Conditions: Healthy Study Participants
Keywords: brivaracetam Healthy Study Participants Phase 1 BRV
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: yes

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

Detailed description:

Arms:
arm 1: Study participants randomized to this arm will receive a single dose of brivaracetam tablet (Treatment A) as reference and single dose 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 a single dose of brivaracetam tablet (Treatment A) as reference and single dose of brivaracetam dry syrup (Treatment B) as test in the treatment sequence B-A at pre-specified timepoints.

Interventions: intervention 1: brivaracetam intervention 2: brivaracetam
Intervention descriptions: intervention 1: Study participants will receive a single-dose of brivaractam tablet (reference - Treatment A) administered orally. intervention 2: Study participants will receive a single-dose of brivaractam dry syrup (test - Treatment B) administered orally.

Protocol document:
Prot_000.pdf: 
UCB 
 
11 Jan 2022 
Clinical Study Protocol 
Brivaracetam 
EP0110 
 
 
 
Confidential 
Page 1 of 68 
A SINGLE-DOSE, OPEN-LABEL, RANDOMIZED, 2-WAY 
CROSS-OVER STUDY TO ASSESS THE BIOEQUIVALENCE 
BETWEEN BRIVARACETAM TABLET AND DRY SYRUP IN 
HEALTHY MALE JAPANESE STUDY PARTICIPANTS 
PROTOCOL EP0110 AMENDMENT 1.0 
PHASE 1 
 
SHORT TITLE: 
A single-dose study to assess the bioequivalence between brivaracetam tablet and dry syrup in 
healthy Japanese study 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 
 
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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Clinical Study Protocol 
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EP0110 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Type of amendment 
Original Protocol 
25 Feb 2021 
Not applicable 
Amendment 1.0 
11 Jan 2022 
Not applicable  
Amendment 1.0 (11 Jan 2022) 
Overall Rationale for the Amendment 
EP0110 Protocol Amendment 1.0, dated 11 Jan 2022, was completed to: 
• Implement the appropriate COVID-19 precautions during the global pandemic.  
• Add COVID-19 vaccination guidance. 
• Align the time points for collection of 12-lead ECG and vital sign assessments and remove 
the nonessential 0.5h postdose ECG assessment. 
• Reduce the volume of water ingested with the BRV tablet and dry syrup formulations to 
align with Japan’s guideline for bioequivalence studies. 
• Align the limits for blood loss resulting in exclusion from the study with Japan’s blood 
donation standards. 
• Add an excipient to the former list for the dry syrup preparation.  
• Lengthen the allowable deviation from scheduled time for PK blood samples at predose (0h). 
• Provide additional clarification for BRV background information and study-specific 
procedures. 
• Correct minor typographical errors and inconsistencies. 
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Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Corrected the primary endpoints 
presented in the Objectives and 
Endpoints table. 
Error correction. 
Section 1.1 Synopsis  
Section 3 Objectives and 
endpoints 
Added that the secondary endpoints 
are the incidence of TEAEs and 
treatment-emergent SAEs  
Clarification. 
Section 1.1 Synopsis 
Section 1.2 Schema 
Section 1.3 Schedule of 
Activities 
Section 4.1 Overall design 
Revised the duration of the 
Screening Period from 20 days (2 to 
21 days before administration of 
IMP) to 27 days (2 to 28 days before 
administration of IMP). 
Screening Period extended by 
7 days to better disperse the 
number of potential study 
participants attending Screening 
Visits to minimize the spread of 
COVID-19 infection during the 
global pandemic. 
Section 1.1 Synopsis 
Revised the maximum total study 
duration from 41 to 48 days to reflect 
the 7-day extension of the Screening 
Period. 
Screening Period extended by 
7 days to better disperse the 
number of potential study 
participants attending Screening 
Visits to minimize the spread of 
COVID-19 infection during the 
global pandemic. 
Section 1.2 Schema 
Revised the treatment sequences for 
Dosing Period 2 (A-B or B-A). 
Error correction. 
Section 1.3 Schedule of 
Activities 
Replaced the 12-hour post dose vital 
signs assessment with an 8-hour 
timepoint. 
Adjusted to align with the 8-hour 
ECG measurement time point. 
Section 1.3 Schedule of 
Activities 
Removed the 0.5 hour postdose 
12-lead ECG assessment. 
Reduced the number of 
assessments based upon the PK 
of BRV. 
Section 1.3 Schedule of 
Activities 
Section 8.2.3 
Electrocardiograms 
Clarified text describing the 
Screening (Visit 1) ECG, which 
includes the collection of 3 Baseline 
values, measured at 2- to 5-minute 
intervals. 
Clarification of study 
procedures. 
Section 1.3 Schedule of 
Activities 
Clarified footnote ‘f’ to state that 
Randomization will occur for Dosing 
Period 1 only, either on Day -1 or 
Day 1 before any assessment of 
Day 1. 
Clarification of study 
procedures. 
Section 1.3 Schedule of 
Activities 
Added that IMP administration will 
occur under fasting conditions. 
Alignment with the descriptive 
text in Section 5.3.4. 
Section 2.2 Background 
Revised text to state that study 
N01258 has completed. 
Update. 
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Section 2.2 Background 
Added that the 1 BRV formulation 
currently used of the 2 oral 
formulations developed for the 
pediatric program is the oral solution 
(10mg/mL). 
Clarification. 
Section 5.2 Exclusion 
criteria 
Exclusion criterion 8 was revised to 
include that participants will be 
excluded if they receive a 
COVID-19 vaccine within 7 days of 
the first administration of IMP. 
Revised to reduce the impact of 
vaccination side reactions on 
evaluations conducted in this 
study. 
Section 5.2 Exclusion 
criteria 
For exclusion criterion 14, the 
former symbol (>) was revised to 
reflect that study participants would 
be excluded if they experienced 
blood loss of ≥400mL within 
90 days or ≥200 within 30 days. 
Alignment with blood donation 
standards in Japan. 
Section 5.3.4 Food intake 
times 
Clarified text to state that a predose 
blood sample will be obtained prior 
to the study participant’s first dose of 
IMP. 
Clarification of study 
procedures. 
Section 5.3.4 Food intake 
times 
Section 6.1 Treatments 
administered 
Adjusted the amount of water that 
would be administered with the BRV 
tablet from 240mL to 200mL.  
Adjusted the amount of water that 
the study participant would rinse the 
dosing container and then ingest 
from 140mL to 100mL. 
Alignment with Japanese 
guideline for BE studies that 
provides the range of 100 to 
200mL of water with IMP 
administration.  
Section 5.3.5 Other 
restrictions 
Revised text stating that all study 
participants would be contacted by 
telephone 1 day prior to admission 
for assessing COVID-19 signs and 
symptoms to state that this would 
occur before admission and as close 
to admission as feasible. 
Enhanced flexibility for the 
Investigator/site staff. 
Section 6.1 Treatments 
administered 
Added light anhydrous silicic acid to 
the list of excipients for BRV dry 
syrup. 
Revised due to changes in the 
composition of the BRV dry 
syrup administered in the study.  
Section 6.5.1 Permitted 
concomitant treatments 
(medications and therapies) 
Revised text stating that COVID-19 
vaccines would be permitted during 
the study to specify that they would 
only be permitted up to 7 days prior 
to the initiation of IMP 
administration. 
Revised to reduce the impact of 
vaccination side reactions on 
evaluations conducted in this 
study. 
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Section 6.5.2 Prohibited 
concomitant treatments 
(medications and therapies) 
Clarify that COVID-19 vaccines are 
prohibited within 7 days of first IMP 
administration and during the study 
until SFU. 
Revised to reduce the impact of 
vaccination side reactions on 
evaluations conducted in this 
study. 
Section 8.1 
Pharmacokinetics 
Increased the allowable deviation 
from scheduled time for PK blood 
samples at predose (0h) from 
15 minutes to 30 minutes. 
Enhanced flexibility for the 
Investigator/site staff. 
Section 8.2.2 Vital signs 
Clarified text stating that vital signs 
will be assessed with the study 
participant in a supine position 
following at least 5 minutes of rest. 
Clarification of study 
procedures. 
Section 9.1 Definition of 
analysis sets 
Revised text to state that study 
participants will be excluded from 
the PK-PPS if their predose 
concentrations are greater than 5% of 
the corresponding Cmax value in both 
Dosing Periods, rather than in either 
Dosing Period. 
Error correction. 
Section 9.3.1 
Pharmacokinetic analyses 
Revised text to state that PK 
analyses will be performed on the SS 
and statistical analyses will be 
performed on the PK-PPS.  
Clarification. 
Section 9.5 Handling of 
protocol deviations 
Added text to clarify that data will 
not yet be available at the time of the 
Data Evaluation Meeting to define 
the final PK-PPS, based upon the 
definition of PK-PPS provided in 
Section 9.1.  
Clarification. 
Section 9.8 Determination 
of sample size 
Added text to clarify that a total of 
19 participants will provide a power 
of 90% at the 5% significance level 
(one-sided) to declare BE. 
Clarification 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Revised that clinical laboratory tests 
would be performed by a central 
laboratory to state that they will be 
performed by a local laboratory. 
The single site for this study has 
a certified local clinical 
laboratory available. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Added WBC count to the list of 
hematology parameters to be 
assessed.  
Error correction. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Revised that instead of a urine 
alcohol screen, an alcohol breath test 
would be performed. 
Error correction. 
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Clinical Study Protocol 
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EP0110 
 
 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
+32 2 386 2421 
Email 
DS_ICT@ucb.com 
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EP0110 
 
 
 
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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ............................................................................................... 11 
1.1 
Synopsis ....................................................................................................................... 11 
1.2 
Schema ......................................................................................................................... 13 
1.3 
Schedule of Activities .................................................................................................. 15 
2 
INTRODUCTION ........................................................................................................... 18 
2.1 
Study Rationale ............................................................................................................ 19 
2.2 
Background .................................................................................................................. 20 
2.3 
Benefit/Risk Assessment ............................................................................................. 20 
2.3.1 
Risk assessment for coronavirus disease 2019 .................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 22 
4 
STUDY DESIGN ............................................................................................................. 23 
4.1 
Overall design .............................................................................................................. 23 
4.2 
Scientific rationale for study design ............................................................................ 24 
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 ............................................................................. 26 
5.3.3 
Activity ................................................................................................................ 27 
5.3.4 
Food intake times ................................................................................................. 27 
5.3.5 
Other restrictions ................................................................................................. 27 
5.4 
Screen failures .............................................................................................................. 27 
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 ........................................................................................................ 32 
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 STUDY PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 32 
7.1 
Discontinuation of IMP................................................................................................ 32 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 32 
7.2 
Study participant discontinuation/withdrawal from the study ..................................... 33 
7.3 
Lost to follow up .......................................................................................................... 33 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 34 
8.1 
Pharmacokinetics ......................................................................................................... 34 
8.2 
Safety assessments ....................................................................................................... 37 
8.2.1 
Clinical safety laboratory assessments ................................................................ 37 
8.2.2 
Vital signs ............................................................................................................ 38 
8.2.3 
Electrocardiograms .............................................................................................. 38 
8.2.4 
Physical examination ........................................................................................... 38 
8.3 
Adverse events and serious adverse events ................................................................. 38 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 38 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 39 
8.3.3 
Follow up of AEs and SAEs ................................................................................ 39 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 39 
8.3.5 
Pregnancy ............................................................................................................ 40 
8.3.6 
Adverse events of special interest ........................................................................ 40 
8.4 
Safety signal detection ................................................................................................. 40 
8.5 
Treatment of overdose ................................................................................................. 40 
8.6 
Efficacy assessments .................................................................................................... 40 
8.7 
Genetics........................................................................................................................ 40 
8.8 
Pharmacodynamics ...................................................................................................... 40 
8.9 
Biomarkers ................................................................................................................... 40 
8.10 
Health economics ......................................................................................................... 40 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 40 
9.1 
Definition of analysis sets ............................................................................................ 41 
9.2 
General statistical considerations ................................................................................. 41 
9.3 
Planned outcome analyses ........................................................................................... 42 
9.3.1 
Pharmacokinetic analyses .................................................................................... 42 
9.4 
Planned safety analyses................................................................................................ 42 
9.4.1 
Primary safety analyses ....................................................................................... 42 
9.4.2 
Other safety analyses ........................................................................................... 43 
9.4.2.1 
Clinical laboratory assessments ................................................................. 43 
9.4.2.2 
Vital signs .................................................................................................. 43 
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9.4.2.3 
Electrocardiograms .................................................................................... 43 
9.4.2.4 
Physical examination ................................................................................. 43 
9.5 
Handling of protocol deviations................................................................................... 43 
9.6 
Handling of dropouts or missing data .......................................................................... 43 
9.7 
Planned interim analysis and data monitoring ............................................................. 43 
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 .................................................................................... 46 
10.1.4 
Data protection ..................................................................................................... 46 
10.1.5 
Data quality assurance ......................................................................................... 46 
10.1.5.1 
Case Report Form completion ................................................................... 47 
10.1.5.2 
Apps ........................................................................................................... 47 
10.1.6 
Source documents ................................................................................................ 47 
10.1.7 
Study and site closure .......................................................................................... 48 
10.1.8 
Publication Policy ................................................................................................ 48 
10.2 
Appendix 2: Clinical Laboratory Tests ........................................................................ 49 
10.3 
Appendix 3: Adverse Events – Definitions and Procedures for Recording, Evaluating, 
Follow up, and Reporting ............................................................................................ 50 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ....... 55 
10.5 
Appendix 5: Genetics ................................................................................................... 58 
10.6 
Appendix 6: Liver Safety – Suggested Actions and Follow-up Assessments ............. 59 
10.7 
Appendix 7: Medical Device Adverse Events (AEs), Adverse Device Effects (ADEs), 
Serious Adverse Events (SAEs) and Device Deficiencies: Definition and Procedures 
for Recording, Evaluating, Follow up, and Reporting ................................................. 62 
10.8 
Appendix 8: Rapid Alert Procedures ........................................................................... 63 
10.9 
Appendix 9: Country-specific Requirements............................................................... 64 
10.10 Appendix 10: Abbreviations and Trademarks ............................................................. 65 
10.11 Appendix 11: Protocol Amendment History ............................................................... 66 
11 REFERENCES ................................................................................................................ 67 
SPONSOR DECLARATION .................................................................................................. 68 
 
LIST OF TABLES 
Table 1-1: 
Schedule of Activities ...................................................................................... 16 
Table 6-1: 
Treatments administered .................................................................................. 29 
Table 8-1: 
Pharmacokinetic blood sampling scheme ........................................................ 36 
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Table 8-2: 
Irrelevant time deviations for PK sampling ..................................................... 37 
Table 10-1: 
Highly Effective Contraceptive Methods for female partners ......................... 56 
Table 10-2: 
Liver Chemistry Stopping Criteria and Follow-Up Assessments .................... 59 
 
LIST OF FIGURES 
Figure 1-1: 
Schematic diagram ........................................................................................... 14 
Figure 7-1: 
Liver chemistry stopping algorithm ................................................................. 32 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: A single-dose, open-label, randomized, 2-way cross-over study to assess the 
bioequivalence between brivaracetam (BRV) tablet and dry syrup in healthy male Japanese study 
participants. 
Short Title: A single-dose study to assess the bioequivalence between BRV tablet and dry syrup 
in healthy Japanese study 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. This study aims to assess the 
bioequivalence between the BRV 50mg tablet and BRV 50mg as dry syrup formulations. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the bioequivalence between 
the BRV 50mg tablet and BRV 50mg as dry 
syrup after a single oral dose in healthy 
Japanese male study participants 
Primary Endpoints: 
• 
Cmax 
• 
AUC(0-t) 
Secondary 
• 
To evaluate the safety and tolerability of 
2 oral dosage forms of BRV in healthy 
Japanese male study participants 
Secondary endpoints: 
• 
Incidence of TEAEs 
• 
Incidence of treatment-emergent SAEs 
Other 
Other PK Objective: 
• 
To evaluate other PK parameters of 2 oral 
dosage forms of BRV in healthy Japanese 
male study participants 
The other PK endpoints will be calculated: 
• 
AUC 
• 
AUCextr 
• 
CL/F 
• 
Vz/F 
• 
MRT 
• 
tmax 
• 
t½ 
• 
λz 
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Objectives 
Endpoints 
Other Safety Objective: 
• 
To further evaluate the safety and tolerability 
of 2 oral dosage forms of BRV in healthy 
Japanese male study participants 
Other safety endpoints will be assessed during the 
study: 
• 
Changes in clinical laboratory test parameters 
(ie, hematology, clinical chemistry, and 
urinalysis) 
• 
Changes in vital signs (SBP, DBP, pulse rate, 
respiratory rate, and body temperature) 
• 
12-lead ECG parameters and findings 
• 
Physical examinations 
λz=first order terminal elimination rate constant; AUC=area under the curve from 0 to infinity; AUC(0-t)=area 
under the curve from 0 to the time of the last quantifiable concentration; AUCextr=extrapolated AUC; 
BRV=brivaracetam; CL/F=total clearance after oral administration; Cmax=maximum concentration; 
DBP=diastolic blood pressure; ECG=electrocardiogram; MRT=mean residence time (ie, of the unchanged drug 
in the systemic circulation); PK=pharmacokinetics; SAE=serious adverse event; SBP=systolic blood pressure; 
t1/2=terminal elimination half-life; TEAE=treatment-emergent adverse event; tmax=time of Cmax; Vz/F=apparent 
volume of distribution 
Overall Design 
EP0110 is a single-center, single-dose, open-label, randomized, 2-way cross-over study designed 
to assess the bioequivalence between the BRV 50mg tablet and BRV 50mg as dry syrup 
formulations in healthy Japanese male study participants after oral administration under fasted 
conditions. In addition, safety and tolerability of BRV will be evaluated. 
Study participants will enter a Screening Period (2 to 28 days before administration of 
investigational medicinal product [IMP]) and eligible study participants will start Dosing 
Period 1. The Dosing Period consists of 2 periods (Dosing Period 1 and Dosing Period 2) of 
4 days each with a single administration on Day 1 of each Dosing Period. The Dosing Periods 
will be separated by a Wash-Out Period (at least 7 days and no more than 10 days between the 
2 administrations for each study participant) and followed by a Safety Follow-Up (SFU) Visit, 
7 to 9 days after the last administration of IMP. Study participants who prematurely discontinue 
the IMP/study are to return for a Withdrawal Visit, 7 to 9 days after the last IMP administration. 
Refer to the study schematic in Figure 1-1. 
On Day 1 of each Dosing Period, the study participants will receive 1 of the following treatments 
in randomized order under fasting conditions: 
• Treatment A – a single dose of BRV 50mg tablet 
• Treatment B – a single dose of BRV 50mg as dry syrup (1.25g of granules for oral solution 
4% w/w) 
The activities to be performed during the Dosing Periods are presented in the Schedule of 
Activities (Table 1-1). 
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Number of Study participants 
A total of 24 study participants are planned to be randomized and complete the study; however, 
additional study participants may be randomized in case some study participants discontinue the 
study early (not only limited to coronavirus disease 2019 [COVID-19] circumstances). 
Treatment Groups and Duration 
The total duration of the study for an individual study participant is 17 days to 48 days and will 
include: 
• A Screening Period (2 to 28 days before IMP administration) 
• Two Dosing Periods (4 days each, with IMP administration on Day 1 of each Dosing Period) 
• A Wash-out Period following Dosing Period 1 (7 to 10 days between the 2 IMP 
administrations) 
• An SFU Visit/Withdrawal Visit (7 to 9 days after the last IMP administration) 
Refer to Figure 1-1 for the study design. 
In the Treatment A/Treatment B sequence, on Day 1 of Dosing Period 1, each study participant 
will receive a single dose of BRV tablet formulation (50mg). On Day 1 of Dosing Period 2, these 
same study participants will receive a single dose of BRV 50mg as dry syrup formulation (1.25g 
of granules for oral solution 4% w/w). 
In the Treatment B/Treatment A sequence, on Day 1 of Dosing Period 1, each study participant 
will receive a single dose of BRV 50mg as dry syrup formulation (1.25g of granules for oral 
solution 4% w/w). On Day 1 of Dosing Period 2, these same study participants will receive a 
single dose of BRV tablet formulation (50mg). 
The Dosing Periods will be separated by a Wash-out Period of at least 7 days and no more than 
10 days between the 2 IMP administrations. Study participants will be discharged following 
Dosing Period 1 (on Day 3 of Dosing Period 1; 48 hours after IMP administration) with an 
appointment for their next check-in for Dosing Period 2. Study participants will check in 1 day 
before Dosing Period 2, which should start after the Wash-out Period (at least 7 days and no 
more than 10 days between the 2 IMP administrations). Study participants will be discharged 
after Dosing Period 2 (on Day 3 of Dosing Period 2; 48 hours after IMP administration) and will 
return to the study site for SFU Visit assessments, 7 to 9 days after the last IMP administration. 
Study participants who prematurely discontinue the IMP/study are to return for a Withdrawal 
Visit, 7 to 9 days after the last IMP administration. 
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; IMP=investigational medicinal product; SFU=Safety Follow-Up 
a Following a Screening Period (2 to 28 days before IMP administration), each study participant 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. Treatment A – a single dose of BRV 50mg tablet and Treatment B – a single 
dose of BRV 50mg as dry syrup (1.25g of granules for oral solution 4% w/w). 
b Each Dosing Period is 4 days (Day -1 to Day 3) with a single administration of IMP on Day 1 of each Dosing 
Period. For each Dosing Period, study participants will be admitted to the study site on Day -1 (1 day before 
dosing). Study participants will receive IMP on Day 1 and will be discharged in the morning of Day 3, 
approximately 48 hours after the administration of IMP. 
c The 2 Dosing Periods will be separated by a Wash-Out Period of 7 to 10 days between IMP administrations. 
d An SFU Visit will occur 7 to 9 days after the last administration of IMP. Study participants who prematurely 
discontinue the IMP/study will be encouraged to undergo Withdrawal Visit procedures within 7 to 9 days after the 
last administration of IMP. 
 
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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 
Dosing Period 1 or 2 a 
SFU/Withdrawal b 
V1 
V2 or V3 
V4 
2 to 28 days 
before 
administration 
of IMP 
Check in 
Day -1 
Day 1 
Day 2 
Day 3 
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 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
Height and weight 
X 
 
 
 
 
 
Viral serology (HBsAg, HCV, HIV, and 
syphilis) 
X 
 
 
 
 
 
Urine drug test and alcohol breath test 
X 
X 
 
 
 
 
COVID-19 precautions c 
X 
X 
 
 
 
X 
Vital signs d 
X 
 
X 
X 
X 
X 
Clinical laboratory tests (hematology, 
clinical chemistry, and urinalysis) 
X 
 
 
 
X 
X 
Randomization e 
 
X f 
 
 
 
12-lead ECG g 
X 
 
X 
X 
X 
X 
IMP administration h 
 
 
X 
 
 
 
Blood sampling for PK i 
 
 
X 
X 
X 
 
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Table 1-1: 
Schedule of Activities 
Procedure 
Screening 
Dosing Period 1 or 2 a 
SFU/Withdrawal b 
V1 
V2 or V3 
V4 
2 to 28 days 
before 
administration 
of IMP 
Check in 
Day -1 
Day 1 
Day 2 
Day 3 
7 to 9 days after the 
last administration of 
IMP 
Recording of prior and concomitant 
medication and procedures 
X 
X 
X 
X 
X 
X 
Recording of AEs 
X 
X 
X 
X 
X 
X 
Confinement 
 
X 
X 
X 
X 
 
AE=adverse event; 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 
a Each study participant will enter 2 Dosing Periods, separated by a Wash-Out Period of 7 to 10 days between IMP administrations. Dosing Period 2 will start 
after the Wash-out Period (at least 7 days and no more than 10 days between the 2 IMP administrations). 
b An SFU visit will occur 7 to 9 days after the last administration of IMP. Study participants who prematurely discontinue the IMP/study should be encouraged 
to undergo Withdrawal Visit procedures within 7 to 9 days after the last administration of IMP. 
c COVID-19 precautions as described in Section 2.3.1 and Section 5.3.5. 
d Vital signs are taken at the Screening Visit, at predose, 4, 8, 24, and 48 hours postdose, and at the SFU Visit/Withdrawal Visit. 
e Each study participant will be randomly assigned to 1 of 2 treatment sequences (A-B or B-A) before dosing in Period 1, after all Day -1 assessments have been 
completed. 
f Randomization occurs only for Dosing Period 1, either on Day -1 or Day 1 before any assessment of Day 1. 
g 12-lead ECGs are recorded at Screening, at predose, 1, 4, 8, 24, and 48 hours postdose, and at the SFU Visit/Withdrawal Visit. At predose on Day 1 of each 
Dosing Period, 3 Baselines values will be measured at 2- to 5-minute intervals. 
h IMP administration: BRV 50mg will be administered as a 50mg tablet (Treatment A [reference]) or as dry syrup (1.25g of BRV granules for oral solution 4% 
w/w; Treatment B [test]) under fasting conditions. 
i Blood samples for PK analysis are collected at predose, and 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose. Allowable 
deviations from these scheduled PK sampling times are provided in Table 8-2. 
 
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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 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 in Japan. 
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 time to reach maximum plasma concentration (tmax) is 1h (range: 0.25 to 3h) after dosing 
in fasting study participants. The 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 study 
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 3h 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 9h in healthy adults. It decreases to 6.3h following repeated administration at high 
doses (800mg/day). More than 95% of the dose, including less than 9% as unchanged BRV, is 
excreted in the urine within 72h 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. Combination of these 2 pathways leads to the 
formation of the hydroxyacid metabolite (ucb-107092-1). These 3 metabolites are not 
pharmacologically active. Weak metabolic auto-induction, resulting in a 14% increase in BRV 
clearance, was only observed at high doses (800mg/day). There is no evidence of chiral inversion 
of BRV. In a PK and pharmacodynamic (PD) interaction study in healthy study participants, 
BRV increased the effects of alcohol on psychomotor function, attention, and memory, although 
there was no clinically relevant PK interaction. 
Safety profile in clinical pharmacology studies 
Over 25 clinical pharmacology studies with BRV have been conducted in healthy study 
participants, with the highest single dose given being BRV 1400mg. 
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Safety data were pooled (Pool Phase 1) for all completed clinical pharmacology studies with the 
exception 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. N01209 and EP0117 studies in healthy male Japanese 
study participants, were also included in Pool Phase 1. N01069, a Phase 2a study in study 
participants with photosensitive epilepsy, is included in Pool Phase 1 due to its single-dose study 
design, which was similar to a clinical pharmacology study. Pool Phase 1 includes study 
participants who received BRV oral tablets, capsules, and solution, and study participants who 
received solution for intravenous (iv) injection. Pool Phase 1 included 220 study participants in 
the placebo group and 729 study participants in the BRV Overall group. Treatment-emergent 
adverse events (TEAEs) were reported for 67 study participants (30.5%) in the placebo group 
and 586 study 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 study 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 study participants, a total 
of 11 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 administration in healthy male Japanese study participants, 
the most commonly reported TEAEs were somnolence, dizziness, and nausea. 
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 adjunctive therapy in the treatment of POS with or without 
secondary generalization in pediatric study participants with epilepsy aged from 4 to <16 years 
of age in Japan. In addition to tablets and solution for injection, a dry syrup formulation is being 
developed specifically for the Japanese market mainly to allow dose adjustment by body weight 
in pediatric patients. 
While the PK of the tablet has been studied extensively in healthy study participants and in 
patients with various forms of epilepsy, the PK of the dry syrup formulation has not been 
evaluated in studies. 
As patients may switch from the dry syrup to the tablet, or vice versa, and as dry syrup is 
favorable in pediatric patients, it is important to know whether the same dose may be maintained 
and if the dry syrup formulation shows the PK performance of the tablet formulation. 
For that reason, a bioequivalence study between the tablet and dry syrup formulations is required 
by the Pharmaceuticals and Medical Devices Agency. Since both formulations are of the 
, a single-dose study is sufficient to determine bioequivalence. The 
therapeutic dose will vary between patients, but a dose of 50mg bid is the most commonly used 
dose. For that reason, the dose of 50mg was selected for this study. Since the PK of BRV is 
linear over the therapeutic dose range, the bioequivalence results of this study should be 
applicable to other doses as well. 
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This study aims to assess the bioequivalence between the BRV 50mg tablet and BRV 50mg as 
dry syrup formulations in healthy adult male study participants. 
A 2-treatment and 2-period randomized cross-over design will be used to compare the PK profile 
of single dosing of the BRV tablet formulation to the BRV dry syrup formulation. Study 
participants will be administered 1 of the 2 BRV formulations during each of the 2 Dosing 
Periods in a Treatment A (tablet [reference])/Treatment B (dry syrup [test]) or Treatment B (dry 
syrup [test])/Treatment A (tablet [reference]) sequence with a Wash-out Period in between. 
2.2 
Background 
Brivaracetam is a chemical relative of the antiepileptic drug levetiracetam (LEV 
[Keppra®/E-Keppra®]). Like LEV, BRV displays a high and selective interaction with a binding 
site SV2A. However, the binding affinity of BRV for SV2A is approximately 10-fold higher. 
This binding site appears to be the major target for its pharmacological activity. Unlike LEV, 
BRV also reduces voltage-dependent sodium currents. Brivaracetam also reverses the inhibitory 
effects of negative allosteric modulators on gamma-aminobutyric acid- and glycine-induced 
currents. Brivaracetam is extensively metabolized, but seizure protection appears to be 
associated with the parent compound. 
Brivaracetam has primarily been studied as oral (tablet) adjunctive therapy in study participants 
with refractory epilepsy, a conversion to monotherapy indication for POS, and adjunctive 
therapy for other indications (Unverricht–Lundborg disease, postherpetic neuralgia, acute 
repetitive seizures, and essential tremor). In addition, an iv formulation of BRV has been studied 
in study participants with epilepsy (N01258) and also has been evaluated as a replacement for 
oral BRV in adult Japanese study 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 currently in use. 
The BRV clinical development program includes 4 studies of BRV as adjunctive therapy in 
pediatric study participants with epilepsy (N01263, N01266, EP0065, and N01349). 
The primary objective of this study is to demonstrate the bioequivalence between the BRV 50mg 
tablet and BRV 50mg as dry syrup formulations. 
2.3 
Benefit/Risk Assessment 
The healthy study participants included in this study will receive no medical benefit from 
participation. 
In addition to the most frequently reported adverse events (AEs) described in Section 2, the 
potential risks in the study include: 
• Electrocardiogram stickers on the study participants' chests and limbs may cause some local 
irritation and may be uncomfortable to remove. Study 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 
study participant, and it is possible that bruising, and/or inflammation, and/or hematoma may 
occur at the site of cannulation. 
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In the BRV drug development program, the 50mg dose has been shown to be well tolerated in 
healthy study participants. 
More detailed information about the known and expected risks and reasonably expected AEs of 
BRV may be found in the IB. 
2.3.1 
Risk assessment for coronavirus disease 2019 
Brivaracetam is an inhibitor 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 a single dose, on Day 1 of 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 study participants. 
Therefore, the risk of the study 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 study participants may have additional contact (eg, 
commute to the site) and have additional human contact (eg, with site staff and other study 
participants of the clinical study). 
Screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at the 
time of study entry is not currently recommended by the Sponsor and will only be conducted if 
required by local regulatory and healthcare guidance. 
On each visit to the study site, study participants will be asked about their potential exposure to 
SARS-CoV-2 infection (contacts, family members, etc.) in accordance with the study site’s own 
procedures and local regulatory/healthcare authority guidance. Refer to Section 5.3.5 for further 
details. 
Study participants will be closely monitored for any signs 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. If symptoms and/or clinical signs of infection are 
identified, the Investigator will decide whether these findings will be handled as suspected or 
confirmed COVID-19. The use of testing for SARS-CoV-2 will be determined by reference to 
the regulatory and healthcare guidance in place locally at the time. 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 study participant may be discharged from the study site, and whether 
this will be to their home or another healthcare facility. 
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3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the bioequivalence between 
the BRV 50mg tablet and BRV 50mg as dry 
syrup after a single oral dose in healthy 
Japanese male study participants 
Primary Endpoints: 
• 
Cmax 
• 
AUC(0-t) 
Secondary 
• 
To evaluate the safety and tolerability of 
2 oral dosage forms of BRV in healthy 
Japanese male study participants 
Secondary endpoints: 
• 
Incidence of TEAEs 
• 
Incidence of treatment-emergent SAEs 
Other 
Other PK Objective: 
• 
To evaluate other PK parameters of 2 oral 
dosage forms of BRV in healthy Japanese 
male study participants 
The other PK endpoints will be calculated: 
• 
AUC 
• 
AUCextr 
• 
CL/F 
• 
Vz/F 
• 
MRT 
• 
tmax 
• 
t½ 
• 
λz 
Other Safety Objective: 
• 
To further evaluate the safety and tolerability 
of 2 oral dosage forms of BRV in healthy 
Japanese male study participants 
Other safety endpoints will be assessed during the 
study: 
• 
Changes in clinical laboratory test parameters 
(ie, hematology, clinical chemistry, and 
urinalysis) 
• 
Changes in vital signs (SBP, DBP, pulse rate, 
respiratory rate, and body temperature) 
• 
12-lead ECG parameters and findings 
• 
Physical examinations 
λz=first order terminal elimination rate constant; AUC=area under the curve from 0 to infinity; AUC(0-t)=area 
under the curve from 0 to the time of the last quantifiable concentration; AUCextr=extrapolated AUC; 
BRV=brivaracetam; CL/F=total clearance after oral administration; Cmax=maximum concentration; 
DBP=diastolic blood pressure; ECG=electrocardiogram; MRT=mean residence time (ie, of the unchanged drug 
in the systemic circulation); PK=pharmacokinetics; SAE=serious adverse event; SBP=systolic blood pressure; 
t1/2=terminal elimination half-life; TEAE=treatment-emergent adverse event; tmax=time of Cmax; Vz/F=apparent 
volume of distribution 
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4 
STUDY DESIGN 
4.1 
Overall design 
EP0110 is a single-center, single-dose, open-label, randomized, 2-way cross-over study designed 
to assess the bioequivalence between the BRV 50mg tablet and BRV 50mg as dry syrup 
formulations in healthy Japanese male study participants after oral administration under fasted 
conditions. In addition, safety and tolerability of BRV will be evaluated. 
Study participants will enter a Screening Period (2 to 28 days before administration of IMP) and 
eligible study participants will start Dosing Period 1. The Dosing Period consists of 2 periods 
(Period 1 and Period 2) of 4 days each with a single administration on Day 1 of each Dosing 
Period. The Dosing Periods will be separated by a Wash-Out Period (at least 7 days and no more 
than 10 days between the 2 administrations for each study participant) and followed by an SFU 
Visit, 7 to 9 days after the last administration of IMP. Study participants who prematurely 
discontinue the IMP/study are to return for a Withdrawal Visit, 7 to 9 days after the last IMP 
administration. 
On Day 1 of each Dosing Period, the study participants will receive 1 of the following treatments 
in randomized order under fasting conditions: 
• Treatment A – a single dose of BRV 50mg tablet 
• Treatment B – a single dose of BRV 50mg as dry syrup (1.25g of granules for oral solution 
4% w/w) 
During each of the 2 Dosing Periods (ie, Period 1 and Period 2), study participants will be 
admitted to the study site 1 day before administration of IMP. After an overnight fast of at least 
10 hours, in the morning of Day 1 of each Dosing Period, a blood sample for PK assessments 
will be obtained to determine the Baseline value, and then study participants will receive the 
dose of IMP (Treatment A or Treatment B). Study participants will remain fasting for 4 hours 
after dosing. Blood samples will be taken at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 
24, 36, and 48 hours after administration of IMP for the determination of the plasma 
concentrations of BRV. A total of 17 blood samples will be taken from each study participant per 
each Dosing Period for PK assessments. Study participants will be discharged in the morning of 
the final day (Day 3) of each Dosing Period, approximately 48 hours after the administration of 
IMP, provided there are no medical objections in the opinion of the Investigator (refer to study 
schematic in Figure 1-1). 
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 (SBP, DBP, pulse rate, respiratory rate, and body temperature), electrocardiogram 
(ECGs), and completion of physical examinations. 
A detailed time and events schedule is presented in Section 1.3. 
A total of 24 study participants are planned to be randomized and complete the study; however, 
additional study participants may be randomized in case some study participants discontinue the 
study early (not only limited to COVID-19 circumstances). 
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4.2 
Scientific rationale for study design 
The primary objective of this study is to demonstrate the bioequivalence between the BRV 50mg 
tablet and BRV 50mg as dry syrup formulations. Therefore, this study employs a standard 
2-treatment and 2-period randomized cross-over design (where a single dose of treatment is 
given in each Dosing Period under fasted conditions). 
4.3 
Justification for dose 
The Japanese bioequivalence guideline recommends a single-dose study with a usual clinical 
dose. Therefore, this study employs a 50mg dose of BRV. 
4.4 
End of study definition 
A study 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 study 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 
Study participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Study participant must be between 20 to 50 years of age (inclusive) at the time of signing the 
Informed Consent Form (ICF). 
Type of study participant and disease characteristics 
2. Study participant is overtly healthy as determined by medical evaluation including medical 
history, physical examination, laboratory tests, and cardiac monitoring. 
3. Study 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 be not clinically 
significant for participation in the study. 
4. Study participant is of Japanese descent as evidenced by appearance and verbal confirmation 
of familial heritage (a study participant has all 4 Japanese grandparents born in Japan). 
Weight 
5. Body weight of at least 50kg and body mass index (BMI) within the range 18 to 30kg/m2 
(inclusive) at the Screening Visit. 
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Sex 
6. Study participant is male. 
7. Study participant must agree to use contraception as detailed in Appendix 4 (Section 10.4) of 
the protocol starting from Screening through at least 2 days after the last dose of IMP and 
refrain from donating sperm during this period. 
Informed consent 
8. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of the 
protocol, which includes compliance with the requirements and restrictions listed in the ICF 
and in this protocol. 
5.2 
Exclusion criteria 
Study participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Study 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 study participant’s ability to participate in this study. 
2. Study 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. Study participant has a current history of alcohol or drug use disorder, as defined in 
Diagnostic and Statistical Manual of Mental Disorders (DSM) V, or within the previous 
6 months. 
4. Study participant has a known hypersensitivity to any components of the IMP formulations. 
5. Alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase 
(ALP) >1.0x upper limit of normal (ULN). 
6. Bilirubin >1.0xULN (isolated bilirubin <1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%). 
7. 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 study 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). 
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 ULN the 
study participant will be considered to not meet the exclusion criteria. 
Prior/Concomitant therapy 
8. Study participant has used other drugs, including over-the-counter medications, 
herbal/traditional medicines, or dietary supplements (excluding medicines for external use), 
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with the exception of paracetamol (Section 6.5.1), within 14 days before first administration 
of IMP or has received a COVID-19 vaccine within 7 days of initiating IMP. 
9. Study 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. Study participant has participated in another study of an IMP (and/or an investigational 
device) within the previous 30 days or 5 times the half-life (whichever is longer) or is 
currently participating in another study of an IMP (and/or an investigational device). 
Diagnostic assessments 
11. Study participants with clinically relevant abnormalities in a standard 12-lead ECG at 
Screening Visit as judged by the Investigator. 
12. Study 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. Study participant tests positive for alcohol breath test and/or urine drug test at the Screening 
Visit or on Day -1. 
Other exclusions 
14. Study 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. Study 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. Consumption of more than 600mg of caffeine/day (1 cup of coffee contains approximately 
100mg of caffeine, 1 cup of tea approximately 30mg, and 1 glass of cola approximately 
20mg). 
17. Consumption of restricted food specified in Section 5.3.1 within 7 days before first 
administration of the IMP. 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
• Study participants must refrain from consumption of grapefruit within 7 days before the start 
of IMP until completion of the study. 
5.3.2 
Caffeine, alcohol, and tobacco 
• During each Dosing Period, study participants must 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 pharmacokinetic (PK) sample. 
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• During each Dosing Period, study participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample. 
• Use of nicotine-containing products will not be allowed from within 30 days before IMP 
administration until after the final follow-up visit. 
5.3.3 
Activity 
• Study participants will abstain from strenuous exercise for 96 hours before each blood 
collection for clinical laboratory tests. Study 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. 
Study participants will fast overnight (≥10 hours) in the study site the day before IMP dosing. A 
predose blood sample will be obtained before they receive the dose of IMP. Study participants 
will remain fasting for 4 hours after IMP dosing. 
Study 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 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 
Due to the exceptional circumstance of the evolving COVID-19 pandemic, study 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 study 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. 
In addition, study participants will be asked for any contact with a person who has confirmed 
infection. If applicable, study participants may be referred to the local health care system. 
Physical distancing and person-to-person contact restrictions will be applied and explained to 
study participants while staying at the study site. Study participants will be asked to use surgical 
face masks and/or gloves as guided by local requirements. 
For details on the risk assessment for COVID-19, refer to Section 2.3.1. 
5.4 
Screen failures 
Screen failures are defined as study 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 study 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
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includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
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 ULN the study 
participant will be considered as 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 
Treatment 
Treatment A (Reference) 
Treatment B (Test) 
Intervention name 
BRV 
BRV 
Type 
Drug 
Drug 
Dose formulation 
Tablet 
Dry syrup 
Active dose 
BRV 50mg  
BRV 50mg 
Unit dose strength 
1 tablet of 50mg 
1.25g of granules for oral solution 
4% w/w 
Dosage level 
Single dose 
Single dose 
Route of 
administration 
Oral 
Oral 
Dosing instructions 
Tablet will be administered with 
200mL water. 
Dry syrup will be mixed with 50mL 
of 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. 
 
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 
and polypropylene caps. Each bottle 
will be labeled as required per 
country requirements. 
Dry syrup will be provided in 
high-density polyethylene bottles 
and polypropylene caps. Each bottle 
will be labeled as required per 
country requirements. 
Excipients 
• 
Croscarmellose sodium 
• 
Lactose monohydrate 
• 
Betadex 
• 
Lactose anhydrous 
• 
Magnesium stearate 
• 
Polyvinyl alcohol 
• 
Titanium dioxide (E171) 
• 
Macrogol 3350 
• 
Talc 
• 
Iron oxide yellow (E172) 
• 
Iron oxide black (E172) 
• 
• 
• 
• 
• 
• 
BRV=brivaracetam; IMP=investigational medicinal product 
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6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm 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 study participants enrolled in the study may receive IMP and only authorized site staff may 
supply or administer IMP. All IMPs 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 study participant to store the IMP following the 
instructions on the label. 
Further guidance and information 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 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 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 study 
participants to the treatment sequence as per the crossover design, Treatment A/Treatment B or 
Treatment B/Treatment A. 
The study site will generate the randomization lists (a main list and a replacement list) for the 
treatment sequence (Treatment A/Treatment B or Treatment B/Treatment A) allocation. These 
randomization lists will be reviewed by the Clinical Trial Statistician at UCB to ensure that the 
code meets the study requirements. 
In addition to the main randomization list, a randomization replacement list will be provided in 
order to replace withdrawn study participants; the replacement study participant will receive the 
same treatment sequence as the corresponding withdrawn study participant. 
6.3.1 
Procedures for maintaining and breaking the treatment blind 
Not applicable; this is an open-label study. 
6.4 
Treatment compliance 
Study 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) 
Paracetamol (acetaminophen) for the treatment of mild symptoms (eg, headache or pain relief) 
not exceeding 1g per dose is permitted with a total of 10g within 2 weeks and until 48 hours 
before the first administration of IMP. 
Study participants will be allowed to receive a COVID-19 vaccine up to 7 days prior to the 
initiation of IMP administration. Vaccine administration will be entered as a prior medication in 
the eCRF. Study participant continuation in case of a vaccine-related AE will be as per 
Investigator judgement. 
Except for the medications noted above, no concomitant medication is allowed during this study. 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
With the exception of paracetamol, all prescription or OTC 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. COVID-19 
vaccines are prohibited within the 7 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 study 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 
study participant can continue in the study or must be withdrawn. 
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6.6 
Dose modification 
No dose modifications are allowed during the study. 
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 study participants; therefore, no treatment will 
be provided after the end of the study. 
7 
DISCONTINUATION OF IMP AND STUDY 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 study participant meets one of the conditions outlined (Figure 7-1) or if the Investigator 
believes that it is in the best interest of the study participant. 
Investigational medicinal product will be discontinued immediately and permanently for a study 
participant if liver chemistry stopping criteria are met. 
Figure 7-1: Liver chemistry stopping algorithm 
 
ALT=alanine transaminase; AST=aspartate aminotransferase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal 
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Evaluation of potential drug-induced liver injury (PDILI) must be initiated as described in the 
protocol. If study 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 
Study participant discontinuation/withdrawal from the study 
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care. 
A study 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. 
If the study 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 study 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. 
Study participants should be withdrawn from the study if any of the following events occur: 
1. Study participant withdraws his consent. 
2. Study participant develops an illness that would interfere with his continued participation. 
3. Study participant is noncompliant with the study procedures in the opinion of the 
Investigator. 
4. Study participant takes prohibited concomitant medications as defined in this protocol. 
5. The Sponsor or a regulatory agency requests withdrawal of the study 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 (see Section 2.3.1 for further details). 
Study participants who discontinue the study early for reasons other than IMP-related safety may 
be replaced upon agreement with the Investigator and Sponsor. Replacement study participants 
will receive the same treatment sequence that was assigned to the study participant who dropped 
out. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a study participant in advance. 
7.3 
Lost to follow up 
A study 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. 
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The following actions must be taken if a study participant fails to return to the study site for 
Dosing Period 2 or the SFU Visit: 
• The site must attempt to contact the study participant and reschedule the missed visit as soon 
as possible and counsel the study participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the study participant wishes to and/or should 
continue in the study. 
• Before a study participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the study participant (at least 1 phone call and 
1 written message to the study 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 study participant, must be recorded in the 
source documents. The eCRF must document the primary reason for withdrawal. 
Should the study 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.  
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Table 1-1). 
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 study 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 study 
participants meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all study participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Procedures conducted as part of the study participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedule of Activities. 
The maximum amount of blood collected from each study 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 
Pharmacokinetics 
Blood samples of approximately 4mL will be collected for measurement of plasma 
concentrations of BRV as specified in the Schedule of Activities (Table 1-1) Instructions for the 
collection and handling of biological samples will be provided by the Sponsor. The actual date 
and time (24h 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. 
 
 
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The primary and other PK endpoints are provided in Section 3. These will be calculated by the 
Quantitative Clinical Development within 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: 
• AUC 
Area under the curve from 0 to infinity 
• AUC(0-t) 
Area under the curve from 0 to the time of the last quantifiable 
concentration 
• AUCextr 
Extrapolated AUC 
• MRT 
Mean residence time (ie, of the unchanged drug in the systemic circulation) 
• Cmax 
Maximum concentration 
• tmax 
Time of Cmax 
• t½ 
Terminal elimination half-life 
• Vz/F 
Apparent volume of distribution 
• CL/F 
Total clearance after oral administration 
• λz 
First order terminal elimination rate constant 
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 
Good Laboratory Practice regulations of the Organisation for Economic Co-operation and 
Development. 
Blood sampling time for PK analysis is provided in Table 8-1. 
Table 8-1: 
Pharmacokinetic blood sampling scheme 
BRV 
Formulation 
Dose 
Collection time 
(per Dosing Period) 
Number of 
samples 
(per Dosing 
Period) 
Tablet 
(reference)  
Single 
On Day 1 at 0 (predose), 0.25, 0.5, 0.75, 1.0, 
1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48h 
postdose 
17 
Dry syrup 
(test) 
Single 
On Day 1 at 0 (predose), 0.25, 0.5, 0.75, 1.0, 
1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48h 
postdose 
17 
Total 
 
 
34 
BRV=brivaracetam; h=hours 
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Study site should aim to collect PK samples at the nominal time points to the extent possible. 
However, the following maximum deviations from scheduled sampling times considered 
irrelevant for PK are defined in Table 8-2. 
Table 8-2: 
Irrelevant time deviations for PK sampling 
PK blood sampling times 
Deviation from scheduled time considered irrelevant 
0h (predose) 
Within 30min 
0.25 to 1.5h 
2min 
2 to 8h 
5min 
12 to 16h 
30min 
24 to 48h 
60min 
h=hours; min=minutes; PK=pharmacokinetic 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Table 1-1). 
8.2.1 
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 (Table 1-1). 
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 Case Report Form 
(CRF). 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 last dose of IMP should be repeated until the values return to normal or 
Baseline or are no longer considered clinically significant by the Investigator or UCB Study 
Physician. 
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 (Table 1-1). 
If laboratory values from non-protocol 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 CRF. 
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8.2.2 
Vital signs 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, respiratory rate, and 
axillary 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, pulse and 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 ECG (except at predose on Day 1 of each Dosing Period, when 3 Baseline values 
will be measured at 2- to 5-minute intervals) will be obtained as outlined in the Schedule of 
Activities (see Table 1-1) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT intervals, and QT interval corrected (QTc). 
All ECG recordings should be taken with the study participant resting in the supine position for 
at least 10 minutes before the recording. 
8.2.4 
Physical examination 
A complete 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. 
A brief physical examination will include, at a minimum, assessments of the skin, respiratory 
system, cardiovascular system, and abdomen (liver and spleen). 
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. 
8.3 
Adverse events and serious adverse events 
The definitions of an AE or an SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the study participant (or, when appropriate, by a caregiver, 
surrogate, or the study 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 study 
participant to discontinue the IMP (see Section 7). 
Confirmed COVID-19 cases will be recorded as AEs. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF until the follow-up 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 
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protocol, must be reported in the CRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that 
recurred or worsened after the initial visit. 
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 study participant, and to also inform study 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 
non-leading verbal questioning of the study 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 study 
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 study 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 by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of study 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 (IRB), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) 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. 
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8.3.5 
Pregnancy 
Details of all pregnancies in female partners of male study participants will be collected after the 
start of IMP and until the end of the study. 
If a partner pregnancy is reported, the Investigator must immediately inform the Sponsor within 
24 hours 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 
study participant. 
8.4 
Safety signal detection 
Not applicable for this study. 
8.5 
Treatment of overdose 
Not applicable; all single doses will be administered by study staff. 
8.6 
Efficacy assessments 
Efficacy will not be assessed in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.10 
Health economics 
Not applicable. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan. 
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9.1 
Definition of analysis sets 
The following analysis sets will be defined: 
Enrolled Set 
All study participants who sign the ICF will be included in the Enrolled Set. 
Randomized Set 
All enrolled study participants who are randomized will be included in the Randomized Set. 
Safety Set 
All randomized study participants who receive at least 1 dose of the IMP will be included in the 
Safety Set (SS). 
Pharmacokinetic Per-Protocol Set 
All randomized study participants who are included in the SS, have no important protocol 
deviations that are considered to impact the study participant’s data validity for analysis of the 
primary study objective, and have a sufficient number of bioanalytical assessments to calculate 
reliable estimates for the primary pharmacokinetic parameters for both treatments will be 
included in the Pharmacokinetic Per-Protocol Set (PK-PPS). 
If a study participant’s predose concentration is greater than 5% of the corresponding Cmax value 
in both Dosing Periods, the study participant will be excluded from the PK-PPS. If this occurs in 
1 of the 2 Dosing Periods, but not in the other Dosing Period, data of the other Dosing Period 
will be used. Furthermore, since the study participant will be entered as a random effect in the 
ANOVA, the data of the single Dosing Period can still be used for the bioequivalence 
assessment. 
If vomiting occurs at or before 2 times of the median tmax, the study participant will be excluded 
from the PK-PPS. 
The reasons for exclusion of study participants from any of the analysis sets will be listed. 
9.2 
General statistical considerations 
Statistical evaluation will be performed by the Sponsor or designee and supervised by the 
Exploratory Statistics Department of UCB. Statistical analysis and generation of tables, figures, 
and study participant data listings will be performed using SAS Version 9.3 or higher. A 
noncompartmental analysis (NCA) will be performed using Phoenix WinNonlin® Version 8.0 or 
higher (Certara L.P., Princeton, NJ, USA) for PK parameter estimation. 
A complete set of listings containing both all documented data and all calculated data will be 
generated. Missing data will not be imputed. Outlier detection and statistical analysis of outliers 
will not be performed. 
For categorical endpoints, the number and percentage of study participants in each category will 
be presented. The denominator for percentages will be based on the number of study participants 
appropriate for the purpose of the analysis. For continuous endpoints, descriptive statistics will 
include number of study participants, mean, standard deviation, median, minimum, and 
maximum. Geometric mean, geometric coefficient of variation (CV), and 95% confidence 
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interval (CI) for the geometric mean will also be presented in the descriptive statistics for plasma 
concentrations and PK parameters. 
9.3 
Planned outcome analyses 
9.3.1 
Pharmacokinetic analyses 
Pharmacokinetic analyses will be performed on the SS. Statistical analyses will be performed on 
the PK-PPS. 
Descriptive statistics will be used to describe PK parameters for each treatment. 
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 semi-logarithmic and linear scales. 
The bioavailability of BRV dry syrup (1.25g of granules for oral solution 4% w/w, 
corresponding to 50mg of BRV) (test) will be compared with BRV 50mg dose administered as a 
50mg tablet (reference). 
The parameters Cmax and AUC(0-t) will be evaluated according to a univariate model of analysis 
of variance, adapted to crossover experimental designs. The model will include the treatment, the 
period, and sequence as fixed effects. The study participant (nested to the sequence) will be the 
random effect. The dependent variables will be logarithmically (ln) transformed prior to 
statistical testing, following the usual recommendations. The 90% confidence intervals (CIs) of 
the adjusted test/reference geometric mean ratio will be calculated. Bioequivalence between the 
test (dry syrup) and reference (tablet) formulations will be concluded if the 90% CI limits for 
Cmax and AUC(0-t) fall fully within 80% to 125%. 
The MIXED procedure in SAS software will be used for this analysis. 
For tmax, a distribution-free 90% CI (Hodges-Lehmann’s method) will be calculated for the 
median differences between each test and the reference. 
9.4 
Planned safety 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 
Primary 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. Further detail on the rules for attributing AEs to a Dosing Period, 
and to single dose within a Dosing Period, will be included in the SAP. 
Adverse events will be summarized descriptively by treatment (tablet or dry syrup), Primary 
System Organ Class, and Preferred Term according to the MedDRA terminology. Additional 
tables will summarize AEs by severity and relationship to IMP as well as, if applicable, separate 
tables for AEs leading to withdrawal from the study and SAEs. 
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9.4.2 
Other safety analyses 
9.4.2.1 
Clinical laboratory assessments 
Clinical laboratory variables (hematology and clinical chemistry) and changes from Baseline will 
be summarized using descriptive statistics by BRV formulation at each time point, as applicable. 
Urinalysis data and laboratory values outside the reference range will be listed. 
9.4.2.2 
Vital signs 
Vital signs variables (SBP, DBP, pulse 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 variables (PR, QRS, QT intervals, and QTc) 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. The purpose of this review meeting 
will be to examine all protocol deviations, define the PK-PPS (see Section 9.1), and to verify the 
quality of the data. If PK parameters are needed to define PK-PPS, it will be performed based on 
the ADPP (Pharmacokinetic Parameters Analysis Data). 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). Protocol deviations (eg, missing assessments or visits) related 
to COVID-19 will be listed separately. 
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 
Not applicable. 
9.8 
Determination of sample size 
A total of 24 study participants are planned to be randomized and complete the study; however, 
additional study participants may be randomized in case some study participants discontinue the 
study early (not only limited to the COVID-19 circumstances). 
Previous BRV PK studies (N01287, N01185, N01118, N01081, and N01075) provide estimates 
of the intrastudy study participant variability (CV%) approximately ranging from 10% to 23% 
(median 18%) for Cmax and from 4% to 12% (median 6%) for AUC. 
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Provided that the ratio of expected means is equal to 1.00 and assuming a CV% of 20%, 19 study 
participants in total provide a power of 90%, at the 5% level of significance (one-sided), to 
declare that the true geometric means ratio is in the range of 80% to 125%. 
In the case of the true mean difference of 5% (the ratio of 0.95 or 1.05), a power of 90% would 
be reached with 24 study participants completing 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, 
International Council for Harmonisation-Good Clinical Practice (ICH-GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB that complies with the 
requirements of the current ICH-GCP version or applicable country-specific regulations will be 
responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent Form (ICF), IB, Investigator’s curriculum vitae (if applicable), advertisement (if 
applicable), and all other study 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 study participants or others, and any protocol deviations, to eliminate 
immediate hazards to study 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 study 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 study 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 each concerned country. 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. 
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10.1.3 
Informed consent process 
Study 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. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the study participant in both oral and written form by the 
Investigator (or designee). Each study 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 study 
participant, or his legal representative, and by the person who conducted the informed consent 
discussion (Investigator or designee). The study participant or his legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, each study 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 
UCB staff (or designee) will affirm and uphold the study participant’s confidentiality. 
Throughout this study, all data forwarded to UCB (or designee) will be identified only by the 
study 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 
study 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 study participant’s study participation, and autopsy 
reports for deaths occurring during the study). 
The study 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 study participant. 
The study 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 
Data quality assurance 
All study 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 CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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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 study 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 relocate or 
move the study-related files to a location other than that specified in the Sponsor’s Trial Master 
File. 
10.1.5.1 
Case Report Form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
CRFs and in all required reports. 
Any change or correction to the CRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the CRF. 
Detailed instructions will be provided in the CRF Completion Guidelines. 
10.1.5.2 
Apps 
No apps will be used in the study. 
10.1.6 
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). 
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 study participant’s source documents. 
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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). 
10.1.7 
Study and site closure 
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 study participants by the Investigator 
• Discontinuation of further IMP development 
10.1.8 
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. 
Authorship will be determined by mutual agreement and in line with 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 study participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
• 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 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
WBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry a 
Blood Urea 
Nitrogen 
(BUN) 
Potassium 
Aspartate Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose  
Calcium 
Alkaline phosphatase 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase 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) 
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 aminotransferase; eCRF=electronic Case Report Form; INR=international normalized ratio; 
MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume; RBC=red blood cell; SAE=serious adverse event; 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 
injury (possible Hy’s Law), and must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). 
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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 study 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 study 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 study 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 study 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 CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the study participant’s medical 
records to UCB in lieu of completion of the UCB/AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all study participant identifiers, with the exception of the study 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 study 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 (NCI-CTCAE) 
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 assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he 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 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 one 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 study participant is lost to follow up. 
This follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
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 
• 
The primary mechanism for reporting an SAE to UCB will be the paper SAE data collection 
tool. 
• 
Facsimile transmission of the sop-af-004166 SAE Report Form for Development Product 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 study participants 
Male study 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 study participants must refrain from donating sperm for the duration of the 
study and for 2 days after the last dose of IMP. 
Male study 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. 
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Table 10-1: Highly Effective Contraceptive Methods for female partners 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation b 
• 
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 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (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 
study participant. 
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 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 study 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 last dose of IMP 
Collection of pregnancy information 
Male study participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male study 
participant’s female partner who becomes pregnant while the male study 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 
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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 
Study participants with potential drug-induced liver injury 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 study participants in the case of IMP 
discontinuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury 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 study 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 study participants who have ALT >5 ULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values). 
Phase 1 liver chemistry stopping criteria are designed to assure study participant safety and to 
evaluate liver event etiology. 
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 electronic Case 
Report From (eCRF), and complete an SAE 
data collection tool if the event also met 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: 
• 
Viral hepatitis serology c 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• 
Obtain blood sample for pharmacokinetic 
(PK) analysis within 1 hour after the most 
recent dosed 
• 
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH) 
• 
Fractionate bilirubin if total bilirubin 
 2xULN 
• 
Complete blood count with differential to 
assess eosinophilia 
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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 
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 study participants weekly until liver 
function abnormalities resolve, stabilize, or 
return to Baseline 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury (eg, fatigue, 
nausea, vomiting, right upper quadrant pain), 
or hypersensitivity, on the adverse event 
(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: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma 
globulins 
• 
Serum acetaminophen adduct high 
performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen 
contribution to liver injury in study 
participants with definite or likely 
acetaminophen use in the preceding week 
[James et al, 2009]) NOTE: Not required in 
China 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver imaging and/or liver biopsy 
eCRFs 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic 
Case Report Form; INR=international normalized ratio; MCH=mean corpuscular hemoglobin; MCHC=mean 
corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; SAE=serious 
adverse event; ULN=upper limit of normal; WBC=white blood cell 
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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 study 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 Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (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 
ADE 
adverse device effect 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
app 
application 
AST 
aspartate aminotransferase 
BRV 
brivaracetam 
CRF 
Case Report Form 
CRO 
contract research organization 
CYP 
cytochrome P450 
COVID-19 
coronavirus disease 2019 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
iv 
intravenous 
LEV 
levetiracetam 
PDILI 
potential drug-induced liver injury 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
POS 
partial-onset seizures 
QTc 
QT interval corrected 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
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 global amendment 1.0 is 
located directly before the Table of Contents. 
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11 
REFERENCES 
Food and Drug Administration. Guidance for Industry. Drug-induced liver injury: premarketing 
clinical evaluation. US Dept of Health and Human Services, Center for Drug Evaluation and 
Research, Center for Biologics Evaluation and Research, 07/2009. 
ISO 14155:2011 Clinical Investigations of medical devices for human subjects – Good Clinical 
Practice. 
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; 37:1779-1784. 
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;154:1662-1667. 
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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:
ep0110-protocol-amendment-1.0
Version:
1. 0
Document Number:
CLIN-000182810
Title:
EP0110 Protocol Amendment 1.0
Approved Date:
12 Jan 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 11-Jan-2022 22:15:06 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Jan-2022 00:58:38 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Jan-2022 03:18:48 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Jan-2022 06:47:43 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
AMENDMENT 1 
Study: EP0110 
Product: Brivaracetam 
 
A SINGLE-DOSE, OPEN-LABEL, RANDOMIZED, 2-WAY 
CROSS-OVER STUDY TO ASSESS THE BIOEQUIVALENCE 
BETWEEN BRIVARACETAM TABLET AND DRY SYRUP IN 
HEALTHY MALE JAPANESE STUDY PARTICIPANTS 
 
A single-dose study to assess the bioequivalence between 
brivaracetam tablet and dry syrup in healthy Japanese study 
participants 
 
Sponsor Name: UCB Biopharma SRL 
 
Legal Registered Address: Allée de la Recherche 60, 1070 Brussels BELGIUM 
Regulatory Agency Identifier Number(s):  
Registry 
ID 
CTN Number 
2021-7493 
 
 
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 ................................................................................................................ 5 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
1.1 
Objectives and Endpoints .............................................................................................. 7 
1.2 
Study design ................................................................................................................... 8 
1.3 
Schedule of Activities .................................................................................................... 9 
2 
STATISTICAL HYPOTHESES ...................................................................................... 11 
3 
SAMPLE SIZE DETERMINATION .............................................................................. 11 
4 
POPULATIONS FOR ANALYSIS ................................................................................. 12 
4.1 
Enrolled Set .................................................................................................................. 12 
4.2 
Randomized Set ........................................................................................................... 12 
4.3 
Safety Set ..................................................................................................................... 12 
4.4 
Pharmacokinetic Per Protocol Set ................................................................................ 12 
5 
STATISTICAL ANALYSES .......................................................................................... 12 
5.1 
General Considerations ................................................................................................ 12 
5.1.1 
General study level definitions ............................................................................ 14 
5.1.1.1 
Analysis Time Points ................................................................................. 14 
5.1.1.2 
Protocol Deviations ................................................................................... 16 
5.1.1.3 
Treatment assignment and treatment groups ............................................. 16 
5.1.1.4 
Center pooling strategy ............................................................................. 17 
5.1.1.5 
Coding dictionaries .................................................................................... 17 
5.1.1.6 
Multicenter studies .................................................................................... 17 
5.1.1.7 
Handling of dropouts or missing data ....................................................... 17 
5.2 
Participant Dispositions ............................................................................................... 17 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 18 
6.1 
Demographics and other baseline characteristics ........................................................ 18 
6.2 
Medical history and concomitant diseases ................................................................... 19 
6.3 
Prior and concomitant medications .............................................................................. 19 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 20 
8 
EFFICACY ANALYSES ................................................................................................ 20 
9 
PHARMACOKINETICS ................................................................................................. 20 
9.1 
Plasma concentration-time profiles.............................................................................. 20 
9.2 
Primary/other pharmacokinetic variables .................................................................... 21 
9.2.1 
Derivation of primary/other pharmacokinetic variables and descriptive 
summaries ............................................................................................................ 21 
9.3 
Primary Endpoint(s) Analysis ...................................................................................... 22 
9.3.1 
Definition of endpoint(s) ..................................................................................... 22 
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9.3.2 
Main analytical approach ..................................................................................... 22 
9.4 
Other Endpoint(s) Analysis.......................................................................................... 23 
9.4.1 
Definition of endpoint(s) ..................................................................................... 23 
9.4.2 
Main analytical approach ..................................................................................... 23 
10 SAFETY ANALYSES ..................................................................................................... 24 
10.1 
Extent of Exposure ....................................................................................................... 24 
10.2 
Adverse Events ............................................................................................................ 24 
10.2.1 
Secondary Endpoints ........................................................................................... 26 
10.2.2 
Other Adverse Events .......................................................................................... 26 
10.3 
Other Safety Assessments ............................................................................................ 27 
10.3.1 
Clinical laboratory evaluations ............................................................................ 27 
10.3.1.1 
Laboratory values over time ...................................................................... 28 
10.3.1.2 
Individual Subject Changes of Laboratory Values .................................... 28 
10.3.1.3 
Potential drug-induced liver injury ............................................................ 29 
10.3.2 
Vital Signs ........................................................................................................... 29 
10.3.2.1 
Vital Sign Values Over Time .................................................................... 29 
10.3.2.2 
Individual Subject Changes of Vital Sign Values ..................................... 29 
10.3.3 
Electrocardiograms .............................................................................................. 29 
10.3.3.1 
Electrocardiogram Values Over Time ....................................................... 30 
10.3.3.2 
Individual Subject Changes of Electrocardiograms Values ...................... 30 
10.3.4 
Other safety endpoint(s) ...................................................................................... 30 
10.4 
Other Analyses ............................................................................................................. 30 
10.5 
Subgroup analyses ....................................................................................................... 31 
10.6 
Interim Analyses .......................................................................................................... 31 
10.7 
Data Monitoring Committee (DMC) or Other Review Board ..................................... 31 
11 SUPPORTING DOCUMENTATION ............................................................................. 31 
11.1 
Appendix 1 Non-key analysis specifications ............................................................... 31 
11.1.1 
Baseline characteristics and demographics ......................................................... 31 
11.1.2 
Protocol deviations .............................................................................................. 31 
11.1.3 
Medical history .................................................................................................... 31 
11.1.4 
Prior/concomitant/follow-up medications ........................................................... 32 
11.1.5 
Data derivation rules ............................................................................................ 32 
11.1.6 
AEs of Special Interest ........................................................................................ 32 
11.1.7 
Potentially Clinically Significant Criteria for Safety Endpoints ......................... 32 
11.1.8 
Compliance .......................................................................................................... 32 
11.2 
Appendix 2: Changes to Protocol-Planned Analyses .................................................. 32 
11.3 
Appendix 3: Standard Reporting Procedures ............................................................... 32 
11.3.1 
PK concentrations ................................................................................................ 32 
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11.3.2 
PK parameters ...................................................................................................... 33 
11.4 
Appendix 4: PK parameter calculations ...................................................................... 34 
12 REFERENCES ................................................................................................................ 36 
 
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VERSION HISTORY 
SAP Version 
Approval Date 
Change 
Rationale 
Final 
02 Mar 2022 
Not Applicable 
Original version 
Amendment 1 
08 Jun 2022 
Update on front page 
and CRF version 
Clarification of CTN 
number 
CRF update 
 
LIST OF ABBREVIATIONS 
 
List of Abbreviations 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the Curve from 0 to Infinity 
AUC(0-t) 
Area under the Curve from 0 to the Time of the Last Quantifiable Concentration 
AUCextr 
Extrapolated AUC 
AUMC 
Area under the First Moment Curve from 0 to Infinity 
BMI 
Body Mass Index 
BRV 
Brivaracetam 
CI 
Confidence Interval 
CL/F 
Total Clearance after Oral Administration 
Clast 
Last Observed (Quantifiable) Concentration 
Cmax 
Maximum (Plasma) Concentration 
CPStat 
Clinical Program Biostatistician 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DEM 
Data Evaluation Meeting 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EOS 
End of Study 
ES 
Enrolled Set 
geoCV 
Geometric Coefficient of Variation 
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List of Abbreviations 
IMP 
Investigational Medicinal Product 
IPD 
Important Protocol Deviation 
λz 
First Order Terminal Elimination Rate Constant 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time  
PDILI 
Potential Drug Induced Liver Injury 
PK 
Pharmacokinetics 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PT 
Preferred Term 
QTcF 
QT interval corrected with Fridericia's formula 
REML 
Restricted Maximum Likelihood 
RS 
Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SFU 
Safety Follow Up 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
t1/2 
Terminal Elimination Half-life 
tlast 
Time of Last Observed (Quantifiable) Concentration 
tmax 
Time of Cmax 
ULN 
Upper Limit of Normal 
Vz/F 
Apparent Volume of Distribution 
 
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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 EP0110. 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: 11 Jan 2022 
• 
Electronic Case Report Form (eCRF) v2.0: 04 Mar 2022  
 
1.1 
Objectives and Endpoints 
Table 1-1: 
Objectives and Endpoints 
Objectives 
 Endpoints 
Primary 
• To demonstrate the bioequivalence between 
    the BRV 50mg tablet and BRV 50mg as dry 
    syrup after a single oral dose in healthy 
    Japanese male study participants 
Primary Endpoints: 
• Cmax 
• AUC(0-t) 
 
Secondary 
• To evaluate the safety and tolerability of 2 oral 
   dosage forms of BRV in healthy Japanese male 
   study participants 
Secondary endpoints: 
• Incidence of TEAEs 
• Incidence of treatment-emergent SAEs 
Other 
Other PK Objective: 
• To evaluate other PK parameters of 2 oral 
   dosage forms of BRV in healthy Japanese male 
   study participants 
 
 
 
 
 
 
 
The other PK endpoints will be calculated: 
• AUC 
• AUCextr 
• CL/F 
• Vz/F 
• MRT 
• tmax 
• t½ 
• λz 
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Table 1-1: 
Objectives and Endpoints 
Objectives 
 Endpoints 
Other Safety Objective: 
• To further evaluate the safety and tolerability 
   of 2 oral dosage forms of BRV in healthy 
   Japanese male study participants 
Other safety endpoints will be assessed during the 
study: 
• Changes in clinical laboratory test parameters 
   (i.e., hematology, clinical chemistry, and 
    urinalysis) 
• Changes in vital signs (SBP, DBP, pulse rate, 
    respiratory rate, and body temperature) 
• 12-lead ECG parameters and findings 
• Physical examinations 
λz=first order terminal elimination rate constant; AUC=area under the curve from 0 to infinity; AUC(0-t)=area under 
the curve from 0 to the time of the last quantifiable concentration; AUCextr=extrapolated AUC; 
BRV=brivaracetam; CL/F=total clearance after oral administration; Cmax=maximum concentration; DBP=diastolic 
blood pressure; ECG=electrocardiogram; MRT=mean residence time (i.e., of the unchanged drug in the systemic 
circulation); PK=pharmacokinetics; SAE=serious adverse event; SBP=systolic blood pressure; t1/2=terminal 
elimination half-life; TEAE=treatment-emergent adverse event; tmax=time of Cmax; Vz/F=apparent volume of 
distribution 
 
1.2 
Study design 
EP0110 is a single-center, single-dose, open-label, randomized, 2-way cross-over study designed 
to assess the bioequivalence between the BRV 50mg tablet and BRV 50mg as dry syrup 
formulations in healthy Japanese male study participants after oral administration under fasted 
conditions. In addition, safety and tolerability of BRV will be evaluated. 
Study participants will enter a Screening Period (2 to 28 days before administration of 
investigational medicinal product [IMP]) and eligible study participants will start the Dosing 
Period 1. The Dosing Period consists of 2 periods (Dosing Period 1 and Dosing Period 2) of 4 
days each with a single administration on Day 1 of each Dosing Period. The Dosing Periods will 
be separated by a Wash-Out Period (at least 7 days and no more than 10 days between the 2 
administrations for each study participant) and followed by a Safety Follow-Up (SFU) Visit, 7 to 
9 days after the last administration of IMP. Study participants who prematurely discontinue the 
IMP/study are to return for a Withdrawal Visit, 7 to 9 days after the last IMP administration. 
Refer to the study schematic in Figure 1-1. 
 
 
 
 
 
 
 
 
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Figure 1-1: Schematic Diagram 
 
 
 
 
On Day 1 of each Dosing Period, the study participants will receive 1 of the following treatments 
in randomized order under fasting conditions: 
• Treatment A – a single dose of BRV 50mg tablet 
• Treatment B – a single dose of BRV 50mg as dry syrup (1.25g of granules for oral solution 
4% w/w) 
 
1.3 
Schedule of Activities 
The Schedule of Activities is provided in Table 1-2. 
 
 
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Table 1-2: Schedule of Activities 
 
Procedure 
Screening 
Dosing Period 1 or 2 a 
SFU/Withdrawal 
b 
V1 
V2 or V3 
V4 
2 to 28 days 
before 
administration 
of IMP 
Check 
in 
Day -1 
Day 1 
Day 2 
Day 3 
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 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
Height and weight 
X 
 
 
 
 
 
Viral serology (HBsAg, 
HCV, HIV, and syphilis) 
X 
 
 
 
 
 
Urine drug test and alcohol 
breath test 
X 
X 
 
 
 
 
COVID-19 precautions c 
X 
X 
 
 
 
X 
Vital signs d 
X 
 
X 
X 
X 
X 
Clinical laboratory tests 
(hematology, clinical 
chemistry, and urinalysis) 
X 
 
 
 
X 
X 
Randomization e 
 
X f 
 
 
 
12-lead ECG g 
X 
 
X 
X 
X 
X 
IMP administration h 
 
 
X 
 
 
 
Blood sampling for PK i 
 
 
X 
X 
X 
 
Recording of prior and 
concomitant medication 
and procedures 
X 
X 
X 
X 
X 
X 
Recording of AEs 
X 
X 
X 
X 
X 
X 
Confinement 
 
X 
X 
X 
X 
 
AE=adverse event; 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 
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a Each study participant will enter 2 Dosing Periods, separated by a Wash-Out Period of 7 to 10 days between IMP 
administrations. Dosing Period 2 will start after the Wash-out Period (at least 7 days and no more than 10 days 
between the 2 IMP administrations). 
b An SFU visit will occur 7 to 9 days after the last administration of IMP. Study participants who prematurely 
discontinue the IMP/study should be encouraged to undergo Withdrawal Visit procedures within 7 to 9 days after 
the last administration of IMP. 
c COVID-19 precautions as described in Section 2.3.1 and Section 5.3.5 of the protocol. 
d Vital signs are taken at the Screening Visit, at predose, 4, 8, 24, and 48 hours postdose, and at the SFU 
Visit/Withdrawal Visit. 
e Each study participant will be randomly assigned to 1 of 2 treatment sequences (A-B or B-A) before dosing in 
Period 1, after all Day -1 assessments have been completed. 
f Randomization occurs only for Dosing Period 1, either on Day -1 or Day 1 before any assessment of Day 1. 
g 12-lead ECGs are recorded at Screening, at predose, 1, 4, 8, 24, and 48 hours postdose, and at the SFU 
Visit/Withdrawal Visit. At predose on Day 1 of each Dosing Period, 3 Baselines values will be measured at 2- to 
5-minute intervals. 
h IMP administration: BRV 50mg will be administered as a 50mg tablet (Treatment A [reference]) or as dry syrup 
(1.25g of BRV granules for oral solution 4% w/w; Treatment B [test]) under fasting conditions. 
i Blood samples for PK analysis are collected at predose, and 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 
36, and 48 hours postdose. Allowable deviations from these scheduled PK sampling times are provided in Table 8-
2 of the protocol. 
 
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) (test) and BRV 50mg tablet (reference) according to Cmax and 
AUC(0-t). 
Null hypothesis (H0): the adjusted test/reference geometric mean ratio is smaller than 80% or 
larger than 125%. 
Alternative hypothesis (H1): the adjusted test/reference geometric mean ratio is within 80% 
to 125%. 
 
The 90% confidence intervals (CIs) of the adjusted test/reference geometric mean ratio will be 
calculated. 
Based on the hypotheses, bioequivalence between the test (dry syrup) and reference (tablet) 
formulations will be concluded if the 90% CI limits for Cmax and AUC(0-t) fall fully within 80% to 
125%.  
 
3 
SAMPLE SIZE DETERMINATION 
A total of 24 study participants are planned to be randomized and to complete the study; 
however, additional study participants may be randomized in case some study participants 
discontinue the study early (not only limited to the COVID-19 circumstances). 
Previous BRV PK studies (N01287, N01185, N01118, N01081, and N01075) provide estimates 
of the intra-participant variability (CV%) approximately ranging from 10% to 23% 
(median 18%) for Cmax and from 4% to 12% (median 6%) for AUC. 
Provided that the ratio of expected means is equal to 1.00 and assuming a CV% of 20%, 19 study 
participants in total provide a power of 90%, at the 5% level of significance (one-sided), to 
declare that the true geometric means ratio is in the range of 80% to 125%. 
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In the case of the true mean difference of 5% (the ratio of 0.95 or 1.05), a power of 90% would 
be reached with 24 study participants completing the study. 
 
4 
POPULATIONS FOR ANALYSIS 
The analysis sets are defined as follows: 
 
4.1 
Enrolled Set 
All study participants who sign the informed consent form (ICF) will be included in the Enrolled 
Set (ES). 
 
4.2 
Randomized Set 
All enrolled study participants who are randomized will be included in the Randomized Set (RS). 
4.3 
Safety Set 
All randomized study participants who receive at least 1 dose of the IMP will be included in the 
Safety Set (SS). 
4.4 
Pharmacokinetic Per Protocol Set 
All randomized study participants who are included in the SS, have no important protocol 
deviations (IPDs) that are considered to impact the study participant’s data validity for analysis 
of the primary study objective,  and have a sufficient number of bioanalytical assessments to 
calculate reliable estimates for the primary pharmacokinetic parameters for both treatments will 
be included in the Pharmacokinetic Per-Protocol Set (PK-PPS). 
 
If a study participant’s predose concentration is greater than 5% of the corresponding Cmax value 
in both Dosing Periods, the study participant will be excluded from the PK-PPS. If this occurs in 
1 of the 2 Dosing Periods, but not in the other Dosing Period, data of the other Dosing Period 
will be used. Furthermore, since the study participant will be entered as a random effect in the 
ANOVA, the data of the single Dosing Period can still be used for the bioequivalence 
assessment. 
If vomiting occurs at or before 2 times of the median tmax of the study, the study participant will 
be excluded 
from the PK-PPS. 
 
5 
STATISTICAL ANALYSES 
5.1 
General Considerations 
Statistical evaluation will be performed by the Sponsor or designee and supervised by the 
Exploratory Statistics Department of UCB. Statistical analysis and generation of tables, figures, 
and study participant data listings will be performed using SAS Version 9.3 or higher. The PK 
noncompartmental analysis (NCA) will be performed using Phoenix WinNonlin® Version 8.2 or 
higher (Certara L.P., Princeton, NJ, USA) for Pharmacokinetics parameters estimation.  
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A complete set of listings containing both all documented data and all calculated data will be 
generated by treatment sequence, unless otherwise specified. Missing data will not be imputed, 
unless otherwise specified. Outlier detection and statistical analysis of outliers will not be 
performed.  
 
Descriptive statistics will be displayed to provide an overview of the study results. 
For categorical endpoints, the number and percentage of study participants in each category will 
be presented. The denominator for percentages will be based on the number of study participants 
appropriate for the purpose of the analysis. For continuous endpoints, descriptive statistics will 
include number of study participants, mean, standard deviation, median, minimum, and 
maximum. The descriptive statistics for plasma concentrations and PK parameters will be 
described in Section 9.1 and Section 9.2.1.  
Unless otherwise noted, the denominator for percentages should be based on the number of 
participants included in the respective analysis set. 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%, do not present a 
decimal. If the percentage is 0, do not present the percentage. Typically, the % sign 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 
• 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. 
Refer to Appendix 3 (Section 11.3.1 and Section 11.3.2) for standard reporting procedures of PK 
concentrations and parameters in listings, tables, and figures. 
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5.1.1 
General study level definitions 
5.1.1.1 
Analysis Time Points 
5.1.1.1.1 
Relative day 
Relative day will be derived with the date of 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 IMP administration + 1 
i.e., the day of 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: 
Relative day = Current date – Date of IMP administration within the same Dosing Period 
e.g., the day prior to the 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 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 IMP administration in Dosing Period 
 
Relative day will be prefixed with ‘+’ and will be calculated as follows: 
Relative day = Current date - Date of IMP administration within the same Dosing Period 
e.g., the day after 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 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. 
 
5.1.1.1.2 
End date of the Dosing Period 
Dosing Periods are specified in section of study periods. 
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5.1.1.1.3 
Study periods 
The total duration of the study for an individual study participant is 17 days to 48 days and will 
include: 
• A Screening Period (2 to 28 days before IMP administration) 
• Two Dosing Periods (4 days each, with IMP administration on Day 1 of each Dosing 
Period) 
• A Wash-out Period following Dosing Period 1 (7 to 10 days between the 2 IMP 
administrations) 
• An SFU Visit/Withdrawal Visit (7 to 9 days after the last IMP administration) 
 
Table 5-1: 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 to 3 
Wash-out Period 
Defined as Relative Day + 3 to + 6 (~ + 9)  
Dosing Period 2 
Defined as Relative Day -1 to 3 
Safety Follow-Up Period 
Defined as Relative Day + 3 to + 6 (~ + 8) 
5.1.1.1.4 
Mapping of assessments performed at Withdrawal 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. 
 
5.1.1.1.5 
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 (e.g., clinical laboratory tests). If no predose results are available for 
Dosing Period 1, then the Screening result will be used as the Baseline result for that Dosing 
Period. 
 
Table 5-2: Definition of Baseline 
Measurement 
Definition of Baseline 
Vital Signs 
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. 
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Measurement 
Definition of Baseline 
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) 
The Screening value for each period. If this 
value is unavailable, unscheduled visit closest to 
and before dosing of the Dosing Period 1 will be 
imputed for both Dosing Period. For Dosing 
Period 2, the latest value in Wash-out Period and 
Dosing Period 2 before dosing can be used if 
any other baseline value is unavailable. 
 
5.1.1.2 
Protocol Deviations 
Important protocol deviations (IPDs) will be summarized by treatment sequence, and overall 
using the SS and PK-PPS. 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 
 
By-participant listings of IPDs as identified in the Data Cleaning Meeting and DEM will be 
provided by treatment sequence, period, treatment (tablet or dry syrup) using the SS. This will 
include deviation type, deviation description, and whether the deviation led to exclusion from the 
PK-PPS. 
Protocol deviations (e.g., missing assessments or visits) related to COVID-19 will be listed 
separately. 
 
5.1.1.3 
Treatment assignment and treatment groups 
Treatment assignment for the SS and PK-PPS 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 treatment group and overall, where 
applicable. The following order will be used in the Tables, Figures and Listings (TFLs): tablet, 
dry syrup and overall, where applicable. 
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For analysis conducted using the ES, an additional group for participants not randomized may be 
displayed, as applicable. 
 
5.1.1.4 
Center pooling strategy 
Not applicable since this study will be conducted at a single site. 
 
5.1.1.5 
Coding dictionaries 
All AEs and medical history will be coded for analysis according to the Medical Dictionary for 
Regulatory Activities (MedDRA®) coding dictionary, using the MedDRA version 18.1. Prior and 
concomitant medications will be coded for analysis using the World Health Organization Drug 
Dictionary (WHO-DD) version Sep. 2017. Medical procedures will not be coded. 
 
5.1.1.6 
Multicenter studies 
Not applicable since this study will be conducted at a single site. 
 
5.1.1.7 
Handling of dropouts or missing data 
Missing data will not be imputed unless otherwise stated. Data from subjects who prematurely 
discontinue the study will be used to the maximum possible extent. 
Partial dates for concomitant medication and AEs will be imputed as described in Section 6.3  
and Section 10.2. 
 
5.2 
Participant Dispositions 
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 
Disposition of participants screened will be summarized using the ES. The number and 
percentage of participants in each analysis set by treatment (tablet or dry syrup) will be 
calculated based on the RS. 
 
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. 
 
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 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. 
 
By-participant listings of visit dates will be presented by treatment sequence using the RS. 
By-participant listings of participant who did not meet study eligibility criteria will be presented 
overall using the ES. 
By-participant listings of participant inclusion in each analysis set will be presented overall using 
the ES. 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. 
 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics and other baseline characteristics 
Demographic variables including age, gender, 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 
treatment (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 
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By-participant listings of lifestyle data will be provided for the RS.  
Viral serology will be listed based on the ES. 
 
6.2 
Medical history and concomitant diseases 
By-participant listings of previous and ongoing medical history and procedure history will be 
provided for the RS. Medical history will include MedDRA SOC and PT, reported condition, 
start date and stop date (or status ongoing, as applicable). Hepatic event supplemental medical 
history will be listed. 
 
6.3 
Prior and concomitant medications  
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 
(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 5.1.1.1.1), duration (unit: day, calculated as stop date – start 
date + 1) and treatments assigned to. A glossary of medication terms including reported term, 
preferred term, and ATC levels 1 and 3 will also be presented. Data handling will be described in 
Section 11.1.4. 
Prior and concomitant medications will be summarized separately for the SS by treatment 
(concomitant medications only) 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 group. 
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. 
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• 
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. 
 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Any dosing deviations will be assessed in the Data Evaluation Meeting (DEM) for possible 
impact on the PK-PPS. 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. 
 
8 
EFFICACY ANALYSES 
Not applicable. 
 
9 
PHARMACOKINETICS 
Pharmacokinetic analyses will be performed on the SS. Statistical analyses will be performed on 
the PK-PPS. 
 
9.1 
Plasma concentration-time profiles 
Blood samples will be collected for measurement of plasma concentrations of BRV at predose, 
and 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose. Allowable 
deviations from these scheduled PK sampling times are provided in Table 8-2 of the protocol. 
Individual concentration-time data will be listed for the SS by treatment sequence.  
Concentration listings will include nominal PK sampling time, actual sampling times relative to 
dose administration, deviation from nominal time, and percent deviation from nominal time, and 
concentrations, day, dosing period and sequence, treatment (tablet or dry syrup).  
Percent deviation (%) = (actual time – scheduled time)/scheduled time * 100. 
Plasma concentration data will be listed and summarized with the descriptive statistics by 
treatment (tablet or dry syrup) and scheduled time for the PK-PPS.  
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 , 
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where ln𝑆𝐷 is the standard deviation of the log transformed values. 
 
Graphical displays of individual plasma concentrations by actual time will be presented on semi-
logarithmic and linear scales.  
Graphical displays of geometric mean concentrations with its corresponding 95% CI (linear scale 
and semi-logarithmic scale) and zoomed geometric mean concentrations between 0 and 6 hr. will 
also be presented by treatment (tablet or dry syrup) and scheduled time on semi-logarithmic and 
linear scales.  
Plasma concentrations will be displayed superimposed in a single plot for both treatments. 
Spaghetti plots will be presented separately for treatment, with profiles for all participants 
superimposed on the same graph. 
Refer to Appendix 2 (Section 11.3.1) for standard reporting procedures of individual values and 
descriptive statistics for plasma concentration data in listings, tables, and figures. 
 
9.2 
Primary/other pharmacokinetic variables 
The primary and other PK parameters distinction is given in Section 9.3.1 and Section 9.4.1. 
 
9.2.1 
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 4, Section 11.4. 
According to the definition of the Pharmacokinetic Per-Protocol Set (PK-PPS) (Section 4.4), all 
randomized study participants who are included in the SS, have no important protocol deviations 
that are considered to impact the study participant’s data validity for analysis of the primary 
study objective, and have a sufficient number of bioanalytical assessments to calculate reliable 
estimates for the primary pharmacokinetic parameters for both treatments will be included in the 
PK-PPS. If study participant’s predose concentration is greater than 5% of the corresponding 
Cmax value in both Dosing Periods, the study participant will be excluded from the PK-PPS. If 
this occurs in 1 of the 2 Dosing Periods, but not in the other Dosing Period, data of the other 
Dosing Period will be used. If vomiting occurs at or before 2 times of the median tmax, the study 
participant will be excluded from the PK-PPS.  
 
The PK parameters will be listed and summarized with descriptive statistics by treatment (tablet 
or dry syrup) for the PK-PPS. For individual Cmax, AUC(0-t) and AUC, ratio of test (dry syrup) 
versus reference (tablet) will be listed by participant and summarized with descriptive statistics 
for the PK-PPS. Both the primary and other PK parameters will be listed by treatment (tablet or 
dry syrup) for subjects excluded from PK-PPS, but included in the SS. 
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) 
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for the geometric mean. The only exception is tmax, for which only median, minimum, and 
maximum will be reported. 
Ping pong plots for individual data in the PK parameters (Cmax, AUC(0-t) and AUC) will also be 
displayed for the PK-PPS. 
Refer to Appendix 3 (Section 11.3.2) for standard reporting procedures of individual values and 
descriptive statistics for PK parameters in listings and tables. 
 
9.3 
Primary Endpoint(s) Analysis 
9.3.1 
Definition of endpoint(s) 
The primary endpoints are defined as follows: 
• 
Maximum concentration, Cmax 
• Area under the curve from 0 to the time of the last quantifiable concentration, AUC(0-t) 
 
9.3.2 
Main analytical approach 
The bioavailability of BRV dry syrup (1.25g of granules for oral solution 4% w/w, 
corresponding to 50mg of BRV) (test) will be compared with BRV 50mg dose administered as a 
50mg tablet (reference). 
The parameters Cmax and AUC(0-t) will be evaluated according to a univariate model of analysis of 
variance, adapted to crossover experimental designs. The model will include the treatment (tablet 
or dry syrup), the dosing period, and treatment sequence as fixed effects. The study participant 
(nested to the sequence) will be the random effect. The dependent variables will be 
logarithmically transformed by natural logarithms (ln) 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 
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approximation will be used to estimate the degree of freedom. Variance component structure will 
be used as covariance in this linear mixed model.  
 
The adjusted test/reference geometric mean ratio and its corresponding 90% confidence intervals 
(CIs) will be calculated. Bioequivalence between the test (dry syrup) and reference (tablet) 
formulations will be concluded if the 90% CI limits for Cmax and AUC(0-t) fall fully within 80% to 
125%.  
 
Inter-participant and intra-participant variability for each parameter will also be derived from these 
analyses as geoCVs. 
Geometric least squares means and the corresponding 90% CI for each treatment (tablet or dry 
syrup) will be provided as well. 
 
9.4 
Other Endpoint(s) Analysis 
9.4.1 
Definition of endpoint(s) 
The other PK endpoints are defined as follows: 
• Area under the curve from 0 to infinity, AUC   
• Extrapolated AUC, AUCextr  
• Total clearance after oral administration, CL/F  
• Apparent volume of distribution, Vz/F 
• Mean residence time (i.e., of the unchanged drug in the systemic circulation), MRT 
• Time of Cmax, tmax  
• Terminal elimination half-life, t½  
• First order terminal elimination rate constant, λz 
 
9.4.2 
Main analytical approach 
AUC will be analyzed using the same linear mixed model as in primary endpoints (see Section 
9.3.2). 
The adjusted test/reference geometric mean ratio and the corresponding 90% CI will be 
calculated.   
Inter-participant and intra-participant variability for each parameter will also be derived from 
analyses using the linear mixed model as geoCVs. Geometric least squares means and the 
corresponding 90% CI for each treatment (tablet or dry syrup) will be provided as well. 
For tmax, a distribution-free 90% CI using Hodges-Lehmann’s method will be calculated for the 
median differences (location shift) between each test and the reference. Median and the 
corresponding 90% CI for each treatment (tablet or dry syrup) will be provided using cumulative 
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binomial probability. If the exact Hodges-Lehmann confidence limits cannot be calculated, 
asymmetric limits will be derived instead of symmetric limits. 
 
10 
SAFETY ANALYSES 
Unless otherwise specified, all summaries will be based on the SS. 
 
10.1 
Extent of Exposure 
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.   
 
10.2 
Adverse Events 
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 pre-treatment 
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. 
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 
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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 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 10-1 for the 
calculation of duration of each AE. AE duration is computed and reported in day and time 
format. 
 
Table 10-1: 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 
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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 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 is on or after IMP administration in Dosing Period 2. 
 
10.2.1 
Secondary Endpoints 
An overview of the occurrence and incidence of TEAEs will be provided by treatment (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 
Summaries of the occurrence and incidence of TEAEs and treatment-emergent SAEs will be 
provided by treatment (tablet or dry syrup) and overall. The summary will present individual 
occurrences as well as number and percentage of (unique) participants, by SOC and PT. These 
summaries will be provided for the following: 
• Incidence of TEAEs 
• Incidence of treatment-emergent SAEs 
 
10.2.2 
Other Adverse Events 
An overview of the occurrence and incidence of TEAEs will be provided by treatment (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 leading to withdrawal from the study 
• 
Drug-related TEAEs 
• 
Severe TEAEs 
• 
All deaths (AEs leading to death) 
• 
TEAEs leading to death 
• 
TEAEs of special interest 
 
Summaries of the occurrence and incidence of TEAEs will be provided by treatment (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 TEAEs leading to withdrawal from the study 
• 
Incidence of Drug-related TEAEs 
• 
Incidence of TEAEs leading to death 
• 
Incidence of TEAEs by maximum severity (intensity) 
• 
Incidence of TEAEs of special interest  
• 
Incidence of non-serious TEAEs above threshold of 5% of participants 
For AEs occurred before the first dose of IMP, the summary will present individual occurrences 
as well as number and percentage of (unique) participants, by primary SOC and PT. 
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Summaries by maximum severity will count each subject at most once within each MedDRA level 
based on the maximum severity within that MedDRA level. 
Adverse events with missing severity (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 treatment (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, period, treatment (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), stop date and time (or ongoing if 
applicable; relative days), the AE duration, pattern of event, severity, relationship, action taken 
and outcome. In addition, the listing will flag TEAEs, SAEs and AE of special interest. A 
glossary of AE terms including reported term, SOC and PT will also be presented. 
 
10.3 
Other Safety Assessments 
10.3.1 
Clinical laboratory evaluations 
Laboratory parameters will be grouped according to the laboratory function panel. 
Category 
Panel 
Parameter 
Hematology 
Red Blood Cell (RBC)  
 
• 
RBC count 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC Indices (MCV, MCH, 
%Reticulocytes)  
Platelet 
• 
Platelet count 
White Blood Cell (WBC)  
• 
WBC count  
WBC Differential  
 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Clinical Chemistry 
Electrolytes  
 
• 
Potassium  
• 
Sodium 
Minerals  
• 
Calcium 
Metabolic  
• 
Glucose  
Kidney function 
• 
Blood Urea Nitrogen (BUN) 
• 
Creatinine 
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Proteins 
• 
Total Protein 
Liver Function  
 
• 
Aspartate Aminotransferase (AST)/ 
Serum Glutamic-Oxaloacetic 
Transaminase (SGOT)  
• 
Alanine Aminotransferase (ALT)/ 
Serum Glutamic-Pyruvic 
Transaminase (SGPT) 
• 
Alkaline phosphatase  
• 
Total and direct bilirubin 
Urinalysis 
Routine urinalysis 
• 
Specific gravity  
• 
pH 
• 
glucose 
• 
protein 
• 
blood, ketones 
• 
bilirubin 
• 
urobilinogen 
• 
nitrite 
• 
leukocyte  
• 
esterase by dipstick  
• 
Microscopic examination (if blood or 
protein is abnormal) 
All clinical laboratory parameters will be listed by treatment sequence, participant, variable and 
period/visit, changes from Baseline (as defined in Section 5.1.1.1.5) for continuous values, flags for 
measurements outside the reference ranges, and relative day (calculated as described in Section 
5.1.1.1.1) for the RS. The listing will include the treatment (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.  
 
10.3.1.1 
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 treatment (tablet or dry 
syrup) at scheduled time point, as applicable. 
 
10.3.1.2 
Individual Subject Changes of Laboratory Values 
Shift tables from Baseline to post-Baseline scheduled time point will be presented by treatment 
(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. 
These summaries will only be presented for selected variables in Section 10.3.1. 
 
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10.3.1.3 
Potential drug-induced liver injury 
A separate listing will present participants who meet one or more of the following potential drug 
induced liver injury (PDILI) criteria at any visit: 
• 
ALT and/ or AST ≥3x Upper limit of normal (ULN) and Total bilirubin <2x ULN who 
do not exhibit temporally associated symptoms of hepatitis or hypersensitivity  
• 
ALT or AST increase ≥3x ULN and Total bilirubin ≥2x ULN  
• 
ALT or AST ≥3x ULN who exhibit temporally associated symptoms of hepatitis or 
hypersensitivity 
Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness. Hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without 
clear alternative cause). 
The listing will display only visits for which at least one of the above criteria was fulfilled for a 
given participant and will display all results obtained at that visit for the specified parameters for 
the SS. 
 
A summary of participants who met the criteria for PDILI will be presented by treatment (tablet 
or dry syrup) and in total.  
By-participant listings of suspected hepatic events will be presented for the SS.  
By-participant listings of family DILI-relevant medical history for PDILI will be presented for 
the RS. 
By-participant listings of information related to potential hepatic event will be presented by 
treatment sequence, and time point and treatment (tablet or dry syrup) for the SS. 
 
10.3.2 
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. 
 
10.3.2.1 
Vital Sign Values Over Time 
Vital signs variables and changes from Baseline will be summarized using descriptive statistics 
by treatment (tablet or dry syrup) at each scheduled time point. 
 
10.3.2.2 
Individual Subject 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, treatment (tablet or dry syrup) and time point for the RS. 
 
10.3.3 
Electrocardiograms 
The following twelve-lead ECG variables will be obtained: heart rate, PR, QRS, QT intervals, 
and QTcF. 
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For the results measured in triplicate, the averaged value at each time point will be used for by-
visit summaries. 
 
10.3.3.1 
Electrocardiogram Values Over Time 
Twelve-lead ECG variables and changes from Baseline will be summarized using descriptive 
statistics by treatment (tablet or dry syrup) at each scheduled time point. 
 
The following cut-points in QTcF (raw data and change from Baseline) will be summarized 
categorically by treatment (tablet or dry syrup) (number and percentage of participants) and 
timepoint.  
 
Raw QTcF data: 
• 
<450msec 
• 
≥450msec to <480msec 
• 
≥480msec to <500msec 
• 
≥500msec 
Change from Baseline QTcF: 
• <30msec 
• ≥30msec to <60msec 
• ≥60msec 
Electrocardiogram findings will be listed for the RS. 
 
10.3.3.2 
Individual Subject Changes of Electrocardiograms Values 
By-participant listings of all twelve-lead ECG variables, change from Baseline and findings will 
be presented by treatment sequence. period, visit, treatment (tablet or dry syrup) and time point 
for the RS. 
 
10.3.4 
Other safety endpoint(s) 
By-participant listings of physical examination data will be presented by treatment sequence, and 
time point and treatment (tablet or dry syrup) for the RS. 
By-participant listings of pregnancy test and alcohol breath test data will be presented for the ES.  
Impact of COVID-19 will be summarized by impact category and overall. By-participant listings 
of impact of COVID-19 will be presented for the ES.  
 
10.4 
Other Analyses 
Not applicable. 
 
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10.5 
Subgroup analyses 
Not applicable. 
 
10.6 
Interim Analyses 
Not Applicable. 
 
10.7 
Data Monitoring Committee (DMC) or Other Review Board 
Not applicable. 
 
11 
SUPPORTING DOCUMENTATION 
11.1 
Appendix 1 Non-key analysis specifications 
11.1.1 
Baseline characteristics and demographics 
The BMI value collected in the eCRF will not be used for this summary. The BMI will be 
recalculated using the following formula and reported to 1 decimal place: 
 
𝐵𝑀𝐼(𝑘𝑔/𝑚2) = 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 𝑎𝑡 𝑠𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔 (𝑘𝑔)
[ℎ𝑒𝑖𝑔ℎ𝑡 𝑎𝑡 𝑠𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔 (𝑚)]2
 
 
11.1.2 
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 (DEM) will be performed. The purpose of this review 
meeting will be to examine all protocol deviations, define the PK-PPS, and to verify the quality 
of the data. If PK parameters are needed to define PK-PPS, it will be performed based on the 
ADPP (Pharmacokinetic Parameters Analysis Data). The data evaluation will also help in 
guiding decisions on how to manage data issues on a case-by-case basis (e.g., missing values, 
dropouts, and protocol deviations). 
Important Protocol Deviations (IPDs) that are considered to impact the study participant’s data 
validity for analysis of the primary study objective will be identified and classified by the 
deviation types listed in the PD specification document. 
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. 
 
11.1.3 
Medical history 
Medical history will be collected at the Screening Visit. 
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11.1.4 
Prior/concomitant/follow-up 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. 
Any medications with missing dates and/or times will be handled as described in Section 6.3 in 
order to classify them as prior or concomitant. 
 
11.1.5 
Data derivation rules 
Not applicable. 
 
11.1.6 
AEs of Special Interest 
The AEs of special interest for BRV are as follows (by PT): autoimmune nephritis, nephritis, 
nephritis allergic, tubulointerstitial nephritis, and uveitis syndrome. 
 
11.1.7 
Potentially Clinically Significant Criteria for Safety Endpoints 
Not applicable. 
 
11.1.8 
Compliance 
Study 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.  
 
11.2 
Appendix 2: Changes to Protocol-Planned Analyses 
Not Applicable. 
 
11.3 
Appendix 3: Standard Reporting Procedures 
11.3.1 
PK concentrations 
When reporting individual data in listings the following rules will apply: 
• Missing data will be reported as NV (no value). 
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• 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).  
• 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”. 
• 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. 
 
11.3.2 
PK parameters 
When reporting individual data in listings the following rules will apply: 
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• 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). 
• 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 (“-“) 
 
11.4 
Appendix 4: 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 11-
1. 
 
Table 11-1: Pharmacokinetic Parameter and Estimation 
Parameter 
Guideline for Derivation 
Cmax and  tmax  
Obtained directly from the observed concentration-time data 
Clast 
Last observed (quantifiable) concentration, obtained directly from the 
observed concentration versus time curve 
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Parameter 
Guideline for Derivation 
AUC(0-t) 
The AUC from zero time (pre-dose) to the time of last quantifiable 
concentration (AUC(0-t) 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 AUC(0-t) is the sum of areas up to the time of the last quantifiable sample: 
 
AUC(0-t) =
 t
0
dt
t
C
)
(
 
 
AUC 
The area from zero time extrapolated to infinite time will be calculated as 
follows:  
AUC= AUC(0-t) +
𝐶𝑙𝑎𝑠𝑡
𝜆𝑧 
where Clast is the last observed quantifiable concentration.  
AUCextr 
The percentage of AUC obtained by extrapolation will be calculated as 
follows:  
 
AUCextr = 
𝐴𝑈𝐶−𝐴𝑈𝐶(0−𝑡)
𝐴𝑈𝐶
×100 
Unless otherwise determined by PK Scientist’s best knowledge and 
judgment, if the AUCextr is greater than 20%, AUCextr and all dependent 
parameters (i.e., AUC, MRT, VZ/F and CL/F) will be flagged in listings and 
excluded from summary tables and statistical analysis of PK parameters. 
The reason for flagging/exclusion will be footnoted in parameter listings. 
 
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. Best fit option should be used in WinNonlin; however, each 
determination must then be checked manually. 
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). Unless otherwise 
determined by PK Scientist’s best knowledge and judgment, if the adjusted 
correlation coefficient (R2 adjusted) is <0.8, λz will be flagged in listings, 
and excluded from the summary tables and statistical analysis of PK 
parameters together with all the λz dependent parameters (i.e., AUCextr, t½, 
AUC, MRT, CL/F and Vz/F). The reason for flagging/exclusion will be 
footnoted in parameter listings  
5. Unless otherwise determined by PK Scientist’s best knowledge and 
judgment, the interval used to determine λz should be equal or greater than 
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Parameter 
Guideline for Derivation 
2-fold the estimated t½. If the interval is less than 2-fold t1/2, λz, together 
with all the derived parameters (i.e., AUCextr, t½, AUC, MRT, CL/F and 
Vz/F), will be flagged in listings and either: (i) excluded from summary 
tables and statistical analysis of PK parameters, or (ii) included and a 
rationale for inclusion will be presented in the analysis documentation. The 
reason for flagging/exclusion will be footnoted in parameter listings. 
6. The t½ will be calculated as follows:  
   
t½ = 
z
z
λ
693
.0
λ
2
Ln

 
CL/F 
Apparent clearance of parent drug will be calculated from:  
CL/F = 
𝐷𝑜𝑠𝑒
𝐴𝑈𝐶 
VZ/F 
Apparent Volume of distribution  
 
 VZ/F = (CL/F)/ z 
 
AUMC 
The area under the first moment curve from zero to infinity: 
𝐴𝑈𝑀𝐶= 𝐴𝑈𝑀𝐶(0−𝑡) + 𝐶𝑙𝑎𝑠𝑡∗𝑡𝑙𝑎𝑠𝑡
𝜆𝑧
+ 𝐶𝑙𝑎𝑠𝑡
𝜆𝑧
2  
 
MRT 
The mean residence time (i.e., of the unchanged drug in the systemic 
circulation) after single oral dose: 𝑀𝑅𝑇=
𝐴𝑈𝑀𝐶
𝐴𝑈𝐶 
 
12 
REFERENCES 
Guideline on performing NCA analysis Global Exploratory Development (GED) -2017 
 
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Approval Signatures
Name:
ep0110-sap-amendment 1
Version:
1. 0
Document Number:
CLIN-000192468
Title:
Statistical Analysis Plan Amendment 1
Approved Date:
09 Jun 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 08-Jun-2022 13:10:53 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 09-Jun-2022 01:58:15 GMT+0000
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