LTFU subjects 
enrolled in English-speaking countries)  
• Change from the Baseline in the Bayley-III scales for 
children <18 months of age at baseline of the core 
study (applicable only to LTFU subjects enrolled in 
English-speaking countries and in countries where a 
validated translation is available)  
• Change from Baseline in PedsQL for subjects 
≥1 month of age (age at initiation of study drug in 
N01266 or core study) 
• Change from Baseline in PedsQL for subjects ≥2 years 
of age (age at initiation of study drug in N01266 or 
core study)  
 
 
 
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Section 5 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 5.1 
A central reader will perform a review of the EEG 
recordings. 
Deleted 
Section 6 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 6.1.1 
-Abstinence from sexual intercourse 
Deleted 
Section 6.1.2 
3a. Male or female subjects having participated in a 
core study and for whom a reasonable benefit from 
long-term administration of BRV is expected. 
3a. Male or female subjects having participated in a 
core study with a confirmed diagnosis of epilepsy 
and for whom a reasonable benefit from long-term 
administration of BRV is expected. 
 
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Section 8 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 8.3.1.1 & 
Section 8.3.1.2 
• 
EEG 
Deleted 
Section 8.3.1.1 & 
Section 8.3.1.2 & 
Section 8.5 & 
Section 8.6 & 
Section 8.8 & 
Section 8.11 
• Bayley-III scales (subjects enrolled in 
English-speaking countries) 
• Bayley-III scales (subjects enrolled in 
English-speaking countries and in countries where a 
validated translation is available) 
Section 8.5 &  
• EEG (for LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have 
typical absence seizures, an EEG of at least 
24 hours that includes hyperventilation and 
intermittent photic stimulation must be 
performed only at V5 and yearly thereafter. 
• EEG (for LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have 
typical absence seizures, an EEG of at least 
1 hour that includes hyperventilation and 
intermittent photic stimulation must be performed 
only at V5 and yearly thereafter. 
Section 8.8 
• EEG (LTFU subjects only) 
For subjects ≥2 years of age at V5 who have typical 
absence seizures, a 24-hour EEG may be performed 
at the Investigator’s discretion. 
• EEG (LTFU subjects only) 
For subjects ≥2 years of age at V5 who have typical 
absence seizures, a 1-hour EEG may be performed at 
the Investigator’s discretion. 
Section 8.11 
• EEG (for LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have 
typical absence seizures, an EEG of at least 
24 hours that includes hyperventilation and 
intermittent photic stimulation must be 
performed 
• EEG (for LTFU subjects only) 
− For subjects ≥2 years of age at V5 who have 
typical absence seizures, an EEG of at least 
1 hour that includes hyperventilation and 
intermittent photic stimulation must be performed 
 
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Section 9 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 9.1.4 
In cases where the partner of a male subject enrolled in 
a clinical study becomes pregnant, UCB will ask the 
Investigator or designee to contact the subject and his 
partner to request consent via the Partner Pregnancy 
Consent form. If the partner agrees to provide 
additional information, the Pregnancy Report and 
Outcome form will be forwarded to the subject’s 
partner for completion. 
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. The health of the child must be 
followed for 12 months after birth for any significant 
medical issues.  
In cases where the partner of a male subject enrolled in a 
clinical study becomes pregnant, the investigator or 
designee is asked to contact the subject to request 
consent of the partner via the Partner Pregnancy Consent 
form that has been approved by the responsible IRB/IEC 
and should be available in the investigator site file. In 
case of questions about the consent process, the 
investigator may contact the UCB/contract research 
organization (CRO) contract monitor for the 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. 
Section 9.2.1 
The total blood volume drawn for clinical laboratory 
assessments will be a maximum of 11mL per sampling, 
which includes 3mL for hematology and 8mL for 
biochemistry. Further details will be provided in the 
laboratory manual. 
The total blood volume drawn for clinical laboratory 
assessments in subjects ≥2 years of age will be a 
maximum of 11mL per sampling, which includes up to 
3mL for hematology and up to 8mL for biochemistry. 
For subjects <2 years of age, the blood volume drawn 
will be typically much smaller and in the range of 1mL 
to 2.5mL. Further details will be provided in the 
laboratory manual. 
 
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Section10 
Section Impacted 
Key components of previous text 
Key components of amended text 
Section 10.2 
A central reader will review and assess all EEGs in a 
standardized manner. 
Deleted 
Section 10.3.2 
The Bayley-III scales are validated only in English. 
The Bayley-III scales are provided in English and in 
countries where a validated translation is available. 
Section 10.3.5 
The PedsQL Measurement Model consists of 
developmentally appropriate forms for pediatric 
subjects 1 month to 24 months, ≥2 years to ≤4 years, 
≥5 years to ≤7 years, ≥8 years to ≤12 years, and 
≥13 years to ≤18 years of age. 
The PedsQL Measurement Model consists of 
developmentally appropriate forms for pediatric subjects 
≥2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to 
≤12 years, and ≥13 years to ≤18 years of age. 
 
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Specific changes to tables in Section 5 
The rationales for the changes are noted in the rationale section above. 
Details of updates to Table 5-1 are as follows: 
Change # 1: 
EEG assessment was removed. 
Change #2 
Footnote  
j The Bayley-III is applicable to subjects enrolled in English-speaking countries only and as 
follows: 
• Core study N01349: all subjects  
• Core study EP0065: subjects <18 months of age at baseline (Screening)  
• Other core studies: subjects <18 months of age at baseline for the core study (as 
indicated in footnote c) 
Has been changed to: 
k  The Bayley-III is applicable to subjects enrolled in countries where a validated translation is 
available only and as follows: 
• Core study N01349: all subjects  
• Core study EP0065: subjects <18 months of age at baseline (Screening)  
• Other core studies: subjects <18 months of age at baseline for the core study (as 
indicated in footnote c) 
Details of updates to Table 5-2 are as follows: 
Change #1 
Footnote 
f 
EEG (for LTFU subjects only) 
• For subjects ≥2 years of age at V5 who have typical absence seizures, an EEG of at 
least 24 hours that includes hyperventilation and intermittent photic stimulation must 
be performed at V5 and yearly thereafter. For subjects prematurely discontinuing 
from the study, a 24-hour EEG may be performed at the EDV at the Investigator’s 
discretion. 
• For subjects <2 years of age at V5, an EEG of at least 24 hours must be performed for 
efficacy assessment at V5 and yearly thereafter until subjects reach 2 years of age. For 
subjects prematurely discontinuing from the study, a 24-hour EEG may be performed 
at the EDV at the Investigator’s discretion. 
Has been changed to: 
f EEG (for LTFU subjects only) 
• For subjects ≥2 years of age at V5 who have typical absence seizures, an EEG of at 
least 1 hour that includes hyperventilation and intermittent photic stimulation must be 
performed at V5 and yearly thereafter. For subjects prematurely discontinuing from 
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the study, a at least 1-hour EEG may be performed at the EDV at the Investigator’s 
discretion. 
• For subjects <2 years of age at V5, an EEG of at least24hours must be performed for 
efficacy assessment at V5 and yearly thereafter until subjects reach 2 years of age. For 
subjects prematurely discontinuing from the study, an at least 24-hour EEG may be 
performed at the EDV at the Investigator’s discretion. 
Change #2 
Footnote 
m Laboratory assessments (hepatic monitoring [ALT, AST, ALP, total bilirubin, and GGT 
only]  are to be done only at the MEV at V4 (M3) and V6 (M9). Urine pregnancy tests are 
to be done at the site for female subjects of childbearing potential at all visits. 
Has been changed to: 
m Additional hepatic monitoring laboratory assessments (ALT, AST, ALP, total bilirubin, and 
GGT only) are to be done only at the MEV at V4 (M3) and V6 (M9). Urine pregnancy tests 
are to be done at the site for female subjects of childbearing potential at all visits. 
Change #3 
Footnote 
q The Bayley-III is applicable to subjects who meet all of the following criteria: are enrolled 
English-speaking countries, were <18 months of age at baseline of the core study, and are 
<42 months of age.  
Has been changed to: 
q The Bayley-III is applicable to subjects who meet all of the following criteria: are enrolled 
English-speaking countries and in countries where a validated translation is avaiable, were 
<18 months of age at baseline of the core study, and are <42 months of age.  
 
 
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16.7 
Protocol Amendment 7 
Rationale for the amendment 
The text in the Section 9.1.4 Pregnancy has been updated to clarify that the Pregnancy Report 
and Outcome form should be completed for all pregnancies.  
Modifications and changes 
The following table provides a list of specific changes to the protocol.
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Section Impacted 
Key components of previous text 
Key components of amended text 
Section 9.1.4 
In cases where the partner of a male subject enrolled in 
a clinical study becomes pregnant, the Investigator or 
designee is asked to contact the subject to request 
consent of the partner via the Partner Pregnancy 
Consent form that has been approved by the responsible 
IRB/IEC and should be available in the Investigator site 
file. In case of questions about the consent process, the 
Investigator may contact the UCB/contract research 
organization 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 SAE reporting information at the 
beginning of this protocol) only after the partner has 
agreed that additional information can be captured and 
has provided the signed Partner Pregnancy Consent 
form. UCB’s PS department is also the primary contact 
for any questions related to the data collection for the 
partner pregnancy, eventual birth, and follow-up. 
A pregnancy becomes an SAE in the following 
circumstances: miscarriage, abortion, or anomaly/birth 
defect of the child. Those SAEs must be additionally 
reported using the Investigator SAE Report form. 
 
The Investigator will complete the Pregnancy Report and 
Outcome form for any pregnancy and send it to UCB’s 
PS department (for contact details see SAE reporting 
information at the beginning of this protocol).  
A pregnancy becomes an SAE in the following 
circumstances: miscarriage, abortion, or anomaly/birth 
defect of the child. Those SAEs must be additionally 
reported using the Investigator SAE Report form. 
In cases where the partner of a male subject enrolled in a 
clinical study becomes pregnant, the Investigator or 
designee is asked to contact the subject to request 
consent of the partner via the Partner Pregnancy Consent 
form that has been approved by the responsible IRB/IEC 
and should be available in the Investigator site file. In 
case of questions about the consent process, the 
Investigator may contact the UCB/contract research 
organization contract monitor for the study. If the partner 
has agreed that additional information can be captured 
and has provided the signed Partner Pregnancy Consent 
form, the Pregnancy Report and Outcome form will be 
completed. UCB’s PS department is the primary contact 
for any questions related to the data collection for the 
partner pregnancy, eventual birth, and follow-up. 
 
 
 
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16.8 
Protocol Amendment 8 
Rationale for the amendment 
The study variables have been reorganized into primary, secondary, and other variables in 
compliance with reporting registries. This recategorization does not affect the type or 
processing of data collected and reported in the study report, as they will be assessed as 
initially planned. The option for subjects to transition to another BRV study has been added, 
and information regarding down-titration for subjects who do not continue BRV treatment 
after completing the study has been added. Text describing the maximum dose of BRV has 
been clarified.  
Modifications have been made to the study conduct to ensure the safety of subjects in 
response to the COVID-19 pandemic. 
Administrative changes include the update of the Sponsor Study Physician and Clinical Trial 
Biostatistician contact details and typographical corrections. 
Modifications and changes 
The following table provides a list of specific changes to the protocol. 
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Section 
impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Study contact 
information 
Sponsor Study Physician 
Name: 
 
Address: UCB Biosciences GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim  
Germany 
Phone: 
 
Fax: 
 
Sponsor Study Physician 
Name: 
 
Address: UCB Biosciences GmbH 
Alfred-Nobel-Straße 10 
40789 Monheim  
Germany 
Phone: 
 
Fax: 
 
Administrative 
change 
Clinical Trial Biostatistician 
Name: 
 
Address: 8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 8010 Arco Corporate Drive, 
 
Raleigh, NC  27617 
United States 
Phone: 
 
Fax: 
 
Administrative 
change 
List of 
abbreviations 
Not applicable. 
COVID-19  
coronavirus (SARS-CoV-2) 
disease 2019 
SARS-CoV-2 severe acute respiratory syndrome 
coronavirus-2 
Administrative 
change 
Section 1 
The maximum allowable BRV dose is 
5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose 
of 200mg/day for subjects with body weight 
>40kg. 
The maximum allowable BRV dose is 
5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose 
of 200mg/day. 
Removal of 
unnecessary text for 
clarification 
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Key components of amended text 
Rationale 
Section 1 
Section 2.3 
Subjects will receive BRV treatment in this study 
for at least 3 years, until approval of BRV has been 
obtained for pediatric subjects in their age range, 
until a managed access program is established as 
allowed per country-specific requirements in 
addition to legal and regulatory guidelines, or until 
the investigational product development in the 
related age range of the pediatric population is 
stopped by the Sponsor, whichever comes first. 
Subjects will receive BRV treatment in this study 
for at least 3 years, until approval of BRV has been 
obtained for pediatric subjects in their age range, 
until a managed access program is established as 
allowed per country-specific requirements in 
addition to legal and regulatory guidelines, until 
subjects transition to another BRV study, or until 
the investigational product development in the 
related age range of the pediatric population is 
stopped by the Sponsor, whichever comes first. 
To allow subjects to 
transition to another 
BRV study 
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Section 
impacted 
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Key components of amended text 
Rationale 
Section 4.1 
Safety variables 
The safety variables include the following: 
• 
AE reporting 
• 
Safety laboratory tests (hematology, 
biochemistry including hepatic monitoring of 
ALT, AST, ALP, total bilirubin, and GGT, and 
endocrinology for all subjects and urinalysis 
for subjects for whom sample collection is 
feasible) (See Section 9.2.1)   
• 
Plasma concentrations of BRV and phenytoin 
(if applicable) 
• 
ECG 
• 
Physical (Tanner scale, if applicable depending 
on subject’s developmental status) and 
neurological examinations  
• 
Psychiatric and mental status 
• 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
• 
Body weight, height, and head circumference 
Primary variables 
• 
Treatment-emergent AEs  
• 
Treatment-emergent serious adverse events 
(SAEs) 
To reorganize the 
study variables in 
compliance with 
reporting registries 
Section 4.2 
Efficacy variables 
For subjects <2 years of age (based on EEG data 
[recorded at least 24 hours]) or subjects with 
absence seizures (based on EEG data): 
• 
Responder rate for total POS defined as the 
percentage of subjects with a ≥50% reduction 
in ADF (average daily frequency) of POS 
Secondary variables 
For subjects ≥2 years of age (based on DRC data): 
• 
Absolute change in 28-days adjusted POS 
frequency from Baseline to the end of the 
Evaluation Period (subjects with POS only) 
• 
Percent change in 28-days adjusted POS 
To reorganize the 
study variables in 
compliance with 
reporting registries 
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Rationale 
recorded on EEG (subjects with POS only)  
• 
Absolute and percent reduction in ADF of POS 
(subjects with POS only) 
• 
50% responder rate for total seizures (all types) 
• 
Absolute and percent reduction in ADF of total 
seizures (all types) 
• 
Seizure freedom (rate and proportion) 
• 
Worsening of other types of seizures (absolute 
and percent) 
In addition, the following efficacy variables will be 
repeated for subjects <2 years of age or subjects 
with absence seizures based on the DRC seizure 
counts: 
• 
Seizure freedom rate over the Evaluation 
Period (all types) by visit and by time intervals 
(6 months, 12 months, etc) 
• 
Proportion of seizure free days over the 
Evaluation Period (all types) and by time 
intervals (6 months, 12 months, etc) 
• 
Absolute and percent worsening in ADF of 
total seizures (all types) 
A descriptive summary of seizure frequency by 
visit based on the DRC data will be also provided 
for these subjects.   
The efficacy variables planned for analysis of 
subjects ≥2 years of age will be based on DRC data 
and will include the following: 
frequency from Baseline to the end of the 
Evaluation Period (subjects with POS only) 
• 
50% responder rate for total seizures (all types) 
For subjects <2 years of age (based on EEG data 
[recorded at least 24 hours]) or subjects with 
typical absence seizures (based on EEG data): 
• 
Absolute change in average daily frequency 
(ADF) of POS (subjects with POS only) 
• 
Percent change in ADF of POS (subjects with 
POS only) 
• 
50% responder rate for total seizures (all types) 
 
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Section 
impacted 
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Key components of amended text 
Rationale 
• 
Responder rate (the percentage of subjects who 
have a ≥50% reduction in seizure frequency 
per 28 days from Baseline for POS)   
• 
Absolute and percent reduction in seizure 
frequency (POS) per 28 days from Baseline to 
the end of the Evaluation Period 
• 
50% responder rate for total seizures (all types) 
• 
Absolute and percent reduction in seizure 
frequency (total seizures) per 28 days from 
Baseline to the end of the Evaluation Period  
• 
Seizure freedom rate over the Evaluation 
Period 
• 
Proportion of seizure-free days over the 
Evaluation Period 
Section 4.3 
Other variables 
The other variables include the following: 
• 
Direct cost parameters: concomitant 
medications, medical procedures, health care 
provider consultations not foreseen by the 
protocol, and hospital stays 
• 
Change from Baseline in the Achenbach 
CBCL score: the Achenbach CBCL/1½-5 for 
children from 1½ to 5 years old and the 
Achenbach CBCL/6-18 for children 6 years 
and older (age at initiation of study drug in 
N01266 or core study) 
Other variables 
For subjects ≥2 years of age (based on DRC data): 
• 
Responder rate (the percentage of subjects who 
have a ≥50% reduction in seizure frequency 
per 28 days from Baseline for POS) 
• 
Absolute change in seizure frequency (total 
seizures) per 28 days from Baseline to the end 
of the Evaluation Period 
• 
Percent change in seizure frequency (total 
seizures) per 28 days from Baseline to the end 
of the Evaluation Period 
To reorganize the 
study variables in 
compliance with 
reporting registries 
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Section 
impacted 
Key components of previous text 
Key components of amended text 
Rationale 
• 
Change from Baseline in the BRIEF-P/BRIEF 
score for subjects ≥2 years of age (age at 
initiation of study drug in N01266 or core 
study) 
• 
Change from the Baseline in the Bayley-III 
scales for children <18 months of age at 
baseline of the core study (applicable only to 
LTFU subjects enrolled in English-speaking 
countries and in countries where a validated 
translation is available)  
• 
Change from Baseline in PedsQL for subjects 
≥2 years of age (age at initiation of study drug 
in N01266 or core study) 
• 
Seizure freedom over the Evaluation Period 
• 
Proportion of seizure-free days over the 
Evaluation Period 
For subjects <2 years of age or subjects with 
absence seizures based on the DRC seizure counts: 
• 
Seizure freedom rate over the Evaluation 
Period (all types) by visit and by time intervals 
(6 months, 12 months, etc.) 
• 
Proportion of seizure-free days over the 
Evaluation Period (all types) and by time 
intervals (6 months, 12 months, etc.) 
• 
Absolute worsening in ADF of total seizures 
(all types) 
• 
Percent worsening in ADF of total seizures (all 
types) 
• 
A descriptive summary of seizure frequency 
by visit based on the DRC data will be also 
provided for these subjects 
In addition for subjects <2 years of age (based on 
EEG data [recorded at least 24 hours]) or subjects 
with absence seizures (based on EEG data):  
• 
Responder rate for total POS defined as the 
percentage of subjects with a ≥50% reduction 
in ADF of POS recorded on EEG 
• 
Absolute change in ADF of total seizures (all 
types) 
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Section 
impacted 
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Key components of amended text 
Rationale 
• 
Percent change in ADF of total seizures (all 
types) 
• 
Seizure freedom (rate and proportion) 
• 
Absolute worsening of other types of seizures 
• 
Percent worsening of other types of seizures 
For subjects with absence seizures: 
• 
Number and type of nonabsence seizure 
For all subjects: 
• 
Physical (including Tanner staging, if 
applicable depending on subject’s 
developmental status) 
• 
Neurological examinations 
• 
Psychiatric and mental status 
• Laboratory tests (hematology, 
biochemistry including hepatic monitoring 
of ALT, AST, ALP, total bilirubin, and 
GGT, endocrinology [follicle-stimulating 
hormone, luteinizing hormone, 
thyroid-stimulating hormone, triiodothyronine, 
and tetraiodothyronine] for all subjects and 
urinalysis for subjects for whom sample 
collection is feasible) (See Section 9.2.1) 
• 
ECG 
• 
Vital signs (blood pressure, pulse rate, and 
body temperature) 
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Section 
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Key components of amended text 
Rationale 
• 
Body weight  
• 
Height and head circumference  
• 
Plasma concentrations of BRV and phenytoin 
(if applicable) 
• 
Direct cost parameters: concomitant 
medications, medical procedures, health care 
provider consultations not foreseen by the 
protocol, and hospital stays 
• 
Change from Baseline in the Achenbach 
CBCL score: the Achenbach CBCL/1½-5 for 
children from 1½ to 5 years old and the 
Achenbach CBCL/6-18 for children 6 years 
and older (age at initiation of study drug in 
N01266 or core study) 
• 
Change from Baseline in the BRIEF-P/BRIEF 
score for subjects ≥2 years of age (age at 
initiation of study drug in N01266 or core 
study) 
• 
Change from the Baseline in the Bayley-III 
scales for children <18 months of age at 
baseline of the core study (applicable only to 
LTFU subjects enrolled in English-speaking 
countries and in countries where a validated 
translation is available)  
• 
Change from Baseline in PedsQL for subjects 
≥2 years of age (age at initiation of study drug 
in N01266 or core study) 
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Rationale 
Section 5.1 
For all subjects enrolled in N01266, the maximum 
BRV dose is 5.0mg/kg/day (2.5mg/kg bid), not to 
exceed a dose of 200mg/day for subjects with body 
weight >40kg. 
For all subjects enrolled in N01266, the maximum 
BRV dose is 5.0mg/kg/day (2.5mg/kg bid), not to 
exceed a dose of 200mg/day. 
Removal of 
unnecessary text for 
clarification 
Following the EDV, subjects will have their BRV 
dose reduced by a maximum of half the dose every 
week for a maximum of 4 weeks until a dose of 
1mg/kg/day (50mg/day for subjects with body 
weights >50kg) is reached. 
Following the EDV, or following the FV for 
subjects who complete the study but do not 
continue BRV treatment, subjects will have their 
BRV dose reduced by a maximum of half the dose 
every week for a maximum of 4 weeks until a dose 
of 1mg/kg/day (50mg/day for subjects with body 
weights >50kg) is reached. 
To add down-
titration information 
for subjects who do 
not continue BRV 
treatment after 
completing the study 
Section 5.1.1 
Subject participation will extend from study entry 
for at least 3 years until approval of BRV has been 
obtained for pediatric subjects in their age range, 
until a managed access program is established as 
allowed per country-specific requirements in 
addition to legal and regulatory guidelines, or until 
the investigational product development in the 
related age range of the pediatric population is 
stopped by the Sponsor, whichever comes first. 
Subject participation will extend from study entry 
for at least 3 years until approval of BRV has been 
obtained for pediatric subjects in their age range, 
until a managed access program is established as 
allowed per country-specific requirements in 
addition to legal and regulatory guidelines, until 
subjects transition to another BRV study, or until 
the investigational product development in the 
related age range of the pediatric population is 
stopped by the Sponsor, whichever comes first. 
To allow subjects to 
transition to another 
BRV study 
Table 5-2 
g No DRC or study drug will be dispensed at the 
FV. 
g No DRC or study drug will typically be dispensed 
at the FV. However, for subjects who complete the 
study but do not continue BRV treatment, study 
drug for down-titration will be dispensed. 
To add down-
titration information 
for subjects who do 
not continue BRV 
treatment after 
completing the study 
Section 5.4 
The maximum allowable BRV dose in N01266 is 
5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose 
of 200mg/day for subjects with body weight 
>40kg. 
The maximum allowable BRV dose in N01266 is 
5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose 
of 200mg/day. 
Removal of 
unnecessary text for 
clarification 
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Section 5.5 
Not applicable. 
Section 5.5 Study conduct due to coronavirus 
(severe acute respiratory syndrome coronavirus-2) 
disease 2019 
The following applies where normal study conduct 
is impacted by coronavirus (severe acute 
respiratory syndrome coronavirus-2 [SARS-CoV-
2]) disease 2019 (COVID-19). The protocol visit 
schedule should be followed to the extent possible, 
considering the individual benefit-risk assessment 
by the Investigator. If necessary, remote visits may 
be conducted and the subjects or caregivers will be 
contacted by telephone or videoconference. 
Remote follow-up, at minimum with a telephone 
call after 3 months, must be done (preferably more 
frequently and as needed to follow-up on subject 
safety assessments).  
If a subject needs to be discontinued and cannot 
come into the study site, then appropriate 
down-titration instructions will be provided, and a 
visit will be scheduled to perform safety 
assessments as soon as possible (see Section 7.2.3 
for down-titration instructions). 
In situations where a subject is unable to return to 
the study site, Investigators will assess and 
document the subject’s safety via telephone 
contact. Based on information gathered from the 
telephone contact, Investigators will confirm 
whether the subject could continue the current 
study treatment based upon the outcome of the 
safety assessment. Subjects’ agreement to 
implement this procedure should be obtained and 
documented prior to implementing any changes. 
Changes in the study treatment supply in this 
To mitigate risk 
related to COVID-19 
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Section 
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Rationale 
situation are described in Section 7.2.4. 
Ad hoc subject contact may be warranted  to 
understand the current health status of the subjects, 
follow up on AEs and inform them of any 
protective measures taken by the study site as a 
result of the COVID-19 pandemic (eg, any 
measures which may limit access to the site or may 
require additional actions by the subject prior to 
entry to the site).    
Investigators and study coordinators may use 
discretion when determining the need to perform a 
home visit (eg, for safety laboratory parameters or 
PK samples). 
If subjects are unable to return to the study site, 
protocol deviations will occur (even if the study 
visit is replaced by a home visit or remote visit) 
(Section 12.6). Investigators must carefully 
document the occurrence of these and any other 
deviations, clearly noting deviations which 
occurred during and in accordance to the 
COVID-19 pandemic.  
If a subject visits another facility for a medical 
issue (or has to switch sites for some 
COVID-19-related reason), the Investigator should 
request contact with the physician providing care 
to provide a detailed explanation of the subject’s 
condition and his/her participation in the study. 
Subjects or caregivers shall be reminded to 
completely collect and keep records of this visit. 
In case laboratory assessments cannot be 
conducted via central laboratory vendor due to 
restricted site access or home visits by 
Investigators are not an option, local laboratory 
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Clinical Study Protocol 
Brivaracetam 
N01266 
 
 
 
Confidential                                                                                                   Page 342 of 346 
Section 
impacted 
Key components of previous text 
Key components of amended text 
Rationale 
safety assessment may need to be conducted, in a 
format that allows the Investigator to receive and 
review these results and include as source 
documentation.   
Deviations to data collection including inability to 
perform some assessments such as EEG, ECG or 
blood collection for safety laboratory assessments 
and PK, or alternative methods of assessment such 
as phone calls should be recorded in the source 
documentation and notated as “not done” in the 
electronic case report form (eCRF). 
In cases where subjects cannot return to the study 
site, and it will not be possible to dispense a new 
DRC, subjects will be instructed to continue 
recording of seizures in a manner that is mutually 
agreed with the Investigator (eg, hand-written 
notes, taking notes on a smart device). Any 
recording of seizures in a manner outside of the 
study DRC must be carefully documented in the 
source medical records (copies or printouts of 
these recordings will be brought to and retained at 
site). 
Section 7.2.2 
The maximum BRV dose will be 5.0mg/kg/day 
(2.5mg/kg bid), not to exceed a dose of 200mg/day 
for subjects with body weight >40kg. 
The maximum BRV dose will be 5.0mg/kg/day 
(2.5mg/kg bid), not to exceed a dose of 
200mg/day. 
Removal of 
unnecessary text for 
clarification 
Section 7.2.3 
All subjects who prematurely discontinue the study 
should complete an EDV and have their BRV dose 
down titrated by a maximum of half the dose every 
week for a maximum of 4 weeks until a dose of 
1mg/kg/day (50mg/day for subjects with body 
weights >50kg) is reached. 
All subjects who prematurely discontinue the study 
should complete an EDV and have their BRV dose 
down titrated by a maximum of half the dose every 
week for a maximum of 4 weeks until a dose of 
1mg/kg/day (50mg/day for subjects with body 
weights >50kg) is reached. Equally, all subjects 
completing the study but switching to treatment 
To add down-
titration information 
for subjects who do 
not continue BRV 
treatment after 
completing the study 
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Clinical Study Protocol 
Brivaracetam 
N01266 
 
 
 
Confidential                                                                                                   Page 343 of 346 
Section 
impacted 
Key components of previous text 
Key components of amended text 
Rationale 
other than BRV should have their BRV dose down 
titrated. 
Section 7.2.4 
Not applicable. 
Section 7.2.4 Alternative study treatment supply 
due to COVID-19 
When a subject can no longer return to the study 
site but will continue in the study, the following 
methods may be used to provide study treatment: 
• 
Site to subject: In instances where site staff can 
ship study treatment dispensed from the site or 
pharmacy supply directly to the subject, or 
• 
Depot to subject: In instances where it is not 
possible for the site staff to access study 
treatment and/or ship study treatment 
dispensed from the site or pharmacy supply 
directly to the subject. 
To mitigate risk 
related to COVID-19 
Section 7.7 
The IMP (oral solution or oral tablets) will be 
supplied to the subject/parent(s)/legal 
representative(s) at the TV(s) (directly enrolled 
subjects only), EV, MEV, FEV, YEV, and at the 
EDV in the case of early discontinuation. 
The IMP (oral solution or oral tablets) will be 
supplied to the subject/parent(s)/legal 
representative(s) at the TV(s) (directly enrolled 
subjects only), EV, MEV, FEV, YEV, and at the 
EDV in the case of early discontinuation. The IMP 
for down-titration will be dispensed at the FV for 
subjects who complete the study but do not 
continue BRV treatment. 
To add down-
titration information 
for subjects who do 
not continue BRV 
treatment after 
completing the study 
Section 8.11 
Not applicable. 
• 
Appointment for the next visit should be 
scheduled for the end of the 4-week 
Down-Titration Period (maximum) if BRV 
treatment is not continued after study 
completion (FV), and study drug for down-
titration should be dispensed 
To add down-
titration information 
for subjects who do 
not continue BRV 
treatment after 
completing the study 
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Clinical Study Protocol 
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N01266 
 
 
 
Confidential                                                                                                   Page 344 of 346 
Section 
impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 9.1.2.1 Not applicable. 
Occurrence of COVID-19 in subjects should be 
reported as either “suspected COVID-19” or 
“confirmed COVID-19.” For subjects where 
COVID-19 is still suspected despite a negative 
viral test, please report as “suspected COVID-19.” 
To document adverse 
events of suspected 
or confirmed 
COVID-19 
Section 11.2 
UCB (or designee) will monitor the study to meet 
the Sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and 
applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are 
adequate. Monitoring of the study may be 
delegated by UCB to a contract research 
organization or a contract monitor. 
UCB (or designee) will monitor the study to meet 
the Sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and 
applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are 
adequate. Monitoring of the study may be 
delegated by UCB to a contract research 
organization or a contract monitor. Remote 
monitoring visits may be conducted during the 
COVID-19 pandemic or under other exceptional 
circumstances as deemed appropriate to ensure 
subjects’ safety. 
To mitigate risk 
related to COVID-19 
Section 12.6 
Not applicable. 
Protocol deviations (eg, missing assessments or 
visits) related to COVID-19 will be documented. 
To clarify that 
protocol deviations 
related to COVID-19 
will be documented 
 
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17 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and 
local laws and requirements. 
I will ensure that all subinvestigators and other staff members read and understand all aspects 
of this protocol. 
I have received and read all study-related information provided to me. 
The objectives and content of this protocol as well as the results deriving from it will be 
treated confidentially, and will not be made available to third parties without prior 
authorization by UCB. 
All rights of publication of the results reside with UCB, unless other agreements were made 
in a separate contract. 
Investigator: 
 
 
__________________________________ 
Printed Name 
 
 
 
__________________________________ 
Date/Signature 
 
 
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N01266 
 
 
 
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18 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
 
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Approval Signatures
Name:
n01266-protocol-amend-8
Version:
1. 0
Document Number:
CLIN-000154982
Title:
N01266 Protocol Amendment 8
Approved Date:
29 Jun 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 26-Jun-2020 18:41:01 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 26-Jun-2020 18:45:55 GMT+0000
Approval
Verdict: Approved
Name:
Capacity: Clinical
Date of Signature: 29-Jun-2020 16:22:58 GMT+0000
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SAP_001.pdf: 
UCB 
 
22 Sep 2021 
Statistical Analysis Plan 
Brivaracetam 
N01266 
 
 
 
Confidential 
Page 1 of 66 
STATISTICAL ANALYSIS PLAN  
Study: N01266 
Product: Brivaracetam 
Open-Label, Single-Arm, Multicenter, Long-Term Study to Evaluate Safety and Efficacy of 
Brivaracetam Used as Adjunctive Treatment in Pediatric Subjects with Epilepsy 
 
SAP/Amendment Number 
Date 
Final SAP 
24 Dec 2013 
Final SAP - Amendment 1 
15 Oct 2019 
Final SAP - Amendment 2 
21 Oct 2020 
Final SAP - Amendment 3 
22 Jun 2021 
Final SAP - Amendment 4 
22 Sep 2021 
 
 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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Statistical Analysis Plan 
Brivaracetam 
N01266 
 
 
 
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Page 2 of 66 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................. 8 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 
Study objectives ........................................................................................................... 10 
2.1.1 
Primary objective ................................................................................................. 10 
2.1.2 
Secondary objective ............................................................................................. 10 
2.1.3 
Other objectives ................................................................................................... 10 
2.2 
Study variables ............................................................................................................. 10 
2.2.1 
Primary variables ................................................................................................. 10 
2.2.2 
Secondary variables ............................................................................................. 11 
2.2.3 
Other variables ..................................................................................................... 11 
2.3 
Study design and conduct ............................................................................................ 13 
2.3.1 
Study design for DE subjects ............................................................................... 13 
2.3.2 
Study design for LTFU subjects .......................................................................... 15 
2.3.3 
Study duration per subject ................................................................................... 15 
2.3.4 
Planned number of subjects and sites .................................................................. 15 
2.4 
Determination of sample size ....................................................................................... 15 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 15 
3.1 
General presentation of summaries and analyses ........................................................ 15 
3.2 
General study level definitions .................................................................................... 16 
3.2.1 
Analysis time points ............................................................................................ 16 
3.2.1.1 
First and final dose of study drug .............................................................. 16 
3.2.1.2 
Relative day ............................................................................................... 16 
3.2.2 
Summaries at Study Entry ................................................................................... 17 
3.2.3 
Study periods ....................................................................................................... 17 
3.2.3.1 
Assignment of safety variables to study periods ....................................... 19 
3.2.4 
Monthly time intervals ......................................................................................... 19 
3.2.5 
Study visit labeling .............................................................................................. 20 
3.2.6 
Last Value on BRV treatment .............................................................................. 21 
3.2.7 
Exposure duration and exposure duration cohorts ............................................... 21 
3.2.8 
Modal dose calculation ........................................................................................ 21 
3.2.9 
Mapping of assessments performed at Early Discontinuation Visit .................... 22 
3.3 
Definition of Baseline values ....................................................................................... 22 
3.4 
Protocol deviations....................................................................................................... 22 
3.5 
Analysis sets................................................................................................................. 23 
3.5.1 
Enrolled Subjects ................................................................................................. 23 
3.5.2 
Safety Set ............................................................................................................. 23 
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Statistical Analysis Plan 
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N01266 
 
 
 
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3.5.3 
Full Analysis Set .................................................................................................. 23 
3.6 
Treatment assignment and treatment groups ............................................................... 23 
3.7 
Site pooling strategy .................................................................................................... 23 
3.8 
Coding dictionaries ...................................................................................................... 23 
3.9 
Possible clinically significant treatment-emergent (PCST) values .............................. 24 
3.10 
Definitions of study-specific derived variables ........................................................... 24 
3.10.1 
Definition of treatment-emergent AE .................................................................. 24 
3.10.2 
Epilepsy related variables .................................................................................... 24 
3.10.3 
Seizures and seizure categories............................................................................ 24 
3.10.3.1 
Derivation of efficacy variables ................................................................ 26 
3.10.4 
Direct cost parameters ......................................................................................... 32 
3.10.4.1 
Medications (AED and non-AED) ............................................................ 32 
3.10.4.2 
Concurrent medical procedures ................................................................. 33 
3.10.4.3 
Additional healthcare provider visits ........................................................ 33 
3.10.4.4 
Hospital stays ............................................................................................ 33 
3.10.5 
Questionnaire data ............................................................................................... 33 
3.10.5.1 
Achenbach CBCL ...................................................................................... 33 
3.10.5.2 
BRIEF scores ............................................................................................. 35 
3.10.5.3 
BRIEF-P scores ......................................................................................... 37 
3.10.5.4 
PedsQL ...................................................................................................... 38 
3.11 
Changes to protocol-defined analyses ......................................................................... 39 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 39 
4.1 
Adjustments for covariates .......................................................................................... 39 
4.2 
Handling of dropouts or missing data .......................................................................... 39 
4.3 
Interim analyses and data monitoring .......................................................................... 40 
4.4 
Multicenter studies ....................................................................................................... 40 
4.5 
Multiple comparisons/multiplicity ............................................................................... 40 
4.6 
Use of an efficacy subset of subjects ........................................................................... 40 
4.7 
Active-control studies intended to show equivalence .................................................. 41 
4.8 
Examination of subgroups ........................................................................................... 41 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 41 
5.1 
Subject disposition ....................................................................................................... 41 
5.2 
Protocol deviations....................................................................................................... 42 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 42 
6.1 
Demographics and Baseline characteristics ................................................................. 42 
6.2 
Medical history and concomitant diseases ................................................................... 43 
6.3 
History of epilepsy ....................................................................................................... 43 
6.3.1 
Epileptic seizure profile ....................................................................................... 43 
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Statistical Analysis Plan 
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6.3.2 
Classification of epileptic syndrome ................................................................... 43 
6.3.3 
History of epileptic seizures ................................................................................ 43 
6.3.4 
Historical seizure count ....................................................................................... 44 
6.4 
Previous and concomitant medications ........................................................................ 44 
6.4.1 
Non-AEDs taken at study entry ........................................................................... 44 
6.4.2 
Number of previous AEDs .................................................................................. 44 
6.4.3 
History of previous AED use ............................................................................... 44 
6.4.4 
History of previous AEDs by reason for AED discontinuation .......................... 45 
6.4.5 
VNS use and Number of AEDs taken at study entry ........................................... 45 
6.4.6 
AEDs taken at study entry ................................................................................... 45 
6.4.7 
Concomitant AEDs .............................................................................................. 45 
6.4.8 
Concomitant Non-AEDs ...................................................................................... 45 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 45 
8 
SAFETY ANALYSES ..................................................................................................... 45 
8.1 
Extent of exposure ....................................................................................................... 45 
8.2 
AEs ............................................................................................................................... 46 
8.2.1 
Overview of TEAEs ............................................................................................ 46 
8.2.2 
Incidences of TEAEs ........................................................................................... 46 
8.2.3 
Incidences of TEAEs of interest .......................................................................... 48 
8.3 
Clinical laboratory evaluations .................................................................................... 48 
8.4 
Vital signs, physical findings, and other observations related to safety ...................... 49 
8.4.1 
Vital signs ............................................................................................................ 49 
8.4.2 
ECGs .................................................................................................................... 50 
8.4.3 
Physical examination ........................................................................................... 50 
8.4.4 
Neurological examination .................................................................................... 50 
8.4.5 
Psychiatric and mental status ............................................................................... 51 
8.4.6 
Vagus nerve stimulation (VNS) status ................................................................ 51 
8.4.7 
Neuro-imaging procedures .................................................................................. 51 
8.4.8 
Assessment of suicidality .................................................................................... 51 
8.4.9 
Reproductive potential and birth control ............................................................. 52 
9 
EFFICACY ANALYSES ................................................................................................ 52 
9.1 
Seizure based variables based on EEG data ................................................................ 52 
9.2 
Seizure based variables based on DRC data ................................................................ 53 
9.3 
Direct cost parameters.................................................................................................. 53 
9.3.1 
Concomitant medications .................................................................................... 53 
9.3.2 
Concurrent medical procedures ........................................................................... 53 
9.3.3 
Additional healthcare provider consultations ...................................................... 54 
9.3.4 
Hospital stays ....................................................................................................... 54 
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Statistical Analysis Plan 
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N01266 
 
 
 
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9.3.5 
Emergency room visits ........................................................................................ 54 
9.4 
Achenbach Child Behavior Checklist .......................................................................... 55 
9.5 
BRIEF-P and BRIEF assessment ................................................................................. 55 
9.6 
Bayley Scales of Infant and Toddler Development, Third Edition ............................. 56 
9.7 
PedsQL assessment ...................................................................................................... 56 
10 PHARMACOKINETICS ................................................................................................. 57 
11 REFERENCES ................................................................................................................ 58 
12 APPENDICES ................................................................................................................. 59 
12.1 
PCST Criteria for Hematology and Biochemistry Parameters .................................... 59 
12.2 
PCST Criteria for Urinalysis ........................................................................................ 61 
12.3 
PCST Criteria for Vital Signs ...................................................................................... 62 
13 AMENDMENTS TO THE SAP ...................................................................................... 64 
 
LIST OF TABLES 
Table 2‒1: 
Visit sequence .................................................................................................. 13 
Table 3‒1: 
Study periods ................................................................................................... 18 
Table 3‒2: 
Definition of monthly interval durations during the first year ......................... 20 
Table 3‒3: 
Exposure duration cohort definitions ............................................................... 21 
Table 3‒4: 
Dose group definitions for calculation of modal dose ..................................... 21 
Table 3‒5: 
Recommended BRV dosing schedule for DE subjects in the Up-Titration 
Period ............................................................................................................... 23 
Table 3‒6: 
Inclusion/Exclusion of EP0065 and N01349 data ........................................... 26 
Table 3‒7: 
EEG interpretation ........................................................................................... 27 
Table 3‒8: 
CBCL/1½-5 checklist ...................................................................................... 34 
Table 3‒9: 
CBCL/6-18 checklist ....................................................................................... 34 
Table 3‒10: 
BRIEF components and subscales ................................................................... 35 
Table 3‒11: 
BRIEF-P components and subscales ............................................................... 37 
Table 8‒1: 
Urinalysis categorization ................................................................................. 48 
 
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Statistical Analysis Plan 
Brivaracetam 
N01266 
 
 
 
Confidential 
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LIST OF ABBREVIATIONS 
ADF 
average daily frequency 
AE 
adverse event 
AED 
antiepileptic drugs 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate aminotransferase 
Bayley-III® 
Bayley Scales of Infant and Toddler Development ®, Third 
Edition 
BRIEF® 
Behavior Rating Inventory of Executive Function® 
BRIEF®-P 
Behavior Rating Inventory of Executive Function®-Preschool 
Version 
BRV 
Brivaracetam 
CBCL 
CS 
Child Behavior Checklist 
Clinical Significance 
DBL 
database lock 
DBP 
diastolic blood pressure 
DE 
directly enrolled 
DEM 
data evaluation meeting 
DRC 
daily record card 
DTV 
Down-Titration Visit 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDV 
Early Discontinuation Visit 
EEG 
electroencephalogram 
ER 
emergency room 
EV 
Entry Visit 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV 
Full Evaluation Visit 
FV 
Final Visit 
GEC 
Global executive composite 
GGT 
gamma glutamyl transferase 
HRQoL 
health-related quality of life 
ICH 
International Conference on Harmonization 
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Statistical Analysis Plan 
Brivaracetam 
N01266 
 
 
 
Confidential 
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ILAE 
International League Against Epilepsy 
LTFU 
long-term follow-up 
MedDRA© 
Medical Dictionary for Regulatory Activities© 
MEV 
Minimal Evaluation Visit 
PCST 
possibly clinically significant treatment-emergent 
PedsQL 
Pediatric Quality of Life Inventory 
PGS 
primary generalized seizure 
PGS* 
primary generalized seizure excluding typical absence seizures 
POS 
partial-onset seizure 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
ScrV 
Screening Visit 
SD 
standard deviation 
SS 
Safety Set 
SV 
Safety Visit 
UV 
Unscheduled Visit 
VNS 
vagal nerve stimulation 
TEAE 
treatment-emergent adverse event 
TV 
Titration Visit 
UNC 
uncategorized 
WHO-DRL 
World Health Organization Drug Reference List 
YEV 
Yearly Evaluation Visit 
 
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Statistical Analysis Plan 
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N01266 
 
 
 
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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 for N01266. An additional subset of the analyses described in this SAP will 
be produced to support regulatory submissions for marketing authorization based on interim 
data. 
The SAP is based on the following study documents: 
• Final protocol, 10 Mar 2011 
• Protocol Amendment 1, 26 Aug 2011 
• Protocol Amendment 2, 09 Dec 2011 
• Protocol Amendment 3, 26 Sep 2012 
• Protocol Amendment 4, 10 Dec 2013 
• Protocol Amendment 5, 14 Dec 2016 
• Protocol Amendment 6, 06 Mar 2018 
• Protocol Amendment 7, 18 Apr 2018 
• Protocol Amendment 8, 25 Jun 2020 
The structure and content of this SAP provides sufficient details to meet the requirements 
identified by the International Conference on Harmonization (ICH) and the Food and Drug 
Administration (FDA) (ICH Guidance on Statistical Principles for Clinical Trials [E9]). 
2 
PROTOCOL SUMMARY 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety and 
efficacy of brivaracetam (BRV) in children with epilepsy. This study is designed for pediatric 
subjects ≥1 month to <17 years of age who have completed other pediatric BRV studies (herein 
referred to as “long-term follow-up” [LTFU] subjects) and for at least 100 subjects ≥4 years to 
<17 years of age with partial-onset seizure (POS) who had not previously enrolled in a pediatric 
BRV study (herein referred to as “directly enrolled (DE) subjects”), with a planned total 
enrollment of approximately 600 subjects. 
The primary objective is to document the long-term safety and tolerability of BRV. The 
secondary objective is to assess the efficacy of BRV during long-term exposure. The other 
objectives are to explore direct cost parameters and to assess the effect of BRV 1) on behavior 
and cognition using the age-appropriate Achenbach Child Behavior Checklist (CBCL/1½-5 or 
CBCL/6-18) for LTFU subjects ≥18 months of age at Baseline of their initial BRV study (herein 
referred to as their “core study”) and for all DE subjects, 2) on cognition using the Behavior 
Rating Inventory of Executive Function® (BRIEF®)/BRIEF®-Preschool Version (BRIEF®-P), 
and 3) on quality of life using the Pediatric Quality of Life Inventory™ (PedsQL™) for LTFU 
subjects ≥2 years of age at the Baseline of the core study and for all DE subjects. The Bayley 
Scales of Infant and Toddler Development®, Third Edition (Bayley-III®) will be used to assess 
LTFU subjects enrolled in English-speaking countries and in countries where a validated 
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Statistical Analysis Plan 
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translation is available and <18 months of age at Baseline of the core study; the Bayley-III will 
not be used to assess DE subjects since all are to be ≥4 years of age. 
The LTFU subjects will enter directly into the Evaluation Period at the Entry Visit (EV) and will 
continue BRV treatment at the individualized dose they were receiving at the completion of their 
core study. Directly enrolled subjects will enter N01266 at the Screening Visit (ScrV) and then 
participate in up to 3 weeks of an Up-Titration Period. If a DE subject demonstrates, in the 
opinion of the Investigator, acceptable tolerability and seizure control on the same daily dose of 
BRV (no lower than 1mg/kg/day) for 7±2 days during the Up-Titration Period, the subject will 
attend the EV and enter the Evaluation Period on that dose. 
BRV (tablet and oral solution) should be administered twice daily (bid) in 2 equally divided 
doses. All LTFU subjects must be able to tolerate the minimum dose specified in the core study 
to be eligible for entry into the Evaluation Period of N01266. All DE subjects must be able to 
tolerate at least 1mg/kg/day during the Up-Titration Period prior to entering the Evaluation 
Period of N01266. 
The maximum allowable BRV dose is 5.0mg/kg/day (2.5mg/kg bid), not to exceed a dose of 
200mg/day. Subjects will receive oral solution or tablets, as appropriate. With the exception of 
dose adjustments for BRV during the Up-Titration Period, which should be made in accordance 
with the protocol-specified guidelines, dose adjustments of BRV and any concomitant 
antiepileptic drugs (AEDs) are allowed at any time based on clinical judgment. 
Subjects will receive BRV treatment in this study for at least 3 years, until approval of BRV has 
been obtained for pediatric subjects in their age range, until a managed access program is 
established as allowed per country-specific requirements in addition to legal and regulatory 
guidelines, until subjects transition to another BRV study, or until the investigational product 
development in the related age range of the pediatric population is stopped by the Sponsor, 
whichever comes first. 
For LTFU subjects, the EV is the first study visit. For DE subjects, the EV occurs after subjects 
have completed the ScrV and at least 1 Titration Visit (TV), and have maintained acceptable 
tolerability and seizure control on the same daily dose of BRV (no lower than the minimum 
specified dose) for 7±2 days of the Up-Titration Period. For subjects who continue in this study 
until it ends, the Evaluation Period will extend from the EV until the final evaluation visit (Final 
Visit, FV). For subjects who prematurely discontinue the study, the Evaluation Period will last 
from the EV until the Early Discontinuation Visit (EDV), followed by a maximum 4-week 
Down-Titration Period, a 2-week Safety (Drug-Free) Period, and a final Safety Visit (SV). 
Subjects already enrolled in N01266 may participate in EP0065 (an intravenous [iv] BRV study 
for pediatric subjects), if eligible, and then resume participation in N01266. 
During the Evaluation Period, Minimal Evaluation Visits (MEVs) and Full Evaluation Visits 
(FEVs) will be performed alternatively every month during the first 3 months and every 3 
months thereafter, with a Yearly Evaluation Visit (YEV) every 12 months. 
Safety variables include adverse events (AEs), safety laboratory assessments (hematology, 
biochemistry including hepatic monitoring of alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], total bilirubin, and gamma-glutamyl 
transferase [GGT], and endocrinology for all subjects and urinalysis for subjects for whom 
sample collection is feasible), plasma concentrations of BRV and phenytoin (if applicable), 
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electrocardiograms (ECGs), vital signs, physical and neurological examinations, psychiatric and 
mental status, body weight, height, and head circumference. 
All efficacy variables will be considered exploratory in nature. Seizure counts will be based on 
the daily record card (DRC) information or electroencephalograms (EEGs) and the disease 
characteristics of each subject. 
Other variables include direct cost parameters (such as concomitant medications, medical 
procedures, health care provider consultations not foreseen by the protocol, and hospital stays) 
and the change in Achenbach CBCL (CBCL/1½-5 or CBCL/6-18), BRIEF-P/BRIEF, and 
PedsQL scores, and the change in Bayley-III scales for subjects enrolled in English-speaking 
countries and countries where a validated translation is available. 
Up to 600 subjects may possibly enroll in this study. The number and location of sites will 
depend on those participating in core studies from which LTFU subjects will be enrolled, and 
those participating in direct enrollment. Sites of direct enrollment will include, but not be limited 
to, sites participating in core studies. 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective is to document the long-term safety and tolerability of BRV. 
2.1.2 
Secondary objective 
The secondary objective is to assess the efficacy of BRV during long-term exposure. 
2.1.3 
Other objectives 
Other objectives include: 
• To explore direct cost parameters 
• To assess the effect of BRV on behavior using the Achenbach CBCL in subjects ≥18 months 
of age 
• To explore the effect of BRV on cognition using the BRIEF-P/BRIEF in subjects ≥ 2 years of 
age 
• To assess the effect of BRV on cognition using the Bayley-III in subjects <18 months of age 
(applicable only to LTFU subjects enrolled in English-speaking countries and countries, 
where a validated translation is available) 
• To explore the effect of BRV on health-related quality of life (HRQoL) using the Pediatric 
Quality of Life Inventory (PedsQL) in subjects ≥ 2 years of age 
2.2 
Study variables 
2.2.1 
Primary variables 
The primary variables include the following: 
• Treatment-emergent AEs 
• Treatment-emergent serious adverse events (SAEs) 
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2.2.2 
Secondary variables 
For subjects ≥2 years of age (based on DRC data): 
• Absolute change in 28-days adjusted POS frequency from Baseline to the end of the 
Evaluation Period (subjects with POS only) 
• Percent change in 28-days adjusted POS frequency from Baseline to the end of the 
Evaluation Period (subjects with POS only) 
• 50% responder rate for total seizures (all types) 
For subjects <2 years of age (based on EEG data [recorded at least 24 hours]) or subjects with 
typical absence seizures (based on EEG data): 
• Absolute change in average daily frequency (ADF) of POS (subjects with POS only) 
• Percent change in ADF of POS (subjects with POS only) 
• 50% responder rate for total seizures (all types) 
2.2.3 
Other variables 
For subjects ≥2 years of age (based on DRC data): 
• Responder rate (the percentage of subjects who have a ≥50% reduction in seizure frequency 
per 28 days from Baseline for POS) 
• Absolute change in seizure frequency (total seizures) per 28 days from Baseline to the end of 
the Evaluation Period 
• Percent change in seizure frequency (total seizures) per 28 days from Baseline to the end of 
the Evaluation Period 
• Seizure freedom over the Evaluation Period 
• Proportion of seizure-free days over the Evaluation Period 
For subjects <2 years of age or subjects with typical absence seizures based on DRC seizure 
counts: 
• Seizure freedom rate over the Evaluation Period (all types) by visit and by time intervals (6 
months, 12 months, etc.) 
• Proportion of seizure-free days over the Evaluation Period (all types) and by time intervals (6 
months, 12 months, etc.) 
• Absolute worsening in ADF of total seizures (all types) 
• Percent worsening in ADF of total seizure (all types) 
• A descriptive summary of seizure frequency by visit based on the DRC data will be also 
provided for these subjects 
In addition, for subjects <2 years of age (based on EEG data [recorded at least 24 hours]) or 
subjects with typical absence seizures (based on EEG data): 
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• Responder rate for total POS defined as the percentage of subjects with a ≥50% reduction in 
ADF of POS recorded on EEG 
• Absolute change in ADF of total seizures (all types) 
• Percent change in ADF of total seizures (all types) 
• Seizure freedom (rate and proportion) 
• Absolute worsening of other types of seizures 
• Percent worsening of other types of seizures 
For subjects with typical absence seizures: 
• Number and type of non-absence seizures 
For all subjects: 
The other variables include the following: 
• Physical examinations (including Tanner staging, if applicable depending on subject’s 
development status)  
• Neurological examinations 
• Psychiatric and mental status 
• Laboratory tests (hematology, biochemistry including hepatic monitoring of ALT, AST, 
ALP, total bilirubin, and GGT, and endocrinology [follicle-stimulating hormone, luteinizing 
hormone, thyroid-stimulating hormone, triiodothyronine, and tetraiodothyronine] for all 
subjects and urinalysis for subjects for whom sample collection is feasible) 
• ECG 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Body weight 
• Height and head circumference 
• Plasma concentrations of BRV and phenytoin (if applicable) 
• Direct cost parameters: concomitant medications, medical procedures, health care provider 
consultations not foreseen by the protocol, and hospital stays 
• Change from Baseline as well as categorical shift from Baseline in the Achenbach CBCL 
score: the Achenbach CBCL/1½-5 for children from 1½ to 5 years old and the Achenbach 
CBCL/6-18 for children 6 years and older (age at initiation of study drug in N01266 or core 
study])  
• Change from Baseline as well as categorical shift from Baseline in the BRIEF-P/BRIEF 
score for subjects ≥ 2 years of age (age at initiation of study drug in N01266 or core study) 
• Change from core study Baseline in the Bayley-III scales for children <18 months of age at 
Baseline of the core study (applicable only to LTFU subjects enrolled in English-speaking 
countries and countries where a validated translation is available) 
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• Change from Baseline in PedsQL for subjects ≥ 2 years of age (age at initiation of study drug 
in N01266 or core study) 
2.3 
Study design and conduct 
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety and 
efficacy of BRV in children with epilepsy. This study is designed for pediatric subjects ≥ 1 
month to < 17 years of age who have completed other pediatric BRV studies (LTFU subjects) 
and for at least 100 subjects ≥ 4 years to < 17 years of age with POS who had not previously 
enrolled in a pediatric BRV study (DE subjects) with a planned total enrollment of 
approximately 600 subjects.  
2.3.1 
Study design for DE subjects 
The screening period comprises the screening visit (ScrV).  
Directly enrolled subjects will begin receiving BRV in the Up-Titration Period at Titration Visit 
1 (TV1) after all inclusion and exclusion criteria are met. The BRV dose will be titrated to 
optimize tolerability and seizure control. Subjects may enter the Evaluation Period after they 
have remained on the same daily dose (no lower than the minimum specified dose) for 7±2 days 
that, in the opinion of the Investigator, has demonstrated acceptable tolerability and seizure 
control. Up to 3 TVs may be needed before entry into the Evaluation Period. 
Evaluation Period starts with the Entry Visit (EV) followed by Minimal Evaluation Visits 
(MEV), Full Evaluation Visits (FEV), Yearly Evaluation Visits (YEV), possibly Unscheduled 
Visits (UV) and Early Discontinuation Visits (EDV), if applicable. For more detailed 
information of visits scheduled, see Table 2‒1  
 
Table 2‒1: 
Visit sequence 
DE subjects 
 
Visit 
Type of visit 
 
ScrV 
Screening 
W1 
TV1a 
TV 
W2 
TV2a 
TV 
W3 
TV3a 
TV 
All subjects 
First year follow-up 
M0 
V1 
EVb 
M1 
V2 
MEV 
M2 
V3 
FEV 
M3 
V4 
MEVc 
M4 
- 
- 
M5 
- 
- 
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M6 
V5 
FEV 
M7 
- 
- 
M8 
- 
- 
M9 
V6 
MEVc 
M10 
- 
- 
M11 
- 
- 
Second and subsequent years follow-upd 
M12 
V7 
YEV 
M15 
V8 
MEV 
M18 
V9 
FEV 
M21 
V10 
MEV 
and every 3 months thereafter 
V11, V12, etc. 
YEV, MEV, etc. 
BRV=brivaracetam; EV=Entry Visit; FEV=Full Evaluation Visit; LTFU=long-term follow-up; M=Month; 
MEV=Minimal Evaluation Visit; ScrV=Screening Visit; TV=Titration Visit; V=Visit; W=Week; YEV=Yearly 
Evaluation Visit 
Note: Visits at W1, W2, W3, and M0 will occur 7±2 days after the previous visit; visits and M1, M2, and M3 will 
occur 30±7 days after the previous visit; visits at M6, M9, M12, M15, M18, M21 and every 3 months thereafter will 
occur 90±15 days after the previous visit. 
“-” denotes that no visit is scheduled in that month. 
a All DE subjects must participate in at least TV1, but may participate in fewer than 3 TVs as described in Section 
7.2.1 of the protocol. 
b For LTFU subjects, the EV is the final evaluation visit of the core study. For DE subjects, the EV represents the 
point of entry into the Evaluation Period. 
c Hepatic monitoring tests only will be performed as described in Section 9.5.1 of the protocol. 
d Subsequent years will follow the same visit schedule. 
In case of early discontinuation, after the EDV, or for subjects who complete the study but do not 
continue BRV treatment, the Down-Titration Period starts with scheduled Down-Titration Visits 
(DTV). Dose will be down titrated by a maximum of half the dose every week for a maximum of 
4 weeks until a dose of 1mg/kg/day is reached. 
After 2 weeks free of study drug, the Safety Period, subjects will complete the Safety Visit (SV). 
The study is defined to be completed if the study status on the study termination form is marked 
as completed. This indicates that all planned visits have taken place. Planned visits are dependent 
on whether a subject discontinues the study or not, and on whether a subject goes into another 
study or takes marketed drug after FV. 
At each visit, the subject/parent(s)/legal representative(s) will receive a DRC, which has to be 
filled in daily by parent(s)/legal representative(s) or subject, if applicable, and returned at the 
next visit. No DRC will be dispensed at the SV or the FV. 
The date and the number of epileptic seizures will be recorded on the DRC, as well as the type of 
seizure (according to individual description of seizures), occurrence of clusters, intake of 
concomitant AEDs, undesirable events with start and end dates, health care provider 
consultations not foreseen per protocol, and changes in concomitant medication, if applicable. 
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The written information will be discussed with the subject/parent(s)/legal representative(s) 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 International League Against Epilepsy 
(ILAE) codes and record the seizure types and frequency on the electronic case report form 
(eCRF); he/she will also confirm the presence of AEs (if applicable). Concomitant medication 
changes, health care provider consultations not foreseen per protocol, and AEs will be reported 
by the Investigator on the specific pages of the eCRF. 
2.3.2 
Study design for LTFU subjects 
At the EV, the progress of DE subjects will become aligned with LTFU subjects. The LTFU 
subjects enter the study in Evaluation Period. The design afterwards is same as with DE, so 
please refer to Section 2.3.1 for more details. 
2.3.3 
Study duration per subject 
Subject participation will extend from study entry for at least 3 years until approval of BRV has 
been obtained for pediatric subjects in their age range, until a managed access program is 
established as allowed per country-specific requirements in addition to legal and regulatory 
guidelines, until subjects transition to another BRV study, or until the investigational product 
development in the related age range of the pediatric population is stopped by the Sponsor, 
whichever comes first. 
Study entry is defined as the EV for LTFU subjects and the ScrV for DE subjects. 
The end of the study is defined as the date of the last visit of the last subject in the study. 
2.3.4 
Planned number of subjects and sites 
N01266 is planned for a total enrollment of approximately 600 subjects, including at least 100 
eligible DE subjects ≥4 years to <17 years of age with POS. 
2.4 
Determination of sample size 
No formal sample size calculation was performed for this study. Originally, up to 500 subjects 
might have possibly enrolled in this study. The original number was based upon the assumption 
that 90% of the subjects having completed a core study will rollover into the present study. 
Planned enrollment now includes approximately 600 subjects, including at least 100 DE subjects, 
with no change in the assumption regarding core study completion. 
3 
DATA ANALYSIS CONSIDERATIONS 
The statistical analysis details are addressed in following sections. Directly enrolled subjects, 
subjects from N01349, EP0065 and other core studies, if applicable, will be analyzed separately 
as well as pooled as an overall study population, no statistical comparison will be performed. 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings and statistical output 
will be performed using SAS® Version 9.4 or higher. All tables and listings will use Courier 
New font size 9. 
 
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Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. The denominator for percentages will be based on the number of subjects appropriate 
for the purpose of analysis. Unless otherwise noted, all percentages will be displayed to 1 
decimal place. No percentage will be displayed for zero counts, and no decimal will be presented 
when the percentage is 100%. For continuous parameters, descriptive statistics will include 
number of subjects (n), mean, standard deviation (SD), median, minimum and maximum. 
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer, 
• Mean, SD, median will use 1 additional decimal place compared to the original data, 
• Minimum and maximum will have the same number of decimal places as the original value. 
All summaries will be descriptive; no statistical hypothesis testing is planned. 
A complete set of listings containing all documented data and all calculated data (eg, change 
from Baseline) will be generated. Data collected during the Up-Titration Period for DE subjects 
will be summarized separately.  
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
First and final dose of study drug 
Unless otherwise noted, all references to the first dose of study drug in this SAP refer to the first 
dose of study drug during N01266 (i.e., not the first dose of study drug from the core study in 
which subjects participated prior to N01266 for LTFU subjects). Unless otherwise noted, all 
references to the final dose of study drug in this SAP refer to the final dose of study drug taken 
across all study periods (ie, the final dose of study drug across the Up-Titration, Evaluation, and 
Down-Titration Periods). 
3.2.1.2 
Relative day 
Relative day will be calculated as follows: 
• for days prior to the first dose of study drug: the current date minus the date of first dose of 
study drug  
• for days on or after the day of first dose of study drug and prior to or on the day of last dose 
of study: the current date minus the date of first dose of study drug plus 1 
• for days after the day of last dose of study drug: the current date minus the date of last dose 
of study drug with a leading “+” 
Relative day will not be calculated for partial or missing dates. 
For monthly time intervals, relative days referring to EV will be calculated as follows (EV 
relative days): 
• for days prior to the first dose of study drug in Evaluation Period: the current date minus the 
date of EV  
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• for days on or after the day of first dose of study drug in Evaluation Period and prior to or on 
the day of last dose of study in Evaluation Period: the current date minus the date of EV 
plus 1 
• for days after the day of last dose of study drug in Evaluation Period: the current date minus 
the date of last dose of study drug within Evaluation Period with a leading “+” 
3.2.2 
Summaries at Study Entry 
Study Entry denotes when all assessments are collected prior to any BRV allocation in N01266. 
For DE subjects, assessments at ScrV will be presented. For LTFU patients selected 
measurements are collected at the final visit and screening of the respective core study. Subjects 
going through N01266-EP0065-N01266 route will have screening data from the original 
screening to N01266. For more details, see corresponding Data Integration Plan. 
3.2.3 
Study periods 
Table 3‒1 shows which study periods are applicable to DE and LTFU subjects: 
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Table 3‒1: 
Study periods 
Period 
Screening Period 
Up-Titration Period 
Evaluation Period 
Down-Titration Period 
Safety Period 
Visit 
ScrV 
TV1 
TV2 
TV2 
EV 
MEV 
FEV 
MEV 
FEV 
MEV 
YEV 
... 
FV/EDV 
DTV 
SV 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
... 
Subjects 
DE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
(x) 
LTFU 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
(x) 
Early Discontinuations 
x 
x 
x 
 (x) – only applicable if the subject does not switch to another BRV study or is taking marketed drug after FV 
 
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The study is divided into 5 periods: Screening Period, Up-Titration Period, Evaluation Period, 
Down-Titration Period, and the Safety Period.  
There is a Screening Period for all DE subjects. For DE subjects, this comprises assessments 
performed prior to the first dose of BRV in N01266. So start date of Screening Period is date of 
written informed consent and end date is the day before first dose of BRV (TV1-1). Although, 
patients in LTFU studies will not attend a screening visit, the screening information comprises 
information collected at various assessments during the core study and consequently will have 
been collected at different times depending on the domain. Domain specific information is 
detailed in Section 3.3.  
The Up-Titration Period is only applicable to DE subjects, and the start date is the date of the 
first dose of BRV. The following algorithm is used to determine the end date: 
• If the subject enters the Evaluation Period, the date 1 day prior to the EV is the end date 
• If the subject does not enter Evaluation Period, the Up-Titration Period ends on the date of 
the final dose of BRV 
For the Evaluation Period, the start date is the date of the first dose of BRV on or after the EV 
date, and the following algorithm is used to determine the end date: 
• If the subject continues the study until it ends, the Evaluation Period ends on the date of FV 
• If the subject prematurely discontinues the study, the date of EDV is the end date 
A discontinued subject or a subject who completes the study but does not continue BRV 
treatment will be considered entering the Down-Titration Period only if the subject has a record 
of at least 1 dose of BRV after the date of EDV. The start date of the Down-Titration Period is 
set as 1 day after the date of EDV, and the Down-Titration Period ends on the date of the final 
dose of BRV (DTV). 
A discontinued subject without any dosing of BRV after the EDV will not have participated in 
the Down-Titration Period, and no artificial Down-Titration Period will be created for the 
purpose of analysis. 
A discontinued subject is considered to have entered the Safety Period if the subject has at least 1 
contact (scheduled visit, unscheduled visit (UV), or telephone contact) after the date of the final 
dose (DTV). The Safety Period starts 1 day after the date of the final dose of BRV irrespective of 
entering the Down-Titration Period, and end date is the date of last contact with the subject. 
3.2.3.1 
Assignment of safety variables to study periods 
In general, safety variables (e.g. AEs) will be allocated to the treatment group based on the dose 
most recently received. Safety outcomes which can be classified into more than 1 study period as 
per Section 3.2.3, based on partial dates of onset, will be classified into a study period based on 
the following prioritization: Up-Titration, Evaluation, Down-Titration, Safety, (for example, an 
AE that can be classified in both the Evaluation and Safety Period based on a partial date of 
onset due to a missing day entry, will be classified into the Evaluation Period). 
3.2.4 
Monthly time intervals 
A month is defined as 30 days and time intervals based on monthly durations are defined as a 
multiple of 30 days (eg, 12 months is defined as 360 days). The definitions of 3- and 6-month 
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intervals are based on the durations in Table 3‒2, which use 30-day months where EV relative 
days as defined in Section 3.2.1.2 will be used: 
Table 3‒2: 
Definition of monthly interval durations during the first year 
Interval 
EV relative days 
Months 1 to 3 
1 to 90 
Months 4 to 6 
91 to 180 
Months 7 to 9 
181 to 270 
Months 10 to 12 
271 to 360 
Months 1 to 6 
1 to 180 
Months 7 to 12 
181 to 360 
Subsequent 3 and 6-month intervals, and 12-month intervals are defined in a similar manner. 
Three-month intervals will be calculated for summaries and analyses of efficacy and safety 
outcomes scheduled to be assessed at each MEV, FEV, YEV and FV. A subject is included in 
the analysis for a 3-month interval if the end of their evaluation period is on or after the final day 
of the 3-month interval and the seizure diary was completed for at least 1 day during the 3-month 
interval. 
Six-month intervals will be calculated for summaries and analyses of efficacy and safety 
outcomes scheduled to be assessed at each FEV, YEV and FV, but not each MEV. Similar to the 
approach for inclusion in 3-month summaries detailed above, a subject is included in the analysis 
for 6-month intervals if the end of their evaluation period is on or after the final day of the 6-
month interval and the seizure diary was completed for at least 1 day during the 6-month 
interval. 
Six and 12-month intervals will be calculated for analyses of seizure freedom. For further 
information on subject inclusion into these calculations, see Section 3.10.3.1. 
For the analysis of AEs, a subject is included in the analysis for a 3-month interval if the end of 
their evaluation period is on or after the first day of the 3-month interval. 
3.2.5 
Study visit labeling 
Visits will be labeled in table summaries (according to the schedule outlined in Table 2‒1) as 
follows: 
• “Screening Visit” 
• “Up-Titration Visit X” 
• “Entry Visit” 
• “Month X” for scheduled visits during the Evaluation Period 
• “Final Visit” 
• “Early Discontinuation Visit” 
• “Down-Titration Visit” 
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• “Safety Visit” 
• “Last Value” (see below in Section 3.2.6 for further information) 
Listings will also include “Unscheduled Visit” as applicable. 
3.2.6 
Last Value on BRV treatment 
The Last Value on BRV treatment for all assessments is the final available result obtained after 
the first dose of BRV and prior to or on the date of the final dose of BRV within evaluation 
period. All scheduled and UV assessments within evaluation period will be considered. Last 
Value will be determined separately for each vital sign, ECG and laboratory parameter. 
3.2.7 
Exposure duration and exposure duration cohorts 
The overall duration of exposure for each subject will be calculated as the date of the final dose 
of BRV minus the date of the first dose of BRV plus 1 day. 
Each subject will be classified into 1 or more of the following exposure duration cohorts based 
on the duration of BRV exposure as calculated above: 
Table 3‒3: 
Exposure duration cohort definitions 
Cohort 
Definition 
All subjects 
≥ 1 day 
> 3 months 
> 90 days 
> 6 months 
> 180 days 
> 9 months 
> 270 days 
> 12 months 
> 360 days 
This categorization will continue in 3-month increments past 12 months up to a time point that 
will be determined based on a review of cumulative exposure on the database performed prior to 
database lock (DBL). 
3.2.8 
Modal dose calculation 
Modal daily doses will be calculated across all study days on or after the day of first dose of 
BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during this period. In the event of a tie, the modal dose will be set to 
the lower of the tied doses. Modal daily dose will be categorized as follows: 
Table 3‒4: 
Dose group definitions for calculation of modal dose 
Dose group label (mg/kg/day) 
>=0.0 to <1.0 
1.0 to < 2.0 
2.0 to < 3.0 
3.0 to < 4.0 
>=4.0 
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For each subject, the mode will then be calculated and they will be assigned to one of the groups 
in Table 3‒4 overall, and by 6-month cohort. 
3.2.9 
Mapping of assessments performed at Early Discontinuation Visit 
Efficacy and safety assessments at an EDV that correspond to a scheduled visit will be 
summarized at the scheduled visit corresponding to the EDV if the assessment was scheduled to 
occur at that visit. Such assessments will also be considered for Last Value on BRV treatment 
(see Section 3.2.6). 
In particular, clinical laboratory parameters, vital signs, and body weight are assessed at all 
Evaluation Period visits, and so all assessments of these variables at EDVs corresponding to a 
scheduled visit will be mapped to the corresponding scheduled visit. 
3.3 
Definition of Baseline values 
Baseline for all study outcomes will be determined using different methods depending on 
whether the subject is LTFU or DE.  
Unless otherwise specified, Baseline values will be determined as follows: 
• DE subjects: the last (most recent) available pre-dose measurement of the corresponding 
outcome will be used as Baseline 
• LTFU subjects:  
− if available, Baseline values from the previous BRV core studies will be used as Baseline 
− otherwise the last (most recent) available measurement assessed between day of final on-
treatment measurement in core study and the day before first BRV administration in 
N01266 will be used as Baseline 
For laboratory parameters, vital signs (systolic blood pressure [SBP], diastolic blood pressure 
[DBP], and pulse rate), body weight, and ECGs, Baseline values will be determined as follows: 
• DE subjects: the last (most recent) available pre-dose measurement of the corresponding 
outcome will be used as Baseline 
• LTFU subjects: the last (most recent) available scheduled or UV assessment up to the day of 
subjects first BRV administration in core study will be used as Baseline (most recent 
measurement up to first BRV administration in core study, not in N01266 as in the general 
definition of Baseline values) 
Baseline will be determined separately for each individual clinical laboratory parameter for 
hematology, biochemistry, endocrinology and urinalysis assessments. 
3.4 
Protocol deviations 
Important protocol deviations are deviations from the protocol which could potentially have a 
meaningful impact on either the primary outcome of safety and tolerability of BRV, or the 
secondary outcome of efficacy of BRV for an individual subject. The criteria for identifying 
important protocol deviations and the classification of important protocol deviations will be 
defined separately in project Data Cleaning Plan. To the extent feasible, rules for identifying 
protocol deviations will be defined without review of the data and without consideration of the 
frequency of occurrence of such deviations. Whenever possible, criteria for identifying important 
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protocol deviations will be implemented algorithmically to ensure consistency in the 
classification of important protocol deviations across all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning meetings 
prior to DBL to confirm exclusion from analysis sets. 
3.5 
Analysis sets 
Disposition will be summarized for Enrolled Subjects. Safety variables will be summarized using 
the Safety Set (SS) and efficacy variables will be summarized using the Full Analysis Set (FAS). 
3.5.1 
Enrolled Subjects 
Enrolled subjects will consist of all subjects with epilepsy who gave informed consent, or for 
whom informed consent was given by parent(s)/legal representative(s). 
3.5.2 
Safety Set 
The SS will consist of all enrolled subjects who took at least 1 dose of study medication in this 
long-term study. 
3.5.3 
Full Analysis Set 
The FAS will be used for the analysis of seizure data and will consist of all subjects in the SS, 
who have at least 1 completed post-Baseline DRC or EEG. 
3.6 
Treatment assignment and treatment groups 
The following table displays the planned titration schedule of BRV for DE subjects during the 
study: 
Table 3‒5: 
Recommended BRV dosing schedule for DE subjects in the Up-
Titration Period 
Week 
Dose per dosing occasion (mg/kg) 
BRV dose per day (mg/kg/day) 
TV1 (1) 
~0.5 
~1.0 
TV2 (2) 
~1.0 
~2.0 
TV3 (3) 
~2.0 
~4.0 
BRV=brivaracetam; TV=Titration Visit; "~"=approximately 
Daily doses will not exceed the maximums of 50mg/day, 100mg/day, and 200mg/day for Weeks 
1, 2, and 3 of up-titration, respectively. 
3.7 
Site pooling strategy 
The number of enrolled subjects for most 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 AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Medications will be coded using the World Health Organization Drug Reference 
List (WHO-DRL). Prior and concomitant medical procedures will not be coded; the reported 
procedures will be retained in the study database. 
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3.9 
Possible clinically significant treatment-emergent (PCST) 
values 
Possible clinically significant treatment-emergent values are any laboratory values, vital signs, or 
ECG parameters meeting the criteria defined in Appendix Section 12.1 which occur any time 
after screening and after the first dose of BRV has been taken. The PCST criteria will only be 
applied to analytes that were routinely collected as designated in the protocol. A list of analytes 
that were to be routinely collected is provided Section 9.2.1 of the protocol. 
PCST criteria are based on the FDA Division of Neuropharmacological Drug Products 
guidelines with some UCB-defined additions. 
3.10 
Definitions of study-specific derived variables 
3.10.1 
Definition of treatment-emergent AE 
AEs will be classified as either pre-treatment or treatment emergent. In the following definitions, 
first dose of BRV refers to the first dose in N01266 (i.e., not the first dose of BRV from the core 
study in which subjects participated prior to N01266 for LTFU subjects). Pre-treatment AEs are 
defined as AEs which had an onset date at least one day prior to the first dose of BRV. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that had onset on or after the 
day of first BRV dose. 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 or after the 
month and year of the first BRV dose or the year of onset (when only the year is specified) is the 
same or after the year of first BRV dose. AEs with a missing onset date will also be classified as 
TEAEs provided the subject received at least one dose of BRV. 
3.10.2 
Epilepsy related variables 
The duration of epilepsy is defined as 
Epilepsy duration (years)
= (Date of informed consent −date of epilepsy diagnosis)/365.25 
Or if actual dates are unknown, then use relative ages instead: 
Epilepsy duration (years) = Age at informed consent −age at epilepsy diagnosis. 
The percent of life with epilepsy is derived as: 
Percent of life with epilsepy =
Epilepsy duration
Age at informed consent ∗100 
3.10.3 
Seizures and seizure categories 
Each seizure code in the clinical database will be mapped to exclusively 1 of the following 
seizure types based on the 1981 ILAE classification: IA, IA1, IA2, IA3, IA4, IB, IB1, IB2, IC, 
IIA, IIB, IIC, IID, IIE, IIF, or III. 
With regard to cluster seizures, study 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. In all the efficacy 
analyses, clusters will be counted as one seizure (i.e. 1 cluster = 1 seizure) and assigned to the 
corresponding seizure type. 
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For the evaluation of this study the categorization of subjects to different seizure categories and 
the analysis by these seizure categories is essential.  
Four different seizure categories need to be distinguished and defined: 
• POS – Partial-onset Seizure 
Subjects are categorized as POS subjects at ScrV if either Partial-Onset Seizure is entered 
on the “ILAE Seizure Classification History” eCRF page at ScrV or if it has been 
reported on “Historical Seizure Count” eCRF page for the last 3 weeks prior to ScrV with 
non-zero value. 
• PGS – Primary Generalized Seizure 
Subjects are categorized as PGS subjects at ScrV if either Typical Absence Seizure, 
Atypical Absence, Myoclonic, Clonic, Tonic, Tonic-clonic or Atonic Seizure is entered 
on the “ILAE Seizure Classification History” eCRF page at ScrV or if one of these 
seizure types has been reported on “Historical Seizure Count” eCRF page for the last 3 
weeks prior to ScrV with non-zero value.  
• PGS* – Primary Generalized Seizure excluding Typical Absence 
Subjects are categorized as PGS* subjects at ScrV if either Atypical Absence, Myoclonic, 
Clonic, Tonic, Tonic-clonic or Atonic Seizure is entered on the “ILAE Seizure 
Classification History” eCRF page at ScrV or if one of these seizure types has been 
reported on “Historical Seizure Count” eCRF page for the last 3 weeks prior to ScrV with 
non-zero value.  
• Typical Absence Seizure 
Subjects are categorized as Typical Absence subjects at ScrV if either Typical Absence 
Seizure is entered on the “ILAE Seizure Classification History” eCRF page at ScrV or if 
it has been reported on “Historical Seizure Count” eCRF page for the last 3 weeks prior 
to ScrV with non-zero value.  
If a subject fulfills the requirements for Typical Absence, he is categorized into Typical Absence. 
Otherwise if the subject fulfills the requirements for PGS*, then he is categorized into PGS*. If 
the subject only fulfills the requirements for POS, then he is categorized into POS. PGS category 
is the union of PGS* and Typical Absence categories. 
For assignment of EP0065 LTFU subjects to seizure categories the “Historical Seizure Count” 
eCRF data will be obtained from appropriate EP0065 analysis dataset, whereas “ILAE Seizure 
Classification History” eCRF data is recorded within N01266. 
Subjects which have been rolled-over from core trial N01263 have already been categorized as 
PGS or POS subjects within core analysis dataset. This categorization will be taken over for 
N01266 study. The assignment of N01263 subjects to PGS subcategories Typical Absence 
Seizure or PGS* will be done based on “ILAE Seizure Classification History” eCRF data from 
N01263 analysis dataset. Subjects who cannot be categorized into any of the above categories 
will be uncategorized (UNC). 
All planned analyses by seizure category (Disposition, Demographic and Baseline 
Characteristics, safety and efficacy analyses) will use these defined categories. The UNC 
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category will be presented in Demographic table as a variable and will not be displayed in the 
tables by seizure category. The UNC will be presented as a seizure category in listings. 
3.10.3.1 
Derivation of efficacy variables 
Efficacy variables will be assessed using the seizure count information recorded on the DRC and 
EEG data. Seizure count information will be evaluated over the Evaluation Period by 3-month 
periods based on the DRC (EV until EDV or FV). For DE subjects, seizure count information 
collected during the Up-Titration Period will be summarized separately. The EEG data will be 
reviewed at 6 months and yearly thereafter and presented by visit or by study period overall (no 
time interval presentations planned for EEG). 
For subjects coming from core studies EP0065 and N01349 no EEG based values are available 
which can be obtained as Baseline for N01266. Consequently, these patients will be excluded 
from any efficacy analysis based on EEG data, where Baseline values are considered. If EEG is 
done in N01266 at any visit after Baseline, data should be used to assess any variables which do 
not require Baseline (e.g. seizure freedom). 
Similarly, EP0065 and N01349 studies do not provide Baseline DRC data as compared to other 
core studies. EP0065 and N01349 subjects will be included/excluded in the planned analyses as 
per following table: 
Table 3‒6: 
Inclusion/Exclusion of EP0065 and N01349 data 
Analysis 
EP0065/N01349 included? 
Absolute/percent change in ADF by EEG/ 
Absolute/percent change in 28-days adjusted (POS) 
seizure frequency by DRC 
No 
Responder Rate by EEG/ DRC 
No 
Absolute/percent worsening by EEG/ DRC 
No 
Seizure free days by DRC  
Yes 
Seizure freedom by EEG/ DRC 
Yes 
Average Daily Frequency 
Yes (but not to be included in change from Baseline) 
New incidence of seizure type 
Yes 
Calculations based on EEG data (LTFU subjects only) 
EEG will be only analyzed for LTFU subjects. The Baseline EEG assessment to confirm POS 
seizures for DE subjects will not be used to derive efficacy variables. EEG assessments for 
subjects <2 years of age take 24 hours whereas for subjects ≥ 2 years of age with typical absence 
seizures only 1-hour EEG assessments were performed. 
If the EEG interpretation is different based on EEG data from central reader and from site 
investigator (response captured in eCRF), then the site investigator interpretation is to be used. 
Please follow this table: 
 
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Table 3‒7: 
EEG interpretation 
 
Site investigator interpretation = 
“normal” 
Site investigator interpretation = 
“abnormal” 
Central reader interpretation = 
“Normal”; 0 seizure counts 
No problem 
Use “Abnormal” with missing 
counts: ADF missing 
Central reader interpretation = 
“Abnormal”; >0 seizure counts 
Use “Normal”; 0 counts 
No problem 
Calculation of average daily frequency (ADF) of seizures  
Average daily frequency (ADF) of seizures based on the EEG data (from central reader or eCRF) 
is calculated differently for 1-hour and 24-hour EEG: 
For 1-hour EEG: 
ADF =  Number of seizures from EEG data source considered for 1 hour EEG x 24  
For 24-hour EEG (with missing information on interpretable hours): 
ADF =  Number of seizures from EEG data source considered for 24 hour EEG  
For 24-hour EEG (with information on interpretable hours): 
ADF = Number of seizures from EEG data source considered for 24 hour EEG
Number of interpretable hours
 x 24 
The ADF will be calculated including all seizure types and additionally for POS seizures and 
PGS seizures, separately. 
For certain endpoints, multiple EEG assessments are to be combined. In this instance, for n 
assessments, average ADF is given as: 
Average ADF =
∑
ADF𝑖
𝑛
𝑖=1
𝑛
 . 
Calculation of absolute change/worsening in ADF of seizures 
Absolute change in ADF is calculated as: 
Absolute Change in ADF =  Baseline ADF −postBaseline ADF. 
Both absolute changes will be calculated, with ADF including all seizure types and additionally 
based on POS seizures only. 
Absolute worsening in PGS ADF is calculated as: 
Absolute Worsening in PGS ADF =  postBaseline PGS ADF −Baseline PGS ADF. 
Calculation of percent change/worsening in ADF of seizures 
Percent change in ADF is calculated as: 
Percent Change in ADF = 
Absolute Change in ADF
Baseline ADF
× 100. 
Both percent changes will be calculated, with ADF including all seizure types and additionally 
based on POS seizures only. 
Percent worsening in PGS ADF is calculated as: 
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Percent Worsening in PGS ADF = 
Absolute Worsening in PGS ADF
Baseline PGS ADF
× 100. 
Calculation of response  
Response is defined to be equal to 1 for Percent Change in ADF >=50% and 0 for <50%. Both 
responses will be calculated, with percent change in ADF including all seizure types and 
additionally based on POS seizures only. 
For subjects <2 years of age response is based on the 24-hour EEGs performed over the 
Evaluation and Down-Titration Period separately. 
For subjects ≥ 2 years of age with typical absence seizures categorization, response is based on 
the 1-hour EEGs performed over the Evaluation and Down-Titration Period separately. 
Calculation of Seizure freedom 
The categorical variable Seizure freedom is defined to be equal to 1 if none of the EEG 
assessments within the reported time period (Evaluation Period or Down-Titration Period) have 
shown occurrence of any seizures and 0 otherwise. 
For subjects <2 years of age seizure freedom is based on the 24-hour EEGs performed over the 
Evaluation and Down-Titration Period separately. 
For subjects ≥ 2 years of age with typical absence seizures categorization, seizure freedom is 
based on the 1-hour EEGs performed over the Evaluation and Down-Titration Period separately.  
Calculation of Seizure freedom rate 
Seizure freedom rate will be determined as follows: 
Seizure freedom rate of Time Period  =  
100 × [Number of subjects who were seizure free over reported Time Period 
Number of subjects who entered reported Time Period 
with at least one evaluable EEG assessment during the Time Period
] 
The denominator includes only those subjects applicable, depending on age group and seizure 
categorization. See calculation of Seizure freedom. 
Calculations based on DRC data 
DRC data will be analyzed for DE and LTFU subjects.  
Calculation of average daily frequency (ADF) of seizures and 28-day adjusted seizure frequency  
Average daily frequency (ADF) of seizures based on the DRC data is calculated over the 
Evaluation Period, by visit and by 3-month time intervals: 
ADF = 
∑
seizure count entered at day i
n
i=1
n
 , 
where n is the number of days with non-missing seizure count entry in the DRC during the 
reporting time period. The reporting time period includes the start date but excludes the stop date 
of the time period.  
For DE subjects, Baseline ADF will take DRC data from ScrV to TV1 into account only. For 
LTFU subjects, Baseline diary data is obtained from Baseline of the core study. 
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The ADF will be calculated including counts for all seizure types and additionally for POS 
seizures only. 
The 28-day adjusted seizure frequency is calculated as: 
28day adjusted seizures frequency =  ADF × 28 
The Baseline 28-day adjusted seizure frequency will be calculated using the Baseline ADF.  
The 28-day adjusted POS seizure frequency will be calculated using the POS ADF respectively. 
Calculation of absolute change/worsening in 28-day adjusted seizure frequency  
Absolute change in 28-day adjusted seizure frequency is calculated as:  
Absolute Change in 28 day adjusted seizure frequency
=  Baseline 28 day adjusted seizure frequency
−postBaseline 28 day adjusted seizure frequency. 
Absolute change in 28-day adjusted POS frequency is calculated similarly including 28-day 
adjusted POS frequencies.  
Absolute worsening in 28-day adjusted seizure frequency is calculated as:  
Absolute Worsening in 28 day adjusted seizure frequency
=  postBaseline 28 day adjusted seizure frequency
−Baseline 28 day adjusted seizure frequency. 
Calculation of percent change/worsening in 28-day adjusted seizure frequency  
Percent change in 28-day adjusted seizure frequency is calculated as: 
Percent Change = Absolute Change in 28 day adjusted seizure frequency
Baseline 28 day adjusted seizure frequency 
× 100 
Percent change in 28-day adjusted POS frequency is calculated similarly including 28-day adjusted POS 
frequencies. 
Percent worsening in 28-day adjusted seizure frequency is calculated as: 
Percent Worsening = Absolute Worsening in 28 day adjusted seizure frequency
Baseline 28 day adjusted seizure frequency 
× 100 
Calculation of response  
Response is defined to be equal to 1 for Percent Change in 28-day adjusted seizure frequency 
>=50% and 0 for <50%. 
Response will be calculated in both ways: based on 28-day adjusted seizure frequency, including 
all seizure types, and based on 28-day adjusted POS frequency, including POS seizures only.  
The responder rate is based on the DRC data performed over Up-Titration, Evaluation and 
Down-Titration Period separately. 
Calculation of Proportion of seizure free days  
The proportion of seizure free days is calculated as:  
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Proportion of Seizure free days = Number of Days with no Seizures on DRC Data
Number of Days of recorded DRC Data 
 
All seizure types will be taken into account. The proportion of seizure free days will be 
calculated over Evaluation Period, by visit and by 3-month time intervals. 
Calculation of Seizure freedom 
The categorical variable Seizure freedom is defined to be equal to 1 if the following criteria are 
fulfilled: 
Criterion 1: A subject completed the reported Time Period  
− Up-Titration Period: for DE subjects only, if at least one eCRF during Up-Titration 
Period is entered (only Baseline/TV1, Baseline/TV1 and TV2 or Baseline/TV1, TV2 and 
TV3 could be entered, dependent on subject’s individual titration)  
− Evaluation Period: if the FV or EDV eCRF page (named FIN) is entered  
− Down-Titration Period: if the eCRF DTV page is entered (DTV is the final visit for the 
Down-Titration Period) 
Criterion 2: The seizure diary was completed for at least 90% of days from start date of the 
appropriate Time Period up to the day prior to the end date of the appropriate Time Period. 
Criterion 3: All entered seizure codes have a count of 0 from the day after start date of 
appropriate Time Period (ie, not including the start date of appropriate Time Period) up to and 
including the end date of the appropriate Time Period. (If a seizure code is entered, a missing 
count will lead to a violation of this criteria, too.) 
If one of the criteria is not fulfilled, Seizure freedom is defined to be equal to 0.  
Seizure freedom will be based on DRC data collected over the Up-Titration, Evaluation and 
Down-Titration Period separately. All seizure types will be taken into account. 
Calculation of Seizure freedom rate 
Seizure freedom rate will be determined as follows: 
Seizure freedom rate of Time Period  =  
100 × [Number of subjects who were seizure free over reported Time Period 
Number of subjects who entered reported Time Period 
with at least one DRC entry during the Time Period 
] 
All seizure types will be taken into account. 
Calculation of Seizure freedom by visit 
The categorical variable Seizure freedom by visit is defined to be equal to 1 if the following 
criteria are fulfilled: 
Criterion 1: The question “Have there been any seizures since the last visit?” has been answered 
with “No” and all entered seizure codes in the DCR have a count of 0 since prior visit. (If a 
seizure code is entered, a missing count will lead to a violation of this criteria, too.) 
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Criterion 2: The seizure diary was completed for at least 90% of days since prior visit. The 
percentage of days for which diary data were entered since the prior visit will be calculated as 
follows: 
% of days diary was done =  
100 × [Days since prior visit - number of days diary was not done in the interval
Days since prior visit
]  
 
If one of the criteria is not fulfilled, Seizure freedom by visit is defined to be equal to 0.  
Seizure freedom by visit will be based on DRC data and eCRF data collected over the Up-
Titration, Evaluation and Down-Titration Period separately. All seizure types will be taken into 
account. 
Calculation of seizure freedom by time interval 
The categorical variable Seizure freedom by time interval is defined to be equal to 1 if the 
following criteria are fulfilled: 
Criterion 1: All entered seizure codes have a count of 0 from the day after start date of 
appropriate time interval (i.e., not including the start date of appropriate time interval) up to and 
including the end date of the appropriate time interval. (If a seizure code is entered, a missing 
count will lead to a violation of this criteria, too.) 
Criterion 2: The seizure diary was completed for at least 90% within the time interval. The 
percentage of days for which diary data was completed within a given 6-month interval will be 
calculated as follows based on a 30-day month: 
% of days diary was done = 100 × [180 −number of days diary was not done in the interval
180
]  
A similar calculation applies for 3-month seizure freedom based on 90 days and 12-month 
seizure freedom based on 360 days. 
If one of the criteria is not fulfilled, Seizure freedom by time interval is defined to be equal to 0.  
Seizure freedom by time interval will be based on DRC data collected over the Up-Titration, 
Evaluation and Down-Titration Period separately. All seizure types will be taken into account.  
Calculation of Incidences for new seizure types 
To calculate incidences of new seizure types and subtypes a shift table from Present at Baseline 
(Yes, No, Missing, Total) to Present during Evaluation Period (Yes, No, Missing, Total) will be 
prepared. Subjects who do not have results for subtypes at Baseline will be presented with “not 
assessed” Baseline results and their respective Evaluation Period result. Whenever only subtype 
information is available the seizure type results will be derived as follows: 
• Seizure type I is Present at Baseline = “Yes” if at least one of the subtypes IA, IB, IC is 
present at Baseline. It is Present at Baseline = “Missing” if data for all subtypes is missing. 
Otherwise, Present at Baseline = “No”.  
(Same rule is to apply to summarize sub-subtypes IA1, IA2, IA3 and IA4 into IA. IA is 
Present at Baseline = “Yes” if at least one of the subtypes IA1, IA2, IA3 or IA4 is present at 
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Baseline. IA is Present at Baseline = “Missing” if data for all sub-subtypes is missing. 
Otherwise, Present at Baseline = “No”.) 
• Seizure type II is Present at Baseline = “Yes” if at least one of the subtypes IIA, IIB, IIC, 
IID, IIE, IIF is present at Baseline. It is Present at Baseline = “Missing” if data for all 
subtypes is missing. Otherwise, Present at Baseline = “No”.  
• Seizure type III does not have subtypes, so derivations are not applicable.  
Incidences are the percentages for seizures which were not present at Baseline but present during 
Evaluation Period: 
Incidence of seizure type =
Count of subjects with seizure (sub)type not 
present at Baseline but present in Evaluation Period
Total number of subjects with seizure (sub)type not present at Baseline 
Incidences will be calculated separately for Down-Titration Period. 
3.10.4 
Direct cost parameters 
Direct cost parameters will be assessed based on concurrent medical procedures, health care 
provider consultations not foreseen by protocol, hospital stays, and emergency room (ER) visits. 
3.10.4.1 
Medications (AED and non-AED) 
Each medication will be classified as either an AED or a non-AED, and classification will be 
conducted at Data Evaluation Meetings (DEM). AED outputs will reflect AED evaluation result 
of concomitant Benzodiazepine from the data review meetings. 
According to the time of intake, medications will be classified into five categories: 
• Prior Medications: For DE subjects, prior medications include any medications that started 
prior to the first dose of study drug in N01266. For LTFU subjects, prior medications include 
any medications that started prior to the first dose in the core study. 
• Previous Medications: Previous medications are a subset of prior medications. For DE 
subjects, previous medications include any medications that started and stopped prior to the 
first dose of study drug in N01266. For LTFU subjects, previous medications include any 
medications that started and stopped prior to the first dose in the core study. 
• Medications at study entry: For DE subjects, medications at study entry include any 
medications taken at ScrV. For LTFU subjects, medications at study entry include any 
medication taken at entry of the core study. 
• Concomitant Medications: Concomitant medications include any medications that were taken 
at least one day in common with study treatment. 
• Follow-up Medications: Follow-up medications include any medication that start after final 
dose of study drug. 
Medications can be either previous or concomitant, not both. Medications with an incomplete 
onset date will be classified as concomitant, and not previous, if the month and year of onset 
(when only the month and year are specified) is the same as the month and year of the first BRV 
dose or the year of onset (when only the year is specified) is the same as the year of first BRV 
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dose. Medications with a missing onset date will also be classified as concomitant, and not 
previous provided the subject received at least one dose of BRV. 
3.10.4.2 
Concurrent medical procedures 
Concurrent medical procedures will be attributed to study periods based on the start date of the 
procedure. Study periods are as defined in Section 3.2.3. 
3.10.4.3 
Additional healthcare provider visits 
Healthcare provider consultations not foreseen by the protocol will be attributed to study periods 
based on the date of consultation. 
3.10.4.4 
Hospital stays 
Hospital stays will be attributed to study periods based on admission date. 
The duration of each hospital stay will be calculated as discharge date minus the admission date 
(Hospitalization Visit Date on the CRF) plus 1 day for hospital stays with a discharge date.  
The durations of hospital stays will be summed within each of the Evaluation, Down-Titration, 
and Safety study periods. Subjects with no hospital stays within a study period will have a 
duration of 0 days for that period. Should distinct records for hospital stays overlap, then the 
days during the overlap will only be counted once. 
Hospital stay durations will be categorized as follows: 1 day, 2-5 days, 6-10 days, 11-15 days 
and >15 days. 
3.10.4.5 
Emergency room visits 
Emergency room (ER) visits will be attributed to study periods based on admission date. 
The duration of each ER visit will be calculated as discharge date minus the admission date (ER 
Visit Date on the CRF) plus 1 day for emergency room visits with a discharge date.  
Both ER visits that result in a subsequent hospital stay and ER visits that do not result in a 
subsequent hospital stay will be counted. 
3.10.5 
Questionnaire data 
For all questionnaire data where different languages or terminology is used between patients, the 
differences in questionnaires will be reviewed in a blinded manner prior to database lock in order 
to determine whether responses may be grouped. 
3.10.5.1 
Achenbach CBCL 
The Achenbach CBCL form is a questionnaire intended to evaluate a child’s competencies and 
behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the 
Achenbach CBCL is used. The Achenbach CBCL/1½-5 checklist is intended for use in children 
aged between 18 months and 5 years and 11 months. For subjects between 6 years and < 17 
years, the Achenbach CBCL/6-18 version is used. The Achenbach CBCL is not applied to 
children below 18 months of age. 
The CBCL/1½-5 checklist comprises 100 questions and the CBCL/6-18 checklist comprises 120 
questions with the response options of: 
• 0=not true (as far as known) 
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• 1=somewhat or sometimes true 
• 2=very true or often true 
The CBCL/1½-5 checklist will be grouped according to syndrome scales according to Table 3‒8 
and the CBCL/6-18 checklist will be grouped according to the empirically based syndrome 
scales in Table 3‒9. 
Table 3‒8: 
CBCL/1½-5 checklist  
Syndrome scale 
Questions 
Aggressive behavior 
8, 15, 16, 18, 20, 27, 29, 35, 40, 42, 44, 53, 58, 66, 69, 
81, 85, 88, 96 
Anxious / depressed 
10, 33, 37, 43, 47, 68, 87, 90 
Attention problems 
5, 6, 56, 59, 95 
Emotionally reactive 
21, 46, 51, 79, 82, 83, 92, 97, 99 
Sleep problems 
22, 38, 48, 64, 74, 84, 94 
Somatic complaints 
1, 7, 12, 19, 24, 39, 45, 52, 78, 86, 93 
Withdrawn 
2, 4, 23, 62, 67, 70, 71, 98 
Table 3‒9: 
CBCL/6-18 checklist 
Syndrome scale 
Questions 
Aggressive behavior 
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 94, 
95, 97, 104 
Anxious / depressed 
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112 
Attention problems 
1, 4, 8, 10, 13, 17, 41, 61, 78, 80 
Rule-breaking behavior 
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101, 
105, 106 
Social problems 
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79 
Somatic complaints 
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g 
Thought problems 
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 100 
Withdrawn / depressed 
5, 42, 65, 69, 75, 102, 103, 111 
The sum of the raw score of values within each syndrome scale will be calculated for each 
subject according to the questionnaire used.  
Standardized T-scores are determined from each subject’s raw syndrome score based on the 
subject’s age and sex. Tables mapping each raw score to the appropriate T-score are provided in 
the CBCL Professional Manual and will be reproduced programmatically. 
Further T-scores will be categorized with regard to clinical significance (CS) to summarize 
categorical shift from Baseline. The legacy categories for CS are defined as follows: 
• If T-score is < 65 then CS category = “Normal” 
• If T-score is 65 - < 70 the CS category = “Borderline” 
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• If T-score is >= 70 then CS category = “Clinically Significant”. 
T-scores will also be categorized using the dichotomous approach with regard to CS to 
summarize categorical shift from Baseline. The categories for CS are defined as follows: 
• If T-score is < 65 then CS category = “Normal” 
• If T-score is 65=< the CS category = “Borderline or Clinical Range” 
Achenbach CBCL will be conducted at ScrV, EV (for DE and LTFU subjects respectively), at 
FEVs, YEVs and FV/EDV. The version of the Achenbach CBCL appropriate to each subject’s 
age should be administered with the following exception: If a subject completed the Achenbach 
CBCL/1½-5 at the Baseline assessment and turns 6 years of age between that assessment and the 
initial YEV, the CBCL/1½-5 should be completed through and including the initial YEV, and 
subsequently the CBCL/6-18 should be completed. Moreover, if a subject was below 18 months 
of age at Baseline but turns ≥ 18 months between Baseline and initial YEV, Achenbach 
CBCL/1½-5 will be assessed at visits after initial YEV. 
The change from Baseline will be calculated using T-scores and raw scores by subtracting the 
Baseline result (ScrV or EV) from the post-Baseline visit result: 
Change from Baseline = Score at postBaseline visit −Score at Baseline 
at each visit in the Evaluation Period, if Baseline value is available. A decrease from Baseline 
(change from Baseline < 0) indicates improvement in behavior, while an increase (change from 
Baseline > 0) indicates worsening. 
3.10.5.2 
BRIEF scores 
The BRIEF form is a questionnaire entered for subjects ≥ 5 years of age to assess subjects’ 
executive functioning. Executive functions broadly encompass a set of cognitive skills that are 
responsible for the planning, initiation, sequencing, and monitoring of complex goal-directed 
behavior.  
The BRIEF form should be used for subjects ≥ 5 years of age, and within the following 
exception: for subjects who completed the BRIEF-P at Baseline assessment and turns 5 years of 
age between that assessment and the initial YEV, the BRIEF-P should be completed through and 
including initial YEV, and subsequently the BRIEF should be completed. 
The questionnaire comprises 86 questions with entry options of N (never; scored as 1 point), S 
(sometimes; scored as 2 points) and O (often; scored as 3 points). Higher scores reflect poorer 
functioning. The questions are categorized in 8 components: Inhibit, Shift, Emotional Control, 
Initiate, Working Memory, Plan/Organize, Organization of Materials and Monitor. Additionally, 
three subscales will be used to calculate subscale scores. 
Table 3‒10 presents which questions belonging to which component and the constitution of 
subscales. 
Table 3‒10: BRIEF components and subscales 
Scale/Index 
Questions 
Inhibit 
38, 41, 43, 44, 49, 54, 55, 56, 59, 65 
Shift 
5, 6, 8, 12, 13, 23, 30, 39 
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Scale/Index 
Questions 
Emotional Control 
1, 7, 20, 25, 26, 45, 50, 62, 64, 70 
Initiate 
3, 10, 16, 47, 48, 61, 66, 71 
Working Memory 
2, 9, 17, 19, 24, 27, 32, 33, 37, 57 
Plan/Organize 
11, 15, 18, 22, 28, 35, 36, 40, 46, 51, 53, 58 
Organization of Materials 
4, 29, 67, 68, 69, 72 
Monitor 
14, 21, 31, 34, 42, 52, 60, 63 
BRI 
All questions from Inhibit, Shift, and Emotional 
Control 
MI 
All questions from Initiate, Working Memory, 
Plan/Organize, Organization of Materials, and Monitor 
GEC Score 
Questions 1-72 
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite. 
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and sex. Tables that map each raw score to the appropriate T-
score are provided in the BRIEF Professional Manual and will be reproduced programmatically. 
In addition, T-scores will be categorized with regard to CS to summarize categorical shift from 
Baseline. The legacy categories for CS are defined as follows: 
• If T-score is 0 - < 50 then CS category = “Normal” 
• If T-score is 50 - < 65 the CS category = “Borderline” 
• If T-score is >= 65 then CS category = “Clinically Significant”. 
T-scores will also be categorized using the dichotomous approach with regard to CS to 
summarize categorical shift from Baseline. The categories for CS are defined as follows: 
• If T-score is < 65 then CS category = “Normal” 
• If T-score is >= 65 then CS category = “Potentially Clinically Significant”. 
Two validity scales will also be derived: Negativity to assess the extent to which the respondent 
answers selected BRIEF items in an unusually negative manner and Inconsistency to assess the 
extent to which the respondent answers similar BRIEF items in an inconsistent manner. The 
Negativity scale is the number of items in 8, 13, 23, 30, 62, 71, 80, 83 and 85 with a score of 3, 
and so has a range of 0 to 9. A score of 4 or less is considered acceptable, 5 to 6 elevated and 7 
or more highly elevated. 
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale 
is the sum of the absolute values of the difference in scores for the items in each item pair, and so 
ranges from 0 to 20. The item pairs are questions 7 and 25, 11 and 22, 27 and 17, 33 and 32, 38 
and 59, 41 and 65, 42 and 63, 44 and 54, 53 and 60, and 55 and 44. A score of 6 or less is 
acceptable, 7 or 8 questionable and 9 or more inconsistent.  
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BRIEF will be conducted at ScrV, EV (for DE and LTFU subjects respectively), at FEVs, YEVs 
and FV/EDV.  
Change from Baseline in BRIEF scores (for raw scores and T-scores) will be calculated as:  
Change from Baseline in BRIEF
= BRIEF score at postBBaseline visit −BRIEF score at Baseline 
at each visit in the Evaluation Period, if Baseline value is available. A change from Baseline < 0 
indicates improvement and a change from Baseline > 0 worsening. 
3.10.5.3 
BRIEF-P scores 
The BRIEF-P is a questionnaire entered for subjects ≥ 2 to < 5 years of age to assess subjects’ 
executive functioning. The questionnaire comprises 63 questions with entry options of N (never; 
scored as 1 point), S (sometimes; scored as 2 points), and O (often; scored as 3 points). Higher 
scores reflect poorer functioning. The questions are categorized in 5 components: Inhibit, Shift, 
Emotional Control, Working Memory and Plan/Organize. Additionally, three subscales will be 
used to calculate subscale scores. 
The BRIEF-P form should be used for subjects ≥ 2 to < 5 years of age, with the following 
exception: for subjects who completed the BRIEF-P at Baseline assessment and turns 5 years of 
age between that assessment and the initial YEV, the BRIEF-P should be completed through and 
including initial YEV, and subsequently the BRIEF should be completed. Moreover, if a subject 
was below 2 years of age at Baseline but turns ≥ 2 years between Baseline and initial YEV, 
BRIEF-P will be assessed at visits after initial YEV. 
Table 3‒11 presents which questions belonging to which component and the constitution of 
subscales. 
Table 3‒11: BRIEF-P components and subscales 
Scale/Index 
Questions 
Inhibit 
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 
62 
Shift 
5,10, 15, 20, 25, 30, 35, 40, 45, 50 
Emotional Control 
1, 6, 11, 16, 21, 26, 31, 36, 41, 46 
Working Memory 
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 
61, 63 
Plan/Organize 
4, 9, 14, 19, 24, 29, 34, 39, 44, 49 
ISCI 
All questions from Inhibit and Emotional Control 
FI 
All questions from Shift and Emotional Control 
EMI 
All questions from Working Memory and 
Plan/Organize 
GEC Score 
1-63 
EMI=Emergent Metacognition Index, FI=Flexibility Index, GEC=Global Executive Composite, ISCI=Inhibitory 
Self Control Index  
Standardized T-scores are determined from each subject’s raw GEC, ISCI, FI, EMI, and 
component scores based on the subject’s age and sex. Tables that map each raw score to the 
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appropriate T-score are provided in the BRIEF-P Professional Manual and will be reproduced 
programmatically.  
Similar to analysis for BRIEF, the T-scores for BRIEF-P will be categorized using the legacy 
and the dichotomous approach to summarize categorical shift from Baseline. The same 
categorization as described in Section 3.10.5.2 applies. 
Two validity scales will also be derived: Negativity to assess the extent to which the respondent 
answers selected BRIEF-P items in an unusually negative manner and Inconsistency to assess the 
extent to which the respondent answers similar BRIEF-P items in an inconsistent manner. The 
Negativity scale is the number of items in 30, 44, 46, 47, 53, 55, 56, 57,59 and 63 with a score of 
3, and so has a range of 0 to10. A score of 2 or less is considered acceptable, 3 as elevated and 4 
or more highly elevated. 
For the Inconsistency scale, there are 10 item pairs of related questions. The Inconsistency scale 
is the sum of the absolute values of the difference in scores for the items in each item pair, and so 
ranges from 0 to 20. The item pairs are questions 1 and 11, 3 and 33, 5 and 45, 10 and20, 11 and 
26, 16 and 21, 18 and 52, 33 and 38, 43 and 52, and 48 and 54. A score of 7 or less is acceptable 
and 8 or more inconsistent.  
BRIEF-P will be conducted at ScrV, EV (for DE and LTFU subjects respectively), at FEVs, 
YEVs and FV/EDV.  
Change from Baseline in BRIEF-P scores (raw scores and T-scores) will be calculated as: 
Change from Baseline in BRIEF −P
= BRIEF −P score at postBaseline visit −BRIEF −P score at Baseline 
at each visit in the Evaluation Period, if Baseline value is available for all BRIEF-P scores (the 5 
scales, 3 Indices and GEC scores). A change from Baseline < 0 indicates improvement and a 
change from Baseline > 0 worsening. 
3.10.5.4 
PedsQL  
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions (Varni et al, 1999). 
The PedsQL Measurement Model consists of developmentally appropriate forms for pediatric 
subjects ≥2 years to ≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 
years of age. PedsQL generic core scores will be calculated for each of the following 4 PedsQL 
scales for subjects ≥ 2 years of age using most recent pre-dose data: 
• Physical functioning 
• Emotional functioning 
• Social functioning 
• School functioning 
The underlying item score values 0 to 4 (representing responses of: never, almost never, 
sometimes, often and almost always) will be transformed by the function: (100 – [response x 
25]) in order to generate scores of 0, 25, 50, 75 and 100 where a higher value represents a better 
HRQoL. 
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Each dimension score is then calculated as the mean of the transformed item scores from items 
of the considered dimension. In the case of item-level missing data, these will be replaced by the 
average of non-missing item scores from the considered dimension, if at least 50% of the items 
from that dimension are non-missing. 
Summary scores will also be generated: 
 
-       the Psychosocial Health Summary Score will be calculated as the mean of items 
(transformed scores after replacement of missing data) from the Emotional, Social, and School 
Functioning dimensions. However, in the case where the Emotional, Social, or the School 
Functioning scores would be missing, the Psychosocial Health summary score will be set to 
missing.  
 
-       the Physical Health Summary score (same as Physical functioning dimension).  
 
-       the Total score will be calculated as the mean of all PedsQL items (transformed scores after 
replacement of missing data). However, in the case where one of the dimension scores (Physical, 
Emotional, Social, or School Functioning) would be missing, the Total score will be set to 
missing. 
PedsQL will be conducted at ScrV, EV (for DE and LTFU subjects respectively), at FEVs, 
YEVs and FV/EDV. The version of the PedsQL appropriate for each subject’s age should be 
completed, with the following exception: If a subject ages up to the next version of the PedsQL 
between the Baseline assessment and the initial YEV, the version that was used at the Baseline 
assessment should be completed through and including the initial YEV, and subsequently the 
version consistent with his/her age at the time of assessment should be completed.  
Change from Baseline in PedsQL score will be calculated as:  
Change from Baseline in PedsQL
= PedsQL score at postBaseline visit −PedsQL score at Baseline 
if Baseline value is available. A change from Baseline > 0 indicates improvement and a change 
from Baseline < 0 worsening. 
3.11 
Changes to protocol-defined analyses 
There are no changes to analyses specified in the protocol. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No statistical testing is planned; therefore, this section is not applicable. 
4.2 
Handling of dropouts or missing data 
The method for handling missing and partial dates for medications and AEs is described in 
Section 3.10.4.1 and Section 3.2.3.1 respectively. Missing AE intensity or relationship will be 
imputed according to worst case scenario with severe intensity and assumed to be related. For 
other safety variables, no imputation methods are planned. 
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Regarding efficacy variables, endpoints using seizure frequency and seizure free days based on 
DRC data will be calculated over non-missing diary days during each study period or time 
interval as described in Section 3.10.3.1; days for which seizure diary data were not obtained will 
not be considered in the calculation of seizure frequency or seizure days. This is applicable to the 
analysis taking all seizure categories into account as well as to the analysis taking only POS 
seizures into account. Generally, compliance with the daily seizure diary is expected to be high 
in a refractory population and, therefore, the impact of missing diary data is expected to be 
minimal. Because the evaluation of efficacy is not the primary objective of this study, and 
because this is an uncontrolled study in a variable setting, which allows individualized 
optimization of dosing of BRV and concomitant AEDs, no summaries assessing the impact of 
missing seizure diary days are planned. 
For subjects who prematurely discontinue during the Up-Titration, Evaluation or Down-Titration 
Period, the calculation of seizure frequency, seizure free days and seizure freedom will be based 
on available seizure diary days while the subject was receiving BRV. This effectively imputes 
the unobserved seizure frequency after discontinuation with the seizure frequency observed prior 
to discontinuation. The presence of such dropouts may influence the evaluation of the long-term 
outcomes for subjects who either do not discontinue or do not discontinue early in the study. 
Therefore, as described below, selected summaries will be produced by exposure duration 
cohorts to allow an assessment of long-term outcomes without the potentially confounding 
influence of earlier discontinuations. 
Endpoints using seizure data from EEG will only include available data. No imputation method 
will be conducted. 
4.3 
Interim analyses and data monitoring 
Due to the single-arm open-label design of this study, no formal interim analysis as such will be 
performed. However, data may be reported prior to the completion of this study to support 
ongoing data cleaning, annual reports, regulatory submissions, and publications.  
For regulatory submissions based on interim cutoffs, overall summaries will consider all 
assessments after the first dose of BRV and prior to or on the date of the clinical cutoff for 
subjects who are ongoing at the time of the clinical cutoff. 
4.4 
Multicenter studies 
Efficacy and safety outcomes will not be assessed for individual investigator sites due to the 
expected low number for enrollment within each investigator site. 
4.5 
Multiple comparisons/multiplicity 
No statistical testing is planned; therefore, this section is not applicable. 
4.6 
Use of an efficacy subset of subjects 
All subjects who receive at least 1 dose of BRV and have at least 1 post-Baseline DRC or EEG 
will be included in efficacy summaries. No additional efficacy subsets are defined for this study. 
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4.7 
Active-control studies intended to show equivalence 
This section is not applicable for this study. 
4.8 
Examination of subgroups 
Selected summaries will be provided for the following subgroups as specified within each of the 
following sections: 
• Previous pediatric BRV study experience, labelled with “Cohort” (LTFU subjects overall and 
by core study, DE subjects) 
• Age group (≥ 1 month to < 2 years of age (28 days to 23 months), ≥ 2 to < 4 years of age, ≥ 4 
to < 12 years of age, ≥ 12 to < 17 years of age) 
• Seizure category (POS, PGS*, Typical Absence, PGS) as defined in Section 3.10.3. 
• Geographical region (North America, Latin America, Western Europe, Eastern Europe, 
Asia/Pacific/Other) 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
An overall summary of disposition will be provided for enrolled subjects, in SS and FAS, and in 
SS by subgroups, separately. The following will be summarized: 
• The number of enrolled subjects 
• The number of screen failures (DE subjects only) 
• The number of subjects in the SS (applicable for enrolled subjects table only) 
• The number of subjects excluded from the SS (applicable for enrolled subjects table only) 
• The number of subjects in the FAS (applicable for enrolled subjects table only) 
• The number of subjects entering the Up-Titration, Evaluation, Down-Titration Period 
• The number of subjects completing the Up-Titration and entering the Evaluation  
• The number of subjects completing the study 
• The number of subjects ongoing in the study (only applicable before final data base lock) 
• The overall number of subjects discontinuing and the number of subjects discontinuing by 
primary reason for discontinuation. If the subject discontinued the study and the termination 
CRF is not available, the reason for discontinuation will be reported as “UNKNOWN”. 
Overall subject disposition will also be summarized by cohort (LTFU vs. DE), and geographical 
region, by seizure category and by core study for the SS. 
The number of subjects by cohort and geographical region will be summarized for the SS. 
The number of subjects in each analysis set (Enrolled Subjects, SS and FAS) will be presented 
by investigator and cohort, including the dates of the first subject in (date of earliest EV for the 
N01266 study) and the last subject out (date of final scheduled or UV). The table will be 
presented overall and by region.  
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The number of subjects and Kaplan-Meier estimates of the percentage of subjects completing 3, 
6, 12, 24, 36, 48 and 60 months of treatment with BRV in the N01266 study will be provided. 
This analysis will be based on duration of exposure to BRV as defined in Section 3.2.7. Subjects 
who have permanently discontinued will be analyzed as events on the final day of treatment with 
BRV; subjects who complete the study will be censored on the final day of treatment with BRV.  
Subjects who transferred sites will be summarized according to their original site. 
Subject disposition will be listed for all subjects enrolled and will include the following 
information: subject status (screen failure, completed or discontinued), date of informed consent, 
date and time of first and last study medication (including relative day for last dose), date of 
premature study termination (if applicable) and primary reason for termination (if applicable) 
and date of last contact. For screen failures the date and reason for screen failure will be listed. 
5.2 
Protocol deviations 
Important protocol deviations are deviations from the protocol, which potentially could have a 
meaningful impact on either the primary efficacy outcome or key safety outcomes for an 
individual subject. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the project Data Cleaning 
Plan. Important protocol deviations will be reviewed as part of the ongoing data cleaning 
meetings prior to database lock to confirm exclusion from analysis sets. 
The number and percentage of subjects with at least 1 important protocol deviation will be 
summarized in SS overall and by category of protocol deviation. This summary will be presented 
overall, by age group, by seizure category and by cohort (see Section 4.8). 
All important protocol deviations will be provided in a data listing. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Demographic and other Baseline characteristic variables will be presented for the SS and will be 
summarized by age group as categorized in Section 4.8, and overall. 
Unless otherwise mentioned, for DE subjects, demographic and Baseline variables will be 
obtained at ScrV, whereas for LTFU subjects, all demographic and Baseline variables will be 
based on data collected at the time of entry into the core study.  
6.1 
Demographics and Baseline characteristics 
Baseline age will be determined at either ScrV (DE subjects) or EV (LTFU subjects). Age will 
be calculated based on an assumed date of birth of January 1 for subjects who only have a year 
of birth based on region-specific regulations. 
Body Mass Index will be calculated as: 
BMI = weight in kilograms
(height in meters)2                        
The age will be calculated as: 
• 
years= (intck('month',brthdtc,rficdtc)-(day(rficdtc) < min(day(brthdtc), day(intnx 
('month', rficdtc, 1)-1) ) )) /12  
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• months = intck('month',birth,somedate) - (day(somedate) < day(birth)); 
 
Age (in years), age (in months), gender, overall racial group (White, Black, Asian, Other), racial 
group (American Indian/Alaskan Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other/Mixed), ethnicity (Hispanic or Latino, not Hispanic or Latino), region 
(North America, Latin America, Western Europe, Eastern Europe, Asia Pacific and others), 
weight (kg), height (cm), BMI (kg/m2), BMI category (< 18.5, 18.5 to < 25, 25 to < 30, ≥ 30 
kg/m2), head circumference (cm) and seizure category at ScrV (POS, PGS*, typical absence 
seizures, PGS, UNC) will be summarized. This summary will be repeated by cohort, by seizure 
category, by core study and by geographical region. 
All demographic and Baseline characteristics will be listed.  
6.2 
Medical history and concomitant diseases 
The number and percentage of subjects with a medical history condition, including both previous 
and ongoing conditions will be summarized overall and by primary MedDRA system organ class 
(SOC) and preferred term (PT). In addition, this summary will also be done by seizure category. 
All medical history data will be listed. 
6.3 
History of epilepsy 
6.3.1 
Epileptic seizure profile 
The number and percentage of subjects experiencing each seizure category at any time prior to 
study entry will be summarized based on the ILAE Seizure Classification History eCRF. 
The overall number and percentage of subjects with a history of Type I (POS), Type II (PGS), or 
Type III (Unclassified) seizures will also be summarized. A subject will be classified as having a 
history of Type I seizures if the subject has a history of Type IA, IB, or IC seizures. A subject 
will be classified as having a history of Type II seizures if the subject has a history of Type IIA1, 
IIA2, IIB, IIC, IID, IIE, or IIF seizures.  
6.3.2 
Classification of epileptic syndrome 
The number and percentage of subjects with each epileptic syndrome will be summarized based 
on the Classification of Epileptic Syndromes eCRF and will include the number and percentage 
of subjects within each of the categories (localization-related, generalized, epilepsies and 
syndromes undetermined whether focal or generalized, and special syndromes) and 
subcategories of epileptic syndromes. Additionally, this summary will be done separately for 
each seizure category. 
6.3.3 
History of epileptic seizures 
History of epileptic seizures, including the number and percentage of subjects with a history of 
status epilepticus, and quantitative summaries of epilepsy duration, age at diagnosis, and percent 
of life with epilepsy will be summarized separately for subjects with POS categorization at 
Baseline and for subjects with PGS categorization at Baseline.  
For derivation of epilepsy duration and percent of life with epilepsy, see Section 3.10.2. 
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6.3.4 
Historical seizure count 
The Historical Seizure Count eCRF records the number of seizures of each type experienced by 
the subject during the 3 weeks prior to study entry. These data will be provided in a subject data 
listing. 
6.4 
Previous and concomitant medications 
A listing of all medications (previous and concomitant) taken during the study will be presented. 
See Section 3.10.4.1 for the definition of previous, concomitant and follow-up medications. 
For the summarization, similar AEDs are grouped and summarized together. For example: 
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 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. 
6.4.1 
Non-AEDs taken at study entry 
Identification of medications as a non-AED will be done using the UCB file: 
AEDs_ATCs_SEP2017_FINAL_benzo_groups_23JUL2019.xls, which reflects AED evaluation 
result of concomitant Benzodiazepine from the data review meetings. Queries should be raised 
for any cases where this disagrees from the value entered in the eCRF field ‘Core AED’. 
The number and percentage of subjects in the SS taking non-AED medications at the time of 
study entry will be summarized by WHO-DRL anatomical main group, therapeutic group and 
preferred drug name.  
6.4.2 
Number of previous AEDs 
The number of AEDs taken prior to study entry will be summarized based on the following 
categorization: 0-1 AEDs, 2-4 AEDs, and ≥ 5 AEDs. Identification of medications as an AED 
will be done using the UCB file: 
AEDs_ATCs_SEP2017_FINAL_benzo_groups_23JUL2019.xls, which reflects AED evaluation 
result of concomitant Benzodiazepine from the data review meetings. This summary will only 
include AEDs which stopped prior to study entry. In addition, this summary will also be done by 
seizure category. 
6.4.3 
History of previous AED use 
The number and percentage of subjects who had taken at least 1 AED prior to study entry will be 
summarized by preferred drug name. Identification of medications as an AED will be done using 
the UCB file: AEDs_ATCs_SEP2017_FINAL_benzo_groups_23JUL2019.xls, which reflects 
AED evaluation result of concomitant Benzodiazepine from the data review meetings. This 
summary will only include AEDs which stopped prior to study entry. Furthermore, the above 
described summary will be repeated by seizure category. 
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6.4.4 
History of previous AEDs by reason for AED discontinuation 
The number and percentage of subjects who had taken at least 1 AED prior to study entry and 
who had discontinued AED will be summarized overall, by reason for discontinuation of 
previous AEDs (insufficient efficacy, remission, adverse drug reaction, tachyphylaxis, unknown, 
other) and by age group in one table. Additionally, this summary will be done by seizure 
category. 
Percentages for each reason for discontinuation will be relative to the number of subjects taking 
each AED. 
6.4.5 
VNS use and Number of AEDs taken at study entry 
Identification of medications as an AED will be done using the UCB file: 
AEDs_ATCs_SEP2017_FINAL_benzo_groups_23JUL2019.xls, which reflects AED evaluation 
result of concomitant Benzodiazepine from the data review meetings. The number and 
percentage of subjects taking 1, 2, and 3 AEDs at the time of study entry overall and separately 
by vagal nerve stimulation (VNS) use at study entry (no VNS or VNS not active versus currently 
active VNS) will be summarized. This analysis will be done by seizure category in addition. 
6.4.6 
AEDs taken at study entry 
The number and percentage of subjects who had taken at least 1 AED at the time of study entry 
by WHO-DRL preferred drug name will be summarized. In addition, this analysis will be done 
by seizure category. Vagal nerve stimulation is allowed and will be counted as a concomitant 
AED. 
6.4.7 
Concomitant AEDs 
The number and percentage of subjects taking concomitant AEDs overall and by WHO-DRL 
preferred drug name will be summarized by age group. In addition, this analysis will be done by 
seizure category. 
6.4.8 
Concomitant Non-AEDs 
The number and percentage of subjects taking concomitant Non-AEDs overall and by WHO-
DRL anatomical main group, therapeutic group and preferred drug name will be summarized 
overall by age group. In addition, this analysis will be done by seizure category. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
BRV compliance will not be assessed due to the complexities associated with the calculation and 
interpretation of BRV compliance for this study. 
BRV dosing will be provided in subject listings. 
8 
SAFETY ANALYSES 
All presentation for safety parameters will be based on the SS and will be summarized by age 
group and seizure category as categorized in Section 4.8, and overall. 
8.1 
Extent of exposure 
The Evaluation Period BRV exposure duration (in months) will be calculated as the date of the 
final dose of BRV during the Evaluation Period minus the date of the first dose of BRV in the 
Evaluation Period plus 1 day divided by 30. The overall study BRV exposure duration (in 
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months) including Up-Titration Period (only DE subjects), Evaluation Period and Down-
Titration Period (only discontinued subjects) will be calculated as the date of the final dose of 
BRV in this study minus the date of the first dose of BRV in this study plus 1 day divided by 30. 
Subject years of exposure are calculated as overall study BRV exposure duration (in months) 
multiplied by 30 divided by 360. 
Both, the evaluation Period BRV exposure duration and the overall study BRV exposure 
duration will be summarized with quantitative descriptive statistics. The number and percentage 
of subjects with the following categories of Evaluation Period BRV exposure durations will also 
be presented: ≤ 6 months, > 6 to ≤ 12 months, > 12 to ≤ 18 months, > 18 to ≤ 24 months, > 24 to 
≤ 30 months, > 30 to ≤ 36 months, and > 36 months. 
The number and percentage of subjects exposed overall and by 6 month exposure durations (<= 
6 months of exposure, > 6 months of exposure, > 12 months of exposure, > 18 months of 
exposure …) will be presented overall and by modal dose category (see Section 3.2.8). 
Additionally, the table will show mean subject years of exposure overall and by modal dose 
categories. 
All BRV exposure data will be listed. 
8.2 
AEs 
8.2.1 
Overview of TEAEs 
The overview of TEAEs will provide numbers and percentages of subjects with any TEAE, with 
any serious TEAE, with any TEAE that led to permanent discontinuation of BRV, with any 
drug-related TEAE, with any severe TEAE and with any drug-related serious TEAE. The 
number and percentage of subjects who died will also be summarized. This summary will be 
provided by age group in the SS. Additionally, it will be presented by core study, geographical 
region and seizure category as well as by modal dose category.  
TEAEs which occurred during Up-Titration Period for DE subjects will be presented separately. 
The criteria for classification of an AE as serious AE can be found in the protocol section 
9.1.1.2. AEs are drug-related, if this is marked accordingly in the eCRF. 
8.2.2 
Incidences of TEAEs 
Incidence summaries will be presented by SOC and PT. These tables will include the number 
and percentage of subjects and number of events by SOC and PT. For the number of subjects by 
PT, if a subject experiences multiple AE within the same PT, then that PT will only be counted 
once. As with the PT, for the number of subjects by SOC, if a subject experiences multiple AEs 
within the same SOC, then that SOC will be counted only once. Percentages will be calculated 
out of the number of subjects at risk in the SS unless otherwise stated. 
Incidence tables are sorted alphabetically by SOC and decreasing by frequency in PT in the 
overall column. In case of ties, PTs are sorted alphabetically. 
The following TEAE summaries will be presented: 
• Incidence of TEAEs 
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• Incidence of TEAEs by 3-month time interval (one table presenting TEAEs starting within 
time intervals and one presenting those ongoing in the time interval) 
• Incidence of drug-related TEAEs by 3-month time interval 
• Incidence of TEAEs by 1-year time interval 
• Incidence of TEAEs by total duration of exposure cohort (as per categories defined in 
Section 3.2.7) 
• Incidence of TEAEs by study period (Up-Titration, Evaluation, Down-Titration, Safety) 
• Incidence of TEAEs by maximum intensity 
• Incidence of drug-related TEAEs 
• Incidence of serious TEAEs 
• Incidence of drug-related serious TEAEs 
• Incidence of TEAEs for TEAEs occurring in at least 5% of subjects 
• Incidence of TEAEs by 3-month time intervals for TEAEs occurring in at least 5% of 
subjects 
• Incidence of TEAEs by 3-month time intervals for TEAEs occurring in at least 5% of 
subjects by geographical region 
• Incidence of non-serious TEAEs occurring in at least 5% of subjects 
• Incidence of non-serious TEAEs occurring in at least 5% of subjects by geographical region 
• Incidence of drug-related TEAEs occurring in at least 5% of subjects  
• Incidence of drug-related TEAEs occurring in at least 5% of subjects by geographical region  
• Incidence of TEAEs leading to permanent discontinuation of BRV 
• Incidence of drug-related TEAEs leading to permanent discontinuation of BRV 
Tables presenting incidence of TEAEs occurring in at least 5% of subjects will include only 
TEAEs occurring on or above the reporting threshold of 5% in any age group or geographical 
region. 
Additionally, following incidence tables will be presented by total duration of exposure 
categories: 
• Incidence of serious TEAEs 
• Incidence of TEAEs leading to permanent discontinuation of BRV 
A subject number table will be provided that identifies subjects with any TEAE after the first 
dose of BRV. This table will be presented by intensity, relationship, treatment-emergence overall 
and by every subcategory of these variables. 
The overview of TEAE, the incidence of TEAEs and incidence of serious TEAEs will be 
presented by age group, by seizure category, by dose group and by core study. 
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8.2.3 
Incidences of TEAEs of interest 
Incidence of TEAEs of interest as per Section 9.1.1.3 in study protocol will be presented 
separately, by age group as well as by age group and 3-month time interval. 
AEs of interest will be identified based on MedDRA search criteria, which are documented 
outside of the SAP. All AEs which are listed in “BRV List of TEAE Topics of Interest Final 24 
Aug 2018.xlsx” document (provided from UCB) and are flagged with “P” or “B” in appropriate 
column are AEs of interest for this study.  
8.3 
Clinical laboratory evaluations 
Clinical laboratory results will be summarized using conventional units. Observed values and 
change from Baseline values for hematology, biochemistry (including hepatic monitoring of 
ALT, AST, ALP, total bilirubin, and GGT) and endocrinology parameters will be summarized 
for Baseline, each scheduled visit in the Evaluation Period, Last Value on Treatment, and the 
Safety Visit (if available). These summaries will be repeated separately for data collected during 
the Up-Titration visits for DE subjects. 
Presentation of urinalysis results will consider subjects by age group for whom sample collection 
is feasible due to the constraints on collection for subjects below 4 years of age in the protocol. 
Following age groups will be presented: >=4 to <12 years, >=12 years to <17 years and overall.  
In microscopic urinalysis, a small sample of urine is centrifuged to remove the liquid. The 
sediment is then examined under a microscope. In the urinalysis laboratory test group, other than 
qualitative responses, a listing of microscopic analysis parameters will be provided; no 
summaries of microscopic analysis findings are planned. 
Response categories are negative, 1+, 2+, and 3+ for the quantitative urinalysis parameters occult 
blood, leukocytes, glucose, protein, and ketones and negative and positive for nitrates. Outcome 
values for these parameters are mapped to the levels Negative, 1+, 2+, and 3+ as follows for 
purposes of summary tables and the determination of PCST: 
Table 8‒1: 
Urinalysis categorization 
Category 
Definition 
Negative 
“Negative”, “NEGATIVE” or other outcomes that clearly reflect a negative finding 
1+ 
“1+”, “+”, “Trace”, “TRACE” or other outcomes that clearly reflect trace amount 
2+ 
“2+” or “++” 
3+ 
“3+”, “+++” or other outcomes that clearly reflect the data above 3+ (eg, “4+”, “5+” etc.) or more 
than 4 plus signs (eg, “++++”, “+++++” etc.) 
For qualitative urinalysis parameters (occult blood, leukocytes, glucose, protein, ketones, and 
nitrates), the number and percentage of subjects with each response category will be summarized 
for Baseline, EV, each scheduled visit during the Evaluation Period for which urinalysis 
parameters were scheduled to be assessed, Last Value on Treatment, and the Safety Visit. 
Percentages for each parameter will be relative to the number of subjects with a microscopic 
urinalysis assessment at each time point. The summary will be repeated for the Up-Titration 
period for DE subjects. 
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The number and percentage of subjects with any post-Baseline PCST value, any PCST low 
value, and any PCST high value for hematology, biochemistry and urinalysis will be summarized 
for the Evaluation and Safety Periods separately and for the Evaluation and Safety Period 
combined by laboratory parameter overall and by age group. PCST criteria for hematology and 
biochemistry are presented in Appendix Section 12.1 A urinalysis value is considered PCST 
abnormal if an upward shift of at least 2 degrees from the Baseline occurs under investigational 
treatment. Percentages will be relative to the number of subjects with an on-treatment 
assessment. 
Observed values and change from Baseline value tables will only present scheduled visits, 
whereas for PCST tables, values reported at an UV will be summarized under the preceding 
scheduled visit if the abnormality was not already reported at the preceding scheduled visit. 
Treatment emergent for this analysis includes any PCST laboratory abnormalities observed 
during the Evaluation Period. 
A subject number table will be provided that identifies subjects with a PCST finding after the 
first dose of BRV for each type of laboratory abnormality. 
All laboratory parameters (planned and unplanned parameters and assessed on scheduled and 
unscheduled visits) will be provided in subject data listings. 
8.4 
Vital signs, physical findings, and other observations related to 
safety 
8.4.1 
Vital signs 
Vital signs, including measurements of blood pressure, supine or sitting pulse rate, and body 
temperature, are assessed after 5 minutes of rest at the ScrV, TV(s), and EV, MEV, FEV, YEV, 
FV, and at the EDV, Down-Titration Visit (DTV), and the SV in the case of early 
discontinuation. For LTFU subjects, at the EV, vital sign data will be obtained from the final 
visit of the core study (if available) and should not be recorded in the eCRF for N01266. If not 
available, vital signs data will be recorded within N01266 as for DE subjects. 
Observed values and change from Baseline value for SBP, DBP, and pulse rate will be 
summarized for Baseline, EV, each visit during the Evaluation Period for which vital signs or 
body weight were assessed, EDV, Last Value on Treatment, FV, the Down-Titration Visit 
(DTV), and the Safety Visit (if available). This summary will be repeated separately for data 
collected during the Up-Titration visits for DE subjects. 
The PCST criteria are based on FDA Division of Neuropharmacological Drug Products 
guidelines with some UCB-defined additions. 
The number and percentage of subjects with any post-Baseline PCST value, any PCST low 
value, and any PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. 
This summary will consider all assessments after the first dose of BRV and prior to or on the 
date of the final dose of BRV (excluding Up-Titration Assessments for DE Subjects). 
Percentages will be relative to the number of subjects with a post-Baseline assessment. This 
summary will be repeated for the Up-Titration Period for DE Subjects. 
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Additionally, the PCST table will be provided stratified by visit for all visits during Evaluation 
Period. Percentages will be relative to the number of subjects with a value at the corresponding 
visit. 
A subject number table will be provided that identifies subjects with a clinically significant 
finding after the first dose of BRV for each type of vital sign abnormality. 
All vital signs will be provided in subject data listings. 
8.4.2 
ECGs 
A standard 12-lead ECG is performed at the ScrV, TV(s), and EV, YEV, FV, and at the EDV in 
the case of early discontinuation. An ECG is performed at the SV only if the ECG results at the 
EDV are abnormal. At the EV, for LTFU subjects, ECG data will be obtained from the final visit 
of the core study (if available) and should not be recorded in the eCRF for N01266. If not 
available, ECG data will be recorded within N01266 as for DE subjects. The Investigator will 
determine whether the results of the ECG are normal or abnormal and assess the clinical 
significance of any abnormalities. 
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding will be summarized overall and by age 
group. This summary will consider all assessments after the first dose of BRV in the Evaluation 
and prior to or on the date of the final dose of BRV. Percentages will be relative to the number of 
subjects with a post-Baseline assessment in the Evaluation Period. This summary will be 
repeated for the Up-Titration Period for DE Subjects. 
Additionally, this table will be provided stratified by visit for all visits during Evaluation Period. 
Percentages will be relative to the number of subjects with an ECG assessment at the 
corresponding visit. Subjects are counted only once at each time point based on the worst 
observed outcome across all abnormalities reported at that time point. 
A subject number table will be provided that identifies subjects with a clinically significant 
finding after the first dose of BRV for each type of ECG abnormality. 
All ECG data will be provided in subject data listings. 
8.4.3 
Physical examination 
A listing of abnormal physical examination findings will be provided; no summaries of physical 
examination findings are planned. Tanner scale will be recorded as part of the physical 
examination where applicable and will also be listed. 
8.4.4 
Neurological examination 
A standard neurological examination is performed at the ScrV and EV (DE subjects only), FEV, 
YEV, FV, and at the EDV and the SV in the case of early discontinuation. For LTFU subjects, at 
the EV, neurological examination data will be obtained from the final visit of the core study and 
should not be recorded in the eCRF for N01266. 
A listing of neurological examination findings will be provided; no summaries of neurological 
examination findings are planned. 
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8.4.5 
Psychiatric and mental status 
Psychiatric and mental status is reported by recording the presence or absence of psychiatric 
symptoms, mental impairment, and behavioral problems at the ScrV and EV (DE subjects only), 
FEV, YEV, FV, and at the EDV and the SV in the case of early discontinuation. For LTFU 
subjects, at the EV, psychiatric and mental status data is obtained from the final visit of the core 
study.  
A listing of abnormal Psychiatric and Mental Status findings will be provided; no summaries of 
Psychiatric and Mental Status findings are planned. 
8.4.6 
Vagus nerve stimulation (VNS) status 
VNS status is recorded at the ScrV, and EV (DE subjects only), MEV, FEV, YEV, FV and at the 
EDV and the SV. For LTFU subjects at the EV, VNS status is obtained from the final visit of the 
core study. 
A listing of VNS status will be provided; no summaries of VNS data are planned (with the 
exception of VNS information recorded on medication pages, see section 6.4). 
8.4.7 
Neuro-imaging procedures 
A brain MRI or brain CT scan (except in Germany) may be recorded prior to the date of the first 
dose of BRV and used as Baseline if no previous report was available within the 2 years prior to 
study entry into N01266. A listing of neuro-imaging findings will be provided; no summaries of 
neuro-imaging findings are planned. Neuro-imaging procedures are only applicable for LTFU 
subjects. 
8.4.8 
Assessment of suicidality 
Suicidality is assessed by trained study personnel using the C-SSRS (Columbia-Suicide Severity 
Rating Scale) for subjects ≥ 6 years of age. This scale will be used for screening as well as to 
assess suicidal ideation and behavior that may occur during the study.  
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. Additional listings will be provided for the subsets of subjects with 
suicidal ideation and the subset of subjects with actual suicide attempts 
Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions on the C-
SSRS: 
• 
 
• 
 
• 
 
• 
 
• 
 
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Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt questions 
on the C-SSRS: 
• 
 
• 
 
 
• 
 
 
8.4.9 
Reproductive potential and birth control 
A listing of reproductive potential and birth control measures for female as well as male subjects 
will be provided; no summaries of these findings are planned. 
9 
EFFICACY ANALYSES 
All presentation for efficacy parameters will be based on the FAS and will be summarized by age 
group (<2 years and ≥2 years of age) and seizure category as categorized in Section 4.8, and 
overall.  
Efficacy variables will be assessed using the seizure count information recorded on the DRC and 
EEG data. Endpoints derived from the DRC will be summarized separately from those derived 
from the EEG. EEG data collected from 24-hour EEG and 1-hour EEG will be presented 
separately. 
Details of the derivations for all efficacy variables are provided in Section 3.10.3.1. 
All summaries of efficacy data are descriptive; no statistical testing will be performed. 
All seizure data and derived endpoints will be listed. Data from Up-Titration Period (DE subjects 
only) and Down-Titration Period will be listed only, if not otherwise mentioned. 
9.1 
Seizure based variables based on EEG data 
EEG summaries will be presented by age group (< 2 years (24 hour EEG), ≥2 years (1 hour 
EEG)) and by seizure category. Outputs will explicitly restrict the analyses on 24 hour EEG to 
subjects < 2 years of age. If we have 1 hour EEG assessments for subjects categorized as < 2 
years of age according to the Baseline age, we will perform sensitivity analyses in which we 
present results only by age group (< 2 years, ≥2 years), irrespective of the type of EEG 
performed. The POS and PGS* results for subjects ≥2 years will be missing, because EEG is 
only performed for subjects within Typical Absence seizure category there. 
All analyses will be based on data assessed in Evaluation Period only. 
Absolute and percent change in ADF will be summarized by age group and seizure category. 
Additionally, absolute and percent change in POS ADF will be summarized similarly. 
Number of responders based on all seizure categories and the corresponding responder rate will 
be presented. Same will be presented for response based on POS only. 
The number and percentage of seizure free subjects (Seizure freedom) will be presented. 
Absolute and percent worsening based on PGS seizure types will be summarized. 
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All raw EEG seizure counts and derived efficacy variables will be listed. 
9.2 
Seizure based variables based on DRC data 
Absolute and percent change in 28-day adjusted seizure frequency and in 28-day adjusted POS 
seizure frequency will be summarized for the Evaluation Period by seizure category. This 
summary will present both age groups to be consistent with EEG summary and worsening based 
on DRC. The corresponding number and percentage of responder in reduction of 28-day adjusted 
seizure frequency and 28-day adjusted POS seizure frequency will be presented separately.  
For subjects < 2 years of age or ≥ 2 years of age with typical absence seizures, absolute and 
percent worsening will be presented. Additionally, the ADF will be summarized by age group, 
seizure category and visit/time period. 
The proportion of seizure free days over Evaluation Period will be summarized using 
quantitative statistics. This summary will be repeated for proportion of seizure free days by visit 
and by 3-month time interval (including only subjects < 2 years of age or >= 2 years of age with 
typical absence seizures). 
Number and percentages of Seizure freedom will be presented over Evaluation Period. This 
summary will be repeated for seizure freedom by visit and by 3-month time interval (including 
only subjects < 2 years of age or >= 2 years of age with typical absence seizures). 
Shift tables presenting the incidences of new seizures will be prepared to show actual 
occurrences of new seizures as well as the percentages based on subjects under risk (subjects 
without particular seizure type at Baseline). 
All raw DRC data and derived efficacy variables will be listed. 
9.3 
Direct cost parameters 
Direct costs will be assessed based on concomitant medications, concurrent medical procedures, 
health care provider consultations not foreseen by protocol, hospital stays, and ER visits. 
All direct cost parameters will be summarized for the SS. 
All direct cost parameters will be listed. 
9.3.1 
Concomitant medications 
The analysis of concomitant medications is described in Section 6.4.7 and Section 6.4.8.  
9.3.2 
Concurrent medical procedures 
The number of concurrent medical procedures per subject will be summarized by 6-month time 
intervals for the corresponding 6-month Exposure Duration Cohorts. Additionally, the number of 
concurrent medical procedures will be summarized for subjects with < 6 months of exposure to 
BRV. The number of concurrent medical procedures per subject will be summarized using the 
categories 0, 1, 2, 3, 4, and 5 or more. Summaries will be provided for the SS. 
Medical procedures are defined to be concurrent, if they start after first dose of BRV and will be 
attributed to 6-month time intervals based on the date of the procedure. For subjects with < 6 
months of exposure to BRV, all medical procedures on or after the first dose of BRV will be 
counted. 
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9.3.3 
Additional healthcare provider consultations 
The number of additional healthcare provider visits per subject will be summarized by 6-month 
time intervals for the corresponding 6-month Exposure Duration Cohorts. Additionally, the 
number of additional healthcare provider visits will be summarized for subjects with < 6 months 
of exposure to BRV. The number of additional healthcare provider visits will be summarized 
using the categories 0, 1, 2, 3, 4, and 5 or more. Summaries will be provided for the SS. 
Additional healthcare provider visits will be attributed to 6-month time intervals based on the 
date of the procedure. For subjects with < 6 months of exposure to BRV, all additional healthcare 
provider visits on or after the first dose of BRV will be counted. 
The number of additional healthcare provider visits will be summarized by type of provider 
(General Practitioner, Specialist Physician, Nurse, or Other) and by 6-month time intervals for 
the corresponding 6-month Exposure Duration Cohorts, and for subjects with < 6 months of 
exposure to BRV. Percentages will be relative to the total number of health care provider visits 
within each 6-month time interval (for summaries by exposure duration cohorts) or the total 
number of healthcare provider visits for subjects with < 6 months of exposure to BRV. As above, 
this summary will be provided for the SS. 
9.3.4 
Hospital stays 
The number of hospital stays per subject will be summarized by 6-month time intervals for the 
corresponding 6-Month Exposure Duration Cohorts. Additionally, the number of hospital stays 
will be summarized for subjects with < 6 months of exposure to BRV. The number of hospital 
stays will be summarized using the categories 0, 1, 2, 3, 4, and 5 or more. Summaries will be 
provided for the SS. 
Hospital stays will be attributed to 6-month time intervals based on the date of the admission. 
For subjects with < 6 months of exposure to BRV, all hospital stays on or after the first dose of 
BRV will be counted. 
The number and percentage of subjects with specified categories of duration of hospital stays 
will be summarized by 6-month time intervals and the 6-Month Exposure Duration Cohorts. 
Additionally, the number and percentage of specified categories of hospital stays will be 
summarized for subjects with < 6 months of exposure to BRV. Duration of hospital stays will be 
summarized descriptively for the SS. 
The number and percentage of subjects with hospitals stays by duration categories as defined in 
Section 3.10.4.4 will be summarized by 6-month time intervals for the corresponding 6-Month 
Exposure Duration Cohorts. Additionally, this table will be produced for subjects with < 6 
months of exposure to BRV. 
9.3.5 
Emergency room visits 
The number of ER visits per subject will be summarized by 6-month time intervals for the 
corresponding 6-month Exposure Duration Cohorts, and for subjects with < 6 months of 
exposure to BRV. The number of ER visits per subject will be summarized using the categories 
0, 1, 2, 3, 4, and 5 or more. Summaries will be provided for the SS. 
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ER visits will be attributed to 6-month time intervals based on the date of the ER visit. For 
subjects with < 6 months of exposure to BRV, all ER visits on or after the first dose of BRV will 
be counted. 
9.4 
Achenbach Child Behavior Checklist 
The Achenbach CBCL is completed at the ScrV (DE subjects only), FEV, YEV, FV, and at the 
EDV in the case of early discontinuation. For LTFU subjects (except for those from core studies 
EP0065 and N01349), at the EV, the Achenbach CBCL score is obtained from the Baseline of 
the core study and should not be recorded in the eCRF for N01266. For DE subjects, the 
Achenbach CBCL completed at the ScrV and for EP0065 LTFU subjects the Achenbach CBCL 
completed at the EV, will be the Baseline assessment. For LTFU subjects from core study 
N01349 Achenbach CBCL Baseline assessment is not available, as this questionnaire was not 
performed in core study N01349 and not recorded at EV in N01266 study. 
Calculated T-score values and raw score values and the corresponding change from Baseline for 
each CBCL/1½-5 syndrome (aggressive behavior, anxious / depressed, attention problems, 
emotionally reactive, sleep problems, somatic complaints, withdrawn) will be summarized for 
each scheduled visit during the Evaluation Period if available. 
Calculated T-score and raw score values and corresponding change from Baseline for each 
CBCL/6-18 syndrome (aggressive behavior, anxious / depressed, attention problems, rule-
breaking behavior, social problems, somatic complaints, thought problems, and withdrawn / 
depressed) will be summarized for each scheduled visit during the Evaluation Period if available. 
Additionally, for all CBCL/1½-5 syndromes as well as CBCL/6-18 syndromes, shift tables for T-
scores will be done. These shift tables are based on T-score legacy categorization “Normal”, 
Borderline” or “Clinical Significant” and the dichotomous approach “Normal” or “Borderline or 
Clinical Range” as described in Section 3.10.5.1 and will summarize the shift from Baseline for 
each visit during the Evaluation Period if available and for the last assessment. These shift tables 
will not include LTFU subjects from core studies N01349 as Baseline values are not available 
from this study.  
All Achenbach CBCL data will be listed. Data assessed on unscheduled visits will be included in 
listings only. 
 
9.5 
BRIEF-P and BRIEF assessment 
The BRIEF-P/BRIEF assessments are completed at the ScrV (DE subjects only), FEV, YEV, 
FV, and at the EDV in the case of early discontinuation. For LTFU subjects (except those 
coming from core studies N01349, EP0065 and N01263), at the EV of N01266, the BRIEF-
P/BRIEF score will be obtained from Baseline of the core study and should not be recorded in 
the eCRF for N01266. For DE subjects and LTFU subjects from core study EP0065, the Baseline 
BRIEF-P/BRIEF should be completed at the ScrV. As BRIEF-P/BRIEF questionnaires have not 
been recorded in core studies N01263 and N01349 and as this data was not collected at EV of 
N01266, no Baseline values are available for those LTFU subjects within N01266.  
The BRIEF-P or BRIEF appropriate for each subject’s age should be completed, with the 
following exception: For subjects who completed the BRIEF-P at the Baseline assessment and 
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turn 5 years of age between that assessment and the initial YEV, the BRIEF-P should be 
completed through and including the initial YEV, and subsequently the BRIEF should be 
completed. 
Calculated T-score and raw score values and corresponding change from Baseline (if available) 
for the 3 indexed scores (Inhibitory Self-Control, Flexibility and Emergent Metacognition) and 
the GEC for the BRIEF-P questionnaire will be summarized for each visit during the Evaluation 
Period where the questionnaire is entered. 
Calculated T-score and raw score values and corresponding change from Baseline (if available) 
for the 2 indexed scores (Behavioral Regulation and Metacognition) and the GEC for the BRIEF 
questionnaire will be summarized for each visit during the Evaluation Period where the 
questionnaire is entered. 
In addition, for all indexed scores and GEC for BRIEF as well as BRIEF-P questionnaire, shift 
tables for T-scores will be done. These shift tables are based on T-score legacy categorization 
“Normal”, Borderline” or “Clinical Significant” and the dichotomous approach “Normal” or 
“Potentially Clinically Significant” as described in Section 3.10.5.2 and Section 3.10.5.3 
respectively and will summarize the shift from Baseline for each visit during the Evaluation 
Period where the questionnaire is entered. These shift tables will not include LTFU subjects from 
core studies N01349 and N01263 as Baseline values are not available from these studies, 
All BRIEF-P and BRIEF assessment data (including validity scores negativity and 
inconsistency) will be listed. 
9.6 
Bayley Scales of Infant and Toddler Development, Third Edition 
Bayley-III scales are completed within the core study (except for EP0065) if the subject is 
enrolled in an English-speaking country or a country where a validated translation is available, 
and data should not be recorded in the eCRF in N01266. If not stated otherwise, the EV data 
from core study will be obtained as EV data for N01266. For LTFU subjects coming from 
N01349, the Bayley-III data recorded at FV of N01349 will be obtained as EV data for N01266. 
Subjects that have been rolled-over from core study EP0065 will complete the Bayley-III 
questionnaire at the EV of N01266. For N01263 LTFU subjects, the Baseline Bayley-III 
questionnaire data of the core study will be obtained as EV data for N01266. Directly enrolled 
subjects will not have data of this type as they are enrolled at an older age than the cohort of ≥ 18 
to ≤ 42 months covered by this assessment.  
The Bayley-III scales will be completed for LTFU subjects at the FEV, YEV, FV, and at the 
EDV in the case of early discontinuation.  
The sum of scaled scores entered on the eCRF, and change from Baseline for the cognitive scale, 
language composite scale, motor composite scale, and social-emotional scales, as well as the 
adaptive behavior scale, will be summarized at Baseline and each visit during the Evaluation 
Period, if available. All recorded raw scores, scaled scores, composite scores, percentile rank and 
growth scores will be listed. 
9.7 
PedsQL assessment 
The PedsQL is completed at the ScrV (DE subjects only), FEV, YEV, FV, and the EDV in the 
case of early discontinuation. For LTFU subjects (except those from core studies EP0065, 
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N01349 and N01263), at the EV, the PedsQL score will be obtained from Baseline of the core 
study for subjects ≥ 2 years and is not recorded in the eCRF in N01266. For DE subjects the 
Baseline PedsQL is completed at the ScrV, for LTFU subjects from core study EP0065 the 
Baseline PedsQL is completed at the EV of N01266. Within core studies N01349 and N01263 
PedsQL assessment was not performed. Furthermore, PedsQL assessment was not done at the 
EV of N01266 for N01263 and N01349 LTFU subjects. Therefore, Baseline PedsQL is not 
available for those LTFU subjects. 
For subjects <5 years of age only parent-report-scores for PedsQL are available, for subjects >=5 
years of age self-reporting scores as well as parent-reporting scores for PedsQL might be 
available. Self-reporting and parent-reporting scores will be summarized separately. Complete 
score-related data will be listed.  
Calculated values and change from Baseline (if available) for the total scale score, psychosocial 
health score and each of the 4 scale scores will be summarized for each visit during the 
Evaluation Period where the questionnaire is entered. Subgroup summaries by age will be 
performed using the age groupings for which different questionnaires are entered; ≥ 2 to ≤ 4 
years, ≥ 5 to ≤ 7 years, ≥ 8 to ≤12 years, and ≥ 13 to ≤ 18 years. 
All PedsQL data will be listed. 
10 
PHARMACOKINETICS  
Pharmacokinetic samples will be taken for determination of BRV plasma concentration on FEV 
and on FV or EDV. In addition to the scheduled assessments, it should be obtained whenever a 
subject experience an SAE.  
Subjects receiving phenytoin as a concomitant AED during the study will have blood samples 
collected at the ScrV (DE subjects only), FEV, YEV, FV, or at the EDV in the case of early 
discontinuation and Safety Visit (SV) to monitor phenytoin plasma concentrations. The PK 
samples will also be taken for determination of phenytoin plasma concentration, if applicable. 
The plasma concentrations data will only be listed. 
 
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11 
REFERENCES 
National Center for Health Statistics in collaboration with the National Center for Chronic 
Disease Prevention and Health Promotion. 2000. http://www.cdc.gov/growthcharts (accessed 23 
Dec 2013). 
J W Varni The PedsQL: measurement model for the pediatric quality of life inventory 
https://www.pedsql.org/index.html 
 
 
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12 
APPENDICES 
12.1 
PCST Criteria for Hematology and Biochemistry Parameters 
Parameter 
Age Range 
UNIT 
Abnormality Criteria  
Hematology 
Hematocrit 
<2y 
% 
≤27 
>45 
≥2y - <18y 
≤29 
>47 
Hemoglobin 
<2y 
g/dL 
≤9.0 
>15.0 
≥2y - <18y 
≤9.5 
>16.0 
WBC/Leukocytes 
<12y 
109/L 
<3.5 
>15.0 
≥12y 
<3.0 
>12.0 
Lymphocytes 
<6m 
% 
≤30.0 
≥6m - <6y 
≤22.0 
≥6y - <18y 
≤12.0 
≥80.0 
Basophils 
>1m 
% 
≥3.0 
Eosinophils 
>1m 
% 
≥10.0 
Monocytes 
>1m 
% 
≥20.0 
Platelets 
>1m 
109/L 
≤100 
>600 
RBC/ Erythrocytes 
<2y 
1012/L 
<3.0 
≥2y 
<3.5 
Biochemistry 
AST (SGOT) 
<14y 
U/L 
>180 
≥14y 
>144 
ALT (SGPT) 
 
 
 
1y - <18y 
U/L 
>90 
Alkaline Phosphatase 
<4y 
U/L 
>690 
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Parameter 
Age Range 
UNIT 
Abnormality Criteria  
≥4y - <10y 
>834 
≥10y - <17y 
>1174 
GGT 
<6m 
U/L 
>522 
≥6m - <1y 
>279 
≥1y - <13y 
>66 
≥13y - <18y 
>126 
Total Bilirubin 
>1m 
mg/dL 
≥1.5 
Total Protein 
2m-<1y 
g/dL 
<3.0 
>10.0 
≥1y 
<4.3 
>10.0 
Albumin 
<1y 
g/dL 
<1.6 
>6.0 
≥1y 
<2.4 
>7.0 
BUN 
<1y 
mg/dL 
>21 
≥1y 
>30 
Urea 
<1y 
mg/dL 
>42 
≥1y 
>60 
Creatinine 
1y - <10y 
mg/dL 
>0.9 
≥10y - <16y 
>1.4 
Creatinine Clearancea 
All 
mL/min 
<70 
Calcium 
<1y 
mg/dL 
<6.9 
>12.2 
1y - <18y 
<7.4 
>11.7 
Phosphorous 
<1y 
mg/dL 
<1.8 
>8.2 
≥1y 
 
<1.8 
>7.4 
Potassium 
<1y 
mEq/L 
<3.0 
>6.5 
≥1y 
<3.0 
>5.8 
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Parameter 
Age Range 
UNIT 
Abnormality Criteria  
Sodium 
>1m 
mEq/L 
≤130 
≥150 
Glucose 
>1m 
mg/dL 
<50 
>180 
Total Cholesterol 
1y - <18y 
mg/dL 
>250 
LDL (calculated) 
1y - <18y 
mg/dL 
>140 
HDL 
≤2y 
mg/dL 
<10 
>2y 
<20 
Triglycerides 
<1y 
mg/dL 
>750 
≥1y 
>250 
Uric Acid 
<1y 
mg/dL 
>7.7 
1y - <13y 
>6.5 
≥13y - <18y 
>8.6 
Thyroxine (T4) 
<1y 
ug/dL 
≤4.3 
≥18.4 
≥1y 
≤3.8 
≥13.5 
Globulin 
<1y 
g/dL 
<1.0 
>3.8 
≥1y 
<1.2 
>4.4 
m=month; y=year.  
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CrCl=creatinine 
clearance; dL=deciliter; GGT= gamma-glutamyltransferase; HDL=high density lipoprotein; LDL=low density 
lipoprotein; L=liter; μg=microgram; m=month (defined as 30 days); mg=milligram; PCST=possibly clinically 
significant treatment-emergent; U=unit; y=years (defined as 365.25 days) 
aSchwartz equation (subjects <12):  CrCl ml/min=[Height (cm) * 0.55] / serum creatinine  
  Cockroft equation (subjects >12): Male: CrCl ml/min=[(140-age) x body weight (kg)] / (72 x serum creatinine); 
Female: CrCl ml/min=[(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85 
Note: A month is defined as 30 days; a year is defined as 365.25 days. 
 
 
12.2 
PCST Criteria for Urinalysis 
Qualitative urine parameters are generally reported by a descriptive score, which differs among 
laboratories. For data analysis purpose, a four-point scale is used. Five-point, six-point, or seven-
point scales will be collapsed into a four-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 five-point scale 
into a four-point scale, the lowest 2 positive results will be combined (see example below).  
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Conversion of results in a five-point scale into a four-point scale 
Original Five-point Scale 
Four-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 
The original scale and four-point scale for PCST of each urinalysis parameter is described in the 
table below. 
Urinalysis 4-point scales for PCST criteria 
PARAMETER 
Negative 
1+ 
2+ 
3+  
Protein 
Negative 
Trace, 30 mg/dL 
100 mg/dL 
≥300 mg/dL,  
≥1000 mg/dL 
Glucose 
Negative  
 
100 mg/dL, 250 
mg/dL 
500 mg/dL 
≥1000 mg/dL 
Ketones 
Negative 
Trace, 15 mg/dL 
40 mg/dL 
≥80 mg/dL,  
≥160 mg/dL 
Hemoglobin (Occult 
blood) 
Negative 
Trace, Small 
Moderate 
Large 
Leukocyte  
Esterase 
Negative 
Trace, Small 
Moderate 
Large 
Erythrocytes or 
Leukocytes 
1-5 
6-10 
11-20 
21-25 
 
>25 
For parameters which cannot have negative values their lowest two positive values will be in 
category “Negative”. For parameters which can have negative values their lowest two positive 
values will be at category 1+. 
12.3 
PCST Criteria for Vital Signs 
Parameter (Unit) 
Age Range 
Abnormality criteria 
Pulse Rate 
(beats/minute) 
<6m 
<100 
>180 
≥6m - <3y 
<90 
>150 
≥3y - <12y 
<60 
>130 
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Parameter (Unit) 
Age Range 
Abnormality criteria 
≥12y - <17y 
<50 
>120 
Systolic Blood 
Pressure (mmHg) 
<6m 
<60 
>100 
≥6m - <3y 
<70 
>120 
≥3y - <12y 
<80 
>140 
≥12y - <17y 
<90 
>160 
Diastolic Blood 
Pressure (mmHg) 
<6m 
<40 
>65 
≥6m - <3y 
<45 
>75 
≥3y - <12y 
<50 
>80 
≥12y - <17y 
<50 
>105 
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 
 
≥17y 
A decrease/increase from Baseline 
of ≥ 10% 
m=month, y=year. 
Note: A month is defined as 30 days; a year is defined as 365.25 days. 
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13 
AMENDMENTS TO THE SAP 
SAP amendment 1 
SAP amendment 1 includes changes based on Protocol amendment 5 and Protocol amendment 6: 
Changes based on Protocol amendment 5 (PA05): 
• Duration of study at least 3 years (no longer approx. 3 years) 
• Subjects will receive oral solution or tablets, as appropriate (independent if they are < 7 years 
or ≥ 7 years of age). 
• Reference to serious AEs added 
• Reference to AEs of interest added 
• “Core study” terminology: “previous BRV study” has been changed to “core study” 
• Subjects ≥ 2 years of age with typical absence seizures have at least a 24-hour EEG, instead 
of a 1-hour EEG 
Changes based on Protocol amendment 6 (PA06): 
• PedsQL for LTFU subjects will only be assessed for subjects with ≥2 years of age at Baseline 
of core study (no longer for subjects < 2 years) 
• Bayley Scale for LTFU subjects will be assessed in English-speaking countries and countries 
where a validated translation is available  
Changes not based on PA05/PA06: 
• Add descriptions and derivation rules for seizure categories at ScrV used for efficacy and 
safety analysis in Section 3.10.3  
• Update of descriptions and derivation rules of Efficacy variables in Section 2.2.2, Section 3.9 
and Section 9.1. 
• Update of derivation rules for EV and Baseline values for LTFU subjects based on data 
availability in core studies and N01266, for example for EEG, ECG, vital signs as well as 
questionnaire data 
• Clarification for subgroup analyses (by age group, by cohort, by core study, by geographic 
region, by dose group, by seizure category) 
SAP amendment 2 
SAP amendment 2 includes following changes: 
• SAP is based on Protocol Amendment 8, 25 Jun 2020. 
• According to the update in the specification of important protocol deviations, the maximum 
allowable BRV dose is 5.0mg/kg/day, not to exceed a dose of 200mg/day for all subjects. 
Body weight condition has been deleted. 
• The end of study possibility because of subject’s transition to another BRV study has been 
added. 
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• Study variables have been organized in primary, secondary and other variables according to 
protocol amendment 8. 
• The section 3.10.3 Seizures and seizure categories has been updated to give more details on 
how subjects are categorized into seizure categories. Description has been specified to 
explain in which subjects will be categorized if requirements for more than one category 
would be fulfilled. 
• Absence Seizure category has been renamed to Typical Absence Seizure category according 
to the data evaluation meeting 2 decisions. 
• For the efficacy EEG data, it has been clarified which data to use if central reader and site 
investigator interpretation of EEG differ. Moreover, the number of interpretable hours of 24 
hours EEG will be considered in ADF calculation. 
• Reduction has been renamed in “Change” according to protocol amendment 8. 
• Worsening as categorical variable is not needed anymore as per protocol and has been 
deleted. 
• In Section 3.10.4.1 Medications (AED and non-AED), it has been added that the AED 
outputs will reflect AED evaluation result of concomitant Benzodiazepine from the data 
review meetings. 
• In Section 3.10.5.1 the Achenbach CBCL T-score categories have been corrected. 
• Clarification of the definition of prior medications and medication at study entry for LTFU 
subjects has been added. 
• Within the age groups the group ≥ 2 to < 12 years of age has been split into ≥ 2 to < 4 years 
of age, ≥ 4 to < 12 years of age. 
• Overall subject disposition will be presented by core study. 
• The grouping of similar AEDs is applicable to all analyses by preferred term and not limited 
to history of prior AED use only. 
• Concomitant Non-AEDs will be summarized by anatomical main group, therapeutic group 
and preferred drug name. 
• In Section 8.2.2 Incidences of TEAEs, tables by geographical region have been added. 
• In Section 9.1 Seizure based variables based on EEG data the sensitivity analyses have been 
added in case of subjects received 1 hour and 24 hours EEG. 
• In Section 9.2 Seizure based variables based on DRC data corrections have been made 
according to data evaluation meeting 2 decisions. 
• Analyses of pharmacokinetics have been deleted in Section 10 according to data evaluation 
meeting 2 decisions. 
SAP amendment 3 
SAP amendment 3 includes following changes: 
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• Dichotomous approach for clinically significant ranges for T-scores added for BRIEF, 
BRIEF-P, and CBCL questionnaires 
• Raw score values and change from baseline for BRIEF, BRIEF-P, and CBCL questionnaires 
added 
• Age calculation added 
• Term “special” removed from AE of interest 
• PedSQL missing data clarification added 
SAP amendment 4 
SAP amendment 4 includes following changes: 
• In Section 3.10.3 added a description of how subjects with UNC seizure category should be 
displayed in tables and listings 
• In section 3.10.3.1 Derivation of efficacy variables has been updated to give more details on 
how N01349 subjects should be analyzed. 
• Age calculation updated 
 
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Approval Signatures
Name:
n01266-sap-amend-4
Version:
1. 0
Document Number:
CLIN-000177638
Title:
N01266 - Statistical Analysis Plan
Amendment 4
Approved Date:
22 Sep 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 20-Sep-2021 02:50:56 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 22-Sep-2021 14:17:05 GMT+0000
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