Clinical trial NCT06312566
Conditions: Healthy Study Participants
Keywords: brivaracetam Healthy Study Participants Phase 1 BRV
Sponsor: UCB Biopharma SRL
Start date: 2024-03-25; Completion date: 2024-06-04
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of the study is to demonstrate the bioequivalence between the BRV tablet and BRV dry syrup after multiple oral doses in healthy male Japanese participants.

Detailed description:

Arms: arm 1: Study participants randomized to this arm will receive multiple doses of brivaracetam tablet (Treatment A) as reference and multiple doses of brivaracetam dry syrup (Treatment B) as test in the treatment sequence A-B at pre-specified timepoints. arm 2: Study participants randomized to this arm will receive multiple doses of brivaracetam tablet (Treatment A) as reference and multiple doses of brivaracetam dry syrup (Treatment B) as test in the treatment sequence B-A at pre-specified timepoints.
Interventions: intervention 1: brivaracetam (BRV) tablet intervention 2: brivaracetam (BRV) dry syrup
Intervention descriptions: intervention 1: Study participants will receive multiple-doses of brivaracetam tablet (reference - Treatment A) administered orally. intervention 2: Study participants will receive multiple-doses of brivaracetam dry syrup (test - Treatment B) administered orally.

Protocol documents:
Prot_000.pdf: 
UCB 
 
14 Dec 2023 
Clinical Study Protocol 
Brivaracetam 
EP0231 
 
 
 
Confidential 
Page 1 of 70 
A MULTIPLE-DOSE, OPEN-LABEL, RANDOMIZED, 2-WAY 
CROSS-OVER STUDY TO ASSESS THE BIOEQUIVALENCE 
BETWEEN BRIVARACETAM TABLET AND DRY SYRUP IN 
HEALTHY MALE JAPANESE PARTICIPANTS 
 
PROTOCOL EP0231 AMENDMENT 1.0 
PHASE 1 
 
SHORT TITLE: 
A multiple-dose study to assess the bioequivalence between brivaracetam tablet and dry syrup in 
healthy male Japanese participants 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Local Contact: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower  
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
JAPAN 
Regulatory agency identifying number(s): 
EudraCT Number: 
Not applicable 
EU Trial Number: 
Not applicable 
EUDAMED Number: 
Not applicable 
IND Number: 
Not applicable 
IDE Number: 
Not applicable 
NCT Number: 
Not applicable 
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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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Amendment 1 
14 Dec 2023 
Original Protocol 
28 Jul 2023 
Amendment 1 (14 Dec 2023) 
Overall rationale for the amendment 
The purpose of this protocol amendment is to include a description of the option of dissolution 
testing that could be used to determine bioequivalence and to align the protocol with the 
excipients for the development formulation. 
Section # and name 
Description of change 
Brief rationale 
Section 6.1, Treatments 
administered 
The excipients for the BRV 
50mg tablet and BRV dry 
syrup were updated as 
described below. 
BRV 50mg tablet: 
Hypromellose and saccharin 
sodium were added. 
Polyvinyl alcohol, iron oxide 
yellow (E172), and iron oxide 
black (E172) were removed. 
Dry syrup: 
 
 was 
added. 
Aligned to include the 
excipients for the 
development formulation. 
Section 9.3.1, 
Pharmacokinetic analyses 
Added text: In the case that 
the CIs for Cmax,ss and AUCtau 
are not contained in the range 
of 0.80 to 1.25, 
bioequivalence can still be 
concluded if the following 
criteria are met: 1) the point 
estimate of the adjusted GMR 
(Test/Reference) for Cmax,ss 
and AUCtau are contained in 
the range of 0.90 to 1.11, and 
2) in vitro dissolution rates of 
Test (dry syrup) and 
Reference (tablet) 
Updated to include text that 
describes the option of 
dissolution testing that could 
be used to determine 
bioequivalence. 
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Section # and name 
Description of change 
Brief rationale 
formulations are available 
and are deemed similar 
according to the Japanese 
bioequivalence guideline 
(PSEHB/PED Notification 
No. 0319-1, 2020). 
Section 9.8, Determination of 
sample size 
Previous text: In the group 
sequential design for this 
study, an interim analysis will 
be performed for 
bioequivalence or futility 
after approximately 
60 evaluable participants, 
which is at 90% power for 
bioequivalence based on the 
study assumptions. 
New text: In the group 
sequential design for this 
study, an interim analysis will 
be performed for 
bioequivalence or futility 
after approximately 
60 evaluable participants, 
which is at 90% power for 
bioequivalence based on the 
CIs of the adjusted GMR 
(Test/Reference) with the 
study assumptions. 
Updated for clarity. 
Section 11, References 
New text: Ministry of Health, 
Labour and Welfare. 
PSEHB/PED Notification No. 
0319-1 The Partial 
Amendment to Guideline for 
Bioequivalence Studies of 
Generic Products 
19 Mar 2020. 
Added to provide a reference 
for the Japanese 
bioequivalence guideline. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, therefore, have not 
been summarized. 
AUCtau=area under the curve during a dosing interval at steady state; BRV=brivaracetam; 
CI=confidence interval; Cmax,ss=maximum plasma concentration at steady state; 
GMR=geometric mean ratio; No=number; PED=Pharmaceutical Evaluation Division; 
PSEHB=Pharmaceutical Safety and Environmental Health Bureau 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and rest of world for interventional and non-interventional 
clinical studies, (except United States and Canada), please dial: 
+32 2 386 2421 
Email 
Worldwide for interventional clinical studies, please contact: 
DS_ICT@ucb.com 
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TABLE OF CONTENTS 
 
1 
PROTOCOL SUMMARY ................................................................................................. 9 
1.1 
Synopsis ......................................................................................................................... 9 
1.2 
Schema ......................................................................................................................... 11 
1.3 
Schedule of Activities .................................................................................................. 13 
2 
INTRODUCTION ........................................................................................................... 17 
2.1 
Study rationale ............................................................................................................. 18 
2.2 
Background .................................................................................................................. 19 
2.3 
Benefit/Risk assessment............................................................................................... 19 
2.3.1 
Risk assessment for coronavirus disease 2019 .................................................... 20 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 21 
4 
STUDY DESIGN ............................................................................................................. 22 
4.1 
Overall design .............................................................................................................. 22 
4.2 
Scientific rationale for study design ............................................................................ 23 
4.3 
Justification for dose .................................................................................................... 24 
4.4 
End of study definition................................................................................................. 24 
5 
STUDY POPULATION .................................................................................................. 24 
5.1 
Inclusion criteria .......................................................................................................... 24 
5.2 
Exclusion criteria ......................................................................................................... 25 
5.3 
Lifestyle restrictions..................................................................................................... 26 
5.3.1 
Meals and dietary restrictions .............................................................................. 26 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 27 
5.3.3 
Activity ................................................................................................................ 27 
5.3.4 
Food intake times ................................................................................................. 27 
5.3.5 
Other restrictions ................................................................................................. 27 
5.4 
Screen failures .............................................................................................................. 28 
6 
STUDY TREATMENTS ................................................................................................. 28 
6.1 
Treatments administered .............................................................................................. 28 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 30 
6.2.1 
Drug accountability ............................................................................................. 30 
6.3 
Measures to minimize bias: randomization and blinding ............................................ 31 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 31 
6.4 
Treatment compliance .................................................................................................. 31 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 31 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 31 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 31 
6.6 
Dose modification ........................................................................................................ 31 
6.7 
Criteria for study hold or dosing stoppage ................................................................... 32 
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6.8 
Treatment after the end of the study ............................................................................ 32 
7 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 32 
7.1 
Discontinuation of IMP................................................................................................ 32 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 32 
7.2 
Participant discontinuation/withdrawal from the study ............................................... 32 
7.3 
Lost to follow up .......................................................................................................... 33 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 34 
8.1 
Efficacy assessments .................................................................................................... 34 
8.2 
Safety assessments ....................................................................................................... 34 
8.2.1 
Physical examination ........................................................................................... 34 
8.2.2 
Vital signs ............................................................................................................ 34 
8.2.3 
Electrocardiograms .............................................................................................. 34 
8.2.4 
Clinical safety laboratory assessments ................................................................ 35 
8.3 
Adverse events and serious adverse events ................................................................. 35 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 36 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 36 
8.3.3 
Follow up of AEs and SAEs ................................................................................ 36 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 36 
8.3.5 
Pregnancy ............................................................................................................ 37 
8.3.6 
Adverse events of special interest ........................................................................ 37 
8.4 
Safety signal detection ................................................................................................. 37 
8.5 
Treatment of overdose ................................................................................................. 37 
8.6 
Pharmacokinetics ......................................................................................................... 37 
8.7 
Biomarkers ................................................................................................................... 39 
8.8 
Immunogenicity assessments ....................................................................................... 39 
8.9 
Health economics ......................................................................................................... 39 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 39 
9.1 
Definition of analysis sets ............................................................................................ 39 
9.2 
General statistical considerations ................................................................................. 40 
9.3 
Planned outcome analyses ........................................................................................... 40 
9.3.1 
Pharmacokinetic analyses .................................................................................... 40 
9.4 
Planned safety and other analyses................................................................................ 41 
9.4.1 
Secondary safety analyses ................................................................................... 41 
9.4.2 
Other safety analyses ........................................................................................... 42 
9.4.2.1 
Clinical laboratory assessments ................................................................. 42 
9.4.2.2 
Vital signs .................................................................................................. 42 
9.4.2.3 
Electrocardiograms .................................................................................... 42 
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9.4.2.4 
Physical examination ................................................................................. 42 
9.5 
Handling of protocol deviations................................................................................... 42 
9.6 
Handling of dropouts or missing data .......................................................................... 42 
9.7 
Planned interim analysis and data monitoring ............................................................. 42 
9.8 
Determination of sample size ....................................................................................... 43 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 45 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ......................... 45 
10.1.1 
Regulatory and ethical considerations ................................................................. 45 
10.1.2 
Financial disclosure ............................................................................................. 45 
10.1.3 
Informed consent process .................................................................................... 45 
10.1.4 
Data protection ..................................................................................................... 46 
10.1.5 
Committees structure ........................................................................................... 46 
10.1.6 
Dissemination of clinical study data .................................................................... 46 
10.1.7 
Data quality assurance ......................................................................................... 47 
10.1.7.1 
Case report form completion ..................................................................... 47 
10.1.7.2 
Apps ........................................................................................................... 47 
10.1.8 
Source documents ................................................................................................ 47 
10.1.9 
Study and site start and closure ........................................................................... 48 
10.1.10 
Publication policy ................................................................................................ 48 
10.2 
Appendix 2: Clinical laboratory tests .......................................................................... 50 
10.3 
Appendix 3: Adverse events – Definitions and procedures for recording, evaluating, 
follow up, and reporting ............................................................................................... 52 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ......... 57 
10.5 
Appendix 5: Genetics ................................................................................................... 59 
10.6 
Appendix 6: Liver safety – suggested actions and follow-up assessments ................. 60 
10.7 
Appendix 7: Medical device AEs, adverse device effects, SAEs, and device 
deficiencies: Definition and procedures for recording, evaluating, follow-up, and 
reporting ....................................................................................................................... 63 
10.8 
Appendix 8: Rapid alert procedures ............................................................................ 64 
10.9 
Appendix 9: Country-specific requirements ................................................................ 65 
10.10 Appendix 10: Abbreviations and trademarks .............................................................. 66 
10.11 Appendix 11: Protocol amendment history ................................................................. 68 
11 REFERENCES ................................................................................................................ 69 
SPONSOR DECLARATION .................................................................................................. 70 
 
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Brivaracetam 
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LIST OF TABLES 
Table 1-1: 
Schedule of Activities ...................................................................................... 14 
Table 6-1: 
Treatments administered .................................................................................. 29 
Table 8-1: 
Irrelevant time deviations for PK sampling ..................................................... 39 
Table 9-1: 
EP0110 and simulation results of relative bioavailability of BRV tablet 
formulation vs dry syrup formulation .............................................................. 43 
Table 10-1: 
Highly effective contraceptive methods for female partners a ......................... 57 
Table 10-2: 
Liver chemistry stopping criteria and follow-up assessments ......................... 61 
 
LIST OF FIGURES 
Figure 1-1: 
Schematic diagram ........................................................................................... 12 
Figure 4-1: 
Blood sampling scheme ................................................................................... 23 
Figure 7-1: 
Liver chemistry stopping algorithm ................................................................. 32 
 
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Clinical Study Protocol 
Brivaracetam 
EP0231 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: A multiple-dose, open-label, randomized, 2-way cross-over study to assess the 
bioequivalence between brivaracetam (BRV) tablet and dry syrup in healthy male Japanese 
participants 
Short title: A multiple-dose study to assess the bioequivalence between BRV tablet and dry 
syrup in healthy male Japanese participants 
Rationale: 
A dry syrup formulation of BRV is being developed specifically for the Japanese market to allow 
dose adjustment by body weight in pediatric patients and patients with dysphagia. This study 
aims to assess the bioequivalence between the BRV 50mg tablet and BRV 50mg as a dry syrup 
formulation in a multiple-dose setting. 
Objectives and endpoints 
Objectives 
Endpoints 
Primary objective 
• 
To assess bioequivalence between the 
BRV 50mg tablet and BRV 50mg dry syrup 
after multiple oral doses in healthy male 
Japanese participants 
Primary PK endpoints from plasma BRV 
concentrations: 
• 
Cmax,ss 
• 
AUCtau 
Secondary objective 
• 
To evaluate the safety and tolerability of 
multiple oral doses of the BRV 50mg tablet 
and BRV 50mg dry syrup in healthy male 
Japanese participants 
Secondary safety endpoints: 
• 
Incidence of TEAEs 
• 
Incidence of treatment-emergent SAEs 
• 
Incidence of TEAEs leading to discontinuation 
Other objectives 
• 
To evaluate other PK parameters after 
multiple oral doses of the BRV 50mg tablet 
and BRV 50mg dry syrup in healthy male 
Japanese participants 
Other PK endpoints from plasma BRV 
concentrations: 
• 
Ctrough 
• 
CLss/F 
• 
tmax,ss 
• 
To further evaluate the safety and tolerability 
after multiple oral doses of the BRV 50mg 
tablet and BRV 50mg dry syrup in healthy 
male Japanese participants 
Other safety endpoints: 
• 
Change from Baseline in clinical laboratory test 
parameters (ie, hematology, clinical chemistry, 
and urinalysis)  
• 
Change from Baseline in vital signs (SBP, DBP, 
body temperature, respiratory rate, and heart 
rate) 
• 
12-lead ECG parameters and findings 
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Overall design 
EP0231 is a single-center, multiple-dose, open-label, randomized, group sequential design, 
2-way cross-over study to assess the bioequivalence of BRV 50mg tablet and BRV 50mg dry 
syrup in healthy male Japanese participants after oral administration under fasted conditions. In 
addition, the safety and tolerability of BRV will be evaluated. 
Participants will enter a Screening Period (2 to 28 days before administration of investigational 
medicinal product [IMP]), and eligible participants will start the Dosing Period. The Dosing 
Period consists of 2 periods (Dosing Period 1 and Dosing Period 2) of 5 days each (Day -1 to 
Day 4) with a total of 5 administrations of BRV 50mg on Day 1 and Day 2 (morning and 
evening doses 12 hours apart), and Day 3 (morning dose only). 
Participants will receive 1 of the following treatments in each Dosing Period under fasting 
conditions according to randomly assigned treatment sequences (A-B or B-A): 
• Treatment A – multiple doses of BRV 50mg tablets 
• Treatment B – multiple doses of BRV 50mg dry syrup (1.25g of granules for oral suspension 
4% w/w) 
The Dosing Periods will be separated by a Wash-Out Period (minimum of 6 days and preferably 
no more than 10 days between the final dose in Dosing Period 1 and the first dose in Dosing 
Period 2 for each participant) and followed by a Safety Follow-Up (SFU) Visit, 7 to 9 days after 
the last administration of IMP. Participants who prematurely discontinue the IMP/study will be 
encouraged to return for an SFU Visit, 7 to 9 days after the final IMP administration. Refer to the 
study schematic in Figure 1-1. 
The activities to be performed during the Dosing Periods are presented in the Schedule of 
Activities (Section 1.3). 
Number of participants 
Up to approximately 96 participants will be recruited into 2 cohorts to ensure a total of up to 
approximately 90 evaluable participants. After the first cohort (approximately 60 evaluable 
participants) has completed both Dosing Periods, an interim analysis will be performed and an 
internal Data Monitoring Committee (DMC) will determine whether the primary objective is 
achieved, futility of the study is confirmed, or whether the study should continue with 
recruitment of the second cohort (approximately 30 evaluable participants). 
• 
Physical examinations 
AUCtau=area under the curve during a dosing interval at steady state; BRV=brivaracetam; CLss/F=apparent total 
body clearance at steady state; Cmax,ss=maximum plasma concentration at steady state; Ctrough=measured 
concentration at the end of a dosing interval at steady state; DBP=diastolic blood pressure; 
ECG=electrocardiogram; PK=pharmacokinetics; SAE=serious adverse event; SBP=systolic blood pressure; 
TEAE=treatment-emergent adverse event; tmax,ss=time of Cmax,ss 
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Treatment groups and duration 
The total duration of the study for an individual participant is 21 to 53 days and will include: 
• A Screening Period (2 to 28 days before IMP administration) 
• Two Dosing Periods (5 days each, with a total of 5 administrations of BRV 50mg on Day 1 
and Day 2 (morning and evening doses 12 hours apart), and Day 3 (morning dose only) 
• A Wash-Out Period following Dosing Period 1 (minimum of 6 days and preferably no more 
than 10 days between the final dose in Dosing Period 1 and the first dose in Dosing Period 2 
for each participant) 
• An SFU Visit 7 to 9 days after the final IMP administration 
The estimated study duration does not exactly match the length of the study periods as some of 
study periods can overlap. 
Refer to Figure 1-1 for the study design. 
1.2 
Schema 
A schematic of the study design is provided in Figure 1-1. 
 
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Figure 1-1: Schematic diagram 
 
BRV=brivaracetam; DMC=Data Monitoring Committee; IMP=investigational medicinal product; max=maximum; min=minimum; SFU=Safety Follow-Up; 
w/w=weight/weight 
a Following a Screening Period (up to 27 days before the start of Dosing Period 1), eligible participants will be randomly assigned to 1 of 2 treatment sequences 
(A-B or B-A) before dosing in Dosing Period 1, after all Day -1 assessments have been completed. After the first cohort (approximately 60 evaluable 
participants) has completed both Dosing Periods, an interim analysis will be performed, and an internal DMC will determine whether the primary objective is 
achieved, futility of the study is confirmed, or whether the study should continue with recruitment of the second cohort (approximately 30 evaluable 
participants). 
b Each Dosing Period is 5 days each (Day -1 to Day 4). Brivaracetam 50mg will be administered twice daily (morning and evening doses 12 hours apart) as 
50mg tablets (Treatment A [Reference]) or dry syrup (1.25g of BRV granules for oral suspension 4% w/w; Treatment B [Test]). On Day 1 and Day 2, 
participants will fast for at least 2 hours before and after IMP administration. On Day 3, only the morning dose will be administered, and the participants will 
fast for 10 hours before and 4 hours after IMP administration. For each Dosing Period, participants will be admitted to the study site on Day -1 (1 day before 
dosing) and will be discharged on the morning of Day 4, approximately 24 hours after last administration of IMP in each Dosing Period, at the discretion of the 
Investigator. 
c The Dosing Periods will be separated by a Wash-Out Period (minimum of 6 days and preferably no more than 10 days between the final dose in Dosing 
Period 1 and the first dose in Dosing Period 2) for each participant. 
d An SFU Visit will occur 7 to 9 days after the final IMP administration. Participants who prematurely discontinue the IMP/study will be encouraged to return 
for an SFU Visit within 7 to 9 days after the final IMP administration. 
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1.3 
Schedule of Activities 
The Schedule of Activities is provided in Table 1-1. 
 
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Table 1-1: 
Schedule of Activities 
Procedure 
Screening 
Period 
Dosing Period 1 or Dosing Period 2 a 
SFU b 
2 to 28 days 
before 
administration 
of IMP 
Check in 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
7 to 9 days 
after the last 
administration 
of IMP 
Written informed consent 
X 
 
 
 
 
 
 
Demographics, habits, and lifestyle 
X 
 
 
 
 
 
 
Verification of inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Verification of withdrawal criteria c 
 
X 
X 
X 
X 
X 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
Height and weight 
X 
 
 
 
 
 
 
Viral serology (HBsAg, HCV, HIV, and syphilis) 
X 
 
 
 
 
 
 
Alcohol and drug (including cotinine) testing 
X 
X 
 
 
 
 
 
COVID-19 precautions d 
X 
X 
 
 
 
 
X 
Vital signs e 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests (hematology, clinical 
chemistry, and urinalysis) 
X 
X 
 
 
 
X 
X 
Randomization f 
 
X 
 
 
 
 
12-lead ECG g 
X 
 
X 
 
 
X 
X 
IMP administration h 
 
 
X 
X 
X 
 
 
Blood sampling for PK i 
 
 
X 
X 
X 
 
 
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Table 1-1: 
Schedule of Activities 
Procedure 
Screening 
Period 
Dosing Period 1 or Dosing Period 2 a 
SFU b 
2 to 28 days 
before 
administration 
of IMP 
Check in 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
7 to 9 days 
after the last 
administration 
of IMP 
Recording of prior and concomitant medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
Recording of AEs 
X 
X 
X 
X 
X 
X 
X 
Confinement 
 
X 
X 
X 
X 
X j 
 
AE=adverse event; BRV=brivaracetam; COVID-19=coronavirus disease 2019; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; IMP=investigational medicinal product; PK=pharmacokinetic(s); SFU=Safety Follow-Up; 
w/w=weight/weight 
a Each participant will enter 2 Dosing Periods, separated by a Wash-Out Period. Dosing Period 2 will begin after the Wash-Out Period (minimum of 6 days 
and preferably no more than 10 days between the final IMP administration in Dosing Period 1 and the first IMP administration in Dosing Period 2). 
b An SFU Visit will occur 7 to 9 days after the last administration of IMP. Participants who prematurely discontinue the IMP/study will be encouraged to 
undergo an SFU Visit within 7 to 9 days after the last administration of IMP. 
c Confirmation that participants do not fulfill the withdrawal or stopping criteria (Section 7) will occur on Day -1, before dosing on Days 1, 2, and 3, and prior 
to discharge on Day 4. 
d Coronavirus disease 2019 precautions will be performed in alignment with the study site’s local requirements (refer to Section 2.3.1 for additional details). 
e Vital signs (blood pressure [systolic blood pressure and diastolic blood pressure], heart rate, respiratory rate, and body temperature) will be taken at the 
Screening Visit; for each Dosing Period (on Day -1 check in, Day 1 predose and 12 hours postdose [before the evening dose is administered]), Day 2 
[premorning dose] and Day 3 predose, and Day 4 prior to discharge); and at the SFU Visit. 
f Randomization will occur only for Dosing Period 1; either on Day -1 after all assessments for Day -1 are performed or Day 1 before any assessments for 
Day 1 are performed. Each participant will be randomly assigned to 1 of 2 treatment sequences (A-B or B-A). 
g  Single 12-lead ECGs will be recorded at Screening, for each Dosing Period (Day 1 predose and Day 4 prior to discharge), and at the SFU Visit. 
h Investigational medicinal product administration: Brivaracetam 50mg will be administered twice daily (approximately 12 hours apart) as 50mg tablets 
(Treatment A [Reference]) or dry syrup (1.25g of BRV granules for oral suspension 4% w/w; Treatment B [Test]). On Day 1 and Day 2, participants will 
fast for at least 2 hours before and after IMP administration. On Day 3, only the morning dose will be administered, and the participants will fast for 
10 hours before and 4 hours after IMP administration. 
i For each Dosing Period, blood samples for PK analysis will be collected on Day 1 (before the morning and evening doses [0 and 12hr]), Day 2 (before the 
morning and evening doses [24 and 36hr]), and Day 3 (predose [48hr] and 10min, 15min, 20min, 30min, 45min, 60min, 75min, 90min, 2hr, 6hr, 9hr, and 
12hr postdose). 
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Table 1-1: 
Schedule of Activities 
Procedure 
Screening 
Period 
Dosing Period 1 or Dosing Period 2 a 
SFU b 
2 to 28 days 
before 
administration 
of IMP 
Check in 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
7 to 9 days 
after the last 
administration 
of IMP 
j Participants will check out of the clinical unit the morning of Day 4, approximately 24 hours after the final dose of IMP administered, at the discretion of the 
Investigator. 
 
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2 
INTRODUCTION 
Product description 
Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide) is a 
2-pyrrolidone derivative. The current targeted therapeutic indications for BRV in Japan are 
monotherapy and adjunctive therapy in the treatment of focal/partial-onset seizures (POS) with 
or without secondary generalization in patients from 4 years of age with epilepsy. 
Brivaracetam displays a high and selective affinity for the synaptic vesicle protein 2A (SV2A) in 
the brain. Binding to SV2A is believed to be the primary mechanism for BRV anticonvulsant 
activity (Matagne et al, 2008). 
More detailed information regarding the nonclinical and clinical development programs for 
BRV, including all completed and ongoing studies, can be found in the latest version of the 
Investigator’s Brochure (IB). 
Pharmacokinetics 
Brivaracetam is rapidly and completely absorbed throughout the gastrointestinal tract. The 
median tmax is 1hr (range: 0.25 to 3hr) after dosing in fasting participants. The pharmacokinetics 
(PK) of BRV is dose proportional from 10mg to at least 600mg (for single dose). A food-effect 
study involving administration of BRV to healthy participants under fasting conditions and with 
a high-fat, high-calorie meal indicated that under fed conditions the Cmax was decreased by 28% 
and tmax occurred 3hr later, while the AUC remained unchanged. The decrease in absorption rate 
is not clinically significant; therefore, BRV can be taken without regards to meals. 
Brivaracetam follows single-compartment first-order PK, without an apparent distribution phase. 
The volume of distribution is 0.5L/kg, a value that is close to the volume of total body water. 
Brivaracetam is weakly bound to plasma proteins (<20%). The plasma half-life of BRV is 
approximately 9hr in healthy adults. More than 95% of the dose, including less than 9% as 
unchanged BRV, is excreted in the urine within 72hr after dosing. Fecal and expired air 
excretion account for <1% of the dose. 
The main disposition pathway of BRV is by cytochrome P450 (CYP)-independent hydrolysis of 
the acetamide group to the corresponding carboxylic acid (ucb42145) and is thought to be 
mediated by hydrolases. A second disposition pathway involves ω1-hydroxylation 
(ucb-101406-1), which is mediated by CYP2C19. A combination of these 2 pathways leads to 
the formation of the hydroxyacid metabolite (ucb-107092-1). These 3 metabolites are not 
pharmacologically active. There is no evidence of chiral inversion of BRV. In a PK and 
pharmacodynamic interaction study in healthy participants, BRV increased the effects of alcohol 
on psychomotor function, attention, and memory, although there was no clinically relevant PK 
interaction. 
Information regarding the bioequivalence between BRV oral tablet and BRV dry syrup from a 
previous study, EP0110, is presented in Section 2.1. 
Safety profile in clinical pharmacology studies 
Thirty-two clinical pharmacology studies with BRV have been conducted in healthy participants, 
with the highest single dose given being BRV 1400mg. 
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Safety data were pooled (Pool Phase 1) in 2014 for all completed clinical pharmacology studies 
with the exceptions of N01118 (elderly study participants), N01109 (study participants with 
renal impairment), and N01111 (study participants with hepatic impairment), due to the inherent 
differences in these study populations, as well as the 3 formulation studies conducted for BRV 
(EP0113, EP0115, and EP0131). N01209 and EP0117 studies in healthy male Japanese study 
participants, were also included in Pool Phase 1. N01069, a Phase 2a study in participants with 
photosensitive epilepsy, was included in Pool Phase 1 due to its single-dose study design, which 
was similar to a clinical pharmacology study. Pool Phase 1 includes participants who received 
BRV oral tablets, capsules, and solution, and participants who received solution for 
intravenous (iv) injection. Pool Phase 1 included 220 participants in the placebo group and 
729 participants in the BRV Overall group. Treatment-emergent adverse events (TEAEs) were 
reported for 67 participants (30.5%) in the placebo group and 586 participants (80.4%) in the 
BRV Overall group. The most frequently reported TEAEs in Pool Phase 1 included dizziness, 
somnolence, fatigue, headache, euphoric mood, and feeling drunk. Most participants reported 
TEAEs with a maximum intensity of mild. There were no clinically meaningful differences in 
mean changes in hematology and clinical chemistry values or clinically meaningful observations 
in qualitative urinalysis parameters over time in the pooled Phase 1 data. 
In N01209, a single- and multiple-dose PK study in healthy Japanese participants with 
single-dose ranging from BRV 2.5mg to 100mg oral tablets and multiple-doses ranging from 
BRV 2.5mg twice daily (5mg/day) to 50mg twice daily (100mg/day) oral tablets, a total of 
11 adverse events (AEs) were reported, in the following preferred terms: diarrhea, somnolence, 
pharyngolaryngeal pain, asthenia, rash, headache, and dizziness. In EP0117, a study that 
evaluated BRV PK after iv and oral tablets administration in healthy male Japanese participants, 
the most commonly reported TEAEs were somnolence, dizziness, and nausea. 
In EP0110, a single-dose bioequivalence study between BRV 50mg tablet and BRV 50mg as dry 
syrup formation in healthy male Japanese participants, no notable difference was observed in the 
overall incidences of TEAEs after administration of the BRV tablet and dry syrup formulations. 
No major differences in the safety profile were observed between the 2 formulations, and no 
unexpected safety findings were observed during the study. There were no serious TEAEs, 
severe TEAEs, or TEAEs leading to discontinuation or death. 
A thorough QT study demonstrated the absence of an effect of BRV on cardiac repolarization at 
both therapeutic and supratherapeutic doses of BRV. 
2.1 
Study rationale 
Brivaracetam is being developed for monotherapy and adjunctive therapy in the treatment of 
POS with or without secondary generalization in adult and pediatric patients with epilepsy in 
Japan. In addition to tablets, a dry syrup formulation is being developed specifically for the 
Japanese market, mainly to allow dose adjustment by body weight in pediatric patients and 
patients with dysphagia. 
As patients may switch from the dry syrup to the tablet, or vice versa, and dry syrup is favorable 
in pediatric patients and patients with dysphagia, it is important to know whether the dry syrup 
formulation shows a similar PK profile as the tablet formulation. 
A prior study, EP0110, assessed the bioequivalence between the BRV 50mg oral tablet and BRV 
50mg dry syrup by employing a standard single-dose, 2-treatment, and 2-period randomized 
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cross-over design, in alignment with the Japanese bioequivalence guideline (Pharmaceutical 
Safety and Environmental Health Bureau [PSEHB]/Pharmaceutical Evaluation Division [PED] 
Notification No. 0319-1, 2020), which recommends a single-dose study with a usual clinical 
dose. Although all other PK parameters assessed were similar for both formulations (ie, AUC, 
AUCextr, CL/F, VZ/F, MRT, tmax, t½, and λz) and AUC(0-t) met the criteria for bioequivalence, the 
observed Cmax following administration of the tablet was higher than that observed for the dry 
syrup; therefore, bioequivalence was not concluded between the 2 formulations (refer to 
Section 9.8 for additional details). 
A subsequent PK simulation based on the data collected in EP0110 showed that in a multiple 
dose setting, bioequivalence could be established, as the intraparticipant variability for Cmax seen 
in EP0110 decreased while the mean ratio for Cmax increased. 
Based upon the outcome of EP0110 and in alignment with the Japanese bioequivalence guideline 
(PSEHB/PED Notification No. 0319-1, 2020), EP0231 will assess the bioequivalence of the 
same formulations used in EP0110, employing a group sequential design with twice daily dosing 
for a total of 5 doses over 3 days. 
2.2 
Background 
Brivaracetam has primarily been studied as oral (tablet) adjunctive therapy in participants with 
refractory epilepsy, a conversion to monotherapy indication for POS (monotherapy indication 
was approved in the US by an extrapolation strategy from adjunctive therapy). In addition, an 
iv formulation of BRV has been studied in participants with epilepsy (N01258) and has also been 
evaluated as a replacement for oral BRV in adult Japanese participants with POS with or without 
secondary generalization (EP0118). Two oral formulations of BRV were developed for the 
pediatric program; however, only 1 formulation (oral solution; 10mg/mL) is indicated for use. 
For BRV to be available in a second formulation as a dry syrup in Japan, mainly for pediatric 
patients and patients with dysphagia, the primary objective of this study is to assess the 
bioequivalence between the BRV 50mg tablet and BRV 50mg as dry syrup after multiple oral 
doses in healthy male Japanese participants. 
2.3 
Benefit/Risk assessment 
The healthy participants included in this study will receive no medical benefit from participation. 
In addition to the most frequently reported AEs from the pooled BRV safety data described in 
Section 2 (ie, dizziness, somnolence, fatigue, headache, euphoric mood, feeling drunk), the 
potential risks in the study include: 
• Electrocardiogram (ECG) stickers on the participants' chests and limbs may cause some local 
irritation and may be uncomfortable to remove. Participants will be closely monitored to 
ensure any local irritation does not persist. 
• During cannulation, more than 1 attempt may be needed to insert the cannula in a vein of a 
participant, and it is possible that bruising, inflammation, and/or hematoma may occur at the 
site of cannulation. 
In the BRV drug development program, the 50mg dose twice daily has been shown to be well 
tolerated in healthy participants. 
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More detailed information about the known and expected risks and reasonably expected AEs of 
BRV are available in the IB. 
Any risks during the study will be minimized by implementation of the following procedures: 
• The dose to be administered (50mg twice daily) is 50% of the maximum approved daily dose 
as per the US and EU labels (200mg/day). 
• The participants will reside in the clinical unit from the day prior to administration of the first 
dose to approximately 24 hours after administration of the final dose of BRV for each Dosing 
Period. 
• All doses will be administered under medical supervision. 
• All participants will be closely monitored through the measurement of blood pressure, heart 
rate, respiratory rate, and body temperature. In addition, physical examinations will be 
performed on Day -1 and Day 4 of each Dosing Period and 7 to 9 days after the last 
administration of IMP. Electrocardiograms will be performed on Day 1 and Day 4 of each 
Dosing Period and 7 to 9 days after the last administration of IMP. 
2.3.1 
Risk assessment for coronavirus disease 2019 
Brivaracetam is a highly selective ligand of SV2A in the brain. It has anticonvulsant activity and 
is marketed in several countries for treatment of certain forms of epilepsy (focal or POS). 
Brivaracetam is not expected to interact with the immune system or to inhibit innate or adaptive 
immunity. 
The most frequently reported AEs in clinical pharmacology studies were effects on the central 
nervous system (eg, dizziness, somnolence, fatigue, headache, euphoric mood, and feeling 
drunk). 
In this study, 2 BRV formulations (tablet and dry syrup) will be administered in 2 Dosing 
Periods as with a total of 5 administrations of BRV 50mg on Day 1 and Day 2 (morning and 
evening doses 12 hours apart), and Day 3 (morning dose only) each Dosing Period (see 
Figure 1-1). 
Although effects on the central nervous system are possible, it appears to be unlikely that BRV 
has substantial effects that will worsen coronavirus disease 2019 (COVID-19) in infected 
participants. 
Therefore, the risk of the participants to be exposed to the virus that causes COVID-19 is 
expected to be similar to the general population. However, the risk of exposure to infected 
people cannot be completely excluded as the participants may have additional contact (eg, 
commute to the site) and have additional human contact (eg, with site staff and other participants 
of the clinical study). 
Precautions for COVID-19 will be implemented based on local regulations at the study site at the 
time of study conduct and may include, but are not limited to, screening for severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), asking participants about their potential 
exposure to SARS-CoV-2, monitoring participants for any signs and symptoms of COVID-19, 
and testing for SARS-CoV-2. Refer to Section 5.3.5 for further details. 
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In the case that COVID-19 is suspected or confirmed, administration of further IMP to that study 
participant will be suspended, and the Investigator will determine (ideally in discussion with the 
UCB Study Physician) how soon the participant may be discharged from the study site, and 
whether this will be to their home or another healthcare facility. 
3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary objective 
• 
To assess bioequivalence between the BRV 
50mg tablet and BRV 50mg dry syrup after 
multiple oral doses in healthy male Japanese 
participants 
Primary PK endpoints from plasma BRV 
concentrations: 
• 
Cmax,ss 
• 
AUCtau 
Secondary objective 
• 
To evaluate the safety and tolerability of 
multiple oral doses of the BRV 50mg tablet 
and BRV 50mg dry syrup in healthy male 
Japanese participants 
Secondary safety endpoints: 
• 
Incidence of TEAEs 
• 
Incidence of treatment-emergent SAEs 
• 
Incidence of TEAEs leading to discontinuation 
Other objectives 
• 
To evaluate other PK parameters after 
multiple oral doses of the BRV 50mg tablet 
and BRV 50mg dry syrup in healthy male 
Japanese participants 
Other PK endpoints from plasma BRV 
concentrations: 
• 
Ctrough 
• 
CLss/F 
• 
tmax,ss 
• 
To further evaluate the safety and tolerability 
after multiple oral doses of the BRV 50mg 
tablet and BRV 50mg dry syrup in healthy 
male Japanese participants 
Other safety endpoints: 
• 
Change from Baseline in clinical laboratory test 
parameters (ie, hematology, clinical chemistry, 
and urinalysis) 
• 
Change from Baseline in vital signs (SBP, DBP, 
body temperature, respiratory rate, and heart 
rate) 
• 
12-lead ECG parameters and findings 
• 
Physical examinations 
AUCtau=area under the curve during a dosing interval at steady state; BRV=brivaracetam; CLss/F=apparent total 
body clearance at steady state; Cmax,ss=maximum plasma concentration at steady state; Ctrough=measured 
concentration at the end of a dosing interval at steady state; DBP=diastolic blood pressure; 
ECG=electrocardiogram; PK=pharmacokinetics; SAE=serious adverse event; SBP=systolic blood pressure; 
TEAE=treatment-emergent adverse event; tmax, ss=time of Cmax,ss 
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4 
STUDY DESIGN 
4.1 
Overall design 
EP0231 is a single-center, multiple-dose, open-label, randomized, group sequential design, 
2-way cross-over study to assess the bioequivalence of BRV 50mg tablet and BRV 50mg dry 
syrup in healthy male Japanese participants after oral administration under fasted conditions. In 
addition, the safety and tolerability of BRV will be evaluated. 
Participants will enter a Screening Period (2 to 28 days before administration of IMP), and 
eligible participants will start the Dosing Period. The Dosing Period consists of 2 periods 
(Dosing Period 1 and Dosing Period 2) of 5 days each (Day -1 to Day 4) with a total of 
5 administrations of BRV 50mg on Day 1 and Day 2 (morning and evening doses 12 hours 
apart), and Day 3 (morning dose only). 
Participants will receive 1 of the following treatments in each Dosing Period under fasting 
conditions according to randomly assigned treatment sequences (A-B or B-A): 
• Treatment A – multiple doses of BRV 50mg tablets 
• Treatment B – multiple doses of BRV 50mg dry syrup (1.25g of granules for oral 
suspension 4% w/w) 
• In the treatment sequence A-B, on Day 1 and Day 2 of Dosing Period 1, each participant 
will receive twice daily (morning and evening 12 hours apart) a dose of BRV tablet 
formulation (50mg); on Day 3 of Dosing Period 1, each participant will receive a single 
morning dose of BRV tablet formulation (50mg). On Day 1 and Day 2 of Dosing 
Period 2, each participant will receive twice daily (morning and evening 12 hours apart) a 
dose of BRV 50mg dry syrup (1.25g of granules for oral suspension 4% w/w); on 
Day 3 of Dosing Period 2, each participant will receive a single morning dose of BRV 
50mg dry syrup (1.25g of granules for oral suspension 4% w/w). 
• In treatment sequence B-A, on Day 1 and Day 2 of Dosing Period 1, each participant will 
receive twice daily (morning and evening doses 12 hours apart) a dose of BRV 50mg dry 
syrup (1.25g of granules for oral suspension 4% w/w); on Day 3 of Dosing Period 1, each 
participant will receive a single morning dose of BRV 50mg dry syrup (1.25g of granules 
for oral suspension 4% w/w). On Day 1 and Day 2 of Dosing Period 2, each participant 
will receive twice daily (morning and evening doses 12 hours apart) a dose of BRV tablet 
formulation (50mg); on Day 3 of Dosing Period 2, each participant will receive a single 
morning dose of BRV tablet formulation (50mg). 
The Dosing Periods will be separated by a Wash-Out Period (minimum of 6 days and preferably 
no more than 10 days between the final dose in Dosing Period 1 and the first dose in Dosing 
Period 2 for each participant) and followed by an SFU Visit, 7 to 9 days after the last 
administration of IMP. Participants who prematurely discontinue the IMP/study will be 
encouraged to return for an SFU Visit, 7 to 9 days after the final IMP administration. 
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During each of the 2 Dosing Periods (ie, Dosing Period 1 and Dosing Period 2), participants will 
be admitted to the clinical study center on Day -1 (1 day before administration of IMP). 
Participants will fast for at least 2 hours before and 2 hours after each IMP administration on 
Day 1 and Day 2; on Day 3, participants will fast for 10 hours before and 4 hours after the final 
IMP administration. Participants will receive standard meals for breakfast, lunch, and dinner 
during the 5-day in-clinic period. Participants will be discharged on the morning of Day 4 of 
each Dosing Period, approximately 24 hours after the administration of the final dose of IMP, 
provided there are no medical objections in the opinion of the Investigator. 
The blood sampling scheme for the determination of the plasma concentrations of BRV in each 
Dosing Period is shown in Figure 4-1. 
Figure 4-1: Blood sampling scheme 
 
Safety and tolerability will be monitored throughout the study by monitoring of AEs, collecting 
blood and urine samples for the examination of safety laboratory parameters, measurement of 
vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], heart rate, respiratory 
rate, and body temperature), ECGs, and completion of physical examinations per the Schedule of 
Activities (Section 1.3). 
Within the group sequential design, up to approximately 96 participants will be recruited into 
2 cohorts to ensure a total of up to approximately 90 evaluable participants. After the first cohort 
(approximately 60 evaluable participants) has completed both Dosing Periods, an interim 
analysis will be performed and an internal DMC will determine whether the primary objective is 
achieved, futility of the study is confirmed, or whether the study should continue with 
recruitment of the second cohort (approximately 30 evaluable participants). 
4.2 
Scientific rationale for study design 
The primary objective of this study is to assess the bioequivalence between BRV 50mg tablet 
and BRV 50mg dry syrup after multiple oral doses. 
EP0231 will include a larger sample size of healthy male Japanese participants (up to 
approximately 90 evaluable participants) in contrast to a sample size of 24 participants in the 
 
 
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prior bioequivalence study EP0110. This increased sample size in EP0231 is an effort to 
minimize the impact of intraparticipant variability of the Cmax and to increase the Cmax ratio. The 
larger sample size is based on the results from EP0110 and the multiple dose simulation (refer to 
Section 9.8 for additional details). An interim analysis to assess bioequivalence will be 
performed after the first cohort of the group sequential design (approximately 60 evaluable 
participants) has completed both Dosing Periods. If the interim analysis demonstrates 
bioequivalence, the study will be stopped. 
The group sequential design has been selected to maximize the chances of success while 
enabling an early stop of the study (ie, after the first cohort) which may help to reduce the 
number of participants in the study. The study is powered to show bioequivalence in Cohort 1 
(Section 9.8). 
This study will be conducted in healthy male Japanese participants. A dry syrup formulation for 
BRV is being developed specifically for the Japanese market. 
4.3 
Justification for dose 
A dose of 50mg, per administration, was specified for this study as it was used in the prior 
bioequivalence study, EP0110 (refer to Section 2 for additional details). This dose was also 
proposed as the clinical dose in Japan (bioequivalence guideline in Japan) and is already used in 
other countries. In this study, a 50mg dose of BRV will be administered twice daily for a total of 
5 doses to allow steady state to be reached. 
4.4 
End of study definition 
A participant is considered to have completed the study if he has completed both Dosing Periods 
of the study as well as the SFU Visit assessments. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be between 20 to 50 years of age (inclusive) at the time of signing the 
informed consent form (ICF). 
Type of participant and disease characteristics 
2. Participant is overtly healthy as determined by medical evaluation including medical history, 
physical examination, laboratory tests, and cardiac monitoring. 
3. Participant has laboratory values within the reference range at the Screening Visit or has 
values exceeding the reference range but judged by the Investigator to not be clinically 
significant for participation in the study (refer to Section 5.2 for exclusion criteria regarding 
liver function). 
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4. Participant is of Japanese descent as evidenced by appearance and verbal confirmation of 
familial heritage (ie, participant has all 4 Japanese grandparents born in Japan). 
Weight 
5. Participant has a body weight of at least 50kg and body mass index within the range of 
18.0 to 30.0kg/m2 (inclusive) at the Screening Visit. 
Sex 
6. Participant is male. 
7. Participant must agree to use contraception as detailed in Appendix 4 (Section 10.4) starting 
from Screening through at least 2 days after the final dose of IMP and refrain from donating 
sperm during this period. 
Informed consent 
8. Participant is capable of giving signed informed consent as described in Appendix 1 
(Section 10.1), which includes compliance with the requirements and restrictions listed in the 
ICF and in this protocol. 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition including previous or current episode of 
suicidal ideation that, in the opinion of the Investigator, could jeopardize or would 
compromise the participant’s ability to participate in this study. 
2. Participant has any previous or current cardiovascular, respiratory, hepatic, renal, digestive, 
endocrine, or nervous system disorder that may affect absorption, secretion, metabolism, or 
excretion of IMP. 
3. Participant has a current history of alcohol or drug use disorder, as defined in Diagnostic and 
Statistical Manual of Mental Disorders V, or within the previous 6 months. 
4. Participant has a known hypersensitivity to any components of the IMP formulations. 
5. Participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or 
alkaline phosphatase (ALP) ≥1.0x upper limit of normal (ULN). 
6. Participant has bilirubin >1.0xULN (isolated bilirubin <1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
7. Participant has current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 
For randomized participants with a Baseline 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). 
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Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes rescreening. If the repeat values are below the ULN, the 
participant is considered to not meet the exclusion criteria. 
Prior/Concomitant therapy 
8. Participant has used other drugs, including vaccinations, over-the-counter medications, 
herbal/traditional medicines, or dietary supplements within 14 days before the first 
administration of IMP (excluding medicines for external use), with the exception of 
paracetamol, which is only prohibited during the 5 in-clinic days of each Dosing Period 
(Section 6.5.1). 
9. Participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, 
isoniazid, phenytoin, rifampicin) within 2 months before the first administration of IMP. 
Prior/Concurrent clinical study experience 
10. Participant has participated in another study of an IMP (and/or an investigational device) 
within the previous 30 days or within 5 times the half-life (whichever is longer) of the first 
dose of BRV in this study or is currently participating in another study of an IMP (and/or an 
investigational device). 
Diagnostic assessments 
11. Participant with clinically relevant abnormalities in a standard 12-lead ECG at 
Screening Visit as judged by the Investigator. 
12. Participant has a positive result for hepatitis B surface antigen, hepatitis C virus antibody test, 
human immunodeficiency virus antibody test, or syphilis at Screening Visit. 
13. Participant tests positive for alcohol and/or prohibited concomitant drugs (including cotinine) 
at the Screening Visit or on Day -1. 
Other exclusions 
14. Participant has donated blood or plasma or has experienced blood loss ≥400mL within 
90 days, ≥200mL within 30 days, or has donated any blood or plasma within 14 days before 
first administration of IMP. 
15. Participant is a current smoker or has used nicotine-containing products (eg, tobacco, 
patches, gum) within 30 days before the first administration of IMP. 
16. Participant consumes 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). 
17. Participant has consumed grapefruit or grapefruit juice within 7 days before first 
administration of the IMP. 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
• Participants must refrain from consumption of grapefruit until completion of the study. 
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5.3.2 
Caffeine, alcohol, and tobacco 
• During each Dosing Period, participants will abstain from ingesting caffeine- or xanthine-
containing products (eg, coffee, tea, cola drinks, and chocolate) for 48 hours before the start 
of dosing until after collection of the final PK sample. 
• During each Dosing Period, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK sample. 
• During each Dosing Period and the Wash-Out Period, participants will abstain from the use 
of nicotine-containing products for 30 days before the start of dosing until after collection of 
the final PK sample. 
5.3.3 
Activity 
• Participants will abstain from strenuous exercise for 96 hours before each blood collection 
for clinical laboratory tests. Participants may participate in light recreational activities during 
studies (eg, watching television, reading). 
5.3.4 
Food intake times 
The food intake schedule is applicable only on the days of IMP administration and PK sampling. 
Participants will fast for at least 2 hours before and 2 hours after each IMP administration on 
Day 1 and Day 2; on Day 3, participants will fast for 10 hours before and 4 hours after the final 
IMP administration. Participants will receive standard meals for breakfast, lunch, and dinner 
during the 5-day in-clinic period. 
Participants will be allowed water up to 1 hour before the scheduled dosing time. The BRV 
tablet will be administered with 200mL of water. 
The dry syrup will be mixed with 50mL of tap water; after intake, the dosing container will be 
rinsed with 50mL of water, which will also be taken. Then, the dosing container will be rinsed 
with 100mL of water and taken by the study participant. Water will be allowed ad libitum after 
2 hours postdose. 
5.3.5 
Other restrictions 
Even though the COVID-19 pandemic is no longer a global health emergency, participants are 
advised to adhere to local requirements to minimize potential exposure to and/or transmission of 
the virus that causes COVID-19 while ambulatory. 
All participants will be contacted by telephone before admission to the study site (as close to 
admission as feasible) to assess COVID-19 signs and symptoms and will be asked not to come to 
the site in case of suspected infection. 
The study site will adhere to common practices of monitoring participants for any sign and 
symptoms of COVID-19 (eg, fever, dysgeusia [taste loss/change], dysosmia [loss or 
distortion/change of smell], persistent cough, and dyspnea) throughout the study. 
For details on the risk assessment for COVID-19, refer to Section 2.3.1. 
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5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to an IMP treatment sequence. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened after Sponsor approval is given for rescreening. Rescreened participants should be 
assigned a new participant number. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes rescreening. If the repeat values are above the ULN, the 
participant will be considered a screen failure. 
6 
STUDY TREATMENTS 
Investigational medicinal product is defined as any investigational treatment(s), marketed 
product(s), placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol. 
6.1 
Treatments administered 
A summary of the treatments administered is provided in Table 6-1. 
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Table 6-1: 
Treatments administered 
ARM name 
Treatment A (Reference) 
Treatment B (Test) 
Intervention name 
Brivaracetam 
Brivaracetam 
Type 
Drug 
Drug 
Dose formulation 
Tablet 
Dry syrup 
Unit dose strength(s) 
1 tablet of 50mg 
1.25g of granules for oral 
suspension 4% w/w 
Dosage level(s) 
Multiple doses (5 in total; twice 
daily on Day 1 and Day 2 and 
morning dose only on Day 3) 
Multiple doses (5 in total; twice 
daily on Day 1 and Day 2 and 
morning dose only on Day 3) 
Route of 
administration 
Oral 
Oral 
Dosing instructions 
Tablet will be administered with 
200mL water. 
Dry syrup will be mixed with 50mL 
of tap water immediately prior to 
dosing; after intake, the dosing 
container will be rinsed with 50mL 
of water, which will also be taken. 
Then, the dosing container will be 
rinsed with 100mL of water and 
taken by the study participant. 
Use 
Experimental 
Experimental 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and labeling Tablets will be provided in 
high-density polyethylene bottles 
with polypropylene caps. Each 
bottle will be labeled as required per 
country requirements. 
Dry syrup will be provided in 
high-density polyethylene bottles 
with polypropylene caps. Each 
bottle will be labeled as required per 
country requirements. 
Excipients 
Croscarmellose sodium 
Lactose monohydrate 
Betadex (ß-cylcodextrin) 
Lactose anhydrous 
Magnesium stearate 
Hypromellose 
Titanium dioxide (E171) 
Macrogol 3350 
Saccharin sodium 
Talc 
Abbreviations: IMP=investigational medicinal product; w/w=weight/weight  
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6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all IMP received, and any discrepancies are reported and resolved 
before use of the IMP. 
Only participants enrolled in the study may receive IMP, and only authorized site staff may 
supply or administer IMP. All IMP must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the Investigator and authorized site staff. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log on a regular basis (eg, once a week) in 
accordance with local requirements, showing actual and minimum/maximum temperatures 
reached over the time interval. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
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 participant to store the IMP following the 
instructions on the label. 
Further guidance and information on the balance to be used for weighing the IMP and for the 
final disposition of unused IMP are provided in the IMP Handling Manual. 
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-participant 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. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers/partially used), unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB standard operating procedures 
or returned to UCB (or designee). Investigational medicinal product intended for the study 
cannot be used for any other purpose than that described in this protocol. 
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6.3 
Measures to minimize bias: randomization and blinding 
This is an open-label study. Randomization will be involved only in the assignment of 
participants to the treatment sequence as per the cross-over design, treatment sequences A-B or 
B-A. 
The study site will generate the randomization list for the treatment sequences (A-B or B-A) 
allocation. The randomization list will be reviewed by the Clinical Trial Statistician at UCB to 
ensure that the code meets the study requirements. 
6.3.1 
Procedures for maintaining and breaking the treatment blind 
Not applicable; this is an open-label study. 
6.4 
Treatment compliance 
Participant compliance to treatment will be ensured by the administration of IMP under the 
Investigator’s (or designated site personnel’s) supervision. Drug accountability must be recorded 
on the Drug Accountability Form. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are permitted during the study: 
• Paracetamol (acetaminophen) for the treatment of mild symptoms (eg, headache or pain 
relief) is permitted during the study at a maximum dose of 2g/day, except during the 
participant’s 5 in-clinic days (ie, from check-in [Day -1] through discharge [Day 4]) for 
each Dosing Period. 
• Participants are allowed vaccinations up to 14 days prior to the initiation of IMP 
administration. Vaccine administration will be entered as a prior medication in the eCRF. 
No other concomitant medications are allowed during this study. 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
With the exception of paracetamol (Section 6.5.1), all prescription or over-the-counter medicines 
(including herbal/traditional medicines and dietary supplements) are prohibited within 14 days 
before first IMP administration and during the study until SFU, unless required to treat an AE. 
Vaccinations are prohibited within the 14 days prior to the initiation of IMP administration and 
for the duration of the study until SFU. In addition, any hepatic enzyme-inducing drugs (eg, 
glucocorticoids, phenobarbital, isoniazid, phenytoin, rifampicin) are prohibited within 2 months 
before first IMP administration and during the clinical part of the study. 
If a participant 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 participant 
can continue in the study or must be withdrawn. 
6.6 
Dose modification 
No dose modifications are allowed during the study. 
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6.7 
Criteria for study hold or dosing stoppage 
Not applicable. 
6.8 
Treatment after the end of the study 
Not applicable. This is a Phase 1 study in healthy participants; therefore, no treatment will be 
provided after the end of the study. 
7 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of IMP 
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of IMP for abnormal liver function should be considered by the Investigator 
when a participant meets one of the conditions outlined (Figure 7-1) or if the Investigator 
believes that it is in best interest of the participant. 
Investigational medicinal product will be discontinued immediately and permanently for a 
participant if liver chemistry stopping criteria are met. 
Figure 7-1: Liver chemistry stopping algorithm 
 
ALT=alanine aminotransferase; ULN=upper limit of normal 
Evaluation of potential drug-induced liver injury (PDILI) must be initiated as described in this 
protocol. If participants are unable to comply with the applicable monitoring schedule, IMP must 
be discontinued immediately. 
Specific assessments and follow-up actions for PDILI are provided in Appendix 6 (Section 10.6). 
7.2 
Participant discontinuation/withdrawal from the study 
Participants are free to withdraw from the study at any time, without prejudice to their continued 
care. 
A participant may withdraw from the study at any time at his own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
Continue Study Treatment 
Discontinue Study Treatment 
ALT ≥3xULN 
No
Yes
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If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
See the Schedule of Activities (Section 1.3) for data to be collected at the time of study 
discontinuation and follow up and for any further evaluations that need to be completed. 
Participants should be withdrawn from the study if any of the following events occur: 
1. Participant withdraws his consent. 
2. Participant develops an illness that would interfere with his continued participation. 
3. Participant is noncompliant with the study procedures or IMP in the opinion of the 
Investigator. 
4. Participant takes prohibited concomitant medications as defined in this protocol. 
5. The Sponsor or a regulatory agency requests withdrawal of the participant. 
Participants must be withdrawn by the Investigator based on discussion with the Sponsor and 
Medical Monitor under the following circumstance: 
Any confirmed COVID-19 case that warrants discontinuation in the judgment of the 
Investigator or Sponsor to protect the safety of the participant, other participants, or study site 
staff (refer to Section 2.3.1 for additional details). 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a participant in advance. 
7.3 
Lost to follow up 
A participant will be considered lost to follow up if he fails to return for Dosing Period 2 or the 
SFU Visit and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for Dosing 
Period 2 or the SFU Visit. 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (at least 1 phone call and 1 written message 
to the participant) 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 participant, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal. 
Should the participant continue to be unreachable, he will be considered to have withdrawn from 
the study with a primary reason of lost to follow up documented in the eCRF. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue IMP. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 250mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1 
Efficacy assessments 
Not applicable. 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.2.1 
Physical examination 
Physical examination will include, at a minimum, general appearance; ear, nose, and throat; eyes, 
hair, and skin; and assessments of the cardiovascular, respiratory, gastrointestinal, neurological, 
musculoskeletal, and hepatic systems. Height and weight will also be measured and recorded at 
Screening only. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
8.2.2 
Vital signs 
Systolic blood pressure, DBP, heart rate, respiratory rate, and body temperature will be assessed. 
Vital signs will be measured in a supine position after the study participant has rested for at least 
5 minutes and will include SBP and DBP, heart rate, respiratory rate, and body temperature. 
Blood pressure and pulse measurements will be assessed in a quiet setting without distractions 
(eg, television, cell phones), with a completely automated device. Manual techniques will be 
used only if an automated device is not available. 
8.2.3 
Electrocardiograms 
Single 12-lead ECGs will be obtained at Screening, each Dosing Period (Day 1 predose and 
Day 4 prior to discharge), and the SFU Visit using an ECG machine that automatically calculates 
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the heart rate and measures PR, QRS, QT intervals, and QT interval corrected for heart rate with 
Fridericia’s formula (QTcF). 
All ECG recordings should be taken with the study participant resting in the supine position for 
at least 5 minutes before the recording. 
8.2.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
Schedule of Activities for the timing and frequency of these tests (Section 1.3). 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE Section of the eCRF. The 
laboratory reports must be filed with the source documents. Abnormal laboratory findings (ie, 
outside the normal range) will be considered clinically significant based on the Investigator’s 
judgment. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study after the final dose of IMP should be repeated until the values return to 
normal/Baseline, are stabilized, are no longer considered clinically significant by the Investigator 
or UCB Study Physician, or the participant is lost to follow up (as defined in Section 7.3). 
If such values do not return to normal within a period of time judged reasonable by the 
Investigator, the study participant will be referred to his General Practitioner for assessment and 
the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the Laboratory Manual and the Schedule of Activities 
(Section 1.3). 
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE), then the results must be recorded in 
the eCRF. 
8.3 
Adverse events and serious adverse events 
The definition of an AE or an SAE can be found in Appendix 3 (Section 10.3). 
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the IMP or study procedures, or that caused the participant 
to discontinue the IMP (Section 7). 
Confirmed COVID-19 cases will be recorded as AEs. 
For results disclosure on public registries (eg, ClinicalTrials.gov), TEAEs and 
treatment-emergent SAEs will be published. 
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8.3.1 
Time period and frequency for collecting AE and SAE information 
All SAEs will be collected from the signing of the ICF until the SFU Visit at the time points 
specified in the Schedule of Activities (Section 1.3). 
All AEs will be collected from the signing of the ICF until the SFU Visit at the time points 
specified in the Schedule of Activities (Section 1.3). 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that 
recurred or worsened after the initial visit. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
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 participant, and to also inform participants 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. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the Investigator determines that it is no longer clinically significant, the event is otherwise 
explained, or the participant is lost to follow up (as defined in Section 7.3). Further information 
on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification of an SAE by the Investigator to the Sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of an IMP 
under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IMP under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRBs), and investigators. 
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Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female partners of male participants will be collected after the start 
of IMP and until the end of the study. 
If a pregnancy is reported, the Investigator must immediately inform the Sponsor within 
1 working day of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4 (Section 10.4). 
8.3.6 
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 BRV. 
The AEs of special interest for BRV (by preferred term) are as follows: autoimmune nephritis, 
nephritis, nephritis allergic, tubulointerstitial nephritis, and uveitis syndrome. 
“Potential Hy’s Law” (ie, the finding of ≥3xULN ALT and/or AST in conjunction with ≥2xULN 
bilirubin [in absence of ≥2xULN ALP] with no alternative explanation for the biochemical 
abnormality) must ALWAYS be reported to UCB as a serious unexpected AE (ie, not waiting for 
any additional etiologic investigations to have been concluded). Follow-up information should 
then be reported if an alternative etiology is identified during investigation and monitoring of the 
participant. 
8.4 
Safety signal detection 
Not applicable. 
8.5 
Treatment of overdose 
Overdoses are unlikely as all doses will be administered by study staff. There is no specific 
antidote for a BRV overdose. 
However, in the unlikely event, in acute, significant overdose, the stomach may be emptied by 
gastric lavage, and forced diuresis or hemodialysis might be attempted. Treatment for any signs 
of overdose will be symptomatic. The participant should be kept under medical surveillance, and 
blood pressure, heart rate, ECG, and respiratory rate should be monitored. 
8.6 
Pharmacokinetics 
Blood samples of approximately 4mL will be collected for measurement of plasma 
concentrations of BRV as specified in the Schedule of Activities (Section 1.3) Instructions for 
the collection and handling of biological samples will be provided by the Sponsor. The actual 
date and time (24hr clock time) of each sample will be recorded. 
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Samples will be used to evaluate the PK of BRV. Each blood sample will be divided into 
2 aliquots (1 for PK and 1 as a backup). Samples collected for analyses of BRV plasma 
concentration may also be used to evaluate safety aspects related to concerns arising during or 
after the study. 
The primary and other PK endpoints are provided in Section 3. These will be calculated by the 
contract research organization (CRO). Details of the PK methods used for the calculations of the 
parameters are outlined in the Statistical Analysis Plan (SAP). Definitions for these PK endpoints 
are as follows: 
• AUCtau 
area under the curve during a dosing interval at steady state 
• CLss/F 
apparent total body clearance at steady state 
• Cmax,ss 
maximum plasma concentration at steady state 
• Ctrough 
measured concentration at the end of a dosing interval at steady state 
• tmax,ss 
time of Cmax, ss 
Brivaracetam concentration will be determined in study plasma samples using a validated liquid 
chromatography electrospray ionization tandem mass spectrometry bioanalytical method. The 
lower limit of quantification will be 2ng/mL. The assays will be performed in accordance with 
International Council for Harmonisation (ICH) guideline M10 on bioanalytical method 
validation and study sample analysis, January 2023. 
Blood sampling time for PK analysis is provided below, and a blood sampling scheme is 
provided in Figure 4-1. 
• Day 1 (before the morning and evening doses [0 and 12hr post the initial dose]) 
• Day 2 (before the morning and evening doses [24 and 36hr post the initial dose]) 
• Day 3 (before the morning [only] dose [48hr post the initial dose] and 10min, 15min, 20min, 
30min, 45min, 60min, 75min, 90min, 2hr, 6hr, 9hr, and 12hr postdose) 
Study sites should aim to collect PK samples at the nominal time points to the extent possible. 
However, the maximum deviations from scheduled sampling times considered irrelevant for PK 
are defined in Table 8-1. 
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Table 8-1: 
Irrelevant time deviations for PK sampling 
PK blood sampling times 
Deviation from scheduled time considered irrelevant 
Day 1 predose 
-30 to 0min 
Day 2 predose 
-5 to 0min 
Day 3 predose 
-5 to 0min 
Day 3 postdose 10min-1.5hr 
±2min 
Day 3 postdose 2-9hr 
±5min 
Day 3 postdose 12hr 
0 to +5min 
PK=pharmacokinetic 
Pharmacokinetic blood samples should be collected within the allowable range described in 
Table 8-1, and dosing of the IMP should commence at the scheduled time. The time at which the 
administration of IMP begins must be documented. Any changes in the timing or addition of 
time points for any planned study assessments must be documented and approved by the relevant 
study team member and then archived in the Sponsor and site study files, but will not constitute a 
protocol amendment. The IRB will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF. 
8.7 
Biomarkers 
Not applicable. 
8.8 
Immunogenicity assessments 
Not applicable. 
8.9 
Health economics 
Not applicable. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the SAP. 
9.1 
Definition of analysis sets 
The following analysis sets will be defined. The reasons for exclusion of participants from any of 
the below analysis sets will be listed. 
Enrolled Set 
All participants who have signed the ICF will be included in the Enrolled Set. 
Randomized Set 
All enrolled participants who are randomized will be included in the Randomized Set. 
Safety Set 
All randomized participants who received at least 1 dose of the IMP will be included in the 
Safety Set (SS). 
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Pharmacokinetic Set 
All participants who are randomized, receive at least 1 dose of active IMP, and have at least 
1 quantifiable post-Baseline PK measurement will be included in the Pharmacokinetic 
Set (PKS). 
9.2 
General statistical considerations 
Statistical analysis and generation of tables, figures, and data listings will be performed using 
SAS Version 9.4 or higher. 
A complete set of listings containing both all documented data and all calculated data will be 
generated. Missing data will not be imputed. 
For categorical endpoints, the number and percentage of participants in each category will be 
presented. The denominator for percentages will be based on the number of participants 
appropriate for the purpose of the analysis. For continuous endpoints, descriptive statistics will 
include number of participants, mean, standard deviation (SD), median, minimum, and 
maximum. Geometric mean, geometric coefficient of variation (CV), and 95% confidence 
interval (CI) for the geometric mean will also be presented in the descriptive statistics for plasma 
concentrations and PK parameters. 
For PK parameter estimation, a noncompartmental analysis will be performed using Phoenix 
WinNonlin® Version 8.0 or higher (Certara L.P., Princeton, NJ, USA). 
9.3 
Planned outcome analyses 
9.3.1 
Pharmacokinetic analyses 
Statistical analyses will be performed on the PKS. 
All PKS participants who have a sufficient number of bioanalytical assessments to calculate 
reliable estimates for the primary PK parameters for both BRV formulations will be included in 
the statistical analysis. 
If a participant’s predose concentration is greater than 5% of the corresponding Cmax,ss value in a 
Dosing Period, the participant’s data from that Dosing Period will be excluded from the 
statistical analysis. If a participant’s predose concentration is greater than 5% of the 
corresponding Cmax,ss value for both Dosing Periods, the participant will be excluded from the 
statistical analysis. 
If vomiting occurs at or before 2 times the median tmax for the tablet and the dry syrup within a 
Dosing Period, the participant’s data from that period will be excluded from the statistical 
analysis. If vomiting occurs at or before 2 times the median tmax,ss within a Dosing Period, for 
both Dosing Periods, the participant will be excluded from the statistical analysis. 
Descriptive statistics will be used to describe all PK parameters for each BRV formulation. 
Listing of sampling time deviations, individual concentration-time data, and individual PK 
parameters will be generated. Graphical displays of individual and mean concentrations by time 
will also be presented on semilogarithmic and linear scales. 
The bioavailability of BRV dry syrup (1.25g of granules for oral suspension 4% w/w, 
corresponding to 50mg of BRV) (Test) will be compared with BRV 50mg tablet (Reference). 
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The primary PK parameters Cmax,ss and AUCtau will be evaluated according to a linear mixed 
model, adapted to cross-over experimental designs. The model will include treatment (BRV 
formulation), period, and sequence as fixed effects. The participant (nested within the sequence) 
will be included as a random effect. Since the participant is entered as a random effect in the 
linear mixed model, the data from the nonaffected Dosing Period (ie, evaluable data) can still be 
used for the bioequivalence assessment even if the data from the other Dosing Period are 
excluded from the analysis. The dependent variables will be logarithmically (ln) transformed 
prior to statistical testing, following the usual recommendations. The CIs of the adjusted 
geometric mean ratio (GMR) (Test/Reference) will be calculated corresponding to the 
Lan-DeMets alpha spending function approximating a Pocock boundary (Lan and DeMets, 
1983), while maintaining the overall 2-sided significance level of 0.1.  
Bioequivalence between the Test (dry syrup) and Reference (tablet) formulations will be 
concluded if the CIs for Cmax,ss and AUCtau are contained in the range of 0.80 to 1.25. 
In the case that the CIs for Cmax,ss and AUCtau are not contained in the range of 0.80 to 1.25, 
bioequivalence can still be concluded if the following criteria are met: 1) the point estimate of 
the adjusted GMR (Test/Reference) for Cmax,ss and AUCtau are contained in the range of 
0.90 to 1.11, and 2) in vitro dissolution rates of Test (dry syrup) and Reference (tablet) 
formulations are available and are deemed similar according to the Japanese bioequivalence 
guideline (PSEHB/PED Notification No. 0319-1, 2020).  
The MIXED procedure in SAS software will be used for this analysis. 
For tmax,ss, a distribution-free 90% CI (Hodges-Lehmann’s method) will be calculated for the 
median difference between the tablet and the dry syrup formulations. 
9.4 
Planned safety and other analyses 
All safety analyses will be performed using the SS. All safety variables will be summarized by 
BRV formulation (tablet and dry syrup). Safety variables will be listed individually for detailed 
clinical review, when needed. 
9.4.1 
Secondary safety analyses 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) and 
characterized as pretreatment and treatment emergent according to the intake of the IMP. 
Adverse events with a start date prior to the first dose of IMP will be defined as pretreatment 
AEs. A TEAE is defined as any AE with a start date/time on or after the first dose of IMP or any 
unresolved event already present before administration of IMP that worsens in intensity 
following exposure to IMP. 
Adverse events will be summarized descriptively by BRV formulation (tablet or dry syrup), 
Primary System Organ Class, and Preferred Term according to the MedDRA® terminology. 
Additional tables will summarize TEAEs by severity and relationship to IMP as well as, if 
applicable, separate tables for TEAEs leading to withdrawal from the study and treatment-
emergent SAEs. 
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9.4.2 
Other safety analyses 
9.4.2.1 
Clinical laboratory assessments 
Clinical laboratory assessments (hematology and clinical chemistry) and changes from Baseline 
will be summarized using descriptive statistics by BRV formulation at each time point, as 
applicable. Shift tables from Baseline to post-Baseline scheduled time point will be presented by 
BRV formulation, as applicable. Urinalysis data and laboratory values outside the reference 
range will be provided in a listing. 
9.4.2.2 
Vital signs 
Vital signs assessments (SBP, DBP, heart rate, respiratory rate, and body temperature) and 
changes from Baseline will be summarized using descriptive statistics by BRV formulation at 
each time point. 
9.4.2.3 
Electrocardiograms 
Twelve-lead ECG assessments (PR, QRS, QT intervals, and QTcF) and changes from Baseline 
will be summarized using descriptive statistics by BRV formulation at each time point. 
9.4.2.4 
Physical examination 
Physical examination data will be listed. 
9.5 
Handling of protocol deviations 
All protocol deviations will be reviewed on an ongoing basis as part of the data cleaning and 
evaluation process. After all data have been verified/entered into the database, and prior to 
database lock, a Data Evaluation Meeting will be performed for each cohort. The purpose of this 
review meeting will be to examine all protocol deviations, define the PKS (Section 9.1), and to 
verify the quality of the data. If PK parameters are needed to define the PKS, it will be 
performed based on the analysis data set of the pharmacokinetic parameters. The data evaluation 
will also help in guiding decisions on how to manage data issues on a case-by-case basis (eg, 
missing values, dropouts, and protocol deviations). 
Accepted deviations from theoretical time points will be described in the appropriate documents 
and included in the electronic Trial Master File. After the data review, resolution of all issues, 
and documentation of all decisions, the database will be locked. 
9.6 
Handling of dropouts or missing data 
Handling of missing data will be detailed in the SAP. 
9.7 
Planned interim analysis and data monitoring 
The study may consist of 2 cohorts. A formal interim analysis is planned at the end of Cohort 1, 
once approximately 60 evaluable participants have completed the study. If bioequivalence or 
futility is not established in the interim analysis, the final analysis is planned at the end of 
Cohort 2, once all participants (approximately 90) have completed the study (Section 9.8). The 
interim analysis, based on a group sequential design, will be an unblinded analysis performed by 
an internal statistical team independent from the study team and will focus on the analysis for 
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primary PK parameters Cmax,ss and AUCtau. The results will be reviewed by an internal DMC, 
which is independent from the study team, and the following decisions will be made: 
1. Early stopping of the study due to demonstrating bioequivalence at the end of Cohort 1: 
The study will be stopped early, after Cohort 1, if bioequivalence between the Test (dry 
syrup) and Reference (tablet) formulations is established for Cmax,ss and AUCtau 
(Section 9.3.1). 
2. Early stopping of the study for futility at the end of Cohort 1: 
The study will be stopped early, after Cohort 1, in the event that bioequivalence is not 
established and the 1-sided (upper) 95% CI of the adjusted GMR (Test/Reference) is less 
than 0.8700 for Cmax,ss. This corresponds to the GMR of this study being markedly lower than 
that of single-dose bioequivalence study (EP0110). 
3. Continuing to Cohort 2: 
If bioequivalence or futility is not established, the study will continue to Cohort 2, and the 
remaining approximately 30 participants will be randomized. 
9.8 
Determination of sample size 
A total of up to approximately 90 participants are planned to be evaluable for the primary 
endpoint. 
As detailed in Section 9.7, this study may consist of 2 cohorts, with a formal interim analysis 
once Cohort 1 has completed both Dosing Periods. 
The BRV single-dose bioequivalence study (EP0110) between tablet (Reference) and dry syrup 
(Test) provided estimates of the GMR (Test/Reference) of 0.8700 for Cmax and 0.9890 for 
AUC(0-t) and the intraparticipant variability (CV%) of 21.9% for Cmax and 2.7% for AUC(0-t) 
(Table 9-1). The BRV multiple-dose PK simulation results based on the EP0110 study data 
provided estimates of the GMR of 0.9054 for Cmax,ss and 0.9893 for AUCtau and the 
intraparticipant variability (CV%) of 15.3% for Cmax,ss and 2.7% for AUCtau. 
Table 9-1: 
EP0110 and simulation results of relative bioavailability of BRV 
tablet formulation vs dry syrup formulation 
Parameter 
Statistic 
EP0110 
MD Simulation 
Cmax (μg/mL) a 
GMR of dry syrup/tablet 
(Intraparticipant CV%) 
0.8700 (21.9) 
0.9054 (15.3) 
AUC (h*μg/mL) b 
GMR of dry syrup/tablet 
(Intraparticipant CV%) 
0.9890 (2.7) 
0.9893 (2.7) 
AUC=area under the curve; AUC(0-t)=area under the curve from time 0 to the time of the last quantifiable 
concentration; AUCtau=area under the curve during a dosage interval at steady state; BRV=brivaracetam; 
Cmax=maximum plasma concentration; Cmax,ss=maximum plasma concentration at steady state; CV=coefficient 
of variation; GMR=geometric mean ratio; MD=multiple-dose 
a The Cmax,ss was used for MD simulation results, estimated based upon the EP0110 study data. 
b The AUC(0-t) was used for EP0110. The AUCtau was used for MD simulation results, based upon the EP0110 
study data. 
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In the event that EP0231 will have results similar to those observed in EP0110 without any 
improvement by the multiple-dose study design, 116 participants will be needed to provide a 
power of 90% with a fixed design (no interim analysis). However, because this study is 
conducted as a multiple-dose study, it is expected that the PK profile variability will be smaller. 
It is assumed that both the GMR and intraparticipant SD will show improvement (higher GMR 
and smaller intraparticipant SD) compared with the single-dose study (EP0110), closer to those 
shown in the multiple-dose PK simulation results. The study assumptions for GMR and 
intraparticipant CV% (for Cmax) are based on the approximate middle values of those seen in 
EP0110 and the multiple-dose PK simulations based on the EP0110 study data, assuming a GMR 
of 0.89 and intraparticipant SD of 0.183 (corresponding to a CV% of 18.5%).  
In the group sequential design for this study, an interim analysis will be performed for 
bioequivalence or futility after approximately 60 evaluable participants, which is at 90% power 
for bioequivalence based on the CIs of the adjusted GMR (Test/Reference) with the study 
assumptions. Should the assumption regarding variability and GMR not hold, with the study 
consequently not being stopped for demonstrating bioequivalence or futility at the interim 
analysis, this allows the opportunity to enroll a further approximately 30 participants and assess 
bioequivalence after approximately 90 evaluable participants. While maintaining the two 1-sided 
significance level of 0.05, this should be sufficient to state that the true GMR is in the range of 
0.80 to 1.25. The two 1-sided significance levels currently used are 0.03817 for the interim 
analysis and 0.02704 for the final analysis according to the Lan-DeMets alpha spending function 
approximating a Pocock boundary, assuming 60 evaluable participants in Cohort 1 and 30 
evaluable participants in Cohort 2 as the number of participants to be included in the analyses. A 
total of 90 evaluable participants will provide an overall power of >75% even if the GMR and 
intraparticipant CV% remain as observed in EP0110. 
The probability of study stopping for demonstrating bioequivalence for Cohort 1 (power at 
Cohort 1), futility at Cohort 1, and proceeding to Cohort 2 are approximately 91%, 
approximately 1%, and approximately 8%, respectively. If the study continues to Cohort 2, the 
bioequivalence will be assessed after completing Cohort 2. 
In order to ensure a total of up to approximately 90 evaluable participants for the primary 
endpoints, assuming a rate of dropout and nonevaluable participants of approximately 5%, 
64 participants for Cohort 1, 32 participants for Cohort 2, and up to 96 participants in total are 
estimated to be randomized in the study. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB, as defined in local regulations, 
ICH-Good Clinical Practice (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 that complies with the 
requirements of the current ICH-GCP version or applicable country-specific regulations will be 
responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, IB, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
participant-related documents to be used for the study to the IRB for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB for the protocol. 
The Investigator will also promptly report to the IRB all changes in the study, all unanticipated 
problems involving risks to participants or others, and any protocol deviations, to eliminate 
immediate hazards to participants. 
The Investigator will not make any changes in the study or study conduct without IRB approval, 
except where necessary to eliminate apparent immediate hazards to the participants. 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 as allowed. 
As part of the IRB requirements for continuing review of approved studies, the Investigator will 
be responsible for submitting periodic progress reports to the IRB (based on IRB requirements), 
at intervals appropriate to the degree of participant risk involved, but no less than once per year. 
The Investigator should provide a final report to the IRB 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 will also be informed by the Investigator or the Sponsor, as specified by the 
applicable regulatory requirements in Japan. Where applicable, investigators are to provide the 
Sponsor (or its representative) with evidence of such IRB notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the Investigator and/or CRO agreements, as applicable. 
10.1.3 
Informed consent process 
Participant’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. 
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Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee). Each participant will have the opportunity to discuss the study and its alternatives 
with the Investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant, or his legal representative, and by the person who conducted the informed consent 
discussion (Investigator or designee). The participant or his legal representative must receive a 
copy of the signed and dated ICF. As part of the consent process, each participant must consent 
to direct access to his medical records for study-related monitoring, auditing, IRB review, and 
regulatory inspection. 
If the ICF is amended during the study, the Investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB and use of the amended form. 
10.1.4 
Data protection 
The study site will affirm and uphold the participant’s confidentiality. Throughout this study, all 
data forwarded to UCB (or designee) will be identified only by the participant number assigned 
at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB, or representatives of regulatory authorities will be allowed to review that portion of the 
participant’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 participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant must be informed that his personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the participant. 
The participant must be informed that his medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
As described in Section 9.7, a formal interim analysis is planned at the end of Cohort 1 once 
approximately 60 evaluable participants have completed the study. The results will be reviewed 
by an internal DMC, which is independent from the study team. The DMC will make 1 of the 
following decisions: early stopping of the study if the study demonstrates bioequivalence at the 
end of Cohort 1, early stopping of the study if the study is futile at the end of Cohort 1, or 
continuing the study to Cohort 2. Details of the DMC will be provided in the DMC Charters. 
10.1.6 
Dissemination of clinical study data 
A plain language summary of the results of all Phase 1 through 4 clinical studies will be 
developed and shared on UCB’s website. 
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10.1.7 
Data quality assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the Investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. 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. 
10.1.7.1 
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 Case Report Form Completion Guidelines. 
10.1.7.2 
Apps 
No apps will be used in the study. 
10.1.8 
Source documents 
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). 
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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, quality of life 
questionnaires, or video, 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 participant’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). 
10.1.9 
Study and site start and closure 
The start of recruitment 
The start of recruitment is the first participant’s first visit and is also the start date of the clinical 
study. 
Study/site termination 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further IMP development 
10.1.10 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
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Authorship will be determined by mutual agreement and in line with the International Committee 
of Medical Journal Editors authorship requirements. 
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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in the table below will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Indices: 
MCV 
MCH 
WBC Count with 
Differential 
(absolute values 
and percentages): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
WBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry a 
Blood Urea Nitrogen (BUN) 
Potassium 
AST/SGOT 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Fasting Glucose 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, leukocyte, nitrite by 
dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• 
Alcohol breath test and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines) 
• 
Urine cotinine test 
• 
Serology (HIV antibody and antigen, HBsAg, hepatitis C virus antibody, and 
syphilis) 
All study-required laboratory assessments will be performed by a local laboratory. 
The results of each test must be entered into the eCRF. 
ALT=alanine transaminase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; eCRF=electronic Case 
Report Form; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; INR=international 
normalized ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; 
SAE=serious adverse event; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic 
transaminase; ULN=upper limit of normal; WBC=white blood cell 
a Details of liver chemistry stopping criteria and required actions and follow up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 and Section 10.6. All events of ALT ≥3×ULN and bilirubin 
≥2×ULN (>35% direct bilirubin) or ALT ≥3×ULN and INR >1.5, if INR is measured, may indicate severe liver 
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Laboratory 
Assessments 
Parameters 
injury (possible Hy’s Law), and must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). 
Investigators must document their review of each laboratory safety report. 
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10.3 
Appendix 3: Adverse events – Definitions and procedures for 
recording, evaluating, follow up, and reporting 
Definition of AE 
AE definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of IMP, whether or not considered related to the IMP. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of IMP. 
 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from Baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition, including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after IMP administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
 
Events NOT meeting the AE definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is 
not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical events: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
• 
Examples of such events include, but are not limited to, potential Hy’s Law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
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Recording and follow up of AE and/or SAE 
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records 
to UCB in lieu of completion of the UCB/AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all participant identifiers, with the exception of the participant number, will 
be redacted on the copies of the medical records before submission to UCB 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE may be 
either serious or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events should be used as a 
supportive standardization instrument to evaluate AEs and SAEs, but the final intensity grading by the 
Investigator must be mild, moderate, or severe. 
 
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Assessment of causality 
• 
The Investigator is obligated to assess the relationship between IMP and each occurrence of 
each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to IMP administration will be considered and 
investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in 
his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to UCB. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to UCB. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
 
Follow up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
• 
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 participant is lost to follow up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide UCB with a copy of any postmortem findings, including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to UCB within 24 hours of receipt of the 
information. 
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Reporting of SAEs 
SAE reporting to UCB via paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to UCB Drug Safety. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
Contacts for SAE reporting can be found in the Serious adverse event reporting Section At 
The Front Of The Protocol. 
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10.4 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information 
Contraception guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following (during the protocol-defined time frame in Section 5.1): 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 10-1 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition, male participants must refrain from donating sperm for the duration of the study and 
for 2 days after the final dose of IMP. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Table 10-1: Highly effective contraceptive methods for female partners a 
Highly effective contraceptive methods that are user dependent b 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation c 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly effective methods that are user independent c 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
IUD 
• 
IUS 
• 
Bilateral tubal occlusion 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the IMP. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant. 
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IMP=investigational medicinal product; IUD=intrauterine device; IUS=intrauterine hormone-releasing system 
a In case of newly started contraception pills/IUDs, the Investigator should consider the correct timing of 
starting/applying such methods in relation to the menstrual cycle and the manufacturing instruction as to when 
these newly started methods would become effective. 
b Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
c Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during the 
Dosing Period and for at least 3 months after the final dose of IMP. 
Collection of pregnancy information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 1 working day of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to UCB. Generally, the follow up will 
be at least 12 months after the delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver safety – suggested actions and follow-up 
assessments 
Participants with 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. 
Investigators should attempt to obtain information on participants in the case of IMP 
discontinuation to complete the final evaluation. 
Participants 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/or participant withdrawal (if applicable), must be recorded 
in the source documents. The eCRF must document the primary reason for discontinuation of 
IMP. 
A specific monitoring plan must be agreed between the UCB Study Physician and the 
Investigator for participants who have ALT >5×ULN. The monitoring plan should include any 
necessary follow-up assessments (until resolution of the abnormal laboratory values). 
Phase 1 liver chemistry stopping criteria are designed to assure study participant safety and to 
evaluate liver event etiology. 
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Table 10-2: Liver chemistry stopping criteria and follow-up assessments 
Liver chemistry stopping criteria 
ALT-absolute 
ALT ≥3xULN 
If ALT ≥3xULN AND bilirubin  2xULN (>35% direct bilirubin) or INR >1.5, 
report as a serious adverse event (SAE) a,b 
See additional actions and follow-up assessments below 
Required actions and follow-up assessments 
Actions 
Follow-up assessments 
• 
Immediately discontinue study intervention 
• 
Report the event to UCB within 24 hours 
• 
Complete the liver event eCRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE b 
• 
Perform liver function follow-up assessments 
• 
Monitor the study participant until liver 
function test abnormalities resolve, stabilize, or 
return to Baseline (see MONITORING) 
• 
Consider the need for a toxicology screening 
MONITORING: 
If ALT ≥3xULN AND bilirubin 2xULN or 
INR >1.5 
• 
Repeat liver function tests (include ALT, AST, 
ALP, bilirubin) and perform liver function 
follow-up assessments within 24 hours 
• 
Monitor study participant twice weekly until 
liver function test abnormalities resolve, 
stabilize, or return to Baseline 
• 
A specialist or hepatology consultation is 
recommended 
If ALT ≥3xULN AND bilirubin <2xULN and 
INR ≤1.5: 
• 
Repeat liver function tests (include ALT, AST, 
ALP, bilirubin) and perform liver function 
follow-up assessments within 24 to 72 hours 
• 
Monitor participants weekly until liver 
function abnormalities resolve, stabilize, or 
return to Baseline 
• 
Viral hepatitis serology c 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• 
Obtain blood sample for PK analysis within 
1 hour after the most recent dose d 
• 
Serum CPK and LDH 
• 
Fractionate bilirubin if total bilirubin 
2xULN 
• 
Complete blood count with differential to 
assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury (eg, fatigue, 
nausea, vomiting, right upper quadrant pain), 
or hypersensitivity, on the AE eCRF 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications eCRF 
• 
Record alcohol use on the liver event alcohol 
intake eCRF 
If ALT ≥3xULN AND bilirubin 2xULN or 
INR >1.5: 
• 
Antinuclear antibody, antismooth muscle 
antibody, Type 1 antiliver kidney microsomal 
antibodies, and quantitative total IgG or 
gamma globulins 
• 
Serum acetaminophen protein adducts 
(quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use in 
the preceding week) will be measured using a 
validated assay. 
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Table 10-2: Liver chemistry stopping criteria and follow-up assessments 
Liver chemistry stopping criteria 
ALT-absolute 
ALT ≥3xULN 
If ALT ≥3xULN AND bilirubin  2xULN (>35% direct bilirubin) or INR >1.5, 
report as a serious adverse event (SAE) a,b 
See additional actions and follow-up assessments below 
Required actions and follow-up assessments 
Actions 
Follow-up assessments 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver imaging and/or liver biopsy 
eCRFs 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CPK=creatine phosphokinase; eCRF=electronic Case Report Form; HBcAb=hepatitis B core antibody; 
HBsAg=hepatitis B surface antigen; HPLC=high performance liquid chromatography; IgG=immunoglobulin G; 
IgM=immunoglobin M; IMP=investigational medicinal product; INR=international normalized ratio; 
LDH=lactate dehydrogenase; PK=pharmacokinetic; RNA=ribonucleic acid; SAE=serious adverse event; 
ULN=upper limit of normal 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention if ALT ≥3xULN. Additionally, if serum bilirubin 
fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick, 
which is indicative of direct bilirubin elevations suggesting liver injury. 
b All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR >1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis). The INR measurement is not required, and the stated threshold value will 
not apply to participants receiving anticoagulants. 
c Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
d Record the date/time of the PK blood sample draw and the date/time of the last dose of IMP prior to the PK 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the study participant’s 
best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the Study Reference Manual. 
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10.7 
Appendix 7: Medical device AEs, adverse device effects, SAEs, 
and device deficiencies: Definition and procedures for 
recording, evaluating, follow-up, and reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid alert procedures 
Not applicable. 
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10.9 
Appendix 9: Country-specific requirements 
The country-specific requirements for Japan will be provided separately. 
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10.10 
Appendix 10: Abbreviations and trademarks 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BRV 
brivaracetam 
CI 
confidence interval 
CRO 
contract research organization 
CYP 
cytochrome P450 
COVID-19 
coronavirus disease 2019 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
GCP 
Good Clinical Practice 
GMR 
geometric mean ratio 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
iv 
intravenous 
MedDRA® 
Medical Dictionary for Regulatory Activities 
PDILI 
potential drug-induced liver injury 
PED 
Pharmaceutical Evaluation Division 
PK 
pharmacokinetics 
PKS 
Pharmacokinetic Set 
POS 
partial-onset seizures 
PSEHB 
Pharmaceutical Safety and Environmental Health Bureau 
QTcF 
QT interval corrected for heart rate with Fridericia’s formula 
SAE 
serious adverse event 
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SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SFU 
Safety Follow-Up 
SS 
Safety Set 
SV2A 
synaptic vesicle protein 2A 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
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10.11 
Appendix 11: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
before the Table of Contents. 
Amendment 1 (14 Dec 2023) 
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11 
REFERENCES 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-adduct in adults 
with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009;37:1779-84. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-63. 
Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H. Anti-convulsive and 
anti-epileptic properties of brivaracetam (UCB34714), a high-affinity ligand for the synaptic 
vesicle protein, SV2A. Br J Pharmacol. 2008;154:1662-67. 
Ministry of Health, Labour and Welfare. PSEHB/PED Notification No. 0319-1 The Partial 
Amendment to Guideline for Bioequivalence Studies of Generic Products 19 Mar 2020. 
 
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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:
ep0231-protocol-amendment-1
Version:
1. 0
Document Number:
CLIN-000242076
Title:
EP0231 Protocol Amendment 1
Approved Date:
15 Dec 2023
Document Approvals
Approval
Verdict: Approved
Name:
Capacity: Clinical
Date of Signature: 15-Dec-2023 13:10:32 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 15-Dec-2023 14:47:34 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Dec-2023 15:33:31 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Dec-2023 16:34:32 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
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EP0231 
 
 
 
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STATISTICAL ANALYSIS PLAN 
AMENDMENT 1 
Study: EP0231 
Product: Brivaracetam 
 
 A MULTIPLE-DOSE, OPEN-LABEL, RANDOMIZED, 2-WAY 
CROSS-OVER STUDY TO ASSESS THE BIOEQUIVALENCE 
BETWEEN BRIVARACETAM TABLET AND DRY SYRUP IN 
HEALTHY MALE JAPANESE PARTICIPANTS 
 A multiple-dose study to assess the bioequivalence between 
brivaracetam tablet and dry syrup in healthy male Japanese 
participants 
 
Sponsor Name: UCB Biopharma SRL 
Legal Registered Address: Allée de la Recherche 60 1070 Brussels BELGIUM 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
EudraCT Number 
Not Applicable 
EU Trial Number 
Not Applicable 
EUDAMED Number 
Not Applicable 
IND Number 
Not Applicable 
IDE Number 
Not Applicable 
NCT Number 
NCT06312566 
 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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TABLE OF CONTENTS 
VERSION HISTORY ................................................................................................................ 4 
1 
INTRODUCTION ............................................................................................................. 5 
1.1 
Objectives and endpoints ............................................................................................... 5 
1.2 
Study design ................................................................................................................... 6 
2 
STATISTICAL HYPOTHESES ...................................................................................... 10 
2.1 
Multiplicity adjustment ................................................................................................ 10 
3 
POPULATIONS FOR ANALYSIS ................................................................................. 10 
3.1 
Enrolled Set .................................................................................................................. 10 
3.2 
Randomized Set ........................................................................................................... 10 
3.3 
Safety Set ..................................................................................................................... 10 
3.4 
Pharmacokinetic Set..................................................................................................... 11 
4 
STATISTICAL ANALYSES .......................................................................................... 11 
4.1 
General considerations ................................................................................................. 11 
4.1.1 
Analysis time points ............................................................................................ 12 
4.1.1.1 
Relative day for listings ............................................................................. 12 
4.1.1.2 
Analysis periods ........................................................................................ 13 
4.1.2 
Definition of baseline values ............................................................................... 14 
4.1.3 
Mapping of assessments performed at Early Discontinuation Visit .................... 15 
4.1.4 
Treatment assignment and treatment groups ....................................................... 15 
4.1.5 
Multicenter studies ............................................................................................... 15 
4.1.6 
Center pooling strategy ........................................................................................ 15 
4.2 
Primary endpoint analyses ........................................................................................... 15 
4.2.1 
Definition of endpoints ........................................................................................ 15 
4.2.2 
Main analytical approach ..................................................................................... 15 
4.2.3 
Supportive and sensitivity analyses ..................................................................... 17 
4.3 
Secondary endpoint analyses ....................................................................................... 17 
4.3.1 
Secondary endpoints ............................................................................................ 17 
4.3.1.1 
Definition of endpoint(s) ........................................................................... 17 
4.3.1.2 
Main analytical approach .......................................................................... 18 
4.4 
Exploratory endpoint analysis ...................................................................................... 18 
4.5 
Other Safety analyses ................................................................................................... 18 
4.5.1 
Extent of exposure ............................................................................................... 19 
4.5.2 
Adverse events ..................................................................................................... 19 
4.5.3 
Additional safety assessments ............................................................................. 21 
4.5.3.1 
Clinical laboratory evaluations .................................................................. 21 
4.5.3.2 
Vital signs .................................................................................................. 24 
4.5.3.3 
Electrocardiograms .................................................................................... 24 
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4.5.3.4 
Other safety endpoint(s) ............................................................................ 25 
4.6 
Other analyses .............................................................................................................. 25 
4.6.1 
Other endpoints and/or parameters ...................................................................... 25 
4.6.1.1 
Pharmacokinetics ....................................................................................... 25 
4.6.1.2 
Pharmacodynamics .................................................................................... 27 
4.6.1.3 
Population pharmacokinetics..................................................................... 27 
4.6.1.4 
Immunogenicity ......................................................................................... 27 
4.6.1.5 
Genomics ................................................................................................... 27 
4.6.1.6 
Biomarkers ................................................................................................ 27 
4.6.1.7 
Pregnancy outcomes .................................................................................. 27 
4.6.1.8 
Health care utilization related endpoints ................................................... 28 
4.6.1.9 
Health technology assessment related endpoints ...................................... 28 
4.6.2 
Subgroup analyses ............................................................................................... 28 
4.7 
Interim analyses ........................................................................................................... 28 
4.8 
Changes to protocol-planned analyses ......................................................................... 28 
4.9 
Data Monitoring Committee (DMC) or other review board ........................................ 29 
5 
SAMPLE SIZE DETERMINATION .............................................................................. 29 
6 
APPENDIX: SUPPORTING DOCUMENTATION ....................................................... 31 
6.1 
Appendix 1: List of Abbreviations .............................................................................. 31 
6.2 
Appendix 2: Coding dictionaries ................................................................................. 33 
6.3 
Appendix 3: Participant disposition ............................................................................. 33 
6.4 
Appendix 4: Baseline characteristics and demographics ............................................. 34 
6.5 
Appendix 5: Protocol deviations .................................................................................. 35 
6.6 
Appendix 6: Medical /surgical history / concomitant medical procedures .................. 35 
6.7 
Appendix 7: Prior / concomitant medications ............................................................. 35 
6.8 
Appendix 8: Data derivation rules ............................................................................... 36 
6.9 
Appendix 9: AEs of Special Interest ............................................................................ 37 
6.10 
Appendix 10: Potentially Clinically Significant Criteria for safety endpoints ............ 37 
6.11 
Appendix 11: Compliance ........................................................................................... 37 
6.12 
Appendix 12: Standard Reporting Procedures ............................................................. 37 
6.12.1 
PK concentrations ................................................................................................ 37 
6.12.2 
PK parameters ...................................................................................................... 38 
6.13 
Appendix 13: PK parameter calculations .................................................................... 39 
7 
REFERENCES ................................................................................................................ 40 
 
 
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VERSION HISTORY 
SAP Version 
Date 
Change 
Rationale 
Final 
19 Mar 2024 
Not Applicable 
Original version 
Amendment 0.1 
Date of Last Signature 
Update the analysis set 
for PK parameter 
listing in section 
4.6.1.1.2 
To make consistence 
with TLF mock shell 
Amendment 1 
28 Jun 2024 
Update the PK 
parameters that to be 
summarized in section 
4.6.1.1.2; 
Remove percent 
deviation from section 
4.6.1.1.1. 
To make consistence 
with TLF mock shell; 
DEM decision due to 
meaninglessness of 
percent deviation. 
 
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1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of study EP0231. This SAP should be read in 
conjunction with the study protocol amendment 1.0 that provides all necessary background 
information and rationale for the current study and its design. 
 
The SAP is based on the following study documents: 
• 
Protocol Amendment 1.0: 14 Dec 2023 
• 
Electronic Case Report Form (eCRF) v1.0: 21 Dec 2023  
 
1.1 
Objectives and endpoints 
Table 1‒1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary objective  
• To assess bioequivalence between the BRV 
50mg tablet and BRV 50mg dry syrup after 
multiple oral doses in healthy male Japanese 
participants  
Primary PK endpoints from plasma BRV 
concentrations:  
• Cmax,ss  
• AUCtau  
Secondary objective  
• To evaluate the safety and tolerability of 
multiple oral doses of the BRV 50mg tablet and 
BRV 50mg dry syrup in healthy male Japanese 
participants  
Secondary safety endpoints:  
• Incidence of TEAEs  
• Incidence of treatment-emergent SAEs  
• Incidence of TEAEs leading to discontinuation  
Other objectives  
• To evaluate other PK parameters after multiple 
oral doses of the BRV 50mg tablet and BRV 
50mg dry syrup in healthy male Japanese 
participants  
 
Other PK endpoints from plasma BRV 
concentrations:  
• Ctrough  
• CLss/F  
• tmax,ss  
• To further evaluate the safety and tolerability 
after multiple oral doses of the BRV 50mg tablet 
and BRV 50mg dry syrup in healthy male 
Japanese participants  
 
Other safety endpoints:  
• Change from Baseline in clinical laboratory test 
parameters (ie, hematology, clinical chemistry, 
and urinalysis)  
• Change from Baseline in vital signs (SBP, DBP, 
body temperature, respiratory rate, and heart 
rate)  
• 12-lead ECG parameters and findings  
• Physical examinations  
AUCtau=area under the curve during a dosing interval at steady state; BRV=brivaracetam; CLss/F=apparent total 
body clearance at steady state; Cmax,ss=maximum plasma concentration at steady state; Ctrough=measured 
concentration at the end of a dosing interval at steady state; DBP=diastolic blood pressure; ECG=electrocardiogram; 
PK=pharmacokinetics; SAE=serious adverse event; SBP=systolic blood pressure; TEAE=treatment-emergent 
adverse event; tmax,ss=time of Cmax,ss  
 
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1.2 
Study design 
EP0231 is a single-center, multiple-dose, open-label, randomized, group sequential design, 2-
way cross-over study to assess the bioequivalence of BRV 50mg tablet and BRV 50mg dry syrup 
in healthy male Japanese participants after oral administration under fasted conditions. In 
addition, the safety and tolerability of BRV will be evaluated.  
Participants will enter a Screening Period (2 to 28 days before administration of investigational 
medicinal product [IMP]), and eligible participants will start the Dosing Period. The Dosing 
Period consists of 2 periods (Dosing Period 1 and Dosing Period 2) of 5 days each (Day -1 to 
Day 4) with a total of 5 administrations of BRV 50mg on Day 1 and Day 2 (morning and 
evening doses 12 hours apart), and Day 3 (morning dose only).  
Participants will receive 1 of the following treatments in each Dosing Period under fasting 
conditions according to randomly assigned treatment sequences (A-B or B-A):  
• 
Treatment A – multiple doses of BRV 50mg tablets  
• 
Treatment B – multiple doses of BRV 50mg dry syrup (1.25g of granules for oral suspension 
4% w/w)  
The Dosing Periods will be separated by a Wash-Out Period (minimum of 6 days and preferably 
no more than 10 days between the final dose in Dosing Period 1 and the first dose in Dosing 
Period 2 for each participant) and followed by a Safety Follow-Up (SFU) Visit, 7 to 9 days after 
the last administration of IMP. Participants who prematurely discontinue the IMP/study will be 
encouraged to return for an SFU Visit, 7 to 9 days after the final IMP administration. Refer to the 
study schematic in Figure 1-1. 
 
Figure 1-1: Schematic Diagram 
 
BRV=brivaracetam; DMC=Data Monitoring Committee; IMP=investigational medicinal product; max=maximum; 
min=minimum; SFU=Safety Follow-Up; w/w=weight/weight  
a Following a Screening Period (up to 27 days before the start of Dosing Period 1), eligible participants will be 
randomly assigned to 1 of 2 treatment sequences (A-B or B-A) before dosing in Dosing Period 1, after all Day -1 
assessments have been completed. After the first cohort (approximately 60 evaluable participants) has completed 
both Dosing Periods, an interim analysis will be performed, and an internal DMC will determine whether the 
primary objective is achieved, futility of the study is confirmed, or whether the study should continue with 
recruitment of the second cohort (approximately 30 evaluable participants).  
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b Each Dosing Period is 5 days each (Day -1 to Day 4). Brivaracetam 50mg will be administered twice daily 
(morning and evening doses 12 hours apart) as 50mg tablets (Treatment A [Reference]) or dry syrup (1.25g of BRV 
granules for oral suspension 4% w/w; Treatment B [Test]). On Day 1 and Day 2, participants will fast for at least 2 
hours before and after IMP administration. On Day 3, only the morning dose will be administered, and the 
participants will fast for 10 hours before and 4 hours after IMP administration. For each Dosing Period, participants 
will be admitted to the study site on Day -1 (1 day before dosing) and will be discharged on the morning of Day 4, 
approximately 24 hours after last administration of IMP in each Dosing Period, at the discretion of the Investigator.  
c The Dosing Periods will be separated by a Wash-Out Period (minimum of 6 days and preferably no more than 10 
days between the final dose in Dosing Period 1 and the first dose in Dosing Period 2) for each participant.  
d An SFU Visit will occur 7 to 9 days after the final IMP administration. Participants who prematurely discontinue 
the IMP/study will be encouraged to return for an SFU Visit within 7 to 9 days after the final IMP administration. 
The Schedule of Activities is provided in Table 1-2. 
 
 
 
 
 
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Table 1-2: 
Schedule of Activities 
Procedure 
Screening 
Period 
Dosing Period 1 or Dosing 
Period 2 a 
SFU b 
2 to 28 days 
before 
administration 
of IMP 
Check 
in 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
7 to 9 days 
after the last 
administration 
of IMP 
Written informed consent 
X 
 
 
 
 
 
 
Demographics, habits, and 
lifestyle 
X 
 
 
 
 
 
 
Verification of 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Verification of withdrawal 
criteria c 
 
X 
X 
X 
X 
X 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
Height and weight 
X 
 
 
 
 
 
 
Viral serology (HBsAg, HCV, 
HIV, and syphilis) 
X 
 
 
 
 
 
 
Alcohol and drug (including 
cotinine) testing 
X 
X 
 
 
 
 
 
COVID-19 precautions d 
X 
X 
 
 
 
 
X 
Vital signs e 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests 
(hematology, clinical 
chemistry, and urinalysis) 
X 
X 
 
 
 
X 
X 
Randomization f 
 
X 
 
 
 
 
12-lead ECG g 
X 
 
X 
 
 
X 
X 
IMP administration h 
 
 
X 
X 
X 
 
 
Blood sampling for PK i 
 
 
X 
X 
X 
 
 
Recording of prior and 
concomitant medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
Recording of AEs 
X 
X 
X 
X 
X 
X 
X 
Confinement 
 
X 
X 
X 
X 
X j 
 
AE=adverse event; BRV=brivaracetam; COVID-19=coronavirus disease 2019; ECG=electrocardiogram; 
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
IMP=investigational medicinal product; PK=pharmacokinetic(s); SFU=Safety Follow-Up; w/w=weight/weight 
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Table 1-2: 
Schedule of Activities 
Procedure 
Screening 
Period 
Dosing Period 1 or Dosing 
Period 2 a 
SFU b 
2 to 28 days 
before 
administration 
of IMP 
Check 
in 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
7 to 9 days 
after the last 
administration 
of IMP 
a Each participant will enter 2 Dosing Periods, separated by a Wash-Out Period. Dosing Period 2 will begin after 
the Wash-Out Period (minimum of 6 days and preferably no more than 10 days between the final IMP 
administration in Dosing Period 1 and the first IMP administration in Dosing Period 2). 
b An SFU Visit will occur 7 to 9 days after the last administration of IMP. Participants who prematurely 
discontinue the IMP/study will be encouraged to undergo an SFU Visit within 7 to 9 days after the last 
administration of IMP. 
c Confirmation that participants do not fulfill the withdrawal or stopping criteria (Section 7 of the protocol) will 
occur on Day -1, before dosing on Days 1, 2, and 3, and prior to discharge on Day 4. 
d Coronavirus disease 2019 precautions will be performed in alignment with the study site’s local requirements 
(refer to Section 2.3.1 of the protocol for additional details). 
e Vital signs (blood pressure [systolic blood pressure and diastolic blood pressure], heart rate, respiratory rate, 
and body temperature) will be taken at the Screening Visit; for each Dosing Period (on Day -1 check in, Day 1 
predose and 12 hours postdose [before the evening dose is administered]), Day 2 [premorning dose] and Day 3 
predose, and Day 4 prior to discharge); and at the SFU Visit. 
f Randomization will occur only for Dosing Period 1; either on Day -1 after all assessments for Day -1 are 
performed or Day 1 before any assessments for Day 1 are performed. Each participant will be randomly 
assigned to 1 of 2 treatment sequences (A-B or B-A). 
g  Single 12-lead ECGs will be recorded at Screening, for each Dosing Period (Day 1 predose and Day 4 prior to 
discharge), and at the SFU Visit. 
h Investigational medicinal product administration: Brivaracetam 50mg will be administered twice daily 
(approximately 12 hours apart) as 50mg tablets (Treatment A [Reference]) or dry syrup (1.25g of BRV granules 
for oral suspension 4% w/w; Treatment B [Test]). On Day 1 and Day 2, participants will fast for at least 2 hours 
before and after IMP administration. On Day 3, only the morning dose will be administered, and the participants 
will fast for 10 hours before and 4 hours after IMP administration. 
i For each Dosing Period, blood samples for PK analysis will be collected on Day 1 (before the morning and 
evening doses [0 and 12hr]), Day 2 (before the morning and evening doses [24 and 36hr]), and Day 3 (predose 
[48hr] and 10min, 15min, 20min, 30min, 45min, 60min, 75min, 90min, 2hr, 6hr, 9hr, and 12hr postdose). 
j Participants will check out of the clinical unit the morning of Day 4, approximately 24 hours after the final dose 
of IMP administered, at the discretion of the Investigator. 
 
 
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2 
STATISTICAL HYPOTHESES 
The study is aimed to demonstrate the bioequivalence between BRV 50mg dry syrup (1.25g of 
granules for oral solution 4% w/w, corresponding to 50mg of BRV) (Test) and BRV 50mg tablet 
(Reference) after multiple oral doses according to Cmax,ss and AUCtau. 
Null hypothesis (H0): the adjusted Test/Reference geometric mean ratio is smaller than 0.80 
or larger than 1.25. 
Alternative hypothesis (H1): the adjusted Test/Reference geometric mean ratio is within 0.80 
to 1.25. 
 
The confidence intervals (CIs) of the adjusted Test/Reference geometric mean ratio will be 
calculated corresponding to the Lan-DeMets alpha spending function approximating a Pocock 
boundary (Lan and DeMets, 1983), while maintaining the overall 2-sided significance level of 
0.1. 
Based on the hypotheses, bioequivalence between the Test (dry syrup) and Reference (tablet) 
formulations will be concluded if the CIs for Cmax,ss and AUCtau are contained in the range of 0.80 
to 1.25.  
In the case that the CIs for Cmax,ss and AUCtau are not contained in the range of 0.80 to 1.25, 
bioequivalence can still be concluded if the following criteria are met: 1) the point estimate of 
the adjusted GMR (Test/Reference) for Cmax,ss and AUCtau are contained in the range of 
0.90 to 1.11, and 2) in vitro dissolution rates of Test (dry syrup) and Reference (tablet) 
formulations are available and are deemed similar according to the Japanese bioequivalence 
guideline (PSEHB/PED Notification No. 0319-1, 2020).  
 
2.1 
Multiplicity adjustment 
Since the analyses of primary endpoints are planned at the interim analysis and the final analysis, 
Lan-DeMets alpha spending function approximating a Pocock boundary will be applied in order 
to control the overall Type I error rate.   
 
3 
POPULATIONS FOR ANALYSIS 
3.1 
Enrolled Set 
All participants who have signed the informed consent will be included in the Enrolled Set (ES). 
 
3.2 
Randomized Set 
All enrolled participants who were randomized will be included in the Randomized Set (RS). 
 
3.3 
Safety Set 
All randomized participants who received at least 1 dose of the IMP will be included in the 
Safety Set (SS). 
 
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3.4 
Pharmacokinetic Set 
The Pharmacokinetic Set (PKS) consists of all study participants who are randomized, receive at 
least 1 dose of active IMP and have at least 1 quantifiable post-Baseline PK measurement. 
All PKS participants who have a sufficient number of bioanalytical assessments to calculate 
reliable estimates for the primary PK parameters for both BRV formulations will be included in 
the statistical analysis.  
If a participant’s predose concentration on Day 1 is greater than 5% of the Cmax,ss value on Day 3  
in a Dosing Period, the participant’s data from that Dosing Period will be excluded from the 
statistical analysis. If a participant’s predose concentration on Day 1 is greater than 5% of the 
Cmax,ss value on Day 3 for both Dosing Periods, the participant will be excluded from the 
statistical analysis.  
If vomiting occurs at or before 2 times the median tmax,ss for the tablet and the dry syrup within a 
Dosing Period, the participant’s data from that period will be excluded from the statistical 
analysis. If vomiting occurs at or before 2 times the median tmax,ss within a Dosing Period, for 
both Dosing Periods, the participant will be excluded from the statistical analysis. 
If (1) a PK sample is missing and the Cmax,ss is the sample immediately preceding or following 
the missing sample or (2) 2 or more samples are missing, then the participant’s data from that 
period will be excluded from the statistical analysis. 
 
4 
STATISTICAL ANALYSES 
4.1 
General considerations 
Statistical analysis and generation of tables, figures, and data listings will be performed using 
SAS Version 9.4 or higher.  
A complete set of listings containing both all documented data and all calculated data will be 
generated. Missing data will not be imputed.  
For categorical endpoints, the number and percentage of participants in each category will be 
presented. The denominator for percentages will be based on the number of participants 
appropriate for the purpose of the analysis. For continuous endpoints, descriptive statistics will 
include number of participants, mean, standard deviation (SD), median, minimum, and 
maximum. The descriptive statistics for plasma concentrations and PK parameters will be 
described in Section 4.6.1.1.1 and Section 4.6.1.1.2. 
For summaries of demographics and Baseline characteristics: summarize percentages based on 
all participants in the analysis set and include a potential “Missing” category (corresponding to 
participants with missing data at the time of the variable being summarized) as the last row in the 
list of categories being summarized. 
Percentages will be presented to 1 decimal place. If the percentage is 100%, no decimal will be 
presented. If the percentage is 0, no percentage will be presented. Typically, the unit (%) should 
be presented in the column header, but not with each individual value. 
Decimal places for descriptive statistics will always apply the following rules, unless otherwise 
stated: 
• “n” will be an integer 
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• Mean, SD, and median will use one additional decimal place compared to the original 
data  
• CV [%] will be presented with one decimal place  
• Minimum and maximum will have the same number of decimal places as the original 
value 
 
Derived variables in general will display the mean, SD and median to 1 more decimal place than 
the variables used in the derivation. If the number of decimal places reported in the raw data is 
varied then use either the maximum raw number of reported decimal places or 3, whichever is 
the lowest, as a guide for the descriptive statistics. 
If participants have more than one observation for a given time point, the observation closest to 
the intended time point will be used. If both observations are equidistant from the intended time 
point, then the later value will be used. 
Standard reporting procedures of PK concentrations and parameters in listings, tables, and 
figures are described in Appendix 12 (Section 6.12). 
 
The analysis outputs prepared as Interim Analyses (IA) for DMC (IA-DMC),  All Analyses (All) 
are indicated as follows: 
• IA-DMC will be performed at IA for DMC after Cohort 1 is completed. 
• All analyses will be performed either at IA after Cohort 1 is completed or Final Analyses 
(FA) after Cohort 2 is completed. If bioequivalence (BE) or futility is confirmed by DMC 
at IA and the study is terminated at IA early after Cohort 1 is completed, the IA (All) will 
be performed at IA. Otherwise, the FA will be performed after Cohort 2 is completed. 
 
TLF shells will clarify “Interim Analyses (DMC)”, “Interim Analyses (All)” or “Final 
Analyses”. 
 
4.1.1 
Analysis time points 
 
4.1.1.1 
Relative day for listings 
Relative day will be derived with the date of the first IMP administration in each Dosing Period 
as reference for that specific Dosing Period. 
 
For days on the day of IMP administration in each Dosing Period  
 
Relative day will be calculated as follows: 
Relative day = Current date - Date of the first IMP administration + 1 
i.e., the day of the first IMP administration in each Dosing Period will have a relative day of ‘1’. 
 
For days prior to IMP administration in each Dosing Period  
 
Relative day will be prefixed with ‘-’ and calculated as follows: 
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Relative day 
 = Current date – Date of the first IMP administration within the same Dosing Period 
e.g., the day prior to the first IMP administration will have a relative day of ‘-1’. 
 
For days prior to the first IMP administration in the Screening Period 
 
Relative day will be prefixed with ‘-’ and calculated as follows: 
Relative day = Current date – Date of the first IMP administration 
e.g., Screening Visit that is 7 days prior to the first IMP administration will have a relative day of 
‘-7’. 
 
For days after the day of the last IMP administration in Dosing Period 
 
Relative day will be prefixed with ‘+’ and will be calculated as follows: 
Relative day = Current date – Date of the last IMP administration within the same Dosing Period 
e.g., the day after the last IMP administration in a Dosing Period will have a relative day of ‘+1’. 
 
For days after the Dosing Period 
Relative day will be prefixed with ‘+’ and calculated as follows: 
Relative day = Current date – Date of the last IMP administration 
e.g., A certain day in a washout period following Dosing Period 1 that is 7 days after IMP 
administration in Dosing Period 1 will have a relative day of ‘+7’. 
e.g., Safety Follow-Up Visit that is 8 days after the last IMP administration will have a relative 
day of ‘+8’. 
 
Relative day will not be calculated for partial dates. Relative day for partial days will be 
displayed as ‘--’ to distinguish it from missing values which are displayed as blanks. 
 
4.1.1.2 
Analysis periods 
The total duration of the study for an individual study participant is 21 days to 53 days and will 
include: 
• A Screening Period (2 to 28 days before IMP administration) 
• Two Dosing Periods (5 days each, with IMP administration on Day 1 and Day 2 (morning 
and evening doses 12 hours apart), and Day 3 (morning dose only) of each Dosing Period 
• A Wash-out Period following Dosing Period 1 (minimum of 6 days and preferably no more 
than 10 days between the final dose in Dosing Period 1 and the first dose in Dosing Period 2 for 
each participant) 
• An SFU Visit/Withdrawal Visit (7 to 9 days after the last IMP administration) 
 
 
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Table 4-1: Duration of Each Period 
Period 
Duration 
Screening Period  
Prior to the date of first IMP administration (Relative Day -28 to  
-2)  
Dosing Period 1 
Defined as Relative Day -1, 1, 2, 3 and + 1 
Wash-out Period 
Defined as Relative Day + 2 to + 6 (~ + 10)  
Dosing Period 2 
Defined as Relative Day -1, 1, 2, 3 and +1 
Safety Follow-Up Period 
Defined as Relative Day + 2 to + 7 (~ + 9) 
 
4.1.2 
Definition of baseline values 
Baseline will be the last available predose result for each Dosing Period. Each Dosing Period 
will therefore have its own Baseline, independent of the other Treatment Periods unless the data 
collection is not scheduled.  
 
Table 4-2: Definition of Baseline 
Measurement 
Definition of Baseline 
Vital Signs 
Day 1, Pre-dose value in each period. If this 
value is unavailable, Day -1 check in value will 
be imputed in the period. If those values are 
unavailable, the latest available value before 
dosing will be imputed. For Dosing Period 1, the 
latest value in Screening Period and Dosing 
Period 1 before dosing can be used. For Dosing 
Period 2, the latest value in Wash-out Period and 
Dosing Period 2 before dosing can be used.  
12-lead ECG 
Day 1, Pre-dose value in each period. If this 
value is unavailable, the latest available value 
before dosing will be imputed. For Dosing 
Period 1, the latest value in Screening Period 
and Dosing Period 1 before dosing can be used. 
For Dosing Period 2, the latest value in Wash-
out Period and Dosing Period 2 before dosing 
can be used. 
Clinical laboratory tests (hematology, clinical 
chemistry, and urinalysis) 
Day -1, check in value in each period.  
If this value is unavailable, the latest available 
value before dosing will be imputed. For Dosing 
Period 1, the latest value in Screening Period 
and Dosing Period 1 before dosing can be used. 
For Dosing Period 2, the latest value in Wash-
out Period and Dosing Period 2 before dosing 
can be used. Baseline for Dosing Period 1 can be 
used for Dosing Period 2 if any other baseline 
value is unavailable. 
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4.1.3 
Mapping of assessments performed at Early Discontinuation Visit 
Safety assessments made at a withdrawal visit that correspond to a scheduled visit will be 
summarized at the scheduled visit to corresponding to the withdrawal visit if the assessment was 
scheduled to occur at that visit. Such assessments at the withdrawal visit will also be considered 
for safety follow up/ withdrawal visit. 
 
4.1.4 
Treatment assignment and treatment groups 
Treatment assignment for the SS and PKS will be based on the actual treatment received in each 
Dosing Period. 
Listings will be presented by treatment sequence, unless otherwise specified. 
Summaries will be presented by treatment sequence or BRV formulation and overall, where 
applicable. The following order will be used in the Tables, Figures and Listings (TFLs): tablet, 
dry syrup and overall, where applicable. 
For analysis conducted using the ES, an additional group for participants not randomized may be 
displayed, as applicable. 
 
4.1.5 
Multicenter studies 
Not applicable since this study will be conducted at a single site. 
 
4.1.6 
Center pooling strategy 
Not applicable since this study will be conducted at a single site. 
 
4.2 
Primary endpoint analyses 
Statistical analyses will be performed on the PKS. 
The bioavailability of BRV dry syrup (1.25g of granules for oral suspension 4% w/w, 
corresponding to 50mg of BRV) (Test) will be compared with BRV 50mg tablet (Reference). 
 
4.2.1 
Definition of endpoints 
The primary endpoints are defined as follows: 
• Maximum plasma concentration at steady state, Cmax,ss  
• Area under the curve during a dosing interval at steady state, AUCtau 
 
4.2.2 
Main analytical approach 
The primary PK parameters Cmax,ss and AUCtau will be evaluated according to a linear mixed 
model, adapted to cross-over experimental designs. The model will include treatment (BRV 
formulation), period, and sequence as fixed effects. The participant (nested within the sequence) 
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will be included as a random effect. Since the participant is entered as a random effect in the 
linear mixed model, the data from the nonaffected Dosing Period (i.e., evaluable data) can still 
be used for the bioequivalence assessment even if the data from the other Dosing Period are 
excluded from the analysis. The dependent variables will be logarithmically (ln) transformed 
prior to statistical testing, following the usual recommendations.  
 
This linear mixed model is represented as:  
 
𝑙𝑜𝑔(𝑌𝑖𝑗𝑘𝑙) = 𝜇 + 𝑆𝑖(𝑗) + 𝑄𝑗 + 𝐹𝑘 + 𝑃𝑙 + 𝑒𝑖𝑗𝑘𝑙, where 
  
• 
𝑙𝑜𝑔(𝑌𝑖𝑗𝑘𝑙) is the log transformed PK parameter value of the i-th subject (i=1,2,3,..) in the 
j-th sequence (j=1,2); for the k-th treatment (k=1,2) in the l-th period (l=1,2),  
• 
𝜇 is the overall mean,  
• 
𝑆𝑖(𝑗) is the random effect of the i-th subjects nested to the j-th sequence,  
• 
𝑄𝑗 is the fixed effect for the j-th sequence,  
• 
𝐹𝑘 is the fixed effect for the k-th treatment,  
• 
𝑃𝑙 is the fixed effect for the l-th period,  
• 
𝑒𝑖𝑗𝑘𝑙 is the (residual) random error in observing 𝑙𝑜𝑔(𝑌𝑖𝑗𝑘𝑙). 
 
The MIXED procedure in SAS software will be used for this analysis. 
For estimation based on a linear mixed model, covariance matrix applied to the within-subject 
error will be estimated by restricted maximum likelihood (REML). The Kenward-Roger 
approximation will be used to estimate the degree of freedom. Variance component structure will 
be used as covariance in this linear mixed model.  
 
Adjusted geometric mean ratio (GMR) (Test/Reference) and the corresponding CIs will be 
calculated corresponding to the Lan-DeMets alpha spending function approximating a Pocock 
boundary (Lan and DeMets, 1983), while maintaining the overall 2-sided significance level of 
0.1. Bioequivalence between the Test (dry syrup) and Reference (tablet) formulations will be 
concluded if the CIs for Cmax,ss and AUCtau are included in the range of 0.80 to 1.25. [IA-DMC, 
All] 
 
 
SAS code for Lan-DeMets alpha spending function approximating a Pocock boundary 
PROC SEQDESIGN bscale=pvalue; 
Pocock_type: design alpha=0.05 alt=upper stop=reject info=cum(percent_interim,1)  
                                   nstages=2 method=ERRFUNCPOC ; 
RUN;    
Note: percent_interim is the number of participants for PKS at Interim analysis divided 
by 90. 
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For example, if an alpha is derived as 0.03817 for interim analysis, 2-sided (1 - 0.03817 times 2) 
times 100 % confidence interval for GMR will be derived to demonstrate the bioequivalence. 
Accordingly, 2-sided (1 -0.02704 times 2) times 100 % confidence interval for GMR will be 
derived to demonstrate the bioequivalence only if cohort 2 is conducted.  
 
In the case that the CIs for Cmax,ss and AUCtau are not contained in the range of 0.80 to 1.25, 
bioequivalence can still be concluded if the following criteria are met: 
1) The point estimate of the adjusted GMR (Test/Reference) for Cmax,ss and AUCtau are contained 
in the range of 0.90 to 1.11.  
2) In vitro dissolution rates of Test (dry syrup) and Reference (tablet) formulations are available 
and are deemed similar according to the Japanese bioequivalence guideline (PSEHB/PED 
Notification No. 0319-1, 2020).  
 
In parallel, the 1-sided (upper) 95% CI of the adjusted GMR (Test/Reference) for Cmax,ss will be 
calculated to confirm if the upper boundary is less than 0.8700 for Cmax,ss. [IA-DMC] 
 
Inter-participant and intra-participant variability for each parameter will also be derived from 
these analyses as geoCVs. [IA-DMC, All] 
 
Geometric least squares means and the corresponding 90% CI for each treatment (tablet or dry 
syrup) will be provided as well. [IA-DMC, All] 
 
4.2.3 
Supportive and sensitivity analyses 
Not applicable. 
 
4.3 
Secondary endpoint analyses 
All safety analyses will be performed using the SS unless otherwise specified. 
 
4.3.1 
Secondary endpoints 
 
4.3.1.1 
Definition of endpoint(s) 
The secondary endpoints are defined as follows: 
• 
Incidence of TEAE 
• 
Incidence of treatment-emergent SAEs  
• 
Incidence of TEAEs leading to discontinuation  
Adverse events with a start date prior to the first dose of IMP will be defined as pretreatment 
AEs. A TEAE is defined as any AE with a start date/time on or after the first dose of IMP or any 
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unresolved event already present before administration of IMP that worsens in intensity 
following exposure to IMP. 
Missing or partially missing date and/or times will be imputed to determine if an AE is regarded 
as TEAE using the imputation rule described in Section 4.5.2. 
 
4.3.1.2 
Main analytical approach 
An overview of the occurrence and incidence of TEAEs will be provided by BRV formulation 
(tablet or dry syrup), and overall. The overview will present individual occurrences as well as 
number and percentage of (unique) participants experiencing each of the following: 
• TEAEs 
• Treatment-emergent SAEs 
• TEAEs leading to discontinuation 
 
[All] 
 
Summaries of the occurrence and incidence of TEAEs, treatment-emergent SAEs and TEAEs 
leading to discontinuation will be provided by BRV formulation (tablet or dry syrup) and overall. 
The summary will present individual occurrences as well as number and percentage of (unique) 
participants, by System Organ Class (SOC) and Preferred Term (PT). These summaries will be 
provided for the following: 
• Incidence of TEAEs 
• Incidence of treatment-emergent SAEs 
• Incidence of TEAEs leading to discontinuation  
[All] 
 
Adverse event summaries will be ordered by alphabetical SOC and decreasing frequency of PT 
within SOC in the overall column for tables including event counts. For tables including only 
number and percentage of participants, summaries will be ordered by alphabetical SOC and 
decreasing incidence of PT within SOC in the overall column. 
 
4.4 
Exploratory endpoint analysis 
Not applicable. 
 
4.5 
Other Safety analyses 
All safety analyses will be performed using the SS unless otherwise specified. 
 
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4.5.1 
Extent of exposure 
Exposure will be summarized by Dosing Period, BRV formulation (tablet or dry syrup), and 
overall. [All] 
Administration of IMP will be listed by treatment sequence, and Dosing Period for all 
participants in the SS and will include the following information: IMP formulation, date/ time of 
IMP administration and dose. [All] 
 
4.5.2 
Adverse events 
An overview of the occurrence and incidence of TEAEs will be provided by BRV formulation 
(tablet or dry syrup), and overall. The overview will present individual occurrences as well as 
number and percentage of (unique) participants experiencing each of the following: 
• 
Drug-related TEAEs 
• 
Severe TEAEs 
• 
All deaths (AEs leading to death) 
• 
TEAEs leading to death 
• 
TEAEs of special interest 
[All] 
 
Summaries of the occurrence and incidence of TEAEs will be provided by BRV formulation 
(tablet or dry syrup) and overall. The summary will present individual occurrences as well as 
number and percentage of (unique) participants, by primary SOC and PT. These summaries will 
be provided for the following: 
• 
Incidence of Drug-related TEAEs 
• 
Incidence of TEAEs leading to death 
• 
Incidence of TEAEs by maximum intensity 
• 
Incidence of TEAEs of special interest  
• 
Incidence of non-serious TEAEs above threshold of 5% of participants 
[All] 
Summaries by maximum intensity will count each subject at most once within each MedDRA level 
based on the maximum intensity within that MedDRA level. 
Adverse events with missing intensity will be considered as ‘Severe’ events for summary 
purposes but recorded as missing in the listings. Adverse events with missing causal relationship 
to IMP will be considered as ‘Related’ for the tabulations but presented as missing in the listings. 
For the summary of non-serious TEAEs above threshold of 5% of participants, only TEAEs 
which are reported in above 5% of participants within a BRV formulation (tablet or dry syrup) 
will be included. 
Adverse event summaries will be ordered by alphabetical SOC and decreasing frequency of PT 
within SOC in the overall column for tables including event counts. For tables including only 
number and percentage of participants, summaries will be ordered by alphabetical SOC and 
decreasing incidence of PT within SOC in the overall column. 
 
A listing will be presented by treatment sequence, dosing period at onset, BRV formulation 
(tablet or dry syrup)  and participant for all AEs for the ES. This will include reported term, 
SOC, PT, the onset date/time and outcome date/time of the event (including relative days or 
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ongoing if applicable), the AE duration, pattern of event, intensity, relationship, action taken and 
outcome. In addition, the listing will flag TEAEs, SAEs, AEs leading to discontinuation and AEs 
of special interest. [All] 
A glossary of AE terms including reported term, SOC and PT will also be presented. [All]  
 
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 (i.e., 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 (i.e., 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 end/stop dates: 
• If only the month and year are specified, then use the last day of the month 
• If only the year is specified, then use December 31 of the known year 
• If the stop date is completely unknown, do not impute the stop date 
Missing or partially missing date and/or times will be imputed as described in Table 4-3 for the 
calculation of duration of each AE. AE duration is computed and reported in day and time 
format. 
 
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Table 4-3: Calculation Rules for Duration of AEs 
Data Availability 
Onset 
Date/Time 
Outcome 
Date/Time 
Calculation Rules 
Complete data 
D1/T1 
D2/T2 
Duration = 
(D2-D1)*24+(T2-T1) 
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) 
Start time missing 
D1/-- 
D2/T2 
Onset time is substituted by 00:00h. 
Duration=<(D2-D1)*24+T2  
Start and end time 
missing 
D1/-- 
D2/-- 
Duration=<[(D2-D1)+1]*24 
Start day and time 
missing 
--/-- 
D2/T2 
Duration=<(D2-D0)*24+(T2-T0)  
For a participant in the SS, D0 and 
T0 are the date and time of the first 
administration of study medication 
and for screen failures, D0 is the date 
of the Screening Visit date and 
T0=00:00h. 
End day and time 
missing 
D1/T1 
--/-- 
If the stop date is missing, duration 
will not be calculated. 
Start and end date 
missing 
--/-- 
--/-- 
If the stop date is missing, duration 
will not be calculated. 
 
The duration of each AE will be calculated as follows and will be presented in dd:hh:mm format 
where dd represent days, hh: hours, and mm: minutes:  
Duration of AE = End date/time of AE – Start date/time of AE 
 
Adverse events will be assigned to Dosing Periods, based on the onset date/ time of the AE. 
Assignment to Dosing Periods will be done after missing dates have been imputed as described 
above. AE will be assigned to a treatment based on the treatment received in the Dosing Periods 
as follows: 
• Dosing Period 1: the start date/time is on or after IMP administration in Dosing Period 1 
and prior to IMP administration in Dosing Period 2. 
• 
Dosing Period 2: the start date/time is on or after IMP administration in Dosing Period 2. 
 
4.5.3 
Additional safety assessments  
 
4.5.3.1 
Clinical laboratory evaluations 
Laboratory parameters will be grouped according to Appendix 2 of the protocol. 
All clinical laboratory parameters will be listed by treatment sequence, participant, variable and 
period/visit, changes from Baseline (as defined in Section 4.1.2) for continuous values, flags for 
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measurements outside the reference ranges, and relative day (calculated as described in Section 
4.1.1.1) for the RS. The listing will include the BRV formulation (tablet or dry syrup) received at 
the time of measurement if applicable (the treatment received in the corresponding Dosing 
Period will be assigned).  
For the flags for results that are out of reference range, values that are below the lower limit of 
the reference range will be flagged as ‘L’ (low) and values that are above the upper limit of the 
reference range will be flagged as ‘H’ (high).  
Any laboratory variable that are given as ‘<xx’ or ‘>xx’ in the database will be imputed with the 
absolute value of the number without the sign (e.g., <2.2 will be imputed as 2.2) for the 
calculation of descriptive statistics and changes from Baseline.  
[All] 
Additional laboratory tests including serology, alcohol detect test, and urine drug screen will be 
listed for the ES. [All] 
 
4.5.3.1.1 
Laboratory values over time 
For clinical laboratory parameters (hematology and clinical chemistry), observed results and 
changes from Baseline will be summarized using descriptive statistics by BRV formulation 
(tablet or dry syrup) at scheduled time point, as applicable. [All] 
 
4.5.3.1.2 
Individual participant changes of laboratory values 
Shift tables from Baseline to post-Baseline scheduled time point will be presented by BRV 
formulation (tablet or dry syrup). These summaries will present a cross-tabulation of Baseline 
values against post-Baseline values categorized as below reference range, within reference range 
and above reference range. Each cell will include the corresponding number and percentage of 
participants. [All] 
 
4.5.3.1.3 
Potential drug-induced liver injury 
A separate listing will present all visits including unscheduled visits for participants who has any 
incident of ALT and/or AST≥3x Upper limit of normal (ULN), Total bilirubin ≥1.5x ULN or 
ALP > 1.5 x ULN. 
 
The listing will display visits for which at least one of the above criteria was fulfilled for a given 
participant and will display all of the following results obtained at that visit for the specified 
parameters for the SS.  
• 
Potential hepatotoxicity with hepatitis 
• 
Potential hepatotoxicity with  hypersensitivity 
• 
ALT and/ or AST ≥3x ULN and Total bilirubin ≥1.5x ULN at any same visit 
• 
ALT and/ or AST ≥3x ULN and Total bilirubin ≥2x ULN at any same visit 
• 
ALT and/ or AST ≥3x ULN, Total bilirubin ≥2x ULN and ALP <2x ULN at any same 
visit  
[All] 
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A summary of participants who met the following criteria will be presented by BRV formulation 
(tablet or dry syrup) and in total. [All] 
• 
Potential hepatotoxicity with symptoms potentially associated with hepatitis or 
hypersensitivity 
• 
Potential hepatotoxicity without symptoms potentially associated with hepatitis or 
hypersensitivity 
• 
ALT and/ or AST ≥3x ULN and Total bilirubin ≥1.5x ULN at any same visit 
• 
ALT and/ or AST ≥3x ULN and Total bilirubin ≥2x ULN at any same visit 
• 
ALT and/ or AST ≥3x ULN, Total bilirubin ≥2x ULN and ALP <2x ULN at any same 
visit  
 
A summary of participants who met the following criteria at any visit will be presented by BRV 
formulation (tablet or dry syrup) and in total. In addition, individual occurrences will be shown. 
[All] 
 
• 
AST ≥ 3 x ULN 
• 
AST ≥ 5 x ULN 
• 
AST ≥ 8 x ULN 
• 
AST ≥ 10 x ULN 
• 
AST ≥ 20 x ULN 
 
• 
ALT ≥ 3 x ULN 
• 
ALT ≥ 5 x ULN 
• 
ALT ≥ 8 x ULN 
• 
ALT ≥ 10 x ULN 
• 
ALT ≥ 20 x ULN 
 
• 
AST or ALT ≥ 3 x ULN 
• 
AST or ALT ≥ 5 x ULN 
• 
AST or ALT ≥ 8 x ULN 
• 
AST or ALT ≥ 10 x ULN 
• 
AST or ALT ≥ 20 x ULN 
 
• 
Total bilirubin ≥ 1.5 x ULN 
• 
Total bilirubin ≥ 2 x ULN 
 
• 
ALP ≥ 1.5 x ULN 
 
• 
New ratio value (ALT or AST, whichever produced the highest x ULN/ ALP x ULN 
value) of 5 or greater 
By-participant listings of suspected hepatic events will be presented for the SS. [All] 
By-participant listings of family DILI-relevant medical history for PDILI will be presented for 
the RS. [All] 
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By-participant listings of information related to potential hepatic event will be presented by 
treatment sequence, and time point and BRV formulation (tablet or dry syrup) for the SS. [All] 
 
Time course for liver function tests (AST, ALT, ALP and Total bilirubin) will be displayed 
superimposed in a single plot by participant for participants meeting a criterion, ALT and/ or 
AST ≥3x ULN, Total bilirubin ≥2x ULN and ALP <2x ULN at any same visit from the SS.  
[All] 
 
4.5.3.2 
Vital signs 
The following vital signs measurements will be obtained: Systolic Blood Pressure (SBP), 
Diastolic Blood Pressure (DBP), pulse rate, respiratory rate and body temperature. 
 
4.5.3.2.1 
Vital sign values over time 
Vital signs variables and changes from Baseline will be summarized using descriptive statistics 
by BRV formulation (tablet or dry syrup) at each scheduled time point. [All] 
 
4.5.3.2.2 
Individual participant changes of vital sign values 
By-participant listings of all vital sign variables and change from Baseline will be presented 
by treatment sequence, period, visit, BRV formulation (tablet or dry syrup) and time point for the 
RS. [All] 
 
4.5.3.3 
Electrocardiograms 
The following twelve-lead ECG variables will be obtained: heart rate, PR, QRS, QT intervals, 
and QTcF. 
 
4.5.3.3.1 
Electrocardiogram values over time 
Twelve-lead ECG variables and changes from Baseline will be summarized using descriptive 
statistics by BRV formulation (tablet or dry syrup) at each scheduled time point. [All] 
 
The following cut-points in QTcF (raw data and change from Baseline) will be summarized 
categorically by BRV formulation (tablet or dry syrup) (number and percentage of participants) 
and timepoint.  
 
Raw QTcF data: 
• 
<450msec 
• 
≥450msec to <480msec 
• 
≥480msec to <500msec 
• 
≥500msec 
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Change from Baseline QTcF: 
• <30msec 
• ≥30msec to <60msec 
• ≥60msec 
[All] 
Electrocardiogram findings will be listed for the RS. [All] 
 
4.5.3.3.2 
Individual participant changes of electrocardiograms values 
By-participant listings of all twelve-lead ECG variables, and change from Baseline will be 
presented by treatment sequence. period, visit, BRV formulation (tablet or dry syrup) and time 
point for the RS. [All] 
 
4.5.3.4 
Other safety endpoint(s) 
By-participant listings of physical examination data will be presented by treatment sequence, and 
time point and BRV formulation (tablet or dry syrup) for the RS. [All] 
By-participant listings of impact of COVID-19 will be presented for the ES.  [All] 
 
4.6 
Other analyses 
 
4.6.1 
Other endpoints and/or parameters 
The other PK endpoints are defined as follows: 
• Measured concentration at the end of a dosing interval at steady state, Ctrough 
• Apparent total body clearance at steady state, CLss/F  
• Time of maximum plasma concentration at steady state, tmax,ss 
• Time of the last measurable concentration, tlast 
• Area under the curve from time zero (pre-dose) to the last quantifiable concentration, 
AUClast 
• Apparent terminal elimination half-life, t1/2 
• Terminal elimination rate constant, λz 
• Percentage of AUCtau obtained by extrapolation beyond tlast, %AUCex 
 
4.6.1.1 
Pharmacokinetics 
All pharmacokinetic analyses will be performed using the PKS unless otherwise specified. 
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4.6.1.1.1 
Plasma concentration-time profiles 
For each Dosing Period, blood samples for PK analysis will be collected on Day 1 (before the 
morning and evening doses [0 and 12hr]), Day 2 (before the morning and evening doses [24 and 
36hr]), and Day 3 (predose [48hr] and 10min, 15min, 20min, 30min, 45min, 60min, 75min, 
90min, 2hr, 6hr, 9hr, and 12hr postdose). Allowable deviations from these scheduled PK 
sampling times are provided in Table 8-1 of the protocol. Individual concentration-time data will 
be listed for the SS by treatment sequence. [All] 
 
Concentration listings will include nominal PK sampling time, actual sampling times relative to 
dose administration, deviation from nominal time, and concentrations, day, dosing period and 
sequence, formulation (tablet or dry syrup).  
Plasma concentration data will be listed and summarized with the descriptive statistics by BRV 
formulation (tablet or dry syrup) and scheduled time for the PKS. [All] 
 
Descriptive statistics will include number of study participants (N), number of available 
observations (n), mean, standard deviation, median, minimum, and maximum, geometric mean, 
geometric coefficient of variation (CV), and 95% confidence interval (CI) for the geometric 
mean. 
The geoCV will be calculated as 𝑔𝑒𝑜𝐶𝑉(%) = 100 × √exp{(𝑙𝑛𝑆𝐷)2} −1, 
where ln𝑆𝐷 is the standard deviation of the log transformed values. 
 
Graphical displays of geometric mean concentrations with its corresponding 95% CI (linear scale 
and semi-logarithmic scale) on Day 1 to Day 3 and zoomed geometric mean concentrations 
between 0 and 6 hr on Day 3 will also be presented by BRV formulation (tablet or dry syrup) and 
scheduled time on semi-logarithmic and linear scales for the PKS. [IA-DMC, All] 
Graphical displays of individual plasma concentrations by actual time will be presented on semi-
logarithmic and linear scales. 
Plasma concentrations will be displayed superimposed in a single plot for both formulations for 
the PKS. [All] 
Spaghetti plots will be presented on Day 3 up to 12 h post-dose separately for BRV formulation, 
with profiles for all participants superimposed on the same graph for the PKS. [All] 
 
Refer to Appendix 12 (Section 6.12) for standard reporting procedures of individual values and 
descriptive statistics for plasma concentration data in listings, tables, and figures. 
 
4.6.1.1.2 
Derivation of primary/ other pharmacokinetic variables and 
descriptive summaries 
Pharmacokinetic parameters will be calculated by non-compartmental analysis methods from the 
concentration-time data using Phoenix® WinNonlin® (Version 8.2 or higher). 
Actual sampling times will be used for deriving the PK parameters. Pharmacokinetic parameters 
will be estimated according to the guidelines presented in Appendix 13, Section 6.13. 
Cmax,ss, AUC tau, CLss/F, tmax,ss  and Ctrough will be listed by participant and summarized with 
descriptive statistics by BRV formulation (tablet or dry syrup) for the PKS. [IA-DMC, All]  
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For individual Cmax,ss and AUCtau, ratio of Test (dry syrup) versus Reference (tablet) will be 
listed by participant and summarized with descriptive statistics for the PKS. [All] 
The ratios between  the Ctrough after the last dose on Day 3 and the pre-dose concentration before 
each dose with the exclusion of morning dose on Day 1  (Rtrough) will be listed by participant and 
summarized with descriptive statistics for the PKS. [All] 
For tmax,ss, a distribution-free 90% CI using Hodges-Lehmann’s method will be calculated for the 
median differences (location shift) between each Test (dry syrup) and the Reference (tablet). 
Median and the corresponding 90% CI for each treatment (tablet or dry syrup) will be provided 
using cumulative binomial probability. If the exact Hodges-Lehmann confidence limits cannot be 
calculated, asymmetric limits will be derived instead of symmetric limits. [All] 
In addition, all individual PK parameters will be listed by formulation (tablet or dry syrup) for 
the SS. [All] 
The following descriptive statistics will be calculated: mean, SD, geometric mean, geometric 
coefficient of variation (CV), minimum, median and maximum and 95% confidence interval (CI) 
for the geometric mean. The only exception is tmax,ss, for which only median, minimum, and 
maximum will be reported. 
Ping pong plots for individual data in the PK parameters (Cmax,ss and AUCtau) will also be 
displayed for the PKS. [All] 
Refer to Appendix 12 (Section 6.12.2) for standard reporting procedures of individual values and 
descriptive statistics for PK parameters in listings and tables. 
 
4.6.1.2 
Pharmacodynamics 
Not applicable. 
 
4.6.1.3 
Population pharmacokinetics 
Not applicable. 
 
4.6.1.4 
Immunogenicity 
Not applicable. 
 
4.6.1.5 
Genomics 
Not applicable. 
 
4.6.1.6 
Biomarkers 
Not applicable. 
4.6.1.7 
Pregnancy outcomes 
Not applicable. 
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4.6.1.8 
Health care utilization related endpoints 
Not applicable. 
 
4.6.1.9 
Health technology assessment related endpoints 
Not applicable. 
 
4.6.2 
Subgroup analyses 
Not applicable. 
 
4.7 
Interim analyses 
The study may consist of 2 cohorts. A formal interim analysis is planned at the end of Cohort 1, 
once approximately 60 evaluable participants have completed the study. If bioequivalence or 
futility is not established in the interim analysis, the final analysis is planned at the end of Cohort 
2, once all participants (approximately 90) have completed the study (See Section 9.8 of the 
protocol). The interim analysis, based on a group sequential design, will be an unblinded analysis 
performed by an internal statistical team independent from the study team and will focus on the 
analysis for primary PK parameters Cmax,ss and AUCtau. The results will be reviewed by an 
internal DMC, which is independent from the study team, and the following decisions will be 
made:  
1. Early stopping of the study due to demonstrating bioequivalence at the end of Cohort 1:  
The study will be stopped early, after Cohort 1, if bioequivalence between the Test (dry 
syrup) and Reference (tablet) formulations is established for Cmax,ss and AUCtau (Section 
9.3.1 of the protocol).   
2. Early stopping of the study for futility at the end of Cohort 1:  
The study will be stopped early, after Cohort 1, in the event that bioequivalence is not 
established and the 1-sided (upper) 95% CI of the adjusted GMR (Test/Reference) is less 
than 0.8700 for Cmax,ss. This corresponds to the GMR of this study being markedly lower 
than that of single-dose bioequivalence study (EP0110). 
3. Continuing to Cohort 2:  
If bioequivalence or futility is not established, the study will continue to Cohort 2, and 
the remaining approximately 30 participants will be randomized. 
 
4.8 
Changes to protocol-planned analyses 
The following evaluation was added in the protocol amendment dated 14 December 2023. 
In the case that the CIs for Cmax,ss and AUCtau are not contained in the range of 0.80 to 1.25, 
bioequivalence can still be concluded if the following criteria are met:  
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1) The point estimate of the adjusted GMR (Test/Reference) for Cmax,ss and AUCtau are contained 
in the range of 0.90 to 1.11.  
2) In vitro dissolution rates of Test (dry syrup) and Reference (tablet) formulations are available 
and are deemed similar according to the Japanese bioequivalence guideline (PSEHB/PED 
Notification No. 0319-1, 2020). 
 
4.9 
Data Monitoring Committee (DMC) or other review board 
As described in Section 9.7 of the protocol, a formal interim analysis is planned at the end of 
Cohort 1 once approximately 60 evaluable participants have completed the study. The results 
will be reviewed by an internal DMC, which is independent from the study team. The DMC will 
make 1 of the following decisions:  
1) Early stopping of the study if the study demonstrates bioequivalence at the end of Cohort 1.  
2) Early stopping of the study if the study is futile at the end of Cohort 1. 
3) Continuing the study to Cohort 2.  
Details of the DMC will be provided in the DMC Charters. 
 
5 
SAMPLE SIZE DETERMINATION 
A total of up to approximately 90 participants are planned to be evaluable for the primary 
endpoint.  
As detailed in Section 9.7 of the protocol, this study may consist of 2 cohorts, with a formal 
interim analysis once Cohort 1 has completed both Dosing Periods.  
The BRV single-dose bioequivalence study (EP0110) between tablet (Reference) and dry syrup 
(Test) provided estimates of the GMR (Test/Reference) of 0.8700 for Cmax and 0.9890 for 
AUC(0-t) and the intraparticipant variability (CV%) of 21.9% for Cmax and 2.7% for AUC(0-t) 
(Table 5-1). The BRV multiple-dose PK simulation results based on the EP0110 study data 
provided estimates of the GMR of 0.9054 for Cmax,ss and 0.9893 for AUCtau and the 
intraparticipant variability (CV%) of 15.3% for Cmax,ss and 2.7% for AUCtau. 
 
 
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Table 5-1: EP0110 and simulation results of relative bioavailability of BRV tablet 
formulation vs dry syrup formulation  
 
Parameter 
Statistic 
EP0110 
MD Simulation 
Cmax (μg/mL) a 
GMR of dry 
syrup/tablet 
(Intraparticipant 
CV%) 
0.8700 (21.9)  
0.9054 (15.3) 
AUC (h*μg/mL) b 
GMR of dry 
syrup/tablet 
(Intraparticipant 
CV%) 
0.9890 (2.7) 
0.9893 (2.7) 
 
AUC=area under the curve; AUC(0-t)=area under the curve from time 0 to the time of the last quantifiable 
concentration; AUCtau=area under the curve during a dosage interval at steady state; BRV=brivaracetam; 
Cmax=maximum plasma concentration; Cmax,ss=maximum plasma concentration at steady state; CV=coefficient of 
variation; GMR=geometric mean ratio; MD=multiple-dose  
a The Cmax,ss was used for MD simulation results, estimated based upon the EP0110 study data.  
b The AUC(0-t) was used for EP0110. The AUCtau was used for MD simulation results, based upon the EP0110 study 
data.  
 
In the event that EP0231 will have results similar to those observed in EP0110 without any 
improvement by the multiple-dose study design, 116 participants will be needed to provide a 
power of 90% with a fixed design (no interim analysis). However, because this study is 
conducted as a multiple-dose study, it is expected that the PK profile variability will be smaller. 
It is assumed that both the GMR and intraparticipant SD will show improvement (higher GMR 
and smaller intraparticipant SD) compared with the single-dose study (EP0110), closer to those 
shown in the multiple-dose PK simulation results. The study assumptions for GMR and 
intraparticipant CV% (for Cmax) are based on the approximate middle values of those seen in 
EP0110 and the multiple-dose PK simulations based on the EP0110 study data, assuming a GMR 
of 0.89 and intraparticipant SD of 0.183 (corresponding to a CV% of 18.5%). 
 
In the group sequential design for this study, an interim analysis will be performed for 
bioequivalence or futility after approximately 60 evaluable participants, which is at 90% power 
for bioequivalence based on the CIs of the adjusted GMR (Test/Reference) with the study 
assumptions. Should the assumption regarding variability and GMR not hold, with the study 
consequently not being stopped for demonstrating bioequivalence or futility at the interim 
analysis, this allows the opportunity to enroll a further approximately 30 participants and assess 
bioequivalence after approximately 90 evaluable participants. While maintaining the two 1-sided 
significance level of 0.05, this should be sufficient to state that the true GMR is in the range of 
0.80 to 1.25. The two 1-sided significance levels currently used are 0.03817 for the interim 
analysis and 0.02704 for the final analysis according to the Lan-DeMets alpha spending function 
approximating a Pocock boundary, assuming 60 evaluable participants in Cohort 1 and 30 
evaluable participants in Cohort 2 as the number of participants to be included in the analyses. A 
total of 90 evaluable participants will provide an overall power of >75% even if the GMR and 
intraparticipant CV% remain as observed in EP0110. 
 
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The probability of study stopping for demonstrating bioequivalence for Cohort 1 (power at 
Cohort 1), futility at Cohort 1, and proceeding to Cohort 2 are approximately 91%, 
approximately 1%, and approximately 8%, respectively. If the study continues to Cohort 2, the 
bioequivalence will be assessed after completing Cohort 2.  
In order to ensure a total of up to approximately 90 evaluable participants for the primary 
endpoints, assuming a rate of dropout and non evaluable participants of approximately 5%, 64 
participants for Cohort 1, 32 participants for Cohort 2, and up to 96 participants in total are 
estimated to be randomized in the study. 
 
6 
APPENDIX: SUPPORTING DOCUMENTATION 
 
6.1 
Appendix 1: List of Abbreviations 
List of Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase  
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Curve 
AUClast 
Area under the Curve from Time Zero (pre-dose) to the Last Quantifiable 
Concentration 
AUCtau 
Area under the Curve during a dosage interval at steady state  
%AUCex 
Percentage of AUCtau Obtained by Extrapolation from Tlast to Time tau 
BE 
Bioequivalence 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BRV 
Brivaracetam 
CI 
Confidence Interval 
CLss/F 
Apparent Total Body Clearance at Steady State  
Cmax,ss 
Maximum Plasma Concentration at Steady State 
COVID-19 
Coronavirus Disease 2019  
Ctrough  
Measured Concentration at the End of a Dosing Interval at Steady State 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation  
DBP 
Diastolic Blood Pressure 
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List of Abbreviations 
DEM 
Data Evaluation Meeting 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form  
ES 
Enrolled Set 
FA 
Final Analyses 
geoCV 
Geometric Coefficient of Variation 
GMR  
Geometric Mean Ratio 
IA 
Interim Analyses 
IMP 
Investigational Medicinal Product  
IPD 
Important Protocol Deviation 
λz 
Terminal Elimination Rate Constant 
LLoQ 
Lower Limit of Quantification 
Max 
Maximum 
MD 
Multiple Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
PDILI 
Potential Drug Induced Liver Injury 
PED 
Pharmaceutical Evaluation Division 
PT 
Preferred Term 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Set 
PSEHB 
Pharmaceutical Safety Environment Health Bureau 
QTc 
QT Interval Corrected for Heart Rate 
QTcF 
QTc Using Fridericia’s Correction 
REML 
Restricted Maximum Likelihood 
RS 
Randomized Set 
Rtrough 
Ratio between the Ctrough after the last dose on Day 3 and the pre-dose concentration 
before each dose with the exclusion of morning dose on Day 1 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
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List of Abbreviations 
SD 
Standard Deviation 
SFU 
Safety Follow-Up 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
t½ 
Apparent Terminal Elimination Half-life 
tlast 
Time of the Last Measurable Concentration 
tmax,ss  
Time of Cmax,ss  
tobs 
Actual Sampling Time at Planned Timepoint tau 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
6.2 
Appendix 2: Coding dictionaries 
Medical history and adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®)), using the MedDRA version 18.1. Medications will be coded 
using the World Health Organization Drug (WHO-Drug) Sep 2017. Medical procedures will not 
be coded. 
 
6.3 
Appendix 3: Participant disposition 
Participant screening and primary reason for screen failure will be summarized using the ES. The 
summary will include the following: 
• 
Number of participants screened 
• 
Number and proportion of participants with screen failures 
• 
Number and proportion of screen failures by primary reason for screen failure 
[All] 
 
Disposition of participants will be summarized using the ES. [All] 
The number and percentage of participants in each analysis set by BRV formulation (tablet or 
dry syrup) will be calculated based on the RS. [IA-DMC, All] 
 
Participants who have started the study, completed the study and discontinued the study will be 
summarized using the RS by treatment sequence. The summary will include the following: 
• 
Number of and proportion of participants who have started the study  
• 
Number of and proportion of participants who have discontinued the study 
• 
Number of and proportion of participants who have completed the study. 
• 
Number of and proportion of participants who have discontinued the study by primary 
reason. 
Participants that started the study are defined as participants that were randomized and dosed. 
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Participants completing the study are those participants completing all Treatment Periods of the 
study as well as the SFU assessment. [IA-DMC, All] 
By-participant listings of participant disposition will be provided by treatment sequence for ES, 
and will include the following: 
• 
Study termination/completion status 
• 
Date of informed consent 
• 
Date of randomization 
• 
Date and time of the first and the last IMP administration 
• 
Date of premature study termination for successfully screened participants dropping out 
of the study  
• 
Date of screen failure for screen failure participants  
• 
Treatment (Period) at discontinuation 
• 
Primary reason for premature study termination, as applicable 
• 
Primary reason for screen failure, as applicable. 
[All] 
 
By-participant listings of visit dates will be presented by treatment sequence using the RS. [All] 
By-participant listings of participant who did not meet study eligibility criteria will be presented 
overall using the ES. [All] 
By-participant listings of participant inclusion in each analysis set will be presented overall using 
the ES. [All] 
By-participant listings of participant excluded from each analysis set will be presented by treatment 
sequence including the reasons for exclusion; the listing will be based on all subjects in the RS. [All] 
 
6.4 
Appendix 4: Baseline characteristics and demographics 
Demographic variables including year of birth, age, gender (Male), race (Asian), ethnicity (not 
Hispanic or Latino), height (cm), body weight (kg), and body mass index (BMI: kg/m2) will be 
listed by treatment sequence for all participants in the ES. Age will be used as recorded on the 
electronic case report form (eCRF) and will not be recalculated. 
 
Demographic and the other baseline characteristic variables at Screening will be summarized by 
BRV formulation (tablet or dry syrup)  and overall based on the SS. 
The continuous variables will be summarized using descriptive statistics, and the categorical 
variables will be summarized using frequency counts and percentages. 
Age will be summarized in both continuous and categorized (as per clinicaltrials.gov 
requirements) format. 
For the clinicaltrials.gov reporting, the age categories will include: 
• 
≤ 18 years 
• 
19 to < 65 years 
• 
≥ 65 years 
[All] 
 
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Lifestyle data will be summarized by BRV formulation for the SS. [All] 
By-participant listings of lifestyle data will be provided by treatment sequence for the RS. [All] 
 
6.5 
Appendix 5: Protocol deviations 
Important protocol deviations (IPDs) will be summarized by treatment sequence, and overall 
using the RS as well as participants from the PKS. The summary will include the following: 
• Number and percentage of participants with no IPDs 
• Number and percentage of participants with at least one IPD 
• Number and percentage of participants by type of protocol deviation 
[IA-DMC, All] 
 
By-participant listings of IPDs as identified in the Data Cleaning Meeting will be provided by 
treatment sequence, period, BRV formulation (tablet or dry syrup) using the RS.  
This will include deviation type, deviation description, and whether the deviation led to 
exclusion from any analysis set. [All] 
Protocol deviations (e.g., missing assessments or visits) related to COVID-19 will be listed 
separately. [All] 
 
6.6 
Appendix 6: Medical /surgical history / concomitant medical 
procedures  
By-participant listings of medical history, surgical /procedure history will be provided by 
treatment sequence for the RS. Medical history will include MedDRA SOC and PT, reported 
condition, start date and stop date (or status ongoing, as applicable). [All] 
A glossary of medical histories including reported term, SOC and PT will also be presented for 
the RS. [All]  
By-participant listings of concomitant medical procedures will be provided by treatment 
sequence for RS. [All] 
Hepatic event supplemental medical history will be listed for the RS. [All] 
 
6.7 
Appendix 7: Prior / concomitant medications 
If a participant takes a medication before the study medication administration, this medication 
will be categorized as ‘prior medication’. This includes medications that started prior to study 
medication administration and continued after. 
Medication not stopped before the date of study medication administration will be classified as 
‘concomitant medication’. Medication will also be labeled as ‘concomitant medication’ when the 
start date is between the date (including the date) of study medication administration and the date 
of the participant’s last study visit. 
From the definitions above, any medication that started prior to dosing and continued after 
dosing will be classified as both prior and concomitant. 
 
Prior and concomitant medications will be listed by treatment sequence and participant for 
participants in the RS and will include the reported term, the anatomical therapeutic chemical 
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(ATC) subgroup (level 1 and 3), preferred term, dose and dose unit, frequency, formulation,  
indication, prior or concomitant classification flag, start and stop dates (including relative day 
calculated as described in Section 4.1.1.1), duration (unit: day, calculated as stop date – start date 
+ 1) and BRV formulation assigned to. [All] 
A glossary of medication terms including reported term, preferred term, and ATC levels 1 and 3 
will also be presented. [All] 
Prior and concomitant medications will be summarized separately for the SS by treatment 
sequence and overall, ATC code (level 1 and 3), and preferred term, including the number and 
percentage of subjects receiving each medication as categorized by the ATC subgroup or 
preferred term. The denominator for percentages will be the number of subjects in the SS for 
each treatment sequence. [All] 
 
In the case of missing dates, the classification of medications as prior or concomitant will be 
performed after imputation of dates as described below. Imputations of missing dates will be 
performed prior to calculation of relative days. 
 
The following rules are applied to impute partial start dates for medications: 
• 
If only the month and year are specified and the month and year of first IMP dose is not 
the same as the month and year of the start date, then use the 1st of the month. 
• 
If only the month and year are specified and the month and year of first IMP dose is the 
same as the month and year of the start date, then use the date/time of first IMP dose. 
• 
If only the year is specified, and the year of first IMP dose is not the same as the year of 
the start date, then use January 1 of the year of the start date. 
• 
If only the year is specified, and the year of first IMP dose is the same as the year of the  
start date, then use the date/time of first IMP dose. 
• 
If the start date is completely unknown, then use the date/time of first IMP dose. 
 
The following rules will be applied for partial stop dates and will be imputed for the calculation 
of duration of each medication: 
• 
If only the month and year are specified, then use the last day of the month. 
• 
If only the year is specified, then use December 31 of that year. 
• 
If the stop date is completely unknown, do not impute the stop date. In this case the 
medication will be assigned to all Dosing Periods subsequent to the medication start date. 
 
Concomitant medications will be assigned to Dosing Periods, based on the time when the 
medication is taken. Assignment to Dosing Periods will be done after missing dates have been 
imputed as described above. Concomitant medications will be assigned to a treatment based on 
the treatment received in the Dosing Periods as follows: 
• 
Dosing Period 1: the start or end date is on or after IMP administration in Dosing Period 
1 and prior to IMP administration in Dosing Period 2 
• 
Dosing Period 2: the start or end date is on or after IMP administration in Dosing Period 2. 
 
6.8 
Appendix 8: Data derivation rules 
Not applicable. 
 
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6.9 
Appendix 9: AEs of Special Interest 
The AEs of special interest for BRV (by preferred term) are as follows: autoimmune nephritis, 
nephritis, nephritis allergic, tubulointerstitial nephritis, and uveitis syndrome. 
 
6.10 
Appendix 10: Potentially Clinically Significant Criteria for safety 
endpoints 
Not applicable. 
 
6.11 
Appendix 11: Compliance 
Any dosing deviations will be assessed in the Data Evaluation Meeting (DEM) for possible 
impact on the PKS. No listing will be provided since study participant compliance to treatment 
will be ensured by the administration of IMP under the Investigator’s (or designated site 
personnel’s) supervision. 
 
6.12 
Appendix 12: Standard Reporting Procedures 
6.12.1 
PK concentrations 
When reporting individual data in listings the following rules will apply: 
• Missing data will be reported as NV (no value). 
• Concentrations below the limit of quantification will be reported as BLQ (below the limit of 
quantification). 
• Concentrations will be listed to the same number of significant figures supplied by the 
bioanalytical laboratory. 
When reporting individual data in figures the following rules will apply: 
• BLQ values prior to Cmax will be set to 0 for purposes of plotting the figure (to capture lag-
time) only for the linear plot.  
• Actual sampling times will be used. 
When summarizing the data in tables the following rules will apply: 
• To calculate descriptive statistics, BLQ values will be set to half the LLOQ value and 
missing values will be excluded. 
• When the total number of BLQ and missing values exceeds one third of the total then only 
minimum and maximum will be reported for this time point. Other descriptive statistics will 
be reported as missing (“-“). The minimum will be reported as “BLQ”. 
• When the summary statistic includes one or more replaced BLQ values then a footnote will 
be included to say, “contains one or more BLQ value replaced by half the LLOQ value”. 
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• A minimum of 3 values are required to calculate summary statistics. If only 2 values are 
available, then these will be presented as the minimum and maximum with other descriptive 
statistics reported as missing (“-“). 
• If no participants have data, only n=0 will be presented. The other descriptive statistics will 
be left blank. 
• Descriptive statistics for plasma concentration data will be reported to the same level of 
precision as the individual data for the minimum and maximum, and to 1 additional decimal 
place or 1 additional significant figure – depending on the reporting format of the original 
data with a maximum of 3 significant digits, i.e., 35.12 will be 35.1, 0.0004649 will be 
0.000465 - for the mean (arithmetic and geometric), median, SD and the 95% CI for the 
geometric mean. 
• Geometric CV will be reported as a percentage to 1 decimal place. 
When summarizing the data in figures the following rules will apply: 
• The data plotted in the figure will match the data presented in the summary table, with the 
exception of missing values prior to Cmax which should be set to 0 in the figure (to capture 
lag-time). 
• Nominal sampling times will be used. 
Both linear and semi-logarithmic scales will be presented. 
 
6.12.2 
PK parameters 
When reporting individual data in listings the following rules will apply: 
• Individual PK parameters will be reported to 3 significant figures. 
• If a parameter cannot be calculated, it will be reported as NE (not estimable i.e., if input data 
is missing which prevents calculation) or NC (not calculable i.e., if the data were available 
but the calculation was considered unreliable). 
When summarizing the data in tables the following rules will apply: 
• The derived PK parameters will be considered as source data and this data without rounding 
will be used for calculation of summary statistics of PK parameters.  
• Descriptive statistics will be reported to 4 significant figures for the mean (arithmetic and 
geometric), median and standard deviation (SD) and to 3 significant figures to the others 
including the 95% CI for the geometric mean.  
• Geometric CV will be reported as a percentage to 1 decimal place.  
• 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 (i.e., not estimable). 
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• 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 (“-“) 
 
6.13 
Appendix 13: PK parameter calculations 
Pharmacokinetic parameters will be calculated by non-compartmental analysis methods from the 
concentration-time data following these guidelines: 
• 
Actual time will be used in the calculation of all derived pharmacokinetic parameters.  
• 
There will be no imputation of missing data.  
• 
BLQ values at the beginning of a subject profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero. Embedded BLQ values (i.e., occurring 
between two measurable data points) and BLQ values occurring post-Cmax will be 
considered missing. 
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 6-1. 
 
Table 6-1: Pharmacokinetic Parameter and Estimation 
Parameter 
Guideline for Derivation 
Cmax,ss, Ctrough, 
tlast and tmax,ss  
Obtained directly from the observed concentration-time data 
AUClast 
The AUC from zero time (predose) to the time of last quantifiable 
concentration will be calculated by a combination of linear and logarithmic 
trapezoidal methods. Unless specifically requested and justified, the linear 
up/log down trapezoidal method will be employed. 
The AUClast is the sum of areas up to the time of the last quantifiable sample: 
 
AUClast=∫𝐶last ∗𝑑𝑡
 t
0
 
AUCtau 
The AUC over the dosing interval will be determined for multiple dose 
studies using the linear up/log down trapezoidal rule. 
 
In case tobs is < tau and tobs is the last non-BLQ/non-missing sample, 
AUCtau will be calculated by extrapolation to time tau using lambda z. If the 
elimination phase cannot be characterized, AUCtau will be set to missing.  
AUCtau values will be flagged based on the PK Scientist’s judgement, based 
on the reliability of extrapolation. 
Note: tobs is the actual sampling time at planned timepoint tau.  
%AUCex 
The percentage of AUCtau obtained by extrapolation will be calculated as 
follows:  
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Parameter 
Guideline for Derivation 
%AUCex =
AUCtau  ꟷ AUClast 
AUCtau  
x100 
 
%AUCex should not exceed 10% for an individual profile. If the %AUCex is 
more than 10%, the individual result should be flagged as all parameters 
depending on AUCtau (i.e. AUCtau, and CLss/F) should be flagged and 
footnoted in parameter listing. If %AUCex is greater than 10% in more than 
20% of the participants, the validity of the study may need to be discussed. 
λz and t½ 
1. The apparent terminal phase rate-constant (λz) will be estimated by linear 
regression of concentration versus time data presented in a log-linear scale. 
2. Data are primarily monotonically decreasing in magnitude and are 
representative of the actual decline in the log concentration-time curve. 
3. Only those data points that are judged to describe the terminal log-linear 
decline will be used in the regression.  
4. A minimum number of three data points in the terminal phase will be used 
in calculating λz with the line of regression starting at any post-Cmax data 
point (Cmax should not be part of the regression slope). The adjusted 
correlation coefficient (R2 adjusted) in general should be greater than 0.90. 
Any value < 0.90 but ≥0.8 will be flagged but may be used at the PK 
Scientist’s best knowledge and judgment. All the derived parameters (i.e. 
λz, t½, AUCtau, CLss/F) will be flagged accordingly. 
5. The interval used to determine λz should be equal or greater than 1.5-fold 
the estimated t½ or otherwise flagged and used for descriptive summaries 
at the PK Scientist’s best knowledge and judgment. All the derived 
parameters (i.e. t½, AUCtau, CLss/F) will be flagged from statistical analysis 
accordingly.  
6. The t½ will be calculated as follows:  
   
t½ = 
z
z
λ
693
.
0
λ
2
Ln

 
Data points may be dropped from the linear regression if the PK Scientist 
considers the reported values to be anomalous.  Any data points so 
designated should remain in the listings and be identified in the study report 
with a rationale for exclusion.  
CLss/F 
Apparent clearance of parent drug will be calculated from:  
CLss/F = Dose/AUCtau  
Rtrough 
Ratio between  the Ctrough after the last dose on Day 3 and the pre-dose 
concentration before each dose with the exclusion of morning dose on Day 
1 
 
7 
REFERENCES 
Lan, K.K.G., and DeMets, D.L. (1983) “Discrete Sequential Boundaries for Clinical Trials.” 
Biometrika. 70(3): 659-63. 
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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


UCB 
 
28 Jun 2024 
Statistical Analysis Plan 
Brivaracetam 
EP0231 
 
 
 
Confidential 
Page 41 of 41 
Ministry of Health, Labour and Welfare (2020) “The Partial Amendment to Guideline for 
Bioequivalence Studies of Generic Products.” PSEHB/PED Notification  0319-1 19 March 2020. 
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.


Approval Signatures
Name:
ep0231-sap amendment 1
Version:
1. 0
Document Number:
CLIN-000259824
Title:
ep0231-sap amendment 1
Approved Date:
28 Jun 2024
Document Approvals
Approval
Verdict: Approved
Name:
Capacity: Clinical
Date of Signature: 28-Jun-2024 09:08:01 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 28-Jun-2024 09:13:19 GMT+0000
PUBLIC COPY 
This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.