Clinical trial NCT04075409
Conditions: Healthy Japanese Participants
Keywords: Padsevonil CYP2C19 Healthy Japanese Participants Pharmacokinetics
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2019-09-30; Completion date: 2019-12-27
Enrollment: 39 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to investigate the pharmacokinetics (PK) of padesevonil in CYP2C19 genotyped healthy male Japanese study participants.

Detailed description:

Arms: arm 1: Participants will receive assigned single and multiple doses of padsevonil. arm 2: Participants will receive assigned single and multiple doses of padsevonil. arm 3: Participants will receive assigned single and multiple doses of padsevonil.
Interventions: intervention 1: Padsevonil
Intervention descriptions: intervention 1: Padsevonil will be administered in predefined dosages.

Protocol documents:
Prot_000.pdf: 
UCB 
 
22 Aug 2019 
Clinical Study Protocol 
Padsevonil 
UP0083 
 
 
 
Confidential 
Page 1 of 68 
AN OPEN-LABEL, PARALLEL GROUP, SINGLE-CENTER STUDY TO 
INVESTIGATE THE PHARMACOKINETIC, SAFETY, AND TOLERABILITY 
PROFILES OF PADSEVONIL IN CYP2C19 GENOTYPED HEALTHY MALE 
JAPANESE STUDY PARTICIPANTS 
PROTOCOL UP0083 AMENDMENT 1 
PHASE 1 
SHORT TITLE: 
A pharmacokinetic, safety, and tolerability study of padsevonil in CYP2C19 genotyped healthy 
male Japanese study participants. 
Sponsor: 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
 
Sponsor in Japan: 
UCB Japan Co. Ltd. 
Shinjuku Grand Tower 
8-17-1 Nishi-Shinjuku 
Shinjuku-ku 
Tokyo 160-0023 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Type of amendment 
Amendment 1 
22 Aug 2019 
Substantial 
Original Protocol 
08 May 2019 
Not applicable 
Amendment 1 (22 Aug 2019) 
Overall Rationale for the Amendment 
This protocol was originally written utilizing a new Standard Operating Procedure (SOP) that 
contains provisions to ensure compliance with the 2017 European Regulatory Guidance on Risk 
Mitigation in First-in-Human and Early Clinical Trials (EMEA/CHMP/SWP/28367/07 Rev. 1). 
That UCB SOP recommends use of the specific study stopping rules for the highest risk early 
phase studies that are recommended in the EU guidance, and these are reflected in the current 
protocol template in use for early phase studies at UCB. However, the UCB SOP does allow for 
those stopping rules to be adapted to match the known risk profile of the product as it passes 
from early phase to late phase development, provided that such adaptation is approved by the 
UCB product-specific Benefit/Risk Team. 
Unfortunately, in drawing up  these current protocols, the first 2 finalized protocols mistakenly 
included the default stopping rules in Protocol Section 7.1.2. These studies are being initiated, 
using these stringent criteria which are not appropriate for a late stage clinical pharmacology 
study of padsevonil, at lower doses or achieve exposure levels anticipated to be no higher, than 
those explored in previous studies. Padsevonil has been administered to over 
313 study participants to date, and the nature and pattern of its adverse effect profile is still 
evolving. In healthy volunteers, the few adverse events that have been severe in intensity have 
been transient, self-limiting, and reduced with repeated administration, with very few resulting in 
withdrawal of the individuals affected. Mitigation of more severe adverse events includes an 
extended titration and tapering of padsevonil dosing, which is known to improve tolerability.  
Accordingly, it is deemed appropriate to replace the current, overly stringent stopping criteria 
which were included in the protocol template specifically to address UCB first-in-man study, a 
first multiple-dose study, and a healthy volunteer study where exposures will exceed those 
previously studied, with criteria more in keeping with the current state of knowledge of the 
product and its stage of development, to ensure that the maximum benefit is derived from studies 
needed to explore its tolerability, pharmacokinetic, pharmacodynamic and interaction profiles 
without any impact on subjects safety & data integrity. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Serious Adverse Event Reporting 
Email address for reporting was 
revised.  
The contact information has 
changed.  
Section 1.1, Synopsis, Overall 
design and Treatment Groups 
and Duration subsections 
The durations of Study Periods 
have been clarified and also 
reflect the addition of new Study 
Day 14.  
See the below rationale 
pertaining to the addition of Day 
14.   
Section 1.1, Synopsis, Overall 
design 
Variant alleles of *4, *5, *6, *7, 
*8, *9, *10 and *12 have been 
deleted.  
The frequencies of these variant 
alleles are deemed to be very low 
in Japanese.  
Section 1.1, Synopsis, Overall 
design 
Revised the duration of stay in 
the study center from Day -1 
until the morning on Day 14.  
This revision was made based on 
the site’s assessment that from 
the safety point of view, the 
paticipants should be checked out 
from the hospital in the morning 
on Day 14, instead of the late 
evening on Day 13. 
Section 1.3, Schedule of 
activities, Table 1-1 
Added Day 14 to the Multiple-
dose Period and required 
activities for this Study Day.  
Indicated that subjects will stay 
in the study center on Day 13.  
See the above rationale.  
Section 1.3, Schedule of 
activities, Table 1-1 
Moved exploratory genotyping 
from Day -1 to Day 1.  
 
Added a footnote n to specify 
that the sample for exploratory 
genotyping is to be obtained prior 
to administration of PSL.  
This is to prevent unnecessary 
blood collection. 
Section 1.3, Schedule of 
activities, Table 1-1 
Footnotes describing the timings 
of PK blood sampling on Day 1 
and on Day 10 have been 
corrected.   
Footnotes describing the timings 
of PK blood sampling on Day 1 
and on Day 10 have been 
corrected. 
Section 1.3, Schedule of 
activities, Table 1-1, Footnote d 
Added further specification 
regarding the limit on total time 
for performing triplicate ECGs.  
Augmented footnote for 
consistency with the text in 
Section 8.4.3.  
Section 4.1, Overall design 
The durations of Study Periods 
have been clarified and also 
reflect the addition of new Study 
Day 14. 
See the above rationale.  
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Section 4.1, Overall design 
Variant alleles of *4, *5, *6, *7, 
*8, *9, *10 and *12 have been 
deleted. 
See the above  rationale 
Section 4.1, Overall design 
Revised the duration of stay in 
the study center from Day -1 to 
24 hours after the last dose to 
Day -1 until the morning on Day 
14. 
See the above rationale.  
Section 6.1, Summary of 
treatment administered, 
Table 6-1 
Deleted 25mg tablets in “Dosage 
Formulation”  
Only 100mg tablets will be used 
as the study treatment. 
Section 7.1.2 
Revised the study hold criteria. 
See overall rationale for the 
amendment.  
Section 7.2, Treatment-emergent 
abnormal laboratory value 
criteria 
Revised abnormal laboratory 
value criteria for absolute counts 
of eosinophils, neutrophils, and 
platelets in 
Discontinuation/withrdrawal 
Criterion 9. 
These values were revised to 
conform with the standard values 
used by the study site 
Section 8.4.3, 
Electrocardiograms 
Revised the limit on total time 
for performing triplicate ECGs . 
This revision was made based on 
the site’s assessment that 9, 
rather than 4 minutes is a unified, 
realistic and manageable time. 
Section 10.2, Protocol-required 
safety laboratory assessments, 
Footnote a 
Revised to add that hematology, 
clinical chemistry, and urinalysis 
on Day -1 are also to be 
performed under fasting 
conditions (as for Screening).  
This revision was made to 
conform to the general procedure 
followed by the study site.  
 
 
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UP0083 
 
 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24 hours) 
Fax 
Japan: +81 3 6864 7400 
Email 
Japan: UCBJ-Safety@ucb.com 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................................... 2 
SERIOUS ADVERSE EVENT REPORTING .......................................................................... 5 
1 
PROTOCOL SUMMARY ............................................................................................... 10 
1.1 
Synopsis ....................................................................................................................... 10 
Protocol title:  ..................................................................................................................... 10 
Short title: 
 ..................................................................................................................... 10 
Rationale: 
 ..................................................................................................................... 10 
Objectives and endpoints: .................................................................................................... 11 
Overall design: ..................................................................................................................... 12 
Number of participants: ....................................................................................................... 12 
Treatment groups and duration: ........................................................................................... 13 
1.2 
Schema ......................................................................................................................... 13 
1.3 
Schedule of activities ................................................................................................... 13 
2 
INTRODUCTION ........................................................................................................... 16 
2.1 
Study rationale ............................................................................................................. 16 
2.2 
Background .................................................................................................................. 16 
2.3 
Benefit/risk assessment ................................................................................................ 17 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 18 
4 
STUDY DESIGN ............................................................................................................. 20 
4.1 
Overall design .............................................................................................................. 20 
4.2 
Scientific rationale for study design ............................................................................ 21 
4.3 
Justification for dose .................................................................................................... 21 
4.4 
End of study definition................................................................................................. 21 
5 
STUDY POPULATION .................................................................................................. 21 
5.1 
Inclusion criteria .......................................................................................................... 22 
5.2 
Exclusion criteria ......................................................................................................... 23 
5.3 
Lifestyle restrictions..................................................................................................... 25 
5.3.1 
Meals and dietary restrictions .............................................................................. 25 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 26 
5.3.3 
Activity ................................................................................................................ 26 
5.4 
Screen failures .............................................................................................................. 26 
5.4.1 
Rescreening .......................................................................................................... 26 
6 
STUDY TREATMENT ................................................................................................... 27 
6.1 
Treatment administered ............................................................................................... 27 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 28 
6.2.1 
Drug accountability ............................................................................................. 28 
6.3 
Measures to minimize bias........................................................................................... 29 
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6.4 
Treatment compliance .................................................................................................. 29 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 29 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 29 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 29 
6.5.3 
Rescue medication ............................................................................................... 30 
6.6 
Dose modification ........................................................................................................ 30 
6.7 
Treatment after the end of the study ............................................................................ 30 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 30 
7.1 
Discontinuation of study medication ........................................................................... 30 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 30 
7.1.2 
Criteria for study hold/stopping due to adverse events ....................................... 31 
7.1.3 
Temporary discontinuation .................................................................................. 32 
7.2 
Participant discontinuation/withdrawal from the study ............................................... 32 
7.3 
Lost to follow up .......................................................................................................... 33 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 34 
8.1 
Efficacy assessments .................................................................................................... 34 
8.2 
Pharmacokinetics ......................................................................................................... 34 
8.3 
Pharmacodynamics ...................................................................................................... 35 
8.4 
Safety assessments ....................................................................................................... 35 
8.4.1 
Physical examination ........................................................................................... 35 
8.4.2 
Vital signs ............................................................................................................ 35 
8.4.3 
Electrocardiograms .............................................................................................. 36 
8.4.4 
Clinical safety laboratory assessments ................................................................ 36 
8.4.5 
Suicidal risk monitoring ...................................................................................... 36 
8.4.6 
Psychiatric and mental status ............................................................................... 37 
8.5 
Adverse events ............................................................................................................. 37 
8.5.1 
Time period and frequency for collecting adverse events and serious adverse 
events information ............................................................................................... 37 
8.5.2 
Method of detecting adverse events and serious adverse events ......................... 38 
8.5.3 
Follow up of adverse events and serious adverse events ..................................... 38 
8.5.4 
Regulatory reporting requirements for serious adverse events ............................ 38 
8.5.5 
Pregnancy ............................................................................................................ 38 
8.5.6 
Adverse events of special interest ........................................................................ 39 
8.6 
Safety signal detection ................................................................................................. 39 
8.7 
Treatment of overdose ................................................................................................. 39 
8.8 
Genetics........................................................................................................................ 40 
8.9 
Biomarkers ................................................................................................................... 40 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 40 
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9.1 
Definition of analysis sets ............................................................................................ 40 
9.2 
General statistical considerations ................................................................................. 41 
9.3 
Planned efficacy/outcome analyses ............................................................................. 41 
9.3.1 
Analysis of the primary efficacy/primary endpoint ............................................. 41 
9.4 
Planned pharmacokinetic analysis ............................................................................... 41 
9.5 
Planned safety analyses................................................................................................ 42 
9.6 
Handling of protocol deviations................................................................................... 42 
9.7 
Handling of dropouts or missing data .......................................................................... 43 
9.8 
Planned interim analysis and data monitoring ............................................................. 43 
9.9 
Determination of sample size ....................................................................................... 43 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 43 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ......................... 43 
10.1.1 
Regulatory and ethical considerations ................................................................. 43 
10.1.2 
Financial disclosure ............................................................................................. 44 
10.1.3 
Informed consent process .................................................................................... 44 
10.1.4 
Data protection ..................................................................................................... 45 
10.1.5 
Committees structure ........................................................................................... 45 
10.1.6 
Data quality assurance ......................................................................................... 45 
10.1.6.1 
Case Report Form completion ................................................................... 46 
10.1.6.2 
Apps ........................................................................................................... 46 
10.1.7 
Source documents ................................................................................................ 46 
10.1.8 
Study and Site Closure ......................................................................................... 47 
10.1.9 
Publication Policy ................................................................................................ 47 
10.2 
Appendix 2: Clinical laboratory tests .......................................................................... 48 
10.3 
Appendix 3: Adverse events – definitions and procedures for recording, evaluating, 
follow up, and reporting ............................................................................................... 50 
10.3.1 
Recording and follow up of adverse events and/or serious adverse events ......... 52 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ......... 55 
10.4.1 
Contraception guidance ....................................................................................... 55 
10.4.1.1 
Male study participants ............................................................................. 55 
10.4.1.2 
Collection of pregnancy information......................................................... 56 
10.5 
Appendix 5: Genetics ................................................................................................... 57 
10.6 
Appendix 6: Liver safety – suggested actions and follow up assessments .................. 58 
10.7 
Appendix 7: Medical device incidents – definition and procedures for recording, 
evaluating, follow up, and reporting ............................................................................ 61 
10.8 
Appendix 8: Rapid alert procedures ............................................................................ 62 
10.9 
Appendix 9: Country-specific requirements ................................................................ 63 
10.10 Appendix 10: Abbreviations and trademarks .............................................................. 64 
10.11 Appendix 11: Protocol amendment history ................................................................. 66 
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11 REFERENCES ................................................................................................................ 67 
SPONSOR DECLARATION .................................................................................................. 68 
 
LIST OF TABLES 
Table 1-1: 
Schedule of activities ....................................................................................... 14 
Table 3-1: 
Study objectives and endpoints ........................................................................ 19 
Table 6-1: 
Summary of treatment administered ................................................................ 27 
Table 10-1: 
Highly effective contraceptive methods .......................................................... 56 
Table 10-2: 
Phase 1 liver chemistry stopping criteria and follow up assessments ............. 59 
 
LIST OF FIGURES 
Figure 7-1: 
Liver chemistry stopping algorithm ................................................................. 31 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: 
An open-label, parallel group, single-center study to investigate the pharmacokinetic (PK), 
safety, and tolerability profiles of padsevonil (PSL) in cytochrome P450 family 2 subfamily C 
member 19 (CYP2C19) genotyped healthy male Japanese study participants. 
Short title: 
A PK, safety, and tolerability study of PSL in CYP2C19 genotyped healthy male Japanese study 
participants. 
Rationale: 
Padsevonil has been demonstrated in vitro to be a time-dependent inhibitor of CYP2C19 
(NCD2279, NCD2095). Limited data collected in UP0039 (PK study in Japanese and Caucasian 
study participants) suggested a weak effect of the CYP2C19 genotype on PSL disposition. 
Additionally, according to the Food and Drug Administration (FDA) draft guidance, a 
comparison of the PK parameters between poor metabolizers (PMs) and extensive metabolizers 
(EMs) can substitute for a drug-drug interaction (DDI) study with a strong inhibitor for the 
particular pathway such as CYP2C19 (Food and Drug Administration, 2017). It is therefore 
important to consider the implications of the CYP2C19 genotype on PSL clearance with the 
concomitant use of PSL and other drugs. 
This study aims to determine the contribution of CYP2C19 in PSL metabolism. The results of 
the study will be used to inform on the DDI potential of PSL with CYP2C19 inhibitors and 
inducers as well as any dosing adjustments based on CYP2C19 genetic variations. 
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Objectives and endpoints: 
Objectives 
Endpoints 
Primary 
 
To investigate the PK of PSL in 
CYP2C19 genotyped healthy male 
Japanese study participants (extensive, 
intermediate, and poor metabolizers) 
 
The primary PK endpoints are the following: 
 
PK parameters of PSL in plasma: 
◦ 
single-dose (Cmax, AUC(0-t), AUC, t1/2, and 
tmax) and  
◦ 
multiple-dose (Cmax,ss, AUCτ, t1/2, and tmax,ss) 
 
The other PK endpoints are the following: 
 
PK parameters of PSL in plasma: 
◦ 
single-dose (Cmax,bw, AUC(0-t),bw, and 
AUC,bw) and  
◦ 
multiple-dose (CLss/F, Cmax,ss,bw, and 
AUCτ,bw) 
 
PK parameters of PSL metabolites (
 
) in plasma: 
◦ 
single-dose (Cmax, AUC(0-t), AUC, t1/2, tmax, 
Cmax,bw, AUC(0-t),bw, AUC,bw, and m/p [based 
on Cmax and AUC]) and  
◦ 
multiple-dose (Cmax,ss, AUCτ, t1/2, tmax,ss, 
Cmax,ss,bw, AUCτ,bw, and m/p [based on Cmax 
and AUC]) 
 
PSL and its metabolites (
 
 in urine after single- and multiple-dose 
(Ae, fe, CLr) 
 
Additional PK parameters of PSL metabolites 
(
) in urine (CLform) 
Secondary 
 
To evaluate the safety and tolerability of 
PSL in healthy male Japanese study 
participants 
 
The primary safety endpoint is the following: 
 
Adverse events 
 
The other safety endpoints are the following: 
 
Vital signs (PR, RR, SBP, DBP, and body 
temperature) 
 
12-lead ECG parameters 
 
Physical examination findings 
 
Clinical laboratory test results (hematology, 
clinical chemistry, and urinalysis) 
DBP=diastolic blood pressure; ECG=electrocardiogram; m/p=metabolite to parent ratio; PK=pharmacokinetics; 
PR=pulse rate; PSL=padsevonil; RR=respiratory rate; SBP=systolic blood pressure 
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Overall design: 
This is a Phase 1, open-label, parallel group, single-center study to investigate the PK, safety, 
and tolerability profiles of PSL in CYP2C19 genotyped healthy male Japanese study 
participants. 
The study consists of a Screening Period, a Single-dose Period, a Multiple-dose Period, and a 
Safety Follow-up (SFU) Visit. The maximum total duration of the study is 49 days for each 
study participant, including the Screening Period (up to 28 days), the Single-dose Period (6 days, 
including Check-in on Study Day -1 and PSL single-dosing on Study Day 1 to Study Day 5, 
inclusive), the Multiple-dose Period (9 days, including PSL dosing on Study Day 6 to 
Study Day 12, inclusive), and the SFU Visit (maximum of 8 days after the last dose of PSL on 
Study Day 12). 
The study participants will be examined for CYP2C19 genotyping (variant alleles: *2, *3, and 
*17) during the Screening Period and grouped as follows: 
 Extensive metabolizers (*1/*1), 
 Intermediate metabolizers (*1/*2, *1/*3), 
 Poor metabolizers (*2/*2, *2/*3, *3/*3). 
Other metabolizers who have the variant allele of *17 will be excluded from the study. Study 
participants will not be genotyped, if rescreened. 
Study participants who meet all of the inclusion and none of the exclusion criteria will check into 
the study center on Day -1 (prior to the single dose [SD]). A SD of PSL 200mg will be 
administered in the morning on Day 1 of the Single-dose Period. During the Multiple-dose 
Period, PSL will be administered on the following dosage schedule: 
 PSL 100mg twice a day (BID) on Day 6. 
 PSL 200mg BID from Day 7 to Day 9. 
 PSL 200mg in the morning on Day 10; PSL 100mg in the evening on Day 10. 
 PSL 100mg BID from Day 11 to Day 12. 
Padsevonil will be administered with 240mL water 30 minutes after a completion of a light meal 
for the morning dose and 30 minutes after a completion of a standard meal for the evening dose. 
During the Single-dose and Multiple-dose Periods, study participants will stay in the study center 
from the afternoon on Day -1 (prior to the SD) until the morning on Day 14. 
Study participants will undergo serial conventional venous blood and urine sampling to measure 
plasma and urine concentrations of PSL and its metabolites as well as safety monitoring. 
Number of participants: 
A total of 39 study participants (13 study participants per CYP2C19 genotype group) will be 
enrolled. If more than 2 study participants dropout in each group, additional study participants 
will be recruited at the discretion of the Investigator and Sponsor. 
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Treatment groups and duration: 
The maximum total duration of the study is 49 days for each study participant, including the 
Screening Period (up to 28 days), the Single-dose Period (6 days, including Check-in on 
Study Day -1 and PSL single-dosing on Study Day 1 to Study Day 5, inclusive), the Multiple-
dose Period (9 days, including PSL dosing on Study Day 6 to Study Day 12, inclusive), and the 
SFU Visit (maximum of 8 days after the last dose of PSL on Study Day 12). 
1.2 
Schema 
Not applicable. 
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 
Study Period 
Screening 
Period 
(28 days) 
Single-dose Period 
Multiple-dose Period 
SFU 
Or Withdrawal 
Visit 
(maximum of 8 
days after the 
last dose) a 
Study Day 
-29 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2C19 genotyping  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory genotyping 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, habits, 
lifestyle 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication/medical 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Psychiatric and mental status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Drug screen, ethanol breath 
test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBV, HCV, HIV, 
syphilis) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Table 1-1: 
Schedule of activities 
Study Period 
Screening 
Period 
(28 days) 
Single-dose Period 
Multiple-dose Period 
SFU 
Or Withdrawal 
Visit 
(maximum of 8 
days after the 
last dose) a 
12-lead ECGd 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
PSL administration 
 
 
Xe 
 
 
 
 
Xf 
Xg 
Xg 
Xg 
Xh 
Xi 
Xi 
 
 
 
PK blood sampling 
 
 
Xj 
Xj 
Xj 
 
 
 
 
 
 
Xk 
 
 
 
 
 
PK urine sampling 
 
 
Xl 
Xl 
Xl 
Xl 
Xl 
 
 
 
 
Xm 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stay in study center 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; CYP2C19=cytochrome P450 family 2 subfamily C; ECG=electrocardiogram; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-up Visit 
a The Safety Follow-up Visit will be performed 7 days (+1 day) after the last administration of PSL. Idem for the Withdrawal Visit, if applicable. 
b A complete physical examination will be conducted at Screening and SFU. A brief physical examination will be conducted at all other visits, including at 
discharge. 
c On dosing days, vital signs will be performed predose and 3 hours postdose. Blood pressure measurements  will be performed in both supine and standing 
positions for orthostatic measurement at Screening (supine BP after the study participant has been lying down for 5 minutes and then standing BP after 
1 minute and 3 minutes) and in a supine position for routine BP measurements at all assessments. 
d 12-lead ECG will be performed after a rest of ≥5 minutes at Screening and at predose, 24 hours postdose, and at the SFU Visit. All ECG recordings will be 
performed in triplicate but no more than 2 to 3 minutes apart. The full set of triplicates should be completed in less than 9 minutes. 
e PSL 200mg will be administered in the morning on Day 1 during the Single-dose Period. 
f PSL 100mg will be administered in the morning and evening on Day 6 during the Multiple-dose Period. 
g PSL 200mg will be administered in the morning and evening from Day 7 to Day 9 during the Multiple-dose Period. 
h PSL 200mg and 100mg will be administered in the morning and evening, respectively, on Day 10 during the Multiple-dose Period. 
i PSL 100mg will be administered in the morning and evening from Day 11 to Day 12 during the Multiple-dose Period. 
j Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours postdose. 
k Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the morning dose. 
l Predose and 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose. 
m 0 to 12 hours after the morning dose. 
n Predose. 
 
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2 
INTRODUCTION 
2.1 
Study rationale 
Preclinical investigations (NCD2194) have shown that PSL is mainly metabolized by CYP3A4 
with a minor contribution from CYP2C19. The clinical DDI interaction with carbamazepine, a 
potent CYP3A4 inducer (UP0002) confirmed the major contribution of CYP3A4 to PSL 
clearance as the exposure of PSL was reduced by approximately 80% when coadministered with 
carbamazepine. The contribution of CYP3A4 to PSL clearance was further confirmed in the DDI 
clinical study with erythromycin 500mg BID, a moderate CYP3A4 inhibitor (UP0057) as the 
exposure of PSL was increased approximately 2-fold with concomitant administration of 
erythromycin. 
Padsevonil has been demonstrated in vitro to be a time-dependent inhibitor of CYP2C19 
(NCD2279, NCD2095). This has been confirmed in the cocktail DDI clinical study (UP0013) 
where PSL showed a moderate increase in the exposure of omeprazole, a CYP2C19 probe 
substrate. Padsevonil also demonstrated time-dependent PK with decreased clearance following 
repeated administration at a dose of 100mg BID and higher. This is most likely due to 
autoinhibition of the CYP2C19 pathway involved in PSL metabolism. 
Limited data collected in UP0039 (PK study in Japanese and Caucasian study participants) 
suggested a weak effect of the CYP2C19 genotype on PSL disposition. This effect is more 
pronounced after a SD compared with repeated dosing, consistent with autoinhibition of 
CYP2C19. 
As a consequence of the potential contribution of CYP2C19 in PSL clearance, strong inhibitors 
and inducers of CYP2C19 are excluded from global Phase 2b and Phase 3 studies. 
According to the FDA draft guidance, a comparison of the PK parameters between PMs and 
EMs can substitute for a DDI study with a strong inhibitor for the particular pathway such as 
CYP2C19 (Food and Drug Administration, DRAFT GUIDANCE, 2017). It is therefore 
important to consider the implications of the CYP2C19 genotype on PSL clearance with the 
concomitant use of PSL and other drugs. 
The goal of UP0083 is to determine the contribution of CYP2C19 in PSL metabolism. The 
results of the study will be used to inform on the DDI potential of PSL with CYP2C19 inhibitors 
and inducers as well as any dosing adjustments based on CYP2C19 genetic variations. 
2.2 
Background 
More than 50 million people worldwide suffer from epilepsy (World Health Organization, 2018). 
An imbalance between excitatory and inhibitory neurotransmission is widely recognized as a key 
factor leading to epilepsy. Consequently, drugs currently used in the treatment of epilepsy aim to 
restore this balance. In fact, most of the current antiepileptic drugs (AEDs) modulate neuronal 
transmission by either blocking voltage-gated sodium channels or acting on inhibitory/excitatory 
receptors located at the postsynaptic level. 
The gamma-aminobutyric acid type a receptor alpha1 subunit (GABAA) receptor mediates the 
bulk of inhibitory neurotransmissions in the brain. Allosteric modulation of inhibitory GABAA 
receptors by the central benzodiazepine receptor (cBZR) site offers robust protection against 
seizures (Riss et al, 2008). However, their clinical use as AEDs is limited due to an unfavorable 
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side effect profile (eg, drowsiness, ataxia, amnesia, paradoxical aggression), as well as the 
development of tolerance to anticonvulsant effects. 
Compounds binding to SV2A proteins on synaptic vesicles are characterized by broad-spectrum 
efficacy against both generalized and partial seizures in preclinical models, and this protective 
activity strongly correlates with their binding affinity (Kaminski et al, 2008). The function of 
SV2B and SV2C subtypes is not well established, but they share a high degree of sequence 
homology to SV2A and localization within synaptic vesicles (Wan et al, 2010; Janz and Südhof, 
1999). Levetiracetam (LEV), exemplifying a SV2A related mechanism of action, displays 
prominent clinical efficacy in patients with different forms of epilepsy (Klitgaard and Verdru, 
2007). 
Compounds with dual activity at SV2A and GABAA receptors are expected to have superior 
efficacy to those drugs working through only one of these mechanisms. Preclinical data in 
animal models of epilepsy support this assumption with compelling synergistic interaction 
observed between LEV and AEDs with GABAergic mechanisms of action (Kaminski et al, 
2009). This synergistic interaction was particularly pronounced when combinations of LEV and 
benzodiazepines were tested and a significant increase in anticonvulsant potency of these drugs 
was observed associated with a higher therapeutic index. 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic SV2 proteins 
and postsynaptic cBZR sites on the GABAA receptor. At presynaptic sites, PSL binds with high 
affinity to all 3 subtypes of the SV2 protein (ie, SV2A, SV2B, and SV2C), and with moderate 
affinity to postsynaptic cBZR sites. Pharmacological results obtained in rodent models of either 
partial or generalized seizures in humans show that PSL provides potent and efficacious seizure 
suppression, suggesting a broad-spectrum profile. Furthermore, PSL revealed potent and 
efficacious seizure suppression in models of drug-refractory epilepsy, suggesting superior 
efficacy against seizures refractory to currently used AEDs. Specifically, in the rat amygdala 
kindling model, a model of refractory focal epilepsy, PSL was the only compound that produced 
seizure freedom at doses that can be administered in humans. Valproate, brivaracetam, 
clonazepam, diazepam, and phenobarbital only produced seizure freedom at plasma exposures 
that exceeded the maximum human exposures multiple times over. Padsevonil is not associated 
with loss of anticonvulsant efficacy after repeated administration in mice, suggesting reduced 
potential for the development of tolerance. Because of its unique properties, PSL is currently 
being proposed as adjunctive treatment for nondrug-resistant focal seizures in patients with 
epilepsy. 
2.3 
Benefit/risk assessment 
Overall, the clinical pharmacology and clinical studies in drug-resistant epilepsy demonstrated 
the adverse event (AE) profile of PSL is generally consistent with the pharmacological activity 
of the product, and as expected in the context of early dose escalation studies in healthy study 
participants and patients with epilepsy. The safety findings to date suggest that the AEs 
experienced by study participants receiving single and repeated doses of PSL are limited 
principally to central nervous system effects. The AEs tend to be dose related in frequency and 
intensity, self-limiting, and tend to decrease in intensity over the first few days of dosing. 
Reported acute psychiatric serious adverse events (SAEs) are consistent with AEs of other 
AEDs, including SV2A ligands. Events were transient, acute, and required admission to 
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psychiatric care and medical treatment. The events in healthy study participants (n=2) occurred 
early after initiation or cessation of PSL which was done without titration or tapering. The 
psychotic effect in an epilepsy study participant (EP0069) emerged after dramatic improvement 
in seizure control and electroencephalogram activity a few weeks after the start of PSL, 
suggesting a “forced normalization” (Clemens, 2005, Loganathan et al, 2015). Dose reduction of 
PSL and medical treatment resulted in complete resolution of psychosis within days, as the 
treatment with PSL continued. The occurrence of acute psychiatric SAEs in these three study 
participants administered PSL highlights the need to consider the possibility of significant 
psychiatric AEs and to maintain vigilance for such effects. The mitigation plan for acute 
psychiatric SAEs involves gradual titration and taper, which are known to improve tolerability of 
AEDs and monitoring for psychiatric and mental status changes. 
Despite the occurrence of several electrocardiogram (ECG) findings (including different types of 
ectopy) both in healthy study participants and study participants with epilepsy, an independent 
expert cardiologist reviewed data from Phase 1 and Phase 2 and determined that none of these 
findings were assessed as being likely to be related to PSL. No clinically significant 
echocardiographic findings (only minor/trace or Grade 1 findings) have been observed in studies 
EP0069 and EP0073 and all echocardiograms were assessed as normal. There are currently no 
data to suggest that the drug has an AE on cardiovascular function other than a minimal lowering 
effect on blood pressure (BP). The degrees of reduction seen in both systolic blood pressure 
(SBP) and diastolic blood pressure (DBP) are consistent with the GABAA targeted mechanism 
of action of PSL and do not appear likely to have a clinically significant effect in therapeutic use. 
As a precaution, and in view of the nonclinical histopathological cardiac findings, 
echocardiogram screening of study participants at Baseline and ongoing echocardiogram 
monitoring during treatment and posttreatment have been implemented in the studies that have a 
>3-week treatment duration. To date, no clinically significant echocardiogram findings (only 
minor/trace or Grade 1 findings) have been observed. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PSL may be found in the Investigator’s Brochure (IB). The current IB reflects 
the safety profile of PSL as it is known and may change with the accumulation of additional data. 
The healthy study participants included in this study will receive no medical benefit from 
participation. The risks from taking part in the study will be minimized through the selection of 
appropriate dose levels, selection of appropriate study participants defined by the 
inclusion/exclusion criteria, and safety monitoring. 
3 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints for this study are presented in Table 3-1. 
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Table 3-1: 
Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
To investigate the PK of PSL in 
CYP2C19 genotyped healthy male 
Japanese study participants (extensive, 
intermediate, and poor metabolizers) 
 
The primary PK endpoints are the following: 
 
PK parameters of PSL in plasma: 
◦ 
single-dose (Cmax, AUC(0-t), AUC, t1/2, and tmax) 
and  
◦ 
multiple-dose (Cmax,ss, AUCτ, t1/2, and tmax,ss) 
 
The other PK endpoints are the following: 
 
PK parameters of PSL in plasma: 
◦ 
single-dose (Cmax,bw, AUC(0-t),bw, and AUC,bw) 
and  
◦ 
multiple-dose (CLss/F, Cmax,ss,bw, and AUCτ,bw) 
 
PK parameters of PSL metabolites (
 
) in plasma: 
◦ 
single-dose (Cmax, AUC(0-t), AUC, t1/2, tmax, 
Cmax,bw, AUC(0-t),bw, AUC,bw, and m/p [based on 
Cmax and AUC]) and  
◦ 
multiple-dose (Cmax,ss, AUCτ, t1/2, tmax,ss, 
Cmax,ss,bw, AUCτ,bw, and m/p [based on Cmax and 
AUC]) 
 
PSL and its metabolites (
 
) in urine after single- and multiple-dose (Ae, fe, 
CLr) 
 
Additional PK parameters of PSL metabolites 
(
) in urine (CLform) 
Secondary 
 
To evaluate the safety and tolerability 
of PSL in healthy male Japanese study 
participants 
 
The primary safety endpoint is the following: 
 
Adverse events 
 
The other safety endpoints are the following: 
 
Vital signs (PR, RR, SBP, DBP, and body 
temperature) 
 
12-lead ECG parameters 
 
Physical examination findings 
 
Clinical laboratory test results (hematology, clinical 
chemistry, and urinalysis) 
DBP=diastolic blood pressure; ECG=electrocardiogram; m/p=metabolite to parent ratio; PK=pharmacokinetics; 
PR=pulse rate; PSL=padsevonil; RR=respiratory rate; SBP=systolic blood pressure 
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4 
STUDY DESIGN 
4.1 
Overall design 
This is a Phase 1, open-label, parallel group, single-center study to investigate the PK, safety, 
and tolerability profiles of PSL in CYP2C19 genotyped healthy male Japanese study 
participants. 
A study participant who provides written informed consent will be screened within 28 days 
before the Single-dose Period. 
The study consists of a Screening Period, a Single-dose Period, a Multiple-dose Period, and a 
SFU Visit. The maximum total duration of the study is 49 days for each study participant, 
including the Screening Period (up to 28 days), the Single-dose Period (6 days, including Check-
in on Study Day -1 and PSL single-dosing on Study Day 1 to Study Day 5, inclusive), the 
Multiple-dose Period (9 days, including PSL dosing on Study Day 6 to Study Day 12, inclusive), 
and the SFU Visit (maximum of 8 days after the last dose of PSL on Study Day 12). 
The study participants will be examined for CYP2C19 genotyping (variant alleles: *2, *3, and 
*17) during the Screening Period and grouped as follows: 
 Extensive metabolizers (*1/*1), 
 Intermediate metabolizers (*1/*2, *1/*3), 
 Poor metabolizers (*2/*2, *2/*3, *3/*3). 
Other metabolizers who have the variant allele of *17 will be excluded from the study. Study 
participants will not be genotyped, if rescreened. 
A sufficient number of study participants will be screened to ensure that 13 study participants are 
included in each group. 
Study participants who meet all of the inclusion and none of the exclusion criteria will check into 
the study center on Day -1 (prior to the SD). A SD of PSL 200mg will be administered in the 
morning on Day 1 of the Single-dose Period. During the Multiple-dose Period, PSL will be 
administered on the following dosage schedule: 
 PSL 100mg BID on Day 6. 
 PSL 200mg BID from Day 7 to Day 9. 
 PSL 200mg in the morning on Day 10; PSL 100mg in the evening on Day 10. 
 PSL 100mg BID from Day 11 to Day 12. 
Padsevonil will be administered with 240mL water 30 minutes in after a completion of a light 
meal for the morning dose and 30 minutes in after a completion of a standard meal for the 
evening dose. During the Single-dose and Multiple-dose Periods, study participants will stay in 
the study center from the afternoon on Day -1 (prior to the SD) until the morning on Day 14. 
Study participants will undergo serial conventional venous blood and urine sampling to measure 
plasma and urine concentrations of PSL and its metabolites as well as safety monitoring. 
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Study participants will return to the study center for the SFU Visit 7 (±1) days after the final dose 
of PSL. 
4.2 
Scientific rationale for study design 
Padsevonil has been demonstrated in vitro to be a time-dependent inhibitor of CYP2C19 
(NCD2279, NCD2095). Limited data collected in UP0039 (PK study in Japanese and Caucasian 
study participants) suggested a weak effect of the CYP2C19 genotype on PSL disposition. This 
effect is more pronounced after a SD compared with repeated dosing, consistent with 
autoinhibition of CYP2C19. 
As a consequence of the potential contribution of CYP2C19 in PSL clearance, strong inhibitors 
and inducers of CYP2C19 are excluded from global Phase 2b and Phase 3 studies. 
According to the FDA draft guidance, a comparison of the PK parameters between PMs and 
EMs can substitute for a DDI study with a strong inhibitor for the particular pathway such as 
CYP2C19. Healthy male Japanese adults were chosen as a study population because the 
frequency of CYP2C19 PMs is estimated to be approximately 20% in the Japanese population 
whereas in the Caucasian population it is 1% to 3%. 
4.3 
Justification for dose 
The dosages of PSL for this study will be 200mg SD, 200mg BID, and 100mg BID for titration 
and tapering (Section 4.1). The 200mg SD was used to evaluate the safety, tolerability, and PK 
of PSL in healthy Japanese and Caucasian study participants in UP0039. The 200mg BID is 
being evaluated in global Phase 2 and Phase 3 studies as a potential dose for registration and 
approval. In addition, while this dose is lower than the maximum tolerated dose (MTD; 400mg 
BID), it is considered adequate for the purposes of this study while not exposing healthy study 
participants to the MTD. 
4.4 
End of study definition 
A study participant is considered to have completed the study if he has completed all periods of 
the study including the last scheduled procedure shown in the Schedule of activities 
(Section 1.3). 
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule 
of activities (Section 1.3) for the last study participant in the study. 
The maximum study duration per study participant is 49 days, including up to 28 days for 
Screening and 21 days on study (ie, from Day -1 through the SFU Visit). 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
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5.1 
Inclusion criteria 
Study participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age: 
1. The study participant must be 20 to 55 years of age inclusive, at the time of signing the 
informed consent. 
Type of study participant and disease characteristics: 
2. The study participant is overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring. 
Note: Study participant has clinical laboratory test results within the local reference ranges or 
values that are considered as not clinically relevant by the Investigator and approved by the 
UCB Study Physician. Lab parameters outside the reference ranges can be retested and if the 
retest result is within the reference range or considered as clinically not relevant the study 
participant will be allowed in the study. 
3. The 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: 
4. The study participant has a body weight ≥50kg and body mass index within the range [18 to 
30] kg/m2 (inclusive). 
Sex: 
5. The study participant is male. 
A male study participant must agree to use contraception as detailed in Appendix 4 
(Section 10.4) of this protocol during the Treatment Period and for ≥7 days after the last dose 
of study medication and refrain from donating sperm during this period. 
Informed consent: 
6. The study participant is capable of giving signed informed consent as described in 
Appendix 1 (Section 10.1) which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF). 
7. The study participant must be considered reliable and capable of adhering to the protocol, 
according to the judgment of the Investigator, and is capable of communicating satisfactorily 
with the Investigator. 
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5.2 
Exclusion criteria 
Study participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. The study participant has any medical or psychiatric condition that, in the opinion of the 
Investigator, could jeopardize or would compromise the study participant’s ability to 
participate in this study, such as a history of schizophrenia, or other psychotic disorder, 
bipolar disorder, or severe unipolar depression. The presence of potential psychiatric 
exclusion criteria will be determined based on the psychiatric history collected at the 
Screening Visit. 
2. The study participant has a history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrinological, hematological, or neurological disorders, capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk 
when taking the study intervention; or interfering with the interpretation of data. 
3. The study participant has history of chronic alcohol or drug abuse within the previous 
6 months. 
4. The study participant has a positive predrug/alcohol screen (to include at a minimum 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines). 
Note: A study participant with a positive finding on the alcohol and/or drug screen may still 
be enrolled at the discretion of the Investigator if a plausible clinical explanation exists (eg, 
prior or concomitant medication use). 
5. The study participant has a known hypersensitivity to any components of the study 
medication or comparative drugs (and/or an investigational device) as stated in this protocol. 
6. The study participant has a history of unexplained syncope or a family history of sudden 
death due to long QT syndrome. 
7. The study participant has abnormal blood pressure. 
Note: This includes both the routine and orthostatic hypotension BP assessments. For routine 
BP, the study participant must have BP and pulse rate within normal range in the supine 
position after 5 minutes of rest (SBP: 90mmHg to 145mmHg; DBP: 40mmHg to 95mmHg; 
and pulse rate: 40bpm to 100bpm). Any values marginally (ie, no more than 5mmHg) outside 
the normal range but considered not clinically significant by the Investigator would be 
allowed. In case of an out of range result, 1 repeat will be allowed. If the readings are out of 
range again, the study participant will not be included. 
8. The study participant has lymphoma, leukemia, or any malignancy within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have been resected 
with no evidence of metastatic disease for 3 years. 
Suicidality 
9. The study participant has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has had suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
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“Screening/Baseline” version of the Columbia-Suicide Severity Rating Scale (C-SSRS) at 
Screening. 
Prior/Concomitant therapy 
10. The study participant has past or intended use of over-the-counter or prescription medication 
including herbal medications within 2 weeks or 5 half-lives prior to dosing. Specific 
medications listed in Section 6.5.1 may be allowed. 
11. The study participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, 
phenobarbital, isoniazid, phenytoin, rifampicin, etc.) within 2 months prior to dosing. In case 
of uncertainty, the Medical Monitor should be consulted. 
Prior/Concurrent clinical study experience 
12. The study participant has previously received PSL in this or any another study. 
13. The study participant has participated in another study of an investigational medicinal 
product (IMP) (and/or an investigational device) within the previous 30 days prior to 
Screening (or within 5 half-lives, whichever is longer) or is currently participating in another 
study of an IMP (and/or an investigational device). 
Diagnostic assessments 
14. The study participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
or alkaline phosphatase (ALP) >1.0x upper limit of normal (ULN). 
15. The study participant has bilirubin >1.0xULN (isolated bilirubin >1.0xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 
16. The study participant has current or chronic history of liver disease or known hepatic or 
biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 
Note: Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be 
repeated once for confirmation. This includes rescreening. 
17. The study participant has any clinically relevant ECG finding at the Screening Visit or at 
Baseline. Study participant has an abnormality in the 12-lead ECG that, in the opinion of the 
Investigator, increases the risks associated with participating in the study. In addition, any 
study participant with any of the following findings will be excluded: (a) QT interval 
corrected for heart rate using Bazett’s formula (QTcB) or Fridericia’s formula (QTcF) 
>450ms in study participants in 2 of 3 ECG recordings; (b) other conduction abnormalities 
(defined as PR interval ≥220ms); (c) irregular rhythms other than sinus arrhythmia or 
occasional, rare supraventricular or rare ventricular ectopic beats. In case of an out of range 
result, 1 repeat will be allowed. If out of range again, the study participant cannot be 
included. 
NOTE A: The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-read or 
manually over-read. 
NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual study participant should be determined prior to initiation of the study. In other 
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words, several different formulas cannot be used to calculate the QTc for an individual study 
participant and then the lowest QTc value used to include or discontinue the study 
participant. 
18. The study participant has presence of hepatitis B surface antigen at Screening or within 
3 months prior to dosing. 
19. The study participant has positive hepatitis C antibody test result at Screening or within 
3 months prior to starting study intervention. 
NOTE: Study participants with positive hepatitis C antibody due to prior resolved disease 
can be enrolled if a confirmatory negative hepatitis C ribonucleic acid (RNA) test is 
obtained. 
20. The study participant has positive human immunodeficiency virus antibody test or syphilis at 
Screening or within 3 months prior to dosing. 
Other exclusions 
21. The study participant has made a blood or plasma donation or has had a comparable blood 
loss (>450mL) within the last 30 days prior to Screening. Blood donation during the study is 
not permitted. 
22. The study participant has a consumption of more than 600mg of caffeine/day (200mL of 
coffee contains approximately 100mg of caffeine, 200mL of black tea approximately 30mg, 
and 200mL of cola approximately 20mg). 
23. The study participant smokes more than 5 cigarettes per day (or equivalent) or has done so 
within 6 months prior to Screening. 
24. The study participant ingests grapefruit, passion fruit, or pawpaw (as beverage, fruit, or 
supplements) within 72 hours before each administration of study medication. If this is the 
case at the start of the study, study participants may be rescreened. 
25. The study participant has a diet that deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the Investigator. 
26. The study participant has undergone sudden and/or extreme changes in exercise levels for 
2 weeks prior to Screening Visit. 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
 The study participant must refrain from consumption of grapefruit, passion fruit, or pawpaw 
(as beverage, fruit, or supplements) from 3 days before the start of study medication until 
after the final dose. 
 All morning doses will be administered in the ante meridiem and all evening doses will be 
administered in the post meridiem. 
 Study participants will complete a light meal 30 minutes prior to each morning dose of PSL 
and a standard meal 30 minutes prior to each evening dose of PSL. On days when PK 
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assessments will be taken, study participants will complete a standardized meal (same 
macronutrient will be administered for minimizing covariates) in the afternoon and evening. 
 PSL will be administered orally with 240mL water. Between 1 hour predose and 2 hours 
postdose, the total intake of beverages should be limited to 100mL. Water will be available 
ad libitum except for between 1 hour before and 2 hours after dosing. 
5.3.2 
Caffeine, alcohol, and tobacco 
 During each dosing session, study participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 48 hours before 
the start of dosing until after collection of the final PK sample. 
 During each dosing session, study participants will abstain from alcohol for 24 hours before 
the start of dosing until leaving the study center. 
 Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit. 
5.3.3 
Activity 
 Study participants will abstain from strenuous exercise from 3 days before each blood 
collection for clinical laboratory tests. Study participants may participate in light recreational 
activities during the study (eg, watching television, reading). 
5.4 
Screen failures 
Screen failures are defined as study participants who consent to participate in the clinical study 
but are not subsequently entered in the study. 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 includes demography, 
screen failure details, eligibility criteria, and any SAE. 
5.4.1 
Rescreening 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened (at the discretion of the Investigator). Study participants may be rescreened under 
conditions including but not limited to the following: 
 Study participant ingests grapefruit, passion fruit, or pawpaw (as beverage, fruit, or 
supplements) within 72 hours before each administration of study medication. 
 If a study participant does meet the exclusion criteria at Screening or on Day -1 due to an 
out-of-range laboratory result or a minor illness, he can be rescreened once at the discretion 
of the Investigator. 
 Study participants may be included if the repeat values for the laboratory screening criteria 
are within normal ranges and/or if repeat values show normalization of the out-of-range 
safety laboratory values, and/or after the study participant makes a complete recovery from 
the mild illness and if all other screening criteria are met. 
 Study participant has a positive drug test for substances of abuse. 
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Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation; if the results are out of range again, the study participant cannot be 
included. 
In any case of uncertainty, this should be discussed with the Medical Monitor. 
Rescreened study participants will be assigned the same study participant number as for the 
initial Screening. 
6 
STUDY TREATMENT 
Study treatment or study medication is defined as any investigational treatment intended to be 
administered to a study participant according to the study protocol. 
6.1 
Treatment administered 
A summary of the treatment administered is provided in Table 6-1. 
Table 6-1: 
Summary of treatment administered 
Study Treatment Name: 
PSL 
Dosage formulation: 
100mg tablets 
Unit dose strength(s)/Dosage level(s): 
100mg, 100mg BID, 200mg, 200mg BID 
Route of administration: 
Oral 
Dosing instructions: 
Padsevonil will be administered with 
240mL of water. The use of beverages 
between 1 hour predose and 2 hours 
postdose should be limited to a maximum of 
100mL (in order to keep groups comparable 
with respect to period of dosing). Study 
participants will complete a light meal 
30 minutes prior to each morning dose and a 
standard meal 30 minutes prior to the 
evening dose. 
Single-dose Period: PSL 200mg SD in the 
morning on Day 1. 
Multiple-dose Period: PSL 100mg BID on 
Day 6, 200mg BID from Day 7 to Day 9, 
200mg SD ante meridiem on Day 10, 
100mg SD post meridiem on Day 10, and 
100mg BID from Day 11 to Day 12. 
Treatments will be administered in an 
open-label fashion. Study participants will 
be dosed in an upright position and will 
remain semi-recumbent until 4 hours 
afterwards. 
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Table 6-1: 
Summary of treatment administered 
Study Treatment Name: 
PSL 
Packaging and labeling: 
Padsevonil tablets are manufactured, 
packaged, and labeled according to Good 
Manufacturing Practice guidelines and 
applicable laws or regulations. 
Manufacturer: 
UCB 
BID=twice per day; min=minute; PSL=padsevonil; SD=single dose 
6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medication received and any discrepancies are reported 
and resolved before use of the study medication. 
Only study participants enrolled in the study may receive study medication and only authorized 
site staff may supply or administer study medication. All study medications 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. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication 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 study medication 
following the instructions on the label. 
Further guidance and information for the final disposition of unused study medication are 
provided in the ‘UP0083 IMP Handling Manual’ (IP Instruction for Handling). 
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record study medication dispensing and return 
information on a by-participant basis and will serve as source documentation during the course 
of the study. Details of any study medication 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 study medication until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
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The Investigator must ensure that the study medication is used only in accordance with the 
protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedure 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. 
6.3 
Measures to minimize bias 
This is an open-label study. 
At Screening, each study participant will be assigned a unique 5-digit study participant number 
from a range of numbers supplied by UCB Clinical Data Operations, Technology, and Standards. 
6.4 
Treatment compliance 
Study participant compliance will be ensured by the administration of study medication by 
designated site personnel. Drug accountability must be recorded on the Drug Accountability 
form. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medication is permitted during the study: 
 Paracetamol for the treatment of mild symptoms (eg, headache or other pain), given at most 
every 6 hours to 8 hours, not exceeding 2g/day, and with a total of no more than 5g over 
7 days. 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications are prohibited during the study: 
 With the exception of permitted concomitant treatments listed in Section 6.5.1, all 
prescription or nonprescription medicines are prohibited within 2 weeks or 5 half-lives 
whichever is longer of the respective drug prior to first administration of PSL and during the 
clinical part of the study unless required to treat an AE. This includes all over-the-counter 
remedies, vitamins and herbal, and dietary supplements (including St. John’s Wort). 
 Hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, isoniazid, phenytoin, 
rifampicin, etc.) should not be used within 2 months prior to dosing. In case of 
uncertainty, the Medical Monitor should be consulted. 
 Drugs of unknown half-lives are prohibited within 2 weeks before administration of PSL and 
during the clinical part of the study, unless required to treat an AE. 
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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6.5.3 
Rescue medication 
Not applicable. 
6.6 
Dose modification 
No PSL dose modifications are permitted during the study for an individual study participant 
unless necessary to protect study participant’s safety or well-being. 
6.7 
Treatment after the end of the study 
There are no plans for continued study participant care or treatment after the end of the study. 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Study medication will be stopped if the study participant develops a medical condition (or 
laboratory abnormality or ECG change) that, in the opinion of the Investigator, compromises the 
study participant’s ability to participate or compromises the study participant’s safety. 
In all cases the study participant should be followed until the condition has resolved as agreed by 
the Investigator and the UCB Study Physician. If a study participant discontinues study 
medication, no restart will be allowed. 
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study medication for abnormal liver function should be considered by the 
Investigator when a study participant meets 1 of the conditions outlined in Figure 7-1 or if the 
Investigator believes that it is in best interest of the study participant. 
Study medication will be discontinued immediately and permanently for a study participant if 
liver chemistry stopping criteria are met. 
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Figure 7-1: Liver chemistry stopping algorithm 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal 
Specific assessments and follow up actions for potential drug-induced liver injury (PDILI) are 
provided in Appendix 6 (Section 10.6). 
7.1.2 
Criteria for study hold/stopping due to adverse events 
In recognition of the advanced status of the development program for PSL, the following study 
hold/stopping rules will apply to this study. 
In the event that either or both of the following criteria are met, a safety review will be 
immediately initiated: 
 The occurrence of a serious adverse reaction (SAR) (ie, an SAE considered at least possibly 
related to the study medication) in 2 study participants, where those SARs occur in the same 
body system. 
 The occurrence of a severe nonserious adverse reaction (ie, severe nonserious AEs 
considered at least possibly related to the study medication) in 3 study participants, where 
those severe adverse reactions: 
 Occur in the same body system, and 
 Lead to withdrawal of the affected participant 
The safety review will be conducted by an internal, study-specific Safety Monitoring Committee 
comprised of the Investigator and appropriate members of the UCB Study Team (such as the 
Study Physician, Safety Physician, Clinical Project Manager, and Clinical Pharmacologist), as 
quickly as possible, to review the available data and determine whether it is appropriate to 
continue dosing at the next scheduled dosing point. This will take the form of a risk/benefit 
Refer to the Liver Safety Required Actions and Follow up Assessments section in 
Appendix 6. 
Report as an SAE if possible Hy’s Law case: AST/ALT ≥3xULN and Bilirubin ≥2xULN 
(>35% direct) or INR>1.5, if measured 
(Note: INR value not applicable to patients on anticoagulants) 
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evaluation from the perspective of the individual study participants. In making this evaluation, 
account will be taken of the potential risks of sudden discontinuation of study medication, 
particularly in participants who may be taking higher dose levels, and whether or not a tapering 
period, and its duration/speed, should be undertaken. 
The Safety Monitoring Committee will also decide whether it is appropriate to continue the study 
with or without dose adaptations, additional safety assessments, or other changes in design. If 
such changes are deemed necessary to protect the wellbeing of participants, further dosing in the 
study will be suspended while a substantial amendment is submitted to the Country(ies) Health 
Authority and Research Ethics Committee(s), and the study will not restart until that amendment 
has been approved. 
If the Safety Monitoring Committee cannot be convened before the next scheduled dosing point, 
the Investigator will make an independent evaluation as to whether it is appropriate to continue 
dosing pending the review. 
Detailed procedures for reporting SAEs and other safety events which may meet study 
hold/stopping criteria, are provided in Appendix 3 (Section 10.3). 
7.1.3 
Temporary discontinuation 
If a study participant discontinues study medication, no restart will be allowed. 
7.2 
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. The study participant develops a clinically relevant medical condition (physical or 
psychiatric) that, in the opinion of the Investigator, jeopardizes or compromises the study 
participant’s ability to participate in the study or made it unsafe to continue. 
2. The study participant is noncompliant with the study procedures or medications in the 
opinion of the Investigator. 
3. The study participant takes prohibited concomitant medications as defined in this protocol. 
4. The study participant withdraws his consent. 
5. The Sponsor or a regulatory agency requests withdrawal of the study participant. 
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6. The study participant has changes in the ECG that are regarded as clinically significant 
and/or that worsen over time. An ECG shows an absolute value for QTcB or QTcF ≥500ms 
or ≥60ms above Baseline. 
7. The study participant develops a second- or third-degree atrioventricular block or another 
clinically relevant change in ECG as determined by the Investigator. 
8. The study participant has active suicidal ideation without a specific plan as indicated by a 
positive response (“Yes”) to Question 4 of the “Since Last Visit” version of the C-SSRS. The 
study participant should be referred immediately to a mental healthcare professional and may 
be withdrawn from the study based upon the Investigator’s judgment of benefit/risk of 
continuing the study participant in the study on PSL. 
 The study participant has active suicidal ideation with a specific plan as indicated by a 
positive response (“Yes”) to Question 5 of the “Since Last Visit” version of the C-SSRS. 
The study participant should be referred immediately to a mental healthcare professional 
and must be withdrawn from the study. 
9. The study participant is suspected of having a serious multiorgan hypersensitivity reaction. 
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
Sponsor by the Investigator using the following algorithm: 
 An AE or laboratory value (as defined below) suggestive of internal organ involvement 
including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, 
pancreatitis, myositis, arthritis, or hematologic system involvement combined with at 
least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia. 
 Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
◦ 
Eosinophils percentage ≥10%. 
◦ 
Eosinophils absolute ≥5.0×102/μL. 
◦ 
Neutrophils absolute <15.0×102/μL. 
◦ 
Platelets absolute ≤10.0×104/μL. 
Withdrawn study participants should follow the taper schedule, if possible, unless faster 
discontinuation is considered necessary in the medical judgment of the Investigator. Investigators 
should attempt to obtain information on study participants in the case of withdrawal. 
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 repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a study participant fails to return to the clinic for a 
required study 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 
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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 (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the study participant should continue or discontinue study 
medication. 
Adherence to the study design requirements, including those specified in the Schedule of 
activities (Section 1.3), 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 (Section 1.3). 
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 500mL per study 
participant. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1 
Efficacy assessments 
Not applicable. 
8.2 
Pharmacokinetics 
Whole blood samples (conventional venous blood sampling) will be collected for measurement 
of plasma concentrations of PSL and its metabolites and urine samples will also be collected for 
measurement of urine concentrations of PSL and its metabolites as specified in the Schedule of 
activities (Section 1.3). The actual date and time (24-hour clock time) of each sample will be 
recorded. 
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Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files, but will not constitute a protocol amendment. 
Instructions and additional details regarding PK sampling are provided in the Laboratory 
Manual. 
8.3 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.4 
Safety assessments 
The safety and tolerability of single and multiple doses of PSL will be monitored by evaluation 
of AEs, clinical laboratory test results, vital signs (pulse rate, respiratory rate, SBP, DBP, and 
body temperature), 12-lead ECG parameters, psychiatric and mental status, physical examination 
findings, and suicidal risk monitoring. Planned time points for all safety assessments are 
provided in the Schedule of activities (Section 1.3). 
8.4.1 
Physical examination 
Physical examinations will be performed at Screening and at the time points specified in 
Section 1.3. 
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. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
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. 
8.4.2 
Vital signs 
Pulse rate, respiratory rate, BP, and body temperature will be assessed as outlined in the 
Schedule of activities (see Section 1.3). 
Body temperature may be measured by either oral or aural route at the discretion of the site, but 
must be performed using the same method in any individual study participant on all occasions. 
Blood pressure measurements will be performed in both supine and standing positions for 
orthostatic measurement at Screening (supine BP after the study participant has been lying down 
for 5 minutes and then standing BP after 1 minute and 3 minutes) and in a supine position for 
routine BP measurements at all assessments. Blood pressure and pulse measurements will be 
assessed with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
Blood pressure and pulse measurements should be preceded by ≥5 minutes of rest for the study 
participant in a quiet setting without distractions (eg, television, cell phones). 
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Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
1 BP measurement. 
8.4.3 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the Schedule of activities (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 7 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary. 
All ECG recordings should be taken with the study participant resting in the supine position for 
≥5 minutes before the recording. 
At each time point at which Triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 to 3 minutes apart. The full set 
of triplicates should be completed in less than 9 minutes. 
8.4.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of activities (Section 1.3) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those, which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the study participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study medication should be repeated until the 
values return to normal or Baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
If such values do not return to normal/Baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the Schedule of activities (Section 1.3). 
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
8.4.5 
Suicidal risk monitoring 
All study participants will undergo suicidal risk evaluation at Screening and at the time points 
indicated on the Schedule of activities (Section 1.3). 
Padsevonil is considered to be an AED. Suicidal ideation and behavior have been reported in 
patients treated with antiepileptic agents in several indications. A meta-analysis of randomized 
placebo-controlled studies of AEDs has also shown a small increased risk of suicidal ideation 
and behavior. The mechanism of this risk is not known and the available data do not exclude the 
possibility of an increased risk for PSL. 
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Suicidality will be assessed by trained study personnel using the C-SSRS. This scale will be used 
for Screening as well as to assess suicidal ideation and behavior that may occur during the study. 
All study participants will complete the “Screening” version of the C-SSRS at Screening 
(assessing the past 6 months) and the “Baseline” Version of the C-SSRS at Day -1, followed by 
Day 8, Day 13, and at SFU, as indicated on the Schedule of activities (Section 1.3). 
Study participants being treated with PSL should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior. Families and 
caregivers of study participants being treated with PSL should be instructed to monitor study 
participants for the emergence of unusual changes in behavior, as well as the emergence of 
suicidal ideation and behavior, and to report such symptoms immediately to the study 
Investigator. Consideration should be given to discontinuing PSL in study participants who 
experience signs of suicidal ideation or behavior. 
8.4.6 
Psychiatric and mental status 
All study participants will undergo psychiatric/mental status evaluation at Screening and at the 
time points indicated on the Schedule of activities (Section 1.3). 
The psychiatric and mental status of participating study participants will be closely monitored. 
Assessment of specific domains of psychiatric and cognitive symptoms will be performed by a 
staff member trained in the identification of psychiatric symptoms. 
The parameters that will be evaluated are orientation, attention, memory, mood, calculus, 
behavior, and thinking or feeling. These parameters will be assessed as normal or abnormal and 
then determined whether clinically significant. If present and abnormal, psychiatric symptoms, 
mental impairment, and behavioral problems will be assessed as to whether they are clinically 
significant. 
8.5 
Adverse events 
The definitions of an AE or 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 study medication or study procedures, or that caused 
the study participant to discontinue PSL or UP0083 (see Section 7). 
8.5.1 
Time period and frequency for collecting adverse events and serious 
adverse events information 
All AEs and SAEs will be collected from the signing of the ICF and at the time points specified 
in the Schedule of activities (Section 1.3). 
Medical occurrences that begin before the start of study medication but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF and not the AE section. 
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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 study 
medication), 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 study medication 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 AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.5.2 
Method of detecting adverse events and serious adverse events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the study participant is the preferred method to inquire about 
AE occurrences. 
8.5.3 
Follow up of adverse events and serious adverse events 
After the initial AE/SAE report, the Investigator is required to proactively follow each study 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as 
defined in Section 8.5.6), 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). 
8.5.4 
Regulatory reporting requirements for serious adverse events 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of study participants and the safety of a 
study medication 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 a study medication under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected SARs according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary. 
An Investigator who receives an Investigator safety report describing a 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/IEC, if appropriate according to local requirements. 
8.5.5 
Pregnancy 
Details of all pregnancies in female partners of male study participants will be collected after the 
start of study medication and until 30 days after the birth for any significant medical issues. In 
certain circumstances, the Sponsor may request that follow up is continued for a period longer 
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than 30 days. If the study participant is lost to follow up and/or refuses to give information, 
written documentation of attempts to contact the study participant needs to be provided by the 
Investigator and filed at the site. The Sponsor’s Patient Safety (PS) department is the primary 
contact for any questions related to the data collection for the pregnancy, eventual birth, and 
follow up. 
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). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
8.5.6 
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 a UCB product/compound. No AEs of special interest have been identified for 
PSL to date, with the exception of potential Hy’s Law as described below. 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
study participant. 
8.6 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that investigators, clinical study participants, 
regulatory authorities, and IRB/IECs will be informed appropriately and as early as possible. 
The UCB Study Physician or medically qualified designee/equivalent will conduct an ongoing 
review of SAEs and perform ongoing SAE reconciliations in collaboration with the PS 
representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory, or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.7 
Treatment of overdose 
For this study, any dose of PSL greater than that prescribed in the protocol will be considered an 
overdose. Overdose events are only considered AEs or SAEs if there are associated clinical signs 
and symptoms or if the act of taking the excess study medication itself is an AE or SAE (eg, 
suicide attempt). 
UCB does not recommend specific treatment for an overdose. Padsevonil will not be 
self-administered by the study participant. 
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In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the study participant for any AE/SAE and laboratory abnormalities until 
study medication can no longer be detected systemically (≥3 days). 
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
medication if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the study participant. 
8.8 
Genetics 
Whole blood samples will be collected for CYP2C19 genotyping during the Screening Period, as 
specified in the Schedule of activities (Section 1.3). After CYP2C19 genotyping, the study 
participants will be grouped as described in Section 4.1. 
Archive blood samples for exploratory genotyping of drug metabolizing enzymes, drug 
transporters, and other biomarkers will be collected as specified in the Schedule of activities 
(Section 1.3). 
Instructions and additional details regarding CYP2C19 and exploratory genotyping sampling are 
provided in the Laboratory Manual. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). Deviations in analyses from the final SAP will be documented in the 
clinical study report. 
9.1 
Definition of analysis sets 
The following are the defined analysis sets: 
 Enrolled Set: All study participants who signed the informed consent. 
 Safety Set (SS): All enrolled study participants who received at least 1 dose of PSL. 
 Pharmacokinetic Per Protocol Set (PK-PPS): PK-PPS is a subset of the SS, consisting of 
those study participants who had no important protocol deviations affecting the PK 
parameters and for whom a sufficient number of samples are available to determine at least 
1 PK parameter. 
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9.2 
General statistical considerations 
Statistical evaluation will be performed by the Sponsor or designee and supervised by the Early 
Development Statistics Department of UCB. All statistical analyses will be performed using 
SAS® Version 9.4 or later (SAS Institute, Cary, NC, USA). 
For continuous variables, summary statistics will include number of study participants, mean, 
median, standard deviation, minimum, and maximum (geometric mean and geometric coefficient 
of variation [CV] for plasma concentrations and PK parameters). Categorical endpoints will be 
summarized using number of study participants, frequency, and percentages. Missing data will 
not be imputed. Individual plasma concentration and PK parameters will be presented using 
3 significant digits. 
If not otherwise stated, Baseline will be the last assessment prior to dosing. Measurement of 
specific Baseline values will be described in the SAP. 
9.3 
Planned efficacy/outcome analyses 
9.3.1 
Analysis of the primary efficacy/primary endpoint 
As efficacy was not evaluated in this study, there will be no primary efficacy endpoint. 
9.4 
Planned pharmacokinetic analysis 
Pharmacokinetic parameters of PSL and its metabolites (
 and 
 in plasma (Cmax, tmax, AUC(0-t), AUC, t1/2, CL/F, Cmax,ss, tmax,ss, 
AUCτ, and CLss/F) will be estimated using noncompartmental analysis with Pharsight Phoenix® 
WinNonlin® v6.3 (or higher) software. Other PK parameters of PSL and its metabolites in 
plasma or urine will be derived with SAS v9.4 (or higher). For calculation of the plasma PK 
parameters, the actual blood sampling time points will be used in order to determine the PK 
parameters. The calculation of metabolite to parent ratio (m/p), based on Cmax and AUC will be 
described in the SAP. 
All PK analyses will be performed using the PK-PPS. Distribution of the CYP2C19 genotypes 
will be presented. The individual plasma concentration of PSL and its metabolites will be 
summarized by genotype group and nominal sampling time, and PK parameters of PSL and its 
metabolites will be summarized by genotype group using descriptive statistics (number of 
observations (n), geometric mean, lower and upper 95% confidence interval (CI), geometric CV, 
arithmetic mean, standard deviation, CV, median, minimum, and maximum) and graphical 
displays. 
The following PK parameters of PSL and its metabolites between genotype groups will be 
graphically displayed (scatter plot, box plot) and compared using analysis of variance on the 
log-transformed parameters and estimation of the geometric ratio of PK parameters between 
genotype groups with their 90% CI will be provided for: 
 Single-dose: PSL and metabolites: Cmax, AUC(0-t), AUC, Cmax,bw, AUC(0-t),bw, AUC,bw, Ae, fe 
and CLr; PSL metabolites: CLform. 
 Multiple-dose: PSL and metabolites: Cmax,ss, AUCτ, Cmax,ss,bw, AUCτ,bw, CLss/F, Ae, fe, CLr; 
PSL metabolites: CLform. 
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The 3 comparisons of interest are the following (in sequential ordering): 
 EM versus PM. 
 Intermediate metabolizer (IM) versus PM. 
 EM versus IM. 
The comparison “EM versus PM” will be firstly evaluated and then the 2 other comparisons 
against IMs only if the comparison EM versus PM is nonequivalent. 
Interpretation of results will be performed by comparing the 90% CI interval of geometric mean 
ratio with the acceptance range of 50% to 200%. 
9.5 
Planned safety analyses 
All safety analyses will be performed using the SS. All safety variables will be listed and 
summarized by genotype group and time point. 
Individual listings of AEs will be provided. These listings will include the following information: 
gender, age, body height, body weight, race, genotype group, system organ class (SOC), and 
preferred term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA®), 
AEs as reported, start and end with relative days to study medication administration, duration, 
intensity, seriousness and relationship to study medication, action taken, and final outcome. The 
start and stop of each AE will be given as absolute and relative to the time of study medication 
administration. 
A treatment-emergent adverse event (TEAE) is defined as any event that emerges during 
treatment having been absent pretreatment, or worsens relative to the pretreatment state. 
Treatment-emergent AEs will be summarized in frequency tables displayed by SOC and PT 
according to MedDRA. The incidence of TEAEs and drug-related TEAEs will be summarized, 
ordered by primary SOC and PT. 
The incidence of TEAEs will also be summarized in frequency tables by intensity. 
Safety laboratory measurements, vital signs, and 12-lead ECGs parameters will be tabulated by 
group and period using descriptive statistics. 
Data of assessment of suicidality (C-SSRS) will be listed. 
Physical examinations abnormalities will be listed. 
9.6 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol, which potentially could have a 
meaningful impact on study conduct or on the primary PK outcome for an individual study 
participant. Furthermore, study participants will be excluded from PK-PPS only when there is 
documented evidence that they received no treatment. The criteria for identifying important 
protocol deviations and the classification of important protocol deviations will be defined within 
the relevant protocol deviation specification document, which is part of the study Data Cleaning 
Plan. To the extent feasible, rules for identifying protocol deviations will be defined without 
review of the data and without consideration of the frequency of occurrence of such deviations. 
Whenever possible, criteria for identifying important protocol deviations will be implemented 
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algorithmically to ensure consistency in the classification of important protocol deviations across 
all study participants. 
9.7 
Handling of dropouts or missing data 
The methods for handling dropouts will be described in the SAP. Data of study participants 
prematurely terminating the study will be used to the maximum possible extent. No procedures 
for replacing missing data are intended. If a Baseline value is missing or not reliable, the last 
value before administration of study medication will serve as Baseline. 
9.8 
Planned interim analysis and data monitoring 
No formal interim analyses are planned. Details about the safety analyses will be provided in the 
SMC Charter. 
9.9 
Determination of sample size 
Considering the primary objective, and based on UP0057 (with PSL 100mg BID), the 
inter-participant CV of AUCτ was estimated to be 39% (PSL). Using an inter-participant CV of 
39%, a total sample size of 33 study participants (11 study participants per CYP2C19 genotype 
group) provides approximately 80% power for concluding that CYP2C19 genotype has no 
impact on the PK (using acceptance range of 0.5 to 2.0) based on expected ratio of 1.3 in PSL 
AUCτ between CYP2C19 groups at a significance level of α=0.05. 
In order to account for dropouts, the sample size will be increased by 20% (in total 39 study 
participants). 
If more than 2 study participants dropout in each group, additional study participants will be 
recruited at the discretion of the Investigator and Sponsor. 
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/IEC, as defined in local regulations, 
International Council for Harmonisation (ICH)-Good Clinical Practice (GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, 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/IEC for its review and 
approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to study participants or others, and any protocol 
deviations, to eliminate immediate hazards to study participants. 
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The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the 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/IEC as allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of study participant risk involved, but no less 
than once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the Investigator and/or contract research organization 
agreements, as applicable. 
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/IEC 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/IEC and use of the amended form. 
The study participant may withdraw his consent to participate in the study at any time. A study 
participant is considered as enrolled in the study when he has signed the ICF. An eCRF must not 
be started, nor may any study specific procedure be performed for a given study participant, 
without having obtained his written consent to participate in the study. 
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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/IEC, 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/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
The SMC will always be comprised of the Investigator, the Sponsor’s medical representative, the 
scientific lead, and a PK expert where appropriate. Other experts may be included in this group 
or consulted at the discretion of the Sponsor. 
10.1.6 
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 eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC 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, complete, and verifiable 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 are to be retained by the Investigator until ≥2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or ≥2 years have elapsed since the formal 
discontinuation of clinical development of the study medication/investigational device. These 
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documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or by an agreement with UCB (Committee for Proprietary Medicinal 
Products [CPMP]/ICH/135/95, 2002 [Section 4.9.5]). The Investigator will contact UCB for 
authorization prior to the destruction of any study records or in the event of accidental loss or 
destruction of any study records. The Investigator will also notify UCB should he relocate or 
move the study-related files to a location other than that specified in the Sponsor’s trial master 
file. 
10.1.6.1 
Case Report Form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports.’ 
Any change or correction to the eCRF should be dated, initialed, and explained (if necessary) 
and should not obscure the original entry. Use of correction fluid is not permitted. 
Corrections made after the Investigator’s review and signature of the completed eCRF will be 
resigned and dated by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
electronic eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the electronic 
eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.1.6.2 
Apps 
Not applicable. 
10.1.7 
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 
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by the Investigator and become a permanent part of the study participant’s source documents. 
The Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.8 
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. The study site 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/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of study participants by the Investigator 
 Discontinuation of further study medication development 
10.1.9 
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 a 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, respectively. 
 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 
Hematologya 
Platelet Count 
RBC Indices: 
MCV 
MCH 
% Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistrya,b 
BUN 
Potassium 
AST/SGOT 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Glucose 
(unfasted) 
Calcium 
ALP 
 
Routine 
Urinalysisa 
 
Specific gravity 
 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and 
leukocyte 
 
Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
 
Drug screen (to include at minimum: amphetamines, cocaine, opiates, 
cannabinoids, and benzodiazepines) 
 
Serology (HIV-1/2 Ab, HBsAg, HCV-Ab, syphilis) 
The results of each test must be entered into the eCRF. 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; eCRF=electronic Case Report Form; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C virus 
antibody; HIV-1/2=human immunodeficiency virus-1/2; MCV=mean corpuscular volume; MCH=mean 
corpuscular hemoglobin; RBC=red blood cells; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum 
glutamic-pyruvic transaminase; WBC=white blood cells 
a Hematology, clinical chemistry, and urinalysis asssessments will be performed under fasting conditions at 
Screening and  Day -1, and nonfasting conditions at all other assessments. 
b 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×upper limit of normal (ULN) 
and bilirubin 2×ULN (>35% direct bilirubin) or ALT 3×ULN and international normalized ratio (INR) >1.5, if 
INR 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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Investigators must document their review of each laboratory safety report. 
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10.3 
Appendix 3: Adverse events – definitions and procedures for 
recording, evaluating, follow up, and reporting 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study medication, whether or not considered related 
to the study medication. 
 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 study medication. 
 
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 study medication administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected DDI. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
medication 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). 
A 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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10.3.1 
Recording and follow up of adverse events and/or serious adverse 
events 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the eCRF. 
 It is not acceptable for the Investigator to send photocopies of the study participant’s 
medical records to UCB in lieu of completion of the UCB AE/SAE eCRF page. 
 There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all 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 a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
 An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE 
may be either serious or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events should be used 
as a supportive standardization instrument to evaluate AEs and SAEs but the final intensity 
grading by the Investigator must be mild, moderate, or severe. 
 
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Assessment of Causality 
 The Investigator is obligated to assess the relationship between study medication 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 study medication 
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 a 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. 
 If a study participant dies during participation in the study or during a recognized follow 
up period, the Investigator will provide UCB with a copy of any post-mortem findings 
including histopathology. 
 New or updated information will be recorded in the originally completed eCRF. 
 The Investigator will submit any updated SAE data to the UCB within 24 hours of receipt 
of the information. 
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Reporting of SAEs 
SAE Reporting to UCB via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE to UCB will be the electronic data 
collection tool. 
 If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section). 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) 
or to the UCB Study Physician by telephone. 
 Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT 
REPORTING. 
 
SAE Reporting to UCB via Paper eCRF 
 Facsimile transmission of the SAE paper eCRF is the preferred method to transmit this 
information to the UCB Study Physician. 
 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 eCRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT 
REPORTING. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy 
information 
10.4.1 
Contraception guidance 
10.4.1.1 
Male study participants 
Male study participants with female partners of childbearing potential are eligible to participate 
if they agree to 1 of the following during the Treatment Period and for ≥7 days after the last dose 
of study medication (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 ≥7 days after the final dose of study medication. 
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 Treatment Period and for ≥7 days after the last dose of study medication. 
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Table 10-1: Highly effective contraceptive methods 
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 b 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the woman of child bearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
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 study medication. 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. 
NOTES: 
a 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. 
b For females, hormonal contraception may be susceptible to interaction with the study medication, which may 
reduce the efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be 
utilized during the treatment period and for ≥90 days after the last dose of study medication. 
10.4.1.2 
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. This applies only to male study participants who receive study medication. 
 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 24 hours 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 the Sponsor. Generally, the follow up will 
be ≥12 months after the delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver safety – suggested actions and follow up 
assessments 
Study participants with PDILI must be assessed to determine if study medication 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 study 
medication discontinuation to complete the final evaluation. 
Study participants with PDILI should not be withdrawn from the study until investigation and 
monitoring are complete. All results of these evaluations and observations, as well as the 
reason(s) for study medication 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 study medication. 
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). 
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Table 10-2: Phase 1 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 SAEa,b 
See additional actions and follow up assessments below 
Required Actions and Follow up Assessments 
Actions 
Follow Up Assessments 
 
Immediately discontinue study intervention. 
 
Report the event to UCB within 24 hours. 
 
Complete the liver event eCRF, and complete an 
SAE data collection tool if the event also met 
the criteria for an SAEb. 
 
Perform liver function follow up assessments. 
 
Monitor the study participant until liver function 
test abnormalities resolve, stabilize, or return to 
Baseline (see MONITORING). 
 
Consider the need for a toxicology screening. 
MONITORING: 
If ALT ≥3xULN AND bilirubin 2xULN or INR 
>1.5 
 
Repeat liver function tests (include ALT, AST, 
ALP, bilirubin) and perform liver function 
follow up assessments within 24 hours. 
 
Monitor study participant twice weekly until 
liver function test abnormalities resolve, 
stabilize, or return to Baseline. 
 
A specialist or hepatology consultation is 
recommended. 
 
If ALT ≥3xULN AND bilirubin <2xULN and 
INR ≤1.5: 
 
Repeat liver function tests (include ALT, AST, 
ALP, bilirubin) and perform liver function 
follow up assessments within 24 to 72 hours. 
 
Monitor study participants weekly until liver 
function abnormalities resolve, stabilize, or 
return to Baseline. 
 
Viral hepatitis serologyc. 
 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend. 
 
Serum CPK and LDH. 
 
Fractionate bilirubin, if total bilirubin 
 2xULN. 
 
Complete blood count with differential to 
assess eosinophilia. 
 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE eCRF. 
 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications eCRF. 
 
Record alcohol use on the liver event alcohol 
intake eCRF. 
If ALT ≥3xULN AND bilirubin 2xULN or 
INR >1.5: 
 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total IgG or 
gamma globulins. 
 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in study 
participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). 
 
Liver imaging (ultrasound, magnetic 
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resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver imaging and/or liver biopsy 
eCRFs. 
Ab=antibody; AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransaminase; CPK=creatine phosphokinase; eCRF=electronic Case Report Form; HBcAb=hepatitis B core 
antibody; HBsAg=hepatitis B surface antigen; HPLC=high performance liquid chromatography; 
IgG=immunoglobulin G; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PK=pharmacokinetic; SAE=serious adverse event; ULN=upper limit of normal 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention if ALT 3xULN and bilirubin 2xULN. 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. 
 
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10.7 
Appendix 7: Medical device incidents – 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 
Not applicable. 
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10.10 
Appendix 10: Abbreviations and trademarks 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice a day 
BP 
blood pressure 
cBZR 
central benzodiazepine receptor 
CI 
confidence interval 
CV 
coefficient of variation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CPMP 
Committee for Proprietary Medicinal Products 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EM 
extensive metabolizer 
FDA 
Food and Drug Administration 
GABAA 
gamma-aminobutyric acid type a receptor alpha1 subunit 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
intermediate metabolizer 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
LEV 
levetiracetam 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
PDILI 
potential drug-induced liver injury 
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PK 
pharmacokinetics 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PM 
poor metabolizer 
PS 
Patient Safety 
PSL 
padsevonil 
PT 
preferred term 
QTc 
QT interval corrected 
QTcB 
QT interval corrected for Bazett’s formula 
QTcF 
QT interval corrected for Fridericia’s formula 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
single dose 
SFU 
Safety Follow-up 
SOC 
system organ class 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
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10.11 
Appendix 11: Protocol amendment history 
Not applicable. 
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11 
REFERENCES 
Clemens B. Forced normalization precipitated by lamotrigine. Seizure. 2005;14(7):485-9. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Food and Drug Administration. DRAFT GUIDANCE. Guidance for Industry. Clinical Drug 
Interaction Studies - Study Design, Data Analysis and Clinical Implications. US Dept of Health 
and Human Services, Center for Drug Evaluation Research, Oct 2017. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of acetaminophen-Protein adducts in adults with acetaminophen overdose and 
acute liver failure. Drug Metab Dispos. 2009; 37(8):1779-84. 
Janz R, Südhof TC. SV2C is a synaptic vesicle protein with an unusually restricted localization: 
anatomy of a synaptic vesicle protein family. Neuroscience. 1999;94(4):1279-90. 
Kaminski RM, Matagne A, Leclercq K, Gillard M, Michel P, Kenda B, et al. SV2A protein is a 
broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure 
protection in models of both partial and generalized epilepsy. Neuropharmacology. 
2008;54(4):715-20. 
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in 
epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia. 2009;50(3):387-97. 
Klitgaard H, Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert 
Opin Drug Discov. 2007;2(11):1537-45. 
Loganathan MA, Enja M, Lippmann S. Forced normalization: epilepsy and psychosis 
interaction. Innov Clin Neurosci. 2015;12(5-6):38-41. 
Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and 
pharmacokinetics. Acta Neurol Scand. 2008;118(2):69-86. 
Wan QF, Zhou ZY, Thakur P, Vila A, Sherry DM, Janz R, Heidelberger R. SV2 acts via 
presynaptic calcium to regulate neurotransmitter release. Neuron. 2010;66(6):884-95. 
World Health Organization. Epilepsy. Available from: 
http://www.who.int/mediacentre/factsheets/fs999/en/ [Accessed 23 May 2018]. 
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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:
up0083-protocol -amend-1
Version:
1. 0
Document Number:
CLIN-000138957
Title:
UP0083 Protocol Amendment 1
Approved Date:
27 Aug 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 23-Aug-2019 14:13:26 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 26-Aug-2019 16:02:19 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Aug-2019 12:18:26 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
Padsevonil (UCB0942) 
UP0083 
 
 
 
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Page 1 of 37 
 
STATISTICAL ANALYSIS PLAN 
Study: UP0083 
Product: Padsevonil (UCB0942)  
 
 
AN OPEN-LABEL, PARALLEL GROUP, SINGLE-CENTER 
STUDY TO INVESTIGATE THE PHARMACOKINETIC, SAFETY, 
AND TOLERABILITY PROFILES OF PADSEVONIL IN 
CYP2C19 GENOTYPED HEALTHY MALE JAPANESE STUDY 
PARTICIPANTS 
 
PHASE 1 
SAP/Amendment Number Date 
Final SAP 
16 Dec 2019 
Amendment 1 
10 Feb 2020 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1 
INTRODUCTION ............................................................................................................. 6 
2 
PROTOCOL SUMMARY ................................................................................................. 6 
2.1 
Objectives and endpoints ............................................................................................... 6 
2.2 
Study design and conduct .............................................................................................. 7 
2.3 
Determination of sample size ....................................................................................... 11 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 11 
3.1 
General presentation of summaries and analyses ........................................................ 11 
3.2 
General study level definitions .................................................................................... 12 
3.2.1 
Relative day ......................................................................................................... 12 
3.2.2 
Study periods ....................................................................................................... 13 
3.3 
Definition of Baseline values ....................................................................................... 13 
3.4 
Protocol deviations....................................................................................................... 13 
3.5 
Analysis sets................................................................................................................. 14 
3.5.1 
Enrolled Set ......................................................................................................... 14 
3.5.2 
Safety Set ............................................................................................................. 14 
3.5.3 
Pharmacokinetic Per-Protocol Set ....................................................................... 14 
3.6 
Treatment assignment and treatment groups ............................................................... 14 
3.7 
Center pooling strategy ................................................................................................ 15 
3.8 
Coding dictionaries ...................................................................................................... 15 
3.9 
Changes to protocol-defined analyses ......................................................................... 15 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 15 
4.1 
Adjustments for covariates .......................................................................................... 15 
4.2 
Handling of dropouts or missing data .......................................................................... 15 
4.2.1 
PK results ............................................................................................................. 15 
4.2.2 
Safety laboratory data .......................................................................................... 16 
4.2.3 
Electrocardiogram data ........................................................................................ 16 
4.2.4 
Incomplete dates and times .................................................................................. 16 
4.3 
Handling of repeated and unscheduled measurements ................................................ 18 
4.4 
Handling of measurements obtained at the early withdrawal visit .............................. 19 
4.5 
Interim analyses and data monitoring .......................................................................... 19 
4.6 
Multicenter studies ....................................................................................................... 19 
4.7 
Multiple comparisons/multiplicity ............................................................................... 19 
4.8 
Use of an efficacy subset of participants ..................................................................... 19 
4.9 
Active-control studies intended to show equivalence .................................................. 19 
4.10 
Examination of subgroups ........................................................................................... 19 
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5 
STUDY POPULATION CHARACTERISTICS ............................................................. 19 
5.1 
Participant disposition .................................................................................................. 19 
5.2 
Protocol deviations....................................................................................................... 20 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 20 
6.1 
Demographics .............................................................................................................. 20 
6.2 
Other Baseline characteristics ...................................................................................... 21 
6.3 
Medical history and concomitant diseases ................................................................... 21 
6.4 
Prior and concomitant medications .............................................................................. 21 
6.4.1 
Prior medication definition .................................................................................. 21 
6.4.2 
Concomitant medication definition ..................................................................... 21 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 22 
8 
EFFICACY ANALYSES ................................................................................................ 22 
9 
PHARMACOKINETICS ................................................................................................. 22 
9.1 
Descriptive figures, Summaries and Listings .............................................................. 23 
9.2 
Statistical analysis of pharmacokinetics variables ....................................................... 24 
9.3 
Derivations of pharmacokinetic parameters ................................................................ 24 
10 SAFETY ANALYSES ..................................................................................................... 25 
10.1 
Extent of exposure ....................................................................................................... 25 
10.2 
Adverse events ............................................................................................................. 25 
10.3 
Clinical laboratory evaluations .................................................................................... 27 
10.4 
Vital signs, Electrocardiograms, and other observations related to safety .................. 28 
10.4.1 
Vital signs ............................................................................................................ 28 
10.4.2 
Electrocardiograms .............................................................................................. 29 
10.4.3 
Other safety variables .......................................................................................... 30 
10.4.3.1 
Physical examination ................................................................................. 30 
10.4.3.2 
Suicidal risk monitoring ............................................................................ 30 
11 OTHER ANALYSES ...................................................................................................... 30 
12 REFERENCES ................................................................................................................ 31 
13 APPENDICES ................................................................................................................. 32 
14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 33 
14.1 
AMENDMENT 1......................................................................................................... 33 
15 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN ................................. 36 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 37 
 
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UP0083 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice a day 
BP 
blood pressure 
cBZR 
central benzodiazepine receptor 
CI 
confidence interval 
CV 
coefficient of variation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CPMP 
Committee for Proprietary Medicinal Products 
DBP 
diastolic blood pressure 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EM 
extensive metabolizer 
ES 
Enrolled Set  
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GABAA 
gamma-aminobutyric acid type a receptor alpha1 subunit 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
intermediate metabolizer 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
LF 
linearity factor 
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Statistical Analysis Plan 
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UP0083 
 
 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
m/p 
Metabolite/parent 
MTD 
maximum tolerated dose 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetics 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PM 
poor metabolizer 
PS 
Patient Safety 
PSL 
Padsevonil 
PT 
preferred term 
QTc 
QT interval corrected 
QTcB 
QT interval corrected for Bazett’s formula 
QTcF 
QT interval corrected for Fridericia’s formula 
RAUC 
accumulation ratio based on AUC 
RCmax 
accumulation ratio based on Cmax 
Rm/p 
accumulation ratio of m/p 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
single dose 
SFU 
Safety Follow-up 
SOC 
system organ class 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
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Statistical Analysis Plan 
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UP0083 
 
 
 
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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 UP0083 study. It also defines the summary tables, 
listings, and figures to be included in the final clinical study report (CSR) according to the 
protocol. 
This SAP is based on, and assumes familiarity with, the following documents: 
 Original Protocol (08 May 2019), Amendment 1 (22 Aug 2019) 
Unless specified below, the study will be analyzed as described in the most recent version of 
protocol. If any protocol amendment necessitates a substantial change to the statistical analysis 
of the study data, this SAP will be amended accordingly. If, after database lock, additional 
analyses are required to supplement the planned analyses described in this SAP, these changes 
will be described in the clinical study report, together with the rationale. However, if analysis 
definitions have to be modified or updated prior to database lock, an SAP amendment will be 
required.  
The content of this SAP is compatible with the International Council for Harmonisation 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips, A. et al. 2003). 
UCB is the Sponsor and PAREXEL is the Contract Research Organization (CRO) for this study. 
2 
PROTOCOL SUMMARY 
2.1 
Objectives and endpoints 
Objectives 
Endpoints 
Primary  
To evaluate the plasma PK of PSL in 
CYP2C19 genotyped healthy male Japanese 
study participants (extensive, intermediate, 
and poor metabolizers) 
 
Single dose: Cmax, AUC(0-t), AUC, t1/2 and tmax 
 
Multiple-dose: Cmax,ss, AUCτ, t1/2 and tmax,ss 
Secondary  
To evaluate the safety and tolerability of PSL 
in healthy male Japanese study participants 
Incidence of TEAEs  
Other 
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Statistical Analysis Plan 
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UP0083 
 
 
 
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Objectives 
Endpoints 
To evaluate the plasma PK of PSL and its 
major metabolites 
 
) in CYP2C19 genotyped 
healthy male Japanese study participants 
(extensive, intermediate, and poor 
metabolizers) 
For PSL: 
 
Single-dose: Cmax,bw, AUC(0-t),bw, AUC,bw AUC(0-12) 
and CL/F 
 
Multiple-dose: CLss/F, Cmax,ss,bw, AUCτ,bw, 
accumulation ratios based on AUC and Cmax (RAUC 
and RCmax) and linearity factor (LF) 
For PSL metabolites:  
 
Single-dose: Cmax, AUC(0-t), AUC, t1/2, tmax, Cmax,bw, 
AUC(0-t),bw, AUC,bw, AUC(0-12) and metabolite to 
parent ratios (m/p) based on Cmax and AUC 
 
Multiple-dose: Cmax,ss, AUCτ, t1/2, tmax,ss, 
Cmax,ss,bw, AUCτ,bw, m/p based on Cmax,ss and 
AUCτ, RCmax, RAUC and accumulation ratio of m/p 
based on AUC (Rm/p) 
To evaluate the urine PK of PSL and its 
major metabolites in CYP2C19 genotyped 
healthy male Japanese study participants 
(extensive, intermediate, and poor 
metabolizers) 
For PSL and its metabolites: Single and Multiple-dose: 
Ae, fe, CLr 
Additional PK parameters of PSL metabolites 
(desmethyl and carboxy acid) in urine (CLform) 
To evaluate the safety and tolerability of PSL 
in healthy male Japanese study participants 
 
Vital signs (PR, RR, SBP, DBP, and body 
temperature) 
 
12-lead ECG parameters 
 
Physical examination findings 
 
Clinical laboratory test results (hematology, 
clinical chemistry, and urinalysis) 
DBP=diastolic blood pressure; ECG=electrocardiogram; m/p=metabolite to parent ratio; PK=pharmacokinetics; 
PR=pulse rate; PSL=padsevonil; RR=respiratory rate; SBP=systolic blood pressure, TEAE=treatment-emergent 
adverse event.  
2.2 
Study design and conduct 
This is a Phase 1, open-label, parallel group, single-center study to investigate the PK, safety, 
and tolerability profiles of PSL in CYP2C19 genotyped healthy male Japanese study 
participants. 
The study consists of a Screening Period, a Single-dose Period, a Multiple-dose Period, and a 
Safety Follow up (SFU) Visit. The maximum total duration of the study is 49 days for each study 
participant, including the Screening Period (up to 28 days), the Single-dose Period (6 days, 
including Day -1 and PSL single-dose on Day 1 followed by a 4 day washout), the Multiple-dose 
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Statistical Analysis Plan 
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UP0083 
 
 
 
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Period (9 days, including PSL dosing on Day 6 to 12 and study participants checkout of the 
center on Day 14), and the SFU Visit (maximum of 8 days after the last dose of PSL on Day 12). 
The study participants will be examined for CYP2C19 genotyping (variant alleles: *2, *3, and 
*17) during the Screening Period and grouped as follows: 
 Extensive metabolizers (*1/*1), 
 Intermediate metabolizers (*1/*2, *1/*3), 
 Poor metabolizers (*2/*2, *2/*3, *3/*3). 
Other metabolizers who have the variant allele of *17 will be excluded from the study. Study 
participants will not be genotyped, if rescreened. 
A total of 39 study participants (13 study participants per CYP2C19 genotype group) will be 
enrolled. If more than 2 study participants dropout in each group, additional study participants 
will be recruited at the discretion of the Investigator and Sponsor. 
The schedule of activities is provided in Table 2-1. 
 
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Statistical Analysis Plan                                                                       Padsevonil (UCB0942) 
 
 
 
 
 
 
 
UP0083 
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                                                                    Page 9 of 37 
 
Table 2-1: 
Schedule of activities 
Study Period 
Screening 
Period 
(28 days) 
Single-dose Period 
Multiple-dose Period 
SFU 
Or Withdrawal 
Visit 
(maximum of 8 
days after the 
last dose) a 
Study Day 
-29 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP2C19 genotyping  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory genotyping 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, habits, 
lifestyle 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication/medical 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Psychiatric and mental status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Drug screen, ethanol breath 
test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (HBV, HCV, HIV, 
syphilis) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Statistical Analysis Plan                                                                       Padsevonil (UCB0942) 
 
 
 
 
 
 
 
UP0083 
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Study Period 
Screening 
Period 
(28 days) 
Single-dose Period 
Multiple-dose Period 
SFU 
Or Withdrawal 
Visit 
(maximum of 8 
days after the 
last dose) a 
12-lead ECGd 
X 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
PSL administration 
 
 
Xe 
 
 
 
 
Xf 
Xg 
Xg 
Xg 
Xh 
Xi 
Xi 
 
 
 
PK blood sampling 
 
 
Xj 
Xj 
Xj 
 
 
 
 
 
 
Xk 
 
 
 
 
 
PK urine sampling 
 
 
Xl 
Xl 
Xl 
Xl 
Xl 
 
 
 
 
Xm 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stay in study center 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; CYP2C19=cytochrome P450 family 2 subfamily C; ECG=electrocardiogram; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-up Visit 
a The Safety Follow-up Visit will be performed 7 days (+1 day) after the last administration of PSL. Idem for the Withdrawal Visit, if applicable. 
b A complete physical examination will be conducted at Screening and SFU. A brief physical examination will be conducted at all other visits, including at 
discharge. 
c On dosing days, vital signs will be performed predose and 3 hours postdose. Blood pressure measurements will be performed in both supine and standing 
positions for orthostatic measurement at Screening (supine BP after the study participant has been lying down for 5 minutes and then standing BP after 
1 minute and 3 minutes) and in a supine position for routine BP measurements at all assessments. 
d 12-lead ECG will be performed after a rest of ≥5 minutes at Screening and at predose, 24 hours postdose, and at the SFU Visit. All ECG recordings will be 
performed in triplicate but no more than 2 to 3 minutes apart. 
e PSL 200mg will be administered in the morning on Day 1 during the Single-dose Period. 
f PSL 100mg will be administered in the morning and evening on Day 6 during the Multiple-dose Period. 
g PSL 200mg will be administered in the morning and evening from Day 7 to Day 9 during the Multiple-dose Period. 
h PSL 200mg and 100mg will be administered in the morning and evening, respectively, on Day 10 during the Multiple-dose Period. 
i PSL 100mg will be administered in the morning and evening from Day 11 to Day 12 during the Multiple-dose Period. 
j Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours postdose. 
k Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the morning dose. 
l Predose and 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours postdose. 
m 0 to 12 hours after the morning dose. 
 
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Statistical Analysis Plan 
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UP0083 
 
 
 
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2.3 
Determination of sample size 
Considering the primary objective and based on UP0057 (with PSL 100mg BID), the inter 
participant CV of AUCτ was estimated to be 39% (PSL). Using an inter-participant CV of 39%, a 
total sample size of 33 study participants (11 study participants per CYP2C19 genotype group) 
provides approximately 80% power for concluding that CYP2C19 genotype has no impact on the 
PK (using acceptance range of 0.5 to 2.0) based on expected ratio of 1.3 in PSL AUCτ between 
CYP2C19 groups at a significance level of α=0.05. 
In order to account for dropouts, the sample size will be increased by 20% (in total 39 study 
participants). 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical evaluation will be performed by PAREXEL. The datasets will follow the UCB 
analysis data model (ADaM) data specifications. 
All statistical analysis and generation of tables, figures, participant data listings, and statistical 
output will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, NC, USA). The 
PK noncompartmental analysis (NCA) will be performed using Phoenix WinNonlin®v6.3 (or 
higher). 
Continuous variables will be summarized by treatment period, visit and timepoint (where 
applicable) including number of participants (n), mean, standard deviation (SD), median, 
minimum, maximum and confidence intervals (CI) for the mean where stated in the SAP. 
Geometric coefficient of variation (geoCV), geometric mean and 95% CI for the geometric mean 
will also be presented in the descriptive statistics for the PK concentration data for PSL and its 
metabolites. In all outputs the confidence limits will be restricted to the possible values that the 
variable can take. 
When reporting descriptive statistics, the following rules will apply in general (except for PK 
concentration data): 
 N will be an integer 
 Mean, SD, and median will use 1 additional decimal place – compared to the original data 
 Coefficient of variation (CV) (%) will be presented with one decimal place 
 Minimum and maximum will be reported using the same number of decimal places as the 
original value 
 If no participants have data at a given timepoint, then only n=0 will be presented. If n<3, then 
only the n, minimum and maximum will be presented. If n=3, then only n, minimum, median 
and maximum will be presented. The other descriptive statistics will be left blank. 
When reporting individual values and descriptive statistics for PK concentration data (plasma PK 
of PSL and PSL metabolites), the following rules will be applied: 
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Statistical Analysis Plan 
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 Individual values for PK concentration data will be reported to the same level of precision as 
the raw data received from the bioanalytical laboratory 
 Minimum and maximum of PK concentration data will be reported using the same level of 
precision as the raw data 
 Mean (arithmetic and geometric), median and SD will be reported using 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 
 95% CI for the geometric mean will use be reported using 1 additional decimal place 
compared to the value which the confidence interval is constructed 
 Geometric CV will be reported as a percentage to 1 decimal place 
When reporting individual values and descriptive statistics for PK parameters (plasma PK of 
PSL and PSL metabolites), the following rules will apply with regard to rounding and precision: 
 Individual values for PK parameters will be reported to 3 significant figures 
 Descriptive statistics for PK parameters should be rounded to 4 significant figures for the 
mean, median and SD and to 3 for the others 
Categorical variables will be summarized by treatment period, visit and timepoint (where 
applicable) with frequency counts and percentages. 
When reporting relative frequencies or other percentage values, the following rules apply: 
 For values where all participants fulfill certain criteria, the percentage value will be displayed 
as 100 
 For values where the absolute frequency is 0, there will be no percentage presented at all.  
 All other percentage displays will use one decimal place. 
Data listings containing all documented data and all derived data will be generated. 
3.2 
General study level definitions 
3.2.1 
Relative day 
The relative day of an event will be derived with the date of first dose of investigational 
medicinal product (IMP), here PSL as reference.  
Relative days for an event or measurement occurring before the date of first dose are calculated 
as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= 𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 
The relative day for an event or measurement occurring on the date of first dose is 1. The relative 
day for an event or measurement occurring after the reference date to the date of the last dose 
will be calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= (𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑜𝑠𝑖𝑛𝑔) + 1  
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Statistical Analysis Plan 
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For events or measurements occurring after the date of last dose, relative day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= + (𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒) 
There is no relative Day 0. Relative day will not be calculated for partial dates in cases where 
relative day is shown in a participant data listing. In such cases, relative day should be presented 
as ‘--‘ in the relevant participant data listing. 
3.2.2 
Study periods 
For each participant completing the study, the expected maximum duration of participation will 
be approximately 49 days with a maximum of 8 days exposure to PSL, and will consist of the 
following periods: 
 Screening Period: Day -29 to Day -2 
 Single-dose Period: Day -1 to Day 5 
 Multiple-dose Period: Day 6 to Day 14 
 SFU or Withdrawal Visit (maximum of 8 days after the last dose) 
3.3 
Definition of Baseline values 
In general, Baseline will be the last non-missing assessment prior to dosing. The definition for 
each measurement is described below: 
 
Hematology, serum chemistry, urinalysis: Baseline is defined as Day -1. If Day -1 value is 
missing the Screening value will be used. 
 
Vital Signs: Baseline is defined as predose on Day 1. If predose on Day 1 is missing or 
multiple assessments occur, the last measure prior to dosing will be used. 
 
ECG: The mean of the last three measurements predose on Day 1 will be taken as Baseline. 
If there are less than three replicates at Day 1 predose, the mean of the available replicates 
(predose) will be taken as baseline. 
3.4 
Protocol deviations 
Important protocol deviations (IPDs) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on the primary PK outcome for an individual 
participant. Furthermore, participants will be excluded from the safety analysis only when there 
is documented evidence that they received no treatment. The criteria for identifying IPDs and the 
classification of IPDs will be defined within the protocol deviation specification document.  
IPDs will include the following categories: 
 Inclusion/exclusion criteria deviations 
 Withdrawal criteria 
 Prohibited concomitant medication use 
 Incorrect treatment or dose 
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Statistical Analysis Plan 
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 Procedural non-compliance 
 Visit schedule deviations 
 Study drug administration deviations (including incorrect treatment received, handling and 
storage deviations and incorrect dosage received) 
 Any vomiting episode(s) (that could impact PK concentrations)  
 Missing data 
 Other 
All IPDs will be reviewed as part of the ongoing data cleaning process and data evaluation. After 
all data have been verified/coded/entered into a database, a data evaluation meeting (DEM) will 
be performed.  
At least one DEM will be performed at the following time: 
 Prior to the final analysis after all data have been verified/coded/entered into the database 
Additional DEMs may be conducted as deemed necessary. 
The purpose of these DEM reviews will be to review all protocol deviations, define the analysis 
sets, and check the quality of the data. The reviews will also help decide how to manage 
problems in the participants’ data (e.g. missing values, withdrawals and protocol deviations).  
Accepted deviations from scheduled time points will be described in the appropriate documents 
and included in the Study Master File. After the pre-analysis review, resolution of all issues, and 
documentation of all decisions (including inclusion into each of the analysis sets) at the final 
DEM, the database will be locked. 
3.5 
Analysis sets 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all participants who have signed an informed consent form 
for this study.  
3.5.2 
Safety Set 
The Safety Set (SS) will consist of all enrolled participants who receive at least 1 dose of PSL. 
3.5.3 
Pharmacokinetic Per-Protocol Set 
The Pharmacokinetic Per Protocol Set (PK-PPS) will be a subset of the SS, consisting of those 
study participants who had no important protocol deviations affecting the PK parameters and for 
whom a sufficient number of samples are available to determine at least 1 PK parameter. 
3.6 
Treatment assignment and treatment groups 
Unless stated otherwise, listings will be presented by study participant and genotype (Extensive, 
Intermediate and Poor Metabolizers), and summaries will be presented by treatment period 
(Single-dose Period and Multiple-dose Period) and genotype. 
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Study participants who meet all of the inclusion and none of the exclusion criteria will check into 
the study center on Day -1 (prior to the single dose [SD]). A SD of PSL 200mg will be 
administered in the morning on Day 1 of the Single-dose Period. During the Multiple-dose 
Period, PSL will be administered on the following dosage schedule: 
 PSL 100mg twice a day (BID) on Day 6 
 PSL 200mg BID from Day 7 to Day 9 
 PSL 200mg in the morning on Day 10; PSL 100mg in the evening on Day 10 
 PSL 100mg BID from Day 11 to Day 12 
3.7 
Center pooling strategy 
The study is planned to be performed at a single center. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using the latest available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®). Medications will be coded according 
to the World Health Organization Drug Dictionary (WHODD). Medical procedures will not be 
coded. 
3.9 
Changes to protocol-defined analyses 
 The endpoint to evaluate the safety and tolerability of PSL in healthy male Japanese study 
participants has been changed from AEs to incidence of TEAEs to align with the summaries 
of interest  
 The following PK parameters of PSL and its metabolites have been included for 
completeness: AUC(0-12), RAUC, RCmax, LF and Rm/p based on AUC (for metabolites only).  
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
In general, there will be no imputation of missing data unless otherwise stated below. If a 
Baseline value is missing or not medically implausible, the last value before administration of 
PSL will serve as Baseline. Missing data for PK results and safety laboratory data will be 
handled as described in the sections below. 
4.2.1 
PK results 
Measurements of plasma PK concentrations that are below the limit of quantification (BLQ) will 
be imputed with half of the lower limit of quantification (LLOQ) for the purpose of calculating 
the geometric mean and its 95% CI, the geometric CV, the arithmetic mean and SD for 
summaries and figures. Descriptive statistics of concentrations will be calculated if at least 2/3rd 
of the individual data points are quantifiable (≥LLOQ). 
The following rules will apply for the summaries, listings and figures: 
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 If no participants have data, only “n=0” will be presented. The other descriptive statistics will 
be left blank. 
 Descriptive statistics of plasma concentrations will be calculated if at most 1/3rd of the 
individual data points are missing or are not quantifiable (<LLOQ) at the given time-point. 
Values that are BLQ will be replaced by the numerical value of the LLOQ/2 in this instance. 
However, if n<3, then only n, minimum and maximum will be presented, and the median will 
also be presented if n=3. The other descriptive statistics will be left blank. 
 For the calculation of plasma PK parameters, all BLQ values occurring prior to Cmax will be 
replaced by “0”, except for embedded BLQ values (between two measurable data points) 
which will be treated as missing. Post-Cmax BLQ values will be treated as missing. The 
Pharmacokinetic analysis will be performed in accordance to the User guide for Clinical 
Pharmacokinetics Modeling and Simulation version8 issued by UCB. 
 The geometric CV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data: 
Geometric CV (%) = sqrt[(exp (SD^2) – 1)] x 100 
 The 95% CI for the geometric mean should be left blank if the SD is 0.  
 For the individual figures, any concentrations that are BLQ will be regarded as missing, with 
the exception of predose BLQ measurements on Day 1 and Day 10, which will be imputed 
with zero for linear scale plots. 
 Values below the LLOQ will be reported as BLQ in the listings. 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ in the safety laboratory data will be the same as those 
described for PK data in Section 4.2.1.  
4.2.3 
Electrocardiogram data 
For the 12-lead ECG data, all calculations of changes from Baseline and descriptive statistics 
will be based on the mean of the triplicate assessments at each timepoint. In the event that there 
are not 3 available measurements at a given timepoint, the mean will be calculated based on the 
number of measurements for which data are provided. 
4.2.4 
Incomplete dates and times 
Partial dates may be imputed for the following reasons: 
 Classification of AEs as treatment-emergent 
 Classification of medications as prior or concomitant 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
Partial start date  
The following rules will be applied for partial start dates: 
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 If only the month and year are specified and the month and year of the first dose of study 
medication 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 study 
medication is the same as the month and year of the start date, then use the date of the first 
dose of study medication. If this results in an imputed start date that is after the specified end 
date, then use the 1st of the month, or the date of Screening if this is later (if the latter 
imputation results in an end date that is earlier than the start date, then use the 1st of the 
month). If the imputed date is the date of dosing then time will be imputed as the start time of 
the dosing (ie, event will be regarded as treatment-emergent) 
 If only the year is specified, and the year of the first dose of study medication is not the same 
as the year of the start date then use 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 study medication is the same as 
the year of the start date, then the date of the first dose of study medication will be used. If 
this results in an imputed start date that is after the specified end date, then January 01, or the 
date of screening if this is later will be used (if the latter imputation results in an end date that 
is earlier than the start date, then January 01 will be used). If the imputed date is the date of 
first dose of study medication then time will be imputed as the start time of the study 
medication intake (ie, event will be regarded as treatment-emergent) 
 If the start date is completely unknown, then use the date of dosing. If this results in an 
imputed start date that is after the specified end date, then use January 01 of the year of the 
end date, or the date of Screening if this is later. 
Missing start time 
Missing start times will be imputed as 00:00h or with the time of dosing for events occurring on 
the date of administration of PSL. 
Partial stop date 
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 
Calculation of duration of each AE when there being missing or partially missing date and/or 
time 
Missing or partially missing dates and/or times will be imputed as described in Section 4.2.4. AE 
duration is computed and reported in day and time format: xx d hh:mm. Duration is not 
calculated when the outcome date is missing. 
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Table 4-1: 
Calculation rules for duration of adverse events 
Data availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Complete data 
D1/T1 
D2/T2 
Duration = [(D2 – D1)*24 + (T2 – T1)]/24 d 
End time missing 
D1/T1 
D2/-- 
End time is substituted by time 23:59h (=23.98 in 
decimal format) 
Duration = <[(D2 – D1)*24 + (23.98 – T1)]/24 d 
Start time missing 
D1/-- 
D2/T2 
Onset time is substituted by time 00:00h 
Duration = <[(D2 – D1)*24 + T2]/24 d 
Start and end time 
missing  
D1/-- 
D2/-- 
Duration = <D2 – D1 + 1 
Start day and time 
missing 
--/-- 
D2/T2 
Duration = [(D2 – D0)*24 + (T2 – T0)]/24 d 
For a participant in the FAS, D0 and T0 are the 
date and time of first administration of study 
medication and for screen failures, D0 is the date 
of the screening visit and T0 = 00:00h 
End day and time 
missing  
D1/T1 
--/-- 
If the stop date is missing, duration will not be 
calculated. 
Start and end date 
missing 
--/-- 
--/-- 
If the stop date is missing, duration will not be 
calculated. 
FAS=full analysis set. 
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. The following general rules will apply to all repeated and unscheduled 
measurements: 
 For repeated measurements obtained prior to the first dose of study medication the latest 
value (which may be scheduled or unscheduled) will be used in the calculation of the 
descriptive statistics 
 For repeated measurements obtained at the designated Baseline visit, the latest value (which 
may be scheduled or unscheduled) will be defined as the Baseline provided that this occurred 
prior to the first dose of study medication 
 Unscheduled and repeated measurements will not be used in the descriptive statistics at time 
points after first dose of study medication 
 Unscheduled measurements performed for the Early Withdrawal (EW) visit will be assigned 
to the EOS visit (Section 4.4) and analyzed accordingly as an EOS visit. 
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4.4 
Handling of measurements obtained at the early withdrawal 
visit 
Participants who withdraw early from the study for any reason, including those withdrawn from 
study medication, will be asked to return for the EOS Visit 7 to 7 days (+/- 1 day) after last 
intake of study medication and will then enter the SFU Period and will undergo the same 
assessments performed at the EOS Visit. 
4.5 
Interim analyses and data monitoring 
No formal interim analyses are planned. Details about the safety analyses will be provided in the 
SMC Charter. 
4.6 
Multicenter studies 
Not applicable. 
4.7 
Multiple comparisons/multiplicity 
Not applicable. 
4.8 
Use of an efficacy subset of participants 
Not applicable. 
4.9 
Active-control studies intended to show equivalence 
Not applicable. 
4.10 
Examination of subgroups 
Not applicable. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Participant disposition 
A study participant is considered to have completed the study if he has completed all periods of 
the study including the last scheduled procedure shown in the Schedule of activities in the 
protocol.  
The number and percentage of participants who were enrolled into the study, participants who 
completed or prematurely discontinued the study, as well as the reason for discontinuation will 
be summarized by genotype group and overall based on the SS.  
The number and percentage of participants who discontinued due to AEs will be separately 
summarized by genotype group and overall based on the SS. 
The number and percentage of participants included into each of the analysis sets will be 
summarized by genotype group and overall based on the ES. Percentages will be based on the ES 
for this summary. 
Finally, screen failure reasons will be summarized by overall, based on the ES. A listing of 
participants who did not meet study eligibility criteria will also be presented. 
In addition, the following listings will be presented: 
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 Participant disposition (ES) 
 Study discontinuation (SS) 
 Visit dates (SS) 
 Participant analysis sets (ES) 
The listing of participant disposition will include the date of informed consent, date and time of 
first and last dose of study medication, date of premature termination and primary reason (if 
applicable), and primary reason (if applicable) and date of final contact. 
The listing of study discontinuation will include the reason for discontinuation and the number of 
days on study medication. 
The number of days on study medication will be calculated as follows: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑜𝑛 𝑠𝑡𝑢𝑑𝑦 𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 
=  𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 – 𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 +  1 
5.2 
Protocol deviations 
Important protocol deviations (IPDs) will be identified and classified by the deviation types in 
the IPD document. 
Any samples that are obtained outside the tolerance window permitted at the specified timepoint 
will be discussed at the DEM and any possible exclusion from analysis will be documented 
accordingly. 
A listing of all IPDs identified at the DEM will be presented by genotype group based on the SS 
and will include the deviation type and description. The number and percentage of participants in 
the SS with IPDs will be summarized by genotype group. The denominator for the percentages 
will be the number of participants in the SS. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Description of the analysis of demographic and baseline characteristics of the participants is 
presented in this section. In listings, data will be presented typically sorted by participant number 
within each genotype group. 
6.1 
Demographics 
All demographic characteristics obtained during the Screening Period will be summarized by 
genotype group and overall for the SS. This summary will include age (in years), sex (male), 
weight (kg), height (cm), body mass index (BMI in kg/m2), race (Asian), ethnicity (Not Hispanic 
or Latino), ethnic subgroup (Japan) and CYP2C19 genotype. 
The summary of age will include descriptive statistics and categorical summaries, the latter 
based on requirements for clinicaltrials.gov reporting (≤18, 19 to <65, and ≥65 years) and the 
European Union Drug Regulating Authorities Clinical Trials (EudraCT) reporting (<18, 18 to 
<65, 65 to <85, and ≥85 years).  
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A by-participant listing of demographic characteristics as well as the date of birth will be 
presented for the ES. 
6.2 
Other Baseline characteristics 
Lifestyle information (alcohol use, tobacco use, caffeinated beverage uses and illicit drug use) 
will be summarized by genotype group and overall for the SS and will be listed for the ES. 
6.3 
Medical history and concomitant diseases 
Medical history will be listed and summarized (in an incidence table) for the SS for all 
participants, by MedDRA system organ class (SOC) and preferred term (PT). The reported term 
will be included in the listing. The summary will include the number and percentage of 
participants and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the ‘All Participants’ column. 
Procedure history will be listed separately by the procedure reported term based on the SS. 
Concomitant medical procedures will be provided as a by-participant listing based on the 
reported term for SS. 
6.4 
Prior and concomitant medications 
Prior and concomitant medications will be listed for SS, respectively, by WHODD Anatomical 
Main Group (Level 1), Pharmacological Subgroup (Level 3) and PT.  
Tabulations will be presented for prior and concomitant medications separately where prior 
medications will be summarized by genotype and concomitant medications will be summarized 
by treatment period and genotype. Prior medications which continued into the treatment period 
will also be classified as concomitant and will be included in both summaries. The reported term 
will be included in the listing.  
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in the ‘All Participants’ column. 
6.4.1 
Prior medication definition 
Prior medications include any medications that started prior to date of the first dose of PSL. 
6.4.2 
Concomitant medication definition 
Concomitant medications are medications taken after the first dose of PSL and/or the SFU 
Period. Concomitant medications will be attributed to the treatment period in which they start. 
Thus, any medication taken on Day 1 through Day 5 will be attributed to the Single-Dose Period; 
any medications taken after the first dose of PSL on Day 6 through Day 14 (including SFU) will 
be attributed to the Multiple-Dose Period. 
If a medication starts prior to PSL administration and stopped after the first PSL administration 
or stopped during the Single-Dose Period, then that medication will be classified as both prior 
and concomitant for Single-Dose Period only. If a medication starts prior to PSL administration 
and is stopped during the Multiple-Dose Period, then that medication will be classified as prior 
and concomitant for both Single and Multiple-Dose Periods. 
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Any medications with missing dates and/or times will be handled as described in Section 4.2.1 in 
order to classify them as prior or concomitant. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Administration of PSL will be performed under the supervision of the Investigator (or designee) 
and the Investigator (or designee) will check the study participant’s hands and the oral cavity 
immediately after dosing to confirm ingestion of the study medication. Compliance will be 
monitored by drug accountability and by drug assay for PSL (using the drug concentration in the 
blood/plasma). Compliance with the study medication is defined as consumption by the study 
participant that confirms 100% with the planned dosage. 
Drug administration/consumption will be recorded and any discrepancies with the dosing 
regimen will be explained. Dosing deviations will be included in the listing of IPDs where 
applicable. 
No formal calculations of compliance will be presented as all study medication is administered 
on site. 
8 
EFFICACY ANALYSES 
Not applicable. 
9 
PHARMACOKINETICS  
The calculation of the PK parameters of PSL and its metabolites 
 
 will be performed by the Quantitative Clinical Development Department, 
PAREXEL. 
Pharmacokinetic concentrations and PK parameters will be summarized by treatment period 
(Single-dose and Multiple-dose) and genotype group (EM, IM and PM) using the PK-PPS and 
listed by treatment period, genotype and study participant using the SS. Figures of summaries 
will be based on the PK-PPS and figures of individual concentrations will be based on the SS.  
Pharmacokinetic parameters of PSL and its metabolites will be calculated using the actual blood 
sampling times.  
The primary plasma PK parameters for PSL include:  
 Single-dose: Cmax, AUC(0-t), AUC, t1/2, and tmax  
 Multiple-dose:  Cmax,ss, AUCτ, t1/2, and tmax,ss 
The other plasma PK parameters for PSL include: 
 Single-dose: Cmax,bw, AUC(0-t),bw, AUC,bw, AUC(0-12) and CL/F 
 Multiple-dose: CLss/F, Cmax,ss,bw, AUCτ,bw, RAUC, RCmax, and LF 
The other plasma PK parameters for PSL metabolites include:  
 Single-dose: Cmax, AUC(0-t), AUC, t1/2, tmax, Cmax,bw, AUC(0-t),bw, AUC,bw, AUC(0-12) and 
m/p based on Cmax and AUC 
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 Multiple-dose: Cmax,ss, AUCτ, t1/2, tmax,ss, Cmax,ss,bw, AUCτ,bw, m/p based on Cmax,ss and 
AUCτ, RAUC, RCmax, and Rm/p based on AUC 
In addition, the PK parameters of PSL and its metabolites in urine after single and multiple-dose 
include: Ae, fe, CLr and CLform (for PSL metabolites only). 
9.1 
Descriptive figures, Summaries and Listings 
Individual plasma and urine concentrations of PSL will be listed separately by treatment period 
and genotype and will include the actual and nominal sampling times and the deviation between 
them. All deviations will be calculated relative to the first dose (single-dose) or the last morning 
dose (multiple-dose) of study medication. Any samples that are obtained outside the tolerance 
window permitted at the specified time point will be discussed at the DEM and any possible 
exclusion from analysis will be documented accordingly.  
The plasma concentration and the PK parameters (plasma and urine) of PSL and its metabolites 
will be summarized by treatment period, genotype and nominal sampling times using descriptive 
statistics (number of available observations [n], arithmetic mean, median, SD, minimum, 
maximum, geometric mean, geometric CV and 95% CI for the geometric mean [assuming 
lognormally distributed data]). Values below the LLOQ will be reported with a clear sign (flag 
variable in the dataset) indicating that they were below the LLOQ. 
The amount of urinary excretion of PSL (mg) per time interval after oral administration of PSL 
will be summarized by treatment period (SD: Day 1-5; MD: Day 10) and genotype using 
descriptive statistics. 
Individual participant plasma concentration-time profiles of PSL and its metabolites will be 
displayed graphically overlaid on the same plot by treatment period in linear and semi-
logarithmic scale.  
Combined individual (spaghetti) plots for PSL and its metabolites will be displayed by treatment 
period and genotype with all participants overlaid on the same plot (linear and semi-logarithmic 
scale). 
Geometric mean profiles of plasma concentrations for PSL and its metabolites over time will be 
presented, with genotype overlaid on the same plot, in both linear and semi-logarithmic scale. 
For the linear scale plot only, the lower and upper 95% confidence interval (CI) for the 
geometric mean will be displayed. 
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times.  
The following PK parameters of PSL and its metabolites will be graphically displayed (scatter 
plot, box plot) by genotype:  
 Single-dose: PSL and metabolites: Cmax, AUC(0-t), AUC, Cmax,bw, AUC(0-t),bw, AUC,bw, CL/F, 
Ae, fe and CLr; PSL metabolites: CLform and m/p based on AUC 
 Multiple-dose: PSL and metabolites: Cmax,ss, AUCτ, Cmax,ss,bw, AUCτ,bw, CLss/F, Ae, fe, CLr 
and RAUC; PSL: LF; PSL metabolites: CLform, m/p based on AUC and Rm/p based on AUC 
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9.2 
Statistical analysis of pharmacokinetics variables 
The following PK parameters of PSL and its metabolites will be compared between genotype 
groups using analysis of variance (ANOVA) on the log-transformed parameters: 
 Single-dose: PSL and metabolites: Cmax, AUC(0-t), AUC, Cmax,bw, AUC(0-t),bw, AUC,bw, CL/F, 
Ae, fe and CLr; PSL metabolites: CLform and m/p based on AUC 
 Multiple-dose: PSL and metabolites: Cmax,ss, AUCτ, Cmax,ss,bw, AUCτ,bw, CLss/F, Ae, fe, CLr 
and RAUC; PSL: LF; PSL metabolites: CLform, m/p based on AUC and Rm/p based on AUC 
Point estimates for the ratio of geometric means and the respective 2 sided 90% CIs will be 
computed using the least squares means and the root mean squares of error, based on of the log-
transformed data with subsequent exponential transformation.  
The 3 comparisons of interest are the following (in sequential ordering): 
 EM versus PM 
 IM versus PM 
 EM versus IM 
The comparison “EM versus PM” will be firstly evaluated and then the 2 other comparisons 
against IMs will be performed only if the comparison EM versus PM is nonequivalent. 
Interpretation of results will be performed by comparing the 90% CI interval of geometric mean 
ratio with the acceptance range of 50% to 200%. 
9.3 
Derivations of pharmacokinetic parameters 
 AUC will be calculated as AUC = AUC(0-t) + Clast/λz, where Clast is the last quantifiable 
plasma concentration and λz is the apparent terminal elimination rate constant. 
 AUC(0-t) will be calculated using the linear-up log-down trapezoidal rule. If single data points 
for plasma concentrations are missing, the parameter will be derived by interpolating with 
regard to the 2 neighboring non-missing concentrations. 
 t½ will be calculated as ln 2/λz where a simple linear regression (slope = -λz) of natural log 
(ln) concentration vs time for data points in the terminal phase of the concentration-time 
curve. 
 Metabolite to parent ratio (m/p) based on Cmax will be calculated using Cmax of metabolite 
divided by Cmax of parent (PSL) and Cmax,ss of metabolite divided by Cmax,ss of parent for 
single and multiple dose respectively. 
 Metabolite to parent ratio (m/p) based on AUC will be calculated using AUC of metabolite 
divided by AUC of parent and AUCτ of metabolite divided by AUCτ of parent for single and 
multiple dose respectively. 
 Body weight (BW) normalized parameters (ie, Cmax,bw, AUC(0-t),bw, AUC,bw, Cmax,ss,bw, and 
AUCτ,bw) will be calculated using the following formula where BW is measured on Day -1: 
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𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟𝑏𝑤= 𝑃𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟 × 𝐵𝑊
70  
 CLr will be calculated as Ae/AUC and Ae/AUCτ for single and multiple dosing respectively. 
 fe will be calculated as Ae/Dose for PSL and as (Ae of metabolite/Dose) x (molecular weight 
(MW) parent/MW metabolite) where the MW of PSL is 432.8, the MW of metabolite 
is 419, the MW of metabolite 
. 
 CLform will be calculated as (Ae of metabolite/AUC of parent) x (MW parent/MW metabolite) 
for single-dose period and as (Ae of metabolite/AUCτ of parent) x (MW parent/MW 
metabolite) for multiple-dose period. 
 Accumulation ratio of Cmax (RCmax) will be calculated using Cmax,ss following multiple dosing 
divided by Cmax following a single dose for PSL and its metabolites. 
 Accumulation ratio of AUC (RAUC) will be calculated using AUCτ following multiple 
dosing divided by AUC(0-12) following a single dose for PSL and its metabolites. 
 Accumulation ratio of m/p based on AUC (Rm/p) will be calculated using m/p [based on 
AUC] following multiple dosing divided by m/p [based on AUC] following a single dose. 
 Linearity factor will be calculated using AUCτ following multiple dosing divided by AUC 
following a single dose for PSL. 
10 
SAFETY ANALYSES 
Safety analyses will be carried out in the SS unless otherwise stated. In listings, data will be 
presented by participant number and time point within each genotype group. 
10.1 
Extent of exposure 
All study medication administration details will be listed by treatment period and participant. 
The listing will include the date and time of administration of the morning and evening dose, 
depending on the treatment period.  
10.2 
Adverse events 
All Adverse events (AEs) will be coded using the MedDRA® and characterized as pretreatment 
and treatment emergent according to the intake of the study medication. AEs with a start date 
prior to the first dose of study medication will be defined as pretreatment AEs. A treatment 
emergent AE (TEAE) is defined as any AEs with a start date/time on or after the first dose of 
study medication or any unresolved event already present before administration of study 
medication that worsens in intensity following exposure to the treatment. Where dates are 
missing or partially missing, AEs will be assumed to be treatment emergent, unless there is clear 
evidence to suggest that the AE started prior to the first dose of study medication. Missing or 
partially missing dates for AEs will be handled as described in Section 4.2.4. 
AEs will be attributed to the treatment period in which they start. Thus, all AEs starting after the 
first intake of PSL through Day 5 will be attributed to Single-Dose Period; all AEs starting after 
PSL intake on Day 6 will be attributed to the Multiple-Dose Period and AEs starting more than 
168 hours post last dose of PSL will be attributed to the SFU period. 
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All AEs will be recorded in the Case Report form (CRF) from the time of informed consent until 
study completion or termination. All AEs will be coded (see Section 3.8) and categorized by 
intensity (mild/moderate/severe) and relationship (related/not related) to study drug PSL as 
judged by the Investigator. 
The number and percentage of participants who experience TEAEs will be summarized by 
MedDRA SOC, PT, treatment period, genotype and by characterization according to the intake 
of PSL.  
The occurrence and incidence of TEAEs will also be summarized by intensity and relationship to 
PSL. TEAEs leading to discontinuation and serious TEAEs will also be summarized by 
treatment group and by characterization according to the intake of PSL. 
Summaries of TEAEs will include the following:  
 Incidence of TEAEs (overview including number and percentage of participants with any 
TEAEs, serious TEAEs, discontinuations due to TEAEs, drug-related TEAEs, severe TEAEs 
and TEAEs leading to death; event counts will also be included)  
 Incidence of TEAEs  
 Incidence of serious TEAEs  
 Incidence of TEAEs by relationship  
 Incidence of TEAEs by intensity 
 Incidence of TEAEs by maximum relationship  
 Incidence of TEAEs by maximum intensity  
 Incidence of TEAEs leading to discontinuation by relationship   
 Incidence of fatal TEAEs by relationship  
 Incidence of serious TEAEs by relationship  
 Incidence of non-serious TEAEs above reporting threshold of 5% of participants   
Summary tables will contain counts of study participant, percentages of study participants in 
parentheses and the number of events where applicable. A participant who has multiple events in 
the same SOC or PT will be counted only once in the participant counts but all events will be 
included. 
In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Participants who experience the same event multiple times will be included in 
the most related category for tabulations by maximum relationship. Events with missing 
relationship will be considered as ‘Related’ but recorded as missing in the listings.  
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in 
the listings. 
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Adverse event summaries will be ordered alphabetically by SOC and decreasing frequency of PT 
within SOC. 
A listing for all AEs will be presented by participant, treatment period and will include the onset 
date/time and outcome date/time of the event (including relative days), the AE duration 
(derived), time to onset (derived), pattern of event, intensity, relationship, action taken and 
outcome. In addition, the listing will flag AEs that led to discontinuation, TEAEs and SAEs. 
10.3 
Clinical laboratory evaluations 
Laboratory data and changes from baseline for numeric variables will be summarized and listed 
by genotype group, treatment period and across time. Any laboratory measurements that are 
BLQ or ALQ will be handled as described in Section 4.2.2.  Values outside the reference range 
will be flagged in the listings, and in addition, will be listed separately. For the definition of 
Baseline values see Section 3.3. 
A separate listing will present the participants who meet one or more of the following criteria at 
any treatment period or time point: 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase ≥3x upper 
limit of normal (ULN) 
 Alkaline phosphatase ≥2xULN 
 Total bilirubin increase ≥2xULN 
The listing will display only treatment periods and time points for which at least one of the above 
criteria was fulfilled for a given participant and will display all results obtained at that treatment 
period or time point for the specified variables. 
A summary of participants who meet the criteria for potential drug-induced liver injury (PDILI) 
will be presented together with any additional relevant data collected, if applicable. 
Clinical chemistry and hematology parameters will be summarized by genotype group, treatment 
period and timepoint for both absolute values and changes from Baseline. 
Laboratory variables will be grouped according to the laboratory function panel (Table 10.1) and 
categorized as normal, high or low, if applicable, based on the reference range supplied by the 
analytical laboratory. For selected variables that are identified in Table 10.1 the change in 
category from Baseline will be presented in shift tables at all post- Baseline time points. 
Table 10.1: Laboratory measurements 
Protocol-required safety laboratory assessments 
Laboratory 
Assessments 
Parameters 
Hematology a 
Platelet Count 
RBC Indices: 
MCV, MCH,  
% Reticulocytes 
WBC Count with Differential: 
Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils 
RBC Count 
Hemoglobin 
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Protocol-required safety laboratory assessments 
Laboratory 
Assessments 
Parameters 
Hematocrit 
Clinical 
Chemistry a 
BUN 
Potassium 
AST/SGOT 
Total and direct bilirubin 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
Glucose (unfasted) 
Calcium 
ALP 
 
Routine 
Urinalysis a 
 Specific gravity 
 pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
 Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
 Drug screen (to include at minimum: amphetamines, cocaine, opiates, 
cannabinoids, and benzodiazepines) 
 Serology (HIV-1/2 Ab, HBsAg, HCV-Ab, syphilis) 
The results of each test must be entered into the eCRF. 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; eCRF=electronic Case Report Form; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C virus 
antibody; HIV-1/2=human immunodeficiency virus-1/2; MCV=mean corpuscular volume; MCH=mean corpuscular 
hemoglobin; RBC=red blood cells; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-
pyruvic transaminase; WBC=white blood cells 
a Hematology, clinical chemistry, and urinalysis assessments will be performed under fasting conditions at 
Screening and non-fasting conditions at all other assessments. 
The following additional laboratory variables will be listed separately: 
 Serology (HBsAg, HCV-Ab, syphilis) 
 Drug screen(amphetamines, cocaine, opiates, cannabinoids, and benzodiazepines) 
10.4 
Vital signs, Electrocardiograms, and other observations related 
to safety 
10.4.1 
Vital signs 
The following vital sign measurements will be taken prior to blood sampling, where applicable.  
 Systolic and diastolic blood pressure (mmHg) 
 Pulse rate (beats per minute) 
 Respiratory rate (breaths per minute) 
 Body temperature (°C) 
Descriptive statistics will be reported for all vital sign measurements in both standing and supine 
position. Observed results and changes from Baseline will be summarized by genotype group, 
treatment period and timepoint.  
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A by-participant listing of all vital sign measurements and change from Baseline will be 
presented by genotype group and timepoint. 
The number and percentage of participants with treatment-emergent markedly abnormal 
(TEMA)/potentially clinically significant (PCS) vital sign values as calculated by the criteria 
outlined in Table 10‒2 will be summarized by vital sign variables and time point and will be 
presented by genotype group and overall. 
Table 10‒2: TEMA/PCS criteria for vital signs 
Variable 
Unit 
Lowa 
Higha 
Systolic blood pressure 
mmHg 
Value <90 and/or  
≥20 decrease from Baseline 
Value >140 and/or  
≥20 increase from Baseline 
Diastolic blood pressure 
mmHg 
Value <50 and/or  
≥15 decrease from Baseline 
Value >90 and/or  
≥15 increase from Baseline 
Pulse rate 
bpm 
Value <45 and/or  
≥15 decrease from Baseline 
Value >90 and/or  
≥15 increase from Baseline 
bpm=beats per minute; PCS=potentially clinically significant; TEMA=treatment-emergent markedly abnormal. 
a Both conditions must be satisfied for a measurement to be considered potentially clinically significant. 
10.4.2 
Electrocardiograms 
12-lead ECG will be recorded 3 times at each time point. The individual mean at each time point 
will be calculated as raw parameters for descriptive analysis. The individual mean and change 
from baseline will be summarized using descriptive statistics by treatment period, genotype and 
timepoint.  
The following ECG parameters will be derived from digitally recorded 12-lead ECGs.  
 Heart rate (HR) [beats per minute] 
 RR interval [msec] 
 PR interval [msec] 
 QRS interval [msec] 
 QT interval [msec] 
 QTcF interval [msec]: QT interval corrected by Fridericia formula 𝑄𝑇𝑐𝐹 [𝑚𝑠𝑒𝑐] =
𝑄𝑇 [𝑚𝑠𝑒𝑐]
√𝑅𝑅 [𝑠𝑒𝑐]
3
  
If available in the database, the QT corrected for heart rate using Bazett’s formula (QTcB) will 
also be included in the listings and tabulations. 
The individual measurements and the mean of the triplicate measurements will be reported in the 
by-participant listings. The listing will also include the change from Baseline based on the mean 
of the triplicate measurements at each timepoint, and will be presented by treatment period, 
genotype group and timepoint. 
Measured values and changes from Baseline will be summarized by treatment period, genotype 
group and timepoint (based on the mean of the triplicate values at each timepoint). Mean change 
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from Baseline in QTcF will be summarized by treatment period, genotype and timepoint and 
plotted over time by genotype. Figures will be presented with all treatment periods overlaid on 
the same plot by genotype. 
In addition, the following cut-points in QTcF (raw data and change from Baseline) based on the 
mean of the triplicate data, will be summarized categorically (number and percentage of 
participants) by treatment period, genotype and timepoint. 
For observed data:  
 
<450msec 
 
≥450 to <480msec 
 
≥480 to <500msec 
 
≥500msec 
For change from Baseline:  
 
 <30msec  
 
≥30 to <60msec 
 
≥60msec 
All ECG findings for the individual triplicate measurements will be listed separately. 
Any incomplete triplicate measurements at a given timepoint will be handled as described in 
Section 4.2.3. 
10.4.3 
Other safety variables 
10.4.3.1 
Physical examination 
Participants with abnormalities in the physical examination will be listed including details of the 
abnormality. 
10.4.3.2 
Suicidal risk monitoring 
Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al, 2011) data will be listed. 
Module of the questionnaire, time point, question and the associated response will be listed for 
all the visits days where this questionnaire is collected. 
11 
OTHER ANALYSES  
Not applicable. 
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12 
REFERENCES 
Phillips, A. and Haudiquet, V. (2003), ICH E9 guideline ‘Statistical principles for clinical trials’: 
a case study. Statist. Med., 22: 1-11. doi:10.1002/sim.1328 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia 
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266 77. 
UCB GLOBAL EXPLORATORY DEVELOPMENT PHARMACOMETRICS User Guide for 
Clinical Pharmacokinetics Modeling & Simulation. Version 8.0 – 04/JUL/12 
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13 
APPENDICES 
Not applicable. 
 
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14 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP) 
14.1 
AMENDMENT 1 
Rationale for the amendment 
The SAP amendment is to accommodate the review comments to the dry run TFLs received 
from the Data Evaluation Meeting conducted on 28-Jan-2020. 
Modifications and changes 
Global changes 
NA 
Specific changes 
 4.2.1 PK results/ 1st and 2nd para 
The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geometric CV) is 0. Measurements of PK concentrations that are below the limit of 
quantification (BLQ) and which are occurring prior to tmax will be imputed with half of the 
lower limit of quantification (LLOQ/2), except for embedded BLQ values (between two 
measurable data points) which will be treated as missing, for the purpose of calculating the 
geometric mean and its 95% CI, the geometric CV, the arithmetic mean and SD for 
summaries and figures. Post tmax, BLQ values will be treated as missing calculated if at least 
2/3rd of the individual data points are quantifiable (≥LLOQ). 
For all individual PK concentration figures any concentrations that are BLQ will be regarded 
as missing, with the exception of predose BLQ measurements which will be imputed with 
“LLOQ/2” for linear scale plots. 
Has been changed to: 
Measurements of plasma PK concentrations that are below the limit of quantification (BLQ) 
will be imputed with half of the lower limit of quantification (LLOQ) for the purpose of 
calculating the geometric mean and its 95% CI, the geometric CV, the arithmetic mean and 
SD for summaries and figures. Descriptive statistics of concentrations will be calculated if at 
least 2/3rd of the individual data points are quantifiable (≥LLOQ). 
 4.2.1 PK results/ 3rd bullet 
For plasma concentrations, 
Has been changed to: 
For the calculation of plasma PK parameters, 
 4.2.1 PK results/ 4th bullet 
On calculating the geometric mean and its 95% CI, the geometric CV, the arithmetic mean 
and SD, measurements of PK concentrations that are below the limit of quantification (BLQ) 
will be imputed with the numerical value of the LLOQ/2. 
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Has been changed to: 
Removed. 
 4.2.1 PK results/ 7th bullet 
predose BLQ measurements on Day 10 
Has been changed to: 
predose BLQ measurements on Day 1 and Day 10 
 5.1 Participant disposition/ 2nd para 
the reason for discontinuation will be summarized by genotype group and overall based on 
the ES 
Has been changed to: 
the reason for discontinuation will be summarized by genotype group and overall based on 
the SS. 
 5.1 Participant disposition/ 5th para 
Finally, screen failure reasons will be summarized by genotype group and overall, based on 
the ES. A listing of participants who did not meet study eligibility criteria will also be 
presented by genotype group and overall. 
Has been changed to: 
Finally, screen failure reasons will be summarized by overall, based on the ES. A listing of 
participants who did not meet study eligibility criteria will also be presented. 
 6.1 Demographics/ 2nd para 
The summary of age will include descriptive statistics and categorical summaries, the latter 
based on requirements for clinicaltrials.gov reporting: 
• ≤18 years 
• 19 to <65 years 
• ≥65 years 
Has been changed to: 
The summary of age will include descriptive statistics and categorical summaries, the latter 
based on requirements for clinicaltrials.gov reporting: (≤18, 19 to <65, and ≥65 years) and 
the European Union Drug Regulating Authorities Clinical Trials (EudraCT) reporting (<18, 
18 to <65, 65 to <85, and ≥85 years). 
 9.3 Derivations of pharmacokinetic parameters / 2nd bullet 
AUC(0-t) will be calculated using the linear trapezoidal rule. If single data points for plasma 
concentrations are missing, the parameter will be derived by interpolating with regard to the 
2 neighboring non-missing concentrations. 
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Has been changed to: 
AUC(0-t) will be calculated using the linear-up log-down trapezoidal rule. If single data 
points for plasma concentrations are missing, the parameter will be derived by interpolating 
with regard to the 2 neighboring non-missing concentrations. 
 10.3 Clinical laboratory evaluations/ Last para 
Serology (HIV-1/2 Ab, HBsAg, HCV-Ab, syphilis) 
Has been changed to: 
Serology (HBsAg, HCV-Ab, syphilis) 
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15 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
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Approval Signatures
Name:
UP0083-sap-amemdment-1
Version:
1. 0
Document Number:
CLIN-000148986
Title:
up0083 SAP Amendment 1
Approved Date:
13 Feb 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 11-Feb-2020 13:10:20 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 13-Feb-2020 12:09:03 GMT+0000
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