An Open-Label, Parallel-Group, Pharmacokinetic Study of Padsevonil in Study Participants With Either Normal Hepatic Function or With Moderately Impaired Hepatic Function (Child-Pugh Class B)
Phase: PHASE1
Conditions: Healthy Study Participants, Impaired Hepatic Function
Sponsor: UCB Biopharma S.P.R.L.

UCB 
 
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Clinical Study Protocol 
Padsevonil 
UP0056 
 
 
 
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AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC 
STUDY OF PADSEVONIL IN STUDY PARTICIPANTS WITH 
EITHER NORMAL HEPATIC FUNCTION OR WITH 
MODERATELY IMPAIRED HEPATIC FUNCTION 
(CHILD-PUGH CLASS B) 
PROTOCOL UP0056 
PHASE 1 
Short title: 
A pharmacokinetic, safety, and tolerability study of padsevonil in healthy study participants or 
those with moderate hepatic insufficiency 
Sponsor: 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
IND Number: 
135622 
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 
Original Protocol 
02 Jul 2019 
Not applicable 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
USA: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................................... 2 
SERIOUS ADVERSE EVENT REPORTING .......................................................................... 3 
1 
PROTOCOL SUMMARY ................................................................................................. 8 
1.1 Synopsis ............................................................................................................................. 8 
1.2 Schema ............................................................................................................................. 10 
1.3 Schedule of Activities ...................................................................................................... 13 
2 
INTRODUCTION ........................................................................................................... 17 
2.1 Study rationale ................................................................................................................. 17 
2.2 Background ...................................................................................................................... 17 
2.3 Benefit/risk assessment .................................................................................................... 18 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 20 
4 
STUDY DESIGN ............................................................................................................. 21 
4.1 Overall design .................................................................................................................. 21 
4.2 Scientific rationale for study design................................................................................. 21 
4.3 Justification for dose ........................................................................................................ 21 
4.4 End of study definition ..................................................................................................... 22 
5 
STUDY POPULATION .................................................................................................. 22 
5.1 Inclusion criteria .............................................................................................................. 22 
5.2 Exclusion criteria ............................................................................................................. 23 
5.3 Lifestyle restrictions ......................................................................................................... 27 
5.3.1 
Meals and dietary restrictions .............................................................................. 27 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 27 
5.3.3 
Activity ................................................................................................................ 27 
5.4 Screen failures .................................................................................................................. 28 
5.4.1 
Rescreening .......................................................................................................... 28 
6 
STUDY TREATMENTS ................................................................................................. 28 
6.1 Treatments administered .................................................................................................. 28 
6.2 Preparation, handling, storage, and accountability requirements .................................... 29 
6.2.1 
Drug accountability ............................................................................................. 29 
6.3 Measures to minimize bias: randomization and blinding ................................................ 30 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 30 
6.3.1.1 
Maintenance of study medication blind .................................................... 30 
6.3.1.2 
Breaking the treatment blind in an emergency situation ........................... 30 
6.4 Treatment compliance ...................................................................................................... 30 
6.5 Concomitant medication(s)/treatment(s).......................................................................... 30 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 30 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 31 
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6.5.3 
Rescue medication ............................................................................................... 31 
6.6 Dose modification ............................................................................................................ 31 
6.7 Treatment after the end of the study ................................................................................ 31 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 31 
7.1 Discontinuation of study medication ............................................................................... 31 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 31 
7.1.1.1 
Participants with normal hepatic function ................................................. 31 
7.1.1.2 
Participants with impaired hepatic function .............................................. 32 
7.1.2 
Criteria for study hold due to adverse events ...................................................... 33 
7.2 Participant discontinuation/withdrawal from the study ................................................... 33 
7.3 Lost to follow up .............................................................................................................. 35 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 35 
8.1 Pharmacokinetics ............................................................................................................. 36 
8.2 Plasma protein binding .................................................................................................... 37 
8.3 Pharmacodynamics .......................................................................................................... 37 
8.4 Safety assessments ........................................................................................................... 37 
8.4.1 
Physical examination ........................................................................................... 37 
8.4.2 
Vital signs ............................................................................................................ 37 
8.4.3 
Electrocardiograms .............................................................................................. 37 
8.4.4 
Clinical safety laboratory assessments ................................................................ 38 
8.4.5 
Suicidal risk monitoring ...................................................................................... 38 
8.4.6 
Psychiatric and mental status ............................................................................... 39 
8.5 Adverse events ................................................................................................................. 39 
8.5.1 
Time period and frequency for collecting AE and SAE information .................. 39 
8.5.2 
Method of detecting AEs and SAEs .................................................................... 39 
8.5.3 
Follow-up of AEs and SAEs ................................................................................ 40 
8.5.4 
Regulatory reporting requirements for SAEs ...................................................... 40 
8.5.5 
Pregnancy ............................................................................................................ 40 
8.5.6 
Adverse events of special interest ........................................................................ 41 
8.6 Safety signal detection ..................................................................................................... 41 
8.7 Efficacy assessments ........................................................................................................ 41 
8.8 Treatment of overdose ..................................................................................................... 41 
8.9 Genetics ............................................................................................................................ 42 
8.10 Biomarkers ....................................................................................................................... 42 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 42 
9.1 Definition of analysis sets ................................................................................................ 42 
9.2 General statistical considerations ..................................................................................... 42 
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9.3 Planned safety and other analyses .................................................................................... 43 
9.3.1 
Pharmacokinetic analyses .................................................................................... 43 
9.3.2 
Safety analyses ..................................................................................................... 43 
9.4 Planned efficacy/outcome analyses ................................................................................. 44 
9.5 Handling of protocol deviations ....................................................................................... 44 
9.6 Handling of dropouts or missing data .............................................................................. 44 
9.7 Planned interim analysis and data monitoring ................................................................. 44 
9.8 Determination of sample size ........................................................................................... 44 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 45 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations ............................. 45 
10.1.1 
Regulatory and ethical considerations ................................................................. 45 
10.1.2 
Financial disclosure ............................................................................................. 46 
10.1.3 
Informed consent process .................................................................................... 46 
10.1.4 
Data protection ..................................................................................................... 46 
10.1.5 
Committees structure ........................................................................................... 47 
10.1.6 
Data quality assurance ......................................................................................... 47 
10.1.6.1 
Case Report form completion .................................................................... 47 
10.1.6.2 
Apps ........................................................................................................... 48 
10.1.7 
Source documents ................................................................................................ 48 
10.1.8 
Study and site closure .......................................................................................... 48 
10.1.9 
Publication policy ................................................................................................ 49 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................ 50 
10.3 Appendix 3: Adverse events – definitions and procedures for recording, evaluating, 
follow up, and reporting ................................................................................................... 52 
10.3.1 
Definition of AE .................................................................................................. 52 
10.3.2 
Definition of SAE ................................................................................................ 53 
10.3.3 
Recording and follow up of AE and/or SAE ....................................................... 55 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............. 59 
10.4.1 
Definitions ........................................................................................................... 59 
10.4.1.1 
Woman of childbearing potential .............................................................. 59 
10.4.2 
Contraception guidance ....................................................................................... 59 
10.4.2.1 
Male participants ....................................................................................... 59 
10.4.2.2 
Pregnancy testing ...................................................................................... 60 
10.4.2.3 
Collection of pregnancy information......................................................... 60 
10.5 Appendix 5: Genetics ....................................................................................................... 63 
10.6 Appendix 6: Liver safety – suggested actions and follow up assessments ...................... 64 
10.7 Appendix 7: Medical device incidents – definition and procedures for recording, 
evaluating, follow up, and reporting ................................................................................ 67 
10.8 Appendix 8: Rapid alert procedures ................................................................................ 68 
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10.9 Appendix 9: Country-specific requirements .................................................................... 69 
10.10 
Appendix 10: Abbreviations and trademarks ........................................................ 70 
10.11 
Appendix 11: Protocol amendment history ........................................................... 72 
11 REFERENCES ................................................................................................................ 73 
SPONSOR DECLARATION .................................................................................................. 74 
 
LIST OF TABLES 
Table 1-1: 
Criteria to determine Child-Pugh score ........................................................... 11 
Table 1-2: 
Study design ..................................................................................................... 12 
Table 1-3: 
Schedule of activities ....................................................................................... 14 
Table 3-1: 
Objectives and endpoints ................................................................................. 20 
Table 6-1: 
Study medications administered ...................................................................... 29 
Table 8‒1: 
Irrelevant time deviations for PK sampling ..................................................... 36 
Table 10-1: 
Highly effective contraceptive methods .......................................................... 61 
Table 10-2: 
Phase I liver chemistry stopping criteria and follow up assessments .............. 65 
 
LIST OF FIGURES 
Figure 7-1: 
Liver chemistry stopping algorithm ................................................................. 32 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: 
An open-label, parallel-group, pharmacokinetic study of padsevonil in study participants with 
either normal hepatic function or with moderately impaired hepatic function 
(Child-Pugh Class B) 
Short title: 
A pharmacokinetic, safety, and tolerability study of padsevonil in healthy study participants or 
those with moderate hepatic insufficiency 
Rationale: 
Padsevonil (PSL) is currently being investigated for the treatment of focal-onset seizures in adult 
patients with drug-resistant epilepsy. Epilepsy is a disorder that increases significantly with age 
(Kilpatrick and Lowe, 2002). Impairment of renal and hepatic function is common in the elderly 
and may alter metabolism and excretion of a drug and its metabolites. Thus, PSL is likely to be 
administered in patients who have impaired hepatic function and, as a consequence, this may 
impact the efficiency of the study drug. 
This study aims to evaluate the effect of moderate hepatic insufficiency on pharmacokinetic 
(PK), safety, and tolerability following single and multiple oral doses of PSL. Padsevonil is 
predominately cleared hepatically, and hepatic insufficiency may affect some pathways of 
hepatic/gut drug metabolism and has also been associated with other changes, such as changes in 
absorption, plasma protein binding, transport, and tissue distribution. As PSL is predominantly 
hepatically cleared, impairment of hepatic function anticipates increased exposures. These 
changes may be particularly prominent in patients with impaired hepatic function 
(CPMP/EWP/2339/02, 2005; Food and Drug Administration [FDA] Guidance for Industry, 
2003). 
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Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the plasma PK of PSL in 
hepatically impaired and non-hepatically 
impaired study participants 
 
Single dose: Cmax, AUC0-t, AUC 
 
Multiple dose: Cmax,ss, AUCτ  
Secondary 
 
To evaluate the safety and tolerability of PSL 
in hepatically impaired and non-hepatically 
impaired study participants 
 
Incidence of TEAEs, SAEs, and TEAEs 
leading to discontinuation 
Other 
 
To evaluate plasma PK of PSL and its major 
metabolites (
 
and 
in 
hepatically impaired and non-hepatically 
impaired study participants 
For PSL metabolites: 
 
Single dose: AUC, AUC0-t, and Cmax 
 
Multiple dose: AUCτ and Cmax,ss  
For PSL and its metabolites: 
 Single dose: tmax, t1/2, AUC0-12, and 
metabolic ratios of AUC and Cmax 
 Multiple dose: tmax, t1/2, ss, Ctrough, metabolic 
ratios of AUCτ and Cmax,ss 
For PSL: 
 
Single dose: CL/F 
 
Multiple dose: CLss/F 
 
Bound and unbound plasma concentration of 
PSL in 2 samples. 
 
To evaluate the urine PK of PSL and its major 
metabolites (
 
and 
 in 
hepatically impaired and non-hepatically 
impaired study participants 
 
Amount excreted and metabolic ratio of 
amount excreted, CLR, and fe 
 
To evaluate the safety and tolerability of PSL 
in hepatically impaired and non-hepatically 
impaired study participants 
 
Changes in safety laboratory data (hematology, 
clinical chemistry, and urinalysis) 
 
Changes in vital signs (PR, BP, RR, and body 
temperature) 
 
Changes in 12-lead ECG assessment  
 
Physical examination findings 
BP=blood pressure; ECG=electrocardiogram; PK=pharmacokinetic(s); PSL=padsevonil; PR=pulse rate; 
RR=respiratory rate; SAE=serious adverse event; TEAE=treatment-emergent adverse event 
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Overall design 
This is a Phase 1, open-label study to evaluate the effect of moderate hepatic insufficiency on 
PK, safety, and tolerability following single and multiple oral doses of PSL. 
The study includes a total of up to 24 study participants (Cohort A [approximately 
12 participants] with normal hepatic function, and Cohort B [approximately 12 participants] with 
moderate hepatic insufficiency). 
All cohorts will be initially matched for gender and then subsequently by weight to allow 
comparison across cohorts, if feasible. In each group there will be a homogenous repartition 
between male and female study participants with at least 2 study participants per gender. 
Screening of study participants will be up to 28 days prior to entry into the clinic. Prior to the 
start of the open-label, Single-Dose Treatment Period, the participants will check in to the clinic 
and complete Baseline procedures and assessments preceding the first administration of study 
medication. This will then be followed by a Washout Period before the start of a Multiple-Dose 
Treatment Period. A second Washout Period will be undertaken before the participants have their 
End of Study (EOS) Visit. Please see the Schedule of Activities (Table 1-3) for more specific 
details. 
Number of participants 
Up to 24 study participants will be enrolled overall. Approximately 12 study participants per 
cohort will be included. Dropouts will be replaced at the discretion of the Investigator and 
Sponsor.  
Treatment groups and duration 
The maximum total duration for the study participants is 46 days; it will consist of a Screening 
Period, Baseline, 2 Treatment Periods, 2 Washout Periods, and an EOS Visit. 
1.2 
Schema 
A table of criteria to define Child-Pugh score along with classification for hepatic insufficiency 
is presented in Table 1-1. For those participants with hepatic insufficiency, only study 
participants classified as moderate with a Child-Pugh score of 7 to 9 inclusive will be enrolled. A 
detailed schematic diagram of the study is provided in Table 1-2. 
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Table 1-1: 
Criteria to determine Child-Pugh score 
Measure 
1 Point 
2 Points 
3 Points 
Total serum bilirubin (mg/dL) 
<2.0 
2.0 to 3.0 
>3.0 
Serum albumin (g/dL) 
>3.5 
2.8 to 3.5 
<2.8 
Prothrombin time (sec prolonged), 
OR 
INR (ratio) 
<4 
4 to 6 
>6 
<1.70 
1.70 to 2.30 
>2.30 
Ascites 
Absent 
Slight 
Moderate or 
participant is on 
medication(s) to 
control ascites 
Hepatic encephalopathy 
None 
Grade 1 or 2 
Grade 3 or 4 or 
participant is on 
medication(s) to 
prevent 
encephalopathy 
 
 
 
 
Total points 
Hepatic insufficiency classification 
5 to 6 
A-Mild 
7 to 9 
B-Moderate 
10 to 15 
C-Severe 
INR=international normalized ratio 
 
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Table 1-2: 
Study design 
Cohort A (Healthy Study Participants) and Cohort B (Child-Pugh Hepatic Insufficiency Classification of Moderate) 
(n=approximately 12 per cohort) 
 
Single Dose 
Multiple Dose 
 
Treatment Period 
Washout Period 
Treatment Period 
Washout Period EOS/ETV 
Day 
1 
2 to 5 
6 to 7 
8 
9 
10 
11 
12 
(AM) 
12 
(PM) 
13 to 17 
18 
PSL Dose 
(mg) 
100 AM only 
100 
BID 100 BID 100 BID 100 BID 
100 
AM 
only 
 
 
Blood Sample 
PK 
PK (each day) 
PK 
PK 
PK 
PK 
PK 
PK 
PK (until Day 17) 
Urine Sample 
PK 
PK (each day) 
 
PK 
 
 
BID=twice daily; EOS=End of Study; ETV=Early Termination Visit; PK=pharmacokinetic; PSL=padsevonil 
 
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1.3 
Schedule of Activities 
The Schedule of Activities is presented in Table 1-3. 
 
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Table 1-3: 
Schedule of activities 
 
 
 
Single Dose 
Multiple Dose 
 
Procedures 
Screening Baseline Treatment Period Washout Period 
Treatment Period 
Washout 
Period 
EOSa ETV 
Study Days 
-28 to -3 
-2 
-1 
1 
2 to 5 
6 to 7 
8 
9 
10 
11 
12 
13 to 17 
18 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Admit to clinic 
 
Xb 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and 
baseline characteristics 
X 
 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria verification 
X 
 
X 
 
 
 
 
 
 
 
 
 
General 
medical/medications/ 
procedures history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Participant 
identification card 
assigned 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Determination of the 
Child-Pugh class  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidality Risk 
Assessment (C-SSRS)c 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Physical examinationd 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Psychiatric and mental 
status evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testf 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
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Table 1-3: 
Schedule of activities 
 
 
 
Single Dose 
Multiple Dose 
 
Procedures 
Screening Baseline Treatment Period Washout Period 
Treatment Period 
Washout 
Period 
EOSa ETV 
Study Days 
-28 to -3 
-2 
-1 
1 
2 to 5 
6 to 7 
8 
9 
10 
11 
12 
13 to 17 
18 
Determination of the 
prothrombin and INR 
values 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, serum 
chemistry, urinalysisg 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Serology (HIV, HepB 
and HepC) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGh 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Urine and cotinine drug 
screen, and alcohol 
breath test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Recording of adverse 
events/medical 
procedures 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer PSL 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Study drug 
accountability 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Blood sampling for 
PSL PK levelsi 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Additional blood 
sample PPBj 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine collection for 
PSL PKk 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
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Table 1-3: 
Schedule of activities 
 
 
 
Single Dose 
Multiple Dose 
 
Procedures 
Screening Baseline Treatment Period Washout Period 
Treatment Period 
Washout 
Period 
EOSa ETV 
Study Days 
-28 to -3 
-2 
-1 
1 
2 to 5 
6 to 7 
8 
9 
10 
11 
12 
13 to 17 
18 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CBC=complete blood count; C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EOS=End of Study; ETV=Early Termination Visit; 
h=hour(s); Hep B=hepatitis B; Hep C=hepatitis C; HIV=human immunodeficiency virus; INR=international normalized ratio; PK=pharmacokinetic; 
PPB=plasma protein binding; PSL=padsevonil; WOCBP=women of childbearing potential 
a If a participant discontinues early, EOS procedures should be completed as the ETV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete the Washout Period and complete EOS assessments following the last dose of study medication. 
b For convenience, the study participant may check-in to the clinic on the evening of Day -2. No study procedures will take place on Day -2. Study participants 
will be confined to the clinic from the time of check-in until check-out on Day 18. 
c All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months) and Baseline (Day -1), 
followed by the “Since Last Visit” version at subsequent visits. 
d Complete physical examinations will be performed on the days indicated. A brief physical examination will be conducted in a symptom-directed manner and 
only if clinically indicated (Section 8.4.1). 
e Vital signs will be performed before each morning dose of PSL, and if feasible, at the same times as ECGs are performed. 
f A serum pregnancy test will be performed for each WOCBP at Screening and a urine pregnancy test will be performed at any subsequent time points. 
g Laboratory safety assessments (hematology, chemistry, and urinalysis) will be performed before the morning dose of PSL. 
h A 12-lead ECG will be performed after a rest of at least 5 minutes. All ECG recordings will be performed in triplicate and should be sufficiently separated so 
they have a different ‘minute’ on the timestamp, and all are done within 4 minutes. 
i Pharmacokinetic blood samples will be taken at the following time points: Predose and 15 minutes, 30 minutes, 45 minutes, 1h, 1.5h, 3h, 4h, 5h, 6h, 8h, 12h, 
24h (Day 2), 48h (Day 3), 72h (Day 4), and 96h (Day 5) postdose. On Days 8, 9, 10, and 11, PK samples will be taken at predose. On Day 12, PK blood 
samples will be taken at the following time points: predose and 15 minutes, 30 minutes, 45 minutes, 1h, 1.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h (Day 13), 48h 
(Day 14), 72h (Day 15), and 96h (Day 16) postdose. 
j Two blood samples will be collected after multiple doses at steady state (Day 12 predose and 1.5h postdose [~tmax]) for PPB. 
k Urine for PK assessment will be collected from all study participants on Day 1 at predose and from 0h to <12h and 12h to <24h, on Day 2 from 24h to <48h, on 
Day 3 from 48h to <72h, on Day 4 from 72h to <96h, (before the 8am cutoff on Day 5) postdose. Urine for PK assessment will also be collected from all study 
participants on Day 12 from 0h to <12h postdose. 
 
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2 
INTRODUCTION 
2.1 
Study rationale 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic vesicle protein 2 
(SV2) isoforms and postsynaptic central benzodiazepine receptor (cBZR) sites on the 
gamma-aminobutyric acid type A (GABAA) receptor that has shown compelling, broad-range 
efficacy in several preclinical models of epilepsy conducted by UCB. Padsevonil is cleared via 
metabolism involving the cytochrome (CYP) pathway; the formation of the 2 major metabolites, 
 and 
), is 
mainly mediated by CYP3A4, with potential involvement of CYP2C19. Padsevonil is currently 
being investigated for the treatment of focal onset seizures in adult patients with drug-resistant 
epilepsy. Epilepsy is a disorder that increases significantly with age (Kilpatrick and Lowe, 2002). 
Impairment of renal and hepatic function is common in the elderly and may alter metabolism and 
excretion of a drug and its metabolites. Thus, PSL is likely to be administered in patients also 
with hepatic insufficiency. 
Hepatic impairment can adversely affect some pathways of hepatic and gut drug metabolism and 
has also been associated with changes in absorption, plasma protein binding, transport, and tissue 
distribution. As PSL is predominately cleared hepatically, changes in these absorption, 
distribution, metabolism, and excretion aspects may be expected in study participants with 
impaired hepatic function (CPMP/EWP/2339/02, 2005; FDA Guidance for Industry, 2003). 
Therefore, UP0056 is designed to evaluate the effect of moderate hepatic insufficiency on the 
PK, safety, and tolerability of PSL given orally either as a single dose or multiple doses. 
2.2 
Background 
More than 50 million people worldwide experience epilepsy (World Health Organization 
[WHO], 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 GABAA receptor mediates the bulk of inhibitory neurotransmissions in the brain. Allosteric 
modulation of inhibitory GABAA receptors by the cBZR site offers robust protection against 
seizures (Riss et al, 2008). However, their clinical use as AEDs is limited due to an unfavorable 
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). 
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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 the 
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 therapy in the treatment of focal-onset seizures in adult patients 
with drug-resistant 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 adverse effects of 
other AEDs, including SV2A ligands. Events were transient, acute, and required admission to 
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” (Loganathan et al, 2015; Clemens, 2005). 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 effects in these 3 study 
participants administered PSL highlights the need to consider the possibility of significant 
psychiatric adverse effects and to maintain vigilance for such effects. The mitigation plan for 
acute psychiatric effects involves gradual titration and taper, which are known to improve 
tolerability of AEDs. 
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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 studies 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 initial 
clinical efficacy studies, and all echocardiograms were assessed as normal. There are currently 
no clinical data to suggest that the drug has an adverse effect 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 post-treatment 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 study participants (healthy participants and those with moderate hepatic insufficiency) 
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. 
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3 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints for this study are presented in Table 3-1. 
Table 3-1: 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the plasma PK of PSL in 
hepatically impaired and non-hepatically 
impaired study participants 
 
Single dose: Cmax, AUC0-t, AUC 
 
Multiple dose: Cmax,ss, AUCτ  
Secondary 
 
To evaluate the safety and tolerability of PSL 
in hepatically impaired and non-hepatically 
impaired study participants 
 
Incidence of TEAEs, SAEs, and TEAEs 
leading to discontinuation 
Other 
 
To evaluate plasma PK of PSL and its major 
metabolites 
 
and 
 in 
hepatically impaired and non-hepatically 
impaired study participants 
For PSL metabolites: 
 
Single dose: AUC, AUC0-t, and Cmax 
 
Multiple dose: AUCτ and Cmax,ss 
For PSL and its metabolites: 
 Single dose: tmax, t1/2, AUC0-12, and 
metabolic ratios of AUC and Cmax 
 Multiple dose: tmax, t1/2, ss, Ctrough, metabolic 
ratios of AUCτ and Cmax,ss 
For PSL: 
 
Single dose: CL/F 
 
Multiple dose: CLss/F 
 
Bound and unbound plasma concentration of 
PSL in 2 samples. 
 
To evaluate the urine PK of PSL and its major 
metabolites (
 
and 
 in 
hepatically impaired and non-hepatically 
impaired study participants 
 
Amount excreted and metabolic ratio of 
amount excreted, CLR, and fe 
 
To evaluate the safety and tolerability of PSL 
in hepatically impaired and non-hepatically 
impaired study participants 
 
Changes in safety laboratory data (hematology, 
clinical chemistry, and urinalysis) 
 
Changes in vital signs (PR, BP, RR, and body 
temperature) 
 
Changes in 12-lead ECG assessment 
 
Physical examination findings 
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BP=blood pressure; ECG=electrocardiogram; PK=pharmacokinetic(s); PSL=padsevonil; PR=pulse rate; 
RR=respiratory rate; SAE=serious adverse event; TEAE=treatment-emergent adverse event 
4 
STUDY DESIGN 
4.1 
Overall design 
This is a Phase 1, open-label study to evaluate the effect of moderate hepatic insufficiency on 
PK, safety, and tolerability following single and multiple oral doses of PSL. The study design is 
shown in Table 1-2. 
A study participant who provides written informed consent will be screened within 28 days of 
first Treatment Period. Baseline procedures will be performed within 1 day of the first Treatment 
Period. Study participants will be included in a single- and multiple-dose study of PSL. The 
study will include up to 24 study participants divided into 2 cohorts (Cohort A [approximately 
12 participants] with no hepatic insufficiency and Cohort B [approximately 12 participants] with 
Child-Pugh classified moderate hepatic insufficiency). 
Both cohorts will be initially matched for gender and then subsequently by weight to allow 
comparison across cohorts, if feasible. Hepatically impaired participants will be recruited first 
and subsequent sexes and weight matched controls will be included, if feasible. In each group 
there will be a homogenous repartition between male and female study participants with at least 
2 study participants per gender. 
All activities will be completed as per the Schedule of Activities (Table 1-3). Screening and 
Baseline assessments will be followed by the Single-Dose Treatment Period and a Washout 
Period before entering the Multiple-Dose Treatment Period. The participants will then then 
undergo a second Washout Period before completing the EOS Visit. 
4.2 
Scientific rationale for study design 
In healthy volunteers without hepatic impairment, the concentration-time profiles of both PSL 
and 
 demonstrated a biphasic disposition with a 
terminal elimination half-life (t1/2) of approximately 6 hours for the parent, and 10 to 14 hours for 
the metabolite, which were independent of dose. However, steady state was achieved after 
2 to 3 days of treatment for both moieties, and the accumulation ratio for the parent was 
approximately 1.7 (range 1.59 to 2.11), which was greater than predicted by the single dose PK 
(N01386). 
As PSL is cleared hepatically, exposure to drug in hepatically impaired participants could 
increase primarily due to a reduction in PSL clearance, among other factors. This can be 
illustrated by an increase in t1/2, a prolonged washout time, and an increased time to reach steady 
state with multiple dosing. To facilitate the design of this study, a doubling of t1/2 and time to 
steady state has been assumed in hepatically impaired participants. Therefore, the Washout 
Period required to capture the t1/2 of the 
 has been 
calculated to be 5 to 6 days (assumes a t1/2 of 28 hours) and the time to steady state has been 
calculated to be 4 to 6 days. 
4.3 
Justification for dose 
The maximum tolerated dose (MTD) of PSL was identified as repeat dosing of 400mg twice 
daily (BID) in Phase 1 studies. In this study, the planned doses are well under the MTD, and 
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100mg BID is one of the dose levels currently being investigated in the 2 pivotal efficacy studies 
(EP0091 and EP0092). Padsevonil is predominantly cleared hepatically; therefore, an increase of 
exposure of PSL is expected in these hepatically impaired participants. A dose of 100mg BID 
was selected to allow collection of PK and tolerability data in vulnerable participants who may 
have less tolerance to PSL as compared with healthy participants. In addition, selection of a dose 
level of 100mg BID, which is 4-fold lower than the MTD, provides an opportunity to 
characterize the effect of liver disease on PSL PK without exploring PSL exposure beyond the 
one achieved at the MTD. 
4.4 
End of study definition 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last scheduled procedure shown in the EOS Visit in the Schedule of 
Activities (Table 1-3). 
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule 
of Activities for the last participant in the study globally. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply at 
Screening and at Baseline (Day -1): 
Inclusion criteria for ALL study participants 
1. Participant must be male or female 18 to 70 years of age, inclusive, at the time of signing the 
informed consent. 
2. Participant must have body weight of at least 50kg (males) or 45kg (females) and body mass 
index within the range 18 to 38kg/m2 (inclusive). 
3. Participant must be 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) and in this protocol. 
4. Participant must be considered reliable and capable of adhering to the protocol, according to 
the judgment of the Investigator, and must be capable of communicating satisfactorily with 
the Investigator. 
5. Participants must meet the following requirements to be included in the study: 
 A male participant must agree to use contraception as detailed in Appendix 4 
(Section 10.4) of this protocol during both Treatment Periods and for at least 7 days after 
the last dose of study medication and refrain from donating sperm during this period. 
 A female participant is eligible to participate if she is not pregnant (see Appendix 4; 
Section 10.4), not breastfeeding, and at least 1 of the following conditions applies: 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4) 
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OR 
A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4 (Section 10.4) during both Treatment Periods and for at least 90 days (or 
5 terminal half-lives) after the final dose of study medication. 
Specific inclusion criteria for study participants WITHOUT hepatic insufficiency 
6. Participants must be healthy as determined by medical evaluation, including medical history, 
physical examination, laboratory tests, and cardiac monitoring. 
Note: Participant has clinical laboratory test results within the local reference ranges or 
values that are considered not clinically relevant by the Investigator and approved by the 
UCB Study Physician. Laboratory parameters outside the reference ranges can be retested, 
and if the retest result is within the reference range or considered clinically not relevant, the 
study participant will be allowed in the study. 
Specific inclusion criteria for study participants WITH moderate hepatic 
insufficiency 
7. Participant must have characteristics that will meet the clinical criteria usually found in 
participants with chronic hepatic insufficiency, as determined by medical history and 
physical examinations (eg, echography, scintigraphy, biopsy, or some specific laboratory 
values as evidence) conducted within 3 weeks prior to the start of the Single-Dose Treatment 
Period. The degree of severity of hepatic impairment will be determined according to the 
classification of Child-Pugh (a score from 7 to 9 for Class B-moderate classification). 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply at Screening or at 
Baseline (Day -1): 
Exclusion criteria for ALL study participants 
1. Participant is, in the judgment of the Investigator, likely to be unreliable or noncompliant or 
uncooperative during the study. 
2. Participant has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or 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 Screening Visit. 
3. Participant has a known hypersensitivity to any components of the study medication as stated 
in this protocol. Participant has sensitivity to any of the study interventions, or components 
thereof, or drug or other allergy that, in the opinion of the Investigator or UCB Study 
Physician, contraindicates participation in the study. 
4. Participant has a lifetime history of suicide attempt (including an 
 
), or 
 as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the “Screening/Baseline” 
version of the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening or at Baseline 
(Day -1). 
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5. Participant has participated in another study of an investigational medicinal product (IMP) 
within the previous 1 month (or 5 half-lives, whichever is longer) prior to Screening, or is 
currently participating in another study of an IMP. 
6. Participant has had 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. 
7. Participant is unable to tolerate oral medication or has a history of gastrointestinal bypass 
surgery. 
8. Participant has past or intended use of over-the-counter or prescription medication including 
herbal remedies and hepatic enzyme inhibitors within 2 weeks or 5 half-lives prior to dosing, 
particularly for participants with hepatic impairment where t1/2 may be prolonged. Specific 
medications listed in Section 6.5.1 may be allowed. Participant has used hepatic 
enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, phenytoin, isoniazid, or 
rifampicin, etc.) within 2 months prior to dosing unless required to treat an AE. This does not 
include oral contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal hormone 
replacement therapy (HRT) or implants, patches, or intrauterine devices (IUDs) /intrauterine 
systems (IUSs) delivering progesterone (for female study participants) or acetaminophen 
with a maximal dose of 2g/day or with a maximum of 10g over 15 days. In case of 
uncertainty, the UCB Study Physician should be consulted. 
9. Participant has a history of chronic alcohol or drug abuse within the previous 12 months. 
Participant has a positive pre-study drug/alcohol screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines). A 
participant with a positive finding on the drug screen may still be enrolled at the discretion of 
the Investigator if a plausible clinical explanation exists (eg, prior or concomitant medication 
use). 
10. Participant has any clinically relevant ECG finding at the Screening Visit or at Baseline 
(Day -1). 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 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 the result is out-of-range again, the study participant cannot be included. 
NOTE A: The QTcB or QTcF is either machine-read or manually over-read.  
NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In other words, 
several different formulas cannot be used to calculate the QT interval corrected (QTc) for an 
individual participant and then the lowest QTc value used to include or discontinue the 
participant. 
11. Participant has a history of unexplained syncope or a family history of sudden death due to 
long QT syndrome. 
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12. Participant has renal impairment as indicated by an estimated glomerular filtration rate 
(GFR) <60mL/min, calculated by using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (Levey, 2009): 
GFRCKD-EPI = 141 x min(Scr/κ, 1)α x max (Scr/κ, 1)-1.209 x 0.993Age x 1.018 [if female]  
x 1.159 [if Black] 
Where Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1, 
and max indicates the maximum of Scr/κ or 1 
13. Participant tests positive for human immunodeficiency virus-1/2 antibody (HIV-1/2Ab) at 
Screening or within 3 months prior to the first dose of study medication. 
14. 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. 
15. Participant has received blood or plasma derivatives within the 6 months preceding 
Screening. 
16. 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). 
17. Participant smokes more than 10 cigarettes per day (or equivalent) or has done so within 
6 months prior to the Screening Visit. 
18. Participant ingests grapefruit, passion fruit, or pawpaw (as beverage, fruit, or supplements) 
within 72h before each administration of study medication. If this is the case at the start of 
the study, study participants may be rescreened. 
19. Female participant tests positive for pregnancy, plans to get pregnant during participation in 
the study, or is breastfeeding. 
20. Participant has a diet that deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the Investigator. 
21. Participant has undergone sudden and/or extreme changes in exercise levels for 2 weeks prior 
to Screening Visit. 
Specific exclusion criteria for study participants WITHOUT hepatic insufficiency 
22. Participant has a history or presence of cardiovascular (eg, cardiac insufficiency, coronary 
heart disease, hypertension, arrhythmia, tachyarrhythmia, or myocardial infarction), 
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. Symptomatic or asymptomatic orthostatic hypotension at Screening 
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defined as a 20mmHg or more decrease in SBP, or 10mmHg or more decrease in DBP after 
1 and 3 minutes standing with the arm relaxed at the side (time zero begins after the study 
participant is upright). Five minutes of supine rest is used as baseline. 
23. Participant tests positive for hepatitis B surface antigen, or Hepatitis C virus antibody 
(HCV-Ab) at Screening or within 3 months prior to the first dose of study medication. 
NOTE: Participants with positive HCV-Ab due to prior resolved disease can be enrolled if a 
confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained. The HCV RNA 
testing is optional and participants with negative HCV-Ab test are not required to also 
undergo Hepatitis C RNA testing. 
24. Participant must have BP and pulse rate (PR) within normal range in the supine position after 
5 minutes rest (SBP: 90mmHg to 150mmHg; DBP: 40mmHg to 95mmHg; PR: 40bpm to 
100bpm). 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. 
25. Participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or 
alkaline phosphatase (ALP) >1.0x upper limit of normal (ULN). 
26. Participant has bilirubin >1.0xULN (isolated bilirubin >1.0xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
27. 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: For participants with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, a 
baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the electronic Case Report Form (eCRF). 
If participant has >ULN ALT, AST, or ALP that does not meet the exclusion limit at 
Screening, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing 
clinically relevant increase. In case of a clinically relevant increase, inclusion of the study 
participant must be discussed with the UCB Study Physician. 
28. Participant has tests results with ALT, AST, or ALP up to 25% above the exclusion limit 
may be repeated once for confirmation. This includes rescreening. 
29. Participant has gastrointestinal disease with the potential to influence absorption, including 
motility disorders. 
Specific exclusion criteria for study participants WITH moderate hepatic 
insufficiency 
Participants with moderate hepatic insufficiency will not be eligible for inclusion in this study if 
any of the following criteria apply at Screening or Baseline (Day -1): 
30. Participant must have vital sign parameters defined as: supine BP after at least 5 minutes rest 
and standing after 1 and 3 minutes rest must be within normal range 
(SBP: 90mmHg to 180mmHg; DBP: 40mmHg to 105mmHg; PR: 50bpm to 100bpm). 
31. Results of laboratory tests must be within the reference ranges except those usually found to 
be abnormal in study participants with moderate hepatic insufficiency. A study participant 
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with other values outside the normal range may be included in the study if, in the opinion of 
the Investigator, these values are of no clinical significance for the participant with moderate 
hepatic insufficiency and after approval of the UCB Study Physician has been obtained. 
32. Participants with moderate hepatic insufficiency and derived and associated clinical and 
laboratory findings of moderate hepatic insufficiency are allowed as long as they do not have 
other clinically important systemic disease such as psychiatric illness, or uncontrolled 
diabetes (based on medical history, physical examination, ECG, and/or routine laboratory 
data). The study participant may not have diseases that might confound the results of the 
study or cause additional risks during administration of PSL. 
33. Participant has acute liver failure of any etiology. 
34. Participant has biliary cirrhosis. 
35. Participant has used any drug indicated for the medical care of moderate hepatic 
insufficiency that is not established in dose and schedule for at least 14 days before the first 
liver function test (except paracetamol with a maximal dose of 2g/day or with a maximum of 
10g over 15 days). 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
 Participants will complete a light meal 30 minutes prior to each morning dose of PSL and 
will complete a standard meal 30 minutes prior to the evening dose. The standardized meal 
composition and timing should be consistent for all days the participant is on study. On days 
when PK assessments will be taken, study participants will complete a standardized meal 
(same macronutrient will be administered for minimizing covariates) in the afternoon and 
evening. 
 Padsevonil will be administered orally with 8oz (240mL) water. Between 1h predose and 
2h postdose, the total intake of beverages should be limited to 100mL. 
 The participant must not ingest grapefruit, starfruit, and pawpaw (as beverage, fruit, or 
supplements) within 72h before the study medication administration. These fruits are not 
allowed during the Treatment Period and throughout the study. 
5.3.2 
Caffeine, alcohol, and tobacco 
 During dosing, participants will abstain from ingesting caffeine- or xanthine-containing 
products (eg, coffee, tea, cola drinks, and chocolate) for 48h before the start of dosing until 
after collection of the final PK sample. 
 During the study, participants will abstain from alcohol for 24 hours before the start of 
dosing until after collection of the final PK sample. 
5.3.3 
Activity 
 Participants will abstain from strenuous exercise for 24 hours before each blood collection 
for clinical laboratory tests and during the study. Participants may participate in light 
recreational activities during the study (eg, watching television, reading). 
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5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
5.4.1 
Rescreening 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Study participants may be rescreened under conditions such as the following: 
 Study participant ingests grapefruit (as beverage, fruit, or supplements) within 72 hours 
before each administration of study medication. 
 If a study participant does not meet the enrollment criteria at Screening or on Day -1 due to 
an out-of-range laboratory result or a minor illness, he/she can be rescreened once at the 
discretion of the Investigator. Provided all enrollment criteria are met at the second 
screening, the study participant can be included. 
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. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes rescreening and only applies to healthy participants. 
Rescreened participants will be assigned a new participant number. 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), or placebo 
intended to be administered to a study participant according to the study protocol. 
6.1 
Treatments administered 
A summary of the treatments administered is provided in Table 6-1. Treatments will be 
administered in an open-label fashion and participants will be dosed in an upright position and 
will remain semi-recumbent until 4 hours after dosing. 
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Table 6-1: 
Study medications administered 
Study Medication Name: 
Padsevonil 
Dosage formulation: 
Tablets 
Unit dose strength(s): 
100mg 
Route of administration: 
Oral 
Dosing instructions: 
Dosing instructions are provided in the UP0056 IMP Handling Manual 
(IMP Instructions for Handling). 
Packaging and labeling: 
PSL tablets are manufactured, packaged, and labeled according to Good 
Manufacturing Practice guidelines and applicable laws and regulations. 
Manufacturer: 
UCB 
IMP=investigational medicinal product; PSL=padsevonil 
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 medications received and any discrepancies are reported 
and resolved before use of the study medication. 
Only participants enrolled in the study may receive study medication and only authorized site 
staff may supply or administer study medication. All study medication 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 UP0056 IMP Handling Manual (IMP Instructions for Handling). 
Further guidance and information for the final disposition of unused study medication are 
provided in the UP0056 IMP Handling Manual (IMP Instructions 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 
procedures or returned to UCB (or designee). Investigational medicinal product intended for the 
study cannot be used for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: randomization and blinding 
This study is an open-label, non-randomized study; therefore, no study personnel or study 
participants will be blinded and no randomization will occur. 
Each participant will receive a 5-digit number assigned at Screening that serves as the participant 
identifier throughout the study. The participant number will be required in all communication 
between the Investigator and designee. 
6.3.1 
Procedures for maintaining and breaking the treatment blind 
6.3.1.1 
Maintenance of study medication blind 
This is not applicable as this is an open-label study. 
6.3.1.2 
Breaking the treatment blind in an emergency situation 
This is not applicable as this is an open-label study. 
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 use of concomitant medications during this study by participants without hepatic 
insufficiency should be avoided unless necessary to treat AEs or unless approved on a 
case-by-case basis prior to enrollment (eg, hormonal contraceptives). The use of any concomitant 
medications should be approved by the Sponsor in advance, in writing, when possible. The 
following concomitant medications are permitted during the study: 
 Paracetamol for the treatment of mild symptoms (eg, headache or other pain), given at most 
every 6h to 8h, not exceeding 2g/day, and with a total of no more than 10g over 15 days. 
 Inhaled corticosteroids for seasonal rhinitis. 
 Oral contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal HRT or 
implants, patches, or IUDs/IUSs delivering progesterone (for female participants). 
Use of other chronic medication by study participants with moderate hepatic insufficiency, not 
interfering with the endpoints of the study and at the discretion of the UCB Study Physician, will 
be permitted. 
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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 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 UCB Study Physician 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 UCB Study Physician and a decision will be made whether the study 
participant can continue in the study or must be withdrawn. 
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. 
6.7 
Treatment after the end of the study 
There are no plans for participant continued care 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 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. Investigators should contact the UCB Study 
Physician, in advance, whenever possible, to discuss the withdrawal of a participant. No restart 
will be allowed. 
7.1.1 
Liver chemistry stopping criteria 
The liver stopping criteria in this study will differ between those participants with normal hepatic 
function and those with impaired hepatic function. 
7.1.1.1 
Participants with normal hepatic function 
Discontinuation of study medication for abnormal liver function should be considered by the 
Investigator when a healthy participant meets 1 of the conditions outlined in Figure 7-1 or if the 
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Investigator believes that it is in best interest of the participant. Study medication will be 
discontinued immediately and permanently for a healthy participant if liver chemistry stopping 
criteria are met. 
If clinically concerning deteriorations in liver chemistry findings occur in a participant with 
established moderate hepatic insufficiency, then study medication will be discontinued 
immediately and permanently. 
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). 
7.1.1.2 
Participants with impaired hepatic function 
In view of the differing degrees of hepatic impairments anticipated among this subset of 
participants, the fixed criteria detailed in Figure 7-1 are inappropriate. 
Accordingly, any significant elevation of AST, ALT, bilirubin, or international normalized ratio 
(INR) values should be discussed with the UCB Study Physician and, in the context of the 
Baseline and pre-study levels typical for the individual and their overall clinical condition, a 
decision reached as to whether the case should be handled as a PDILI. 
As a guide, a doubling of any value is expected to represent a threshold for this evaluation. 
If a PDILI case is so identified, then the participant will be evaluated in accordance with the 
requirements of Appendix 6 (Section 10.6), adapted as necessary to match the circumstances. 
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7.1.2 
Criteria for study hold 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 ARs 
 occur in the same body system, and 
 lead to the 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 Study 
Physician, Safety Physician, Clinical Project Manager, 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 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 (see Section 10.3). 
7.2 
Participant discontinuation/withdrawal from the study 
Participants are free to withdraw from the study at any time, without prejudice to their continued 
care. 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
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If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she 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 (Table 1-3) for data to be collected at the time of early 
termination/study discontinuation and follow up and for any further evaluations to be completed. 
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 makes it unsafe to continue. 
2. Participant is noncompliant with the study procedures or medications in the opinion of the 
Investigator. 
3. Participant takes prohibited concomitant medications as defined in this protocol. 
4. Participant withdraws his/her consent. 
5. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
6. The Sponsor or a regulatory agency requests withdrawal of the participant. 
7. The study participant has changes in the ECG that are regarded as clinically significant 
and/or that worsen over time. 
8. The study participant has an ECG that shows an absolute value for QTcB or QTcF ≥500ms 
or ≥60ms above Baseline. 
9. The study participant develops a second- or third-degree atrioventricular block or another 
clinically relevant change in ECG as determined by the Investigator. 
10. 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 the benefit/risk of 
continuing the study participant in the study on PSL. 
11. 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. 
12. 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. 
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 Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
◦ 
Eosinophils percentage ≥10%. 
◦ 
Eosinophils absolute ≥0.5G/L. 
◦ 
Neutrophils absolute <1.5G/L. 
◦ 
Platelets absolute ≤100G/L. 
Investigators should attempt to obtain follow-up information on study participants in the case of 
withdrawal. 
Investigators should contact the UCB Study Physician, whenever possible, to discuss the 
withdrawal of a participant in advance. 
Participants who are withdrawn will be replaced at the discretion of the Investigator and 
Sponsor. 
7.3 
Lost to follow up 
A participant will be considered lost to follow up if he or she 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 participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (at least 1 phone call and 1 written message 
to the participant), and document his/her effort (date and summary of the phone call and copy 
of the written message in the source documents), to complete the final evaluation. All results 
of these evaluations and observations, together with a narrative description of the reason(s) 
for considering the participant lost to follow up, must be recorded in the source documents. 
The electronic eCRF must document the primary reason for withdrawal. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow up documented in the eCRF. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Table 1-3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the UCB Study Physician immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
medication. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Table 1-3), is essential and required for study conduct. 
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All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and confirm eligibility or record reasons for screening failure, as 
applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedule of Activities. 
The maximum amount of blood collected from each 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 
Pharmacokinetics 
Whole blood and urine samples will be collected for measurement of plasma and urine 
concentrations of PSL and its metabolites, as specified in the Schedule of Activities (Table 1-3). 
Additional samples may be collected at additional time points during the study if warranted and 
agreed upon between the Investigator and the Sponsor. 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24h clock time) of each sample will be recorded. 
Samples collected for analyses of PSL plasma and urine concentration may also be used to 
evaluate safety aspects related to concerns arising during or after the study. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files, but will not constitute a protocol amendment. The institutional review board 
(IRB)/independent ethics committee (IEC) will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF. 
Instructions and additional details regarding PK sampling are provided in the Laboratory 
Manual. 
The maximum deviations from scheduled sampling times considered irrelevant for PK are 
defined in Table 8‒1. 
Table 8‒1: 
Irrelevant time deviations for PK sampling 
PK blood sampling times 
Deviation from scheduled time considered irrelevant 
0 hours (predose) 
Within 60 minutes predose 
0.25 to 1.5 hours 
2 minutes 
2 to 8 hours 
5 minutes 
12 hours 
15 minutes 
24 to 96 hours  
60 minutes 
PK=pharmacokinetic 
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8.2 
Plasma protein binding 
Selected plasma samples (see Schedule of Activities, Table 1-3) will be collected and archived 
for future determination of ex-vivo plasma protein binding of PSL and, if feasible, its metabolites 
 and 
. If these investigations are performed, they will be 
described and reported as an addendum to the clinical study report (CSR). 
8.3 
Pharmacodynamics 
Not applicable. 
8.4 
Safety assessments 
The safety and tolerability of a single or multiple doses of PSL will be monitored by evaluation 
of AEs, vital signs (oral body temperature, PR, respiratory rate [RR], BP), 12-lead ECG 
parameters, physical examination findings, suicidal risk monitoring, psychiatric and mental 
status examination, and clinical laboratory test results. Planned time points for all safety 
assessments are provided in the Schedule of Activities (Table 1-3). 
8.4.1 
Physical examination 
Physical examinations will be performed at the time points specified in Table 1-3. A complete 
physical examination will include, at a minimum, general appearance; ear, nose, and throat; eyes, 
hair, and skin; abdomen; assessments of the Cardiovascular, Respiratory, Gastrointestinal 
Neurological, Musculoskeletal, and Hepatic systems; and mental status. Height and weight will 
also be measured and recorded. 
A brief physical examination will be conducted in a symptom-directed manor and only if 
clinically indicated. A brief physical examination will include, at a minimum, assessments of 
general appearance, 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 
Oral temperature, PR, RR, and BP will be assessed. 
Blood pressure and pulse measurements will be assessed in a supine position 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 at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones). 
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 ECGs will be obtained as outlined in the Schedule of Activities (see 
Table 1-3) using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 7.2 for QTc withdrawal criteria and any additional 
QTc readings that may be necessary. 
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All ECG recordings should be taken with the study participant resting in the supine position for 
≥5 minutes before the recording. 
8.4.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
Schedule of Activities for the timing and frequency. 
The Investigator must review the laboratory reports, document this reviews, 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 laboratory findings that change considerably or that increased in 
frequency or intensity more than expected as compared with the clinical profile known to the 
Investigator from the study participant’s history or Screening Period. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or at the EOS Visit should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or UCB Study Physician. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the UCB Study Physician notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the Laboratory Manual or equivalent document and the Schedule 
of Activities. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in 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 
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. 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). 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/Baseline” version of the C-SSRS during Screening (assessing the past 6 months) and 
Baseline (Day -1), followed by the “Since Last Visit” version at the visits indicated on the 
Schedule of Activities (Table 1-3). 
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 participants who have been treated with PSL should be instructed to monitor 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 Investigator. Consideration should be 
given to discontinuing PSL in participants who experience signs of suicidal ideation or behavior. 
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8.4.6 
Psychiatric and mental status 
The psychiatric and mental status of 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 Psychiatric and Mental Status 
assessment will be performed according to the Schedule of Activities (see Table 1-3). 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 participant. 
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 participant to discontinue PSL or UP0056 (see Section 7). 
8.5.1 
Time period and frequency for collecting AE and SAE 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 (Table 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, not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24h, as indicated in 
Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24h 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 participant, and to also inform 
participants of the need to inform the Investigator of any SAE within this period. Serious AEs 
that the Investigator thinks may be associated with the 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 AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.5.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious 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 
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 SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of 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, IRB/IEC, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review the document 
and 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 participants and, if indicated, female partners of male 
participants will be collected after the start of study medication and until 12 months after the 
birth for any significant medical issues. In certain circumstances, UCB may request that follow 
up is continued for a period longer than 12 months. If the study participant is lost to follow up 
and/or refuses to give information, written documentation of attempts to contact the study 
participant, or their female partner, needs to be provided by the Investigator and filed at the site. 
UCB’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 pregnancy is reported, the Investigator must immediately inform the Sponsor within 24h of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
Section 10.4). 
The participant should be withdrawn from the study as soon as pregnancy is known (by positive 
pregnancy test), and the following should be completed: 
 The participant should return for an Early Discontinuation Visit. 
 The participant should immediately stop the intake of the study medication as instructed at 
the Early Discontinuation Visit. 
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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 be concluded). Follow-up information should then be 
reported if an alternative etiology is identified during investigation and monitoring of the 
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, study participants, 
regulatory authorities, and IRBs/IECs can be informed appropriately. 
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 
Efficacy assessments 
Not applicable. 
8.8 
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/or 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. 
In the event of an overdose, the Investigator should: 
1. Contact the UCB Study Physician immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
medication can no longer be detected systemically (at least 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 UCB Study Physician (determined on a case-by-case basis). 
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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 UCB Study Physician based on the clinical evaluation of the participant. 
8.9 
Genetics 
Not applicable. 
8.10 
Biomarkers 
Not applicable. 
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 CSR. 
9.1 
Definition of analysis sets 
The following are the defined analysis sets: 
 Enrolled Set: All study participants who have signed the informed consent. 
 Full analysis Set (FAS): All enrolled study participants who received at least one dose of 
study medication. Analysis of this set will be according to the treatment the participants 
actually received. 
 Pharmacokinetic Per Protocol Set (PK-PPS): the PK-PPS is a subset of the FAS, 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 
one PK parameter. 
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 
three 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. 
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9.3 
Planned safety and other analyses 
9.3.1 
Pharmacokinetic analyses 
Pharmacokinetic parameters will be determined by non-compartmental analysis with Pharsight 
Phoenix® WinNonlin® v6.3 (or higher) software using the PK-PPS. 
Pharmacokinetic parameters of PSL and its major metabolites (
 
 will be computed using the actual blood sampling time points. 
The plasma concentration-time profiles, urine amounts, and PK parameters of PSL and its 
metabolites will be summarized by cohort (group), treatment period, and day using descriptive 
statistics (number of available observations, arithmetic mean, standard deviation, geometric 
mean, and CV of the geometric mean, median, minimum, and maximum). 
Individual plasma PSL and metabolites concentration-time profiles will be displayed graphically 
on a linear-linear scale and semi-logarithmic scale (including spaghetti plots). Geometric mean 
plasma concentrations-time curves, including 95% confidence intervals (CIs), will be displayed 
by cohort. 
For the Single- and Multiple-Dose Treatment Periods, PK parameters (including AUC, AUCτ, 
Cmax,ss, and Cmax) of PSL will be compared between the 2 cohorts (healthy and hepatically 
impaired participants) using analysis of variance (ANOVA) as follows: point estimates for the 
ratio of geometric means between healthy and hepatically impaired participants and the 
respective 2-sided 90% CIs will be computed using the least squares means and the root mean 
squares of error from the ANOVA of the log-transformed data with subsequent exponential 
transformation. Interstudy participant variability of PK parameters will be derived from these 
analyses. 
Graphical representation of the data (eg, Scatter plots) and/or linear regression analysis of the 
primary PK parameters (AUC and Cmax) of PSL and metabolites against the Child-Pugh 
parameters of total bilirubin, albumin, and prothrombin time will be also provided, if feasible. 
9.3.2 
Safety analyses 
All safety analyses will be performed using the FAS. All safety variables will be listed and 
summarized by cohort. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) and 
characterized as pretreatment and treatment-emergent according to the intake of the study 
medication. The occurrence and incidence of treatment-emergent AEs (TEAEs) will be 
summarized by MedDRA system organ class and preferred term and by Treatment Period, 
intensity, and by cohort. The occurrence and incidence of TEAEs will also be summarized by 
intensity and relationship to the study medication as judged by the Investigator. 
Treatment-emergent adverse events leading to discontinuation and SAEs will also be 
summarized. 
Laboratory variables and changes from Baseline will be summarized at each time point by 
cohort. Shift tables from Baseline to each post-Baseline time point will be presented. Values 
outside the reference range will be flagged in the listings. The out-of-normal range values will be 
displayed. Any PDILI events will be listed. 
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Vital sign variables (PR, RR, SBP, and DBP) and changes from Baseline will be summarized at 
each time point by cohort. Frequency tables of values outside the normal ranges will be produced 
by cohort and time point. 
Electrocardiograms 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 (time-matched Baseline day of each Treatment Period, when applicable) 
will be summarized by descriptive statistics at each time point by cohort. 
Assessment of suicidality (C-SSRS) will be listed. 
Physical examination abnormalities will be listed. 
9.4 
Planned efficacy/outcome analyses 
As efficacy is not being evaluated in this study, there is no primary efficacy endpoint. 
9.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol that potentially could have a 
meaningful impact on study conduct or on the primary PK outcomes for an individual study 
participant. Furthermore, study participants will be excluded from the FAS 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 
algorithmically to ensure consistency in the classification of important protocol deviations across 
all study participants. 
Important protocol deviations will be reviewed as part of an ongoing data cleaning process prior 
to database lock to confirm exclusion from analysis sets. 
9.6 
Handling of dropouts or missing data 
The methods for handling dropouts will be described in the SAP. 
Dropouts will be replaced at the discretion of the Investigator and Sponsor. 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. 
9.7 
Planned interim analysis and data monitoring 
No interim analysis or data monitoring are planned in this study. 
9.8 
Determination of sample size 
No formal sample size calculation is required for a hepatic insufficiency study. Up to 24 study 
participants will be included with approximately 12 participants per cohort; this is considered 
sufficient to meet the study objectives. 
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Based on the FDA guidance (FDA Guidance for Industry, 2003) regarding a two-fold change in 
AUC, exploratory sample size estimation was performed assuming the following: 
 Log-normal distribution on AUCss 
 Inter-study participant CV% of 40% 
 Detection of a two-fold change in AUCss, which is equivalent to a 50% reduction in total 
body clearance 
A sample size of 12 in each group will have >90% power to detect a fold change in means 
(expected ratio) of 2.000 assuming that the CV is 0.400 using a 2-sample t-test with a 
0.050 1-sided significance level. 
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-Good Clinical Practice (ICH-GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/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 
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 participants or others, and any protocol deviations, to 
eliminate immediate hazards to participants. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. 
For minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB requirements for continuing review of approved studies, the Investigator will 
be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
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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 clinical research organization 
agreements, as applicable. 
10.1.3 
Informed consent process 
Participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee). Each participant will have the opportunity to discuss the study and its alternatives 
with the Investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The participant or his/her legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, each participant must 
consent to direct access to his/her 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. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
The participant may withdraw his/her consent to participate in the study at any time. A 
participant is considered as enrolled in the study when he/she has signed the ICF. An eCRF must 
not be started, nor may any study specific procedure be performed for a given participant, 
without having obtained his/her written consent to participate in the study. 
10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the participant number 
assigned. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, and representatives of regulatory authorities will be allowed to review that portion of 
the participant’s primary medical records that directly concerns this study (including, but not 
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limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a participant’s study participation, and autopsy reports for 
deaths occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, or by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
Not applicable. 
10.1.6 
Data quality assurance 
All participant data relating to the study will be recorded on 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 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 at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study medication. These documents should 
be retained for a longer period, however, if required by the applicable regulatory requirement(s) 
or by an agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The Investigator will 
contact UCB for authorization prior to the destruction of any study records or in the event of 
accidental loss or destruction of any study records. The Investigator will also notify UCB should 
he/she 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. 
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Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the 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 
clinic records, charts, laboratory results, printouts, pharmacy records, ECG or other printouts, or 
completed scales, for example. Source documents should be kept in a secure, limited access area. 
Source documents that are computer-generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the participant’s source documents. The 
Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.8 
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. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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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 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 participants are detailed in 
Section 5.1 and Section 5.2 of this 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 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Coagulation panel 
INR 
Clinical 
Chemistrya 
Blood Urea Nitrogen 
(BUN) 
Potassium 
Aspartate Aminotransferase 
(AST)/ Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose 
Calcium 
Alkaline phosphatase 
 
Routine 
Urinalysisb 
 Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte by dipstick. If protein or blood or leukocytes are abnormal 
(positive), a microscopic examination of the sediment will be performed. 
Other Screening 
Tests 
 Follicle-stimulating hormone (at Screening only) to confirm postmenopausal status 
in female study participants 
 Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines) 
 Pregnancy test: Serum human chorionic gonadotropin (hCG) test (as needed for 
women of childbearing potential) 
 Serology (HIV 1 and 2 Ab, HBsAg, HCV-Ab) > 
The results of each test must be entered into the eCRF. 
a Details of liver chemistry stopping criteria and required actions and follow up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Section 10.6. All events of ALT ≥3×ULN) and bilirubin ≥2×ULN 
(>35% direct bilirubin) or ALT≥3×ULN and INR >1.5, if INR measured, may indicate severe liver injury 
(possible Hy’s Law) and must be reported as an SAE (excluding studies of hepatic insufficiency or cirrhosis). 
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b  Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
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 
10.3.1 
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 drug-drug interaction. 
 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. 
 
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Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
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d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle) which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Important medical events: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
Examples of such events include, but are not limited to, potential Hy’s Law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
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10.3.3 
Recording and follow up of AE and/or SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the eCRF. 
 It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to UCB in lieu of completion of the UCB AE/SAE eCRF page. 
 There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to UCB. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with 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 one 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 Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to UCB. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to UCB. 
 The Investigator may change his/her opinion of causality in light of follow up information 
and send a SAE follow up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
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Follow-up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
 An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the participant is lost to follow up. 
This follow up requirement applies to AEs, SAEs, and AEs of special interest. 
 If a participant dies during participation in the study or during a recognized Follow-Up 
Period, the Investigator will provide UCB with a copy of any 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 UCB within 24 hours of receipt of the 
information. 
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. 
 
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SAE Reporting to UCB via Paper CRF 
 Facsimile transmission of the SAE paper CRF 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 CRF 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 
Definitions 
10.4.1.1 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
 Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.4.2 
Contraception guidance 
10.4.2.1 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the protocol-defined time frame in Section 5.1: 
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
 Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 10-1 when having penile-vaginal intercourse with a 
WOCBP who is not currently pregnant. 
In addition, male participants must refrain from donating sperm for the duration of the study and 
for 7 days after the final dose of study medication. 
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Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame and for 7 days after the final dose of study medication. 
10.4.2.2 
Pregnancy testing 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected  
 Serum beta human chorionic gonadotropin (hCG) pregnancy testing will be performed at 
Screening. 
 Additional urine beta hCG pregnancy testing will be performed at predose on Day -1 and at 
the EOS/Early Termination Visit. The result must be negative prior to dosing the study 
participant. 
10.4.2.3 
Collection of pregnancy information 
10.4.2.3.1 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10-1. 
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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 (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 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 WOCBP 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 participant. 
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 participants in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study medication, which may reduce the 
efficacy of the contraceptive method. In this case, an appropriate additional barrier method of contraception should 
be utilized during the Treatment Period and for at least 90 days after the final dose of study medication.  
10.4.2.3.2 
Male participants with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 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 at least 12 months after the delivery date. Any termination of the pregnancy will be 
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reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
10.4.2.3.3 
Female participants who become pregnant 
 The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, the follow up will be at least 12 months after the 
delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to the study medication by the 
Investigator will be reported to the Sponsor as described in Section 8.5.5. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver safety – suggested actions and follow up 
assessments 
Participants with PDILI must be assessed to determine if study medication must be discontinued. 
In addition, all concomitant medications and herbal supplements that are not medically necessary 
should be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete a 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 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 >5x ULN and participants with hepatic 
impairment who show a doubling of their Baseline AST, ALT, bilirubin, or INR values. 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 participant safety and to evaluate 
liver event etiology (Table 10-2). 
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Table 10-2: Phase I liver chemistry stopping criteria and follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
For participants without hepatic insufficiency 
ALT-absolute 
ALT≥3xULN 
If ALT ≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) OR INR >1.5, 
report as an SAE.a,b 
See additional actions and follow up assessments listed below 
Suggested Actions and Follow-up Assessments 
Actions 
Follow-Up Assessments 
 
Report the event to the UCB within 24 hours. 
 
Complete the liver event eCRF, and complete a SAE 
data collection tool if the event also met the criteria 
for an SAE.b 
 
Perform liver chemistry follow up assessments. 
 
Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to baseline 
(see MONITORING). 
MONITORING: 
If ALT 3xULN AND bilirubin 2xULN or INR 
>1.5: 
 
Repeat liver chemistry tests (include ALT, aspartate 
transaminase [AST], alkaline phosphatase, bilirubin) 
and perform liver event follow up assessments within 
24 hours. 
 
Monitor participant twice weekly until liver 
chemistry 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 chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
chemistry follow up assessments within 24 to 
72 hours. 
 
Monitor participants weekly until liver chemistry 
abnormalities resolve, stabilize, or return to baseline. 
 
Viral hepatitis serology.c 
 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend. 
 
Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
 
Fractionate bilirubin, if total bilirubin 
2xULN. 
 
Obtain 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 high 
performance liquid chromatography 
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(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James et al, 2009].) 
NOTE: Not required in China. 
 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver 
disease; complete liver imaging and/or 
liver biopsy eCRFs. 
For participants with moderate hepatic insufficiency 
 
Participants with moderate hepatic insufficiency whose liver function deteriorates dramatically on 
study medication will be managed in a comparable manner, in accordance with their hepatic status. 
AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CPK=creatine phosphokinase; eCRF=electronic Case Report Form; HBsAg=hepatitis B virus surface antigen; 
HPLC=high performance liquid chromatography; IgG=immunoglobulin G; IgM=immunoglobulin M; 
INR=international normalized ratio; LDH=lactate dehydrogenase; RNA=ribonucleic acid; SAE=serious adverse 
event; ULN=upper limit of normal 
a  Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation 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 
insufficiency or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to 
participants receiving anticoagulants. 
c Hepatitis A IgM antibody; HBsAg and HCV-Ab; 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 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BID 
twice daily 
BP 
blood pressure 
cBZR 
central benzodiazepine receptor 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
coefficient of variation 
CYP 
cytochrome 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GABAA 
gamma-aminobutyric acid type A 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HCV-Ab 
hepatitis C virus antibody 
HIV-1/2Ab 
human immunodeficiency virus-1/2 antibody 
HRT 
hormone replacement therapy 
IB 
Investigator’s brochure 
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ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
LEV 
levetiracetam 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PR 
pulse rate 
PS 
Patient Safety 
PSL 
Padsevonil 
QTc 
QT interval corrected 
QTcB 
QT interval corrected for Bazett’s formula 
QTcF 
QT interval corrected for Fridericia’s formula 
RNA 
ribonucleic acid 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
serious adverse reaction 
SBP 
systolic blood pressure 
SV2 
synaptic vesicle protein 2 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
 
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10.11 
Appendix 11: Protocol amendment history 
Not applicable. 
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11 
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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. 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Approval Signatures
Name:
UP0056-protocol
Version:
1. 0
Document Number:
CLIN-000134923
Title:
UP0056-protocol
Approved Date:
09 Jul 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 04-Jul-2019 06:34:15 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-Jul-2019 15:41:21 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-Jul-2019 19:15:52 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 09-Jul-2019 07:36:48 GMT+0000
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof.