Clinical trial NCT03405714
Conditions: Epilepsy
Keywords: Epilepsy Brivaracetam Briviact Open-label pediatric intravenous
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2018-06-01; Completion date: 2020-11-04
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) administered intravenously (iv) in subjects \>= 1 month to \< 16 years of age with epilepsy.

Detailed description:

Arms: arm 1: Brivaracetam will be administered to various age-based cohorts. Cohort 1: Subjects \>=12 to \<16 years; Cohort 2: Subjects \>=6 to \<12 years; Cohort 3: Subjects \>=2 to \<6 years; Cohort 4: Subjects 1 month to \<2 years. Enrollment will be sequential by descending age beginning with Cohort 1. For each cohort, the first half will receive a 15-minute iv infusion. The Data Monitoring Committee (DMC) will then review safety and, as available, PK data to make the following recommendations: the progression of the current cohort (up to 2-minute iv bolus infusion) and progression to initiate enrollment in the preceding cohort.
Interventions: intervention 1: Brivaracetam
Intervention descriptions: intervention 1: * Pharmaceutical form: Solution for iv injection
* Route of administration: intravenous use
* Concentration: 10 mg/ml

Protocol documents:
Prot_000.pdf: 
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EP0065 
 
 
 
 
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PROTOCOL EP0065 AMENDMENT 1 
A MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE 
PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF 
INTRAVENOUS BRIVARACETAM IN SUBJECTS ≥1 MONTH 
TO <16 YEARS OF AGE WITH EPILEPSY  
PHASE 2 
 
EudraCT Number: 2016-002452-25 
IND Number: 103908 
 
 
UCB BIOPHARMA SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
17 Mar 2017 
Not applicable 
Protocol Amendment 1 
19 Jun 2019 
Nonsubstantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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EP0065 
 
 
 
 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB BIOPHARMA SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Sponsor Study Physician 
Name: 
 
, MD, PhD 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone:  
 
 
Fax: 
 
Clinical Project Manager 
Name: 
, PhD 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Fax: 
 
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Clinical Trial Biostatistician 
Name: 
, MSc 
Address: 
UCB Celltech 
Bath Road, 208 
Berkshire 
Slough SL1 3WE 
UK 
Phone: 
 
Clinical Monitoring Contract Research Organization 
Name: 
PRA Health Sciences 
Address: 
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
UNITED STATES 
Phone: 
+1 919 786 8200 
Fax: 
+1 919 786 8201 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
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 ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 14 
3 
STUDY OBJECTIVES .................................................................................................... 15 
4 
STUDY VARIABLES ..................................................................................................... 16 
4.1 Pharmacokinetic variables ............................................................................................... 16 
4.2 Safety variables ................................................................................................................ 16 
4.2.1 
Primary safety variables ...................................................................................... 16 
4.2.2 
Other safety variables .......................................................................................... 16 
5 
STUDY DESIGN ............................................................................................................. 16 
5.1 Study description ............................................................................................................. 16 
5.1.1 
Study duration per subject and definition for start/end of study.......................... 19 
5.1.2 
Planned number of subjects and sites .................................................................. 19 
5.1.3 
Anticipated regions and countries ....................................................................... 19 
5.2 Schedule of study assessments ......................................................................................... 19 
5.3 Rationale for study design and selection of dose ............................................................. 26 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 27 
6.1 Inclusion criteria .............................................................................................................. 27 
6.2 Exclusion criteria ............................................................................................................. 28 
6.3 Withdrawal criteria .......................................................................................................... 29 
6.3.1 
Potential drug-induced liver injury investigational medicinal product 
discontinuation criteria ........................................................................................ 30 
7 
STUDY TREATMENT(S) .............................................................................................. 31 
7.1 Description of investigational medicinal products .......................................................... 31 
7.1.1 
Film-coated tablets for oral administration .......................................................... 31 
7.1.2 
Oral solution ........................................................................................................ 31 
7.1.3 
Solution for iv injection ....................................................................................... 31 
7.2 Treatments to be administered ......................................................................................... 31 
7.2.1 
Screening, IOB Treatment, and iv PK Periods .................................................... 32 
7.2.2 
Down-Titration Period ......................................................................................... 33 
7.3 Packaging ......................................................................................................................... 33 
7.4 Labeling ........................................................................................................................... 33 
7.5 Handling and storage requirements.................................................................................. 34 
7.6 Drug accountability .......................................................................................................... 34 
7.7 Procedures for monitoring subject compliance ................................................................ 34 
7.8 Concomitant medication(s)/treatment(s).......................................................................... 35 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 35 
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7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 35 
7.8.3 
Rescue medication ............................................................................................... 35 
7.9 Blinding ............................................................................................................................ 35 
7.10 Randomization and numbering of subjects ...................................................................... 35 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 36 
8.1 Visit 1 (Day -10 to Day-1 for OLB, RxB, and IIB subjects; Day -20 to Day -11 for IOB 
subjects) ........................................................................................................................... 36 
8.2 Visit 2 (Day -10 to Day -1; IOB subjects only) ............................................................... 36 
8.3 Visit 3 (Day 1) through Visit 12 (Day 6) ......................................................................... 37 
8.4 TC-1 (Day 2 to Day 9) (all subjects who received iv BRV) ............................................ 38 
8.5 TC-2 38 
8.6 Visit 13 ............................................................................................................................. 38 
8.7 TC-3 39 
8.8 Unscheduled Visit ............................................................................................................ 39 
9 
ASSESSMENT OF PHARMACOKINETIC VARIABLES ........................................... 39 
10 ASSESSMENT OF SAFETY .......................................................................................... 40 
10.1 Adverse events ................................................................................................................. 40 
10.1.1 
Definitions ........................................................................................................... 40 
10.1.1.1 
Adverse event ............................................................................................ 40 
10.1.1.2 
Serious adverse event ................................................................................ 40 
10.1.1.3 
Adverse events of special interest ............................................................. 41 
10.1.2 
Procedures for reporting and recording adverse events ....................................... 42 
10.1.2.1 
Description of adverse events .................................................................... 42 
10.1.2.2 
Rule for repetition of an adverse event...................................................... 42 
10.1.2.3 
Additional procedures for reporting serious adverse events ..................... 42 
10.1.3 
Follow up of adverse events ................................................................................ 43 
10.1.4 
Pregnancy ............................................................................................................ 44 
10.1.5 
Suspected transmission of an infectious agent via a medicinal product .............. 45 
10.1.6 
Overdose of investigational medicinal product ................................................... 45 
10.1.7 
Safety signal detection ......................................................................................... 45 
10.2 Laboratory measurements ................................................................................................ 45 
10.2.1 
Evaluation of PDILI ............................................................................................ 46 
10.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 51 
10.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 51 
10.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 51 
10.2.1.4 
Follow-up evaluation ................................................................................. 53 
10.3 Other safety measurements .............................................................................................. 53 
10.3.1 
ECG ..................................................................................................................... 53 
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10.3.2 
Vital signs ............................................................................................................ 54 
10.3.3 
Assessment of suicidality .................................................................................... 55 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 56 
11.1 Adherence to protocol ...................................................................................................... 56 
11.2 Monitoring ....................................................................................................................... 56 
11.2.1 
Definition of source data ..................................................................................... 57 
11.2.2 
Source data verification ....................................................................................... 57 
11.3 Data handling ................................................................................................................... 57 
11.3.1 
Case Report form completion .............................................................................. 57 
11.3.2 
Database entry and reconciliation ........................................................................ 58 
11.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 58 
11.4 Termination of the study .................................................................................................. 58 
11.5 Archiving and data retention ............................................................................................ 58 
11.6 Audit and inspection ........................................................................................................ 59 
11.7 Good Clinical Practice ..................................................................................................... 59 
12 STATISTICS ................................................................................................................... 59 
12.1 Definition of analysis sets ................................................................................................ 59 
12.2 General statistical considerations ..................................................................................... 59 
12.3 Planned PK analyses ........................................................................................................ 60 
12.4 Planned safety analyses .................................................................................................... 60 
12.4.1 
Analysis of safety variables ................................................................................. 60 
12.4.1.1 
Primary safety variables ............................................................................ 60 
12.4.1.2 
Other safety variables ................................................................................ 60 
12.5 Handling of protocol deviations ....................................................................................... 60 
12.6 Handling of dropouts or missing data .............................................................................. 61 
12.7 Planned interim analysis and data monitoring ................................................................. 61 
12.8 Determination of sample size ........................................................................................... 61 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 61 
13.1 Informed consent ............................................................................................................. 61 
13.2 Subject identification cards .............................................................................................. 62 
13.3 Institutional Review Boards and Independent Ethics Committees .................................. 62 
13.4 Subject privacy ................................................................................................................. 63 
13.5 Protocol amendments ....................................................................................................... 63 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 63 
15 REFERENCES ................................................................................................................ 64 
16 APPENDIX ...................................................................................................................... 65 
16.1 Protocol Amendment 1 .................................................................................................... 65 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ....................................... 67 
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18 SPONSOR DECLARATION .......................................................................................... 68 
 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of Study Assessments (Screening Period through end of iv PK 
Period) .............................................................................................................. 20 
Table 5‒2: 
Schedule for iv PK Period ECGs, vital signs, and PK sampling (15-min 
BRV infusion) .................................................................................................. 23 
Table 5‒3: 
Schedule for iv PK Period ECGs, vital signs, and PK sampling (bolus [up 
to 2-min BRV infusion]) .................................................................................. 24 
Table 5‒4: 
Schedule of study assessments for Down-Titration and Safety (BRV-free) 
Periods (subjects not continuing into the Long‑Term, Open‑Label Study) ... 25 
Table 7‒1: 
BRV dosing during the Screening, IOB Treatment, and iv PK Periods .......... 32 
Table 10‒1: 
Anticipated serious adverse events for the pediatric epilepsy population ....... 41 
Table 10‒2: 
Laboratory parameters ..................................................................................... 46 
Table 10‒3: 
Required investigations and follow up for PDILI............................................ 48 
Table 10‒4: 
PDILI laboratory measurements ...................................................................... 52 
Table 10‒5: 
PDILI information to be collected ................................................................... 53 
Table 10-6: 
PCS Abnormality criteria for the measurement of blood pressure .................. 55 
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LIST OF FIGURES 
Figure 5‒1: 
Schematic of sequential cohort enrollment during the iv PK Period ............... 18 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
bid 
twice daily  
BP 
blood pressure 
BRV 
brivaracetam 
CDMS 
clinical data management system 
CRF 
Case Report form  
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
GCP 
Good Clinical Practice 
HLA 
human leukocyte antigen 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IIB 
Initiating iv BRV 
IMP 
investigational medicinal product 
IOB 
Initiating Oral BRV 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
iv 
intravenous  
MedDRA® 
Medical Dictionary for Regulatory Activities® 
OLB 
Open-label BRV 
PCS 
possibly clinically significant  
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic(s) 
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PK-PPS 
PK Per-protocol Set 
POS 
partial-onset seizures 
PS 
Patient Safety 
q12h ±2h 
every 12 hours ±2 hours 
RR 
respiratory rate 
RxB 
Prescribed-BRV 
SAE 
serious adverse event 
SD 
standard deviation  
SOP 
standard operating procedure 
SS 
Safety Set 
SS-iv 
Safety Set-iv 
SV2A 
synaptic vesicle protein 2A 
TC 
Telephone Contact 
ULN 
upper limit of normal 
VNS 
vagus nerve stimulation 
 
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1 
SUMMARY 
EP0065 is a Phase 2, multicenter, open-label study with a primary objective of evaluating the 
pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) administered as a 
15-minute intravenous (iv) infusion and an iv bolus (up to 2-minute infusion) in subjects 
≥1 month to <16 years of age with epilepsy. 
The following subjects will be eligible for enrollment in EP0065: 
 Open-label BRV (OLB) subjects: currently receiving oral BRV as participants in a 
long-term, open-label study 
 Prescribed-BRV (RxB) subjects: currently receiving prescribed oral BRV from commercial 
supply 
 Initiating Oral BRV (IOB) subjects: not currently receiving BRV; first dose of BRV in 
EP0065 will be oral tablet or solution 
 Initiating iv BRV (IIB) subjects: not currently receiving BRV; first dose of BRV in EP0065 
will be administered intravenously 
EP0065 includes the following consecutive periods: 
Subjects 
Screening Period 
1 to 10 days 
IOB Treatment 
Period 
2 to 10 days 
iv PK Period 
1 to 6 days 
OLB 
Oral BRV 
Not applicable 
iv BRV 
RxB 
Oral BRV 
Not applicable 
iv BRV 
IOB 
No BRV 
Oral BRV 
iv BRV 
IIB 
No BRV 
Not applicable 
iv BRV 
BRV=brivaracetam; IIB=Initiating iv BRV; IOB=Initiating Oral BRV; iv=intravenous; 
OLB=Open-label BRV; PK=pharmacokinetic RxB=Prescribed-BRV 
Note: Oral BRV will be administered as tablets or oral solution. Tablets will be administered 
orally, and oral solution will be administered either orally or by enteric administration (eg, 
feeding tube) based on subject need. 
During the Screening Period, OLB and RxB subjects will continue to receive oral BRV (tablet or 
oral solution) in accordance with their long-term, open-label study dosing or prescribed dosing, 
respectively. The IOB and IIB subjects will not receive BRV during the Screening Period. 
Eligible OLB, RxB, and IIB subjects will progress directly from the Screening Period to the 
iv PK Period, whereas IOB subjects will enter a 2- to 10-day IOB Treatment Period in which 
they receive oral BRV before progressing to the iv PK Period. The initial oral BRV dose in the 
IOB Treatment Period is 2mg/kg/day. 
During the iv PK Period, iv BRV will be administered every 12 hours ±2 hours (q12h ± 2h). All 
subjects will receive 1 to 2 consecutive doses of BRV; however, based on medical need, subjects 
may receive up to 10 consecutive doses of iv BRV. Blood sampling for PK analyses (herein 
referred to as “PK sampling”) will occur with the first iv BRV administration and with 1 other iv 
BRV administration. For OLB, RxB, and IOB subjects, the first iv BRV dose will be equivalent 
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(mg-to-mg) to the final dose of oral BRV prior to the first iv dose. For IIB subjects, the first iv 
BRV dose will be 1mg/kg, not to exceed 50mg for subjects with body weights ≥50kg. For all 
subjects, iv BRV doses may be adjusted at the Investigator’s discretion after PK sampling for 
2 iv doses; however, no doses may exceed the maximum doses indicated below. During the 
iv PK Period, BRV may only be administered by iv infusion.  
At the completion of the iv PK Period, subjects who will continue oral BRV treatment should 
enroll in a long-term, open-label BRV study. Subjects who have received ≥4 doses of BRV and 
do not plan to continue treatment with BRV after completion of the iv PK Period or who 
discontinue BRV treatment during the study will have a Down-Titration Period of up to 4 weeks 
(28 days) for gradual discontinuation of BRV and a Safety (BRV-free) Period of 2 weeks 
(14 days) after the final dose of BRV. Subjects who have received <4 doses of BRV may have 
BRV down titrated at the discretion of the Investigator. 
For IOB and IIB subjects, the maximum BRV dose is 4mg/kg/day (2mg/kg twice daily [bid]). 
For OLB and RxB subjects, the maximum BRV dose is 5mg/kg/day (rounded) in recognition of 
the possibility that some of these subjects may be using this dose when they enter EP0065. 
Throughout the study, no subjects may receive a dose greater than BRV 200mg/day. Oral 
BRV will be administered in equally divided doses bid.  
It is planned for approximately 50 enrolled subjects to receive iv BRV in the following 
age-based cohorts (approximately 12 subjects/cohort), with approximately half of the subjects in 
each cohort receiving iv BRV as a 15-minute (±3 minutes) infusion and half receiving iv BRV as 
a bolus (up to 2-minute infusion). 
 Cohort 1: ≥12 to <16 years  
 Cohort 2: ≥6 years to <12 years  
 Cohort 3: ≥2 to <6 years  
 Cohort 4: 1 month to <2 years  
Enrollment will be sequential by descending age beginning with Cohort 1. For each cohort, the 
first half will receive the 15-minute infusion. The Data Monitoring Committee (DMC) will then 
meet to review safety and PK data, as available. After the DMC safety review, the remaining half 
in that cohort will receive iv BRV as a bolus (up to 2-minute infusion), and the next cohort may 
begin the 15-minute infusion. Subjects may receive bolus infusions only after subjects in the 
preceding cohort have completed bolus infusions. 
The DMC will meet no less than approximately every 6 months commensurate with enrollment.  
The PK variables are the plasma concentrations of BRV (parent compound only) before, during, 
and after the first and 1 subsequent administration of iv BRV.  
The primary safety variables are adverse events (AEs) and withdrawals due to AEs. Other safety 
variables are clinical laboratory parameters (hematology, chemistry, and endocrinology), and 
urinalysis. Clinically significant new or worsened abnormalities discovered during physical and 
neurological examinations will be recorded as AEs. Other safety variables also include 12-lead 
electrocardiogram (ECG), and vital signs (blood pressure [BP], pulse rate, respiratory rate [RR], 
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and temperature), all of which will be assessed with increased frequency during the iv PK 
Period.  
The maximum study duration for an individual subject will be 68 days. Approximately 60 sites 
in Europe and North America are planned for participation in EP0065. 
2 
INTRODUCTION 
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 was granted in the EU, US, and Australia for patients 16 years of age 
and older with epilepsy and in Canada for patients 18 years of age and older with epilepsy. 
Epilepsy affects all races of both sexes at any age from the first hour of life to extreme old age. 
The prevalence of epilepsy is 1% to 2% of the population and 4% of pediatric population in 
those developed countries where they have been studied; this is probably double in resource-poor 
countries (Banerjee and Hauser, 2008). In the US, the overall incidence of epilepsy ranges from 
35.5 to 48 per 100,000 person-years and the prevalence ranges from 4.7 to 6.8 per 1000 
population (Theodore et al, 2006). The incidence of new-onset epilepsy in the pediatric 
population is 44.5 per 100,000 persons per year (Wirrell et al, 2011). Within the pediatric 
population, the incidence is highest in children <5 years of age (approximately 60 to 100 per 
100,000 person-years), decreasing to approximately 25 to 45 per 100,000 person-years in 
adolescents and young adults (Wirrell et al, 2011; Hauser et al, 1993).  
In the US, 57% of newly diagnosed patients were classified as having POS (Zarrelli et al, 1999; 
Hauser et al, 1993). In the general population, the incidence of pediatric patients with epilepsy 
with POS is approximately 16 to 80 per 100,000 (Wirrell, et al, 2011; Banerjee and Hauser, 
2008; Hauser et al, 1993).  
The existing treatment options for POS in the pediatric population generally follow the treatment 
options for adults with the same disorder; clinical experience demonstrates that children may 
have results comparable to adults with administration of the conventional antiepileptic drugs 
(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.  
To date, oral formulations of BRV have been studied in the ongoing BRV pediatric development 
program as follows:  
N01263 is a completed open-label, multicenter, fixed 3-step up-titration, adjunctive therapy 
study of the PK, safety, and efficacy of BRV in 100 subjects ≥1 month to <16 years of age 
with epilepsy. Doses of BRV (oral solution) were adjusted by body weight and did not 
exceed a maximum of 50mg/day, 100mg/day, and 200mg/day for each titration step. A total 
of 100 subjects enrolled in N01263: 99 subjects received study drug and were included in the 
Safety Set. Results from N01263 indicate that BRV was generally well tolerated and that the 
safety profile in pediatric subjects was consistent with the known safety profile in adult 
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subjects. In general, there were no clinically meaningful changes in laboratory parameters, 
vital signs, or ECG parameters. Trough plasma BRV concentrations increased proportionally 
to the dose.  
N01266 is an ongoing open-label, multicenter study to evaluate the long-term safety and 
efficacy of bid administration of BRV oral solution and oral tablets in pediatric subjects with 
epilepsy who are receiving ≥ 1 AED other than BRV; the maximum allowable BRV dose is 
5mg/kg/day not to exceed 200mg/day in subjects with body weights >40kg. N01266 was 
initially designed as a long-term follow-up to N01263, which enrolled only subjects with 
either focal epilepsy or generalized epilepsy but was amended to also allow direct enrollment 
of subjects 4 years to <17 years of age who have focal epilepsy. Over 200 subjects have 
enrolled in N01266. 
In addition to oral formulations, iv formulations of AEDs are particularly helpful as short-term 
replacements when use of oral formulations is not possible or feasible (eg, pre and postoperative 
patients, patients with acute gastrointestinal disorders, patients with acute swallowing disorders). 
Brivaractem injection has been approved for use as adjunctive therapy in the treatment of POS in 
patients 16 years of age and older with epilepsy and may be used when oral administration of 
BRV is temporarily not feasible. Treatment with BRV may be initiated with tablets, oral 
solution, or solution for injection. 
The current study, EP0065, is planned to evaluate the PK, safety, and tolerability of iv BRV 
administered as a 15-minute infusion and bolus (up to 2-minute infusion) in subjects ≥1 month to 
<16 years of age with epilepsy.  
The iv dose for subjects initiating BRV in this study was predicted in N01331, which modeled 
based on PK data from N01263 and N01256 (BRV adult study) and simulated the BRV iv 
concentrations in pediatric subjects. Based on the results of N01331, in the pediatric population 
1 month to <17 years of age, an iv injection 15-minute infusion or bolus (up to 2-minute 
infusion) of 4mg/kg/day (2mg/kg bid) regimen (with a maximum of 200mg/day [100mg bid] for 
subjects with body weights ≥50kg) results in plasma concentrations in the same range as seen in 
adults receiving 200mg/day (100mg bid), the maximum recommended dose in adults with POS. 
These data support using a mg-to-mg equivalent to the oral dose for OLB and RxB subjects. As 
demonstrated in the concentration-effect analysis CL0258 using levetiracetam PK and 
pharmacodynamic (PD) data from adults and children and BRV PK and PD data in adults 
(N01358) and PK data in children (N01263), in subjects 4 to 16 years of age, similar 
weight-normalized doses are needed to achieve the same efficacy as compared with adults, with 
a maximum response at 4mg/kg/day. 
More detailed information regarding the nonclinical and clinical development programs for BRV 
is provided in the Investigator’s Brochure. 
3 
STUDY OBJECTIVES 
The primary objective is to evaluate the PK, safety, and tolerability of BRV administered as a 
15-minute iv infusion and iv bolus (up to 2-minute infusion) in subjects ≥1 month to <16 years 
of age with epilepsy. 
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4 
STUDY VARIABLES 
4.1 
Pharmacokinetic variables 
 Plasma concentration of BRV (parent compound only) before, during, and after iv BRV 
administration 
4.2 
Safety variables 
4.2.1 
Primary safety variables 
 Adverse events throughout the study  
 Subject withdrawals due to AEs 
4.2.2 
Other safety variables 
 12-lead ECG values before, during, and after each iv BRV administration  
 BP, pulse rate, RR, and temperature values before, during, and after each iv BRV 
administration  
 Clinical laboratory parameters (hematology, chemistry, and endocrinology) pre and 
posttreatment 
 Urinalysis parameters pre and posttreatment 
5 
STUDY DESIGN 
5.1 
Study description 
EP0065 is a Phase 2 multicenter, open-label study to evaluate the PK, safety, and tolerability of 
iv BRV administered as a 15-minute iv infusion and an iv bolus (up to 2-minute infusion) in 
subjects ≥1 month to <16 years of age with epilepsy.  
It is planned for approximately 50 enrolled subjects to receive iv BRV in the following 
age-based cohorts (approximately 12 subjects/cohort): 
 Cohort 1: ≥12 to <16 years  
 Cohort 2: ≥6 years to <12 years  
 Cohort 3: ≥2 to <6 years  
 Cohort 4: 1 month to <2 years  
The following subjects will be eligible for enrollment in EP0065: 
 OLB subjects: currently receiving oral BRV as participants in a long-term, open-label study 
 RxB subjects: currently receiving prescribed oral BRV from commercial supply 
 IOB subjects: not currently receiving BRV; first dose of BRV in EP0065 will be oral tablet 
or solution 
 IIB subjects: not currently receiving BRV; first dose of BRV in EP0065 will be by iv 
infusion 
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For OLB and RxB subjects, the maximum BRV dose is 5mg/kg/day (rounded). For IOB and IIB 
subjects, the maximum BRV dose is 4mg/kg/day. Throughout the study, no subject may 
receive a dose greater than BRV 200mg/day. Subjects will receive oral BRV (tablets or oral 
solution) in equally divided doses; BRV oral solution may be given by enteric administration 
(eg, by feeding tube) based on subject need. 
The EP0065 study periods and visits are described below. The PK assessments will be made 
during the iv PK Period only and safety data will be collected throughout the study, with 
intensive collection of safety data with each iv BRV dose administered. A Schedule of Study 
Assessments is provided for the Screening through iv PK Periods in Table 5‒1 and for the 
Down-Titration Period and Safety (BRV-free) Periods (for subjects not continuing BRV) in 
Table 5‒4. 
Screening Period (1 to 10 days) 
During the Screening Period, the OLB and RxB subjects will continue treatment with oral BRV 
using their assigned open-label study supply or prescribed commercial supply, respectively. The 
IOB and IIB subjects will not receive BRV during this period.  
The OLB subjects will temporarily discontinue assessments in their long-term, open-label study 
when they enter EP0065. As such, all assessments for these subjects during the Screening Period 
(and subsequent periods of EP0065) will be recorded in the EP0065 Case Report form (CRF) 
until they return to a long-term, open-label study or discontinue BRV treatment. 
IOB Treatment Period (2 to 10 days of oral BRV treatment; for IOB subjects only) 
Only IOB subjects who meet all eligibility criteria may participate in the IOB Treatment Period. 
No other subjects may participate in this period. 
During the IOB Treatment Period, IOB subjects will initiate treatment with oral BRV 
2mg/kg/day not to exceed 100mg/day for subjects with body weights ≥50kg and must have, at 
minimum, 2 days of treatment with oral BRV before entry into the iv PK Period. Subjects who 
do not enter the iv PK Period will not be eligible for the long-term, open-label study. 
The Investigator is permitted to adjust the oral BRV dose during the IOB Treatment Period in 
accordance with medical judgment (with a maximum dose of 4mg/kg/day, not to exceed 
200mg/day for subjects with body weights ≥50kg); however, subjects must have no change in 
the oral BRV dose for the 2 days prior to entry into the iv PK Period.  
iv PK Period (1 to 6 days, with Day 1 defined as the initial day of iv BRV infusion) 
During the iv PK Period, iv BRV will be administered every 12 hours ±2 hours (q12h ± 2h). All 
subjects are to receive 1 to 2 consecutive doses of BRV; however, based on medical need, 
subjects may receive up to 10 consecutive doses of iv BRV. The PK sampling will occur with the 
first iv BRV administration and with 1 other iv BRV administration.  
The first dose of iv BRV will be as follows: 
 OLB, RxB, and IOB subjects: mg-to-mg equivalent of the oral BRV dose immediately prior 
to the iv PK Period; administered q12h ±2h after prior oral dose 
 IIB subjects: 1mg/kg not to exceed a maximum of 50mg for subjects ≥50kg 
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After subjects have completed PK sampling with 2 iv BRV infusions, the Investigator may adjust 
the BRV dose, but the adjusted dose must not exceed 5mg/kg/day (rounded) for OLB and RxB 
subjects and 4mg/kg/day for IOB and IIB subjects (with the maximums not to exceed 
200mg/day). During the iv PK Period, BRV may only be administered intravenously. Enrollment 
will be sequential by descending age beginning with Cohort 1. For each cohort, the first half will 
receive the 15-minute infusion. The Data Monitoring Committee (DMC) will then meet to 
review safety and, as available, PK data (Figure 5‒1). After the DMC safety review, the 
remaining half in that cohort will receive iv BRV as a bolus (up to 2-minute infusion) and the 
next cohort may begin the 15-minute infusion. Subjects may receive bolus infusions only after 
subjects in the preceding cohort have completed bolus infusions and the DMC have reviewed 
these data. The DMC will meet no less than approximately every 6 months commensurate with 
enrollment. 
 
Figure 5‒1: Schematic of sequential cohort enrollment during the iv PK Period 
 
DMC=Data Monitoring Committee; inf=infusion; iv=intravenous; PK=pharmacokinetic 
Telephone Contact (TC)-1 will occur 1 to 3 days after completing the final iv BRV dose in the 
iv PK Period to facilitate reporting of infusion-site related AEs.  
The schedules for PK sampling, 12-lead ECGs, and vital sign assessments during the iv PK 
Period are provided in Table 5‒2 (15-minute infusion), and Table 5‒3 (bolus [up to 2-minute 
infusion]). 
Down-Titration Period (up to 4 weeks) and Safety (BRV-free) Period (2 weeks) 
Subjects who receive ≥4 doses of BRV during either the IOB Treatment Period or the iv PK 
Period and who do not plan to continue treatment with BRV or who discontinue from the study 
will enter a Down-Titration Period. Subjects who have received <4 doses of BRV may have 
BRV down titrated at the discretion of the Investigator. During the Down-Titration Period, 
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. Subjects not able to receive oral BRV for down titration, may receive iv BRV 
for down titration. In the latter circumstance, the subjects may receive more than 10 consecutive 
>12 years to <16 years
>6 years to <12 years
>2 years to <6 years
15 min inf
bolus
15 min inf
bolus
15 min inf
bolus
N 12
N 12
N 12
N 12
>1 month to <2 years
bolus
15 min inf
DMC
DMC
DMC
DMC
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doses of iv BRV in accordance with the Investigator’s discretion. A 2-week Safety (BRV-free) 
Period will follow the final dose of BRV.  
Safety assessments will be collected throughout this period (Table 5‒4). 
5.1.1 
Study duration per subject and definition for start/end of study 
The maximum possible study duration is 68 days and the maximum period of BRV 
administration is 44 days including a minimum of 1 dose of iv BRV.  
The start of the study is defined as the date the first Informed Consent form (ICF)/Assent form is 
executed. The end of the study is defined as the date of the last visit of the last subject enrolled. 
5.1.2 
Planned number of subjects and sites 
It is planned for approximately 50 enrolled subjects to receive iv BRV. Approximately 60 sites 
are planned. 
5.1.3 
Anticipated regions and countries 
Approximately 60 sites in Europe and North America are planned for participation in EP0065.  
5.2 
Schedule of study assessments 
A schedule of study assessments for the Screening Period through the iv PK Period is provided 
in Table 5‒1, with detailed schedules for PK sampling, ECG, and vital sign assessments during 
the iv PK Period provided in Table 5‒2 (15-min infusion) and Table 5‒3 (bolus [up to 2-minute 
infusion]).  
A schedule of study assessment for subjects who will not continue BRV is provided in Table 5‒4 
(Down-Titration and Safety [BRV-free] Periods).  
Note, possibly clinically significant (PCS) vital sign values are defined as those PCS values 
which occur at any time during the study. Only BP to be collected at 2 hours post initiation of 
infusion. Additional vital sign monitoring, specifically BP is necessary if a low PCS BP value 
occurs at 2 hours after the start of an infusion. Subjects should not be provided iv BRV if the 
latest <1-hour pre-initiation measurement of systolic or diastolic BP is a low PCS value. In this 
case BP measurements should be repeated and the iv BRV infusion be started only after the BP 
does not meet the low PCS criterion anymore. The criteria for BP values to be low or high PCS 
values are described in Table 10-6. 
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Table 5‒1: 
Schedule of Study Assessments (Screening Period through end of iv PK Period) 
Period 
Screening 
IOB Treatment 
iv PK 
 
Unscha 
Visit 
V1 
V2 
V3 to V12 
TC-1 
 
Study Day for 
 
 
 
 
 
OLB, RxB, IIB 
subjects 
-10 to -1 
N/A 
1 to 6 
2 to 9 
N/A 
IOB subjects 
-20 to -11 
-10 to -1 
 
 
 
Assessments 
 
 
 
 
 
Informed consent/as applicable, Assent form  
X 
 
 
 
 
Subject identification card dispensing 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xb 
Xb 
 
 
Demographic data 
X 
 
 
 
 
General medical/procedure history 
X 
 
 
 
 
Historical seizure count 
X 
 
 
 
 
Prior/concomitant medications including AEDs 
X 
X 
X 
X 
X 
Physical examinationc 
X 
 
Xe 
 
 
Tanner stagingd 
 
 
Xb 
 
 
Neurological examinationc 
X 
 
Xe 
 
 
Body weightf 
X 
Xb 
Xb 
 
 
Body height  
X 
 
X 
 
 
Vital signs (BP, pulse rate, RR, temperature) 
X 
X 
Xg 
 
X 
12-lead ECG 
X 
 
Xg 
 
 
Clinical chemistry, hematology, and endocrinology 
X 
 
 
 
 
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Table 5‒1: 
Schedule of Study Assessments (Screening Period through end of iv PK Period) 
Period 
Screening 
IOB Treatment 
iv PK 
 
Unscha 
Visit 
V1 
V2 
V3 to V12 
TC-1 
 
Study Day for 
 
 
 
 
 
OLB, RxB, IIB 
subjects 
-10 to -1 
N/A 
1 to 6 
2 to 9 
N/A 
IOB subjects 
-20 to -11 
-10 to -1 
 
 
 
Urinalysis 
(for subjects for whom sample collection is feasible) 
X 
 
 
 
 
Pregnancy testing (urine; for females of CB potential) 
X 
X 
Xb 
 
 
AEsh 
X 
X 
X 
X 
X 
Withdrawal criteria 
 
X 
X 
X 
X 
C-SSRSi 
X 
X 
Xj 
 
Xk 
PK sampling 
 
 
Xg 
 
 
Dispense/collect oral BRV from EP0065 supply 
 
X 
Xl 
 
 
Administration of iv BRV 
 
 
X 
 
 
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Table 5‒1: 
Schedule of Study Assessments (Screening Period through end of iv PK Period) 
Period 
Screening 
IOB Treatment 
iv PK 
 
Unscha 
Visit 
V1 
V2 
V3 to V12 
TC-1 
 
Study Day for 
 
 
 
 
 
OLB, RxB, IIB 
subjects 
-10 to -1 
N/A 
1 to 6 
2 to 9 
N/A 
IOB subjects 
-20 to -11 
-10 to -1 
 
 
 
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRV=brivaracetam; CB=childbearing; CRF=Case Report form; C-SSRS=Columbia-Suicide 
Severity Rating Scale; ECG=electrocardiogram; IIB=Initiating iv BRV; IOB=Initiating Oral BRV; iv=intravenous; N/A=not applicable; OLB=Open-label BRV; 
PK=pharmacokinetic; RR=respiratory rate; RxB=Prescribed BRV; TC=Telephone Contact; Unsch=Unscheduled; V=Visit 
a Additional assessments may be performed at the Investigator’s discretion.  
b To be performed prior to dispensing/administering the initial dose of BRV in this period (for the PK Period, at Visit 3 only). 
c Complete examinations should be conducted at Visit 1. Brief physical and neurological examinations should be conducted at other designated visits. Clinically new 
or worsened abnormalities must be reported as AEs. 
d The Investigator should use clinical judgment in deciding which subjects are selected for evaluation of Tanner Stage (ie, those subjects who are pubescent). 
e To be performed prior to the initial dose of BRV (Visit 3) and daily thereafter, ideally after the morning dose. 
f Body weight determinations should be made with subjects wearing light clothing and not wearing shoes. 
g Detailed timings for these assessments are provided in Table 5‒2 (15-minute [±3 minutes] infusion) and Table 5‒3 (bolus [up to 2-minute infusion]). 
h Infusion-site related AEs for subjects who have returned to/entered a long-term, open-label study should continue to be recorded in the EP0065 CRF.  
i The C-SSRS will be assessed only in subjects ≥6 years of age. The C-SSRS versions to be used are specified in Section 10.3.3.  
j To be assessed prior to the administration of iv BRV at Visit 3 and after the final iv dose of BRV each day for Visits 4 to 12, as applicable.  
k The C-SSRS will be assessed only in subjects who attend this visit due to safety reasons. 
l To be collected as needed for IOB subjects who will enter the long-term, open-label study. To be dispensed, as needed, for subjects continuing into the 
Down-Titration Period at the final visit of the PK Period. 
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Table 5‒1: 
Schedule of Study Assessments (Screening Period through end of iv PK Period) 
Period 
Screening 
IOB Treatment 
iv PK 
 
Unscha 
Visit 
V1 
V2 
V3 to V12 
TC-1 
 
Study Day for 
 
 
 
 
 
OLB, RxB, IIB 
subjects 
-10 to -1 
N/A 
1 to 6 
2 to 9 
N/A 
IOB subjects 
-20 to -11 
-10 to -1 
 
 
 
Table 5‒2: 
Schedule for iv PK Period ECGs, vital signs, and PK sampling (15-min BRV infusion) 
 
Time relative to initiation of iv BRV infusion 
 
Pre-initiation 
Post-initiation 
 
Assessment 
≤ 1hr 
 
5min 
(±1min) 
10min 
(±1min) 
15mina 
(±2min) 
30min 
(±5min) 
60min 
 (±10min) 
2hr 
 (±15min) 
3hr 
(±15min) 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
(BP, pulse rate, RR, temperature) 
X 
X 
X 
X 
X 
X 
Xc 
 
PK samplingb 
X 
 
 
X 
 
 
 
X 
BP=blood pressure; BRV=brivaracetam; ECG=electrocardiogram; hr=hour(s); min=minute(s); iv=intravenous; PK=pharmacokinetic; PCS=possibly clinically 
significant; RR=respiratory rate 
a To be conducted at the end of infusion. 
b Blood samples for PK analyses will be collected for the initial BRV infusion and 1 subsequent BRV infusion only. Blood samples should be collected after 
completion of the ECG and the vital sign measurements and from a region of the body not used for iv the BRV administration. 
c Only BP to be collected at 2 hours post initiation of infusion. Additional vital sign monitoring, specifically BP is necessary if a low PCS BP value occurs at 2 hours 
after the start of an infusion.  
 
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Table 5‒3: 
Schedule for iv PK Period ECGs, vital signs, and PK sampling (bolus [up to 2-min BRV infusion]) 
 
Time relative to initiation of iv BRV administration 
 
Pre-
initiation 
Post-initiation 
 
Assessment 
≤ 1hr 
 
≤ 2mina 
 
5min 
(±1min) 
 
15min 
(±2min) 
 
30min 
(±5min) 
 
60min 
 (±10min) 
2hr 
 (±15min) 
3hr 
(±15min) 
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
(BP, pulse rate, RR, temperature) 
X 
X 
X 
X 
X 
X 
Xc 
 
PK samplingb 
X 
 
 
X 
 
 
 
X 
BP=blood pressure; BRV=brivaracetam; ECG=electrocardiogram; hr=hour(s); min=minute(s); iv=intravenous; PK=pharmacokinetic; PCS=possibly clinically 
significant; RR=respiratory rate 
a To be conducted during bolus/infusion, if feasible.  
b Blood samples for PK analyses will be collected for the initial BRV infusion and 1 subsequent BRV infusion only. Blood samples should be collected after 
completion of the ECG and the vital sign measurements and from a region of the body not used for the iv BRV administration. 
cOnly BP to be collected at 2 hours post initiation of infusion.  Additional vital sign monitoring, specifically BP is necessary if a low PCS BP value occurs at 2 
hours after the start of an infusion.  
 
 
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Table 5‒4: 
Schedule of study assessments for Down-Titration and Safety (BRV-free) Periods (subjects not 
continuing into the Long‑Term, Open‑Label Study) 
 
Down-Titration 
Safety (BRV-free) 
Visit 
TC-2a 
V13 
TC-3b 
Assessments 
 
 
 
Concomitant medications including AEDs 
X 
X 
X 
Physical examination (brief) 
 
X 
 
Neurological examination (brief) 
 
X 
 
Body height  
 
X 
 
Vital signs (BP, pulse rate, RR, temperature) 
 
X 
 
12-lead ECG 
 
X 
 
Clinical chemistry, hematology, and endocrinology 
 
X 
 
Urinalysis 
(for subjects for whom sample collection is feasible) 
 
X 
 
Pregnancy testing (urine; for females of CB potential) 
 
X 
 
AEs 
X 
X 
X 
Withdrawal criteria 
X 
 
 
C-SSRSc 
 
X 
 
Collect oral BRV  
 
X 
 
AEDs=antiepileptic drug; AEs=adverse events; BP=blood pressure; BRV=brivaracetam; CB=childbearing; C-SSRS=Columbia-Suicide Severity 
Rating Scale; ECG=electrocardiogram; RR=respiratory rate; TC=telephone contact; V=Visit 
a This TC is only applicable to subjects with a Down-Titration Period of more than 2 weeks. The TC should be conducted approximately half way 
through the Down-Titration Period. 
b This TC is only applicable for subjects who have attended Visit 13 and will be conducted approximately 2 weeks after the final dose of BRV. 
c The C-SSRS will be assessed only in subjects ≥6 years of age. The C-SSRS versions to be used are specified in Section 10.3.3. 
 
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5.3 
Rationale for study design and selection of dose 
In 2016, marketing authorization for the use of oral and iv BRV as adjunctive therapy in the 
treatment of POS was granted in the in the EU, US, and Australia for patients 16 years of age 
and older and in Canada for patients 18 years of age and older with epilepsy. The recommended 
starting dosing of BRV is 50mg bid. Based on individual patient tolerability and therapeutic 
response, the dosage may be adjusted down to 25mg bid (50mg/day) or up to 100mg bid 
(200mg/day). Brivaracetam injection can be administered intravenously over 2 to 15 minutes 
when oral administration of BRV is temporarily not feasible. Pharmacokinetic data for BRV 
administered by the oral route are available over the age range from adults down to 1 month of 
age and have demonstrated that BRV is completely absorbed and fully bioavailable orally. In 
adults, BRV iv bolus and oral tablet are bioequivalent.  
Brivaracetam injection was evaluated in N01258, an open-label, multicenter study evaluating the 
safety and tolerability of BRV 200mg/day administered for 4.5 days as a 15-minute iv infusion 
or a 2-minute iv bolus in subjects ≥16 to 70 years of age with epilepsy. Results from N01258 
indicated that iv BRV (as both 15-minute infusion and 2-minute bolus) was well tolerated. The 
AE profile was similar regardless of whether iv BRV was administered as a 2-minute bolus or a 
15-minute infusion. Given these results in older subjects ≥16 years, it is expected that BRV will 
have similar results in younger subjects aged ≥1 month to <16 years of age. 
The PK, safety, and efficacy of BRV in 100 subjects aged ≥1 month to <16 years with epilepsy 
were evaluated in N01263, an open-label, multicenter, fixed 3-step up-titration, adjunctive 
therapy study using an oral solution formulation. All doses were adjusted by body weight and did 
not exceed a maximum of 50mg/day, 100mg/day, and 200mg/day for each titration step. Results 
from N01263 indicated that BRV was generally well tolerated and that the safety profile in 
subjects aged ≥1 month to <16 years was consistent with the known safety profile in adults. 
Trough plasma BRV concentration increased proportionally to BRV dose. 
The iv dose for subjects initiating BRV in this study was predicted in N01331, which modeled 
based on PK data from N01263 and N01256 (BRV adult study) and simulated the BRV iv 
concentrations in pediatric subjects. Based on the results of N01331, in the pediatric population 
1 month to <17 years of age, an iv injection 15-minute infusion or bolus (up to 2-minute 
infusion) of 4mg/kg/day (2mg/kg bid) regimen with a maximum of 200mg/day (100mg bid) 
results in plasma concentrations in the same range as seen in adults receiving 200mg/day (100mg 
bid), the maximum recommended dose in adults with POS. These data support using a mg-to-mg 
equivalent to the oral dose for OLB and RxB subjects. As demonstrated in the 
concentration-effect analysis CL0258 using levetiracetam PK and PD data from adults and 
children and BRV PK and PD data in adults (N01358) and PK data in children (N01263), in 
subjects 4 to 16 years of age, similar weight-normalized doses are needed to achieve the same 
efficacy as compared with adults, with a maximum response at 4mg/kg/day. 
EP0065 has been designed to evaluate the PK, safety, and tolerability of iv dosing of BRV in 
subjects 1 month to <16 years of age, as iv formulations are particularly helpful as short-term 
replacement of oral formulations for patients unable to take oral products (eg, pre and 
postoperative patients, patients with acute gastrointestinal disorders). For OLB and RxB subjects, 
the maximum BRV dose is 5mg/kg/day (rounded) to allow for the possibility that these subjects 
enter EP0065 on this dose. Dose selection for IOB and IIB subjects was based on the results 
obtained in N01331 and the recommended dose of BRV as adjunctive therapy in the treatment of 
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POS in patients 16 years of age and older with epilepsy. For IOB and IIB subjects, the starting 
BRV dose (2mg/kg/day [1mg/kg bid]) and maximum BRV dose (4mg/kg/day [2mg/kg bid]) in 
subjects with body weights <50kg approximate the 100mg/day (50mg bid) starting dose and 
200mg/day (100mg bid) maximum dose recommended for use in adults. No subjects enrolled in 
EP0065 are permitted have a dose that exceeds a maximum of 200mg/day (100mg bid) as 
consistent with the maximum recommended dose. 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
1. Subject or the parent(s) or legal representative of the subject has signed and dated an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
ICF. The ICF or a specific Assent form, where required, will be signed and dated by minors. 
2. The Investigator considers the subject/legal representative to be reliable and able to comply 
with all study requirements.  
3. Subject is male or female from ≥1 month to <16 years of age. For subjects who are <1 year 
from birth and who were preterm infants, the corrected gestational age should be used for this 
entry requirement. The corrected gestational age is calculated by subtracting the number of 
weeks born before 37 weeks of gestation from the chronological age. 
4. Subject weighs ≥3kg (6.6lbs). 
5. Subject has a diagnosis of epilepsy. 
6. Subject is an acceptable candidate for venipuncture and iv infusion. 
7. Subject being treated with ≥1 AED (including BRV) without a change of dose regimen for at 
least 7 days prior to Screening. 
8. Subject is not being treated with vagus nerve stimulation (VNS), OR the subject is being 
treated with VNS and the settings have been constant for ≥ 7 days prior to Screening. 
9. For female subjects, the subject is 
 Not of childbearing potential  
-OR- 
 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 
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 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: Intra Uterine Device, diaphragm with spermicide, male or 
female condom with spermicide   
 Abstinence from sexual intercourse 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria are met:  
1. Subject has previously received iv BRV in this study. 
2. Subject is pregnant or nursing. 
3. Subject has any medical, neurological, or psychiatric condition that, in the opinion of the 
Investigator, could jeopardize the subject’s health or compromise the subject’s ability to 
participate. 
4. Subject is being treated with BRV at a dose >5mg/kg/day (rounded) or >200mg/day for 
subjects with body weights >40kg. 
5. Subject requires or is likely to require a change in concomitant AED(s), dose of concomitant 
AED(s), or formulation of AED(s) during the 7 days prior to the iv PK Period. 
6. Subject is likely, in the opinion of the Investigator, to require rescue medication during the 
IOB Treatment or iv PK Periods. 
7. Subject is ≥6 years of age and 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 positive responses (“Yes”) to either Question 4 or Question 5 of the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening. 
8. Subject is participating in a long-term, open-label BRV study and meets any of the must 
withdraw criteria for that study. 
9. Subject has any medical condition that could reasonably be expected to interfere with the 
absorption, distribution, metabolism, or excretion of BRV. 
10. Subject has a clinically relevant ECG abnormality, in the opinion of the Investigator. 
11. Subject has experienced generalized convulsive status epilepticus in the 28 days prior to 
Screening or during the Screening Period. 
12. Subject has a known hypersensitivity to a pyrrolidone derivative(s) or any of the components 
of the oral or iv formulations of BRV. 
13. Subject has a history of severe adverse hematologic reaction to any drug. 
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14. Subject has >1.5x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). 
For randomized subjects with a baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the CRF. 
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at Screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening.  
15. Subject has chronic liver disease. 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. The following criteria for subject withdrawal from EP0065 are outlined below. Additional 
discontinuation criteria for potential drug-induced liver injury are presented in Section 6.3.1. 
Subjects must be withdrawn from the study if any of the following events occur: 
1. Subject experiences intolerable AEs and AEs associated with BRV administration that, in the 
opinion of the Investigator, precludes further participation in this study. 
2. Sponsor or a regulatory agency requests withdrawal of the subject. 
3. Subject becomes pregnant during the study, as evidenced by a positive pregnancy test. 
4. 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. 
5. Investigator decides that withdrawal from further participation would be in the subject’s best 
interest. 
6. For subjects ≥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” version of 
the C-SSRS. The subject should be referred immediately to a Mental Healthcare Professional 
and must be withdrawn from the study. 
Participation in this study may be discontinued for any of the following reasons: 
7. Subject experiences generalized convulsive status epilepticus. 
8. Subject has any clinically relevant change in medical or psychiatric condition (if in the 
opinion of the Investigator, the change in condition warrants discontinuation from this study). 
9. Subject takes prohibited concomitant medications as defined in this protocol (Section 7.8.2). 
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10. Subject and/or delegated caregiver is noncompliant with study procedures or medication, in 
the opinion of the Investigator. 
11. For subjects ≥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” version of C-
SSRS. The subject should be referred immediately to a Mental Healthcare Professional and 
may be withdrawn from the study based upon the Investigator’s judgment of benefit/risk of 
continuing the subject in the study/on study medication. 
 Investigators should attempt to obtain information on subjects in the case of withdrawal; 
subjects who withdraw from the study without down titration of BRV should complete the 
Visit 13 (Table 5‒4). 
For subjects considered lost to follow up, the Investigator should make an effort (at least 1 phone 
call and 1 written message to the subject), and document his/her effort (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative description 
of the reason(s) for removing the subject, must be recorded in the source documents. The CRF 
must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
6.3.1 
Potential drug-induced liver injury 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). 
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Evaluation of PDILI must be initiated as described in Section 10.2.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The CRF must document the primary 
reason for IMP discontinuation. 
7 
STUDY TREATMENT(S) 
7.1 
Description of investigational medicinal products 
Information pertaining to excipients and tablet coatings for the IMP used in this study is 
provided in the Investigator’s Brochure.  
7.1.1 
Film-coated tablets for oral administration 
Tablet strengths: BRV 10mg, 25mg, 50mg, 75mg, and 100mg 
7.1.2 
Oral solution 
Concentration: BRV 10mg/mL 
7.1.3 
Solution for iv injection 
Concentration: BRV 10mg/mL  
7.2 
Treatments to be administered 
For BRV tablets, the mg dosage for the oral tablet treatment should be calculated to match as 
closely as possible the mg/kg based dosage. Tablets of BRV 10mg, 25mg, 50mg, 75mg, and 
100mg are supplied and may be combined, as needed, to achieve the calculated mg/kg dose. 
Tablets and solution must not be used together to comprise an individual dose. 
The dose of oral solution will be measured using the appropriate syringes (1mL, 3mL, and/or 
10mL) with an adaptor able to fit the bottle sizes. Oral solution should not be mixed with other 
liquids prior to administration.  
For 15-min iv infusions, a calibrated infusion pump should be used for delivering the iv BRV 
dose at a constant rate over the target duration assigned. A previously unused vial must be 
administered for each dose. Dilution is not required prior to administration of iv BRV. The BRV 
solution for iv injection can be diluted as needed in any of the following diluents:  
 0.9% sodium chloride injection  
 Lactated Ringer’s injection  
 5% dextrose injection  
The total volume of diluent should be calculated not to exceed a total volume of fluid intake/day 
based on the Holliday-Segar equation as follows:  
 For children weighing ≤10kg: 100mL/kg body weight 
 For children weighing >10 to ≤20kg: 1000mL + 50mL/kg for each kg body weight ≥10kg 
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 For children weighing ≥20kg: 1500mL + 20mL/kg for each kg body weight ≥20kg 
Brivaracetam will be dispensed using interactive response technology (IRT). 
7.2.1 
Screening, IOB Treatment, and iv PK Periods 
Dosing information for BRV during the Screening, IOB Treatment, and iv PK Periods is 
provided in Table 7‒1.  
Table 7‒1: 
BRV dosing during the Screening, IOB Treatment, and iv PK Periods 
 
Study Period 
 
 
Screening 
(1-10 days) 
IOB Treatment 
(2-10 days)a 
iv PK 
(1-6 days)b 
 
Subjects 
Dose (oral) 
Dose (oral) 
First dose 
(iv) 
Subsequent 
dose(s) (iv) 
Maximum BRV 
Dose 
OLB 
Per 
Long-Term, 
Open-Label 
study 
N/A 
mg-to-mg 
equivalent to 
last oral dose 
Equivalent to 
first iv dose 
until PK 
sampling is 
completed. 
5mg/kg/day 
(rounded) nte. 
200mg/day for body 
weight ≥40kg  
RxB 
As prescribed 
N/A 
mg-to-mg 
equivalent to 
last oral dose 
Equivalent to 
first iv dose 
until PK 
sampling is 
completed. 
5mg/kg/day 
(rounded) nte. 
200mg/day for body 
weight ≥40kg 
IOB 
Not receiving 
BRV 
Subjects <50kg: 
2mg/kg/day  
 
Subjects ≥50kg: 
nte. 100mg/day 
mg-to-mg 
equivalent to 
last oral dose 
Equivalent to 
first iv dose 
until PK 
sampling is 
completed. 
4mg/kg/day 
nte. 200mg/day for 
body weight ≥50kg 
IIB 
Not receiving 
BRV 
N/A 
Subjects 
<50kg: 
1mg/kg 
Subjects 
≥50kg: 
50mg 
Equivalent to 
first iv dose 
until PK 
sampling is 
completed. 
4mg/kg/day nte. 
200mg/day for body 
weight ≥50kg 
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Study Period 
 
 
Screening 
(1-10 days) 
IOB Treatment 
(2-10 days)a 
iv PK 
(1-6 days)b 
 
Subjects 
Dose (oral) 
Dose (oral) 
First dose 
(iv) 
Subsequent 
dose(s) (iv) 
Maximum BRV 
Dose 
bid=twice daily; BRV=brivaracetam; IIB=Initiating iv BRV; IOB=Initiating Oral BRV; iv=intravenous; 
LT=Long-term; N/A=not applicable; nte.=not to exceed; OL=Open-label; OLB=Open-label BRV; 
PK=pharmacokinetic; q12h=every 12 hours; RxB=Prescribed BRV 
Note: Oral BRV will be administered in equally divided doses bid as either tablets or oral solution. Tablets will be 
administered orally and oral solution will be administered either orally or by enteric administration (eg, feeding 
tube) based on subject need. 
Note: Intravenous BRV will be administered as a 15-minute (±3 minutes) infusion or bolus (up to 2-minute 
infusion), as assigned and will be administered q12hours ± 2 hours. 
a Dose adjustment is allowed at the Investigator’s discretion provided the adjusted dose does not exceed the 
maximum dose indicated in the rightmost column of this table and does not occur within 2 days of entry into the 
iv PK Period. 
b Dose adjustment is allowed at the Investigator’s discretion provided that PK sampling has been completed for 
2 doses and the adjusted dose does not exceed the maximum dose indicated in the rightmost column of this table 
and does not occur within 2 days of entry into the iv PK Period. 
7.2.2 
Down-Titration Period 
All subjects who have received ≥4 doses of BRV during either the IOB Treatment Period or the 
iv PK Period and who will not continue BRV 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 for 
subjects with body weights ≥50kg) is reached. Subjects who have received <4 doses of BRV 
may have BRV down titrated at the discretion of the Investigator. Subjects not able to receive 
oral BRV for down titration, may receive iv BRV for down titration. In the later circumstance, 
the subjects may receive more than 10 consecutive doses of iv BRV in accordance with the 
Investigator’s discretion. 
The OLB subjects who discontinue BRV during the Screening Period will return to the 
long-term, open-label study for down titration of BRV.  
7.3 
Packaging 
Primary packaging: 
 Tablets for oral administration: high-density polyethylene bottles with child-resistant closure 
containing tablets of BRV 10mg, 25mg, 50mg, 75mg, and 100mg 
 Oral solution: 300mL amber glass bottles with child-resistant closure 
 Solution for iv injection: 6mL clear Type I glass vials with bromobutyl rubber stopper 
containing 5mL (50mg) of BRV 
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. 
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7.5 
Handling and storage requirements 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the Investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label. Additional 
information pertaining to the handling of BRV, a Schedule V drug, is provided in the IMP 
Handling Manual. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual.  
7.6 
Drug accountability 
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the Sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed, taking into account local laws and regulations. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
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 containers must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB standard operating 
procedures (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 
At each visit after IMP is dispensed, subjects/guardians must return all unused IMP and empty 
IMP containers. Drug accountability must be done in 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. 
Site personnel who are administering iv BRV will record information about all doses 
administered, including the target dose, actual dose administered, and the dates and times of 
initiation and completion of each iv administration. If the actual dose is less or more than the 
target dose, the reason a partial or excessive dose was administered will be recorded.  
Intravenous solution will be administered under supervision of the Investigator or his/her 
designee. The noninjected volume will be recorded in the CRF. Compliance with the 
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recommended duration of the iv administration will also be assessed by recording the start time 
and the stop time in the CRF.  
Subjects who receive <75% or >125% of the planned BRV dose will be considered 
noncompliant. 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. 
7.8 
Concomitant medication(s)/treatment(s) 
For any treatment other than the IMP, including over-the-counter products, an accurate record 
must be kept in the clinic chart (source documentation) and in the CRF. Concomitant 
medications should be recorded on the concomitant AED page or the concomitant non AED 
medication page of the CRF, according to the indication. New medications should be recorded in 
the CRF 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 CRF. 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
All treatments are permitted with the exception of those listed in Section 7.8.2.  
Vagus nerve stimulation is allowed and will be counted as a concomitant AED. A stable 
ketogenic diet is allowed. 
7.8.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medication is prohibited during the study: 
 Levetiracetam 
7.8.3 
Rescue medication 
Investigators may administer rescue medication in accordance with medical judgment at any 
time during the study. No rescue medication will be supplied by UCB. 
7.9 
Blinding 
This is an open-label study; no blinding is required. 
7.10 
Randomization and numbering of subjects 
Subjects will not be randomized in EP0065.  
For OLB subjects, the unique identification number assigned to them in the open-label study will 
be used to identify them and maintain subject confidentiality throughout EP0065.  
The RxB, IOB, and IIB subjects will be assigned a unique identification number for 
identification and to maintain subject confidentiality. To enroll these subjects, the Investigator or 
designee will contact the IRT and provide brief details about the subject to be enrolled. Each 
subject will receive a 5-digit number assigned at screening that serves as the subject identifier 
throughout the study. The subject number will be required in all communication between the 
Investigator or designee and the IRT regarding a particular subject. Subject numbers and kit 
numbers will be tracked via the IRT.  
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8 
STUDY PROCEDURES BY VISIT 
Days are provided relative to Day 1, the first day of the iv PK Period. 
8.1 
Visit 1 (Day -10 to Day-1 for OLB, RxB, and IIB subjects; Day -20 
to Day -11 for IOB subjects) 
 Signing and dating of written ICF by parent(s)/legal representative(s) 
 Signing and dating of Assent form by the subject (if applicable, according to age and local 
requirements) 
The following assessments should be performed only after the ICF and Assent form (if 
applicable) procedures described immediately above are completed:  
 Subject identification card dispensing 
 Inclusion/exclusion criteria 
 Demographic data 
 General medical/procedure history 
 Historical seizure count 
 Prior and concomitant medications including AEDs 
 Physical examination (complete) 
 Neurological examination (complete) 
 Body weight (before BRV dispensed) 
 Body height 
 Vital signs (BP, pulse rate, RR, and temperature) 
 12-lead ECG 
 Clinical chemistry, hematology, and endocrinology  
 Urinalysis for subjects for whom urine sample collection is feasible 
 Pregnancy testing for females of childbearing potential (urine test) 
 AEs  
 C-SSRS (for subjects ≥6 years of age); version per Section 10.3.3 
8.2 
Visit 2 (Day -10 to Day -1; IOB subjects only) 
 Inclusion/exclusion criteria (before BRV dispensed) 
 Concomitant medications including AEDs 
 Body weight (before BRV dispensed) 
 Vital signs BP, pulse rate, RR, and temperature 
 Pregnancy testing for females of childbearing potential (urine) 
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 AEs 
 C-SSRS (for subjects ≥6 years of age); version per Section 10.3.3 
 Withdrawal criteria 
 Dispense oral BRV 
8.3 
Visit 3 (Day 1) through Visit 12 (Day 6) 
 Inclusion/exclusion criteria (Visit 3 only; prior to iv BRV administration) 
 Concomitant medications including AEDs 
 Physical examination (brief) (at Visit 3 prior to the initial dose of BRV and daily thereafter, 
ideally after the morning dose of BRV each day) 
 Tanner staging at Visit 3 prior to iv BRV administration only. The Investigator should use 
clinical judgment in deciding which subjects are selected for evaluation of Tanner Stage (ie, 
those subjects who are pubescent).  
 Neurological examination (brief) (at Visit 3 prior to iv BRV administration and daily 
thereafter, ideally after the morning dose of BRV each day) 
 Body weight (Visit 3 only, prior to iv BRV administration)  
 Body height 
 Vital signs (BP, pulse rate, RR, and temperature) (see Table 5‒2 and Table 5‒3 for timing 
relative to initiation of iv BRV administration). The criteria for BP values to be low or high 
PCS values are described in Table 10-6 . 
 12-lead ECG (see Table 5‒2 and Table 5‒3 for timing relative to initiation of iv BRV 
administration) 
 Pregnancy testing for females of childbearing potential (urine test) (Visit 3 only, prior to iv 
BRV administration) 
 AEs 
 Withdrawal criteria 
 C-SSRS (for subjects ≥6 years of age); version per Section 10.3.3 (Visit 3 prior to iv BRV 
administration  and, for subjects who receive ≥2 doses of iv BRV and who will enter the 
Down-Titration Period, at their final visit of the iv PK Period [Visit 4 to 12, as applicable]) 
 PK sampling (see Table 5‒2 and Table 5‒3 for timing relative to initiation of iv BRV 
administration)  
 Collect oral BRV (as needed for IOB subjects who will enter the long-term, open-label 
study)  
 Dispense oral BRV (at final visit of this period and only for subjects who will enter the 
Down-Titration Period) 
 iv BRV administration 
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Subjects who are continuing into the long-term, open-label study after their final dose of iv BRV, 
will re-enter (OLB subjects)/enter (RxB, IOB, and IIB subjects) that study at the completion of 
assessments associated with the final iv dose of iv BRV.  
8.4 
TC-1 (Day 2 to Day 9) (all subjects who received iv BRV) 
Telephone Contact-1 (TC-1) should occur 1 to 3 days after the final dose of iv BRV. The 
primary purpose of this contact is to collect information pertaining to possible infusion-related 
AEs. Subjects who report new or worsened infusion-site related AEs should return for an 
Unscheduled Visit as soon as possible. 
 Concomitant medications including AEDs 
 AEs 
 Withdrawal criteria 
8.5 
TC-2 
Telephone Contact-2 is only applicable to subjects who participate in the Down-Titration Period 
for more than 2 weeks; TC-2 should be conducted approximately half way through the 
Down-Titration Period. 
 Concomitant medications including AEDs 
 AEs  
 Withdrawal criteria 
8.6 
Visit 13 
This visit is applicable only to subjects who have participated in the Down-Titration Period or to 
subjects who need to withdraw from the study and do not need to have BRV down titrated. 
 Concomitant medications including AEDs 
 Physical examination (brief) 
 Neurological examination (brief) 
 Body height 
 Vital signs (BP, pulse rate, RR, and temperature) 
 12-lead ECG 
 Clinical chemistry, hematology, and endocrinology 
 Urinalysis for subjects for whom urine sample collection is feasible 
 Pregnancy testing for females of childbearing potential (urine test) 
 AEs  
 C-SSRS (for subjects ≥6 years of age); version per Section 10.3.3 
 Collect oral BRV  
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8.7 
TC-3 
Telephone Contact-3 is only applicable to subjects who have completed Visit 13 and should be 
conducted 2 weeks after the final dose of BRV. 
 Concomitant medications including AEDs 
 AEs  
8.8 
Unscheduled Visit 
If an Unscheduled Visit is needed, then the following assessments will be performed. Additional 
assessments can be performed at the Investigator’s discretion. 
 Concomitant medications including AEDs. 
 Vital signs (BP, pulse rate, RR, and temperature). 
 AEs. 
 Withdrawal criteria 
 C-SSRS for subjects ≥6 years of age using the version indicated in Section 10.3.3. If an 
Unscheduled Visit is conducted due to safety reasons, a C-SSRS assessment will be 
performed with the subject during the visit. If the Unscheduled Visit is conducted for reasons 
other than safety 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 
this visit. 
9 
ASSESSMENT OF PHARMACOKINETIC VARIABLES 
The PK sampling will be performed in accordance with the schedule provided in Table 5‒2 
(15-minute [±3 minutes] infusion) and Table 5‒3 (bolus [up to 2-minute infusion]). Additional 
PK sampling may be performed at the discretion of the Investigator, especially in the event of a 
relevant treatment-emergent AE. 
Blood samples should be collected after completion of the ECG and the vital sign measurements 
and from a region of the body not used for the iv BRV administration. The date, start, and stop 
time of each iv administration and the date and time of each PK sampling must be recorded. 
Per subject, the maximum amount of blood collected for PK analyses and clinical laboratory 
assessments will not exceed a maximum of 3% of the subject’s total blood volume within 
4 weeks. 
Details of plasma sample collection and processing, sample labeling, and shipment will be 
provided in the laboratory manual.  
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10 
ASSESSMENT OF SAFETY 
10.1 
Adverse events 
10.1.1 
Definitions 
10.1.1.1 
Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF/Assent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the CRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the subject’s history or the Baseline Period. 
10.1.1.2 
Serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. A serious adverse event (SAE) must meet 1 or more of the following criteria: 
 Death 
 Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
 Significant or persistent disability/incapacity 
 Congenital anomaly/birth defect (including that occurring in a fetus) 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious 
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 10.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.) 
 Initial inpatient hospitalization or prolongation of hospitalization 
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
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admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
10.1.1.2.1 
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.  
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 10.1.2.3. 
Table 10‒1: Anticipated serious adverse events for the pediatric epilepsy 
population 
MedDRA SOC 
MedDRA PT 
Congenital, familial and genetic disorders 
Teratogenicity 
General disorders and administrative 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. 
10.1.1.3 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. For this study, the AEs of special interest include:  
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 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. 
10.1.2 
Procedures for reporting and recording adverse events 
The subject and/or caregiver (including parent/legal guardian) will be given the opportunity to 
report AEs spontaneously. A general prompt will also be given at each study visit to detect AEs. 
For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study at each visit. 
The AEs should be recorded in the CRF at only the first visit at which they are reported and 
subsequently only if there is a change.  
10.1.2.1 
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 CRF and 
source documents should be consistent. Any discrepancies between the subject’s and/or 
caregivers 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 AE CRF (including judgment of relationship to IMP) are described 
in the CRF Completion Guidelines. 
10.1.2.2 
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 
10.1.2.3 
Additional procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
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section at the front of the protocol). The Investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE Report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database. 
An Investigator SAE Report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English.  
It is important for the Investigator, when completing the SAE Report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE Report form. 
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the Investigator of any SAE within this period. Serious AEs that the 
Investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study. 
Upon receipt of the SAE Report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure for BRV. 
10.1.3 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events is provided in Section 10.2.1.4. 
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
Investigator must provide a justification. The follow up will usually be continued for 30 days 
after the subject has discontinued his/her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
If new or worsened infusion-site related AEs are reported during TC-1, the subject should return 
for an Unscheduled Visit as soon as possible for further assessment. 
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10.1.4 
Pregnancy 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see SAE reporting information at the 
beginning of this protocol). The subject should be withdrawn from the study as soon as 
pregnancy is known (by positive pregnancy test), and the following should be completed: 
 The subject should immediately stop the intake of BRV or be down-titrated as instructed by 
the Investigator. 
 For subjects who have BRV down-titrated: 
 Return for Visit 13. 
 TC-3 should be scheduled 2 weeks after the subject has discontinued BRV. 
The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the Investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
be available in the Investigator site file. In case of questions about the consent process, the 
Investigator may contact the UCB/contract research organization (CRO) contract monitor for the 
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 a SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form. 
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10.1.5 
Suspected transmission of an infectious agent via a medicinal 
product 
A suspected transmission of infectious agent is defined as any infection that is temporally related 
to the administration of the medicinal product with no other likely cause. The medical monitor 
should be contacted immediately. No further medicinal product from that specific batch should 
be administered. Infections should be treated according to normal clinical practice. 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the CRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
10.1.6 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the CRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
10.1.7 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study. 
For further details please refer to Section 12.7.  
10.2 
Laboratory measurements 
Laboratory assessments for safety (including hematology, chemistry, 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 supplies (labels, needles, tubes) and a 
study-specific laboratory manual, which will explain how to use the supplies and how to ship the 
samples to the central laboratory.  
Pregnancy tests (urine) for female subjects of childbearing potential will be performed locally. 
Table 10‒2 provides a list of laboratory parameters that will be assessed. 
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Table 10‒2: Laboratory parameters 
Hematology 
Chemistry 
Urinalysisa 
Endocrinology 
Pregnancyb 
WBC 
Glucose 
Glucose 
FSH 
β-hCG (urine) 
RBC 
Sodium 
Ketones 
LH 
 
Hemoglobin 
Potassium 
Occult blood 
TSH 
 
Hematocrit 
Calcium 
Protein 
T3 
 
Platelet count 
Chloride 
Nitrites 
T4 
 
Lymphocytes (number, %) 
Bicarbonate 
Leukocytes 
 
 
Monocytes (number, %) 
Phosphorus 
(inorganic) 
Microscopic 
examinationc 
 
Neutrophils (number, %) 
Total protein 
 
 
 
Eosinophils (number, %) 
Albumin 
 
 
 
Basophils (number, %) 
Total bilirubin 
 
 
 
MCH 
ALP 
 
 
 
MCHC 
AST 
 
 
 
MCV 
ALT 
 
 
 
 
GGT 
 
 
 
 
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; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating 
hormone; WBC=white blood cell 
a Urinalysis will be performed in subjects for whom urine sample collection is feasible. 
b For female subjects of childbearing potential only.  
c Includes bacteria, cells, casts, and crystals for all samples. 
For blood samplings, methods to minimize pain are recommended (eg, topical anesthetic or 
microsamplings may be used). Per subject, the maximum amount of blood collected for clinical 
laboratory assessments and PK analyses will not exceed a maximum of 3% of the subject’s total 
blood volume within 4 weeks. 
10.2.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and Sponsor within 24 hours of learning 
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of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 10.1.1.3), and, if applicable, also reported as an 
SAE (see Section 10.1.2.3 ).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 10‒3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.2.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 10.2.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable CRF 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. 
The table below summarizes the approach to investigate PDILI. 
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Table 10‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULNb 
NA 
Hepatology consult.c 
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and subject 
discussed with 
Medical Monitor 
ASAP. 
Immediate, 
permanent IMP 
discontinuation. 
 
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 10.2.1.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d 
 
≥3xULN 
NA 
Yes 
Immediate, 
temporary or 
permanent, IMP 
discontinuation. 
≥5xULN 
(and ≥2x 
baseline) 
<2xULN 
No 
Discussion with 
Medical Monitor 
required.  
Hepatology consult 
required if ALT/AST 
≥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 10.2.1.3). 
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Table 10‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
(and ≥2x 
baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met. 
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 10.2.1.2). 
IMP discontinuation 
required if any of 
the following occur: 
 Subject cannot 
comply with 
monitoring 
schedule.  
 Liver chemistry 
values continue to 
increase  
 Liver chemistry 
values remain 
≥3xULN (and 
≥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 10‒3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare 
practitioner; IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include 
eosinophilia (>5%), rash, and fever (without clear alternative cause). 
b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
c Details provided in Section 10.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d Unless an alternative monitoring schedule is agreed by the Investigator and UCB responsible physician. Determination of stabilization is at the 
discretion of the Investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
 
 
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10.2.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the subject must be discussed with the Medical Monitor as 
soon as possible. If required, the subject must also be discussed with the local hepatologist. The 
local hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. If determined necessary, this discussion should be followed by a full 
hepatology assessment (see Section 10.2.1.3) and SAE report (if applicable). 
10.2.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 10‒3 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. 
10.2.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 10‒4 (laboratory measurements) and Table 10‒5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the Sponsor on the 
corresponding CRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory. 
The following measurements are to be assessed: 
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Table 10‒4: 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 10‒5: 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 
10.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events will require follow-up monitoring as described in 
Table 10‒4. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the Investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
10.3 
Other safety measurements 
All safety assessments are to be conducted at the times specified in the Schedules of Study 
Assessments (Table 5‒1 and Table 10-6). During the iv PK Period, intensive assessments of 
ECGs and vital signs are to be conducted at the times specified in Table 5‒2 (15-minute 
[±3 minutes] infusion) and Table 5‒3 (bolus [up to 2-minute infusion]). 
10.3.1 
ECG 
Standard 12-lead ECGs 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. 
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The original ECG tracing will be signed or initialed and dated by the Investigator, and retained 
as part of the source documentation. 
10.3.2 
Vital signs 
Vital signs assessments will include BP (systolic and diastolic), pulse rate, RR, and temperature. 
Vital sign assessments will be performed after the subject is at rest for at least 3 minutes, when 
feasible. If subjects have an abnormal vital sign value, the measurement will be repeated at the 
Investigator’s discretion.  
Possibly clinically significant (PCS) vital sign values are defined as those PCS values which 
occur at any time during the study. Additional monitoring of BP is necessary if a low PCS BP 
value occurs at 2 hours after the start of an infusion (Section 5.2). An overview of PCS 
abnormality criteria for BP is presented in Table 10-6.  
 
 
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Table 10-6: PCS Abnormality criteria for the measurement of blood pressure 
Parameter 
Age range 
Abnormality criteria 
Systolic blood 
pressure 
(mmHg) 
<6m 
<60 
>100 
6m - <3y 
<70 
>120 
3y - <12y 
<80 
>140 
12y - <17y 
<90 
>160 
≥17y 
≤ 90 and a decrease from Baseline of ≥20 
≥ 180 and an increase from Baseline of ≥20 
Diastolic blood 
pressure 
(mmHg) 
<6m 
<40 
>65 
6m - <3y 
<45 
>75 
3y - <12y 
<50 
>80 
12y - <17y 
<50 
>105 
≥17y 
<50 and a decrease from Baseline of ≥15 
>105 and an increase from Baseline of ≥ 15 
m=month, PCS=possibly clinically significant; y=year. A month is defined as 30 days; a year is defined as 365.25 
days. 
10.3.3 
Assessment of suicidality 
Suicidal ideation and behavior 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 assessments (Section 5.2). 
The Investigator’s decision about subject continuation in the study or subject withdrawal from 
the study if the subject has a positive response to the C-SSRS Question 4, should be based on the 
benefit/risk balance for continuation or discontinuation of study treatment in view of the 
individual subject circumstances, condition, attained efficacy, causality, alternative risk 
management options, etc. Details of the case must be documented by the Investigator (Principal 
Investigator or other medically qualified staff conducting the C-SSRS) and provided to UCB via 
the SAE reporting process.  
All subjects who are ≥6 years of age will complete the following version of the C-SSRS as 
indicated: 
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 OLB subjects:  
 “Since Last Visit” version at all visits 
 RxB, IOB, and IIB subjects: 
 “Baseline/Screening” version at Visit 1  
 “Since Last Visit” version at subsequent visits 
 Subjects who become 6 years of age during EP0065: 
 "Already Enrolled" version at the first visit at which the subject is 6 years of age  
 “Since Last Visit” version at subsequent visits 
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. 
11 
STUDY MANAGEMENT AND ADMINISTRATION  
11.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
Sponsor. 
After implementation of such measure, the Investigator must notify the Clinical Project Manager 
of the Sponsor within 24 hours and follow any local regulatory requirements. 
11.2 
Monitoring 
Monitoring of the study will be delegated by UCB to a CRO. The CRO will monitor the study to 
meet the Sponsor’s monitoring SOPs, ICH-GCP guideline, and applicable regulatory 
requirements, and to ensure that study initiation, conduct, and closure are adequate.  
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 CRFs 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 CRFs, ensure that all protocol 
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requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
11.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Printouts of CRF screens are not considered acceptable 
source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, or video, for example. Source documents should be kept in a secure, limited 
access area. 
Original laboratory results and ECGs 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 facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records 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 CRF 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 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
electronic CRFs and in all required reports. 
Any change or correction to the CRF 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 electronic 
CRF. 
Detailed instructions will be provided in the CRF Completion Guidelines. 
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11.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. The data are entered into the electronic CRFs once and are subsequently verified. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed. 
11.3.3 
Subject Screening and Enrollment log/Subject Identification Code list 
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log. 
The Investigator will keep a Subject Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each subject. 
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
11.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study. 
11.5 
Archiving and data retention  
The Investigator will maintain adequate records for the study, including CRFs, 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 IMP. 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 
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relocate or move the study-related files to a location other than that specified in the Sponsor’s 
study master file. 
11.6 
Audit and inspection 
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities. 
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory 
requirements. 
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee). 
11.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
12 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan. 
12.1 
Definition of analysis sets 
The Safety Set iv (SS-iv) will include subjects who received at least 1 dose of iv BRV. The SS-iv 
will be the primary analysis set for the analysis of safety data. 
The Safety Set (SS) will include subjects who received at least 1 dose of BRV (oral or iv). 
Selected safety summaries will be presented for the SS. 
The PK Per-protocol Set (PK-PPS) will include all subjects in the SS having provided at least 
1 measurable postdose plasma sample (with recorded sampling time) during the iv PK Period 
with documented iv BRV intake times. 
12.2 
General statistical considerations 
All computations for the non-PK analyses will be performed using SAS® version 9.3 or later 
(SAS Institute, NC, USA).  
Selected disposition, exposure, demographic, and baseline summaries will be presented by 
cohort and infusion duration (15-minute [±3 minutes] infusion and bolus [up to 2-minute 
infusion]), cohorts overall, and across all subjects. Descriptive statistics will be displayed to 
provide an overview of the Baseline characteristics, PK, safety, and tolerability results. For 
categorical variables, these will consist of the number and percentage of subjects in each 
category. The denominator and percentage will be based on the number of subjects appropriate 
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for the purpose of analysis. For continuous variables, display of descriptive statistics will 
generally include n (number of subjects), mean, standard deviation (SD), median, minimum, and 
maximum. 
12.3 
Planned PK analyses 
Descriptive statistics for BRV plasma concentrations, including but not limited to geometric 
mean and coefficient of variation percentages, will be computed for pre-bolus/infusion and at the 
post-bolus/infusion time points on each for iv BRV administration during the iv PK Period. 
12.4 
Planned safety analyses 
Safety data will be reported in epochs that include the pre-bolus/infusion period(s), the 
bolus/infusion period(s), the period(s) immediately post-bolus/infusion, and period(s) between 
each subsequent bolus/infusion(s). These data will include vital signs, ECGs, and AE reporting.  
12.4.1 
Analysis of safety variables 
Descriptive statistics for the safety variables will be presented by cohort and infusion duration, 
cohorts overall, and all subjects overall. Additional summaries will include a summary of the 
OLB, RXB, IOB, and IIB groups by cohort and infusion duration. 
12.4.1.1 
Primary safety variables 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be summarized by MedDRA System Organ Class and 
Preferred Term. 
The primary safety variables will be summarized for the iv PK Period for the SS-iv. Summaries 
of adverse events will also be presented by study period for the SS and epochs relative to 
bolus/infusion for the SS-iv. 
12.4.1.2 
Other safety variables 
Inferential statistical tests are not planned for the other safety variables. In general, for 
continuous safety variables including ECG measurements including corrected QT interval, and 
vital sign measurements, the descriptive analyses (n, mean, SD, median, minimum, maximum) 
for the actual measurement and its change from baseline (defined as most recent pre-iv BRV 
measurement) will be presented by epochs relative to bolus/infusion. When analyzing categorical 
data, the number and percentage of subjects in each category will be presented. In addition, shift 
tables may be used to evaluate the number and percentage of subjects having a different post-iv 
BRV status when compared with their pre-iv BRV status for each bolus/infusion. Changes in 
vital signs and ECG parameters will be presented graphically for epochs relative to 
bolus/infusion. 
12.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on the primary safety outcomes for an individual subject. The criteria for 
identifying important protocol deviations will be defined within the appropriate protocol-specific 
document. Important protocol deviations will be reviewed as part of the ongoing data cleaning 
process and data evaluation. All important deviations will be identified and documented prior to 
database lock to confirm exclusion from analysis sets. 
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12.6 
Handling of dropouts or missing data 
No specific procedure is foreseen for handling dropouts or missing data. 
12.7 
Planned interim analysis and data monitoring 
No formal interim analysis is planned for this study.  
For the first cohort, after the first half of the subjects receive the 15-minute infusion(s), the DMC 
will meet to review safety (as indicated in the DMC charter) and, as available, PK data. For 
subsequent cohorts, the DMC will review data for bolus infusions of the previous cohort and the 
15-minute infusions of the current cohort. The DMC will meet no less than approximately every 
6 months commensurate with enrollment. 
12.8 
Determination of sample size 
The primary objective of the study is to evaluate the PK, safety, and tolerability of BRV given 
intravenously. The plan for approximately 50 enrolled subjects (4 cohorts of 
approximately12 subjects each) to receive iv BRV was deemed clinically appropriate for the 
evaluation of the PK, safety, and tolerability of iv BRV administration in subjects ≥1 month to 
<16 years of age with epilepsy. No formal sample size calculation has been performed. 
13 
ETHICS AND REGULATORY REQUIREMENTS 
13.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the Investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the Investigator. 
Prior to participation in the study, the written Informed Consent form should be signed and 
personally dated by the subject, or his/her legal representative, and by the person who conducted 
the informed consent discussion (Investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent form. As part of 
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. In addition, a 
Consent form or a specific Assent form, where required, will be signed and dated by minors. 
Any subject who becomes 16 years of age during EP0065 must sign and date the Informed 
Consent form according to local regulations. 
If the ICF/Assent 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 Authorization form. 
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The subject or legal representative may withdraw consent for the subject to participate in the 
study at any time. A subject is considered as enrolled in the study when the subject or legal 
representative has signed the ICF form/Assent form. A CRF must not be started, nor may any 
study specific procedure be performed for a given subject, without having obtained the written 
consent of the subject or legal guardian for the subject to participate in the study. 
13.2 
Subject identification cards 
Upon signing the ICF and Assent form (as applicable), the subject or legal representative will be 
provided with a subject identification card in the language of the subject. The Investigator will 
fill in the subject identifying information and medical emergency contact information. The 
Investigator will instruct the subject to keep the card with him/her at all times. 
13.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB (or designee) 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 (or designee) will forward copies of 
the protocol, ICF/Assent 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 IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
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Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
13.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study). 
13.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
14 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable. 
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15 
REFERENCES 
Banerjee PN, Hauser WA. Epilepsy: A comprehensive textbook. In: Engel J, Pedley TA, editors. 
Incidence and prevalence. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2008. 
p. 45-56. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Hadjiloizou SM, Bourgeois BFD. Antiepileptic drug treatment in children. Expert Rev 
Neurother. 2007;7:179-93. 
Hauser WA, Annegers JF, Kurlank LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34:453-68. 
Theodore WH, Spencer SS, Wiebe, S, Langfitt JT, Ali A, Shafer PO. Epilepsy in North America: 
a report prepared under the auspices of the global campaign against epilepsy, the International 
Bureau for Epilepsy, the International League Against Epilepsy, and the World Health 
Organization. Epilepsia. 2006;47:1800-22. 
Wirrell, EC, Grossardt BR, Wong-Kisiel LC, Nickels KC. Incidence and classification of 
new-onset epilepsy and epilepsy syndromes in children in Olmsted County, Minnesota from 
1980 to 2004: a population-based study. Epilepsy Res. 2011;95;110-8. 
Zarrelli MM, Beghi E, Rocca WA, Hauser WA. Incidence of epileptic syndromes in Rochester, 
Minnesota: 1980-1984. Epilepsia. 1999;40:1708-14. 
 
 
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16 
APPENDIX 
16.1 
Protocol Amendment 1 
Rationale 
This nonsubstantial amendment is based on DMC recommendation, as a precaution additional 
safety monitoring has been added to the protocol. This precaution was not based on any related 
AE or reported symptoms. Additional vital sign measurements, specifically blood pressure, and 
criteria for further iv BRV dose allocation were added to further investigate blood pressure 
changes and ensure safety. Additionally, height measurements have been collected at various 
visits since the onset of the study, while these were inadvertently absent from the list of 
assessments. The protocol has therefore been aligned.  
Specific changes 
Section # and name 
Description of change 
Brief rationale 
Study contact information 
Updated Sponsor Study 
Physician, Clinical Project 
Manager, and Clinical Trial 
Biostatistician 
Recent changes in study 
contacts 
Section 5.2 Schedule of study 
assessments 
Added definition of PCS 
 
Added cross reference to BP 
PCS values Table 10-6 
Added text regarding 
additional safety monitoring 
and criteria for further iv and 
BRV dose allocation 
Absent from previous version 
 
To clearly define BP PCS 
values 
To further investigate BP and 
ensure safety 
Table 5-1 Schedule of Study 
Assessments (Screening 
Period through end of iv PK 
Period) 
Added body height 
assessment 
Added this text that was 
inadvertently omitted during 
protocol development 
Table 5-2 Schedule for iv PK 
Period ECGs, vital signs, and 
PK sampling (15-min BRV 
infusion) 
Added BP assessment along 
at 2hrs post infusion start and 
accompanying footnote 
Added description of when 
additional BP monitoring is 
required 
To further investigate BP and 
ensure safety 
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Section # and name 
Description of change 
Brief rationale 
Table 5-3 Schedule for iv PK 
Period ECGs, vital signs, and 
PK sampling (bolus [up to 
2-min BRV infusion]) 
Added BP assessment along 
at 2hrs post infusion start and 
accompanying footnote 
Added description of when 
additional BP monitoring is 
required 
To further investigate BP and 
ensure safety 
Table 5-4 Schedule of study 
assessments for Down-
Titration and Safety (BRV-
free) Periods (subjects not 
continuing into the Long-
Term, Open-Label Study) 
Added body height 
assessment 
Added this text that was 
inadvertently omitted during 
Protocol development 
Section 8.1 Visit 1 (Day -10 
to Day -1 for OLB, RxB, and 
IIB subjects; Day -20 to Day -
11 for IOB subjects) 
Added body height 
assessment 
Added this text that was 
inadvertently omitted during 
Protocol development 
Section 8.3 Visit 3 (Day 1) 
through Visit 12 (Day 6) 
Added body height 
assessment 
 
 
Added a cross reference to 
BP PCS values Table 10-6 
Added this text that was 
inadvertently omitted during 
Protocol development 
 
To clearly define BP PCS 
values 
Section 8.6 Visit 13 
Added body height 
assessment 
Added this text that was 
inadvertently omitted during 
Protocol development 
Section 10.3.2 Vital signs 
Added text regarding 
additional safety monitoring 
 
Added Table 10-6 PCS 
abnormality criteria for the 
measurement of BP 
To further investigate BP and 
ensure safety 
 
To describe the criteria for 
systolic and diastolic BP to 
be low or high PCS 
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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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EP0065 
 
 
 
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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:
ep0065-protocol-amendment-1
Version:
1. 0
Document Number:
CLIN-000135150
Title:
EP0065 Protocol-Phase 2-Open-label
Approved Date:
20 Jun 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 19-Jun-2019 11:57:23 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Qualified Person
Date of Signature: 19-Jun-2019 12:12:50 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 20-Jun-2019 10:09:09 GMT+0000
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SAP_001.pdf: 
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25 Sep 2020  
Statistical Analysis Plan 
Brivaracetam 
EP0065 
 
 
 
Confidential 
Page 1 of 55 
 
STATISTICAL ANALYSIS PLAN  
 
Study: EP0065  
Product: Brivaracetam 
A MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE 
PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF INTRAVENOUS 
BRIVARACETAM IN SUBJECTS ≥1 MONTH TO <16 YEARS OF AGE WITH 
EPILEPSY 
  
 
 
SAP/Amendment Number Date 
Final SAP 1.0 
26 Mar 2018 
Final SAP 2.0 
28 Mar 2018 
Final SAP 3.0 
26 Sep 2019 
Final SAP 4.0 
19 May 2020 
Final SAP 5.0 
25 Sep 2020 
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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EP0065 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 
Study objectives ............................................................................................................. 7 
2.1.1 
Primary objectives ................................................................................................. 7 
2.2 
Study variables ............................................................................................................... 7 
2.2.1 
Pharmacokinetic variables ..................................................................................... 7 
2.2.2 
Safety variables ...................................................................................................... 7 
2.2.2.1 
Primary safety variables .............................................................................. 7 
2.2.2.2 
Other safety variables .................................................................................. 7 
2.3 
Study design and conduct .............................................................................................. 7 
2.4 
Determination of sample size ....................................................................................... 10 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 10 
3.1 
General presentation of summaries and analyses ........................................................ 10 
3.2 
Analysis time points ..................................................................................................... 11 
3.2.1 
First and last dose of iv BRV ............................................................................... 11 
3.2.2 
First and last dose of oral BRV ............................................................................ 11 
3.2.3 
Relative day and time .......................................................................................... 11 
3.2.4 
Relative time from previous iv infusion .............................................................. 11 
3.2.5 
Analysis periods ................................................................................................... 12 
3.2.6 
Exposure duration ................................................................................................ 12 
3.2.7 
Age and age at first diagnosis .............................................................................. 13 
3.2.8 
Duration of epilepsy ............................................................................................ 13 
3.2.9 
Amount of Time and number of days of each PCST prior to TEAE onset ......... 14 
3.3 
Body mass index (BMI) ............................................................................................... 14 
3.4 
Definition of Baseline values ....................................................................................... 14 
3.5 
Protocol deviations....................................................................................................... 15 
3.6 
Analysis sets................................................................................................................. 15 
3.6.1 
Safety Set iv (SS-iv) ............................................................................................ 15 
3.6.2 
Safety Set (SS) ..................................................................................................... 15 
3.6.3 
Pharmacokinetic Per-protocol Set ....................................................................... 15 
3.7 
Treatment assignment and treatment groups ............................................................... 15 
3.8 
Center pooling strategy ................................................................................................ 15 
3.9 
Coding dictionaries ...................................................................................................... 15 
3.10 
Changes to protocol-defined analysis .......................................................................... 16 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 16 
4.1 
Adjustments for covariates .......................................................................................... 16 
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4.2 
Handling of dropouts or missing data .......................................................................... 16 
4.2.1 
General imputation rule for incomplete dates ..................................................... 16 
4.2.2 
Handling of partial date of birth .......................................................................... 17 
4.2.3 
Handling of prior and concomitant medications with partial or missing date ..... 17 
4.2.4 
Handling of adverse events with partial or missing date ..................................... 17 
4.2.5 
Handling of study medication with partial or missing date ................................. 19 
4.2.6 
Handling of epilepsy diagnosis with missing date .............................................. 19 
4.2.7 
Potential impact of Coronavirus Disease 2019 on dropouts or missing data ...... 19 
4.3 
Interim analyses and data monitoring .......................................................................... 20 
4.3.1 
DMC meetings ..................................................................................................... 20 
4.3.2 
Interim analysis .................................................................................................... 21 
4.4 
Multicenter studies ....................................................................................................... 21 
4.5 
Multiple comparisons/multiplicity ............................................................................... 21 
4.6 
Use of an efficacy subset of subjects ........................................................................... 21 
4.7 
Examination of subgroups ........................................................................................... 21 
4.8 
Time points by infusion duration ................................................................................. 21 
4.9 
Handling of data from open-label study ...................................................................... 22 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 23 
5.1 
Subject disposition ....................................................................................................... 23 
5.2 
Protocol deviations....................................................................................................... 24 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 24 
6.1 
Demographics and other Baseline Characteristics ....................................................... 24 
6.2 
Medical history and ongoing diseases ......................................................................... 25 
6.3 
Prior and concomitant medications .............................................................................. 26 
6.3.1 
Summaries for non-AEDs .................................................................................... 26 
6.3.2 
Summaries for AEDs ........................................................................................... 26 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 26 
8 
EFFICACY ...................................................................................................................... 27 
9 
PHARMACOKINETICS ................................................................................................. 27 
9.1 
Pharmacokinetics ......................................................................................................... 27 
9.2 
Pharmacodynamics ...................................................................................................... 27 
10 SAFETY ANALYSIS ...................................................................................................... 27 
10.1 
Extent of exposure ....................................................................................................... 27 
10.2 
Adverse Events ............................................................................................................ 28 
10.2.1 
AE summaries ...................................................................................................... 28 
10.2.2 
AE Listings .......................................................................................................... 30 
10.3 
Medical procedures ...................................................................................................... 30 
10.4 
Clinical laboratory evaluations .................................................................................... 30 
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EP0065 
 
 
 
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10.4.1 
Hematology, Chemistry and Urinalysis Parameters ............................................ 30 
10.4.2 
Potential Drug Induced Liver Injury .................................................................... 31 
10.5 
Vital signs, physical findings, and other observations related to safety ...................... 32 
10.5.1 
Vital signs and body weight ................................................................................ 32 
10.5.2 
Electrocardiograms (ECGs) ................................................................................. 33 
10.5.3 
Medical Resource Use ......................................................................................... 34 
10.5.4 
Health Care Provider Consultations Not Foreseen by the Protocol..................... 34 
10.5.5 
Physical examination ........................................................................................... 34 
10.5.6 
Tanner Stage ........................................................................................................ 34 
10.5.7 
Neurological examination .................................................................................... 34 
10.5.8 
Assessment of suicidality .................................................................................... 34 
11 REFERENCES ................................................................................................................ 35 
12 APPENDICES ................................................................................................................. 36 
12.1 
Laboratory parameters ................................................................................................. 36 
12.2 
PCS criteria .................................................................................................................. 37 
12.2.1 
Hematology .......................................................................................................... 37 
12.2.2 
Biochemistry ........................................................................................................ 39 
12.2.3 
Urinalysis ............................................................................................................. 42 
12.2.4 
Vital Signs ........................................................................................................... 43 
12.2.5 
ECG ..................................................................................................................... 46 
12.3 
PDILI ........................................................................................................................... 47 
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) (IF 
APPLICABLE) ................................................................................................................ 48 
13.1 
Changes in SAP from final version 1.0 to final version 2.0 ........................................ 48 
13.2 
Changes in SAP from final version 2.0 to final version 3.0 ........................................ 48 
13.3 
Changes in SAP from final version 3.0 to final version 4.0 ........................................ 52 
13.4 
Changes in SAP from final version 4.0 to final version 5.0 ........................................ 54 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 55 
 
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Statistical Analysis Plan 
Brivaracetam 
EP0065 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
bid 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BRV 
brivaracetam 
CDISC 
Clinical Data Interchange Standards Consortium 
COVID-19 
Coronavirus Disease 2019 
CS 
clinically significant 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DOB 
Date of birth 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ER 
emergency room 
h 
hour 
IIB 
initiating iv BRV 
Inf 
infusion 
IOB 
initiating Oral BRV 
IPD 
Important protocol deviation 
iv 
intravenous 
LOQ 
limit of quantification 
Max 
maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
minimum 
NCS 
not clinically significant 
OLB 
open-label BRV 
PCS 
Possibly clinically significant 
PCST 
possibly clinically significant treatment-emergent  
PDILI 
Potential Drug Induced Liver Injury 
PK 
pharmacokinetics 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PQ/PR interval 
time from the beginning of the P wave until the beginning of the QRS 
complex 
PT 
preferred term 
PTAE 
pre-treatment adverse event 
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Statistical Analysis Plan 
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EP0065 
 
 
 
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QRS duration 
duration of the combination of three of the graphical deflections seen on 
ECG 
QT interval 
time between the start of the Q wave and the end of the T wave in ECG 
QTcB 
QT interval corrected for heart rate (Bazett’s formula) 
QTcF 
QT interval corrected for heart rate (Fridericia’s formula) 
RR 
respiratory rate 
RR-interval 
time between successive Rs in ECG 
RxB 
Prescribed-BRV 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
Standard deviation 
SOC 
system organ class 
SS 
Safety Set 
SS-iv 
Safety Set-iv 
TC 
Telephone contact 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VNS 
Vagus Nerve Stimulation 
WHODD 
World Health Organization drug dictionary 
 
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Statistical Analysis Plan 
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EP0065 
 
 
 
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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 EP0065. This SAP is based upon the following documents: Final 
Protocol Amendment 1.0: 19 Jun 2019. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objectives 
The primary objective of this study is to evaluate the pharmacokinetics (PK), safety, and 
tolerability of brivaracetam (BRV) administered as a 15-minute iv infusion and iv bolus (up to 2-
minute infusion) in subjects ≥1 month to <16 years of age with epilepsy. 
2.2 
Study variables 
2.2.1 
Pharmacokinetic variables 
• Plasma concentration of BRV (parent compound only) before, during, and after iv BRV 
administration. 
2.2.2 
Safety variables 
2.2.2.1 
Primary safety variables 
• Adverse events (AEs) throughout the study 
• Subject withdrawals due to AEs 
2.2.2.2 
Other safety variables 
• 12-lead ECG values before, during, and after each iv BRV administration 
• Blood pressure (BP), pulse rate, respiratory rate (RR), and temperature values before, 
during, and after each iv BRV administration 
• Clinical laboratory parameters (hematology, chemistry, and endocrinology) pre and post 
treatment 
• Urinalysis parameters pre and post treatment 
Post treatment parameters will be only available for subjects who down titrate and perform 
Visit 13 assessments. 
2.3 
Study design and conduct 
EP0065 is a Phase 2 multicenter, open-label study to evaluate the PK, safety, and tolerability of 
iv BRV administered as a 15-minute iv infusion and an iv bolus (up to 2-minute infusion) in 
subjects ≥1 month to <16 years of age with epilepsy. 
Study medication is defined by iv infusion of BRV administered as a 15-minute iv infusion or an 
iv bolus (up to 2-minute infusion). Oral BRV can be administered during EP0065 but will not be 
considered as study medication for EP0065. 
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Statistical Analysis Plan 
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EP0065 
 
 
 
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Approximately 50 enrolled subjects will receive iv BRV in the following age-based cohorts 
(approximately 12 subjects/cohort): 
• Cohort 1: ≥12 to <16 years 
• Cohort 2: ≥6 years to <12 years 
• Cohort 3: ≥2 to <6 years 
• Cohort 4: ≥1 month to <2 years 
The age at Screening Visit will be the determining factor for age cohort assignment. Each age 
cohort will have approximately 50% of subjects with iv BRV infusion and 50% with bolus BRV. 
The following subjects will be eligible for enrollment in EP0065: 
• Open-label BRV (OLB) subjects: currently receiving oral BRV as participants in a long-
term, open-label study 
• Prescribed BRV (RxB) subjects: currently receiving prescribed oral BRV from commercial 
supply 
• Initiating Oral BRV (IOB) subjects: not currently receiving BRV; first dose of BRV in 
EP0065 will be oral tablet or solution 
• Initiating iv BRV (IIB) subjects: not currently receiving BRV; first dose of BRV in EP0065 
will be by iv Infusion 
For OLB and RxB subjects, the maximum BRV dose is 5mg/kg/day (rounded). For IOB and IIB 
subjects, the maximum BRV dose is 4mg/kg/day. Throughout the study, no subject may receive 
a dose greater than BRV 200mg/day. Subjects will receive oral BRV (tablets or oral solution) in 
equally divided doses; BRV oral solution may be given by enteric administration (eg, by feeding 
tube) based on subject need. 
The EP0065 study periods and visits are described below. The PK assessments will be made 
during the iv PK Period only and safety data will be collected throughout the study, with 
intensive collection of safety data with each iv BRV dose administered. A Schedule of Study 
Assessments is provided in the protocol for the Screening through iv PK Periods and for the 
Down-Titration Period and Safety (BRV-free) Periods (for subjects not continuing BRV). 
• Screening Period (1 to 10 days) 
During the Screening Period, the OLB and RxB subjects will continue treatment with oral BRV 
using their assigned open-label study supply or prescribed commercial supply, respectively. The 
IOB and IIB subjects will not receive BRV during this period. 
The OLB subjects will temporarily discontinue assessments in their long-term, open-label study 
when they enter EP0065. As such, all assessments for these subjects during the Screening Period 
(and subsequent periods of EP0065) will be recorded in the EP0065 Case Report form (CRF) 
until they return to a long-term, open-label study or discontinue BRV treatment. 
• IOB Treatment Period (2 to 10 days of oral BRV treatment; for IOB subjects only) 
Only IOB subjects who meet all eligibility criteria may participate in the IOB Treatment Period. 
No other subjects may participate in this period.  
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EP0065 
 
 
 
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During the IOB Treatment Period, IOB subjects will initiate treatment with oral BRV 
2mg/kg/day not to exceed 100mg/day for subjects with body weights ≥50kg and must have, at 
minimum, 2 days of treatment with oral BRV before entry into the iv PK Period. Subjects who 
do not enter the iv PK Period will not be eligible for the long-term, open-label study.  
The Investigator is permitted to adjust the oral BRV dose during the IOB Treatment Period in 
accordance with medical judgment (with a maximum dose of 4mg/kg/day, not to exceed 
200mg/day for subjects with body weights ≥50kg); however, subjects must have no change in 
the oral BRV dose for the 2 days prior to entry into the iv PK Period. 
• iv PK Period (1 to 6 days, with Day 1 defined as the initial day of iv BRV infusion) 
During the iv PK Period, iv BRV will be administered every 12 hours ±2 hours (q12h ± 2h). All 
subjects are to receive 1 to 2 consecutive doses of BRV; however, based on medical need, 
subjects may receive up to 10 consecutive doses of iv BRV. The PK sampling will occur with the 
first iv BRV administration and with 1 other iv BRV administration. 
The first dose of iv BRV will be as follows: 
• OLB, RxB, and IOB subjects: mg-to-mg equivalent of the oral BRV dose immediately prior 
to the iv PK Period; administered q12h ±2h after prior oral dose 
• IIB subjects: 1mg/kg not to exceed a maximum of 50mg for subjects ≥50kg 
After subjects have completed PK sampling with 2 iv BRV infusions, the Investigator may adjust 
the BRV dose, but the adjusted dose must not exceed 5mg/kg/day (rounded) for OLB and RxB 
subjects and 4mg/kg/day for IOB and IIB subjects (with the maximums not to exceed 
200mg/day). During the iv PK Period, BRV may only be administered intravenously. Enrollment 
will be sequential by descending age beginning with age-based Cohort 1. For each age cohort, 
the first half will receive the 15-minute infusion. The Data Monitoring Committee (DMC) will 
then meet to review safety and, as available, PK data. After the DMC safety review, the 
remaining half in that age cohort will receive iv BRV as a bolus (up to 2-minute infusion) and 
the next age cohort may begin the 15-minute infusion. Subjects may receive bolus infusions only 
after subjects in the preceding age cohort have completed bolus infusions and the DMC have 
reviewed these data. The DMC will meet no less than approximately every 6 months 
commensurate with enrollment. 
Telephone contact (TC)-1 will occur 1 to 3 days after completing the final iv BRV dose in the iv 
PK Period to facilitate reporting of infusion-site related AEs. 
• Down-Titration Period (up to 4 weeks) and Safety (BRV-free) Period (2 weeks) 
Subjects who receive ≥4 doses of BRV during either the IOB Treatment Period or the iv PK 
Period and who do not plan to continue treatment with BRV or who discontinue from the study 
will enter a Down-Titration Period. Subjects who have received <4 doses of BRV may have 
BRV down titrated at the discretion of the Investigator. During the Down-Titration Period, 
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. Subjects not able to receive oral BRV for down titration, may receive iv BRV 
for down titration. In the latter circumstance, the subjects may receive more than 10 consecutive 
doses of iv BRV in accordance with the Investigator’s discretion. A 2-week Safety (BRV-free) 
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Period will follow the final dose of BRV. In this SAP, the Down-Titration period is considered 
part of the Follow-Up period, which is described more in Section 3.2.4.  
Safety assessments will be collected throughout these periods. 
2.4 
Determination of sample size 
The primary objective of the study is to evaluate the PK, safety, and tolerability of BRV given 
intravenously. The plan for approximately 50 enrolled subjects (4 age cohorts of approximately 
12 subjects each) to receive iv BRV was deemed clinically appropriate for the evaluation of the 
PK, safety, and tolerability of iv BRV administration in subjects ≥1 month to <16 years of age 
with epilepsy. No formal sample size calculation has been performed. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be carried out using SAS Version 9.3 or higher. All summaries will be descriptive; no 
statistical hypothesis testing is planned. All tables and listings will use Courier New font size 9. 
Tables, figures and listings (TFL) will be displayed for the defined analysis sets. If the Safety Set 
(SS) and the Safety Set-iv (SS-iv) consist of the same number of subjects, TFLs will only be 
presented for the SS-iv. 
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 the 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, unless otherwise stated.  
Decimal places for descriptive statistics will always apply the following rules unless otherwise 
stated: 
• “n” will be an integer 
• Mean, SD, geometric mean, and median will use 1 additional decimal place compared to the 
original data 
• CV [%] will be presented with 1 decimal place 
• Minimum and maximum will have the same number of decimal places as the original value 
However, the maximum number of decimals displayed will not exceed 4. 
All summaries, unless otherwise stated, will be presented overall for all subjects, by age cohorts 
(Cohort 1: ≥12 to <16 years, Cohort 2: ≥6 years to <12 years, Cohort 3: ≥2 to <6 years, Cohort 4: 
≥1 month to <2 years), and by infusion duration (15-minute iv infusion and iv bolus (up to 
2-minute infusion)). Selected tables will be provided in addition by subject groups (OLB, RxB 
and IOB combined, and IIB), or by scheduled assessment timepoints as defined in Section 4.8 . 
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Selected summaries will be repeated by the country of enrollment (Hungary and rest of the 
World). 
A complete set of listings containing all documented data and relevant derived data (eg, change 
from Baseline) will be generated. Summary tables will only contain data from subjects and visits 
which have been foreseen by the protocol, eg. in the event data will be captured after TC-1 when 
it is not required, this data will only be listed and not summarized. 
3.2 
Analysis time points 
3.2.1 
First and last dose of iv BRV 
Unless otherwise noted, all references to the first dose of iv BRV in this SAP refer to the first 
dose of iv BRV during EP0065.  
Unless otherwise noted, all references to the last dose of iv BRV in this SAP refer to the last dose 
of iv BRV in this study.  
3.2.2 
First and last dose of oral BRV 
Unless otherwise noted, all references to the first dose of oral tablet or solution BRV in this SAP 
refer to the first dose of oral tablet or solution of BRV dispensed during EP0065. 
Unless otherwise noted, all references to the last dose of oral tablet or solution BRV in this SAP 
refer to the last dose of oral tablet or solution of BRV dispensed during EP0065. 
3.2.3 
Relative day and time 
Relative Day is defined as the day relative to the first infusion of BRV. Relative day will not be 
calculated for partial dates. 
If the current date occurred on or after the day of first dose of iv BRV and prior to or on the day 
of last iv BRV dose, the relative day will be calculated as the current date minus the date of first 
dose of iv BRV plus 1 (eg, the day of first dose of iv BRV will be Day 1).  
If the current date occurred prior to the first dose of iv BRV, the relative day will be calculated as 
date of first dose of iv BRV minus the current date (eg, the day prior to first dose of iv BRV will 
be Day -1).  
If the current date occurred after the last dose of iv BRV, the relative day will be calculated as 
the current date minus the date of last dose of iv BRV including a “+” to denote post-treatment 
days (eg, the day after the last dose of iv BRV will be Day +1). 
In order to have a better insight into the times of AEs, laboratory samples, ECG and vital signs 
collections relative to the administration of BRV, the relative time will be calculated, by 
subtracting the time of first iv BRV administration from the start time of the event. The relative 
time will be displayed in hours and minutes for relative times ≤24 hours before and after the first 
iv BRV administration. For relative times >24 hours the relative times will be calculated in days 
as described above. 
3.2.4 
Relative time from previous iv infusion 
Relative time from previous iv infusion initiation will be derived for AE listings. It will be 
displayed in hours and minutes and will be calculated using the following formula: 
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relative time from previous iv infusion initiation
=  𝐴𝐸 𝑠𝑡𝑎𝑟𝑡 𝑡𝑖𝑚𝑒  –  previous infusion start time  
3.2.5 
Analysis periods 
This study consists of a Screening Period, an IOB Treatment Period, an iv PK Period, a Follow-
up Period and a Safety (BRV-free) Period, see Section 2.3 for more details on these periods. 
Start of Screening Period is defined as the date of enrollment and end of Screening Period is 
defined as immediately before first allocated BRV treatment. 
Start of IOB Treatment Period is defined as the date of first allocated oral BRV treatment and 
end of IOB Treatment Period is defined as immediately before first iv BRV treatment. 
Start of iv PK Period is defined as the date and time of first allocated iv BRV treatment and end 
of iv PK Period is defined as 12 hours after start of last iv BRV treatment. 
Start of Follow-up Period is defined as 12 hours after start of last iv BRV treatment and end of 
Follow-up Period is defined for the following scenarios: 
• Subjects who transition study: as TC-1 
• Subjects who do not transition and do not down-titrate: as end of study 
• Subjects who down-titrate: as 12 hours after start of last down-titration treatment. 
Only subjects who down-titrate have a Safety (BRV-free) Period. Start of Safety Period is 
defined as immediately after the end of Follow-up Period (>12 hours after start of last down-
titration treatment) and end is defined as end of study. 
3.2.6 
Exposure duration 
In EP0065 study medication is defined as iv BRV. 
The date and time of first study medication is defined as the start of first iv BRV infusion date 
and time according to the standard CRF page. The date and time of last study medication is 
defined as the start of last iv BRV infusion reported on the standard trial termination eCRF.  
Days with unknown or zero dosing for the respective BRV formulation (iv, tablet, oral solution, 
oral, all) which occur between the start and end date of the respective BRV formulation will be 
included in the exposure calculation. For example, a day with missing or zero dosing between 
the first and last iv BRV dose will be included in the iv BRV exposure duration (days) and iv 
BRV exposure duration (hours) calculation.  
The iv BRV exposure duration will be calculated separately in hours and days. Duration of iv 
BRV exposure in days will be calculated using the following formula: 
iv BRV exposure duration (days) 
=  start date and time of the last iv BRV 
− start date and time of the first iv BRV  +  1 day 
Duration of iv BRV exposure in hours will be calculated using the following formula: 
iv BRV exposure duration (hours) 
=  start date and time of the last iv BRV 
− start date and time of the first iv BRV  +  1 hour 
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The duration of oral BRV exposure will be calculated in days only by administration method 
(tablets or oral solution) and over both administration methods separately for the IOB Treatment 
Period and Follow-up Period. The duration of oral BRV will be calculated separately for each 
period using the following formulas: 
Oral BRV exposure duration from tablets during period (days) 
=  end date of last BRV tablet during period
− start date of first BRV tablet during period +  1 day 
Oral BRV exposure duration from oral solution during period (days) 
=  end date of last oral solution BRV during period
− start date of first oral solution BRV during period +  1 day 
Overall Oral BRV exposure duration during period (days) 
=  end date of last oral BRV during period
− start date of first oral BRV during period +  1 day 
The overall BRV duration (oral BRV and iv BRV exposure) in days will be calculated using the 
following formula: 
Overall BRV exposure duration (days) 
=  end date of latest BRV (either oral or iv)
− start date of first BRV (either oral or iv)  +  1 day 
3.2.7 
Age and age at first diagnosis 
The age at Screening Visit will be the determining factor for age cohort assignment (see 
Section 2.3 and Section 3.7). For subjects aged 2 years and above, age will be displayed in years, 
otherwise age will be displayed in months. The age at first diagnosis of epilepsy will be 
calculated in years and months for all subjects, and will be derived applying all rules for missing 
data imputation (Section 4.2). Age at first diagnosis in years will be calculated with the 
following formula: 
Age at first diagnosis (years)
= (Date of first diagnosis of epilepsy –  Date of birth) / 365.25 
For the calculation of age at first diagnosis in months consider 1 month = (365.25/12) days: 
Age at first diagnosis (months)
= (Date of first diagnosis of epilepsy –  Date of birth) / (365.25/12) 
3.2.8 
Duration of epilepsy 
Duration of epilepsy will be calculated in years and months, and will be derived applying all 
rules for missing data imputation (Section 4.2 ).  
Duration of epilepsy in years will be calculated with the following formula:  
Duration of epilepsy (years)
= (Date of informed consent –  Date of first diagnosis of epilepsy) 
/ 365.25 
For the calculation of the duration of epilepsy in months consider 1 month = (365.25/12) days: 
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Duration of epilepsy (months)
= (Date of informed consent –  Date of first diagnosis of epilepsy) 
/ (365.25/12) 
Summary statistics for both durations will be calculated and displayed to 2 decimal places. 
3.2.9 
Amount of Time and number of days of each PCST prior to TEAE 
onset 
The definition of PCST for ECG, Laboratory values and vital signs are described in the relevant 
sub-sections in Section 10. PCSTs are described in Appendix 12.2. The definition of TEAE is in 
Section 10.2  
 
For each TEAE with at least one PCST value at the time of or prior to the adverse event, the 
number of days and where possible time prior to each TEAE onset relative to each observed 
PCST will be calculated and displayed. Time prior to each TEAE will only be calculated in days, 
hours and minutes where the time and date of the TEAE and PCST is available. Imputed AE 
times will not be used for missing AE times. When the time is missing for the PCST and/or 
TEAE, but the date of the TEAE is the same or later than the PCST, the TEAE will be assumed 
to have occurred after the PCST, and only number of days prior to TEAE onset will be 
calculated.  
 
The formula for time prior to TEAE onset is as follows: 
Time prior to TEAE onset =  TEAE start day and time  –  start day and time of PCST  
 
The formula for number of days prior to TEAE onset is as follows:  
Number of days prior to TEAE onset =  TEAE start day –  PCST start day 
 
 
3.3 
Body mass index (BMI) 
BMI will be calculated using weight and height at Screening Visit with the following formula: 
BMI (kg/m²) = 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
[ℎ𝑒𝑖𝑔ℎ𝑡 (𝑚)]² 
 
3.4 
Definition of Baseline values 
Baseline for laboratory variables (blood chemistry, hematology, and endocrinology), vital signs, 
body weight, and quantitative electrocardiography (ECG) variables is defined as the latest 
assessment prior to the first infusion of iv BRV. Both scheduled and unscheduled assessments 
from the central laboratory are considered.  
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3.5 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on the primary outcomes for an individual subject. The criteria for identifying 
important protocol deviations will be defined within the appropriate protocol-specific document. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process and 
data evaluation. Important deviations will be identified and documented prior to database lock to 
confirm exclusion from the Pharmacokinetic Per-protocol Set (see Section 3.6.3). 
3.6 
Analysis sets 
3.6.1 
Safety Set iv (SS-iv) 
The Safety Set iv (SS-iv) will include subjects who received at least 1 dose of iv BRV. The SS-iv 
will be the primary analysis set for the analysis of safety data. 
3.6.2 
Safety Set (SS) 
The Safety Set (SS) will include subjects who received at least 1 dose of BRV (oral or iv). 
Selected safety summaries will be presented for the SS (see also Section 3.1). 
3.6.3 
Pharmacokinetic Per-protocol Set 
The Pharmacokinetic Per-protocol Set (PK-PPS) will include all subjects in the SS-iv having 
provided at least 1 measurable post-dose plasma sample (with recorded sampling time) during 
the iv PK Period with documented iv BRV infusion times and without important protocol 
deviations impacting the interpretability of the PK analyses. 
3.7 
Treatment assignment and treatment groups 
This is an open-label study with a single treatment arm. The age at Screening Visit will be the 
determining factor for age cohort assignment. Subjects are summarized in the following age 
based cohorts (approximately 12 subjects/cohort):  
• Cohort 1: ≥ 12 to < 16 years 
• Cohort 2: ≥ 6 years to < 12 years 
• Cohort 3: ≥ 2 to < 6 years 
• Cohort 4: ≥ 1 month to < 2 years 
3.8 
Center pooling strategy 
The expected number of subjects for most sites is low. In general, it will not be feasible to adjust 
statistical analysis for site effect and there are no plans to present any study outcomes by site. No 
pooling strategy is defined for this study. 
3.9 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18.1. Medications will be coded using the World Health Organization Drug 
Dictionary (WHODD) version Sep 2017. Medical procedures are not coded. 
 
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3.10 
Changes to protocol-defined analysis 
As iv BRV is defined as the study medication the following parts of the PK-PPS definition were 
further clarified: "subjects in the SS-iv" instead of "subjects in the SS" and "infusion times" 
instead of "intake times". Furthermore, the term “without important protocol deviations 
impacting the interpretability of the PK analyses” was added to the definition of PK-PPS.  
 
Vital sign and ECG summary tables will summarize the subject data for each timepoint but not 
as stated in the protocol (pre-bolus/infusion period, the bolus/infusion period, the period 
immediately post-bolus/infusion, and period between each subsequent bolus/infusion). Adverse 
events tables will not summarize the subject data as specified in the protocol (pre-bolus/infusion 
period, the bolus/infusion period, the period immediately post-bolus/infusion, and period 
between each subsequent bolus/infusion). Instead AEs will be summarized by time relative to 
most recent bolus/infusion start time (≤5 minutes, >5 to ≤15 minutes, >15 to ≤60 minutes, >60 
minutes to ≤12 hours and >12 hours).  
 
 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No statistical testing is planned; therefore, this section is not applicable for this study. 
4.2 
Handling of dropouts or missing data 
No imputation of missing values is planned unless otherwise noted. Imputations for missing or 
partial dates for AEs and concomitant medications will be applied to determine if an 
event/medication is to be considered treatment-emergent or concomitant. Such imputations will 
only be performed for classifications and calculations; in the listings all data will be shown as 
recorded on the eCRF. Across PK, only reported data will be used.  
 
4.2.1 
General imputation rule for incomplete dates 
Where necessary for the calculation of derived variables, partial dates will be completed using 
the earliest calendar date based on the partial date provided. This rule is valid for all partial dates 
with the exception of the following: 
• Date of birth (DOB) 
• Start and stop dates of concomitant medication 
• Start and stop date of adverse events 
• Start and stop dates of study medication 
• Date of epilepsy diagnosis 
Completely missing dates will not be replaced and the corresponding derived variables will be 
set to missing. 
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4.2.2 
Handling of partial date of birth 
Date of birth (DOB) will not be collected in full form from all subjects due to country 
differences. The SDTM interpretation guide notes that partial ages should be imputed by using 1 
Jan and the provided year, or 1st of the month when month/year is provided. However, in 
pediatric studies this could be problematic when calculating age at diagnosis or time since 
diagnosis. Since in the eCRF age as well as DOB will be captured, partial DOB will be imputed 
by using the enrollment date and the age to back calculate the DOB; using 1st of the month for 
the day. That is, if a subject is 3 months old and was enrolled in Jun 2018, it will not be imputed 
as DOB = 1 Jan 2018. In this case it will be imputed as DOB = 1 Mar 2018, providing an age of 
approximately 3 months.  
4.2.3 
Handling of prior and concomitant medications with partial or 
missing date 
Any medications with incomplete start and end dates will be handled according to the following 
rules for classification as prior and concomitant and for the calculation of relative study days. 
Such imputations will only be performed for these classifications and calculations; in the listings 
all data will be shown as recorded on the eCRF. 
Imputation of Partial Start Dates 
• If only the month and year are specified and the month and year of first dose of iv BRV is not 
the same as the month and year of the start date, then use the 1st of the month. 
• If only the month and year are specified and the month and year of first dose of iv BRV is the 
same as the month and year of the start, then use the date of first dose of iv BRV. 
• If only the year is specified, and the year of first dose of iv BRV is not the same as the year 
of the start date, then use 1 Jan of the year of the start date. 
• If only the year is specified, and the year of first dose of iv BRV is the same as the year of 
the start date, then use the date of first dose of iv BRV.   
• If the start date is completely unknown and the stop date is unknown or not prior to the date 
of first dose of iv BRV, then use the date of first dose of iv BRV. 
Imputation of Partial Stop Dates 
• If only the month and year are specified, then use the last day of the month. 
• If only the year is specified, then use 31 Dec of that year. 
• If the stop date is completely unknown, do not impute the stop date. 
In the event of ambiguity or incomplete data which makes it impossible to determine whether a 
medication was concomitant or not, the medication will be considered as concomitant. 
4.2.4 
Handling of adverse events with partial or missing date 
Any AEs with incomplete onset and outcome (end) dates/times will be handled according to the 
following rules for classification as treatment-emergent. Such imputations will only be 
performed for these classifications; in the listings all data will be shown as recorded on the 
eCRF. 
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Imputation of Partial AE Onset Dates 
• If only the month and year are specified and the month and year of first dose of iv BRV or 
oral BRV from IOB Treatment Period is not the same as the month and year of AE onset, 
then use the 1st of the month of onset. 
• If only the month and year are specified and the month and year of first dose of iv BRV is the 
same as the month and year of AE onset, then use the date/time of first dose of iv BRV. 
• If only the month and year are specified and the month and year of first dose of iv BRV is not 
the same as the month and year of AE onset, but the month and year of first dose of oral 
BRV during the IOB Treatment Period is the same then use the date/time of first dose of oral 
BRV. 
• If only the year is specified, and the year of first dose of iv BRV or oral BRV from IOB 
Treatment Period is not the same as the year of AE onset, then use 1 Jan of the year of onset. 
• If only the year is specified, and the year of first dose of iv BRV is the same as the year of 
AE onset, then use the date/time of first dose of iv BRV. 
• If only the year is specified and the year of first dose of iv BRV is not the same as the year of 
AE onset, but the year of first dose of oral BRV during the IOB Treatment Period is the same 
then use the date/time of first dose of oral BRV. 
• If the AE onset date is completely unknown, then use the date\time of first dose of iv BRV. 
• If the AE onset time of the event is unknown, impute it as 00:00 unless the known part of the 
AE onset date is the same as the date of first iv BRV dose; in this case impute the time of 
first dose of iv BRV dose. 
Imputation of Partial AE End Dates 
• If only the month and year are specified, then use the last day of the month. 
• If only the year is specified, then use 31 Dec of that year. 
• If the AE resolved and the resolution date is completely unknown, then do not impute the 
resolution date. 
In the event of ambiguity or incomplete data which makes it impossible to determine whether an 
AE was treatment emergent or not, the AE will be considered as treatment emergent. 
With respect to AEs, events with missing intensity will be assumed to be severe. Events with 
missing relationship to iv BRV per the investigator will be assumed to be related.  
Data handling for worsened AEs is provided below. The standard AE eCRF has the outcome of 
“worsened” to be used when there is an increase in the intensity of an AE. The definition of 
“worsened” is when the AE is still present but at a heightened intensity. The eCRF instructions 
dictate to complete a new AE screen with the event term of the worsened event.  
Note that the outcome of “worsened” is not allowed terminology within the CDISC standards. In 
the SDTM.AE, the data is mapped to the outcome “Not Recovered/Not Resolved”. The outcome 
of “Worsened” will be kept in SDTM.SUPPAE. For subject data listings, the convention will be 
used to map SDTM terminology of “Not Recovered/Not Resolved”. 
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4.2.5 
Handling of study medication with partial or missing date 
No imputation should be performed for missing study medication start dates. This field on the 
eCRF should not be partial or missing. 
For partial or missing date of last dose of study medication, the following imputation rules will 
be applied for the purpose of calculating overall exposure: 
• If the day is missing (but month and year available), impute the last dose date as the earliest 
of the last day of the month or the date of last contact reported on the trial termination eCRF; 
if day and month are both missing (only year available), impute the last dose date as the 
earliest of the last day of the year or the date of last contact on the trial termination eCRF. 
• If a subject died and has a partial or missing last dose date, the last dose date is to be set to 
the date of death. If there is a partial date of last dose and the month/year are prior to the 
month and year of the date of death, follow partial date imputation rules. 
• If the last dose date is completely missing and no information could be obtained from data 
cleaning exercises, the last dose date should be imputed as the date of last contact according 
to the study termination eCRF. A review of the data for subjects with completely missing last 
dose dates should be performed to ensure that the imputation does not result in an unrealistic 
value for duration of exposure. 
Imputed date of last dose dates should only be used for calculation of the duration of exposure. 
The date as recorded on the eCRF should be presented in subject data listings (no imputed dates 
should be included in subject data listings). 
4.2.6 
Handling of epilepsy diagnosis with missing date 
Imputation methods should be applied for missing or partial epilepsy diagnosis date. 
• If the month and year are available, the diagnosis date will be imputed as the later of the 
following dates: the first day of the month or the subject’s birthdate (imputed DOB if only 
partial DOB is captured). 
• If only a year is available, the later of the following dates will be imputed: 1 Jan of the year 
or the subject’s birthdate (imputed DOB if only partial DOB is captured). 
• Completely missing dates will not be replaced, and the corresponding derived variables will 
be set to missing. 
 
4.2.7 
Potential impact of Coronavirus Disease 2019 on dropouts or 
missing data 
The Coronavirus Disease 2019 (COVID-19) pandemic may cause disruption in the conduct of 
ongoing clinical trials including treatment and study withdrawals, subjects missing study visits, 
and/or visits being performed remotely instead of at site. Therefore, for subjects enrolled after 
30th May 2020, an additional eCRF page will be foreseen. Sites will complete this page in case a 
subject was impacted by coronavirus during the study. The COVID-19 Impact eCRF page will 
include the timing and impact of COVID-19, and relationship to COVID-19 (i.e. whether the 
subject has confirmed/suspected COVID-19 infection, or whether its general circumstances 
around COVID-19 without infection).   
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4.3 
Interim analyses and data monitoring 
4.3.1 
DMC meetings 
Data will be presented to and reviewed by a DMC during the course of the study. For the first 
age cohort, after the first half of the subjects receive the 15-minute infusion(s), the DMC will 
meet to review safety (as indicated in the DMC charter) and, as available, PK data. For 
subsequent cohorts, the DMC will review data for bolus infusions of the previous cohort and the 
15-minute infusions of the current cohort. The DMC will meet no less than approximately every 
6 months commensurate with enrollment. The DMC members will be defined in the DMC 
charter. 
At each DMC meeting, the DMC will make recommendations regarding study aspects including:  
• Continuation of the study as planned 
• Modification of the study or particular expansion cohort(s) 
• Suspension of the study or particular expansion cohort(s) 
Age cohorts for enrollment are detailed in the schematic in Figure 5-1. Notably, the schematic of 
sequential cohort enrollment (Figure 5-1) differs from the one provided in the protocol. Ages 
were changed from “≥12 years to ≤16 years” to “≥12 years to <16 years”, “≥6 years to ≤12 
years” to “≥6 years to <12 years” and “≥2 years to ≤6 years” to “≥2 years to <6 years”. This 
difference is because the protocol has age boundaries of sequential cohort enrollment defined 
differently in the schematic to the text, but in practice sites have enrolled using the text.   
 
  
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4.3.2 
Interim analysis 
No formal interim analysis was planned in this study. The last planned DMC occurred after all 
subjects aged 2 to <6 years had completed the study, and all subjects aged 1 month to <2 years 
on 15-minute infusion had completed the study, and the recommendation was to continue the 
study. However, enrollment was temporarily stopped due to the impact of COVID-19. Therefore, 
all outputs will be delivered twice, firstly an interim CSR using all data from subjects aged 2 to 
<6 years and subjects aged 1m to <2 years on 15-min infusion to support ongoing submission 
work, and secondly a final CSR using all subjects.  
4.4 
Multicenter studies 
Analysis will not be assessed for individual investigator sites due to the low expected number for 
enrollment within each investigator site. 
4.5 
Multiple comparisons/multiplicity 
No statistical testing is planned; therefore, this section is not applicable for this study. 
4.6 
Use of an efficacy subset of subjects 
No efficacy data are collected; therefore, this section is not applicable for this study. 
4.7 
Examination of subgroups 
There is no subgroup analysis planned. However, the majority of summaries will be presented 
for all subjects, and separately by age cohort, by infusion duration and by subject group. In 
addition, selected summaries of Important protocol deviations (IPDs), AEs, vital signs and ECG 
findings and parameters will be provided by country of enrollment (Hungary and rest of the 
World). 
4.8 
Time points by infusion duration 
The time points relative to infusion initiation for respective assessments will be as follows: 
In case value of blood pressure at the “≤1 hr pre-infusion with low PCS BP” time point is low 
PCS, the additional timepoint will be listed only and not included in summary tables.  
• Vital signs time points for 15 min infusion:  
− ≤ 1 hr before initiation of iv BRV  
− 5 min after initiation of iv BRV  
− 10 min after initiation of iv BRV 
− 15 min after initiation of iv BRV 
− 30 min after initiation of iv BRV 
− 60 min after initiation of iv BRV. 
− 2 hr after initiation of iv BRV, only SBP and DBP will be collected. 
• Vital Signs time points for Bolus:  
− ≤ 1 hr before initiation of iv BRV  
− ≤ 2 min after initiation of iv BRV  
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− 5 min after initiation of iv BRV  
− 15 min after initiation of iv BRV 
− 30 min after initiation of iv BRV 
− 60 min after initiation of iv BRV 
− 2 hr after initiation of iv BRV, only SBP and DBP will be collected. 
• Electrocardiogram time points for 15 min infusion:  
− ≤ 1 hr before initiation of iv BRV  
− 5 min after initiation of iv BRV  
− 10 min after initiation of iv BRV 
− 15 min after initiation of iv BRV 
− 30 min after initiation of iv BRV 
− 60 min after initiation of iv BRV 
− 2 hr after initiation of iv BRV 
• Electrocardiogram time points for Bolus:  
− ≤ 1 hr before initiation of iv BRV  
− ≤ 2 min after initiation of iv BRV  
− 5 min after initiation of iv BRV  
− 15 min after initiation of iv BRV 
− 30 min after initiation of iv BRV 
− 60 min after initiation of iv BRV 
− 2 hr after initiation of iv BRV 
• Pharmacokinetic time points for 15 min infusion and Bolus:  
− ≤ 1 hr before initiation of iv BRV  
− 15 min after initiation of iv BRV 
− 3 hr after initiation of iv BRV. 
4.9 
Handling of data from open-label study 
Medical and procedural history, AEs, and prior and concomitant medication data for subjects 
coming from open-label study will only be documented within the open-label study and will be 
transferred into EP0065. 
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5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
Subjects who were screen failures, broken down by primary reason for screening failure, will be 
presented overall for all subjects screened. 
A summary of disposition of subjects will be provided for all screened subjects. The date of first 
subject in (date of first Screening Visit), date of last subject out (date of last contact), number of 
subjects screened, number of subjects in each analysis set (SS-iv, SS and PK-PPS), number of 
subjects in the SS-iv receiving 15 minutes infusion and number of subjects in the SS-iv receiving 
bolus infusion will be summarized overall, by country and by investigator site. Subjects who 
transferred sites will be summarized according to their original site.  
A summary of disposition of analysis sets will be provided for the SS including the number and 
percentage of subjects receiving 15 minutes infusion / bolus in each analysis set: 
• The number and percentage of subjects in the SS 
• The number and percentage of subjects in the SS-iv 
• The number and percentage of subjects in the PK-PPS 
A summary of disposition and discontinuation reasons will be presented overall for the SS-iv and 
the SS. The following information is included:  
• The number and percentage of subjects starting the study, defined as having signed an 
informed consent. 
• The number and percentage of subjects completing the study, defined as having received at 
least 1 iv BRV dose and completed at least one assessment at TC-1. This definition differs to 
the completed subjects from the eCRF. 
• The overall number and percentage of subjects discontinuing the study early, and the number 
and percentage of subjects discontinuing by primary reason for discontinuation 
• The number and percentage of subjects starting the Screening Period 
• The number and percentage of subjects completing the Screening Period 
− Complete is defined as a non-missing informed consent date. 
• The reasons for discontinuing during the Screening Period 
• The number and percentage of subjects starting the IOB treatment Period 
− Start is defined by attending Visit 2. 
• The number and percentage of subjects completing the IOB treatment Period 
− Complete is defined as receiving oral BRV for at least 2 days during the IOB treatment 
period.  
• The reasons for discontinuing during the IOB treatment period 
• The number and percentage of subjects starting the iv PK Period 
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− Start is defined by attending Visit 3.  
• The number and percentage of subjects completing the iv PK Period 
− Completed is receiving at least one iv BRV dose during the iv PK Period. 
• The reasons for discontinuing during the iv PK Period. 
• The number and percentage of subjects starting down-titration (Follow-up Period) 
− Start is defined by having at least one down-titration BRV treatment.  
• The number and percentage of subjects starting the Safety Period 
− A subject is considered as starting the Safety Period if their date of study termination is at 
least 12 hours after the last BRV treatment received during down-titration.  
A summary of discontinuations due to AEs for the SS-iv will present the number and percentage 
of subjects who discontinued this study due to AEs overall, and by type of AE. The table will be 
repeated for the SS. 
The following listings will be provided for all subjects screened: subjects who did not meet study 
eligibility criteria, subject disposition, subject analysis sets, subjects excluded from at least one 
analysis set, study discontinuation, and visit dates. 
5.2 
Protocol deviations 
IPDs defined in the IPD specification document, and additionally identified at the data evaluation 
meetings, will be listed. In addition, the number and percentage of subjects with at least one 
important protocol deviation will be summarized overall and by category of important protocol 
deviation for the SS-iv and the SS. The number and percentage of subjects with no important 
protocol deviations will also be summarized. These summaries will be presented overall and by 
age group for all subjects, and by infusion duration. A separate summary will be presented by 
country of enrollment (Hungary and rest of the World) for all subjects and by infusion duration. 
All completed COVID-19 Impact eCRF pages, and other IPDs will be discussed in important 
protocol deviation meetings, including whether the deviation may have been caused by COVID-
19.   
All data collected from the COVID-19 Impact eCRF page will be listed.   
 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics and other Baseline Characteristics 
Demographic variables will be presented for the SS-iv and the SS. The variables to be presented 
are: 
• Age at entry into EP0065 (in years for subjects aged >2 years at study entry, in months for 
subjects aged <= 2 years at study entry) 
• Age at first diagnosis (in years and in months) (as defined in Section 3.2.7 ) 
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• Duration of epilepsy (in years and in months) (as defined in Section 3.2.8 ) 
• Categorized age at entry into EP0065: 
− EudraCT age categories: ≥1 month to <24 months, ≥24 months to <12 years, ≥12 to 
<16 years 
− Age categories for submission: ≥1 month to <4 years, ≥4 to <16 years 
• Gender (male, female) 
• Subject group (OLB, RxB, IOB, and IIB) 
• Weight at Screening (kg) 
• Weight at baseline (kg) 
• Weight group at baseline (<50 kg, ≥50 kg) 
• Height at Screening (cm) 
• BMI at Screening (kg/m2) (as defined in Section 3.3)  
• Racial group (American Indian/Alaskan Native, Asian, Black, Native Hawaiian or Other 
Pacific Islander, White, Other/Mixed)  
• Ethnicity (Hispanic or Latino or Not Hispanic or Latino) 
• Country (Countries may include Czech Republic, France, Germany, Hungary, Italy, Ireland, 
Mexico, Poland, Spain, USA) 
• VNS Status (VNS not used, VNS used; if used: VNS active, VNS not active) 
The following listings will be provided by age cohort for all subjects screened:  
• demographics at Screening 
• childbearing potential at Screening 
• historical seizure count (describing the type and number of seizures experienced in the 3 
weeks prior to Screening) 
• diagnosis of epilepsy (describing the primary disease, date of first epilepsy diagnosis and 
history of status epilepticus prior to the 1-month period before Screening) 
• vagus nerve stimulation status at Screening 
• family medical history (family medical history is only collected for subjects with potential 
drug-induced liver injury and will describe the medical conditions including start and stop 
dates) 
• lifestyle (lifestyle information is only collected for subjects with potential drug-induced liver 
injury and will describe the alcohol- and illicit drug use within past 6 months) 
6.2 
Medical history and ongoing diseases 
The number and percentage of subjects with a medical history condition, including both previous 
and ongoing conditions at the time of study entry (Screening), are summarized separately overall 
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and by MedDRA primary system organ class (SOC) and preferred term (PT) for the SS-iv. 
Additionally, the number and percentage of subjects with ongoing medical conditions are 
summarized overall (i.e. any ongoing medical conditions at Screening) and by primary SOC and 
PT. A subject data listing for the previous and ongoing medical history conditions will be 
provided for the SS together with the medical history glossary. 
6.3 
Prior and concomitant medications 
Prior medications include any medications that started prior to the date of first dose of iv BRV. 
Only prior medication which is ongoing or has an end date in the 2 weeks prior to screening will 
be included in summaries. Prior medication with an end date prior to the 2 weeks before 
screening will be listed only. Concomitant medications are medications taken on at least one day 
in common with the iv PK Treatment Period. Medications may be both prior and concomitant. 
Medications which started after the day of the last iv BRV treatment will be categorized as 
follow-up medications. 
For OLB subjects only medication which started during the EP0065 study will be recorded in the 
EP0065 study. Information of medication which started before EP0065 study start will come 
from the respective OLB study. Only medications with a stop date < 14 days prior to start date of 
EP0065 will be summarized in EP0065.  
Antiepileptic drugs (AED) will be identified using an internal UCB AED list (file: 
AEDs_ATCs_SEP2017_FINAL_benzo_groups_23JUL2019.xls). 
Subject data listings for prior, concomitant and follow-up AEDs, and prior, concomitant and 
follow-up non-AEDs will be provided separately together with a listing of medication glossary 
including all reported medications. 
6.3.1 
Summaries for non-AEDs 
The number and percentage of subjects taking non-AED medications prior to first iv BRV and 
concomitantly with iv BRV will be summarized separately overall, and by anatomical main 
group (Anatomical Therapeutic Chemical [ATC] classification level 1), therapeutic subgroup 
(ATC classification level 2), and preferred drug name for the SS-iv. Subjects reporting multiple 
medications within an ATC class are counted once per medication and class. 
6.3.2 
Summaries for AEDs 
The number and percentage of subjects taking AED medications prior to first iv BRV and 
concomitantly with iv BRV will be summarized separately overall, and by WHODD preferred 
drug name for the SS-iv. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Information reported on the eCRF drug accountability (iv formulation) will be listed. The data 
from the eCRF Drug Accountability (oral solution and tablets) will also be listed. No summaries 
of drug accountability are planned.  
BRV iv and oral dosing compliance will be evaluated through the review of important protocol 
deviations. 
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8 
EFFICACY 
This section is not applicable for this study. 
9 
PHARMACOKINETICS  
9.1 
Pharmacokinetics 
Plasma concentration of BRV (parent compound only) before, during and after iv BRV 
administration will be summarized and listed for the PK-PPS.  
Descriptive statistics will be calculated for each timepoint by infusion duration, visit and age 
cohort. These statistics will also be repeated by visit and weight group (<50 kg, ≥50 kg) and by 
visit and subject group (OLB, RxB and IOB combined, and IIB separately). Descriptive statistics 
will include: the number of observed values, geometric mean, 95% confidence interval for 
geometric mean, geometric CV, mean, SD, median, minimum value and maximum value. Values 
below LOQ will be set to LOQ for all calculations. 
Box plots of plasma concentration of BRV at each timepoint (15 minutes and 3 hours) will be 
produced for each age cohort by visit. Infusion duration will be marked using different symbols. 
Box plots of plasma concentration of BRV at each timepoint (15 minutes and 3 hours) will be 
produced for each infusion duration by visit. Age groups will be marked using different symbols. 
A listing for plasma sample collection times and concentrations of BRV will be provided. 
9.2 
Pharmacodynamics 
This section is not applicable for this study. 
10 
SAFETY ANALYSIS 
All analyses for extent of exposure and safety are performed for the SS-iv. Selected tables will 
be performed on the SS. 
Inferential statistical tests are not planned for the safety variables. 
10.1 
Extent of exposure 
The duration of iv BRV exposure, as defined in Section 3.2.6, will be summarized as continuous 
parameters (once in hours and once in days) for the iv PK Period on the SS-iv. The number and 
percentage of subjects who received 0, 1, 2, 3, …, 10 BRV infusions will be displayed for the 
SS-iv. Handling of missing study medication data is described in Section 4.2.5. Mean iv BRV 
dose (mg/kg) will be summarized as continuous parameters for the iv PK Period for the SS-iv. 
This table will be presented by age groups for all subjects, by infusion duration and by weight 
(<50kg and ≥50kg).   
The duration of overall oral BRV exposure, oral BRV exposure from tables and oral BRV 
exposure from oral solution as defined in Section 3.2.6, will be summarized as continuous 
parameters (in days) separately for the IOB Treatment Period and the Follow-up Period for the 
SS. 
The overall BRV duration (oral BRV and iv BRV exposure), as defined in Section 3.2.6, will be 
summarized as a continuous parameter (in days) for the SS-iv and SS respectively.  
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The following listings will be provided for the SS unless otherwise stated:  
• study medication administration, which displays relevant information about the BRV iv 
dosing including the start and stop time of each infusion, the target dose and whether the 
target dose was delivered. 
• BRV exposure, which displays relevant information about the BRV iv and oral dosing 
including the number of infusions received, and the total BRV exposure. 
• Oral BRV dosing during study 
• Oral BRV administration from oral solution 
• Oral BRV administration from tablets  
10.2 
Adverse Events 
All adverse events (AEs) occurring during EP0065 (ie, after signing of the ICF) must be 
reported. For subjects who transition to study N01266, any AEs which began after the first dose 
of BRV in N01266 but prior to TC-1 of EP0065 will be considered as during EP0065 and 
N01266. Pre-treatment adverse events (PTAEs) are defined as AEs that had onset strictly prior to 
the date/time of the first BRV medication taken during EP0065. For OLB subjects, where the AE 
started prior to EP0065 enrollment, information will come from the respective OLB study. 
Treatment-emergent adverse events (TEAEs) are defined as those events which started on or 
after the first BRV medication taken during the EP0065 study. Subjects who began the study on 
BRV treatment (OLB and RxB subjects) will be assumed to have taken BRV treatment on the 
first day of screening. Timing of an AE being treatment emergent varies by subject group: all 
AEs are treatment emergent for RxB and OLB subjects; all AEs on or after the IOB Treatment 
Period are treatment emergent for IOB subjects; all AEs on or after the iv PK Period are 
treatment emergent for IIB subjects. 
Data handling rules for management of missing or partial start or stop dates for adverse events 
should follow those defined in the Section 4.2.4. The classification of TEAE will be done after 
imputation of any partial start dates. 
10.2.1 
AE summaries 
All AE tables will be summarized separately over all AEs and by MedDRA SOC and MedDRA 
PT. The number and percentage of subjects experiencing each event at least once will be 
summarized. All summaries will be sorted alphabetically by SOC and by frequency of events 
within PTs, starting with the most frequent event overall. All summaries are for all study periods 
combined (Screening, IOB treatment, iv-PK, Follow-up, and Safety (BRV free) Period) unless 
otherwise indicated. Only the first occurrence of a TEAE of a particular PT will be included in 
incidence calculations, but all occurrences of TEAEs of the same PT will be included in counts 
of TEAEs. For summaries by study period, AEs are assigned only to the period on which they 
began. TEAEs of interest is a selection of TEAEs identified by UCB to be of interest to BRV. 
The following summaries will be produced overall and by age cohort, for all subjects and 
separately by infusion duration, and subject group for the SS-iv: 
• Incidence of AEs – Overview (number and percentage of subjects with at least one: AE, 
TEAE, serious TEAE, non-serious TEAE, TEAE of interest, TEAE requiring dose change, 
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drug-related TEAE, drug-related serious TEAE, and severe TEAE, as well as the number and 
percentage of subjects who discontinued due to a TEAE, had permanent withdrawal of BRV 
due to a TEAE, had an AE leading to death, and had a TEAE leading to death) 
• Incidence of TEAEs 
• Incidence of TEAEs Leading to Study Discontinuation 
• Incidence of Serious TEAEs 
The following AE summaries will be produced overall and by age cohort, for all subjects and 
separately by infusion duration for the SS-iv: 
• Incidence of PTAEs 
• Incidence of TEAEs by Maximum Intensity  
Each subject will be counted at most once per primary SOC or PT according to the maximum 
intensity of all AEs within that SOC or PT. Severe intensity will be assumed for AEs for 
which intensity is not specified. 
• Incidence of TEAEs by Maximum Relationship  
Drug-related AEs are AEs for which the relationship to trial medication is specified as related 
or AEs for which relationship is not specified. 
• Incidence of TEAEs of Interest 
• Incidence of Non-serious TEAEs Occurring in at least 5% of Subjects 
• Incidence of Serious TEAEs by Relationship to BRV 
• Incidence of Fatal TEAEs by Relationship to BRV 
The following summaries will also be produced by country of enrollment (Hungary and rest of 
the World) for all subjects, by infusion duration and by subject group for the SS-iv: 
• Incidence of AEs – Overview 
• Incidence of TEAEs  
The following summary will also be produced by country of enrollment (Hungary and rest of the 
World) for all subjects and by infusion duration for the SS-iv: 
• Incidence of TEAEs by Maximum Intensity  
The following summaries will be produced overall and by age cohort and study period, for all 
subjects and separately by infusion duration and subject group for the SS: 
• Incidence of TEAEs by Study Period 
• Incidence of TEAEs Leading to Study Discontinuation by Study Period 
• Incidence of Serious TEAEs by Study Period 
The following summaries will be produced overall and by age cohort and study period, for all 
subjects and by infusion duration for the SS: 
• Incidence of TEAEs by Maximum Intensity by Study Period 
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• Incidence of TEAEs by Maximum Relationship by Study Period 
The following TEAE summaries will be produced overall and by age cohort for the SS: 
• Incidence of Serious TEAEs - Subject Numbers 
• Incidence of TEAEs Leading to Study Discontinuation - Subject Numbers  
Additionally, incidence of TEAEs will be summarized by categorized relative time infusion for 
all subjects, and by age cohort for the SS-iv. The time of each AE relative to the start of the 
previous iv infusion will be calculated as described in Section 3.2.4 and categorized into 0-<=5 
minutes, >5 -<=15 minutes, >15 to <=60 minutes, >60 - <=12 hours and >12 hours. 
10.2.2 
AE Listings 
All AEs reported during the study will be provided in subject data listings for the SS. These 
listings will include, but is not limited to AE onset date and time, relationship to study 
medication and whether the AE is of special interest. AE's of special interest are a selection of 
adverse events, of particularly interest for this study chosen prior to first subject in, and are 
captured in the CRF.  
The following AE listings will be provided: 
• Glossary table for all AEs, where the terms included on the table should match those 
presented in other AE displays 
• All AEs 
• All serious AEs 
• All AEs leading to study discontinuation 
• Listing of all deaths 
• TEAEs of interest 
• All AEs which worsened during the study (The definition of “worsened” is when the AE is 
still present but at a heightened intensity.) 
• TEAEs in relation to previous PCSTs (Listing will contain PCST of each type that occurred 
from vital signs, ECG and laboratory values in relation to the time prior to the onset of each 
AE which occurred after the respective PCST (see Section 3.2.9)). 
Should it occur, any uncoded AEs should be designated as “UNCODED CLASS” at all 
MedDRA levels, and such AEs should be included in summary tables and subject data listings 
based on this classification (eg, SOC and PT set to UNCODED CLASS). 
10.3 
Medical procedures 
Medical procedures prior to study entry and during the study will be listed separately. 
10.4 
Clinical laboratory evaluations 
10.4.1 
Hematology, Chemistry and Urinalysis Parameters 
Laboratory values will be collected according to the protocol schedule of study assessments. In 
case a laboratory test is repeated at one visit, the latest measurement will be used for summary 
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tables. For continuous laboratory variables (including hematology and chemistry) summary 
statistics of Baseline values, Visit 13 values, and change from Baseline will be presented overall 
and by age cohort, for all subjects, and by infusion duration at each study visit for the SS-iv. For 
categorial urinalysis laboratory variables summary statistics of Visit 1 and Visit 13 values will be 
presented overall and by age cohort, for all subjects, and by infusion duration for the SS-iv. 
Shifts from Baseline to Visit 13 based on the normal range (ie, low, normal, high, and missing) 
for each hematology, and chemistry lab parameter will be presented for subjects who have a 
Baseline and Visit 13 measurement overall and by age cohort, for all subjects and by infusion 
duration for the SS-iv. Shifts from Baseline to Visit 13 based on the categorization of each 
urinalysis lab parameter will be presented for subjects who had done a Baseline and Visit 13 
measurement, overall and by age cohort, for all subjects and by infusion duration for the SS-iv. 
The number and percentage of subjects with possibly clinically significant treatment-emergent 
(PCST) for each laboratory variable (i.e. PCST low value, PCST high value) for hematology, 
biochemistry (including Thyroxine (T4)) and urinalysis will be summarized overall and by age 
cohort, for all subjects, and by infusion duration. The criteria for a laboratory value to be PCST 
is defined in Appendix 12.2, but note, only laboratory variables that meet PCST criteria at 
Visit 13, but not Baseline will be considered as PCST. 
The number of occurrences of each unique PCST type will be tabulated by timepoint within each 
visit within each subject, and include relevant criterion: gender, age, race, timepoint, visit, 
subject group and infusion duration. In addition, the number of subjects with at least one PCST 
will be displayed for each age cohort. 
The following listings will be provided: all laboratory results of clinical chemistry, hematology, 
urinalysis including an indicator as to which met the criteria for PCST. A separate listing will 
contain all additional laboratory tests performed and sample takes. 
10.4.2 
Potential Drug Induced Liver Injury 
A summary of the number and percentage of subjects who met PDILI criteria at any visit and at 
Visit 13 will be summarized overall, and by age cohort for all subjects and by infusion group. 
Results from local laboratory should be included, if applicable. Subjects who meet one or more 
of the criteria for potential drug-induced liver injury (PDILI) at Visit 1 or Visit 13 will be listed. 
The listing will display only visits for which at least one of the criteria for PDILI (see 
Appendix 12.3) was fulfilled for a given subject, and will display all results obtained at that visit 
for the specified variables associated with PDILI. Potential Hy’s law cases will be flagged.  
All potential drug-induced liver injury (PDILI) events require immediate action, testing, and 
monitoring (see Appendix 12.3). 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 included but not limited to those listed in laboratory measurements. 
Additional PDILI information will also be listed. If specific PDILI information collected 
separately is matching to the entries in the standard eCRF pages collected for all subjects, the 
specific PDILI information will be added to the corresponding listing for the standard eCRF 
information. For information collected on top (eg, family history of PDILI, lifestyle) a new 
listing will be generated. 
Suspected hepatic events will be listed. 
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10.5 
Vital signs, physical findings, and other observations related to 
safety 
10.5.1 
Vital signs and body weight 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], respiratory rate [RR], 
temperature, pulse rate) and body weight will be collected according to the protocol schedule of 
study assessments.  
Observed values of body weight will be summarized for each visit by infusion duration, and by 
subject group for the SS-iv.  
Observed values of SBP, DBP, RR, temperature and pulse rate will be summarized for each time 
point (as defined in Section 4.8) within each visit. Change from Baseline for SBP, DBP, RR, 
temperature, and pulse rate will be summarized for all post-Baseline time points within each 
visit. Tables will be provided overall and by age cohort, for all subjects and by infusion duration, 
and by subject group for the SS-iv. Observed values for SBP, DBP, RR, temperature, and pulse 
rate at each timepoint will be plotted as a line for each subject in line graphs by visit (Visit 1 to 3, 
then for each visit individually i.e. Visit 4, 5, etc), age cohort and infusion duration. Abnormal 
values defined by the PCST criteria will be marked using symbols. 
Vital signs PCS/PCST definitions are located in Appendix 12.2.4. Vital signs PCST events (i.e. 
Treatment-emergent vital signs PCS) are defined as events which started on or after the first 
BRV medication taken during the EP0065 study that meet PCS criteria. Subjects who began the 
study on BRV treatment (OLB and RxB subjects) will be assumed to have taken BRV treatment 
on the first day of screening. Therefore, timing of a PCS being treatment emergent (i.e. a PCST) 
varies by subject group: all PCS are treatment emergent for RxB and OLB subjects; all PCS on 
or after the IOB Treatment Period are treatment emergent for IOB subjects; all PCS on or after 
the iv PK Period are treatment emergent for IIB subjects. 
All vital signs measurements (scheduled and unscheduled) which are taken after the first BRV 
medication during the EP0065 study will be assessed to determine if they meet PCST criteria. 
The number and percentage of subjects that meet the criteria for any PCST value, a high PCST 
value and a low PCST value at each timepoint and visit will be presented for each variable 
individually overall and by age cohort for all subjects and by infusion duration. A separate 
summary will be presented by country of enrollment (Hungary and rest of the World) for all 
subjects and by infusion duration. Percentages will be relative to the number of subjects with a 
value at each corresponding timepoint or visit.  
The number of occurrences of each unique PCST type will be tabulated by timepoint within each 
visit for each subject, and include relevant criteria: gender, age, race, timepoint, visit, subject 
group and infusion duration. In addition, the number of subjects with at least one PCST will be 
displayed for each age cohort.  
A subject data listing of all vital sign values will be presented. The listing will contain columns 
indicating which values met the criteria for PCS and PCST. All body weight values will be listed 
and will contain a column indicating the PCS and PCST criteria. 
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10.5.2 
Electrocardiograms (ECGs) 
Standard 12-lead ECGs (heart rate, RR-interval, PQ/PR interval, QRS duration, QT interval, 
QTcB interval) will be performed throughout the study, according to the protocol schedule of 
assessments. The QTcF interval will be calculated using the following formula: 
 
𝑄𝑇𝑐𝐹=
QT 
√RR 
3
 
 
Observed values of ECG parameters will be summarized for each timepoint within each visit. 
Change from Baseline for ECG parameters will be summarized for all post-Baseline timepoints 
within each visit. Tables will be provided overall, and by age cohort for all subjects, and by 
infusion duration, and subject subgroup for the SS-iv. Values for all ECG parameters at each 
timepoint will be plotted as a line for each subject in line graphs by visit (Visit 1 to 3, then for 
each visit individually i.e. Visit 4, 5 etc.), age cohort, and infusion duration. Abnormal values are 
defined by the PCS/PCST criteria (see Appendix 12.2.5) and will be displayed using symbols. 
ECG PCST events (i.e. Treatment-emergent ECG PCS) are defined as events which started on or 
after the first BRV medication taken during the EP0065 study that meet PCS criteria. In subjects 
who begun the study on BRV treatment (OLB and RxB subjects), they will be assumed to have 
taken BRV treatment on the first day of screening. Therefore, timing of a PCS being treatment 
emergent (i.e. a PCST) varies by subject group: all PCS are treatment emergent for RxB and 
OLB subjects; all PCS on or after the IOB Treatment Period are treatment emergent for IOB 
subjects; all PCS on or after the iv PK Period are treatment emergent for IIB subjects.  
All ECG parameter measurements (scheduled and unscheduled) which are taken after the first 
BRV medication during the EP0065 study will be assessed to determine if they meet PCST 
criteria. The number and percentage of subjects that meet the criteria for PCST at each timepoint 
and visit will be presented for each variable individually overall and by age cohort for all 
subjects and by infusion duration. A separate summary will be presented by country of 
enrollment (Hungary and rest of the World) for all subjects and by infusion duration. Percentages 
will be relative to the number of subjects with a value at each corresponding timepoint or visit. 
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG findings, as assessed by the investigator, will be 
summarized for all timepoints within visits overall and by age cohort for all subjects and by 
infusion duration. 
Shift tables will display the number and percentage of subjects having the same and different 
ECG finding (normal/abnormal not clinically significant/abnormal clinically significant) at each 
post-iv timepoint compared to their pre-iv ECG finding in the same visit, for all subjects and by 
age cohort, by infusion duration. Therefore, for subjects on bolus the shift from pre -iv BRV to 
≤2, 5, 15, 30, 60 minutes and 2 hr after initiation of iv BRV result will be displayed, and for 
subjects on 15 minutes infusion the shift from pre -iv BRV to 5, 10, 15, 30, 60 minutes and 2 hr 
after initiation of iv BRV result will be displayed. 
A subject data listing will be provided for 12-lead ECG results and will contain a column 
indicating the PCS and PCST criteria if a subject had abnormal ECG value. A separate listing 
will be provided, displaying the 12-lead ECG findings including a record of whether each 
finding was clinically significant or not.  
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10.5.3 
Medical Resource Use 
Hospitalization and emergency room visits will be listed for the SS. The listing will describe the 
event, date, period of onset, ward and reason for the hospitalization or emergency room visit. No 
summary of hospitalization or emergency room visits are planned. 
10.5.4 
Health Care Provider Consultations Not Foreseen by the Protocol 
Subject data listing will be provided for subjects who consult a health care provider not foreseen 
by the protocol. 
10.5.5 
Physical examination  
Complete physical examinations will be conducted at Visit 1. Brief physical examinations should 
be conducted at other designated visits.  
Clinically new or worsened physical examination findings will be reported as AEs. 
A listing of physical examinations conducted at Visit 1 will be provided; no summaries of 
physical examination are planned. 
10.5.6 
Tanner Stage 
Tanner Stage will be assessed at Visit 3 prior to iv BRV. A Listing of Tanner Stage will be 
provided for subjects who are selected for evaluation of Tanner Stage (ie, those subjects who are 
pubescent).  
10.5.7 
Neurological examination 
Complete neurological examination will be conducted at Visit 1. Brief neurological examination 
should be conducted at other designated visits.  
Clinically new or worsened neurological examination findings will be reported as AEs. 
A listing of neurological examinations conducted at Visit 1 will be provided; no summaries of 
neurological examination are planned. 
10.5.8 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia-Suicide 
Severity Rating Scale). This will be completed according to the protocol schedule of study 
assessments. 
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. All subjects who are ≥6 years of age will 
complete the “Baseline/Screening” version of the C-SSRS at Visit 1 and will complete the 
“Since Last Visit” version at subsequent visits. If a subject becomes 6 years of age during the 
study, the “Already Enrolled” version of the C-SSRS should be used at the first visit at which the 
subject is 6 years of age and use the “Since Last Visit” version at subsequent visits.  
The C-SSRS is not validated for subjects <6 years of age and will not be used for this population 
but signs and symptoms of depression will be assessed at each visit.  
Subject data listings of the data for the C-SSRS will be provided. No summaries of these results 
are planned. 
 
 
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11 
REFERENCES 
This section is not applicable for this study. 
 
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12 
APPENDICES 
12.1 
Laboratory parameters 
Table 12‒1: Laboratory parameters 
Hematology 
Chemistry 
Urinalysisa 
Endocrinology 
Pregnancyb 
WBC 
Glucose 
Glucose 
FSH 
β-hCG (urine) 
RBC 
Sodium 
Ketones 
LH 
 
Hemoglobin 
Potassium 
Occult blood 
TSH 
 
Hematocrit 
Calcium 
Protein 
T3 
 
Platelet count 
Chloride 
Nitrites 
T4 
 
Lymphocytes (number, %) 
Bicarbonate 
Leukocytes 
 
 
Monocytes (number, %) 
Phosphorus 
(inorganic) 
Microscopic 
examinationc 
 
Neutrophils (number, %) 
Total protein 
 
 
 
Eosinophils (number, %) 
Albumin 
 
 
 
Basophils (number, %) 
Total bilirubin 
 
 
 
MCH 
ALP 
 
 
 
MCHC 
AST 
 
 
 
MCV 
ALT 
 
 
 
 
GGT 
 
 
 
 
Uric acid 
 
 
 
 
Urea 
 
 
 
 
Creatinine 
 
 
 
 
Triglycerides 
 
 
 
 
Cholesterol 
 
 
 
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Table 12‒1: Laboratory parameters 
Hematology 
Chemistry 
Urinalysisa 
Endocrinology 
Pregnancyb 
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; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
a 
Urinalysis will be performed in subjects for whom urine sample collection is feasible. 
b 
For female subjects of childbearing potential only.  
c 
Includes bacteria, cells, casts, and crystals for all samples. 
 
12.2 
PCS criteria 
In this section the criteria for laboratory, vital signs and ECG parameters to be considered PCS is 
described. PCST is a treatment emergent PCS event. The definition of PCST for laboratory 
parameters is described in Section 10.4, for vital signs in Section 10.5.1 and ECG is in 
Section 10.5.2. 
12.2.1 
Hematology  
Parameter 
Age 
Range 
UNIT 
(conventional) 
PCS Criteria 
(conventional) 
unit 
(standard) 
PCS Criteria 
(standard) 
Hematocrit 
<2y 
% 
 
≤27 
>45 
% 
≤27 
>45 
2y - <18y 
≤29 
>47 
≤29 
>47 
≥18y 
≤85% of LLN 
≥115% of ULN) 
≤85% of LLN 
≥115% of ULN 
Hemoglobin 
<2y 
g/dL 
≤9.0 
>15.0 
g/L 
≤90 
>150 
2y - <18y 
≤9.5 
>16.0 
≤95 
>160 
≥18y 
≤85% of LLN 
≤85% of LLN 
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Parameter 
Age 
Range 
UNIT 
(conventional) 
PCS Criteria 
(conventional) 
unit 
(standard) 
PCS Criteria 
(standard) 
≥115% of ULN 
≥115% of ULN 
WBC/ 
Leukocytes 
<12y 
109/L 
<3.5 
>15.0 
G/L 
<3.5 
>15.0 
≥12y 
<3.0 
>12.0 
<3.0 
>12.0 
Neutrophils 
Absolute 
>1m 
109/L 
<1.5 
 
G/L 
<1.5 
Lymphocytes 
<6m 
% 
≤30.0 
% 
≤30.0 
6m - <6y 
≤22.0 
≤22.0 
6y - <18y 
≤12.0 
≥80.0 
≤12.0 
≥80.0 
≥18y 
≤10.0 
≥80.0 
≤10.0 
≥80.0 
Basophils 
>1m 
% 
≥3.0 
% 
≥3.0 
Eosinophils 
>1m 
% 
≥10.0 
% 
≥10.0 
Monocytes 
>1m 
% 
≥20.0 
% 
≥20.0 
Platelets 
>1m 
109/L 
≤100 
>600 
G/L 
≤100 
>600 
RBC/ 
Erythrocytes 
<2y 
1012/L 
<3.0 
T/L 
<3.0 
≥2y 
<3.5 
<3.5 
Abbreviations: ANC = absolute neutrophil count; m =month, y = year. A month is defined as 30 
days; a year is defined as 365.25 days. 
 
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12.2.2 
Biochemistry 
Parameter 
Age 
Range 
UNIT 
(conventional) 
PCS Criteria 
(conventional) 
unit 
(standard) 
PCS Criteria 
(standard) 
AST (SGOT) 
<14y 
U/L 
>180 
U/L 
>180 
≥14y 
>144 
>144 
ALT (SGPT) 
1y - <18y 
U/L 
>90 
U/L 
>90 
≥18y 
>123 
>123 
Alkaline 
Phosphatase 
<4y 
U/L 
>690 
U/L 
>690 
4y - <10y 
>834 
>834 
10y - <18y 
>1174 
>1174 
≥18y 
>432 (F) 
>933 (M) 
>432 (F) 
>933 (M) 
GGT 
<6m 
U/L 
>522 
U/L 
>522 
6m - <1y 
>279 
>279 
1y - <13y 
>66 
>66 
13y - <18y 
>126 
>126 
≥18y 
>255 
>255 
Total Bilirubin 
>1m 
mg/dL 
≥1.5 
umol/L 
≥25.656 
Total Protein 
2m-<1y 
g/dL 
<3.0 
>10.0 
g/L 
<30 
>100 
≥1y 
<4.3 
>10.0 
<43 
>100 
Albumin 
<1y 
g/dL 
<1.6 
>6.0 
g/L 
<16 
>60 
≥1y 
<2.4 
<24 
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Parameter 
Age 
Range 
UNIT 
(conventional) 
PCS Criteria 
(conventional) 
unit 
(standard) 
PCS Criteria 
(standard) 
>7.0 
>70 
BUN 
<1y 
mg/dL 
>21 
mmol/L 
>7.497 
≥1y 
>30 
>10.71 
Urea 
<1y 
mg/dL 
>42 
mmol/L 
>7.014 
≥1y 
>60 
>10.02 
Creatinine 
1y - <10y 
mg/dL 
>0.9 
umol/L 
>79.56 
10y - <16y 
>1.4 
>123.76 
≥16y 
>1.6 
>141.44 
Creatinine 
Clearance* 
All 
mL/min 
<70 
mL/s 
<1.169 
Calcium 
<1y 
mg/dL 
<6.9 
>12.2 
mmol/L 
<1.725 
>3.05 
1y - <18y 
<7.4 
>11.7 
<1.85 
>2.925 
≥18y 
<7.9 >11.1 
≤1.975 
≥2.775 
Phosphorous 
<1y 
mg/dL 
<1.8 
>8.2 
mmol/L 
<0.5814 
>2.6486 
≥1y 
<1.8 
>7.4 
<0.5814 
>2.3902 
Potassium 
<1y 
mEq/L 
<3.0 
>6.5 
mmol/L 
<3.0 
>6.5 
≥1y 
<3.0 
>5.8 
<3.0 
>5.8 
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Parameter 
Age 
Range 
UNIT 
(conventional) 
PCS Criteria 
(conventional) 
unit 
(standard) 
PCS Criteria 
(standard) 
Sodium 
>1m 
mEq/L 
≤130 
≥150 
mmol/L 
≤130 
≥150 
Glucose 
>1m 
mg/dL 
<50 
>180 
mmol/L 
<2.775 
>9.99 
Total Cholesterol 
1y - <18y 
mg/dL 
>250 
mmol/L 
>6.475 
≥18y 
>300 
>7.77 
LDL (calculated) 
1y - <18y 
mg/dL 
>140 
mmol/L 
>3.626 
≥18y 
>200 
>5.18 
HDL 
≤2y 
mg/dL 
<10 
mmol/L 
<0.259 
>2y 
<20 
<0.518 
Triglycerides 
<1y 
mg/dL 
>750 
mmol/L 
>8.475 
≥1y 
>250 
>2.825 
Uric Acid 
<1y 
mg/dL 
>7.7 
umol/L 
>457.996 
1y - <13y 
>6.5 
>386.62 
13y - <18y 
>8.6 
>511.528 
≥18y 
>6.8 (F) 
>9.6 (M) 
>404.464 (F) 
>571.008 (M) 
Thyroxine (T4) 
<1y 
ug/dL 
≤4.3 
≥18.4 
nmol/L 
≤55.3453 
≥236.8264 
≥1y 
≤3.8 
≥13.5 
≤48.9098 
≥173.7585 
Globulin 
<1y 
g/dL 
<1.0 
>3.8 
g/L 
<10 
>38 
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Parameter 
Age 
Range 
UNIT 
(conventional) 
PCS Criteria 
(conventional) 
unit 
(standard) 
PCS Criteria 
(standard) 
≥1y 
<1.2 
>4.4 
<12 
>44 
Abbreviations: ALT= alanine aminotransferase; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; dL = deciliter; GGT: gamma-glutamyltransferase; HDL = high density 
lipoprotein; LDL = low density lipoprotein; L = liter; m = month (a month is defined as 30 days) 
mg = milligram; mmol = millimoles; μg = microgram; U = unit; ULN = upper limit of normal; y 
= years (a year is defined as 365.25 days) 
*Schwartz equation (subjects <12):  Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine  
Cockroft equation (subjects >12): Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x 
serum creatinine); Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum 
creatinine)] x 0.85.  
Thyroxine (T4) is an Endocrinology parameter. 
12.2.3 
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).  
Table 12.2: 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. 
Table 12.3: Urinalysis 4-point scales for PCS criteria 
 
Four-point Scale 
PARAMETER 
Negative 
1+ 
2+ 
3+ 
Protein 
Negative 
Trace, 30 mg/dL 
100 mg/dL 
≥300 mg/dL,  
≥1000 mg/dL 
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Four-point Scale 
PARAMETER 
Negative 
1+ 
2+ 
3+ 
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  
1-5 
6-10 
11-20 
21-25 
 
>25 
Leukocytes 
1-5 
6-10 
11-20 
21-25 
 
>25 
For parameters which cannot have negative values their lowest two positive values will be at 
Negative point. For parameters which can have negative values their lowest two positive values 
will be at point 1+. 
12.2.4 
Vital Signs 
Parameter 
Age Range 
PCS Criteria 
Pulse Rate 
(beats/minute) 
 
 
<6m 
<100 
>180 
6m - <3y 
<90 
>150 
3y - <12y 
<60 
>130 
12y - <17y 
<50 
>120 
≥17y 
<50 and a decrease from Baseline of ≥15 
>120 and an increase from Baseline of ≥15 
Systolic Blood Pressure 
(mmHg) 
<6m 
<60 
>100 
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Parameter 
Age Range 
PCS Criteria 
6m - <3y 
<70 
>120 
3y - <12y 
<80 
>140 
12y - <17y 
<90 
>160 
≥17y 
≤ 90 and a decrease from Baseline of ≥20 
≥ 180 and an increase from Baseline of ≥20 
Diastolic Blood 
Pressure (mmHg) 
<6m 
<40 
>65 
6m - <3y 
<45 
>75 
3y - <12y 
<50 
>80 
12y - <17y 
<50 
>105 
≥17y 
<50 and a decrease from Baseline of ≥15 
>105 and an increase from Baseline of ≥ 15 
Respiratory Rate 
(breaths/minute) 
<6m 
<25 
>55 
6m - <3y 
<20 
>45 
3y - <12y 
<15 
>35 
≥12y 
<10 
>25 
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Parameter 
Age Range 
PCS Criteria 
Temperature 
>1m 
>101 0F (38.3 0C) 
Body Weight 
1m - <17y 
Outside of <3% to 97% percentile of the normal 
body weight based on gender and the age of 
subject on date of weight assessmenta 
≥17y 
≥ 10% change from Baseline (an increase or a 
decrease)a 
Abbreviations: m = month, y = year. A month is defined as 30 days; a year is defined as 365.25 
days.  
a source: http://www.cdc.gov/growthcharts/ 
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12.2.5 
ECG 
 
 
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12.3 
PDILI 
Laboratory value 
ALT or AST 
Total bilirubin 
≥3xULNb 
≥2xULNab 
≥3xULN 
NA 
≥5xULN (and ≥2x baseline) 
<2xULN 
≥3xULN (and ≥2x baseline) and <5xULN 
<2xULN 
a If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction 
should be discussed with the Medical Monitor. 
b The criteria of Hy’s Law are (ALT or AST ≥ 3×ULN) and total bilirubin ≥ 2×ULN. 
 
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13 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP) (IF APPLICABLE) 
13.1 
Changes in SAP from final version 1.0 to final version 2.0 
SAP final version 1.0 had a not accepted track change visible, which was accepted and resulted 
in final version 2.0. 
13.2 
Changes in SAP from final version 2.0 to final version 3.0 
• list of abbreviations was updated 
• Section 1 : Updated reference to latest protocol version 
• Section 2.3: 
− Clarification added that oral BRV can be applied during EP0065 but will not considered 
as study medication 
− Added sentence: Each cohort will have approximately 50% of subjects with iv BRV 
infusion and 50% with bolus BRV. 
− Clarification added that the Down-Titration Period is considered part of the Follow-Up 
Period 
• Section 3.1: 
− Moved following sentence from Section 3.6.2 to Section 3.1: If the Safety Set (SS) and 
the Safety Set-iv (SS-iv) consist of the same number of subjects, TFLs will only be 
presented for the SS-iv. 
− Removed summary statistics for PK from this overview section 
− Removed summary statistics by infusion periods 
− Added clarity on which data to summarize and which only be listed 
• Section 3.2.2: Removed the word ‘study’ before BRV as the wording ‘study BRV’ is not 
used anywhere else 
• Section 3.2.3: Added definition of Relative time.  
• Section 3.2.4: Added new section for explanation of derivation of relative time from previous 
iv infusion 
• Section 3.2.5: Corrected grammatical error and added definition for each of the study periods 
• Section 3.2.6: Corrected grammatical errors and added formulas for iv BRV exposure 
duration (days), iv BRV exposure duration (hours), oral BRV exposure duration from tablets, 
oral BRV exposure from oral solution and overall BRV exposure duration (days). 
• Sections about hospital stays and emergency room visits were removed from Section 3 as no 
derivations are planned 
• Section 3.2.7: Added formulas for age at first diagnosis in years and months 
• Section 3.2.8: Added formulas for duration of epilepsy in years and months 
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• Section 3.2.9: Added new section for explanation of derivation of time prior to AE onset 
• Section 3.3: Added ‘weight and height at Screening Visit’ to make clear which variables to 
use for calculation 
• Section 3.4: Wording of definition of Baseline values updated to ‘ latest assessment prior to 
the first infusion of iv BRV’ 
• Section 3.6.2: Moved second sentence to Section 3.1 
• Section 3.10: Added clarification that for vital sign and ECG summary statistics will be 
conducted for each timepoint only i.e. not summarized for the pre-bolus/infusion period, the 
bolus/infusion period, the period immediately post-bolus/infusion, and period between each 
subsequent bolus/infusion as stated in the protocol 
• Section 4.2: Reordered sentences for clarity and add that imputations will only be done for 
classification and calculations and not listed 
• Section 4.2.4: Updated imputation rules for partial AE onset date 
• Section 4.2.5: Replaced ‘minimum’ with ‘earliest’ in ‘minimum of the last day…’ 
• Section 4.7: Updated section to: There is no subgroup analysis planned. However the 
majority of summaries will be analyzed for all subjects, and separately by age cohort, by 
infusion duration and by subject group. 
• Section 4.8: Renamed section from ‘Infusion periods and time points’ to ‘ time points by 
infusion duration’, removed infusion periods and added additional time point of BP 
assessment 
• Section 5.1:  
− Updated wording to be more accurate on which table will be provided by which 
subgroups, analysis sets and overall 
− Added number and percentage for each of the periods for disposition and reason for 
discontinuation summary table 
• Section 6.1:  
− Added variables and clarification which variables will be presented in summary table 
− Added listings on family medical history and lifestyle, and added descriptions where 
required 
• Section 6.2:  
− Replaced ‘concomitant’ with ‘ongoing’ 
− Added analysis set 
• Section 6.3: 
− Added definition of follow-up medications 
− Updated section of AED identification and added new reference listing 
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• Section 6.3.1 and Section 6.3.2: 
− Replaced wording of ‘at the time of study entry’ with ‘prior to first iv BRV’ and ‘subjects 
taking concomitant AED medications’ with ‘concomitantly with iv BRV’ 
− Added overall summary 
• Section 7: Added oral dosing, as both iv and oral BRV will be evaluated through the review 
of IPDs 
• Section 9.1:  
− Removed ‘during administration’ as PK sample will only be taken prior and after iv BRV 
− Added summary table by visit and subject group (OLB, RxB, IOB, and IIB) 
− Reworded paragraph and aligned summary statistics to the ones defined in standard mock 
shells 
• Section 10.1: 
− Corrected grammatical errors 
− Added clarity on summary tables for overall oral BRV exposure, oral BRV exposure 
from tablets, oral BRV exposure from oral solution and overall BRV duration of oral and 
iv exposure 
− Added summary table of overall BRV duration of oral and iv exposure for the SS 
− Completed list of listings and added information on which variables will be described 
• Section 10.2 :  
− Reordered AE section and added separate sections for AE summary tables and AE 
listings 
− Updated definition of TEAE 
− Added clarity to different kind of AE tables and listings 
− Added summary tables for incidence of TEAEs by relative time from bolus/15 minutes 
infusion start time 
− Replaced ‘TEAE’ with ‘AE’ as glossary table will include all AEs not only TEAEs 
− Added listing of timing of TEAE onset in relation to start time of previous iv treatment 
− Added listing of timing of TEAE onset in relation to previous PCSTs 
• Section 10.3: Updated section to make clear medical procedures will be listed only 
• Section 10.4.1: 
− Removed endocrinology as those parameters are not separately categorized in CDISC 
standards 
− Added clarification about which result to use when repeated values are measured at one 
visit 
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− Added analysis set for continuous lab parameters 
− Added summary table for categorial urinalysis parameters at each visit where urinalysis is 
supposed to be collected for the SS-iv 
− Added clarification about the urinalysis shift table  
− Added clarification for laboratory PCST data listing 
− Added listing for all additional laboratory test performed 
• Section 10.4.2: Clarified what will be presented for PDILI 
• Section 10.5.1: 
− Added summary table for body weight by infusion duration, and by subject group for the 
SS-iv 
− Reworded summary tables to clarify that each timepoint will be summarized within each 
visit by infusion duration, and by subject group for the SS-iv 
− Updated wording of line graphs 
− Updated PCST vital sign values as PCST values which occur on or after first 
administration of oral or iv BRV through the end of the study 
− Updated wording of summary table for subject that meets the criteria for any PCST value 
− Added column for PCST to the vital sign listings 
• Section 10.5.2: 
− Added QTcF interval and formulation 
− Reworded vital sign summary tables for continuous and categorical variables to clarify 
that each timepoint will be summarized within each visit by infusion duration, and by 
subject group for the SS-iv 
− Updated wording of line graphs 
− Included all post initiation time points to the shift tables 
− Added ECG listing including a column for PCST 
• Section 10.5.3:  
− Combined the two section for hospital stays and emergency room visits to one section 
− Updated to listings only 
• Section 10.5.5 and Section 10.5.7: Added clarity that listings will provide examination 
conducted at Visit 1 
• Appendix 12.2.3: Added table for conversion of urinalysis four-point scale for PCST criteria 
• Appendix 12.2.4: Updated wording of abnormality criterion for body weight 
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13.3 
Changes in SAP from final version 3.0 to final version 4.0 
• Section 2.3: Removed “application” for better wording in following sentence: “Oral BRV 
application can be applied during EP0065 but will not considered as study medication for 
EP0065” 
• Section 3.2.3: Concomitant medications relative time excluded from this section as unable to 
derive as start and stop time not collected of concomitant medications.  
• Section 3.3: BMI formula rewritten in terms of meters rather than cm 
• Section 3.2.9: Added clarification on calculating time prior to AE onset, and added 
calculation for number of days prior to TEAE onset.  
• Section 3.10: Clarified that AEs will not be summarized the periods specified in the protocol, 
but will be summarized relative to most recent bolus/infusion start time. Slightly reworded 
for clarity.  
• Section 4.2.7: Section added to describe potential impact of COVID-19 on this study and, 
how information about this will be captured and used.  
• Section 4.3:  
• Added clarification on the difference between the sequential cohort enrollment schematic 
diagram between the SAP and protocol. Spilt into two sections (Section 4.3.1 which 
discusses sequential cohort enrollment, where text some has been modified for clarity and 
Section 4.3.2 which has added text on how analysis will be conducted twice due to 
COVID-19, once using all subjects aged 2 to <16 years and 1m to < 2years on 15 -minute 
infusion, and once using all subjects. 
• Section 5.2: Information added to describe how subjects with a completed COVID-19 eCRF 
Impact page will be assessed, and displayed.    
• Section 6.3 Clarification added to describe how prior concomitant medications will be listed 
only if they finish 2 weeks or more prior to screening.  
• Section 9.1: Text added to text to explain that PK summary tables will also be produced by 
infusion duration. Clarification added to explain that the summary tables will be produced by 
the combination of OLB, RxB and IOB groups, and separately for the IIB group.   
• Section 10.1: Additional text added to explain the groups that the exposure table will be 
presented by (all subjects, infusion duration and weight).    
• Section 10.2: Described how an AE occurring after first dose in N1266 but prior to TC-1 will 
be reported in both studies.  
• Section 10.2.1: Clarifications added for study periods and incidence definition.  
• Section 10.5.1: 
− PCST definition modified, so all PCS occurrences in subjects who enter the study on 
BRV (RxB/OLB) are considered treatment-emergent (PCST).  
− Added PCS definition 
− Added column for PCS to vital sign listings 
• Section 10.5.2:  
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Statistical Analysis Plan 
Brivaracetam 
EP0065 
 
 
 
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o Slightly reworded which values will be plotted. 
o PCST definition modified, so all PCS occurrences in subjects who enter the study 
on BRV (RxB/OLB) are considered treatment-emergent (PCST).  
o Added PCS definition 
o Added column for PCS to ECG listings 
• Section 12.2: Clarification added to describe the difference between PCS and PCST.   
• Section 12.2.3: Table 12.3 was updated to reflect consistency within 4-point scale derivation. 
 
 
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Statistical Analysis Plan 
Brivaracetam 
EP0065 
 
 
 
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13.4 
Changes in SAP from final version 4.0 to final version 5.0 
• Section 3.1: Additional text added to describe how selected summaries will be repeated by 
the country of enrollment (Hungary and rest of the World). 
• Section 4.7: Additional text added to describe how some summaries will be analyzed by 
country of enrollment (Hungary and rest of the World). 
• Section 5.2: Added IPD table by country of enrollment.  
• Section 9.1: Added box plots of plasma concentration of BRV for each age cohort at each 
timepoint by visit. Added box plots of plasma concentration of BRV for each infusion 
duration at each timepoint by visit.  
• Section 10.2.1: Added AE tables which will be produced by country of enrollment. 
• Section 10.5.1: Added PCST table which will be produced by country of enrollment. 
• Section 10.5.2: Added ECG PCST tables.   
• Section 12.2.3: Urinalysis 4-point scales for PCS criteria were changed from “1”, ”2”, ”3”, 
”4” to “Negative”, “1+”, ”2+”, “3+”. 
 
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Statistical Analysis Plan 
Brivaracetam 
EP0065 
 
 
 
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Page 55 of 55 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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Approval Signatures
Name:
ep0065-sap-amend-4
Version:
2. 0
Document Number:
CLIN-000161592
Title:
EP0065-Statistical Analysis Plan Amendment 4
Approved Date:
28 Sep 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Qualified Person
Date of Signature: 28-Sep-2020 10:01:05 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 28-Sep-2020 10:45:11 GMT+0000
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