Clinical trial NCT04882540
Conditions: Healthy Participants
Keywords: Epilepsy Healthy participants Phase 1 Brivaracetam
Sponsor: UCB Biopharma SRL
Start date: 2021-05-19; Completion date: 2021-06-08
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to assess the pharmacokinetics, safety, and tolerability of brivaracetam after a single dose and multiple doses in healthy adult Chinese Study Participants.

Detailed description:

Arms: arm 1: This is a Single-Arm study with Single- and Multiple- Dose Periods. Study participants will receive a single dose of brivaracetam (BRV) on Day 1 and will then receive multiple doses of brivaracetam from Day 5-10.
Interventions: intervention 1: brivaracetam
Intervention descriptions: intervention 1: * Pharmaceutical form: Film-coated tablets
* Concentration: 100 mg tablets
* Route of administration: Oral use

Protocol documents:
Prot_000.pdf: 
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EP0101 
 
 
 
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PROTOCOL EP0101 AMENDMENT 2 
AN OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE THE 
PHARMACOKINETICS AND SAFETY OF A SINGLE AND 
MULTIPLE ORAL DOSES OF BRIVARACETAM IN HEALTHY 
ADULT CHINESE SUBJECTS 
PHASE 1 
 
 
 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
26 Sep 2016 
Not applicable 
Protocol Amendment 1 
20 Dec 2019 
Non-substantial 
Protocol Amendment 2 
08 Jan 2021 
Non-substantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Brivaracetam 
EP0101 
 
 
 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Sponsor Study Physician 
Name: 
 
Address: 
Suite 2802 
Raffles City Shanghai Office Tower 
268 Tibet Road Central 
Shanghai 200001 
People’s Republic of China 
Phone: 
 
Fax: 
 
Clinical Project Manager 
Name: 
 
Address: 
Suite 2802 
Raffles City Shanghai Office Tower 
268 Tibet Road Central 
Shanghai 200001 
People’s Republic of China 
Phone: 
 
Fax: 
 
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EP0101 
 
 
 
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Clinical Trial Biostatistician 
Name: 
 
Address: 
Suite 2802 
Raffles City Shanghai Office Tower 
268 Tibet Road Central 
Shanghai 200001  
People’s Republic of China 
Phone: 
 
Fax: 
N/A 
 
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EP0101 
 
 
 
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SERIOUS ADVERSE EVENT REPORTING  
Serious adverse event reporting (24h) 
Fax 
+32 2 386 24 21 
Email 
DS_ICT@ucb.com 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 9 
1 
SUMMARY ..................................................................................................................... 11 
2 
INTRODUCTION ........................................................................................................... 12 
3 
STUDY OBJECTIVES .................................................................................................... 12 
4 
STUDY VARIABLES ..................................................................................................... 12 
4.1 Primary pharmacokinetic variables .................................................................................. 12 
4.2 Secondary pharmacokinetic variables .............................................................................. 13 
4.3 Safety variables ................................................................................................................ 13 
4.3.1 
Primary safety variable ........................................................................................ 13 
4.3.2 
Other safety variables .......................................................................................... 13 
5 
STUDY DESIGN ............................................................................................................. 13 
5.1 Study description ............................................................................................................. 13 
5.1.1 
Study duration per subject ................................................................................... 14 
5.1.2 
Planned number of subjects and sites .................................................................. 14 
5.1.3 
Anticipated regions and countries ....................................................................... 14 
5.2 Schedule of study assessments ......................................................................................... 14 
5.3 Rationale for study design and selection of dose ............................................................. 19 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS. .................................................. 19 
6.1 Inclusion criteria .............................................................................................................. 19 
6.2 Exclusion criteria ............................................................................................................. 20 
6.3 Withdrawal criteria .......................................................................................................... 21 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 22 
6.4 Other study restrictions .................................................................................................... 22 
7 
STUDY TREATMENT ................................................................................................... 22 
7.1 Description of investigational medicinal product ............................................................ 22 
7.2 Treatments to be administered ......................................................................................... 23 
7.3 Packaging ......................................................................................................................... 23 
7.4 Labeling ........................................................................................................................... 23 
7.5 Handling and storage requirements.................................................................................. 23 
7.6 Drug accountability .......................................................................................................... 23 
7.7 Procedures for monitoring subject compliance ................................................................ 24 
7.8 Concomitant medications/treatments ............................................................................... 24 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 24 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 24 
7.9 Blinding ............................................................................................................................ 24 
7.10 Randomization and numbering of subjects ...................................................................... 24 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 24 
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8.1 Screening .......................................................................................................................... 24 
8.2 Day -1 ............................................................................................................................... 25 
8.3 Day 1 ................................................................................................................................ 25 
8.4 Day 2 ................................................................................................................................ 26 
8.5 Day 3 ................................................................................................................................ 26 
8.6 Day 4 ................................................................................................................................ 26 
8.7 Day 5 ................................................................................................................................ 26 
8.8 Day 6 ................................................................................................................................ 27 
8.9 Day 7 ................................................................................................................................ 27 
8.10 Day 8 ................................................................................................................................ 27 
8.11 Day 9 ................................................................................................................................ 27 
8.12 Day 10 .............................................................................................................................. 28 
8.13 Day 11 .............................................................................................................................. 28 
8.14 Day 12 .............................................................................................................................. 28 
8.15 Day 13 .............................................................................................................................. 29 
8.16 Safety Follow-Up Visit .................................................................................................... 29 
9 
ASSESSMENT OF PHARMACOKINETIC/ 
PHARMACODYNAMIC/PHARMACOGENOMIC VARIABLES .............................. 29 
9.1 Blood sampling for determination of PK parameters ...................................................... 29 
10 ASSESSMENT OF SAFETY .......................................................................................... 30 
10.1 Adverse events ................................................................................................................. 30 
10.1.1 
Definitions ........................................................................................................... 30 
10.1.1.1 
Adverse event ............................................................................................ 30 
10.1.1.2 
Serious adverse event ................................................................................ 30 
10.1.1.3 
Adverse events of special interest ............................................................. 31 
10.1.2 
Procedures for reporting and recording adverse events ....................................... 32 
10.1.2.1 
Description of adverse events .................................................................... 32 
10.1.2.2 
Rule for repetition of an adverse event...................................................... 32 
10.1.2.3 
Additional procedures for reporting serious adverse events ..................... 32 
10.1.3 
Follow up of adverse events ................................................................................ 33 
10.1.4 
Pregnancy ............................................................................................................ 33 
10.1.5 
Suspected transmission of an infectious agent via a medicinal product .............. 34 
10.1.6 
Overdose of investigational medicinal product ................................................... 34 
10.1.7 
Safety signal detection ......................................................................................... 34 
10.2 Laboratory measurements ................................................................................................ 35 
10.2.1 
Evaluation of PDILI ............................................................................................ 35 
10.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 38 
10.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 38 
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10.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 38 
10.2.1.4 
Follow-up evaluation ................................................................................. 40 
10.3 Other safety measurements .............................................................................................. 40 
10.3.1 
Physical examination ........................................................................................... 40 
10.3.2 
ECG ..................................................................................................................... 40 
10.3.3 
Vital signs ............................................................................................................ 41 
10.3.4 
Assessment of suicidality .................................................................................... 41 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 41 
11.1 Adherence to protocol ...................................................................................................... 41 
11.2 Monitoring ....................................................................................................................... 41 
11.2.1 
Definition of source data ..................................................................................... 41 
11.2.2 
Source data verification ....................................................................................... 42 
11.3 Data handling ................................................................................................................... 42 
11.3.1 
Case Report form completion .............................................................................. 42 
11.3.2 
Database entry and reconciliation ........................................................................ 42 
11.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 42 
11.4 Termination of the study .................................................................................................. 43 
11.5 Archiving and data retention ............................................................................................ 43 
11.6 Audit and inspection ........................................................................................................ 43 
11.7 Good Clinical Practice ..................................................................................................... 44 
12 STATISTICS ................................................................................................................... 44 
12.1 Definition of analysis sets ................................................................................................ 44 
12.2 General statistical considerations ..................................................................................... 44 
12.3 Planned pharmacokinetic analyses .................................................................................. 44 
12.3.1 
Analysis of the primary pharmacokinetics variable ............................................ 44 
12.4 Planned safety and other analyses .................................................................................... 45 
12.4.1 
Adverse events ..................................................................................................... 45 
12.4.2 
Clinical laboratory test ......................................................................................... 45 
12.4.3 
Vital signs and ECG ............................................................................................ 45 
12.5 Handling of protocol deviations ....................................................................................... 45 
12.6 Handling of dropouts or missing data .............................................................................. 46 
12.7 Planned interim analysis and data monitoring ................................................................. 46 
12.8 Determination of sample size ........................................................................................... 46 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 46 
13.1 Informed consent ............................................................................................................. 46 
13.2 Subject identification cards .............................................................................................. 47 
13.3 Institutional Review Boards and Independent Ethics Committees .................................. 47 
13.4 Subject privacy ................................................................................................................. 48 
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Brivaracetam 
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13.5 Protocol amendments ....................................................................................................... 48 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 48 
15 REFERENCES ................................................................................................................ 48 
16 APPENDICES ................................................................................................................. 49 
16.1 Protocol amendment 1 ..................................................................................................... 49 
16.2 Protocol amendment 2 ..................................................................................................... 60 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ....................................... 77 
18 SPONSOR DECLARATION .......................................................................................... 78 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of study assessments......................................................................... 15 
Table 5‒2: 
Single-Dose Period: schedule for ECGs, vital signs, and PK sampling .......... 17 
Table 5‒3: 
Multiple-Dose Period: schedule for ECGs and vital signs .............................. 18 
Table 5‒4: 
Multiple-Dose Period: schedule for PK sampling ........................................... 18 
Table 10‒1: 
Laboratory measurements ................................................................................ 35 
Table 10‒2: 
Required investigations and follow up for PDILI............................................ 37 
Table 10‒3: 
PDILI laboratory measurements ...................................................................... 39 
Table 10‒4: 
PDILI information to be collected ................................................................... 40 
 
 
 
 
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Brivaracetam 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve from 0 to infinite time 
AUC(0-12),ss 
area under the curve from 0 to 12 hours at steady state  
AUC(0-t) 
area under the plasma concentration-time curve from zero to the time of 
the last measured concentration above the limit of quantification 
bpm 
beats per minute 
BRV 
brivaracetam 
Cav,ss 
average plasma concentration at steady state 
CDMS 
clinical data management system 
CI 
confidence interval 
CL/F 
apparent total body clearance 
CLss/F 
apparent total body clearance at steady state 
Cmax 
maximum plasma concentration 
Cmax,ss 
maximum plasma concentration at steady state 
Cmin,ss 
minimum plasma concentration at steady state 
CPM 
Clinical Project Manager 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DEM 
Data Evaluation Meeting 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HRT 
hormone replacement therapy 
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Brivaracetam 
EP0101 
 
 
 
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ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
λz 
rate constant of elimination 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
OTC 
over-the-counter 
PD 
pharmacodynamic(s) 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PS 
Patient Safety 
PTF  
peak trough fluctuation  
RAUC 
accumulation ratio calculated from AUC at steady state and AUC after 
single dose 
Rmax 
accumulation ratio calculated from Cmax at steady state and Cmax after 
single dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SFU 
Safety Follow-Up 
SOP 
Standard Operating Procedure 
SPD 
Specification of Protocol Deviations 
SS 
Safety Set 
SV2A 
synaptic vesicle protein 2A 
t½ 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach maximum plasma concentration  
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution 
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EP0101 
 
 
 
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1 
SUMMARY 
Brivaracetam (BRV) is a drug with a structure of a 2-pyrrolidinone derivative. Brivaracetam 
displays a high and selective interaction with synaptic vesicle protein 2A (SV2A), a protein 
involved in synaptic vesicle exocytosis and neurotransmitter release. This protein appears to be 
the primary target for BRV’s pharmacological activity. Data in transgenic mice indicate that 
even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated 
epileptogenesis. Brivaracetam demonstrated a potent suppression of seizure activity in a wide 
range of animal models of partial-onset and generalized seizures. 
The clinical tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BRV have been 
extensively studied up to 1400mg single dose and up to 800mg/day in repeated administration. It 
exhibits linear and dose-proportional PK, is rapidly and nearly completely absorbed orally, has a 
terminal elimination half-life (t½) of about 9 hours, and has plasma protein binding of <20%. 
Brivaracetam is extensively metabolized (>90%), primarily by non-cytochrome P450 (CYP) 
dependent hydrolysis of the amide group to a carboxylic acid via amidase, and secondarily 
through CYP2C19-mediated hydroxylation of the side chain. A third hydroxyacid metabolite is 
preferentially generated by CYP2C9-mediated hydroxylation of the carboxylic acid metabolite. 
The 3 metabolites are pharmacologically inactive. 
A Phase 1, placebo-controlled, single and multiple rising dose study in healthy Japanese 
volunteers (N01209) has shown that the disposition of BRV was similar to that in overseas 
populations. Brivaracetam was well tolerated and displayed linear and dose-proportional PK. No 
new observations were made relative to the safety and tolerability profile of BRV. In Japanese 
subjects bearing 2 nonfunctional alleles of the gene coding for the CYP2C19 isoenzyme 
(namely, *2/*2, *2/*3 or *3/*3; representing 25% of the study population), formation of the 
inactive hydroxy metabolite was decreased 10-fold but the plasma clearance (CL/F) of BRV was 
only decreased by 30% (0.70mL/min/kg compared to 0.99mL/min/kg in *1/*1 homozygous 
extensive metabolizers). It was concluded that no BRV dose adaptation is necessary in Japanese 
subjects compared to overseas populations, and, in particular, no dose reduction is needed for 
subjects bearing CYP2C19 mutations. 
This is a Phase 1, single site, open-label, single-dose and multiple-dose PK study of BRV tablets 
in healthy male and female Chinese subjects. A total of 12 subjects (6 males and 6 females) will 
be enrolled in the study. Subjects will be confined to the unit from Day -1 (the day prior to first 
administration of study drug) until Day 13 (72h after the final dose of study drug). Subjects will 
receive a single dose of BRV 100mg under fasting conditions in the Single-Dose Period. Blood 
samples will be taken predose and at specified time points postdose for the determination of the 
PK profile of BRV and metabolites (ucb-42145, ucb-100406-1, and ucb107092-1).  
In the Multiple-Dose Period, the same subjects as in the Single-Dose Period will receive 
BRV 200mg/day (100mg every 12h) under fasting conditions with 200mL of water. Blood 
samples will be taken predose and at specified time points postdose for the determination of the 
PK profile of BRV and metabolites (ucb-42145, ucb-100406-1, and ucb107092-1).  
Subjects will be discharged from confinement in the morning of Day 13, approximately 72h after 
the final administration of study drug, provided there are no medical objections. 
Safety and tolerability of BRV will be monitored throughout the study by monitoring of adverse 
events (AEs), collecting blood and urine samples for the evaluation of safety laboratory 
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Brivaracetam 
EP0101 
 
 
 
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parameters, vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate, 
respiratory rate, and body temperature), and electrocardiograms (ECGs). 
A Safety Follow-Up (SFU) Visit will be performed after the final administration of BRV. The 
assessments performed for the SFU will also be performed for early withdrawals.  
The study objectives are to assess the PK, safety, and tolerability of BRV after a single dose and 
multiple doses of 100mg for 6 days in healthy adult Chinese subjects (male and female). 
2 
INTRODUCTION 
A clinical development program for BRV is underway in China and will support a market 
authorization application/new drug application for BRV in China for the indication of adjunctive 
treatment in subjects 16 years and older with partial-onset seizures whether or not secondarily 
generalized. 
The clinical tolerability, PK, and PD of BRV have been extensively studied up to 1400mg single 
dose and up to 800mg/day in repeated administration. It exhibits linear and dose-proportional 
PK, is rapidly and nearly completely absorbed orally, has a t½ of about 9h, and has plasma 
protein binding of <20%. Brivaracetam is extensively metabolized (>90%), primarily by 
hydrolysis of the amide group to a carboxylic acid supported by non-CYP dependent amidase, 
and secondarily through CYP2C19-mediated hydroxylation of the side chain. A third 
hydroxyacid metabolite is preferentially generated by CYP2C9-mediated hydroxylation of the 
carboxylic acid metabolite. The 3 metabolites are pharmacologically inactive. 
A Phase 1, placebo-controlled, single and multiple rising dose study in healthy Japanese 
volunteers (N01209) has shown that the disposition of BRV was similar to that in overseas 
populations. Brivaracetam was well tolerated and displayed linear and dose-proportional PK. No 
new observations were made relative to the safety and tolerability profile of BRV. In Japanese 
subjects bearing 2 nonfunctional alleles of the gene coding for the CYP2C19 isoenzyme 
(namely, *2/*2, *2/*3 or *3/*3; representing 25% of the study population), formation of the 
inactive hydroxy metabolite was decreased 10-fold but the plasma clearance (CL/F) of BRV was 
only decreased by 30% (0.70mL/min/kg compared to 0.99mL/min/kg in *1/*1 homozygous 
extensive metabolizers). It was concluded that no BRV dose adaptation is necessary in Japanese 
subjects compared to overseas populations, and, in particular, no dose reduction is needed for 
subjects bearing CYP2C19 mutations. 
3 
STUDY OBJECTIVES 
The study objectives are to assess the PK, safety, and tolerability of BRV after a single dose and 
multiple doses of 100mg for 6 days in healthy adult Chinese subjects (male and female). 
4 
STUDY VARIABLES 
4.1 
Primary pharmacokinetic variables 
The primary PK variables are: 
• Concentrations of BRV and 3 metabolites (ucb-42145, ucb-100406-1, and ucb107092-1) in 
plasma  
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• For the single dose: 
− AUC(0-t) of BRV 
− Cmax of BRV 
• For the multiple dose: 
− AUC(0-12),ss of BRV 
− Cmax,ss of BRV 
4.2 
Secondary pharmacokinetic variables 
• For the single dose: 
− tmax, t1/2, λz, MRT, AUC, CL/F, and Vz/F of BRV in plasma  
− Cmax, tmax, t½, λz, AUC(0-t), and AUC of metabolites in plasma 
• For the multiple dose: 
− tmax, t½, λz, Cmin,ss, Cav,ss, CLss/F, and Vz/F of BRV in plasma 
− tmax, t½, λz, Cmax,ss, and AUC(0-12), ss of metabolites in plasma 
− PTF of BRV in steady-state 
− RAUC and Rmax of BRV 
4.3 
Safety variables 
4.3.1 
Primary safety variable 
• Incidence of treatment-emergent AEs (TEAEs)  
4.3.2 
Other safety variables 
• Changes in vital signs (SBP, DBP, pulse rate, respiratory rate, and body temperature) 
• Standard 12-lead ECGs parameters and findings 
• Changes in clinical laboratory test parameters (hematology, blood chemistry, and urinalysis) 
5 
STUDY DESIGN 
5.1 
Study description 
This is a Phase 1, single site, open-label, single and multiple dose PK study of BRV tablets in 
healthy male and female Chinese subjects. Subjects will be confined to the unit from Day -1 (the 
day prior to first administration of study drug) until Day 13. 
A total of 12 subjects (6 males and 6 females) who sign the Informed Consent form and fulfill all 
inclusion and none of the exclusion criteria will be enrolled and will start the Single-Dose 
Period. In the Single-Dose Period, each subject will receive BRV 100mg. In the Multiple-Dose 
Period, the multiple-dose PK and safety of BRV 200mg/day will be evaluated in the same 
subjects as in the Single-Dose Period. 
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In the Single-Dose Period, subjects will receive a single dose of BRV under fasting conditions 
with 200mL water. Blood samples will be taken for the determination of the PK profile of BRV 
and its metabolites (ucb-42145, ucb-100406-1, and ucb107092-1) at predose, and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, and 72h after study drug administration.  
In the Multiple-Dose Period, subjects will receive BRV 200mg/day (100mg every 12h ±15min). 
Subjects will receive BRV under fasting conditions with 200mL water. Blood samples will be 
taken for the determination of the PK profile of BRV and its metabolites (ucb-42145, 
ucb-100406-1, and ucb107092-1) predose prior to the morning dose administration on Day 5 to 
Day 9, and at predosing and at the following time points after the last administration of the 
investigational medicinal product (IMP) on Day 10: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 
48, and 72h.  
Subjects will be discharged from confinement in the morning of Day 13, approximately 72h after 
the final administration of study drug, provided there are no medical objections. 
Safety and tolerability of BRV will be assessed throughout the study by monitoring of AEs, 
collecting blood and urine samples for the evaluation of safety laboratory parameters, measuring 
vital signs (SBP, DBP, pulse rate, respiratory rate, and body temperature), and ECG. 
A SFU will be performed after the final administration of the IMP. The assessments performed 
for the SFU will also be performed for early withdrawals. 
5.1.1 
Study duration per subject 
The anticipated maximum study duration per subject is 43 days (approximately 6 weeks), 
including the Screening Period (up to 28 days), confinement during the Single-Dose and 
Multiple-Dose Periods (13 days), and follow-up examination (2 days after clinic discharge).  
The end of the study is defined as the date of the final visit of the final subject in the study. 
5.1.2 
Planned number of subjects and sites 
A total of 12 healthy (6 male and 6 female) subjects will be enrolled at 1 site. 
5.1.3 
Anticipated regions and countries 
The study will be conducted in China. 
5.2 
Schedule of study assessments
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Table 5‒1: 
Schedule of study assessments  
Activity/Day 
SV 
Treatment Period 
SFU 
Single-Dose 
Multiple-Dose 
D -28 to  
-2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D15 
Pre 
Post 
Informed consent 
X 
 
 
Clinic admission 
X 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
Demographic data 
X 
 
 
Medical history 
X 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Columbia-Suicide 
Severity Rating Scale 
X 
X 
 
X 
Vital signs 
X 
Xa 
Xa 
 
 
Xa 
 
 
Xb 
 
 
Xb 
 
 
Xb 
X 
12-lead ECG 
X 
Xc 
Xa 
 
 
Xa 
 
Xb 
 
 
Xb 
 
 
Xb 
X 
Safety laboratory 
assessmentsd 
X 
X 
X 
X 
 
 
 
Serologye 
X 
 
 
 
 
Drug/alcohol testf 
X 
X 
 
 
 
 
Pregnancy test (serum)g 
X 
 
 
 
 
Pregnancy test (urine)g 
X 
X 
 
 
X 
 
IMP administration 
 
 
 
X 
 
 
 
Xh 
Xh 
Xh 
Xh 
Xh 
Xi 
 
 
 
 
PK blood sampling 
X 
Xa 
Xa 
Xa 
Xa 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
 
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AE=adverse event; BRV=brivaracetam; D=day; ECG=electrocardiogram; HIV=human immunodeficiency virus; IMP=investigational medicinal product; 
PK=pharmacokinetics; Pre=predose; Post=postdose; SFU=Safety Follow-Up; SV=Screening Visit 
a See Table 5‒2 for the schedule for vital signs, ECGs, and PK sampling in the Single-Dose Period. 
b See Table 5‒3 for the schedule for vital signs and ECGs in the Multiple-Dose Period. 
c Three ECGs to be performed at 15min (±5min) intervals within 24h prior to BRV dosing on Day 1 to provide a representative baseline. 
d Hematology including coagulation parameters, clinical chemistry, and urinalysis 
e Hepatitis B surface antigen, Hepatitis C virus antibody, HIV antibody, and syphilis 
f Urine drug screen and alcohol breath test 
g For females of childbearing potential only 
h From Day 5 to Day 9, study drug will be administered in the morning and evening with an interval of 12h (±15min). 
i On Day 10, study drug will be administered only in the morning 12h (±15min) after the last dose. 
j See Table 5‒4 for the schedule for plasma PK sampling in the Multiple-Dose Period. 
 
 
Adverse event/ 
concomitant 
medication/medical 
procedure 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Table 5‒2: 
Single-Dose Period: schedule for ECGs, vital signs, and PK sampling  
 
Time relative to BRV administration 
 
 
Postdose (h) 
Day 1 
Day 2 
Day 3 
Day 4 
 
Assessment 
Predose 
0.25 
0.5 
1 
1.5 
2 
3 
4 
6 
9 
12 
16 
24 
36 
48 
72 
12-lead ECG 
Xa 
-- 
-- 
X 
-- 
X 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signsb 
X 
-- 
-- 
X 
-- 
X 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Blood samples for PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BRV=brivaracetam; DBP=diastolic blood pressure; ECG=electrocardiogram; PK=pharmacokinetics; SBP=systolic blood pressure 
Note: A window of ±15min is allowed for all ECG and vital signs assessments postdose. 
a Three ECGs to be performed at 15min (±5min) intervals within 24h prior to BRV dosing on Day 1 to provide a representative baseline. 
b Vital sign assessments include SBP, DBP, pulse rate, respiratory rate, and body temperature. 
 
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Table 5‒3: 
Multiple-Dose Period: schedule for ECGs and vital signs 
 
Assessment 
Day 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Pre 
Pre 
Postdose (h) 
1 
2 
4 
24 
36 
48 
72 
12-lead ECG 
-- 
-- 
Xa 
-- 
-- 
X 
X 
X 
X 
-- 
-- 
-- 
X 
Vital signsb 
-- 
-- 
Xa 
-- 
-- 
X 
X 
X 
X 
-- 
-- 
-- 
X 
DBP=diastolic blood pressure; ECG=electrocardiogram; Pre=predose; SBP=systolic blood pressure 
Note: A window of ±15min is allowed for all ECG and vital signs assessments postdose. 
a To be performed predose on the morning of Day 7. 
b Vital sign assessments include SBP, DBP, pulse rate, respiratory rate, and body temperature. 
 
Table 5‒4: 
Multiple-Dose Period: schedule for PK sampling  
 
Assessment 
Day 
 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Pre 
Pre 
Pre 
Pre 
Pre 
Pre 
Postdose (h) 
 
 
0.25 
0.5 
1 
1.5 
2 
3 
4 
6 
9 
12 
16 
24 
36 
48 
72 
Blood samples 
for PK  
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK=pharmacokinetics; Pre=predose 
a To be collected predose in the morning 
 
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5.3 
Rationale for study design and selection of dose 
In overseas studies, the clinical tolerability, PK, and PD of BRV have been extensively studied 
up to 1400mg single dose and up to 800mg/day in repeated administration. It exhibits linear and 
dose-proportional PK, is rapidly and nearly completely absorbed orally, has a t½ of about 9h and 
has plasma protein binding of <20%.  
A Phase 1, placebo-controlled, single- and multiple-rising dose study in healthy Japanese 
volunteers (N01209) has shown that the disposition of BRV was similar to that in overseas 
populations. See Section 2 for details. 
Dose selection for the Multiple-Dose Period (200mg/day [100mg every 12h]) was based on the 
expectation that this would be the highest dose in the Phase 3 study. The study is designed to 
provide additional safety and PK data for this dose in Chinese subjects. 
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. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject. 
2. Subject is considered reliable and capable of adhering to the protocol (eg, able to understand 
and complete diaries), visit schedule, or medication intake according to the judgment of the 
Investigator. 
3. Subjects are Chinese males and females born in China between 18 and 45 years of age (both 
inclusive) whose parents are of Chinese origin. 
4a. Pregnancy waiver form signed by subject, if female of childbearing potential. Beta-human 
chorionic gonadotropin test is documented negative within 48 hours before Day 1 and a 
medically accepted method of contraception (hormonal contraception, intrauterine device 
(IUD), implant device, diaphragm with spermicide, bilateral tubal ligation, monogamous 
relationship with vasectomized [for at least 3 months] partner or using condoms with 
spermicidal gel, sexually inactive) is used during the entire duration of the study. 
Male participants with a pregnant or breastfeeding partner or female partner of childbearing 
potential must agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile penetration during the study. 
5. Subjects with body mass index from 19 to 24kg/m2 (both inclusive). Minimum body weight 
is equal to or more than 50kg. 
6. Subjects whose physical and mental conditions are judged to be favorable by the 
Investigators through physical examination and past history. 
7. Subjects with supine blood pressure levels of between 90 to 150 and 60 to 90mmHg 
(inclusive) for systolic and diastolic, respectively, with pulse rate of 50 to 100 beats per 
minute (bpm) (supine position, inclusive) at Screening Visit. 
8. Subjects without clinically relevant abnormalities in a standard 12-lead ECG at Screening 
Visit judged by the Investigators. 
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9. Subjects with laboratory values within the reference range at Screening Visit, or those with 
values exceeding the reference range but judged by the Investigators to be not clinically 
significant to their participation in the study. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has previously participated in this study or has previously been assigned to treatment 
with the medication under investigation in this study. 
2. Subject has participated in another study of an IMP (or a medical device) within the previous 
30 days or is currently participating in another study of an IMP (or a medical device).  
3a. Subject has a history of chronic alcohol or drug abuse within the previous 6 months. Subject 
consumes on average more than 30g alcohol/day (amount corresponds to 750mL beer/day or 
375mL wine/day or 90mL liquor/day) for men and 20g alcohol/day (amount corresponds to 
500mL beer/day or 250mL wine/day or 60mL liquor/day) for women. 
4. Subject has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the subject’s ability to participate in this study. 
5. Pregnant, lactating, or sexually active women with childbearing potential who are not using a 
medically accepted birth control method. 
6. Subject has a known hypersensitivity to any components of the IMP or any of its excipients. 
7a. Subjects with any previous or current cardiovascular, respiratory, hepatic, renal, digestive, 
endocrine, or nervous system disorder that may affect absorption, secretion, metabolism, or 
excretion of the investigational product per Investigator judgment. 
8. Subjects with a chronic or acute condition requiring treatment. 
9. Subjects with known drug sensitivity or allergic reaction to any food. 
10. Subjects who used other drugs including over-the-counter (OTC) products (excluding 
medicine for external use), with the exception of paracetamol, ibuprofen, aspirin, and the 
accepted methods of contraception and hormone replacement therapy (HRT), within 14 days 
before administration of the investigational drug. 
11. Subjects who used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, 
isoniazid, phenytoin, rifampicin) within 2 months before the first administration of study 
drug. 
12. Subjects from whom 400mL of blood or more is drawn within 3 months or 200mL or more 
within 1 month before administration of the IMP for blood donation or other reasons. 
13a. Subject has a consumption of more than 600mg of caffeine/day on average (1 cup of coffee 
contains approximately 100mg of caffeine, 1 cup of tea approximately 30mg, and 1 glass of 
cola approximately 20mg). 
14. Subject smokes more than 5 cigarettes per day or has done so within 6 months prior to 
Screening. 
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15. Subjects who consumed grapefruit (as beverage or fruit) within 1 week before administration 
of the IMP. 
16. Subjects showing a positive result for hepatitis B surface antigen, hepatitis C virus antibody, 
human immunodeficiency virus antibody, or syphilis test at Screening Visit. 
17. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia Suicide 
Severity Rating Scale (C-SSRS) at Screening. 
18a. 
Subject has > upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
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%). 
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the 
exception of Gilbert's syndrome or asymptomatic gallstones). 
For subjects with a screening result >ULN for total bilirubin, a baseline diagnosis and/or the 
cause of any clinically meaningful elevation must be understood and recorded in the 
electronic Case Report form (eCRF). 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. If the repeat values are below ULN the subject will be considered to 
not meet the exclusion criteria.  
19. Subjects who are considered ineligible for the present study by the Investigators. 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. 
Subjects should be withdrawn from the study if any of the following events occur: 
1. Subject develops an illness that would interfere with his/her continued participation. 
2. Subject is noncompliant with the study procedures or medications in the opinion of the 
Investigator. 
3. Subject takes prohibited concomitant medications as defined in this protocol.  
4. Subject withdraws his/her consent. 
5. The Sponsor or a regulatory agency requests withdrawal of the subject. 
6. The Investigators judge that continuation of the study is difficult because of occurrence of 
AEs, etc. 
7. There is a protocol deviation that may affect study results markedly. 
8. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test.  
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Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. For subjects considered as lost to follow up, the Investigator should make an 
effort (at least 1 phone call and 1 written message to the subject), and document his/her effort 
(date and summary of the phone call and copy of the written message in the source documents), 
to complete the final evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in the source 
documents. The eCRF must document the primary reason for withdrawal or discontinuation. 
Investigators should contact the UCB Study Physician or designee, whenever possible, to discuss 
the withdrawal of a subject in advance. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if IMP 
must be discontinued. In addition, all concomitant medications and herbal supplements that are 
not medically necessary should also be discontinued. 
The PDILI criterion below requires immediate discontinuation of IMP: 
• Subjects with ALT or AST ≥ 3 x ULN 
Evaluation of PDILI must be initiated as described in Section 10.2.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
6.4 
Other study restrictions 
All BRV treatments will be administered under fasting conditions. For Day 1 and Day 10, 
subjects will be required to fast for ≥10h prior to dosing and until 3h after IMP administration. 
For Day 5 to Day 9, 2h fasting before and after dosing for morning and night dose is required. 
During fasting, no fluids are allowed except water; however, water is not allowed from 2h 
predose until 1h after the start of treatment (apart from the water taken with the oral dosing). 
Subjects must refrain from smoking and consuming alcohol and caffeine-containing products 
(chocolate, cola, coffee, or tea) from 48h before treatment until Final Discharge from the study. 
Subjects must refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products from 7 days before first drug administration through the end of the study. 
7 
STUDY TREATMENT 
The IMP tablets will be distributed to the clinical study site by the Sponsor under the 
responsibility of UCB Clinical Trial Supplies. 
7.1 
Description of investigational medicinal product 
Oral film-coated tablets of BRV 100mg will be used in this study.  
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7.2 
Treatments to be administered 
During the Single-Dose Period, subjects will receive a single dose of BRV 100mg under fasting 
conditions with 200mL of water. During the Multiple-Dose Period, subjects will receive 
BRV 200mg/day; study drug should be given as 2 equally divided doses administered twice 
daily. Subjects should take tablets according to instructions provided by the Investigator. 
7.3 
Packaging 
Brivaracetam tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations. The IMP is suitably packaged in 
such a way as to protect the IMP from deterioration during transport and storage. 
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 GMP and will include any 
locally required statements.  
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. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The Investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label. 
7.6 
Drug accountability 
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the Sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
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7.7 
Procedures for monitoring subject compliance 
The study drug will be administered under the Investigator’s (or designee’s) supervision. Study 
drug administration date and time will be recorded in the eCRF.  
7.8 
Concomitant medications/treatments 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
With approval from the Investigator, paracetamol, ibuprofen, and aspirin are permitted for the 
treatment of mild symptoms (eg, headache or pain), given at most every 6 to 8h, not exceeding 
1g/day, and with a total of no more than 10g per 14 days. 
Females are allowed to use hormonal contraceptives, implants, patches, or IUDs delivering 
progesterone or post-menopausal HRT.  
Except for the medications noted above, no concomitant medication is allowed during this study. 
7.8.2 
Prohibited concomitant treatments (medications and therapies) 
With the exception of paracetamol, ibuprofen, aspirin, and the accepted methods of 
contraception and HRT, all prescription or OTC medicines are prohibited within 14 days before 
first study drug administration and during the clinical part of the study, unless required to treat an 
AE. In addition, any hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, 
isoniazid, phenytoin, rifampicin) are prohibited within 2 months before first study drug 
administration and during the clinical part of the study. 
If a subject needs or takes any prohibited medication, the Investigator will (where possible) 
discuss with the Sponsor Study Physician and a decision will be made whether the subject can 
continue in the study or must be withdrawn. 
7.9 
Blinding 
This is an open-label study. 
7.10 
Randomization and numbering of subjects 
Subjects who have signed the Informed Consent form will be assigned a unique UCB-assigned 
5-digit subject number that will be used to identify them and maintain subject confidentiality 
throughout the study. 
8 
STUDY PROCEDURES BY VISIT  
8.1 
Screening  
Prior to the start of the any study procedures, the written informed consent form must be signed 
and personally dated by the subject and by the physician who informed the subject on the study. 
Screening procedures (within 28 to 2 days before Day 1) will consist of the following: 
• Verify inclusion and exclusion criteria  
• Obtain demographic data 
• Obtain medical history (past and concomitant diseases) 
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• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature)  
• Perform physical examination 
• Assess C-SSRS 
• Perform 12-lead ECG 
• Perform safety laboratory assessments for hematology, including coagulation, clinical 
chemistry, urinalysis, and serology 
• Perform serum pregnancy test for females of childbearing potential only 
• Perform alcohol breath test and urine drug screen 
• Record AEs 
• Record concomitant medication 
• Record concurrent medical procedures 
When all Screening procedures have demonstrated that all inclusion criteria have been met and 
none of the exclusion criteria apply, the subject can be invited to Day -1. 
8.2 
Day -1 
The Treatment Period consists of 14 in-house days. Subjects will stay in-house from Day -1 (day 
before first dosing) to Day 13. During this time, they will remain under close medical 
surveillance. Throughout the study, subjects will be monitored for AEs, concomitant medication, 
and medical procedures. 
• Check subject into the clinic 
• Check subject eligibility 
• Perform physical examination 
• Assess C-SSRS 
• Perform alcohol breath test and urine drug screen 
• Perform urine dipstick pregnancy test for females of childbearing potential only 
• Record concomitant medication and medical procedures 
• Record AEs 
• Perform 12-lead ECG (3 ECGs will be performed at 15min [±5min] intervals within 24h 
before dosing of BRV on Day 1) 
8.3 
Day 1 
The following procedures will be performed predose: 
• Perform 12-lead ECG (if not performed on Day -1, 3 ECGs will be performed at 15min 
[±5min] intervals within 24h before dosing of BRV on Day 1) 
• Obtain blood samples for safety laboratory assessments and plasma PK 
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• Study drug administration (after all predose assessments are completed) 
The following procedures will be performed postdose: 
• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature) at 1, 2, and 4h postdose. A window of ±15min is allowed. 
• Perform 12-lead ECG at 1, 2, and 4h postdose. A window of ±15min is allowed. 
• Obtain blood samples for plasma PK at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.4 
Day 2 
• Obtain blood sample for plasma PK at 16, 24, and 36h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.5 
Day 3 
• Obtain blood samples for safety laboratory assessments 
• Perform urine dipstick pregnancy test for females of childbearing potential only 
• Obtain blood sample for plasma PK at 48h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.6 
Day 4 
• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature) at 72h (±15min) postdose 
• Perform 12-lead ECG at 72h (±15min) postdose 
• Obtain blood sample for plasma PK at 72h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.7 
Day 5 
The following procedures will be performed predose prior to the morning dose administration: 
• Obtain blood sample for plasma PK 
• Study drug administration (after all predose assessments are completed) in the morning 
The following procedures will be performed postdose: 
• Study drug administration 12h (±15min) after the morning dose 
• Record concomitant medication and medical procedures 
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• Record AEs 
8.8 
Day 6 
The following procedures will be performed predose prior to the morning dose administration: 
• Obtain blood sample for plasma PK 
• Study drug administration (after all predose assessments are completed) in the morning 
12h (±15min) after the last dose 
The following procedures will be performed postdose: 
• Study drug administration 12h (±15min) after the morning dose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.9 
Day 7 
The following procedures will be performed predose prior to the morning dose administration: 
• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature)  
• Perform 12-lead ECG 
• Obtain blood sample for plasma PK 
• Study drug administration (after all predose assessments are completed) in the morning 
12h (±15min) after the last dose 
The following procedures will be performed postdose: 
• Study drug administration 12h (±15min) after the morning dose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.10 
Day 8 
The following procedures will be performed predose prior to the morning dose administration: 
• Obtain blood sample for plasma PK 
• Study drug administration (after all predose assessments are completed) in the morning 
12h (±15min) after the last dose 
The following procedures will be performed postdose: 
• Study drug administration 12h (±15min) after the morning dose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.11 
Day 9 
The following procedures will be performed predose prior to the morning dose administration: 
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• Obtain blood sample for plasma PK 
• Study drug administration (after all predose assessments are completed) in the morning 
12h (±15min) after the last dose 
The following procedures will be performed postdose: 
• Study drug administration 12h (±15min) after the morning dose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.12 
Day 10 
The following procedures will be performed predose: 
• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature)  
• Perform 12-lead ECG  
• Obtain blood sample for plasma PK  
• Study drug administration (after all predose assessments are completed) in the morning 
12h (±15min) after the last dose 
The following procedures will be performed postdose: 
• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature) at 1, 2, and 4h postdose. A window of ±15min is allowed. 
• Perform 12-lead ECGs at 1, 2, and 4h postdose. A window of ±15min is allowed. 
• Obtain blood samples for plasma PK at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.13 
Day 11 
• Obtain blood samples for safety laboratory assessments  
• Obtain blood samples for plasma PK at 16, 24, and 36h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
8.14 
Day 12 
• Obtain blood samples of plasma PK at 48h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
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8.15 
Day 13 
• Perform urine dipstick pregnancy test for females of childbearing potential only 
• Obtain blood samples for safety laboratory assessments 
• Obtain vital sign measurements (SBP, DBP, pulse rate, respiratory rate, and body 
temperature) at 72h (±15min) postdose 
• Perform 12-lead ECG at 72h (±15min) postdose  
• Obtain blood samples for plasma PK at 72h postdose 
• Record concomitant medication and medical procedures 
• Record AEs 
After all scheduled procedures have been performed on Day 13, the subject may be discharged 
from the clinical unit provided that there are no safety concerns in the opinion of the 
Investigator. 
8.16 
Safety Follow-Up Visit  
The subject will return to the clinic 2 days later (Day 15) for the SFU Visit. The following 
procedures will be performed: 
• Perform physical examination 
• Assess C-SSRS 
• Obtain vital signs 
• Perform 12-lead ECG 
• Record concomitant medication and medical procedures 
• Record AEs 
9 
ASSESSMENT OF PHARMACOKINETIC/ 
PHARMACODYNAMIC/PHARMACOGENOMIC VARIABLES 
9.1 
Blood sampling for determination of PK parameters 
At the specified time points, 4mL of blood will be drawn from the subcutaneous vein of the 
forearm with a vacuum tube containing lithium heparin. Within 30 minutes after blood draw, 
samples will be centrifuged at 4°C at about 1600g for 10 minutes to separate plasma. At least 
1mL of plasma will be collected into a polypropylene tube, and the remaining plasma into 
another tube. They will be frozen at −20°C or below until assay. 
A label with the protocol number, Subject Identification Code, dose, sampling date, and 
sampling time will be put on each plasma sample tube. Plasma samples will be packed with dry 
ice and sent to the drug concentration assay center from the medical institution. 
Unless otherwise indicated, any sample taken earlier or later than scheduled is considered a time 
deviation even if the deviation is pharmacokinetically irrelevant. 
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The maximum deviations from scheduled sampling times for PK are defined as follows: 
• 0h (predose): within 30min before dosing 
• 0.25h: ±1min 
• 0.5h: ±2min 
• 1 to 4h: ±3min 
• 6 to 9h: ±6min 
• 12 to 16h: ±12min 
• ≥24h: ±20min 
The unchanged drug and its metabolites (ucb-42145, ucb-100406-1, and ucb107092-1) in plasma 
will be determined with a validated liquid chromatography coupled with mass spectrometry/mass 
spectrometry method. 
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 Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the subject’s history. 
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.) 
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• 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 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.) 
10.1.1.3 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. For this study, the AEs of special interest include:  
• Autoimmune nephritis 
• Nephritis 
• Nephritis allergic 
• Tubulointerstitial nephritis 
• Tubulointerstitial nephritis and uveitis syndrome 
• Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of special interest (ie, without 
waiting for any additional etiologic investigations to have been concluded). In the event of 
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this occurring, permission to contact the subject’s primary healthcare professional would be 
sought to ensure further investigation and follow up. 
10.1.2 
Procedures for reporting and recording adverse events 
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example: 
“Did you notice anything unusual about your health (since your last visit)?” 
In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study. 
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 eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the Adverse Event eCRF (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 
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 
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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. 
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.  
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
Investigator must provide a justification. The follow up will usually be continued for 30 days 
after the subject has discontinued his/her IMP. 
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time. 
10.1.4 
Pregnancy 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol). The subject should be withdrawn from the study 
as soon as pregnancy is known (by positive pregnancy test), and the following should be 
completed: 
• The subject should return for an early discontinuation visit. 
• The subject should immediately stop the intake of the IMP.  
• An SFU Visit should be scheduled 14 days after the subject has discontinued IMP. 
The Investigator must inform the subject of information currently known about potential risks. 
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 
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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 Serious Adverse Event reporting information at the 
beginning of this protocol) only after the partner has agreed that additional information can be 
captured and has provided the signed Partner Pregnancy Consent form. UCB’s PS department is 
also the primary contact for any questions related to the data collection for the partner pregnancy, 
eventual birth, and follow up. 
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form. 
10.1.5 
Suspected transmission of an infectious agent via a medicinal 
product 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
10.1.6 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
10.1.7 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
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signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study. 
10.2 
Laboratory measurements 
The following laboratory parameters will be measured: 
Table 10‒1: Laboratory measurements 
Hematology 
Chemistry 
Urinalysis 
Basophils 
Calcium 
Albumin 
Eosinophils 
Chloride 
Bacteria 
Lymphocytes 
Creatinine 
Crystals 
Atypical lymphocytes 
Magnesium 
Glucose 
Monocytes 
Potassium 
pH 
Neutrophils 
Sodium 
RBC 
Hematocrit 
Glucose 
WBC 
Hemoglobin 
BUN 
Protein 
MCH 
AST 
Bilirubin 
MCHC 
ALP 
Nitrite 
MCV 
ALT 
Urobilinogen 
Platelet count 
GGT 
Ketones 
RBC count 
Total bilirubin 
 
WBC count 
LDH 
 
 
Total cholesterol 
 
 
Albumin 
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma-glutamyltransferase; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; 
WBC=white blood cell 
10.2.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and Sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 10.1.1.3), and, if applicable, also reported as an 
SAE (see Section 10.1.1.2).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 10‒2 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.2.1.1). The local 
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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 10.2.1.3).  
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. 
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. 
The table below summarizes the approach to investigate PDILI. 
 
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Table 10‒2: Required investigations and follow up for PDILI  
Laboratory value 
 
ALT or 
AST 
Total 
bilirubin 
Symptomsa of hepatitis 
or hypersensitivity 
Consultation requirements 
Required testing 
Continued evaluation  
Requires immediate and permanent IMP discontinuation 
≥3xULN 
<2xULN 
No 
Medical Monitor must be notified 
within 24 hours (eg, by laboratory 
alert) and subject discussed with 
Medical Monitor ASAP. 
Must have repeat liver 
chemistry values and 
additional testing 
completed ASAP (see 
Section 10.2.1.3); 
recommended to occur 
within 24 hours at 
Phase 1 unit or with 
HCP. 
Monitoring of liver 
chemistry values required 
once per week until values 
normalize, stabilize, or 
return to within baseline 
values.b 
≥3xULN 
NA 
Yes 
Hepatology consult.c 
Medical Monitor must be notified 
within 24 hours (eg, by laboratory 
alert) and subject discussed with 
Medical Monitor ASAP.  
Monitoring of liver 
chemistry values required 
at least twice per week 
until values normalize, 
stabilize, or return to 
within baseline values.b 
≥3xULN  
≥2xULNd 
NA 
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 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. 
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 If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
 
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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 requires permanent IMP discontinuation (see Section 6.3.1 and Table 10‒2 
for details).  
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The Investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative. 
10.2.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 10‒3 (laboratory measurements) and Table 10‒4 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the Sponsor on the 
corresponding eCRF. If the medical history of the subject indicates a requirement for other 
assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples should be stored, if possible.  
The following measurements are to be assessed: 
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Table 10‒3: PDILI laboratory measurements 
Virology-
related 
Hepatitis A IgM antibody 
HBsAg 
Hepatitis E IgM antibody 
HBcAb-IgM 
Hepatitis C RNA 
Cytomegalovirus IgM antibody 
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain 
heterophile antibody or monospot testing) 
Immunology Anti-nuclear antibody (qualitative and quantitative) 
Anti-smooth muscle antibody (qualitative and quantitative) 
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative) 
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct 
bilirubin 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase 
elevation 
Additional 
Prothrombin time/INRa 
Serum pregnancy test 
PK sample 
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic acid; 
ULN=upper limit of normal 
a Measured only for subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause). 
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The following additional information is to be collected: 
Table 10‒4: PDILI information to be collected 
New or updated information 
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”) 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
• 
Recent travel  
• 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash) 
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Alcohol and illicit drug use 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury 
10.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 10‒2. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the Investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
10.3 
Other safety measurements 
10.3.1 
Physical examination 
A standard physical examination will be performed according to Table 5‒1. Clinically significant 
new or worsened abnormalities will have to be reported as AEs. 
10.3.2 
ECG 
At time points specified in Table 5‒2 and Table 5‒3, 12-lead ECGs will be recorded at supine 
rest (at least 5 minutes), and normal or abnormal will be judged. Heart rate, PR, QRS, QT, and 
time from the beginning of the Q wave to the end of the T wave corrected for heart rate will also 
be recorded. 
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10.3.3 
Vital signs 
At time points specified in Table 5‒2 and Table 5‒3, SBP, DBP, pulse rate, respiratory rate, and 
body temperature in supine and standing positions will be recorded at supine rest (at least 
5 minutes) and 1 minute after standing. 
10.3.4 
Assessment of suicidality 
Suicidality will be assessed by trained study personnel using the C-SSRS. 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 Table 5‒1. 
11 
STUDY MANAGEMENT AND ADMINISTRATION  
11.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
Sponsor. 
After implementation of such measure, the Investigator must notify the Clinical Project Manager 
(CPM) of the Sponsor within 24 hours and follow any local regulatory requirements. 
11.2 
Monitoring 
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a CRO or a contract monitor. 
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The Investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
11.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents.  
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Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Source documents should be kept in a secure, limited access area. 
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, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
11.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 11.2.1. 
11.3 
Data handling 
11.3.1 
Case Report form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the CRF Completion Guidelines. 
11.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. The data are entered into the eCRFs once and are subsequently verified if the study is 
performed using electronic data capture. 
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. 
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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 (Committee for Proprietary Medicinal Products [CPMP]/ICH/135/95, 2002 
[Section 4.9.5]). The Investigator will contact UCB for authorization prior to the destruction of 
any study records or in the event of accidental loss or destruction of any study records. The 
Investigator will also notify UCB should he/she relocate or move the study-related files to a 
location other than that specified in the Sponsor’s trial master file. 
11.6 
Audit and inspection 
The Investigator will permit study-related audits mandated by UCB, 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. 
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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 (SAP). 
12.1 
Definition of analysis sets 
The Safety Set (SS) will consist of all subjects who received at least 1 dose of the IMP.  
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects who are included in 
the SS and also have a sufficient number of bioanalytical assessments to calculate reliable 
estimates for the primary PK parameters.  
The reasons for exclusion of subjects from either of the analysis sets will be listed. 
12.2 
General statistical considerations 
All analysis will be performed using SAS version 9.3 or higher. 
A complete set of raw data listings containing all documented data and all calculated data (eg, 
difference from Baseline) will be generated. In general, summary statistics (n [number of 
available measurements], arithmetic mean, standard deviation [SD], median, minimum, and 
maximum) for quantitative variable and frequency tables for qualitative data will be presented. 
12.3 
Planned pharmacokinetic analyses 
12.3.1 
Analysis of the primary pharmacokinetics variable 
In general, all PK parameter variables will be summarized using the PK-PPS. 
The plasma concentration-time profiles and PK parameters of BRV will be summarized by 
dosage (single and multiple) using descriptive statistics (number of observations [n], geometric 
mean, lower and upper 95% confidence interval [CI], geometric coefficient of variation [CV], 
arithmetic mean, SD and CV, median, and minimum and maximum value). 
Individual concentration-time profiles will be displayed graphically on a linear scale and 
semi-logarithmic scale. Plasma concentrations will be displayed superimposed in 1 plot for both 
dosages. Geometric mean profiles (including corresponding lower and upper limit of 95% CI for 
the linear scale, without CI on the semi-logarithmic scale) will be displayed in the same way. 
On the basis of plasma concentrations of the unchanged BRV and its metabolites obtained for 
each subject, the PK parameter values will be calculated. Pharmacokinetic parameter values will 
be calculated with Phoenix WinNonlinTM. The methodology of PK parameter calculations will 
be detailed in the SAP. 
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12.4 
Planned safety and other analyses 
In general, all safety variables will be summarized using the SS. 
12.4.1 
Adverse events 
All AEs will be characterized as pretreatment or treatment-emergent according to the intake of 
BRV. 
Treatment-emergent AEs will be defined as those events that start on or after the date-time of 
first IMP administration, or whose severity worsens on or after the date of first administration of 
the IMP. Adverse Events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). 
The occurrence and incidence of TEAEs will be summarized by MedDRA system organ class 
and preferred term. The incidence of TEAEs will also be summarized by intensity and 
relationship to BRV. 
Listings of all pretreatment AEs and TEAEs will be provided. 
12.4.2 
Clinical laboratory test 
Laboratory variables and changes from Baseline (Day 1 pre-dose assessment) will be 
descriptively summarized at each time point. Shift tables from Baseline to each post-Baseline 
time point will be presented. Values outside the reference ranges will be flagged in the listings. 
12.4.3 
Vital signs and ECG 
Vital sign variables and changes from Baseline will be descriptively summarized at each time 
point. 
Electrocardiogram parameters (RR interval, PR interval, QRS interval, QT, corrected interval 
between Q and T waves on ECG [Bazett’s Formula Correction], and corrected interval between 
Q and T Waves on ECG [Fridericia Correction]) and change from Baseline will be descriptively 
summarized by scheduled time point. Hereby, Baseline is defined as the mean of triplicate 
measurements of the ECG parameters prior to the first dose of study drug. 
12.5 
Handling of protocol deviations 
In accordance with ICH E3, UCB will report only deviations from the protocol deemed by the 
study team as important. In general, important protocol deviations are those considered to have 
an impact on key safety or PK parameters, or study conduct, and will be identified from various 
sources such as programmed edit checks, programmed listings, and monitoring reports. The 
categories (safety, PK, and conduct) are not fixed and can be adapted, extended, or reduced 
according to the needs of the study. 
The Specification of Protocol Deviations (SPD) document defines the criteria for identifying 
important protocol deviations. 
The SPD and any amendments are authored by the CRO CPM and are based on the final 
protocol and protocol amendment(s), if any. The CRO CPM works in close collaboration with 
the CRO Lead Study Biostatistician and in consultation with the Partner Study Physician. 
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The important protocol deviations are to be reviewed and finalized during the Data Evaluation 
Meeting (DEM). The DEM will take place prior to database lock. Search criteria for potential 
protocol deviations will be detailed in the SPD. 
All important protocol deviations will be listed by subject. 
12.6 
Handling of dropouts or missing data 
If single data points for plasma concentrations are missing, the AUC parameters will be derived 
by interpolating with regard to the 2 neighboring nonmissing concentrations.  
Subjects who drop out from the study before completion of study procedures and for any other 
reason than for safety issues will be replaced with subjects of the same gender after consultation 
with the Sponsor. 
The handling of other missing data will be detailed in the SAP. 
12.7 
Planned interim analysis and data monitoring 
No interim analysis and data monitoring are planned. 
12.8 
Determination of sample size 
Twelve subjects will be allocated to treatment. 
Due to the primary objective of the study being related to PK and safety, no power calculation of 
the study sample size was performed. In the event of dropouts, subjects will be replaced with 
subjects of the same gender after consulting with the Sponsor. 
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 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. 
If the Informed Consent form is amended during the study, the Investigator (or the Sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form. 
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13.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The Investigator will fill in the subject identifying information and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with him/her at all times. 
13.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
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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. 
15 
REFERENCES 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing 
clinical evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, 07/2009.  
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16 
APPENDICES 
16.1 
Protocol amendment 1 
This protocol has been amended to incorporate the following: 
- 
To remove the urine PK sample collection and analysis throughout the protocol. 
- 
To update the study contact information 
- 
To update the company name from SPRL to SRL 
- 
To clarify study variables 
In addition, minor administrative edits including typographical changes for formatting and/or 
spelling errors have been made.  
Modifications and changes 
Global changes 
Clarification of the study protocol title from “single oral dose and multiple oral doses” to “a 
single and multiple oral doses” 
Specific changes 
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Change 1: Update Study contact information 
STUDY 
CONTACT 
INFORAMT
ION 
Clinical Project Manager 
 
UCB Trading (Shanghai) Co. Ltd. 
Suite 2802, Raffles City Shanghai Office Tower 
268 Tibet Road Central, Shanghai 200001 
PEOPLE’S REPUBLIC OF CHINA 
 
 
TBD 
 
UCB Trading (Shanghai) Co. Ltd. 
Suite 2802, Raffles City Shanghai Office Tower 
268 Tibet Road Central, Shanghai 200001 
PEOPLE’S REPUBLIC OF CHINA 
 
 
Remove clinical 
project manager 
STUDY 
CONTACT 
INFORAMT
ION 
Clinical Trial Biostatistician 
 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
JAPAN 
 
 
Clinical Trial Biostatistician 
 
Suite 2802, Raffles City, Shanghai Office 
Tower, 
268 Tibet Road Central, Shanghai 200001 
PRC 
 
Update Clinical 
Trial 
Biostatistician 
 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Change 2: Removed urine concentration of BRV and metabolites text 
Section 1 
1 Summary 
In addition, all urine will be collected and will be used to 
evaluate the urinary concentration of BRV and its 
metabolites.  
In the Multiple-Dose Period, the same subjects as in the 
Single-Dose Period will receive BRV 200mg/day 
(100mg every 12h) under fasting conditions with 200mL 
of water. Blood samples will be taken predose and at 
specified time points postdose for the determination of 
the PK profile of BRV and metabolites (ucb-42145, ucb 
100406-1, and ucb107092-1). In addition, all urine will 
be collected and will be used to evaluate the urinary 
concentration of BRV and metabolites. Blood and urine 
samples will also be used to evaluate the urinary 
excretion of BRV. 
 
1 Summary 
In addition, all urine will be collected and will be 
used to evaluate the urinary concentration of 
BRV and its metabolites.  
In the Multiple-Dose Period, the same subjects 
as in the Single-Dose Period will receive BRV 
200mg/day (100mg every 12h) under fasting 
conditions with 200mL of water. Blood samples 
will be taken predose and at specified time 
points postdose for the determination of the PK 
profile of BRV and metabolites (ucb-42145, ucb 
100406-1, and ucb107092-1). In addition, all 
urine will be collected and will be used to 
evaluate the urinary concentration of BRV and 
metabolites. Blood and urine samples will also 
be used to evaluate the urinary excretion of 
BRV. 
Remove urine 
PK text 
Change 3: Removed urine PK associated tests 
Section 4.1 
4.1 Primary pharmacokinetic variables 
• 
Concentrations of BRV and 3 metabolites (ucb-
42145, ucb-100406-1, and ucb107092-1) in plasma and 
urine 
Concentrations of BRV and 3 metabolites (ucb-
42145, ucb-100406-1, and ucb107092-1) in 
plasma and urine 
Remove urine 
PK text 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 4.2 
4.2 Secondary pharmacokinetic variables 
• 
For the single dose: 
− 
tmax, t1/2, λz , MRT, AUC, CL/F, and Vz/F of 
BRV in plasma  
− 
Cmax, tmax, t½,  λz, AUC(0-t), and AUC of 
metabolites in plasma 
− 
Ae, fe, and CLR of BRV and metabolites in urine 
• 
For the multiple dose: 
− 
tmax, t½, λz, Cmin,ss, Cav,ss, CLss/F, and Vz/F of BRV 
in plasma 
− 
tmax, t½, λz, Cmax,ss, and AUC(0-12), ss  of metabolites 
in plasma 
− 
Ae, fe, and CLR of BRV and metabolites in urine 
− PTF of BRV in steady-state 
4.2 Secondary pharmacokinetic variables 
• 
For the single dose: 
− 
tmax, t1/2, λz , MRT, AUC, CL/F, and 
Vz/F of BRV in plasma  
− 
Cmax, tmax, t½,  λz, AUC(0-t), and AUC of 
metabolites in plasma 
− 
Ae, fe, and CLR of BRV and metabolites 
in urine 
• 
For the multiple dose: 
− 
tmax, t½, λz, Cmin,ss, Cav,ss, CLss/F, and Vz/F 
of BRV in plasma 
− 
tmax, t½, λz, Cmax,ss, and AUC(0-12), ss  of 
metabolites in plasma 
− 
Ae, fe, and CLR of BRV and metabolites 
in urine 
− 
PTF of BRV in steady-state 
Remove urine 
PK text 
Change 4: Clarified study variables 
Section 4.3 
4.3 Pharmacogenomic variable 
4.3 Pharmacogenomic Other variable 
Clarify study 
variables 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 4.4 
4.4 Safety variables 
• 
Adverse events 
• 
Vital signs (blood pressure and pulse rate in supine 
and standing positions) 
• 
Standard 12-lead ECGs 
• 
Clinical laboratory values (hematology, blood 
chemistry, and urinalysis) 
4.4 Safety variables 
4.4.1 
Primary safety variable 
The following will be assessed as primary safety 
variable: 
• 
Incidence of TEAEs from Baseline to SFU 
4.4.2 
Other safety variables 
• 
Changes in vital signs (systolic blood 
pressure [SBP], diastolic blood pressure 
[DBP], blood pressure and pulse rate, in supine 
and standing positions respiratory rate, and 
body temperature) 
• 
Standard 12-lead ECGs parameters and 
findings 
• 
Changes in clinical laboratory values test 
parameters (hematology, blood chemistry, and 
urinalysis) 
Clarify study 
variables 
Change 5: Removed urine PK associated tests 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 5.1  
 
5.1 Study description 
In addition, all urine will be collected (predosing, 0 to 6h, 
6 to 12h, 12 to 24h, 24 to 36h, 36 to 48h, and 48 to 72h 
after administration) and will be used to evaluate the 
urinary concentration of BRV and metabolites.  
In the Multiple-Dose Period, subjects will receive BRV 
200mg/day (100mg every 12 hours). Subjects will 
receive BRV under fasting conditions with 200mL water. 
Blood samples will be taken for the determination of the 
PK profile of BRV and its metabolites (ucb-42145, ucb 
100406-1, and ucb107092-1) predose prior to the 
morning dose administration on Day 5 to Day 9, and at 
predosing and at the following time points after the last 
administration of the IMP on Day 10: 0.25, 0.5, 1, 1.5, 2, 
3, 4, 6, 9, 12, 16, 24, 36, 48, and 72h. In addition, all 
urine will be collected (0 to 12h, 12 to 24h, 24 to 48h, 
and 48 to 72h after the final study drug administration) 
and will be used to evaluate the urinary concentration of 
BRV and its metabolites. Blood and urine samples will 
be collected to evaluate the urinary excretion of BRV. 
 
In addition, all urine will be collected 
(predosing, 0 to 6h, 6 to 12h, 12 to 24h, 24 to 
36h, 36 to 48h, and 48 to 72h after 
administration) and will be used to evaluate the 
urinary concentration of BRV and metabolites.  
In the Multiple-Dose Period, subjects will 
receive BRV 200mg/day (100mg every 12 
hours). Subjects will receive BRV under fasting 
conditions with 200mL water. Blood samples 
will be taken for the determination of the PK 
profile of BRV and its metabolites (ucb-42145, 
ucb 100406-1, and ucb107092-1) predose prior 
to the morning dose administration on Day 5 to 
Day 9, and at predosing and at the following 
time points after the last administration of the 
IMP on Day 10: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 
16, 24, 36, 48, and 72h. In addition, all urine will 
be collected (0 to 12h, 12 to 24h, 24 to 48h, and 
48 to 72h after the final study drug 
administration) and will be used to evaluate the 
urinary concentration of BRV and its 
metabolites. Blood and urine samples will be 
collected to evaluate the urinary excretion of 
BRV. 
Remove urine 
PK text 
Change 6: Removed urine PK from study related tables 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 5.2 
Table 5-1 Schedule of study assessments 
 The PK urine activity was removed from the 
table to include footnote j 
Remove urine 
PK activity 
Section 5.2 
Table 5-2 Single-Dose Period: schedule for ECGs, vital 
signs, and PK sampling 
The urine sample for PK and associated footnote 
b was removed from the table. 
Remove urine 
PK activity 
Section 5.2 
Table 5-4 Multiple-Dose Period: schedule for PK 
sampling 
 The urine sample for PK and associated 
footnote b was removed from the table. 
Remove urine 
PK activity 
Change 7: Removed urine PK from study visits 
Section 8.3 
8.3 Day 1 
The following bullets were removed: 
• 
Obtain urine sample for urine PK 
• 
Obtain urine samples for urine PK at the 
following intervals: 0 to 6h, 6 to 12h, and 12 to 
24h postdose 
Remove urine 
PK activity 
Section 8.4 
8.4 Day 2 
The following bullet was removed: 
• 
Obtain urine samples for urine PK at the 
following intervals: 12 to 24h, 24 to 36h, 36 to 
48h postdose 
Remove urine 
PK activity 
Section 8.5 
8.5 Day 3 
The following bullet was removed: 
• 
Obtain urine samples for urine PK at the 
following interval: 36 to 48h postdose 
Remove urine 
PK activity 
Section 8.6 
8.6 Day 4 
The following bullet was removed: 
• 
Obtain urine samples for urine PK at the 
following intervals: 48 to 72h postdose 
Remove urine 
PK activity 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 8.12 
8.12 Day 10 
The following bullets were removed: 
• 
Obtain urine sample for urine PK 
• 
Obtain urine samples for urine PK at the 
following intervals: 0 to 12h and 12 to 24h 
postdose 
Remove urine 
PK activity 
Section 8.13 
8.13 Day 11 
The following bullet was removed: 
• 
Obtain urine samples for urine PK at the 
following intervals: 12 to 24h and 24 to 48h  
postdose 
Remove urine 
PK activity 
Section 8.14 
8.14 Day 12 
The following bullet was removed: 
• 
Obtain urine samples for urine PK at the 
following intervals: 24 to 48h and 48 to 72h 
postdose 
Remove urine 
PK activity 
Section 8.15 
8.15 Day 13 
The following bullet was removed: 
• 
Obtain urine samples for urine PK at the 
following intervals: 48 to 72h postdose 
Remove urine 
PK activity 
Change 8: Removed urine from PK parameters 
Section 9.1 
9.1 Blood sampling for determination of PK parameters 
The unchanged drug and its metabolites (ucb-42145, ucb-
100406-1, and ucb107092-1) in plasma and urine will be 
determined with a validated liquid chromatography 
coupled with mass spectrometry/mass spectrometry (LC-
MS/MS) method. 
The unchanged drug and its metabolites (ucb-
42145, ucb-100406-1, and ucb107092-1) in 
plasma and urine will be determined with a 
validated liquid chromatography coupled with 
mass spectrometry/mass spectrometry (LC-
MS/MS) method. 
Remove urine 
PK text 
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Brivaracetam 
EP0101 
 
 
 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 9.2 
9.2 Urine for determination of PK parameters 
The entire section 9.2 was deleted and following 
section numbers were adjusted accordingly 
Remove urine 
PK text 
Change 9: Clarified statistical analysis 
Section 12.2 
Section 12.2 General statistical considerations 
All statistical analyses of the PK and safety variables will 
be considered exploratory. Datasets will be analyzed 
using SAS version 9.1.3 or higher. 
All statistical analyses of the PK and safety 
variables will be considered exploratory. 
Datasets will be analyzed performed using SAS 
version 9.1.3 or higher. 
Clarification of 
analysis 
Change 10: Removed urine concentration of BRV and metabolites text and clarified dosages  
Section         
12.3.1 
12.3.1 Analysis of the primary pharmacokinetics variable 
Individual concentration-time profiles will be displayed 
graphically on a linear scale and semi logarithmic scale. 
Plasma concentrations will be displayed superimposed in 
1 plot for both treatments. 
Individual concentration-time profiles will be 
displayed graphically on a linear scale and semi 
logarithmic scale. Plasma concentrations will be 
displayed superimposed in 1 plot for both 
treatments dosages. 
The fifth paragraph was deleted: 
On the basis of urine concentrations of the 
unchanged drug and its metabolites obtained for 
each subject, the PK parameter values will be 
calculated. 
Remove urine 
PK text 
Change 11: Clarified statistical analysis 
Section 12.4 
12.4 Planned safety and other analyses 
In general, all safety variables will be summarized by 
treatment using the SS. 
In general, all safety variables will be 
summarized by treatment using the SS. 
 
Change 12: Created a section sub-header for laboratory information 
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Clinical Study Protocol 
Brivaracetam 
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Key components of revised protocol text 
Rationale 
Section 
12.4.1 
12.4.1 Adverse events 
Laboratory variables and changes from Baseline (Day 1 
pre-dose assessment) will be descriptively summarized at 
each time point. Shift tables from Baseline to each post-
Baseline time point will be presented. Values outside the 
reference ranges will be flagged in the listings. 
12.4.2 Clinical laboratory test 
Laboratory variables and changes from Baseline 
(Day 1 pre-dose assessment) will be 
descriptively summarized at each time point. 
Shift tables from Baseline to each post-Baseline 
time point will be presented. Values outside the 
reference ranges will be flagged in the listings. 
Clarify 
laboratory 
information 
Change 13: Clarified ECG parameters measurement 
Section 
12.4.3 
12.4.3 Vital signs and ECG 
Hereby, Baseline is defined as the mean of triplicate 
measurements of the ECG parameters at predose of Day 
1. 
Hereby, Baseline is defined as the mean of 
triplicate measurements of the ECG parameters 
at predose of Day 1 prior to the first dose of 
study drug. 
Clarify ECG 
parameters 
Change 14: Clarified impact on safety parameters 
Section 12.5 
12.5 Handling of protocol deviations 
In general, important protocol deviations are those 
considered to have an impact on safety or PK parameters, 
or study conduct, and will be identified from various 
sources such as programmed edit checks, programmed 
listings, and monitoring reports. 
The CRO CPM works in close collaboration with the 
CRO Lead Study Biostatistician and in consultation with 
the Partner Study Physician and other CRO study team 
members as appropriate. 
In general, important protocol deviations are 
those considered to have an impact on key safety 
or PK parameters, or study conduct, and will be 
identified from various sources such as 
programmed edit checks, programmed listings, 
and monitoring reports. 
The CRO CPM works in close collaboration 
with the CRO Lead Study Biostatistician and in 
consultation with the Partner Study Physician 
and other CRO study team members as 
appropriate. 
Clarify safety 
parameters 
Change 15: Removed urine as a plasma concentration data point 
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Clinical Study Protocol 
Brivaracetam 
EP0101 
 
 
 
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Protocol 
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Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 12.6 
12.6 Handling of dropouts or missing data 
If single data points for plasma or urine concentrations 
are missing, the AUC parameters will be derived by 
interpolating with regard to the 2 neighboring 
nonmissing concentrations.  
 
If single data points for plasma or urine 
concentrations are missing, the AUC parameters 
will be derived by interpolating with regard to 
the 2 neighboring nonmissing concentrations.  
 
Remove urine 
PK text 
 
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Clinical Study Protocol 
Brivaracetam 
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16.2 
Protocol amendment 2 
This protocol has been amended to incorporate the following: 
- 
To update the study contact information  
- 
To clarify the vital sign measurements  
- 
To remove the genotype sample collection and analysis throughout the protocol 
- 
To clarify assessment windows for vital signs and ECGs 
- 
To modify the contraceptive inclusion criterion to include male subjects 
- 
To change the maximum pulse rate for eligible subjects 
- 
To clarify exclusion criteria for alcohol and drug abuse, medical history, and caffeine 
intake 
- 
To clarify retesting for liver function tests 
- 
To clarify fasting conditions for study drug administration 
- 
To remove the optional hepatic investigation sample collection 
In addition, minor administrative edits including typographical changes for formatting and/or 
abbreviations have been made.  
Modifications and changes 
Specific changes 
 
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Brivaracetam 
EP0101 
 
 
 
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Protocol 
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Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Change 1: Update Study contact information 
STUDY 
CONTACT 
INFORMATI
ON 
Suite 4106 
Suite 41062802 
Update contact 
information 
STUDY 
CONTACT 
INFORMATI
ON 
Clinical Project Manager 
 
Clinical Project Manager 
 
Suite 2802 
Raffles City Shanghai Office Tower 
268 Tibet Road Central 
Shanghai 200001 
People’s Republic of China 
 
 
Add clinical 
project 
manager 
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Key components of revised protocol text 
Rationale 
Change 2: Clarified background information 
Section 1 
Brivaracetam is extensively metabolized (>90%), 
primarily by hydrolysis of the amide group to a 
carboxylic acid supported by non-cytochrome P450 
(CYP) dependent amidase, and secondarily through 
CYP2C19-mediated hydroxylation of the side chain. 
Brivaracetam is extensively metabolized (>90%), 
primarily by hydrolysis of the amide group to a 
carboxylic acid supported by non-cytochrome 
P450 (CYP) dependent hydrolysis of the 
amide group to a carboxylic acid via 
amidasenon-cytochrome P450 (CYP) dependent 
amidase, and secondarily through CYP2C19-
mediated hydroxylation of the side chain. 
Clarify 
background 
information 
Change 3: Clarified vital sign measurements 
Section 1 
vital signs (pulse rate, blood pressure) 
vital signs (systolic blood pressure [SBP], 
diastolic blood pressure [DBP], pulse rate, 
respiratory rate, and body temperaturepulse 
rate, blood pressure) 
Clarify vital 
signs 
measurements 
Section 5.1 
vital signs (pulse rate, blood pressure) 
vital signs (SBP, DBP, pulse rate, respiratory 
rate, and body temperaturepulse rate, blood 
pressure) 
Clarify vital 
signs 
measurements 
Table 5-2 
Vital signs (BP, pulse) 
Vital signsb (BP, pulse) 
b Vital sign assessments include SBP, DBP, 
pulse rate, respiratory rate, and body 
temperature. 
Clarify vital 
signs 
measurements 
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Brivaracetam 
EP0101 
 
 
 
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Protocol 
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Key components of revised protocol text 
Rationale 
Table 5-3 
Vital signs (BP, pulse) 
Vital signsb (BP, pulse) 
b Vital sign assessments include SBP, DBP, 
pulse rate, respiratory rate, and body 
temperature. 
Clarify vital 
signs 
measurements 
Section 8.1 
• 
Obtain vital sign measurements (blood pressure 
[BP] and pulse rate) 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureblood pressure [BP] and pulse rate) 
Clarify vital 
signs 
measurements 
Section 8.3 
• 
Obtain vital sign measurements (BP and pulse 
rate) 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureblood pressure [BP] and pulse rate) 
Clarify vital 
signs 
measurements 
Section 8.6 
• 
Obtain vital sign measurements (BP and pulse 
rate) 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureblood pressure [BP] and pulse rate) 
Clarify vital 
signs 
measurements 
Section 8.9 
• 
Obtain vital sign measurements (BP and pulse 
rate) 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureblood pressure [BP] and pulse rate) 
Clarify vital 
signs 
measurements 
Section 8.12 
• 
Obtain vital sign measurements (BP and pulse 
rate) 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureblood pressure [BP] and pulse rate) 
Clarify vital 
signs 
measurements 
Section 8.15 
• 
Obtain vital sign measurements (BP and pulse 
rate) 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureblood pressure [BP] and pulse rate) 
Clarify vital 
signs 
measurements 
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Clinical Study Protocol 
Brivaracetam 
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Protocol 
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Key components of revised protocol text 
Rationale 
Section 10.3.3 
At time points specified in Table 5‒2 and Table 5‒3, 
blood pressure and pulse rate in supine and standing 
positions will be recorded at supine rest (at least 5 
minutes) and 1 minute after standing. 
At time points specified in Table 5‒2 and Table 
5‒3, SBP, DBP, pulse rate, respiratory rate, 
and body temperatureblood pressure and pulse 
rate in supine and standing positions will be 
recorded at supine rest (at least 5 minutes) and 1 
minute after standing. 
Clarify vital 
signs 
measurements 
Change 4: Clarified indication 
Section 2 
A clinical development program for BRV is underway 
in China and will support a market authorization 
application/new drug application for BRV in China 
for the indication of adjunctive treatment in subjects 
16 years and older with refractory partial-onset 
seizures whether or not secondarily generalized. 
A clinical development program for BRV is 
underway in China and will support a market 
authorization application/new drug application 
for BRV in China for the indication of adjunctive 
treatment in subjects 16 years and older with 
refractory partial-onset seizures whether or not 
secondarily generalized. 
Clarify 
indication 
Change 5: Removed genotype variable 
Section 4.3 
4.3 Other variable 
CYP2C19 (*2,*3) alleles (Genotype) will be 
evaluated. 
4.3 Other variable 
CYP2C19 (*2,*3) alleles (Genotype) will be 
evaluated. 
Remove the 
genotype 
sample 
collection and 
analysis 
Table 5-1 
Genotyping 
Genotyping 
Remove the 
genotype 
sample 
collection and 
analysis 
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Protocol 
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Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 8.3 
• 
Obtain blood samples for safety laboratory 
assessments, genotyping, and plasma PK 
• 
Obtain blood samples for safety laboratory 
assessments, genotyping, and plasma PK 
Remove the 
genotype 
sample 
collection and 
analysis 
Change 6: Clarified assessment windows for vital signs and ECGs and for study drug administration 
Section 5.1 
In the Multiple-Dose Period, subjects will receive 
BRV 200mg/day (100mg every 12 hours). 
In the Multiple-Dose Period, subjects will 
receive BRV 200mg/day (100mg every 12h 
±15min). 
Clarify study 
drug 
administration 
window 
Table 5-1 
c Three ECGs to be performed at 15min intervals 
within 24h prior to BRV dosing on Day 1 to provide a 
representative baseline. 
h From Day 5 to Day 9, study drug will be 
administered in the morning and evening with an 
interval of 12h. 
i On Day 10, study drug will be administered only in 
the morning. 
c Three ECGs to be performed at 15min (±5min) 
intervals within 24h prior to BRV dosing on Day 
1 to provide a representative baseline. 
h From Day 5 to Day 9, study drug will be 
administered in the morning and evening with an 
interval of 12h (±15min). 
i On Day 10, study drug will be administered 
only in the morning 12h (±15min) after the last 
dose. 
Clarify 
assessment 
windows for 
vital signs and 
ECGs and for 
study drug 
administration 
Table 5-2 
a Three ECGs to be performed at 15min intervals 
within 24h prior to BRV dosing on Day 1 to provide a 
representative baseline. 
Note: A window of ±15min is allowed for all 
ECG and vital signs assessments postdose. 
a Three ECGs to be performed at 15min (±5min) 
intervals within 24h prior to BRV dosing on Day 
1 to provide a representative baseline. 
Clarify 
assessment 
windows for 
vital signs and 
ECGs 
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Protocol 
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Key components of revised protocol text 
Rationale 
Table 5-3 
None 
Note: A window of ±15min is allowed for all 
ECG and vital signs assessments postdose. 
Clarify 
assessment 
windows for 
vital signs and 
ECGs 
Change 7: Modified the contraceptive inclusion criteria to include male subjects 
Section 6.1 
4. Pregnancy waiver form signed by subject, if female 
of childbearing potential. Beta-human chorionic 
gonadotropin test is documented negative within 48 
hours before Day 1 and a medically accepted method 
of contraception (hormonal contraception, intrauterine 
device (IUD), implant device, diaphragm with 
spermicide, bilateral tubal ligation, monogamous 
relationship with vasectomized [for at least 3 months] 
partner or using condoms with spermicidal gel, 
sexually inactive) is used during the entire duration of 
the study. 
4a.  Pregnancy waiver form signed by subject, if 
female of childbearing potential. Beta-human 
chorionic gonadotropin test is documented 
negative within 48 hours before Day 1 and a 
medically accepted method of contraception 
(hormonal contraception, intrauterine device 
(IUD), implant device, diaphragm with 
spermicide, bilateral tubal ligation, monogamous 
relationship with vasectomized [for at least 3 
months] partner or using condoms with 
spermicidal gel, sexually inactive) is used during 
the entire duration of the study. 
Male participants with a pregnant or 
breastfeeding partner or female partner of 
childbearing potential must agree to remain 
abstinent from penile-vaginal intercourse or 
use a male condom during each episode of 
penile penetration during the study. 
Modify 
contraceptive 
inclusion 
criterion to 
include male 
subjects 
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Protocol 
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Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Change 8: Changed the maximum pulse rate for eligible subjects 
Section 6.1 
7. Subjects with supine blood pressure levels of 
between 90 to 150 and 60 to 90mmHg (inclusive) for 
systolic and diastolic, respectively, with pulse rate of 
50 to 90bpm (supine position, inclusive) at Screening 
Visit. 
7. Subjects with supine blood pressure levels of 
between 90 to 150 and 60 to 90mmHg (inclusive) 
for systolic and diastolic, respectively, with pulse 
rate of 50 to 90100 beats per minute (bpm) 
(supine position, inclusive) at Screening Visit. 
Change the 
maximum 
pulse rate for 
eligible 
subjects 
Change 9: Clarified exclusion criteria for alcohol and drug abuse, medical history, and caffeine intake 
Section 6.2 
3. Subject has a history of chronic alcohol or drug 
abuse within the previous 6 months. Subject consumes 
more than 30g alcohol/day (amount corresponds to 
750mL beer/day or 375mL wine/day or 90mL 
liquor/day) for men and 20g alcohol/day (amount 
corresponds to 500mL beer/day or 250mL wine/day or 
60mL liquor/day) for women. 
3a. Subject has a history of chronic alcohol or 
drug abuse within the previous 6 months. Subject 
consumes on average more than 30g alcohol/day 
(amount corresponds to 750mL beer/day or 
375mL wine/day or 90mL liquor/day) for men 
and 20g alcohol/day (amount corresponds to 
500mL beer/day or 250mL wine/day or 60mL 
liquor/day) for women. 
Clarify 
exclusion 
criterion for 
alcohol and 
drug abuse 
Section 6.2 
7. Subjects with any previous or current 
cardiovascular, respiratory, hepatic, renal, digestive, 
endocrine, or nervous system disorder that may affect 
absorption, secretion, metabolism, or excretion of the 
investigational product. 
7a. Subjects with any previous or current 
cardiovascular, respiratory, hepatic, renal, 
digestive, endocrine, or nervous system disorder 
that may affect absorption, secretion, 
metabolism, or excretion of the investigational 
product per Investigator judgment. 
Clarify 
exclusion 
criterion for 
medical history 
Section 6.2 
13. Subject has a consumption of more than 600mg of 
caffeine/day (1 cup of coffee contains approximately 
100mg of caffeine, 1 cup of tea approximately 30mg, 
and 1 glass of cola approximately 20mg). 
13a. Subject has a consumption of more than 
600mg of caffeine/day on average (1 cup of 
coffee contains approximately 100mg of 
Clarify 
exclusion 
criterion for 
caffeine intake 
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caffeine, 1 cup of tea approximately 30mg, and 1 
glass of cola approximately 20mg). 
Change 10: Clarified retesting for liver function tests 
Section 6.2 
18. Subject has > upper limit of normal (ULN) of any 
of the following: alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), or total bilirubin (≥1.5xULN total 
bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and 
<1.5xULN, fractionate bilirubin to identify possible 
undiagnosed Gilbert’s syndrome (ie, direct bilirubin 
<35%). 
For subjects with a baseline result >ULN for ALT, 
AST, ALP, or total bilirubin, a baseline diagnosis 
and/or the cause of any clinically meaningful 
elevation must be understood and recorded in the 
electronic Case Report form (eCRF). 
If subject has >ULN ALT, AST, or ALP that does not 
meet the exclusion limit at screening, repeat the tests, 
if possible, prior to dosing to ensure there is no further 
ongoing clinically relevant increase. In case of a 
clinically relevant increase, inclusion of the subject 
must be discussed with the Medical Monitor. 
18a. 
Subject has > upper limit of normal 
(ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase 
(ALP), or total bilirubin (≥1.5xULN total 
bilirubin if known Gilbert’s syndrome). If subject 
has elevations only in total bilirubin that are 
>ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s 
syndrome (ie, direct bilirubin <35%). 
For subjects with a baseline result >ULN for 
ALT, AST, ALP, or total bilirubin, a baseline 
diagnosis and/or the cause of any clinically 
meaningful elevation must be understood and 
recorded in the electronic Case Report form 
(eCRF). 
If subject has >ULN ALT, AST, or ALP that 
does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to 
ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant 
increase, inclusion of the subject must be 
discussed with the Medical Monitor.  
Clarify 
retesting for 
liver function 
tests 
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Protocol 
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Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Current or chronic history of liver disease or 
known hepatic or biliary abnormalities (with 
the exception of Gilbert's syndrome or 
asymptomatic gallstones). 
For subjects with a screening result >ULN for 
total bilirubin, a baseline diagnosis and/or the 
cause of any clinically meaningful elevation 
must be understood and recorded in the 
electronic Case Report form (eCRF). 
Tests that result in ALT, AST, or ALP up to 
25% above the exclusion limit may be 
repeated once for confirmation. If the repeat 
values are below ULN the subject will be 
considered to not meet the exclusion criteria.  
Change 11: Clarified fasting conditions for study drug administration 
Section 6.4 
None 
6.4 Other study restrictions 
All BRV treatments will be administered 
under fasting conditions. For Day 1 and Day 
10, subjects will be required to fast for ≥10h 
prior to dosing and until 3h after IMP 
administration. For Day 5 to Day 9, 2h fasting 
before and after dosing for morning and night 
dose is required. During fasting, no fluids are 
allowed except water; however, water is not 
allowed from 2h predose until 1h after the 
Clarify fasting 
conditions for 
study drug 
administration 
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Key components of revised protocol text 
Rationale 
start of treatment (apart from the water taken 
with the oral dosing). 
Subjects must refrain from smoking and 
consuming alcohol and caffeine-containing 
products (chocolate, cola, coffee, or tea) from 
48h before treatment until Final Discharge 
from the study. 
Subjects must refrain from consuming 
grapefruit, grapefruit juice, and grapefruit-
containing products from 7 days before first 
drug administration through the end of the 
study. 
Change 12: Clarified assessment windows for vital signs and ECGs and for study drug administration during study visits  
Section 8.2 
• 
Perform 12-lead ECG (3 ECGs will be performed 
at 15min intervals within 24h before dosing of 
BRV on Day 1) 
Perform 12-lead ECG (3 ECGs will be 
performed at 15min [±5min] intervals within 24h 
before dosing of BRV on Day 1) 
Clarify 
assessment 
window for 
ECGs 
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Protocol 
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impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 8.3 
The following procedures will be performed predose: 
• 
Perform 12-lead ECG (if not performed on Day -
1, 3 ECGs will be performed at 15min intervals within 
24h before dosing of BRV on Day 1) 
The following procedures will be performed postdose: 
• 
Obtain vital sign measurements (BP and pulse 
rate) at 1, 2, and 4h postdose 
• 
Perform 12-lead ECG at 1, 2, and 4h postdose 
The following procedures will be performed 
predose: 
• 
Perform 12-lead ECG (if not performed on 
Day -1, 3 ECGs will be performed at 15min 
[±5min] intervals within 24h before dosing of 
BRV on Day 1) 
The following procedures will be performed 
postdose: 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureBP and pulse rate) at 1, 2, and 4h 
postdose. A window of ±15min is allowed. 
• 
Perform 12-lead ECG at 1, 2, and 4h 
postdose. A window of ±15min is allowed. 
Clarify 
assessment 
windows for 
vital signs and 
ECGs 
Section 8.6 
• 
Obtain vital sign measurements (BP and pulse 
rate) at 72h postdose 
• 
Perform 12-lead ECG at 72h postdose 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureBP and pulse rate) at 72h (±15min) 
postdose 
• 
Perform 12-lead ECG at 72h (±15min) 
postdose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs 
Section 8.7 
The following procedures will be performed postdose: 
• 
Study drug administration 12h after the morning 
dose 
The following procedures will be performed 
postdose: 
• 
Study drug administration 12h (±15min) 
after the morning dose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs 
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Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 8.8 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 
The following procedures will be performed postdose: 
• 
Study drug administration 12h after the morning 
dose 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 12h 
(±15min) after the last dose 
The following procedures will be performed 
postdose: 
• 
Study drug administration 12h (±15min) 
after the morning dose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs and for 
study drug 
administration 
Section 8.9 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 
The following procedures will be performed postdose: 
• 
Study drug administration 12h after the morning 
dose 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 12h 
(±15min) after the last dose  
The following procedures will be performed 
postdose: 
• 
Study drug administration 12h (±15min) 
after the morning dose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs and for 
study drug 
administration 
Section 8.10 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 
The following procedures will be performed postdose: 
• 
Study drug administration 12h after the morning 
dose 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 12h 
(±15min) after the last dose 
The following procedures will be performed 
postdose: 
• 
Study drug administration 12h (±15min) 
after the morning dose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs and for 
study drug 
administration 
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Clinical Study Protocol 
Brivaracetam 
EP0101 
 
 
 
Confidential 
Page 73 of 78 
Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Section 8.11 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 
The following procedures will be performed postdose: 
• 
Study drug administration 12h after the morning 
dose 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 12h 
(±15min) after the last dose 
The following procedures will be performed 
postdose: 
• 
Study drug administration 12h (±15min) 
after the morning dose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs and for 
study drug 
administration 
Section 8.12 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 
The following procedures will be performed postdose: 
• 
Obtain vital sign measurements (BP and pulse 
rate) at 1, 2, and 4h postdose 
• 
Perform 12-lead ECGs at 1, 2, and 4h postdose 
• 
Study drug administration (after all predose 
assessments are completed) in the morning 12h 
(±15min) after the last dose 
The following procedures will be performed 
postdose: 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureBP and pulse rate) at 1, 2, and 4h 
postdose. A window of ±15min is allowed. 
• 
Perform 12-lead ECGs at 1, 2, and 4h 
postdose. A window of ±15min is allowed. 
Clarify 
assessment 
windows for 
vital signs and 
ECGs and for 
study drug 
administration 
Section 8.15 
• 
Obtain vital sign measurements (BP and pulse 
rate) at 72h postdose 
• 
Perform 12-lead ECG at 72h postdose 
• 
Obtain vital sign measurements (SBP, DBP, 
pulse rate, respiratory rate, and body 
temperatureBP and pulse rate) at 72h (±15min) 
postdose 
• 
Perform 12-lead ECG at 72h (±15min) 
postdose 
Clarify 
assessment 
windows for 
vital signs and 
ECGs 
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Clinical Study Protocol 
Brivaracetam 
EP0101 
 
 
 
Confidential 
Page 74 of 78 
Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Change 13: Removed genotype analysis 
Section 9.2 
9.2 Genotype analysis 
For the genotype analysis, 2.0mL of whole blood will 
be collected in a test tube containing ethylene diamine 
tetraacetic acid disodium salt (EDTA2Na). The 
sample will be sent to a genetic testing facility in a 
condition where individual identification is not 
impossible. 
9.2 Genotype analysis 
For the genotype analysis, 2.0mL of whole blood 
will be collected in a test tube containing 
ethylene diamine tetraacetic acid disodium salt 
(EDTA2Na). The sample will be sent to a genetic 
testing facility in a condition where individual 
identification is not impossible. 
Remove the 
genotype 
sample 
collection and 
analysis 
Change 14: Removed the optional hepatic investigation sample collection 
Section 10.2.1.5 
10.2.1.5 Optional hepatic investigation sample 
collection 
If a subject is undergoing further investigation for 
PDILI and has consented to retrospective genetic 
analysis per local regulations, the subject’s blood 
sample will be shipped to a secure storage facility. 
The blood sample will be retained in the UCB Hepatic 
Investigation Biobank to solely support retrospective 
genetic analyses associated with an adverse 
therapeutic response to BRV. 
Genetic analyses of deoxyribonucleic acid isolated 
from the blood will be contracted by UCB to 
specialized third-party laboratories and analysis will 
be limited to: 
10.2.1.5 Optional hepatic investigation sample 
collection 
If a subject is undergoing further investigation 
for PDILI and has consented to retrospective 
genetic analysis per local regulations, the 
subject’s blood sample will be shipped to a 
secure storage facility. The blood sample will be 
retained in the UCB Hepatic Investigation 
Biobank to solely support retrospective genetic 
analyses associated with an adverse therapeutic 
response to BRV. 
Genetic analyses of deoxyribonucleic acid 
isolated from the blood will be contracted by 
UCB to specialized third-party laboratories and 
analysis will be limited to: 
• 
Uridine 5′-diphospho-
glucuronosyltransferase loci − the loci 
Remove the 
optional 
hepatic 
investigation 
sample 
collection 
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Clinical Study Protocol 
Brivaracetam 
EP0101 
 
 
 
Confidential 
Page 75 of 78 
Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
• 
Uridine 5′-diphospho-glucuronosyltransferase loci 
− the loci responsible for Gilbert’s syndrome 
(hyperbilirubinemia) 
• 
Human leukocyte antigen (HLA) loci − for 
example, HLA-B5701 that has been associated with 
abacavir- and flucloxacillin-induced liver injury 
• 
Absorption, distribution, metabolism, and 
excretion gene loci associated with abnormal 
pharmacokinetics 
Genetic analysis of samples may be performed 
immediately, on a per-study basis, or as part of 
combined analyses across multiple studies belonging 
to the same clinical development program. As a result, 
samples will be retained for 15 years unless clinical 
development of the IMP is terminated, at which point 
all samples will be destroyed. The results determined 
using clinically approved diagnostic tests will be made 
available to the Investigator upon request. 
Subjects may request at any time that their sample be 
removed from the UCB Hepatic Investigation 
Biobank and destroyed, though data from analyses 
already performed will remain on file. All samples, 
associated materials, and data will be kept securely by 
UCB and its agents. A sample destruction request 
should be made in writing to the Investigator who will 
notify the UCB Biorepository Manager (Global 
Exploratory Development, UCB, Slough, SL1 3WE, 
United Kingdom). 
responsible for Gilbert’s syndrome 
(hyperbilirubinemia) 
• 
Human leukocyte antigen (HLA) loci − for 
example, HLA-B5701 that has been associated 
with abacavir- and flucloxacillin-induced liver 
injury 
• 
Absorption, distribution, metabolism, and 
excretion gene loci associated with abnormal 
pharmacokinetics 
Genetic analysis of samples may be performed 
immediately, on a per-study basis, or as part of 
combined analyses across multiple studies 
belonging to the same clinical development 
program. As a result, samples will be retained for 
15 years unless clinical development of the IMP 
is terminated, at which point all samples will be 
destroyed. The results determined using 
clinically approved diagnostic tests will be made 
available to the Investigator upon request. 
Subjects may request at any time that their 
sample be removed from the UCB Hepatic 
Investigation Biobank and destroyed, though data 
from analyses already performed will remain on 
file. All samples, associated materials, and data 
will be kept securely by UCB and its agents. A 
sample destruction request should be made in 
writing to the Investigator who will notify the 
UCB Biorepository Manager (Global 
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Clinical Study Protocol 
Brivaracetam 
EP0101 
 
 
 
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Page 76 of 78 
Protocol 
section(s) 
impacted 
Key components of previous protocol text 
Key components of revised protocol text 
Rationale 
Exploratory Development, UCB, Slough, SL1 
3WE, United Kingdom). 
Change 15: Removed genotype analysis 
Section 12.3.1 
If CYP2C19 poor metabolizers are identified in the 
study, data may also be summarized by CYP2C19 
poor or extensive metabolizer status. 
If CYP2C19 poor metabolizers are identified in 
the study, data may also be summarized by 
CYP2C19 poor or extensive metabolizer status. 
Remove the 
genotype 
sample 
collection and 
analysis 
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Brivaracetam 
EP0101 
 
 
 
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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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Brivaracetam 
EP0101 
 
 
 
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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:
ep0101-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000166592
Title:
EP0101 Protocol Amendment 2
Approved Date:
10 Jan 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 08-Jan-2021 18:46:49 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 09-Jan-2021 00:40:08 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 10-Jan-2021 08:36:35 GMT+0000
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SAP_001.pdf: 
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27 Aug 2021 
Statistical Analysis Plan 
Brivaracetam 
EP0101 
 
 
 
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Page 1 of 26 
 
STATISTICAL ANALYSIS PLAN 
AMENDMENT 1 
Study: EP0101 
Product: Brivaracetam 
AN OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE THE 
PHARMACOKINETICS AND SAFETY OF A SINGLE AND 
MULTIPLE ORAL DOSES OF BRIVARACETAM IN HEALTHY 
ADULT CHINESE SUBJECTS 
PHASE 1 
Sponsor Name: UCB Biopharma SRL 
Legal Registered Address: Allée de la Recherche 60, 1070 Brussels, BELGIUM 
Regulatory Agency Identifier Number(s): CTR20210556 
Registry 
ID 
 ClinicalTrials.gov 
 NCT04882540 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Statistical Analysis Plan 
Brivaracetam 
EP0101 
 
 
 
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TABLE OF CONTENTS 
VERSION HISTORY ................................................................................................................ 4 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1 
INTRODUCTION ............................................................................................................. 6 
1.1 
Objectives and Endpoints .............................................................................................. 6 
1.2 
Study design ................................................................................................................... 7 
2 
STATISTICAL HYPOTHESES ........................................................................................ 8 
3 
SAMPLE SIZE DETERMINATION ................................................................................ 9 
4 
POPULATIONS FOR ANALYSIS ................................................................................... 9 
4.1 
Enrolled Set .................................................................................................................... 9 
4.2 
Safety Set ....................................................................................................................... 9 
4.3 
Pharmacokinetic Per-Protocol Set ................................................................................. 9 
5 
STATISTICAL ANALYSES ............................................................................................ 9 
5.1 
General Considerations .................................................................................................. 9 
5.1.1 
General study level definitions ............................................................................ 10 
5.1.1.1 
Analysis Time Points ................................................................................. 10 
5.1.1.2 
Protocol Deviations ................................................................................... 11 
5.1.1.3 
Treatment assignment and treatment groups ............................................. 12 
5.1.1.4 
Center pooling strategy ............................................................................. 12 
5.1.1.5 
Coding dictionaries .................................................................................... 12 
5.2 
Participant Dispositions ............................................................................................... 12 
5.3 
Primary Endpoint(s) Analysis ...................................................................................... 13 
5.4 
Secondary Endpoint(s) Analysis .................................................................................. 13 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis.................................................................. 13 
5.6 
Safety Analyses ............................................................................................................ 13 
5.6.1 
Extent of Exposure .............................................................................................. 13 
5.6.2 
Adverse Events .................................................................................................... 13 
5.6.3 
Additional Safety Assessments ............................................................................ 14 
5.6.3.1 
Clinical laboratory evaluations .................................................................. 15 
5.6.3.2 
Vital Signs ................................................................................................. 16 
5.6.3.3 
Electrocardiograms .................................................................................... 16 
5.6.3.4 
Other safety endpoint(s) ............................................................................ 17 
5.7 
Other Analyses ............................................................................................................. 17 
5.7.1 
Other endpoints and/or parameters ...................................................................... 17 
5.7.1.1 
Pharmacokinetics ....................................................................................... 17 
5.7.1.2 
Pharmacodynamics .................................................................................... 21 
5.7.1.3 
Genomics ................................................................................................... 21 
5.8 
Subgroup analyses ....................................................................................................... 21 
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EP0101 
 
 
 
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5.9 
Interim Analyses .......................................................................................................... 21 
5.10 
Data Monitoring Committee (DMC) or Other Review Board ..................................... 22 
6 
SUPPORTING DOCUMENTATION ............................................................................. 22 
6.1 
Appendix 1 Non-key analysis specifications ............................................................... 22 
6.1.1 
Baseline characteristics and demographics ......................................................... 22 
6.1.2 
Protocol deviations .............................................................................................. 22 
6.1.3 
Medical history .................................................................................................... 23 
6.1.4 
Prior/concomitant/follow-up medications ........................................................... 23 
6.1.5 
Data derivation rules ............................................................................................ 24 
6.1.5.1 
Handling of dropouts or missing data ....................................................... 24 
6.1.6 
AEs of Special Interest ........................................................................................ 25 
6.1.7 
Compliance .......................................................................................................... 26 
6.2 
Appendix 3: Changes to Protocol-Planned Analyses .................................................. 26 
7 
REFERENCES ................................................................................................................ 26 
 
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Statistical Analysis Plan 
Brivaracetam 
EP0101 
 
 
 
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VERSION HISTORY 
SAP Version 
Approval Date 
Change 
Rationale 
1.0 
<24 May 2021> 
Not Applicable 
Original version 
Amendment 1 
<27 Aug 2021> 
1. Definition of ECG 
baseline (Section 
5.6.3.3) 
2. Summary tables of 
Urinalysis (Section 
5.6.3.1.2) 
3. Handling of BLQ 
values in individual 
concentration 
figures (Section 
5.7.1.1) 
 
1. To be consistent 
with the study 
protocol 
2. To clarify the 
different summary 
tables for different 
data type of 
urinalysis and 
urine sediment 
forms 
3. To comply with 
the UCB NCA 
data handling 
rules 
 
LIST OF ABBREVIATIONS 
Ae 
amount of drug excreted in the urine 
AE 
adverse event 
AUC 
area under the curve from 0 to infinite time 
AUC(0-12),ss 
area under the curve from 0 to 12 hours at steady state 
AUC(0-t) 
area under the plasma concentration-time curve from zero to the time of the last 
measured concentration above the limit of quantification 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
BRV 
brivaracetam 
Cav,ss 
average plasma concentration at steady state 
CI 
confidence interval 
CL/F 
apparent total body clearance 
CLR 
renal clearance 
CLss/F 
apparent total body clearance at steady state 
Cmax 
maximum plasma concentration 
Cmax,ss 
maximum plasma concentration at steady state 
Cmin,ss 
minimum plasma concentration at steady state 
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Statistical Analysis Plan 
Brivaracetam 
EP0101 
 
 
 
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CSR 
clinical study report 
CV 
coefficient of variation 
DEM 
Data Evaluation Meeting 
ECG 
electrocardiogram 
ES 
Enrolled Set 
fe 
fraction of the dose excreted in the urine 
IPD 
Important protocol deviation 
λz 
rate constant of elimination 
LLOQ 
lower limit of quantification 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
PCST 
possibly clinically significant treatment-emergent 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PTF 
peak trough fluctuation 
RAUC 
accumulation ratio calculated from AUC at steady state and AUC after single dose 
Rmax 
accumulation ratio calculated from Cmax at steady state and Cmax after single dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SFU 
safety follow-up 
SPD 
Specification of Protocol Deviations 
SS 
Safety Set 
t½ 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach maximum plasma concentration 
Vz/F 
apparent volume of distribution 
WHO-DRL 
World Health Organization Drug Reference List 
 
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Statistical Analysis Plan 
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EP0101 
 
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report (CSR) for study EP0101. The SAP is based on the following study 
document: Protocol Amendment 2, 08 Jan 2021. 
 
1.1 
Objectives and Endpoints 
Table 1‒1: 
Objectives and Endpoints 
Objectives 
Endpoints 
To assess the pharmacokinetics (PK), 
safety, and tolerability of BRV after a 
single dose and multiple doses of 
100mg for 6 days in healthy adult 
Chinese participants (male and female). 
Primary PK Endpoints: 
• Concentrations of BRV and 3 metabolites 
(ucb-42145, ucb-100406-1, and ucb107092-
1) in plasma   
• For the single dose: 
o AUC(0-t) of BRV 
o Cmax of BRV 
• For the multiple dose: 
o AUC(0-12),ss of BRV 
o Cmax,ss of BRV 
Secondary PK Endpoints: 
• For the single dose: 
o tmax, t1/2, λz, MRT, AUC, CL/F, and 
Vz/F of BRV in plasma 
o Cmax, tmax, t½, λz, AUC(0-t), and AUC of 
metabolites in plasma 
• For the multiple dose: 
o tmax, t½, λz, Cmin,ss, Cav,ss, CLss/F, and 
Vz/F of BRV in plasma 
o tmax, t½, λz, Cmax,ss, and AUC(0-12),ss of 
metabolites in plasma 
o PTF of BRV in steady-state 
o RAUC and Rmax of BRV 
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Statistical Analysis Plan 
Brivaracetam 
EP0101 
 
 
 
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Table 1‒1: 
Objectives and Endpoints 
Objectives 
Endpoints 
 
Primary Safety Endpoints: 
• Incidence of treatment-emergent AEs 
(TEAEs) 
Other Safety Endpoints: 
• Changes in vital signs (SBP, DBP, pulse rate, 
respiratory rate, and body temperature) 
• Standard 12-lead ECGs parameters and 
findings 
• Changes in clinical laboratory test parameters 
(hematology, blood chemistry, and urinalysis) 
 
1.2 
Study design 
This is a Phase 1, single site, open-label, single and multiple dose PK study of BRV tablets in 
healthy male and female Chinese participants. Participants are confined to the clinical trial unit 
from Day -1 (the day prior to first administration of BRV) until Day 13. 
A total of 12 participants (6 males and 6 females) who have signed the informed consent form 
and fulfilled all inclusion and none of the exclusion criteria are planned to be enrolled and will 
start the Single-Dose Period. In the Single-Dose Period, each subject receives a single dose of 
BRV 100mg. In the Multiple-Dose Period, the multiple-dose PK and safety of BRV 200mg/day 
(100 mg every 12h ± 15 min) are evaluated in the same participants as in the Single-Dose Period. 
In the Single-Dose Period, participants will receive a single dose of BRV under fasting 
conditions with 200mL water. Blood samples will be taken for the determination of the PK 
profile of BRV and its metabolites (ucb-42145, ucb-100406-1, and ucb107092-1) at predose, and 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, and 72h after investigational medicinal product 
(IMP) administration (Table 1‒2). 
 
Table 1‒2: 
Single-Dose Period: schedule for ECGs, vital signs, and PK sampling  
 
Time relative to BRV administration 
 
 
Postdose (h) 
Day 1 
Day 2 
Day 3 
Day 4 
 
Assessment 
Predose 
0.25 
0.5 
1 
1.5 
2 
3 
4 
6 
9 
12 
16 
24 
36 
48 
72 
12-lead ECG 
Xa 
-- 
-- 
X 
-- 
X 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signs b 
X 
-- 
-- 
X 
-- 
X 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Blood samples for PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Statistical Analysis Plan 
Brivaracetam 
EP0101 
 
 
 
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Page 8 of 26 
BRV=brivaracetam; DBP=diastolic blood pressure; ECG=electrocardiogram; PK=pharmacokinetics; SBP=systolic blood pressure 
a. Three ECGs to be performed at 15min (±5min) intervals within 24h prior to BRV dosing on Day 1 to provide a representative baseline 
b. Vital sign assessments include SBP, DBP, pulse rate, respiratory rate, and body temperature. 
 
In the Multiple-Dose Period, participants will receive BRV 200mg/day (100mg every 12h 
±15min). Participants will receive BRV under fasting conditions with 200mL water. Blood 
samples will be taken for the determination of the PK profile of BRV and its metabolites (ucb-
42145, ucb-100406-1, and ucb107092-1) predose prior to the morning dose administration on 
Day 5 to Day 9, and at predosing and at the following time points after the last administration of 
the IMP on Day 10: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, and 72h (Table 1‒3). 
Table 1‒3:  Multiple-Dose Period: schedule for ECGs, vital signs, and PK 
sampling  
 
Assessment 
Day 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Pre 
Pre 
Pre 
Pre 
Pre 
Pr
e 
Postdose (h) 
 
0.25 
0.5 
1 
1.5 
2 
3 
4 
6 
9 
12 
16 
24 
36 
48 
72 
12-lead ECG 
-- 
-- 
Xa 
-- 
-- 
X 
-- 
-- 
X 
-- 
X 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Vital signsb 
-- 
-- 
XX
a 
-- 
-- 
X 
-- 
-- 
X 
-- 
X 
-- 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Blood samples 
for PK  
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DBP=diastolic blood pressure; ECG=electrocardiogram; Pre=predose; SBP=systolic blood pressure 
a To be performed predose on the morning of Day 7. 
b Vital sign assessments include SBP, DBP, pulse rate, respiratory rate, and body temperature 
c To be collected predose in the morning. 
 
Participants will be discharged from confinement in the morning of Day 13, approximately 72h 
after the final administration of IMP, provided there are no medical objections. 
Safety and tolerability of BRV will be assessed throughout the study by monitoring of AEs, 
collecting blood and urine samples for the evaluation of safety laboratory parameters, measuring 
vital signs (SBP, DBP, pulse rate, respiratory rate, and body temperature), and ECG. 
A Safety Follow-up (SFU) Visit will be performed after the final administration of the IMP. The 
assessments performed for the SFU will also be performed for early withdrawals. 
The anticipated maximum study duration per participant is 43 days (approximately 6 weeks), 
including the Screening Period (up to 28 days), confinement during the Single-Dose and 
Multiple-Dose Periods (13 days), and follow-up examination (2 days after clinic discharge). 
The end of the study is defined as the date of the final visit of the final participant in the study. 
 
2 
STATISTICAL HYPOTHESES 
No statistical comparisons with hypothetical inference are planned for the primary analysis of the 
pharmacokinetic variables. 
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EP0101 
 
 
 
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3 
SAMPLE SIZE DETERMINATION 
A total of 12 healthy (6 male and 6 female) participants is planned to be enrolled at one site in 
China and allocated to the treatment. 
Due to the primary objective of the study being related to PK and safety, no power calculation of 
the study sample size is performed.  
 
4 
POPULATIONS FOR ANALYSIS 
PK variables are summarized using the Pharmacokinetic Per-Protocol Set (PK-PPS), and safety 
variables are summarized using the Safety Set (SS). 
Subject data listings are prepared for participants with available data (Enrolled Set [ES], SS, or 
PK-PPS), depending on the domain. 
The reasons for exclusion of participants from either of the analysis sets will be listed. 
 
4.1 
Enrolled Set 
The ES consists of all participants who gave informed consent including screen failures. This 
analysis set is also referred to as “All Participants Screened.” 
 
4.2 
Safety Set 
The SS consists of all participants who received at least 1 dose of IMP. 
 
4.3 
Pharmacokinetic Per-Protocol Set 
The PK-PPS consists of all participants who are included in the SS and also have a sufficient 
number of bioanalytical assessments to calculate reliable estimates for the primary PK 
parameters. 
 
5 
STATISTICAL ANALYSES 
 
5.1 
General Considerations 
Statistical analysis and generation of tables, figures, subject data listings, and statistical outputs 
are performed using SAS version 9.3 or higher. Calculations of PK parameters are made with 
Phoenix® WinNonlin® version 8.2 or higher. All tables and listings use Courier New font size 9. 
Descriptive statistics are displayed to provide an overview of the study results. For categorical 
parameters, the number and percentage of participants in each category are presented. The 
denominator for percentages is based on the number of participants appropriate for the purpose 
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of analysis. Unless otherwise noted, all percentages are displayed to 1 decimal place. No 
percentage is displayed for zero counts, and no decimals are presented when the percentage is 
100%. For continuous parameters, descriptive statistics include number of 
participants/observations with available measurements (n), mean, standard deviation (SD), 
median, minimum, and maximum unless otherwise specified. 
For decimal places for descriptive statistics, the following rules are applied unless otherwise 
stated: 
• “n” is an integer. 
• (Arithmetic or geometric) mean, SD, and median use 1 additional decimal place 
compared to the original data. 
• Minimum and maximum have the same number of decimal places as the original value. 
• Coefficient of variance (CV) [%] is presented with 1 decimal place. 
• Confidence interval (CI) has the same number of decimal place as the corresponding 
point estimate. 
A set of data listings containing all documented data and all calculated data (eg, change from 
Baseline) is to be provided.  
 
5.1.1 
General study level definitions 
5.1.1.1 
Analysis Time Points 
5.1.1.1.1 
Relative day 
Relative day is calculated as the current date minus the date of first dose of IMP for days prior to 
the first dose of IMP, and the current date minus the date of first dose of IMP plus 1 for days on 
or after the first dose of IMP (eg, the day of first dose is Day 1 and the day prior to first dose is 
Day -1). Day 1 is composed of predose and postdose portions. Relative day is not calculated for 
partial dates, which will be presented as ‘--’ in the relevant participants data listing. 
 
5.1.1.1.2 
End date of the Treatment Period 
The end date of the Treatment Period (ie, Single-Dose Period + Multi-Dose Period) is either the 
date of Day 13 for participants completing the Treatment Period, or the date of the withdrawal 
for participants who discontinue during the Treatment Period. 
 
5.1.1.1.3 
Study periods and visits  
The following study periods/visits are defined for the classification by study period/visits: 
• Screening Visit: Day -28 to Day -2 
• Treatment Period: Day -1 to Day 13 (14 in-house days) 
• Single-Dose Period: Day -1 to Day 4 
• Multiple-Dose Period: Day 5 to Day 13 
• SFU Visit: Day 15 (2 days after discharge) 
 
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5.1.1.1.4 
Definition of Baseline values 
Baseline for safety outcomes (ie, laboratory variables [blood chemistry, hematology, urinalysis], 
vital signs, and body weight) is defined as the last non-missing value prior to the first dose of 
IMP.  
Baseline should be determined separately for each individual laboratory variable and each 
individual vital sign variable. An exception is blood pressure, where a complete set of both 
systolic and diastolic blood pressure should be selected from the same assessment for Baseline. 
 
5.1.1.2 
Protocol Deviations 
Important protocol deviations (IPDs) are deviations from the protocol which potentially could 
have a meaningful impact on the key safety or PK outcomes or on study conduct for an 
individual subject.  
The criteria for identifying important protocol deviations and the classification of important 
protocol deviations are defined within the protocol-specific document, Specification of Protocol 
Deviations (SPD). To the extent feasible, rules for identifying protocol deviations are defined 
without review of the data and without consideration of the frequency of occurrence of such 
deviations. They are identified from various sources such as programmed edit checks, 
programmed listings, and monitoring reports, and finalized in the SPD during the Data 
Evaluation Meeting (DEM) prior to database lock.  
Any samples that are obtained outside the tolerance window permitted at the specified timepoint 
will be discussed at the DEM and any possible exclusion from analysis will be documented 
accordingly. 
The categories (eg, inclusion/exclusion criteria, withdrawal criteria, Prohibited concomitant 
medication use, treatment/procedure non compliance, and incorrect treatment or dose) are not 
fixed and can be adapted, extended, or reduced according to the needs of the study.  
 
Time deviation of blood sampling for determination of PK parameters 
Unless otherwise indicated, any sample taken earlier or later than scheduled is considered a time 
deviation even if the deviation is pharmacokinetically irrelevant. 
The maximum deviations from scheduled sampling times for PK are defined as follows: 
• 0h (predose): within 30min before dosing 
• 0.25h: ±1min 
• 0.5h: ±2min 
• 1 to 4h: ±3min 
• 6 to 9h: ±6min 
• 12 to 16h: ±12min 
• ≥24h: ±20min 
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5.1.1.3 
Treatment assignment and treatment groups 
As this is a single-arm study, data are summarized only as a whole. 
 
5.1.1.4 
Center pooling strategy 
As this is a single-center study, pooling of centers is not applicable. 
 
5.1.1.5 
Coding dictionaries 
Medical history and AEs are coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 18.1. Medications are be coded using the World Health Organization Drug 
Reference List (WHO-DRL) 201709(B3 format).  Medical procedures are not coded. 
 
5.2 
Participant Dispositions 
A study participant is considered to have completed the study if all periods of the study have 
been completed, including the last scheduled procedure shown in the Schedule of activities in the 
protocol. 
The number of participants screened and screen failures and the primary reason for screen failure 
are summarized for all participants screened (ES). 
The number and percentage of participants who started study (will be defined as participants 
with dose), participants who completed or prematurely discontinued the study, as well as the 
reason for discontinuation will be summarized based on the SS.  
The number and percentage of participants who discontinued due to AEs will be separately 
summarized based on the SS. 
The following listings will be presented: 
- Participants who did not meet study eligibility criteria (ES) 
- Participants disposition (ES) 
- Study discontinuation (SS) 
- Visit dates (SS) 
- Participants analysis sets (ES) 
The listing of participant disposition will include the date of informed consent, date and time of 
first and last dose of IMP, date of premature termination and primary reason (if applicable), and 
date of final contact.  
The listing of study discontinuation will include the reason for discontinuation and the number of 
days on IMP. 
The number of days on IMP will be calculated as the actual days that the participant received at 
least one dose of IMP. 
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5.3 
Primary Endpoint(s) Analysis 
The primary analysis for this study is the PK analysis, outlined in Section 5.7.1.1. 
 
5.4 
Secondary Endpoint(s) Analysis 
The secondary analysis for this study is the safety analysis, outlined in Section 5.6. 
 
5.5 
Tertiary/Exploratory Endpoint(s) Analysis 
Not applicable. 
 
5.6 
Safety Analyses 
All safety analyses are conducted for the SS. Safety measurements are summarized at each 
scheduled time point. 
 
5.6.1 
Extent of Exposure 
All IMP administration details including actual date-time at dosing and dose will be listed by 
dose period and participant.  
 
5.6.2 
Adverse Events 
Adverse events are coded using the MedDRA and are classified as either pre-treatment or 
treatment- emergent. Pre-treatment AEs are defined as AEs which have onset prior to the first 
dose of IMP. Treatment-emergent adverse events (TEAEs) are defined as AEs which have onset 
or worsening severity (relative to pre-treatment) after the first dose of IMP.  
Summaries of TEAEs will include the following: 
• Incidence of TEAEs - overview (including number and percentage of participants with 
any TEAEs, serious TEAEs, discontinuations due to TEAEs, drug-related TEAEs, severe 
TEAEs, TEAEs leading to death, TEAE of special interest, and TEAE related to COVID-
19 vaccination; event counts will also be included) 
• Incidence of TEAEs 
• Incidence of serious TEAEs 
• Incidence of TEAEs of special interest 
• Incidence of TEAEs by maximum relationship 
• Incidence of TEAEs by maximum intensity 
• Incidence of TEAEs leading to discontinuation by relationship 
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• Incidence of fatal TEAEs by relationship 
• Incidence of serious TEAEs by relationship 
• Incidence of non-serious TEAEs above reporting threshold of 5% of participants 
• Incidence of TEAEs related to COVID-19 vaccination 
 
For overview of TEAE and incidence of TEAE tables, AEs will be attributed to the dose period 
in which they start. Thus, all AEs starting after the first intake of BRV and before the intake of 
Day 5 will be attributed to Single-Dose Period; all AEs starting after BRV intake on Day 5 and 
on or before Day 13 will be attributed to the Multiple-Dose Period and AEs starting on or after 
Day 14 will be attributed to the SFU period. 
The number and percentage of participants who experience TEAEs will be summarized by 
MedDRA SOC and PT. Only overview of TEAE and incidence of TEAE tables will be presented 
by dose period (Single-Dose, Multiple-Dose, and SFU period) and overall. Other TEAE tables 
will only be presented overall results.  
Summary tables will contain counts of study participants, percentages of study participants in 
parentheses and the number of events where applicable. A participant who has multiple events in 
the same SOC or PT will be counted only once in the participant counts but all events will be 
included. 
In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Participants who experience the same event multiple times will be included in 
the most related category for tabulations by maximum relationship. Events with missing 
relationship will be considered as ‘Related’ for summary purpose but recorded as missing in the 
listings.  
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in 
the listings. 
Adverse event summaries will be ordered alphabetically by SOC and decreasing frequency of PT 
within SOC. 
A listing for all AEs will be presented by participant and will include the onset date/time and 
outcome date/time of the event (including relative days), the AE duration (derived),  pattern of 
event, intensity, relationship, action taken and outcome. 
 
5.6.3 
Additional Safety Assessments 
 
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5.6.3.1 
Clinical laboratory evaluations 
Values outside the reference range will be flagged in the listings. Measurements of laboratory 
data that are below the limit of quantification (BLQ) will be imputed with half of the lower limit 
of quantification (LLOQ) in the summary tables and will be reported as BLQ in the listings. 
Clinical laboratory (hematology, coagulation, blood chemistry, and urinalysis) parameters are 
assessed at Screening Visit, Day 1-predose, Day 3, and Day 11. 
A serum pregnancy test is performed at Screening Visit and urine pregnancy tests are performed 
at Day -1, Day 3, and Day 13. 
 
5.6.3.1.1 
Hematology, coagulation, and blood chemistry parameters  
The following parameters are measured: 
• Hematology 
WBC, RBC, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, 
lymphocytes*, monocytes*, neutrophils*, eosinophils*, basophils*, atypical lymphocyte 
* Variables are summarized on both absolute value and percentage.  
• Coagulation 
Prothrombin Time (PT), International Normalized Ratio (INR), and activated Partial 
Thromboplastin Time (aPTT). 
• Blood chemistry 
calcium, chloride, creatinine, magnesium, potassium, sodium, glucose, blood urea nitrogen 
(BUN), aspartate aminotransferase (AST (SGOT)), alkaline phosphatase (ALP), alanine 
aminotransferase (ALT(SGPT)), gamma-glutamyltransferase (GGT), total bilirubin, lactate 
dehydrogenase (LDH), total cholesterol, albumin 
A summary of the absolute and change from Baseline values for each hematology, coagulation 
and blood chemistry parameter by scheduled visit will be presented.  
Shift from Baseline to the post-Baseline time point (Day 3, Day 11) based on reference range 
and clinical significance (Normal; Abnormal, Not Clinical Significant; Abnormal, Clinical 
Significant) is provided for all hematology, coagulation and blood chemistry parameters. 
A listing of participants who meet the criteria for potential drug-induced liver injury (PDILI) will 
be presented together with any additional relevant data collected, including: 
• Hy’s Law 
• ALT  
• AST 
• Bilirubin 
• Symptoms Potentially Associated with Hepatotoxicity: Hepatitis 
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• Symptoms Potentially Associated with Hepatotoxicity: Hypersensitivity 
A figure of time course for serum liver function tests for participants meeting potential Hy’s law 
criteria will be presented.  
Hy’s law is defined as: ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in the 
absence of ≥2xULN ALP on the same visit. 
 
5.6.3.1.2 
Urinalysis parameters  
The following parameters are measured: 
• Urinalysis: pH, bilirubin, glucose, ketones, urobilinogen, protein, nitrite 
• Urine Sediment: albumin, bacteria, crystals, RBC, WBC 
The number and percentage of participants with each response category for qualitative urinalysis 
and urine sediment parameters are summarized for the scheduled time points. Percentages are rel
ative to the number of participants with a result for each parameter at each time point. 
Shift from Baseline to the post-Baseline time point (Day 3, Day 11) for observed values 
(negative, trace, 1+, 2+, 3+, etc) is summarized for the above qualitative urinalysis parameters 
(bilirubin, glucose, ketones, urobilinogen, protein, nitrite). 
 
5.6.3.1.3 
Pregnancy test 
Results of serum and urine pregnancy tests are not summarized but are provided in a subject data 
listing. 
 
5.6.3.2 
Vital Signs 
The following parameters are measured: 
• systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiratory rate, 
and body temperature. 
Observed values for the vital sign parameters are summarized with descriptive statistics for the 
scheduled time points. Changes from Baseline (Day1-predose) for each parameter are 
summarized for all post-Baseline time points. 
 
5.6.3.3 
Electrocardiograms 
12-lead ECG will be recorded 3 times at 15min [±5min] intervals within 24h before dosing of 
BRV on Day 1 in order to get representative Baseline. Postdose 12-lead ECG will be recorded 1 
time. The individual mean at Baseline will be calculated as raw parameters for descriptive 
analysis. The definition of Baseline will be the mean of the triplicate measurements predose on 
Day 1 or Day -1. If there are less than three replicates at Day 1 or Day -1 predose, the mean of 
the available replicates (predose) will be taken as Baseline.  
 
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The following parameters are measured: 
• Heart rate, RR interval, PR interval, QRS interval, QT, QTcB*, QTcF** 
*   QT interval corrected for heart rate by Bazett’s formula  
** QT interval corrected for heart rate by Fridericia’s formula 
Observed values for the ECG parameters are summarized with descriptive statistics for the 
scheduled time points. Changes from Baseline for each parameter are summarized for all post-
Baseline time points.  
For QTcB and QTcF, observed values and their changes from Baseline are summarized based on 
the classifications of [<450, 450-<480, 480-<500, ≥500 msec] and [<30, 30-<60, ≥60 msec], 
respectively.  
The individual measurements and the mean of the triplicate measurements will be reported in the 
by-participant listings. The listing will also include the change from Baseline. All ECG findings 
for the individual measurements will be listed separately. 
 
5.6.3.4 
Other safety endpoint(s) 
Physical examination 
Participants with abnormalities in the physical examination will be listed including details of the 
abnormality. 
Suicidal risk monitoring 
Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al, 2011) data where ideation or 
suicidal behavior had been reported will be listed. Module of the questionnaire, time point, 
question and the associated response will be listed. 
 
5.7 
Other Analyses 
5.7.1 
Other endpoints and/or parameters 
5.7.1.1 
Pharmacokinetics 
In general, plasma concentration-time profiles of BRV and its metabolites are summarized by 
dosing period (single and multiple dose) using PK-PPS and listed by subject for the SS. PK 
parameters of BRV and its metabolites are summarized by dosing period (single and multiple 
dose) using the PK-PPS and listed by subject for the SS. 
Descriptive statistics for plasma concentrations of BRV and its metabolites are provided for 
every scheduled time point (see Table 1‒ and Table 1‒3:  
Multiple-Dose Period: schedule for 
ECGs, vital signs, and PK sampling 3) by dosing period. 
Descriptive statistics include the number of values (n), arithmetic mean, SD, geometric mean, 
lower and upper limit of the 95% CI for geometric mean, geometric CV [%], median, minimum 
and maximum values. 
Concentrations BLQ are replaced by half of the LLOQ and missing values are excluded for the 
calculation of descriptive statistics. When the mean includes one or more replaced BLQ values, a 
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footnote of the table should be added "contains one or more BLQ values replaced by half the 
LLOQ value". For each specific time point, only minimum and maximum should be calculated 
in case the number of BLQ and missing values exceed one third of the total; other descriptive 
statistics should be reported as missing (“-“). If minimum and/or maximum is BLQ, keep 
minimum or maximum as “BLQ”. A minimum of 3 values are required to calculate summary 
statistics; if only 2 values are available then these should be presented as the minimum and 
maximum with other descriptive statistics reported as missing (“-“). 
Listings for individual concentrations of BRV and its metabolites including the actual and 
nominal sampling times and the deviation between the actual and nominal sampling times are 
provided. Concentrations that are BLQ are indicated as “BLQ” in the listings. Missing data 
should be reported as “NV” (no value). Concentrations should be listed to the same number of 
significant figures supplied by the bioanalytical laboratory. 
Geometric mean profiles vs nominal time are displayed (including corresponding lower and 
upper limit of 95% CI for the linear scale, without CI on the semi-logarithmic scale) 
superimposing in one plot for all analytes, with one plot for each dosing period. Summary data 
plotted in the figure will match data presented in summary table, except for missing values prior 
to Cmax which will be set to 0 in the figure. 
Individual concentration-time profiles vs scheduled time are displayed graphically on a linear 
scale and semi-logarithmic scale, superimposing in one plot all analytes, and one plot per dosing 
period and per participant. A Spaghetti plot of individual plasma concentrations vs scheduled 
time is displayed by dose period. When reporting individual data in figures, BLQ values prior to 
Cmax will be set to 0 and BLQ values that occur post-Cmax will be considered missing. 
Primary/secondary pharmacokinetic parameters 
Plasma pharmacokinetic parameters as identified above are calculated from the individual drug 
concentration vs. actual time profiles by dosing period. Parameters are calculated for BRV and 
metabolites after single and multiple dose as described in Table 5-4.Table 5-4:
 
Primary/Secondary pharmacokinetic parameters  
Pre-dose sample time is set to 0 prior to performing parameter derivation. Missing pre-dose 
concentrations for Single-Dose period will be replaced by 0. For multiple dose period, the 
analyst should use scientific judgement to assess what action should be taken and a rationale for 
this action should be recorded in the analysis documentation (eg set to 0 if no accumulation is 
expected). 
 
Table 5-4: 
Primary/Secondary pharmacokinetic parameters  
Specimen 
PK Parameter 
BRV 
Metabolitesa 
Notation 
Description 
Single Mult. Single Mult. 
Plasma 
AUC(0-t) 
area under the plasma concentration-time 
curve from zero to the time of the last 
measured concentration above the LOQ 
P 
̶ 
S 
̶ 
AUC(0-12),ss 
area under the curve from 0 to 12 hours at 
steady state 
̶ 
P 
̶ 
S 
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AUC 
area under the curve from 0 to infinite 
time 
S 
̶ 
S 
̶ 
Cmax 
maximum plasma concentration 
P 
̶ 
S 
̶ 
Cmax,ss 
maximum plasma concentration at steady 
state 
̶ 
P 
̶ 
S 
Cmin,ss 
minimum plasma concentration at steady 
state 
̶ 
S 
̶ 
̶ 
Cav,ss 
average plasma concentration at steady 
state 
̶ 
S 
̶ 
̶ 
tmax 
time to reach maximum plasma 
concentration 
S 
S 
S 
S 
t1/2 
terminal elimination half-life 
S 
S 
S 
S 
λz 
rate constant of elimination 
S 
S 
S 
S 
MRT 
mean residence time 
S 
̶ 
̶ 
̶ 
CL/F 
apparent total body clearance 
S 
̶ 
̶ 
̶ 
CLss/F 
apparent total body clearance at steady 
state 
̶ 
S 
̶ 
̶ 
Vz/F 
apparent volume of distribution 
S 
S 
̶ 
̶ 
PTF 
peak-trough fluctuation 
̶ 
S 
̶ 
̶ 
RAUCb 
accumulation ratio calculated from AUC 
at steady state and AUC after single dose 
S 
̶ 
̶ 
Rmax 
accumulation ratio calculated from Cmax,ss 
and Cmax  
S 
̶ 
̶ 
a metabolites of BRV (ucb-42145, ucb-100406-1, and ucb107092-1)  
b AUC0-12 on Day 1will be derived for the calculation of RAUC. 
 
P: Primary, S: Secondary. 
PK parameters in plasma 
• AUC parameters (AUC(0-t), AUC(0-12), AUC(0-12),ss, AUC) [ng·h/mL] 
- The linear up/log down trapezoidal method is used to calculate the AUC 
parameters. 
- AUC(t1-t2) = ∫
𝐶(𝑡)𝑑𝑡
𝑡2
𝑡1
 
- AUC: Calculated as AUC(0-t)+Clast/λz 
▪ If the percentage of extrapolated AUC (AUCextr) is more than 20%, the 
individual result should be excluded from summary statistics along with 
all parameters dependent on AUC. 
• Cmax parameters (Cmax, Cmax,ss) [ng/mL] 
- Obtained directly from the concentration vs. time data 
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• Cmin,ss [ng/mL] 
- Obtained directly from the concentration vs. time data 
• Cav,ss [ng/mL] 
- Calculated as AUC(0-12), ss/12 
• tmax [h] 
- Obtained directly from the concentration vs. time data as a time at which Cmax or 
Cmax,ss is observed. 
• λz [1/h] 
- Estimated at terminal phase by linear regression after natural log-transformation 
of the concentrations. λz is calculated over a time interval using the best fit 
method.  
▪ The time interval should be equal to at least 2 × t1/2 and have at least 3 
data-points not including Cmax. If it is less than 2 half-lives or if there are 
too few data to calculate λz, then the parameter should be excluded from 
summary statistics (along with all parameters dependent on half-life).  
▪ In the case that the R2 for the regression is less than 0.8, the half-life (and 
all parameters dependent on it) should be excluded from summary 
statistics.  
• t1/2 [h] 
- Calculated as ln 2/ λz  
▪ For the parameter, same notation as corresponding λz is noted in the listing 
if the λz has the above-mentioned notation. 
• MRT [h] 
- Calculated after single dose as AUMC/AUC, where AUMC is the area under the 
first moment curve from 0 to infinite time 
- AUMC = AUMC(0-t) + Clast × tlast/ λz + Clast/ λz2 
- AUMC(0-t) = ∫
𝐶(𝑡) × 𝑡 𝑑𝑡
𝑡𝑙𝑎𝑠𝑡
0
 
• CL/F [L/h] 
- Calculated as dose/AUC 
• CLss/F [L/h] 
- Calculated as dose/AUC(0-12),ss  
• Vz/F [L] 
- Calculated as CL/F/λz 
• PTF 
- Calculated as (Cmax,ss-Cmin,ss)/Cav,ss 
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• R (accumulation ratio) (RAUC, Rmax)  
- RAUC is calculated as AUC(0-12),ss / AUC(0-12) 
- Rmax is calculated as Cmax,ss / Cmax 
If any parameter matching an exclusion criterion is included in summary statistics, then the 
rationale will be provided. 
For the determination of the PK parameters, all BLQ values occurring prior to Cmax are replaced 
by 0, except for embedded BLQ values (between two measurable data-points) which are treated 
as missing. Post-Cmax BLQ values are treated as missing.  
The PK parameters are summarized for the PK-PPS by dosing period using descriptive statistics: 
the number of values (n), geometric mean, lower and upper limit of the 95% CI for geometric 
mean, geometric CV [%],arithmetic mean, SD, median, minimum and maximum values. For 
tmax, only n, median, minimum and maximum values are be presented. 
Descriptive statistics should be reported to 4 significant figures for the mean, median and SD, 
and to 3 significant figures for all others. 
If at least two thirds of the participants have a PK parameter reported then descriptive statistics 
will be calculated, otherwise only minimum and maximum will be reported for this PK 
parameter and all other descriptive statistics will be reported as “NE” (not estimable).  
Individual PK parameters of BRV and its metabolites are provided together in the summary 
table. Individual PK parameters will be reported to 3 significant figures. If a parameter cannot be 
calculated, it will be reported in the listing either as “NE” (in case calculation is not possible due 
to missing data) or as “NC” (not calculable, in case data were available but the calculation was 
considered unreliable). Individual PK parameters of BRV and its metabolites for participants 
excluded from the PK-PPS are listed for SS. 
 
5.7.1.2 
Pharmacodynamics 
Not applicable.  
 
5.7.1.3 
Genomics 
Not applicable.  
 
5.8 
Subgroup analyses 
Not applicable.  
 
5.9 
Interim Analyses 
Not applicable.  
 
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5.10 
Data Monitoring Committee (DMC) or Other Review Board 
Not applicable.  
 
6 
SUPPORTING DOCUMENTATION 
 
6.1 
Appendix 1 Non-key analysis specifications 
 
6.1.1 
Baseline characteristics and demographics 
Unless otherwise specified, demographic and Baseline characteristics are summarized for the SS, 
and subject data listings for the demographic and Baseline characteristics are provided for the All 
Subject Screened (ES). 
Demographics  
Age, gender (male/female), weight (kg), height (cm), body mass index (BMI), ethnicity, and 
racial group (Asian) are summarized.   
The age of each subject is calculated as completed years at the date of informed consent. Weight 
is summarized from screening visit. BMI is calculated from the weight and the height at 
screening visit using the following formula:  
BMI(kg/m2)= 10,000×weight (kg)
[height (cm)]2
 
 
Other Baseline characteristics 
Lifestyle information will be summarized based on the SS and will be listed based on the ES. 
Serology, urine drug, and alcohol detection will be listed based on ES. The detailed tests of 
serology and urine drug are listed below: 
• Serology 
Hepatitis B surface antigen, Hepatitis C virus antibody, HIV antibody, and syphilis 
• Urine drug  
Morphine, Tetrahydrocannabinolic acid, Methamphetamine, Dimethylenedioxyamphetamine, 
Ketamine, and Cocaine 
 
 
6.1.2 
Protocol deviations 
The number and percentage of participants with at least 1 IPD are summarized for SS, using the 
categories as defined in the protocol deviation specification.  
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A listing of all IPDs identified at the DEM will be presented based on the SS and will include the 
deviation type and description. 
Impact of COVID-19 on study visits 
The number and percentage of participants with visits impacted by COVID-19 will be 
summarized by impact categories based on the SS. And a listing of visits impacted by COVID-
19 will be presented for all participants based on the ES, including visit, visit date, relative day, 
impact category, relationship to COVID-19 and narrative of the event. 
 
6.1.3 
Medical history 
Medical history  
The number and percentage of participants with a medical history condition, including both 
resolved previously and ongoing conditions at the time of study entry, are summarized overall 
(ie, any previous and ongoing medical history conditions) and by MedDRA primary SOC and 
PT.  
A subject data listing for the previous and ongoing medical history conditions is provided. 
Procedure history  
Prior medical procedures or surgeries are not to be summarized and are only provided in a by-
participant data listing based on the ES. 
 
6.1.4 
Prior/concomitant/follow-up medications 
Tabulations will be presented for prior and concomitant medications separately which the details 
are listed below:  
Prior and concomitant medications 
Medications are categorized as follow: 
• Prior medication 
- Prior medications include any medications that started prior to date of the first dose of 
BRV. 
• Concomitant medication 
o starts before first dose of IMP and is ongoing at day of first dose of IMP 
o starts on or after first dose of IMP 
A listing of prior and concomitant medications, which includes the reported term, the anatomical 
therapeutic chemical subgroup (level 1 and 3) in WHO-DRL, is provided. 
Concomitant medical procedures 
Concomitant medical procedures or surgeries are not to be summarized and are only provided in 
a by-participant data listing based on the ES. 
 
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6.1.5 
Data derivation rules 
6.1.5.1 
Handling of dropouts or missing data 
Participants who drop out from the study before completion of study procedures and for any 
other reason than for safety issues can be replaced with participants of the same gender after 
consultation with the sponsor. 
In general, there will be no imputation of missing data unless otherwise stated below. Handling 
of missing data for PK results is described in Section 5.7.1.1. Safety laboratory data will be 
handled as described in Section 5.6. 
6.1.5.1.1 
Incomplete dates and times 
Partial dates may be imputed for the following reasons: 
• Classification of AEs as treatment-emergent 
• Classification of medications as prior or concomitant 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
  
The following rules will be applied for partial start dates and time: 
• If only the month and year are specified and the month and year of the first dose of IMP is 
not the same as the month and year of the start date, then use the 1st of the month, or the date 
of Screening if this is later (if the latter imputation results in an end date that is earlier than 
the start date, then use the 1st of the month). If time is missing this will be imputed as 00:00 
h 
• If only the month and year are specified and the month and year of the first dose of IMP is 
the same as the month and year of the start date, then use the date of the first dose of IMP. If 
this results in an imputed start date that is after the specified end date, then use the 1st of the 
month, or the date of Screening if this is later (if the latter imputation results in an end date 
that is earlier than the start date, then use the 1st of the month). If the imputed date is the date 
of dosing then time will be imputed as the start time of the dosing (ie, event will be regarded 
as treatment-emergent) 
• If only the year is specified, and the year of the first dose of IMP is not the same as the year 
of the start date then January 01 will be used. If time is missing this will be imputed as 00:00 
h 
• If only the year is specified, and the year of the first dose of IMP is the same as the year of 
the start date, then the date of the first dose of IMP will be used. If this results in an imputed 
start date that is after the specified end date, then January 01, or the date of screening if this 
is later will be used (if the latter imputation results in an end date that is earlier than the start 
date, then January 01 will be used). If the imputed date is the date of first dose of IMP then 
time will be imputed as the start time of the study medication intake (ie, event will be 
regarded as treatment-emergent) 
• If the start date is completely unknown, then use the date of dosing. If this results in an 
imputed start date that is after the specified end date, then use January 01 of the year of the 
end date, or the date of Screening if this is later. 
 
The following rules will be applied for partial stop dates: 
• If only the month and year are specified, then use the last day of the month 
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• If only the year is specified, then use December 31 of the known year 
• If the stop date is completely unknown, do not impute the stop date 
 
Missing or partially missing dates and/or times will be imputed as described in Table below. AE 
duration is computed and reported in day and time format: xx d hh:mm. Duration is not 
calculated when the outcome date is missing. 
 
Table 5‒1: 
Calculation rules for duration of adverse events  
Data availability  
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Complete data 
D1/T1 
D2/T2 
Duration = [(D2 – D1)*24 + (T2 – T1)]/24 d 
End time missing  
D1/T1 
D2/-- 
End time is substituted by time 23:59h 
(=23.98 in 
decimal format) 
Duration = <[(D2 – D1)*24 + (23.98 – 
T1)]/24 d 
Start time missing 
D1/-- 
D2/T2 
If D1 is the same date as the date of first dose 
of IMP, Onset time is substituted by the start 
time of dosing (Tdose).  
Duration = <[(D2 – D1)*24 + (T2 – 
Tdose)]/24 d 
Otherwise the onset time is substituted by 
time 00:00h 
Duration = <[(D2 – D1)*24 + (T2)]/24 d 
Start and end time 
missing 
D1/-- 
D2/-- 
Duration = <D2 – D1 + 1 
 
Start day and time 
missing 
--/-- 
D2/T2 
Duration = [(D2 – D0)*24 + (T2 – T0)]/24 d 
For a participant in the SS, D0 and T0 are the 
date and time of first administration of study 
medication and for screen failures, D0 is the 
date 
of the screening visit and T0 = 00:00h 
End day and time 
missing 
D1/T1 
--/-- 
If the stop date and time are missing, 
duration will not be 
calculated. 
Start and end date 
missing 
--/-- 
--/-- 
If the stop date and time are missing, 
duration will not be 
calculated. 
SS=Safety Set. 
 
6.1.6 
AEs of Special Interest 
The AEs of special interest include: 
• Autoimmune nephritis 
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• 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).  
 
6.1.7 
Compliance 
A study participant is considered compliant with treatment if the participant takes the study IMP 
at all of 12 scheduled time points. Participants who do not take all 12 doses are to be considered 
non-compliant to treatment and are to be discussed at the DEM. A data listing for treatment 
compliance is not provided. 
 
6.2 
Appendix 3: Changes to Protocol-Planned Analyses 
Not applicable. 
 
7 
REFERENCES 
• Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia Suicide Severity Rating Scale: initial validity and internal consistency findings 
from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266 77. 
 
 
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