Clinical trial NCT04013191
Conditions: Elderly Study Participants Adult Study Participants
Keywords: Padsevonil Phase 1 Pharmacokinetic
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2019-07-09; Completion date: 2019-10-03
Enrollment: 28 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the plasma pharmacokinetic of padsevonil in adult and elderly study participants.

Detailed description:

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

Protocol documents:
Prot_000.pdf: 
UCB 
 
29 May 2019 
Clinical Study Protocol 
Padsevonil 
UP0053 
 
 
 
Confidential 
Page 1 of 72 
AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC, 
SAFETY AND TOLERABILITY STUDY OF SINGLE AND 
MULTIPLE ORAL ADMINISTRATIONS OF PADSEVONIL IN 
ADULT AND ELDERLY STUDY PARTICIPANTS 
 
PROTOCOL UP0053 AMENDMENT 1 
PHASE 1 
 
Short title: 
An open-label pharmacokinetic and safety study of single and multiple administrations of 
padsevonil in adult and elderly study participants 
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 
Protocol Amendment 1 
29 May 2019 
Nonsubstantial 
Original Protocol 
07 May 2019 
Not applicable 
Amendment 1 (29 May 2019) 
Overall Rationale for the Amendment 
The protocol has been amended to provide clarification regarding the collection of samples for 
safety laboratory evaluations, pharmacokinetics, and plasma protein binding. The timing was 
corrected for the collection of the samples for plasma protein binding and urine 
pharmacokinetics. The timing for Period 1B (Days 8 to 21) has also been corrected throughout 
the protocol. The protocol has also been amended to make corrections to the text and add further 
clarification regarding the scientific rationale for study design, justification for dose, dose 
modification, and withdrawal criteria. Additionally, the exclusion criteria have been updated to 
exclude study participants with severe renal impairment. 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis Overall design 
Corrected timing for Period 1B to 
Days 8 to 21 
Correction 
Section 1.3 Schedule of activities 
Added recording of adverse events/medical 
procedures on Day 8 
Correction 
Section 1.3 Schedule of activities 
Clarification of footnotes regarding timing 
of collection of samples for safety 
laboratory evaluations, pharmacokinetics, 
and plasma protein binding 
Clarification 
Section 1.3 Schedule of activities 
Corrected collection of plasma protein 
binding and urine pharmacokinetics 
samples from Day 12 to Day 13 
Correction 
Section 4.1.2 Treatment Period 
Corrected timing for Period 1B to 
Days 8 to 21 
Correction 
Section 4.2 Scientific rationale 
for study design 
Edited text 
Clarification 
Section 4.3 Justification for dose 
Edited text 
Clarification 
Section 5.2 Exclusion criteria 
Added exclusion criterion #17 
To exclude study 
participants with 
severe renal 
impairment 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2 Preparation, 
handling, storage, and 
accountability requirements 
Removed the following sentence: The 
Investigator (or designee) will instruct the 
study participant to store the study 
medication following the instructions on the 
label. 
Correction- study 
medication will be 
administered in the 
clinic; therefore, 
storage instructions for 
the participant are 
unnecessary 
Section 6.6 Dose modification 
Edited text  
To align with other 
padsevonil studies 
Section 7.1.2 Criteria for study 
hold due to adverse events 
Section removed 
Section is not required 
because Rapid Alert 
procedures are not 
being used in this 
study 
Section 7.2 Participant 
discontinuation/withdrawal from 
the study 
Added the following withdrawal criterion: 
There is a confirmation of a pregnancy 
during the study, as evidenced by a positive 
pregnancy test. 
To explicitly state that 
study participants with 
a confirmed pregnancy 
should be removed 
from the study 
Section 7.2 Participant 
discontinuation/withdrawal from 
the study 
Edited text regarding the replacement of 
study participants who are withdrawn from 
the study 
To align with other 
padsevonil protocols 
Section 8.2 Plasma protein 
binding 
Edited text 
To clarify the 
reporting of data for 
plasma protein binding 
of PSL and its 
metabolites 
Section 10.2 Appendix 2: 
Clinical laboratory tests 
Edited hematology laboratory assessments 
to include absolute reticulocyte counts 
instead of % reticulocytes 
Correction 
Section 10.4.2 Contraception 
guidance 
Edited text to the following: male study 
participants must refrain from donating 
sperm for the duration of the study and for 
7 days after the final dose of study 
medication 
For consistency with 
Section 5.2 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
US: +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 .......................................................................... 4 
1 
PROTOCOL SUMMARY ................................................................................................. 9 
1.1 Synopsis ............................................................................................................................. 9 
1.2 Schema ............................................................................................................................. 13 
1.3 Schedule of activities ....................................................................................................... 14 
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 
4.1.1 
Screening and Baseline Period ............................................................................ 21 
4.1.2 
Treatment Period ................................................................................................. 21 
4.1.3 
Follow-up Period ................................................................................................. 22 
4.2 Scientific rationale for study design................................................................................. 22 
4.3 Justification for dose ........................................................................................................ 23 
4.4 End of study definition ..................................................................................................... 24 
5 
STUDY POPULATION .................................................................................................. 24 
5.1 Inclusion criteria .............................................................................................................. 24 
Age 
  ............................................................................................................................. 24 
Type of participant and disease characteristics .................................................................... 24 
Weight 
  ............................................................................................................................. 24 
Sex 
  ............................................................................................................................. 25 
Informed consent ................................................................................................................. 25 
5.2 Exclusion criteria ............................................................................................................. 25 
5.3 Lifestyle restrictions ......................................................................................................... 29 
5.3.1 
Meals and dietary restrictions .............................................................................. 29 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 29 
5.4 Screen failures .................................................................................................................. 29 
5.4.1 
Rescreening .......................................................................................................... 29 
6 
STUDY TREATMENTS ................................................................................................. 30 
6.1 Treatments administered .................................................................................................. 30 
6.2 Preparation, handling, storage, and accountability requirements .................................... 30 
6.2.1 
Drug accountability ............................................................................................. 31 
6.3 Measures to minimize bias: randomization and blinding ................................................ 31 
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6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 31 
6.4 Treatment compliance ...................................................................................................... 32 
6.5 Concomitant medication(s)/treatment(s).......................................................................... 32 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 32 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 32 
6.5.3 
Rescue medication ............................................................................................... 32 
6.6 Dose modification ............................................................................................................ 32 
6.7 Treatment after the end of the study ................................................................................ 33 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 33 
7.1 Discontinuation of study medication ............................................................................... 33 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 33 
7.2 Participant discontinuation/withdrawal from the study ................................................... 34 
7.3 Lost to follow up .............................................................................................................. 35 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 36 
8.1 Pharmacokinetics ............................................................................................................. 36 
8.2 Plasma protein binding .................................................................................................... 37 
8.3 Safety assessments ........................................................................................................... 37 
8.3.1 
Clinical safety laboratory assessments ................................................................ 37 
8.3.2 
Vital signs ............................................................................................................ 38 
8.3.3 
Electrocardiograms .............................................................................................. 38 
8.3.4 
Physical examination ........................................................................................... 38 
8.3.5 
Suicidal risk monitoring ...................................................................................... 39 
8.3.6 
Psychiatric and Mental Status .............................................................................. 39 
8.4 Adverse events ................................................................................................................. 39 
8.4.1 
Time period and frequency for collecting AE and SAE information .................. 40 
8.4.2 
Method of detecting AEs and SAEs .................................................................... 40 
8.4.3 
Follow-up of AEs and SAEs ................................................................................ 40 
8.4.4 
Regulatory reporting requirements for SAEs ...................................................... 40 
8.4.5 
Pregnancy ............................................................................................................ 41 
8.4.6 
Adverse events of special interest ........................................................................ 41 
8.5 Safety signal detection ..................................................................................................... 41 
8.6 Treatment of overdose ..................................................................................................... 42 
8.7 Efficacy assessments ........................................................................................................ 42 
8.8 Pharmacodynamics .......................................................................................................... 42 
8.9 Genetics ............................................................................................................................ 42 
8.10 Medical resource utilization and health economics ......................................................... 42 
8.11 Biomarkers ....................................................................................................................... 42 
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9 
STATISTICAL CONSIDERATIONS ............................................................................. 42 
9.1 Definition of analysis sets ................................................................................................ 43 
9.2 General statistical considerations ..................................................................................... 43 
9.3 Planned safety and other analyses .................................................................................... 43 
9.3.1 
Pharmacokinetic analyses .................................................................................... 43 
9.3.2 
Safety analyses ..................................................................................................... 44 
9.4 Planned efficacy/outcome analyses ................................................................................. 44 
9.5 Handling of protocol deviations ....................................................................................... 44 
9.6 Handling of dropouts or missing data .............................................................................. 45 
9.7 Planned interim analysis and data monitoring ................................................................. 45 
9.8 Determination of sample size ........................................................................................... 45 
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 ..................................................................................................... 47 
10.1.5 
Committees structure ........................................................................................... 47 
10.1.6 
Data quality assurance ......................................................................................... 47 
10.1.6.1 
Case Report form completion .................................................................... 48 
10.1.6.2 
Apps ........................................................................................................... 48 
10.1.7 
Source documents ................................................................................................ 48 
10.1.8 
Study and site closure .......................................................................................... 49 
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 ....................................................... 54 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............. 57 
10.4.1 
Definitions ........................................................................................................... 57 
10.4.1.1 
Woman of childbearing potential .............................................................. 57 
10.4.2 
Contraception guidance ....................................................................................... 57 
10.4.2.1 
Male participants ....................................................................................... 57 
10.4.2.2 
Pregnancy testing ...................................................................................... 58 
10.4.2.3 
Collection of pregnancy information......................................................... 58 
10.5 Appendix 5: Genetics ....................................................................................................... 61 
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10.6 Appendix 6: Liver safety – suggested actions and follow-up assessments ..................... 62 
10.7 Appendix 7: Medical device incidents – definition and procedures for recording, 
evaluating, follow-up, and reporting ................................................................................ 64 
10.8 Appendix 8: Rapid alert procedures ................................................................................ 65 
10.9 Appendix 9: Country-specific requirements .................................................................... 66 
10.10 
Appendix 10: Abbreviations and trademarks ........................................................ 67 
10.11 
Appendix 11: Protocol Amendment History ......................................................... 69 
11 REFERENCES ................................................................................................................ 71 
SPONSOR DECLARATION .................................................................................................. 72 
 
LIST OF TABLES 
Table 1-1: 
Study schematic ............................................................................................... 13 
Table 1-2: 
Schedule of activities ....................................................................................... 14 
Table 6-1: 
Treatment administered ................................................................................... 30 
Table 8‒1: 
Irrelevant time deviations for PK sampling ..................................................... 37 
Table 10-1: 
Highly Effective Contraceptive Methods ........................................................ 59 
Table 10-2: 
Phase I liver chemistry stopping criteria and follow-up assessments .............. 62 
 
LIST OF FIGURES 
Figure 7-1: 
Liver Chemistry Stopping Algorithm .............................................................. 33 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: 
An open-label, parallel-group, pharmacokinetic, safety and tolerability study of single and 
multiple oral administrations of padsevonil in adult and elderly study participants 
Short title: 
An open-label pharmacokinetic and safety study of single and multiple administrations of 
padsevonil in adult and elderly study participants. 
Rationale: 
Padsevonil (PSL) is a novel chemical entity with selective affinity for both presynaptic vesicle 
protein 2 isoforms and postsynaptic central benzodiazepine receptor (cBZR) sites on the 
gamma-aminobutyric acid (GABA-A) 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 P450 (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 in adult study participants with epilepsy. The 
treatment of focal-onset seizures is often complex and associated with an increased concern for 
safety and tolerability in the elderly population due to age-related changes altering the 
pharmacokinetics (PK), disposition, and elimination of antiepileptic medicines (Motika and 
Spencer, 2016). Thus, the objective of this Phase 1, open-label study is to evaluate the effect of 
age on PK, safety, and tolerability of single and multiple oral doses of PSL in adult (ages 
18 to 64 years) and elderly (≥65 years) study participants. The study will explore any PK, safety, 
and tolerability differences between the adult and elderly cohort. 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 To evaluate the plasma PK of PSL in adult 
and elderly study participants 
 Single dose: Cmax, AUC0-t, AUC 
 Multiple dose: Cmax,ss, AUCtau  
Secondary 
 To evaluate the urine PK of PSL in adult 
and elderly study participants 
 Amount excreted and metabolic ratio of 
amount excreted 
 To evaluate the safety and tolerability of 
PSL in adult and elderly study participants 
 Incidence of TEAEs, SAEs, and TEAEs 
leading to discontinuation 
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Objectives 
Endpoints 
Other 
 To evaluate the plasma PK of PSL and 2 of 
its major metabolites 
 
 
 in adult and elderly study 
participants 
For PSL metabolites: 
 Single dose: AUC, AUC(0-t), and Cmax 
 Multiple dose: AUCtau and Cmax,ss  
For PSL and its metabolites: 
 Single dose: tmax, t1/2, AUC(0-12) 
 Multiple dose : tmax, t1/2ss, Ctrough, CL/Fss, 
metabolic ratios of AUCtau and Cmax 
For PSL: 
Bound and unbound plasma concentration of 
PSL in two samples. 
 To evaluate the urine PK of PSL and 2 of 
its major metabolites
 
 
 in adult and elderly study 
participants 
For PSL and its metabolites: 
 Single and multiple dose: CLR and fe 
 To evaluate the relationship between 
creatinine clearance and hepatic function 
tests and the PK of PSL and 2 of its major 
metabolites 
 
 in adult 
and elderly study participants. 
For PSL and its metabolites: 
 Single and multiple dose: regression 
analysis with AUC, CL/Fss, and CLR 
vs age, vs creatinine clearance, bilirubin, 
AST, and ALT 
 To evaluate the safety and tolerability of 
PSL in adult and elderly study participants 
 Changes in safety laboratory data 
(hematology, clinical chemistry, and 
urinalysis) 
 Changes in vital signs (pulse rate, BP, 
respiratory rate, and body temperature) 
 Changes in 12-lead ECG assessment 
 Physical examination findings 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BP=blood pressure; 
ECG=electrocardiogram; PK=pharmacokinetic; PSL=padsevonil; SAE=serious adverse event; 
TEAE=treatment-emergent adverse event 
Overall design 
This is a Phase 1, open-label study to evaluate the effect of age on the PK, safety, and tolerability 
of 200mg oral PSL in 2 cohorts of at least 10 adult (18 to 64 years, inclusive) (Cohort A) and 
18 elderly (≥65 years) study participants (Cohort B). The study utilizes a single dose (SD) and a 
multiple dose (MD) design. 
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The study consists of Screening, a Baseline Visit, Treatment Period, and Follow-up Period 
(End-of-Study/End-of-Treatment [EOS/EOT] Visit). 
Screening will be conducted at the study site(s) 3 to 28 days prior to check-in to the study site. 
Eligible study participants in the 2 age cohorts will be matched per gender for body weight if 
feasible, ie, the elderly study participants will be recruited first, and per gender, matched for 
body weight with adult study participants. Individual cases will be discussed with the Sponsor as 
needed. In each age cohort, there will be a homogenous repartition between male and female 
study participants, with at least 3 participants in each gender. To allow for an investigation of 
potential age-dependent effects, the elderly study participant cohort will also preferably include 
the following categories: at least 3 males and 3 females from ≥65 to 74 years old, and at least 
3 males and 3 females ≥75 years old. 
Study participants will check into the study site on Day -1 for the Baseline Visit and will 
undergo assessments as specified in the Schedule of Activities (Table 1-2). 
The Treatment Period consists of Period 1A (PSL SD administration) on Days 1 to 7 and 
Period 1B (PSL MD administration) on Days 8 to 21. 
In Period 1A, study participants will receive a single oral dose of 200mg PSL on Day 1, at 
approximately 8:00am, 30 minutes after a light meal. No study drug will be administered on 
Days 2 to 7; assessments will be conducted during this time as specified in the Schedule of 
Activities (Table 1-2). Days 2 to 7 are designated as a 6-day washout. 
In Period 1B, study participants will receive multiple oral doses of PSL as follows 
(note: twice daily [BID] dosing is achieved with a morning [approximately 8:00am] and evening 
[approximately 8:00pm] dose): 
 Day 8: 50mg PSL BID 
 Day 9: 100mg PSL BID 
 Days 10 to 12: 200mg PSL BID 
 Day 13: A morning dose of 200mg PSL and an evening dose of 100mg PSL 
 Days 14 and 15: 100mg PSL BID 
 Day 16: 50mg PSL BID 
 Days 17 to 21: no PSL administration; 5-day washout 
Throughout the study, plasma and urine samples for PK analysis and safety evaluations will be 
obtained according to the Schedule of Activities (Table 1-2). Adverse events and concomitant 
medications will be recorded throughout the study. Liver function parameters and creatinine 
clearance will be assessed in each study participant. These parameters are influenced by age; 
therefore, the acceptance ranges for these tests are wider for the elderly study participants. 
On Day 22, study participants will complete the EOS/EOT Visit procedures as specified in the 
Schedule of Activities (Table 1-2). 
Dropouts may be replaced at the discretion of the Investigator and Sponsor. 
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Number of participants 
A total of approximately 28 study participants will be enrolled overall in the US (at least 10 adult 
and at least 18 elderly study participants). 
Treatment groups and duration 
The maximum study duration for adult and elderly study participants is 50 days (up to 28 days 
for Screening plus 22 days from Baseline [Day 1] through the EOS/EOT Visit). 
 
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1.2 
Schema 
A schematic of the study design is provided in Table 1-1. 
Table 1-1: 
Study schematic 
 
Cohort A (adults; n=at least 10) and Cohort B (elderly; n=at least 18) 
Treatment Period 
Follow-
up Period 
Period 1A (SD) 
 
Period 1B (MD) 
EOS/ 
EOT 
Visit 
Day 
1 
2 
3 
4 
5 to 7 
8 
9 
10 
11 
12 
13 
morning 
13 
evening 
14 
15 
16 
17 to 21 
22 
 
 
Washout 
 
 
 
 
 
 
 
 
 
 
Washout 
 
PSL 
Dose 
(mg) 
200 
50 
BID 
100 
BID 
200 
BID 
200 
BID 
200 
BID 
200 
100 
100 
BID 
100 
BID 
50 
BID 
  
Plasma Plasma Plasma Plasma 
 
Plasma 
 
Urine 
Urine 
Urine 
Urine 
 
 
 
 
 
 
Urine 
 
 
 
 
 
 
BID=twice daily; EOS=End-of-Study; EOT=End-of-Treatment; MD=multiple dose; PK=pharmacokinetic(s); PSL=padsevonil; SD=single dose 
Note: BID dosing will be at approximately 8:00am and 8:00pm. 
Note: To allow age-dependent effects, elderly study participants will include preferably the following categories: at least 3 males and 3 females from 
≥65 to 74 years old and at least 3 males and 3 females ≥75 years old. The elderly study participants will be analyzed as one group. If an effect of age category is 
observed on PK or safety parameters, the effect of the age category will be explored. 
 
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1.3 
Schedule of activities 
The schedule of activities is provided in Table 1-2. 
Table 1-2: 
Schedule of activities 
Study Period/Visit 
Scr 
BL 
Visit 
Treatment Period 
Follow-up 
Period 
Period 1A (SD) 
 
Period 1B (MD) 
EOS/ 
EOT Visit 
Study Day(s) 
-28  
to -3 
-1 
1 
2 
3 
4 
5-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-21 
22 
 
 
 
Washout 
 
 
 
 
 
 
 
 
 
Washout 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & baseline characteristics  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria verification 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical/procedures history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Participant Identification Card 
assigned 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidality risk evaluation (C-SRSS) a 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Physical examination b 
X 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Psychiatric and Mental Status 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs c 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology, serum chemistry, urinalysis e 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
Serology (HIV, Hep B & C) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG f 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine and cotinine drug screen, alcohol 
breath test  
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Recording of AEs /medical procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1-2: 
Schedule of activities 
Study Period/Visit 
Scr 
BL 
Visit 
Treatment Period 
Follow-up 
Period 
Period 1A (SD) 
 
Period 1B (MD) 
EOS/ 
EOT Visit 
Study Day(s) 
-28  
to -3 
-1 
1 
2 
3 
4 
5-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-21 
22 
 
 
 
Washout 
 
 
 
 
 
 
 
 
 
Washout 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to study center 
 
X g 
 
 
 
 
X g 
 
 
 
 
 
 
 
 
 
 
 
Discharge from study center 
 
 
 
 
 
 
X g 
 
 
 
 
 
 
 
 
 
X g 
X 
Administer PSL 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug accountability 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood sampling for PSL PK levels h 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Additional blood sampling for PPB i 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urine collection for PSL PK j 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Final disposition determination k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE=adverse event; BID=twice daily; BL=Baseline; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EOS=End-of-Study; 
EOT=End-of-Treatment; Hep=hepatitis; HIV=human immunodeficiency virus; MD=multiple dose; PK=pharmacokinetic(s); PPB=plasma protein binding; 
PSL=padsevonil; Scr=screening; SD=single dose; tmax=time to maximum plasma concentration 
a 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. 
b At Screening, Baseline (Day -1) and Day 8, a full physical examination will be performed. On all other days a physical examination is performed, it will be a 
short physical examination (see Section 8.3.4). 
c Vital signs will be performed before each morning dose of PSL; if feasible; vital sign evaluations will follow the same schedule as ECGs. Blood pressure and 
pulse measurements should be preceded by at least 5 minutes of rest for the study participant in a quiet setting without distractions (eg, television, cell phones). 
d Serum pregnancy test will be performed for females of childbearing potential at Screening. Urine pregnancy testing will be performed at all other time points 
indicated.  
e For safety laboratory evaluations that occur on a dosing day, these will be performed before the morning dose/PK sample collection.  
f A 12-lead ECG will be performed after a rest of at least 5 minutes. All ECG recordings will be performed in triplicate at 2 to 3 minute intervals at Screening, 
Baseline (Day -1), predose and 3 hours after the morning dose on each PSL dosing day and EOS/EOT Visit.  
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g Study participants will be confined to the study site starting at Baseline (Day -1) and may be discharged on the morning of Day 5 after the assessments are 
complete, per the discretion of the Investigator. Study participants discharged on Day 5 will be readmitted to the study site on the evening of Day 7. If the 
Investigator deems it acceptable, study participants may be discharged the morning of Day 17. 
h PK plasma samples will be taken at the following time points: (a) Period 1A (single dose): predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48, 
and 72 hours postdose (14 samples); (b) Period 1B (multiple doses): predose (morning dose), and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, and 12h after the morning 
dose (11 samples). 
i Two blood samples will be collected after multiple doses at steady state (Day 13 predose and 1.5h postdose[(~tmax]) for PPB. 
j After the morning urine void and collection of a predose sample (no more than 60 minutes before dosing), PK urine collection will be performed at regular 
intervals on Days 1, 2, 3, and 4 at the following time points: 0 to <12h; 12 to <24h, 24 to <48h, and 48 to <72h after the single dose (4 samples). On Day 13, 
PK urine collection will be performed 0 to 12h after the 200mg PSL morning dose (1 sample). 
k For study participants prematurely terminating or completing the study, final disposition is recorded at the EOS/EOT Visit. All study participants prematurely 
terminating from the study should be encouraged to undergo final evaluation procedures, in accordance with the EOS/EOT Visit schedule, as soon as possible 
after the last dose of study medication. 
 
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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 isoforms and postsynaptic cBZR sites on the GABA-A receptor that has shown 
compelling, broad-range efficacy in several preclinical models of epilepsy conducted by UCB. 
Padsevonil is cleared via metabolism involving the CYP pathway; the formation of the 2 major 
metabolites, 
 
 is mainly mediated by CYP3A4, with potential involvement of CYP2C19. 
Padsevonil is currently being investigated in adult study participants with epilepsy. The 
treatment of focal-onset seizures with anti-epileptic medications is often complex and associated 
with an increased concern for safety and tolerability in the elderly population (Motika and 
Spencer, 2016). Both the prevalence and incidence of epilepsy increase in adults over 60 years 
old, and most new-onset epilepsy seizures are focal and as a result of new neurological 
conditions. The increase in both comorbid medical conditions and concomitant medications in 
elderly patients likely leads to an increase in side effects compared with younger patients. 
Additionally, PK considerations in elderly study participants include a decline in renal function 
associated with differences in clearance and elimination. Of particular relevance to PSL, an 
age-related decline in hepatic function is associated with decreased metabolism of CYP activity 
and a potential increase in serum levels. Moreover, changes in body mass and fat in elderly study 
participants can alter the disposition of drugs, and changes in serum proteins can result in 
changes in the drug free fraction and toxicity. 
An appropriate representation of the geriatric population (including patients with concomitant 
therapies and co-morbidities) is recommended to be enrolled in the clinical development 
program to adequately characterize efficacy and safety in the geriatric population and allow for 
comparisons with the nongeriatric population (Food and Drug Administration Guidance for 
Industry, 2012). A separate study in the geriatric population is desired as it is unlikely that 
sufficient data in elderly study participants (>10%) could be collected from pivotal studies with 
PSL. Thus, the objective of this Phase 1, open-label study is to evaluate the effect of age on the 
PK, safety, and tolerability of single and multiple oral doses of PSL in adult (ages 18 to 64 years) 
and elderly (≥65 years) study participants. 
2.2 
Background 
More than 50 million people worldwide suffer from epilepsy (World Health Organization, 2018). 
An imbalance between excitatory and inhibitory neurotransmission is widely recognized as a key 
factor leading to epilepsy. Consequently, drugs currently used in the treatment of epilepsy aim to 
restore this balance. In fact, most of the current antiepileptic drugs (AEDs) modulate neuronal 
transmission by either blocking voltage-gated sodium channels or acting on inhibitory/excitatory 
receptors located at the postsynaptic level. 
The GABA-A receptor mediates the bulk of inhibitory neurotransmissions in the brain. 
Allosteric modulation of inhibitory GABA-A 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 
unfavourable side effect profile (eg, drowsiness, ataxia, amnesia, paradoxical aggression), as 
well as the development of tolerance to anticonvulsant effects. 
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Compounds binding to synaptic vesicle protein 2A (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 synaptic vesicle protein 2B (SV2B) and synaptic vesicle 
protein 2C (SV2C) subtypes is not well established, but they share a high degree of sequence 
homology to SV2A and localization within synaptic vesicles (Wan et al, 2010; 
Janz and Südhof, 1999). Levetiracetam (LEV), exemplifying a SV2A-related mechanism of 
action, displays prominent clinical efficacy in patients with different forms of epilepsy 
(Klitgaard and Verdru, 2007). 
Compounds with dual activity at SV2A and GABA-A receptors are expected to have superior 
efficacy to those drugs working through only one of these mechanisms. Preclinical data in 
animal models of epilepsy support this assumption with compelling synergistic interaction 
observed between LEV and AEDs with GABAergic mechanisms of action 
(Kaminski et al, 2009). This synergistic interaction was particularly pronounced when 
combinations of LEV and benzodiazepines were tested and a significant increase in 
anticonvulsant potency of these drugs was observed associated with a higher therapeutic index. 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic SV2 proteins 
and postsynaptic cBZR sites on the GABA-A receptor. At presynaptic sites, PSL binds with high 
affinity to all 3 subtypes of the SV2 protein (ie, SV2A, SV2B, and SV2C), and with moderate 
affinity to postsynaptic cBZR sites. Pharmacological results obtained in rodent models of either 
partial or generalized seizures in humans show that PSL provides potent and efficacious seizure 
suppression, suggesting a broad spectrum profile. Furthermore, PSL revealed potent and 
efficacious seizure suppression in models of drug-refractory epilepsy, suggesting superior 
efficacy against seizures refractory to currently used AEDs. Specifically, in the rat amygdala 
kindling model, a model of refractory focal epilepsy, PSL was the only compound that produced 
seizure freedom at doses that can be administered in humans. Valproate, brivaracetam, 
clonazepam, diazepam, and phenobarbital only produced seizure freedom at plasma exposures 
that exceeded the maximum human exposures multiple times over. Padsevonil is not associated 
with loss of anticonvulsant efficacy after repeated administration in mice, suggesting reduced 
potential for the development of tolerance. Because of its unique properties, PSL is currently 
being proposed as adjunctive treatment for focal-onset seizures in patients with epilepsy. 
2.3 
Benefit/risk assessment 
Overall, the clinical pharmacology and clinical studies in drug-resistant epilepsy have 
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 (CNS) 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) following PSL administration are 
consistent with adverse effects of other AEDs, including SV2A ligands. Events reported in PSL 
clinical studies were transient, acute, and required admission to psychiatric care and medical 
treatment. The events in 2 healthy study participants occurred early after initiation or cessation of 
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PSL, which was done without titration or tapering. The psychotic effect in an epilepsy study 
participant emerged after dramatic improvement in seizure control and electroencephalogram 
activity a few weeks after the start of PSL, suggesting a “forced normalization” (Clemens, 2005; 
Loganathan et al, 2015). Dose reduction of PSL and medical treatment resulted in complete 
resolution of psychosis within days as the treatment with PSL continued. The occurrence of 
acute psychiatric SAEs in these 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 and monitoring of psychiatric and mental 
status changes. 
Despite the occurrence of several electrocardiogram (ECG) findings (including different types of 
ectopy) following PSL administration 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 Phase 1 or Phase 2 studies and all echocardiograms were assessed as 
normal. There are currently no data to suggest that PSL 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 GABA-A targeted mechanism of action of PSL and do not appear likely to have a clinically 
significant effect in therapeutic use. As a precaution, and in view of the nonclinical 
histopathological cardiac findings, echocardiogram screening of study participants at Baseline 
and ongoing echocardiogram monitoring during treatment and posttreatment have been 
implemented in the studies that have a >3-week treatment duration. To date, no clinically 
significant echocardiogram findings (only minor/trace or Grade 1 findings) have been observed. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PSL may be found in the Investigator’s Brochure (IB). The current IB reflects 
the safety profile of PSL as it is known and may change with the accumulation of additional data. 
The healthy study participants included in this study will receive no medical benefit from 
participation. The risks from taking part in the study will be minimized through the selection of 
appropriate dose levels, selection of appropriate study participants defined by the 
inclusion/exclusion criteria, and safety monitoring. 
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3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 To evaluate the plasma PK of PSL in adult 
and elderly study participants 
 Single dose: Cmax, AUC0-t, AUC 
 Multiple dose: Cmax,ss, AUCtau  
Secondary 
 To evaluate the urine PK of PSL in adult 
and elderly study participants 
 Amount excreted and metabolic ratio of 
amount excreted 
 To evaluate the safety and tolerability of 
PSL in adult and elderly study participants 
 Incidence of TEAEs, SAEs, and TEAEs 
leading to discontinuation 
Other 
 To evaluate the plasma PK of PSL and 2 of 
its major metabolites 
 
 
 in adult and elderly study 
participants 
For PSL metabolites: 
 Single dose: AUC, AUC(0-t), and Cmax 
 Multiple dose: AUCtau and Cmax,ss  
For PSL and its metabolites: 
 Single dose: tmax, t1/2, AUC(0-12) 
 Multiple dose : tmax, t1/2ss, Ctrough, CL/Fss, 
metabolic ratios of AUCtau and Cmax 
For PSL: 
Bound and unbound plasma concentration of 
PSL in two samples. 
 To evaluate the urine PK of PSL and 2 of 
its major metabolites (
 
 
) in adult and elderly study 
participants 
For PSL and its metabolites: 
 Single and multiple dose: CLR and fe 
 To evaluate the relationship between 
creatinine clearance and hepatic function 
tests and the PK of PSL and 2 of its major 
metabolites 
 
 in adult 
and elderly study participants. 
For PSL and its metabolites: 
 Single and multiple dose: regression 
analysis with AUC, CL/Fss, and CLR 
vs age, vs creatinine clearance, bilirubin, 
AST, and ALT 
 To evaluate the safety and tolerability of 
PSL in adult and elderly study participants 
 Changes in safety laboratory data 
(hematology, clinical chemistry, and 
urinalysis) 
 Changes in vital signs (pulse rate, BP, 
respiratory rate, and body temperature) 
 Changes in 12-lead ECG assessment 
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Objectives 
Endpoints 
 Physical examination findings 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BP=blood pressure; 
ECG=electrocardiogram; PK=pharmacokinetic; PSL=padsevonil; 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 age on the PK, safety, and tolerability 
of oral PSL in 2 cohorts of at least 10 adult (18 to 64 years, inclusive) study participants 
(Cohort A) and 18 elderly (≥65 years) study participants (Cohort B). 
The study utilizes a SD and a MD design. Period 1A is the SD Period and consists of a single 
dose of PSL followed by a Washout Period. Period 1B is the MD Period and consists of PSL 
up-titration, maintenance, and tapering during the Treatment Period, followed by a Washout 
Period. Both adult and elderly study participants will take part in the SD and MD Periods. 
The total study duration for each study participant is up to 28 days for Screening plus 22 days 
from Day 1 through the EOS/EOT Visit (up to 50 days in total). 
A study schema is provided in Table 1-1 and the Schedule of Activities is provided in Table 1-2. 
4.1.1 
Screening and Baseline Period 
Screening will be conducted at the study site 3 to 28 days prior to check-in to the study site. 
Study participants will sign a written informed consent form (ICF) prior to the conduct of any 
study-related procedures. Screening assessments will be conducted as specified in the Schedule 
of Activities (Table 1-2), after which the study participants’ eligibility will be determined on the 
basis of the inclusion/exclusion criteria. 
Eligible study participants in the 2 age cohorts will be matched per gender for body weight if 
feasible; ie, the elderly study participants will be recruited first, and per gender, matched for 
body weight with adult study participants. Individual cases will be discussed with the Sponsor as 
needed. In each age cohort, there will be a homogenous repartition between male and female 
study participants, with at least 3 participants in each gender. To allow for an evaluation of 
potential age-dependent effects, the elderly study participant cohort will also preferably include 
the following categories: at least 3 males and 3 females from ≥65 to 74 years old, and at least 
3 males and 3 females ≥75 years old. 
The Baseline Period will begin when study participants check into the study site on Day -1 and 
undergo Baseline assessments as specified in the Schedule of Activities (Table 1-2). The 
Investigator will ensure clear instructions are provided on prohibited concomitant foods and 
medications that must be avoided. 
4.1.2 
Treatment Period 
The Treatment Period consists of Period 1A (PSL SD administration) on Days 1 to 7 and 
Period 1B (PSL MD administration) on Days 8 to 21. 
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In Period 1A, study participants will receive a single oral dose of 200mg PSL on Day 1, at 
approximately 8:00am, 30 minutes after a light meal has finished. No study drug will be 
administered on Days 2 to 7; assessments will be conducted during this time as specified in the 
Schedule of Activities (Table 1-2). Days 2 to 7 are designated as a 6-day washout. 
In Period 1B, study participants will receive multiple oral PSL doses on Days 8 to 15, followed 
by a 5-day washout (Days17 to 21). Padsevonil will be administered BID, with one dose in the 
morning [approximately 8:00am] and one dose in the evening [approximately 8:00pm]. Each 
morning dose will be administered 30 minutes after a light meal has finished. Each evening dose 
will be administered 30 minutes after a standard meal has finished. The specific PSL dosing 
schedule is as follows: 
 Day 8: 50mg PSL BID 
 Day 9: 100mg PSL BID 
 Days 10 to 12: 200mg PSL BID 
 Day 13: A morning dose of 200mg PSL and an evening dose of 100mg PSL 
 Days 14 and 15: 100mg PSL BID 
 Day 16: 50mg PSL BID 
 Days 17 to 21: no PSL administration; 5-day washout 
Dosing will be stopped in any individual study participant, or across the whole study, if any of 
the relevant individual or study stopping criteria (detailed in Section 7) are met. Decisions about 
dosing or study cessation for individual study participants should be discussed first with the UCB 
Study Physician. 
Throughout the study, plasma and urine samples for PK analysis and safety evaluations will be 
performed according to the Schedule of Activities (Table 1-2). Adverse events and concomitant 
medications will be recorded throughout the study. Liver function parameters and creatinine 
clearance will be assessed in each study participant. These parameters are influenced by age; 
therefore, the acceptance ranges for these tests are wider for the elderly study participants. 
Study participants will be admitted to the study site on Day -1 prior to the start of dosing. Per 
Investigator discretion, study participants may be discharged on the morning of Day 5 through 
the evening of Day 7. Study participants will be readmitted on the evening of Day 7 and will 
remain on site until the morning of Day 17, when they may be discharged with the permission of 
the Investigator. 
4.1.3 
Follow-up Period 
Study participants will return to the study site on Day 22 to complete the Follow-up Period, 
which consists of the EOS/EOT Visit. At this visit, study participants will complete the 
EOS/EOT Visit procedures as specified in the Schedule of Activities (Table 1-2), completing 
their participation in the study. 
4.2 
Scientific rationale for study design 
UP0053 is an initial study to explore the effect of age on PK and safety of PSL in study 
participants. To evaluate age, the study includes 2 age cohorts: adult (ages 18 to 64 years) and 
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elderly (≥65 years) study participants. Furthermore, the elderly cohort is planned to include a 
further age-stratified breakdown of at least 3 males and 3 females from ≥65 to 74 years old and 
at least 3 males and 3 females ≥75 years old. 
To be able to fully characterize the effect of age on PK and safety of PSL, PSL is being 
administered to the same study participants as both SD (Period 1A) and MD (Period 1B). 
Multiple dosing of PSL is included in this study because time-dependent inhibition of apparent 
clearance, resulting in higher PSL exposures, was observed in previous studies, which implies 
that SD PK cannot be extrapolated linearly to a multiple dose profile. 
4.3 
Justification for dose 
During the SD Period, study participants will receive a single oral dose of 200mg PSL. During 
the MD Period, study participants will receive 200mg PSL BID, as well as 50mg PSL BID and 
100mg PSL BID for titration and tapering. Doses up to 400mg BID, including the 200mg BID 
dose, are being evaluated in global PSL Phase 2 and Phase 3 clinical studies intended for 
registration. 
A dose of 400mg PSL is considered the maximum tolerated dose (MTD) based on data from 
Phase 1 studies with PSL. In this study, the planned doses are well under the MTD and 
consistent with the doses being investigated for PSL registration. 
From the tolerability data generated in the PSL Phase 1 and 2 studies, study participants with 
epilepsy appear to tolerate higher doses of PSL (particularly the MTD of 400mg) compared with 
healthy study participants. While the reasons for this are not fully clear, PSL has a dual activity 
at SV2 and GABA-A receptors, and it is assumed that minimizing GABA-A receptor occupancy 
may increase tolerability. In the Phase 1 studies N01383 and UP0036, it has been demonstrated 
that 200mg PSL has minimal but quantifiable GABA-A receptor occupancy while also being 
associated with high and sustained SV2A receptor occupancy. 
Padsevonil is predominantly cleared hepatically, and hepatic function as well as renal function 
decreases with age, which suggests that exposure in elderly study participants might be increased 
due to a reduced hepatic function. Renal clearance of the parent and the desmethyl-metabolite is 
<1% of the dose and only approximately 18% of the dose is excreted in the urine as an inactive 
carboxylic acid metabolite. 
Based on the potential differences in the tolerability of PSL in healthy adults and the elderly, and 
to allow for potential excursions in exposure without encountering tolerability issues at a 
clinically relevant dose, PSL 200mg BID is the selected dose for this study. 
Taking all the above considerations into account, together with the primary and secondary 
objectives for this study, the PSL 200mg dose is deemed sufficient to evaluate the plasma PK, 
safety, and tolerability of PSL. It is likely that differences in either PK or safety and tolerability 
at the PSL 200mg dose can be extrapolated for the PSL 100mg BID and 400mg BID doses to be 
evaluated in the Phase 3 clinical studies intended for registration. Thus, in summary, the doses 
were chosen to provide reasonable exposure while optimizing expected tolerability in the healthy 
adult and elderly study participants because there was no anticipated benefit for the healthy study 
participants. 
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4.4 
End of study definition 
A study 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/EOT Visit in the Schedule 
of Activities (Table 1-2). 
The end of the study is defined as the date of last scheduled procedure shown in the Schedule of 
Activities (Table 1-2) for the last study participant in the study globally. 
The maximum study duration per study participant is 50 days, including up to 28 days for 
Screening and 22 days on study (ie, from Day 1 through the EOS/EOT Visit). 
5 
STUDY POPULATION 
Prospective approvals of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, are not permitted. 
5.1 
Inclusion criteria 
Study participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Study participants in the adult cohort must be ≥18 to 64 years of age at the time of signing 
the ICF. 
2. Study participants in the elderly cohort must be ≥65 years of age at the time of signing the 
ICF. 
Type of participant and disease characteristics 
3. Study participants who are overtly healthy as determined by medical evaluation, including 
medical history, physical examination, laboratory tests, and cardiac monitoring. In addition, 
elderly study participants must be considered to be in general good physical and mental 
health. 
Note: Study participant must have clinical laboratory test results within the local reference 
ranges or values that are considered as not clinically relevant by the Investigator and 
approved by the UCB Study Physician. Lab parameters outside the reference ranges can be 
retested, and if the retest result is within the reference range or considered as clinically not 
relevant the study participant will be allowed in the study. 
Weight 
4. Study participants must have a body weight of at least 50kg for males and 45kg for females, 
and a body mass index within the range of 18 to 32 kg/m2 (inclusive). 
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Sex 
5. Male and/or female study participants must meet the following requirements to be included 
in the study: 
 A male study participant must agree to use contraception as detailed in Appendix 4 
[Section 10.4] during the Treatment Period and for at least 7 days after the last dose of 
study treatment and refrain from donating sperm during this period. 
 A female study participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 10.4]), not breastfeeding, and at least one of the following conditions applies: 
◦ 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4) 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the Treatment Period and for at least 90 days after the last dose 
of study treatment. 
Informed consent 
6. Study participants 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 ICF and in this protocol.  
7. Study participant is considered reliable and capable of adhering to the protocol, according to 
the judgment of the Investigator, and is capable of communicating satisfactorily with the 
Investigator. 
5.2 
Exclusion criteria 
Study participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Study participant has a current or past psychiatric condition that, in the opinion of the 
Investigator, could compromise the study participant’s safety or ability to participate in this 
study, or 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. 
2. Study participant has history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrinological, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk 
when taking the study intervention; or interfering with the interpretation of data. 
3. Study participant has a history of chronic alcohol or drug abuse within the previous 
6 months. A study 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). 
4. Study participant has a positive pre-study drug/alcohol screen (to include at 
minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. 
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Note: A study participant with a positive finding on the alcohol and/or drug screen may still 
be enrolled at the discretion of the Investigator if a plausible clinical explanation exists 
(eg, prior or concomitant medication use) 
5. Study participant has a known hypersensitivity to any components of the study medication as 
stated in this protocol. 
6. Subject has a history of unexplained syncope or a family history of sudden death due to long 
QT syndrome. 
7. Study participant has abnormal blood pressure according to the following: 
Note: This includes both the routine and orthostatic hypotension BP assessments. 
For routine BP, study participants in the adult cohort must have blood pressure and pulse rate 
within normal range in the supine position after 5 minutes rest (SBP: 90mmHg to 145mmHg; 
DBP: 40mmHg to 95mmHg; PR: 40bpm to 100bpm). 
Study participants in the elderly cohort must have BP and pulse rate within normal range in 
the supine position after 5 minutes of rest (SBP: 90mmHg to 170mmHg; DBP: 40mmHg 
to 100mmHg; pulse rate: 40bpm to 110bpm). 
Any values marginally (ie, no more than 5mmHg) outside the normal range but considered 
not clinically significant by the Investigator are allowed. In the case of an out-of-range result, 
1 repeat will be allowed. If the readings are out of range again, the study participant will not 
be included. 
8. Study 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. 
Suicidality 
9. Study participant has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has had suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Screening/Baseline” version of the Columbia-Suicide Severity Rating Scale (C-SSRS) at 
Screening. 
Prior/Concomitant therapy 
10. Study participant has past or intended use of over-the-counter or prescription medication, 
including herbal medications within 2 weeks or 5 half-lives prior to dosing. Specific 
medications listed in Section 6.5.1 may be allowed. 
11. The study participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, 
phenobarbital, isoniazid, phenytoin, rifampicin) within 2 months prior to dosing. In case of 
uncertainty, the UCB Medical Monitor should be consulted. 
Prior/Concurrent clinical study experience 
12. Study participant has previously received PSL in this or another study. 
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13. Study participant has participated in another study of an investigational medicinal product 
(IMP) (and/or an investigational device) within the previous 30 days before Screening (or 
within 5 half-lives for the IMP, whichever is longer) or is currently participating in another 
study of an IMP (and/or an investigational device). 
Diagnostic assessments 
14. Study participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or 
alkaline phosphatase (ALP) >1.0x upper limit of normal (ULN). 
15. Study participant has bilirubin >1.0xULN (isolated bilirubin >1.0xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 
16. Study participant has current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 
Note: For randomized study 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 study 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 Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
17. Study participant has severe renal impairment as indicated by an estimated glomerular 
filtration rate (GFR)<30mL/min, calculated by using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Levey et al, 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 
18. Study participant has any clinically relevant ECG finding at Screening or at Baseline. Study 
participant has an abnormality in the 12-lead ECG that, in the opinion of the Investigator, 
increases the risks associated with participating in the study. In addition, any study 
participant with any of the following findings will be excluded: (a) QT interval corrected for 
heart rate using Bazett’s formula (QTcB) or Fridericia’s formula (QTcF) >450ms in study 
participants in 2 of 3 ECG recordings; (b) other conduction abnormalities (defined as PR 
interval ≥220ms); (c) irregular rhythms other than sinus arrhythmia or occasional, rare 
supraventricular or rare ventricular ectopic beats. In case of an out of range result, 1 repeat 
will be allowed. If out of range again, the study participant cannot be included. 
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NOTE A: The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-read or 
manually over-read. 
NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual study participant should be determined prior to initiation of the study. In other 
words, several different formulas cannot be used to calculate the QTc for an individual study 
participant and then the lowest QTc value used to include or discontinue the study 
participant. 
19. Study participant has the presence of hepatitis B surface antigen at Screening or within 
3 months prior to dosing. 
20. Study participant has a positive hepatitis C antibody test result at screening or within 
3 months prior to starting IP. 
NOTE: Study participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled if a confirmatory negative Hepatitis C ribonucleic acid test is obtained. 
21. Study participant has a positive human immunodeficiency virus antibody test. 
Other exclusions 
22. Study participant has made a blood or plasma donation or has had a comparable blood loss 
(>450mL) within the last 30 days prior to the Screening Visit. Blood donation during the 
study is not permitted. 
23. Study participant has a consumption of more than 600mg of caffeine/day (200mL of coffee 
contains approximately 100mg of caffeine, 200mL of black tea approximately 30mg, and 
200mL of cola approximately 20mg). 
24. Study participant smokes more than 5 cigarettes per day (or equivalent) or has done so within 
6 months prior to Screening. Smoking within 48 hours prior to CNS assessments is 
prohibited. 
25. Study participant ingests grapefruit (as beverage, fruit, or supplements) within 72 hours 
before each administration of study medication. If this is the case at the start of the study, 
study participants may be rescreened. 
26. Female study participant tests positive for pregnancy, plans to get pregnant during 
participation in the study, or is breastfeeding. 
27. Study participant has a diet that deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the Investigator. 
28. Study participant has undergone sudden and/or extreme changes in exercise levels for 
2 weeks prior to Screening. 
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5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
 Study participants must refrain from consumption of grapefruit, starfruit, and pawpaw (as 
beverage, fruit or supplements) from 72 hours before the start of study treatment until after 
the final dose. 
 Study 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. 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. 
 Study participants will take PSL orally with 8oz (240mL) water. The use of beverages 
between 1h predose and 2h postdose should be limited to a maximum of 100mL (in order to 
keep groups comparable with respect to period of dosing). Water will be available ad libitum 
except for between 1 hour before and 2 hours after dosing. 
5.3.2 
Caffeine, alcohol, and tobacco 
 During dosing, study participants will abstain from ingesting caffeine- or xanthine-containing 
products (eg, coffee, tea, cola drinks, and chocolate) for 48 hours before the start of dosing 
until after collection of the final PK sample. 
 During the study, study participants will abstain from alcohol for 24 hours before the start of 
dosing until after collection of the final PK sample. 
 Study participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit. 
5.4 
Screen failures 
Screen failures are defined as study participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure study participants to meet the 
Consolidated Standards of Reporting Trials 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 (ie, screen failures) 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 meet the exclusion 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. 
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 
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laboratory values, and/or after the study participant makes a complete recovery from the mild 
illness and if all other screening criteria are met. 
Rescreened study participants should be assigned a new study participant number. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation; if the results are out of range again, the study participant cannot be 
included. 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Treatments administered 
A summary of the treatment administered is provided in Table 6-1. 
Table 6-1: 
Treatment administered 
Study Treatment Name: 
PSL 
Dosage formulation: 
Tablets 
Unit dose strength(s)/Dosage level(s): 
25mg and 100mg strength for QD and BID dosing 
Route of administration: 
Oral 
Dosing instructions: 
All treatments will be administered orally with 8oz. 
(240mL) water. The use of beverages between 
1h predose and 2h postdose should be limited to a 
maximum of 100mL (in order to keep groups 
comparable with respect to period of dosing). Study 
participants will complete a light meal 30 minutes 
prior to each morning dose of PSL and will complete a 
standard meal 30 minutes prior to the evening dose of 
PSL. 
Treatments will be administered in an open-label 
fashion. Study participants will be dosed in an upright 
position and will remain semi-recumbent until 
4h afterwards. 
Packaging and labeling: 
Padsevonil tablets are manufactured, packaged, and 
labeled according to Good Manufacturing Practice 
guidelines and applicable laws or regulations. 
Manufacturer: 
UCB 
BID=twice per day; PSL=padsevonil; QD=once per day 
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 treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
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Only study participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the UP0053 IMP Handling Manual. 
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. 
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 
Randomization and blinding are not applicable for this open-label study. 
Each study participant will receive a 5-digit number assigned at Screening that serves as the 
study participant identifier throughout the study. The study participant number will be required 
in all communication between the Investigator or designee. 
6.3.1 
Procedures for maintaining and breaking the treatment blind 
Not applicable. 
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6.4 
Treatment compliance 
Study participant compliance will be ensured by the administration of study medication by 
designated site personnel. Drug accountability must be recorded on the Drug Accountability 
form. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are permitted during the study: 
 For elderly study participants with stable conditions, use of chronic medication not 
interfering with the endpoints of the study and at the discretion of the UCB Medical Monitor 
will be permitted. 
 Paracetamol for the treatment of mild symptoms (eg, headache or other pain), given at most 
every 6 to 8h, not exceeding 2g/day, and with a total of no more than 5g over 7 days 
 Inhaled corticosteroids for seasonal rhinitis 
 Oral contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal hormone 
replacement therapy (HRT) or implants, patches, or intrauterine devices/intrauterine 
hormone-releasing systems delivering progesterone (for female study participants) 
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 Medical Monitor should be consulted. 
 Drugs of unknown half-lives are prohibited within 2 weeks before administration of PSL and 
during the clinical part of the study, unless required to treat an AE. 
If a study participant needs or takes any prohibited medication, the Investigator will (where 
possible) discuss with the UCB Medical Monitor 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. 
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6.7 
Treatment after the end of the study 
There are no plans for continued study participant care or treatment after the end of the study. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Study medication will be stopped if the study participant develops a medical condition (or 
laboratory abnormality or ECG change) that, in the opinion of the Investigator, compromises the 
study participant’s ability to participate or compromises the study participant’s safety. 
In all cases, the study participant should be followed until the condition has resolved as agreed 
by the Investigator and the UCB Study Physician. If a study participant discontinues study 
medication, no restart will be allowed. 
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study medication for abnormal liver function should be considered by the 
Investigator when a study participant meets one of the conditions outlined in Figure 7-1 or if the 
Investigator believes that it is in best interest of the study participant. 
Study medication will be discontinued immediately and permanently for a study participant if 
liver chemistry stopping criteria are met. 
Figure 7-1: Liver Chemistry Stopping Algorithm 
 
 
Abbreviations: ALT=alanine 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 are provided 
in Appendix 6 (Section 10.6). 
Continue Study Treatment 
Discontinue Study Treatment 
ALT ≥3xULN 
No
Yes
Refer to the Liver Safety Required Actions and Follow up Assessments section in 
Appendix 6. 
Report as an SAE if possible Hy’s Law case: AST/ALT ≥3xULN and Bilirubin 
≥2xULN (>35% direct) or INR>1.5, if measured 
(Note: INR value not applicable to study participants on anticoagulants) 
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7.2 
Participant discontinuation/withdrawal from the study 
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care. 
A study participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the study participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a study participant withdraws from the study, he/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 1-2) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Study participants should be withdrawn from the study if any of the following events occur: 
1. The study participant develops a clinically relevant medical condition (physical or 
psychiatric) that, in the opinion of the Investigator, jeopardizes or compromises the study 
participant’s ability to participate in the study or makes it unsafe to continue. 
2. The study participant is noncompliant with the study procedures or medications in the 
opinion of the Investigator. 
3. The study participant takes prohibited concomitant medications as defined in this protocol. 
4. The study participant withdraws his or 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 study participant. 
7. The study participant has changes in the ECG that are regarded as clinically significant 
and/or that worsens 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 judgement 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. 
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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. 
 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. 
Withdrawn study participants should follow a taper schedule if possible unless faster 
discontinuation is considered necessary in the medical judgement of the Investigator. 
Investigators should attempt to obtain information on study participants in the case of 
withdrawal. 
Study participants who are withdrawn will be replaced at the discretion of the Investigator and 
Sponsor.  
7.3 
Lost to follow up 
A study 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 study participant fails to return to the clinic for a 
required study visit: 
 The site must attempt to contact the study participant and reschedule the missed visit as soon 
as possible and counsel the study participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the study participant wishes to and/or should 
continue in the study. 
 Before a study participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the study participant (at least 1 phone call and 
1 written message to the participant), and document his/her effort (date and summary of the 
phone call and copy of the written message in the source documents), to complete the final 
evaluation. All results of these evaluations and observations, together with a narrative 
description of the reason(s) for removing the study participant, must be recorded in the 
source documents. The eCRF must document the primary reason for withdrawal. 
Should the study participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up documented in the eCRF. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Table 1-2). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the study participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Table 1-2), is essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential study 
participants meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all study participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Procedures conducted as part of the study participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the Schedule of Activities (Table 1-2). 
The maximum amount of blood collected from each study participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 500mL. 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 1-2) 
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 (24 hour 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. 
Genetic analyses will not be performed on these samples unless consent for this was included in 
the ICF. Study participant confidentiality will be maintained. At visits during which plasma and 
urine samples for the determination of multiple aspects of PSL will be taken, 1 sample of 
sufficient volume can be used. 
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 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 and urine sampling are provided in the 
Laboratory Manual. 
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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  
0.25 to 1.5 hours 
2 minutes 
2 to 8 hours 
5 minutes 
12 hours 
15 minutes 
24 to 48 hours 
60 minutes 
PK=pharmacokinetic 
8.2 
Plasma protein binding 
Selected plasma samples (described in the Schedule of Activities [Section 1.3]) will be collected 
and archived to measure the ex-vivo plasma protein binding of PSL and if feasible its 
metabolites 
. If these investigations are performed, they will be 
described and reported as an attachment to the clinical study report (CSR). 
8.3 
Safety assessments 
The safety and tolerability of SD and MD of PSL will be monitored by evaluation of AEs, 
clinical laboratory test results, vital signs (pulse rate, respiratory rate, SBP, DBP, and body 
temperature), 12-lead ECG parameters, Psychiatric and Mental Status and physical examination 
findings, and suicidal risk monitoring. 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Table 1-2). 
8.3.1 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-2) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are laboratory findings that change considerably or their frequency or 
intensity increases more than expected as compared to 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 EOT/EOS Visit should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or Medical 
Monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
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All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the Laboratory Manual and the Schedule of Activities (Table 1-2). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
8.3.2 
Vital signs 
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed as outlined in 
the Schedule of Activities (Table 1-2). 
Temperature may be measured by either oral or aural route at the discretion of the site, but must 
be performed using the same method in any individual study participant on all occasions. 
Blood pressure measurements will be performed in both supine and standing positions for 
orthostatic measurement at Screening (supine BP after the study participant has been lying down 
for 5 minutes, then standing BP after 1 minute and 3 minutes), and in a supine position for 
routine blood pressure measurements at all assessments. Blood pressure and pulse measurements 
will be assessed with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
study 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 blood pressure measurement. 
8.3.3 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the Schedule of Activities (Table 1-2) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 7 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary. 
All ECG recordings should be taken with the study participant resting in the supine position for 
at least ≥5 minutes before the recording. 
At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
8.3.4 
Physical examination 
Physical examinations will be performed at Screening and the time points specified in 
Section 1.3. 
A complete physical examination will include, at a minimum, general appearance; ear, nose, and 
throat; eyes, hair, and skin; and assessments of the Cardiovascular, Respiratory, Gastrointestinal 
Neurological, Musculoskeletal, and Hepatic systems; and mental status. Height and weight will 
also be measured and recorded. 
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A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
8.3.5 
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” version of the C-SSRS at Visit 1 (assessing the past 6 months) and the “Baseline” 
Version of the C-SSRS at Visit 2, followed by the “Since Last Visit” version at the visits 
indicated on the Schedule of Activities (Table 1-2). 
Study participants being treated with PSL should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior. Families and 
caregivers of study participants being treated with PSL should be instructed to monitor study 
participants for the emergence of unusual changes in behavior, as well as the emergence of 
suicidal ideation and behavior, and to report such symptoms immediately to the study 
Investigator. Consideration should be given to discontinuing PSL in study participants who 
experience signs of suicidal ideation or behavior. 
8.3.6 
Psychiatric and Mental Status 
The psychiatric and mental status of participating subjects 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 at Baseline and all scheduled time points in the Schedule of 
Activities (Table 1-2). 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. 
8.4 
Adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the study participant (or, when appropriate, by a caregiver, 
surrogate, or the study participant’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
study participant to discontinue the PSL or UP0053 (see Section 7). 
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8.4.1 
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 1-2). 
Medical occurrences that begin before the start of study treatment 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 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
The Investigator is specifically requested to collect and report to the Sponsor (or its 
representative) any SAEs (even if the Investigator is certain that they are in no way associated 
with the study medication), up to 30 days from the end of the study for each study participant, 
and to also inform study participants of the need to inform the Investigator of any SAE within 
this period. Serious AEs that the Investigator thinks may be associated with the study medication 
must be reported to the Sponsor 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). 
8.4.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the study participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each study 
participant at subsequent visits/contacts. All SAEs and non-serious AEs of special interest 
(AESIs) (as defined in Section 8.4.6) will be followed until resolution, stabilization, the 
Investigator determines that it is no longer clinically significant, the event is otherwise explained, 
or the study participant is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is given in Appendix 3 (Section 10.3). 
8.4.4 
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 study participants and the safety of a 
study treatment 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 treatment 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. 
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An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate, according to local requirements. 
8.4.5 
Pregnancy 
Details of all pregnancies in female study participants and, if indicated, female partners of male 
study participants, will be collected after the start of study treatment and until 30 days after the 
birth for any significant medical issues. In certain circumstances, the Sponsor may request that 
follow up is continued for a period longer than 30 days. If the study participants is lost to follow 
up and/or refuses to give information, written documentation of attempts to contact the study 
participant needs to be provided by the Investigator and filed at the site. The Sponsor’s Patient 
Safety (PS) department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
If a pregnancy is reported, the Investigator must immediately inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
The study participant should be withdrawn from the study as soon as pregnancy is known (by 
positive pregnancy test), and the following should be completed: 
 The study participant should return for the EOS/EOT Visit. 
 The study participant should immediately stop the intake of the study medication or be 
tapered as instructed at the EOS/EOT Visit. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.6 
Adverse events of special interest 
An AESI 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 AESIs 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 the Sponsor as an AESI (ie, without waiting for any additional 
etiologic investigations to have been concluded). Follow-up information should then be reported 
if an alternative etiology is identified during investigation and monitoring of the study 
participant. 
8.5 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that Investigators, clinical study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The UCB Study Physician or medically qualified designee/equivalent will conduct an ongoing 
review of SAEs and perform ongoing SAE reconciliations in collaboration with the PS 
representative. 
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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. 
8.6 
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 Medical Monitor immediately. 
2. Closely monitor the study participant for any AE/SAE and laboratory abnormalities until 
study treatment 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 
treatment if requested by the UCB Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the UCB Medical Monitor based on the clinical evaluation of the study 
participant. 
8.7 
Efficacy assessments 
Efficacy is not evaluated in this study. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.9 
Genetics 
Genetics are not evaluated in this study. 
8.10 
Medical resource utilization and health economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
8.11 
Biomarkers 
Biomarkers are not evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). Deviations in analyses from the final SAP will be documented in the CSR. 
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9.1 
Definition of analysis sets 
The following are the defined analysis sets: 
 Enrolled Set: All study participants who signed the ICF. 
 Full analysis Set (FAS): All enrolled study participants who signed the ICF and received at 
least one dose of study medication. 
 Pharmacokinetic Per Protocol Set (PK-PPS): PK-PPS is a subset of the FAS, consisting of 
those study participants who had no important protocol deviations affecting the PK 
parameters and had a sufficient number of samples available to determine at least 1 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 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 and urine concentration and PK parameters will be presented 
using 3 significant digits. 
If not otherwise stated, Baseline will be the last assessment prior to dosing. Measurement of 
specific Baseline values will be described in the SAP. 
9.3 
Planned safety and other analyses 
9.3.1 
Pharmacokinetic analyses 
Pharmacokinetics 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 2 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 
2 major metabolites 
 will be summarized by age group (adult 
[18-64 years] and elderly study participants [≥65 years]) and treatment period using descriptive 
statistics. If PK effects by age group are observed (ie, between adult and elderly study 
participants), subgroup analyses may be performed within the elderly age group (age [≥65 to 
74 years old and ≥75 years old] and gender). 
Individual plasma PSL and its major 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 SD and MD periods of the study, primary PK parameters (AUC and Cmax) will be 
assessed in adults and elderly study participants with analysis of variance (ANOVA). Point 
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estimates for the ratio of geometric means between adults and elderly study participants (and per 
category, if deemed necessary), 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. Interparticipant variability on PK parameters 
will be derived from these analyses. 
The relationship between PK parameters of PSL (and metabolites) and creatinine clearance, age 
(numerical), hepatic laboratory parameters (eg, bilirubin, ALT, and AST) will be evaluated using 
a graphical approach or correlation and linear regression techniques. 
9.3.2 
Safety analyses 
All safety analyses will be performed using the FAS. All safety variables will be summarized by 
the age group (adult and elderly study participants) and Treatment Period (SD, MD, and 
overall).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/preferred term and by age group and Treatment Period. The 
occurrence and incidence of TEAEs will also be summarized by intensity and by relationship to 
the study medication. Treatment-emergent AEs leading to discontinuation and SAEs will also be 
summarized. 
Laboratory variables and changes from Baseline will be summarized by descriptive statistics at 
each time point by age group and Treatment Period. Shift tables from Baseline to each 
post-Baseline time point will be presented by Treatment Period. Values outside the reference 
range will be flagged in the listings. 
Vital sign variables (BP and PR, body temperature, and respiration rate) and changes from 
Baseline (pre-dose of each Treatment Period) will be summarized by descriptive statistics at each 
time point by age group and Treatment Period. 
Electrocardiogram parameters will be recorded three times at each time point. The individual 
mean at each time point will be calculated as raw parameters for descriptive analysis. The raw 
parameters and change from Baseline will be summarized by descriptive statistics at each time 
point by age group and Treatment Period. 
Physical examination abnormalities will be listed. 
9.4 
Planned efficacy/outcome analyses 
Not applicable. 
9.5 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary PK outcome for an individual study 
participant. Study participants with an important protocol deviation will be excluded from the 
FAS. Study participants will be excluded from FAS only when there is documented evidence 
that they received no treatment. 
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The criteria for identifying important protocol deviations and the classification of important 
protocol deviations will be captured in the Important Protocol Deviations document. 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 may be replaced following discussion between 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 formal interim analyses are planned. Details about the safety analyses will be provided in the 
Safety Monitoring Committee Charter. 
9.8 
Determination of sample size 
No formal sample size computation has been performed for this study. This PK study will be a 
study of limited size conducted under SD and steady-state conditions to look for sizable 
differences between adult (18 to 64 years of age) and elderly (≥65 years of age) study 
participants. A total of 28 study participants (10 study participants age 18 to 64 years and 
18 study participants age ≥65 years) is planned. 
A sample size of 9 study participants in each age group will have 97% power to detect a fold 
change in means (expected ratio) of 2.0, assuming that the coefficient of variation is 40% using a 
2 group t-test with a 0.05 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 (ICH)-Good Clinical Practice (GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator/Sponsor 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/Sponsor will forward copies of the protocol, ICF, IB, 
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Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other study 
participant-related documents to be used for the study to the IRB/IEC for its review and 
approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to study participants or others, and any protocol 
deviations, to eliminate immediate hazards to study participants. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the study 
participants. For minor changes to a previously approved protocol during the period covered by 
the original approval, it may be possible for the Investigator to obtain an expedited review by the 
IRB/IEC as allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of study participant risk involved, but no less 
than once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the Investigator and/or contract research organization 
agreements, as applicable. 
10.1.3 
Informed consent process 
Study participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the study participant in both oral and written form by the 
Investigator (or designee). Each study participant will have the opportunity to discuss the study 
and its alternatives with the Investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the study 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The study participant or his/her legal 
representative must receive a copy of the signed and dated ICF. As part of the consent process, 
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each study 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 study participant may withdraw his/her consent to participate in the study at any time. A 
study 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 study 
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 study participant’s confidentiality. 
Throughout this study, all data forwarded to UCB (or designee) will be identified only by the 
study participant number assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
study participant’s primary medical records that directly concerns this study (including, but not 
limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a study participant’s study participation, and autopsy 
reports for deaths occurring during the study). 
The study participant must be informed that his/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 study participant. 
The study 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, and by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
The Safety Monitoring Committee will always be comprised of the Investigator, the Sponsor’s 
medical representative, the scientific lead, and a PK expert where appropriate. Other experts may 
be included in this group or consulted at the discretion of the Sponsor. 
10.1.6 
Data quality assurance 
All study participant data relating to the study will be recorded on the eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
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The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of study participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH-GCP, and all applicable regulatory requirements. 
All essential documents are to be retained by the Investigator until 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/investigational device. 
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 
eCRF and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the CRF Completion Guidelines. 
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 study participant’s source documents. 
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The Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.8 
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. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
 Inadequate recruitment of study participants by the Investigator 
 Discontinuation of further study medication development 
10.1.9 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.2 
Appendix 2: Clinical laboratory tests 
 The tests detailed in the table below will be performed by a local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of study participants are detailed in 
Section 5.1 and Section 7, respectively. 
 Additional laboratory tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
 Investigators must document their review of each laboratory safety report. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology1 
Platelet Count  
RBC Indices: 
MCV 
MCH 
Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
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 
(fasting at 
Screening) 
Calcium 
Alkaline phosphatase 
 
Routine 
Urinalysis 
 
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 and estradiol (as needed in women of 
non-childbearing potential only) 
 
Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 
 
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)2 
 Serology (HIV 1 and 2 Ab, HBsAg, HCV-Ab) 
The results of each test must be entered into the eCRF. 
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Laboratory 
Assessments 
Parameters 
NOTES: 
1 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, respectively. All events of 
ALT 3×UL) and bilirubin 2×ULN (>35% direct bilirubin) or ALT 3×ULN and international 
normalized ratio (INR) >1.5, if INR measured, may indicate severe liver injury (possible Hy’s Law) and 
must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
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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. 
 
Events NOT Meeting the AE Definition 
 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the study participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition. 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
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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). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the study participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the study participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is not 
considered an AE. 
d. Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Important medical events: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the study participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
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10.3.3 
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 study participant’s medical 
records to UCB in lieu of completion of the UCB/AE/SAE eCRF page. 
 
There may be instances when copies of medical records for certain cases are requested by UCB. 
In this case, all study participant identifiers, with the exception of the study participant number, 
will be redacted on the copies of the medical records before submission to UCB. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories:  
 
Mild: An event that is easily tolerated by the study participant, causing minimal discomfort and 
not interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE may be either serious 
or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events should be used as a 
supportive standardization instrument to evaluate AEs and SAEs but the final intensity grading by the 
Investigator must be mild, moderate, or severe. 
 
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Assessment of Causality 
 
The Investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE. 
 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The Investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study medication administration will be 
considered and investigated. 
 
The Investigator will also consult the IB and/or Product Information, for marketed products, in 
his/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. 
 
Follow-up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
 An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the study participant is lost to follow 
up. This follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
 If a study participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide UCB with a copy of any post-mortem findings including 
histopathology. 
 New or updated information will be recorded in the originally completed eCRF. 
 The Investigator will submit any updated SAE data to UCB within 24 hours of receipt of the 
information. 
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Reporting of SAEs 
SAE Reporting to UCB via an Electronic Data Collection Tool 
 
The primary mechanism for reporting an SAE to UCB will be the electronic data collection tool. 
 
If the electronic system is unavailable for more than 24 hours, then the site will use the paper SAE 
data collection tool (see next section). 
 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given site, the electronic data collection tool will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the site 
can report this information on a paper SAE form (see next section) or to the UCB Study Physician by 
telephone. 
 
Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT REPORTING. 
 
SAE Reporting to UCB via Paper 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 study 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 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 study participants with female partners of childbearing potential are eligible to participate 
if they agree to ONE of the following during the protocol-defined time frame in Section 5.1: 
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
 Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 10-1 when having penile-vaginal intercourse with a 
WOCBP who is not currently pregnant. 
In addition, male study participants must refrain from donating sperm for the duration of the 
study and for 7 days after the final dose of study medication. 
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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 90 days after the final dose of study medication. 
10.4.2.2 
Pregnancy testing 
 Women of childbearing potential 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 Baseline and on Day 11 of 
the MD Treatment Period. 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 study 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 study participant. 
10.4.2.3.2 
Male participants with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male study 
participant’s female partner who becomes pregnant while the male participant is in this study. 
This applies only to male study participants who receive study medication. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be at least 12 months after the delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
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10.4.2.3.3 
Female participants who become pregnant 
 The Investigator will collect pregnancy information on any female study 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 study 
participant’s pregnancy. The study participant will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the study 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 8.4.5. 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 study participant who becomes pregnant while participating in the study will 
discontinue study medication or 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 
Study participants with potential drug-induced liver injury must be assessed to determine if study 
medication must be discontinued. In addition, all concomitant medications and herbal 
supplements that are not medically necessary should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury should not be withdrawn from the 
study until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for study medication discontinuation and/or study 
participant withdrawal (if applicable), must be recorded in the source documents. The CRF must 
document the primary reason for discontinuation of study medication. 
A specific monitoring plan must be agreed between the UCB Study Physician and the 
Investigator for study participants who have ALT >5 ULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values). 
Phase 1 liver chemistry stopping criteria are designed to assure study participant safety and to 
evaluate liver event etiology (Table 10-2). 
Table 10-2: Phase I liver chemistry stopping criteria and follow-up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT-absolute 
ALT≥3xULN 
If ALT ≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) OR international 
normalized ratio (INR) >1.5, report as a serious adverse event (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 study 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 
 
Viral hepatitis serologyc 
 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
 
Serum creatine phosphokinase and lactate 
dehydrogenase 
 
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 
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phosphatase, bilirubin) and perform liver event 
follow-up assessments within 24 hours. 
 
Monitor study 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 study participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline. 
 
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 assay 
(quantifies potential acetaminophen 
contribution to liver injury in study 
participants with definite or likely 
acetaminophen use in the preceding week 
[James et al, 2009]. 
 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver imaging and/or liver biopsy 
CRFs. 
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 
impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to 
study participants receiving anticoagulants. 
c Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HbcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
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10.7 
Appendix 7: Medical device incidents – definition and 
procedures for recording, evaluating, follow-up, and reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid alert procedures 
Not applicable. 
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10.9 
Appendix 9: Country-specific requirements 
Not applicable. 
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10.10 
Appendix 10: Abbreviations and trademarks 
AE 
adverse event 
AED 
antiepileptic drug 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BID 
twice daily 
BP 
blood pressure 
cBZR 
central benzodiazepine receptor 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CI 
confidence interval 
CNS 
central nervous system 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EOS 
End-of-study  
EOT 
End-of-treatment 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GABA-A 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HCG 
human chorionic gonadotropin 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LEV 
levetiracetam 
MedDRA 
Medical Dictionary for Regulatory Activities 
MD 
multiple dose 
MTD 
maximum tolerated dose 
PK 
pharmacokinetic(s) 
PK-PPS 
pharmacokinetic per protocol set 
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 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD 
single dose 
SV2A 
synaptic vesicle protein 2A 
SV2B 
synaptic vesicle protein 2B 
SV2C 
synaptic vesicle protein 2C 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
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10.11 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment 1 (29 May 2019) 
Overall Rationale for the Amendment 
The protocol has been amended to provide clarification regarding the collection of samples for 
safety laboratory evaluations, pharmacokinetics, and plasma protein binding. The timing was 
corrected for the collection of the samples for plasma protein binding and urine 
pharmacokinetics. The timing for Period 1B (Days 8 to 21) has also been corrected throughout 
the protocol. The protocol has also been amended to make corrections to the text and add further 
clarification regarding the scientific rationale for study design, justification for dose, dose 
modification, and withdrawal criteria. Additionally, the exclusion criteria have been updated to 
exclude study participants with severe renal impairment. 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis Overall design 
Corrected timing for Period 1B to 
Days 8 to 21 
Correction 
Section 1.3 Schedule of activities 
Added recording of adverse events/medical 
procedures on Day 8 
Correction 
Section 1.3 Schedule of activities 
Clarification of footnotes regarding timing 
of collection of samples for safety 
laboratory evaluations, pharmacokinetics, 
and plasma protein binding  
Clarification 
Section 1.3 Schedule of activities 
Corrected collection of plasma protein 
binding and urine pharmacokinetics 
samples from Day 12 to Day 13 
Correction 
Section 4.1.2 Treatment Period 
Corrected timing for Period 1B to 
Days 8 to 21 
Correction 
Section 4.2 Scientific rationale 
for study design 
Edited text 
Clarification 
Section 4.3 Justification for dose 
Edited text 
Clarification 
Section 5.2 Exclusion criteria  
Added exclusion criterion #17 
To exclude study 
participants with 
severe renal 
impairment 
Section 6.2 Preparation, 
handling, storage, and 
accountability requirements 
Removed the following sentence: The 
Investigator (or designee) will instruct the 
study participant to store the study 
medication following the instructions on the 
label. 
Correction- study 
medication will be 
administered in the 
clinic; therefore, 
storage instructions for 
the participant are 
unnecessary 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6 Dose modification 
Edited text  
To align with other 
padsevonil studies 
Section 7.1.2 Criteria for study 
hold due to adverse events 
Section removed 
Section is not required 
because Rapid Alert 
procedures are not 
being used in this 
study 
Section 7.2 Participant 
discontinuation/withdrawal from 
the study 
Added the following withdrawal criterion: 
There is a confirmation of a pregnancy 
during the study, as evidenced by a positive 
pregnancy test. 
To explicitly state that 
study participants with 
a confirmed pregnancy 
should be removed 
from the study 
Section 7.2 Participant 
discontinuation/withdrawal from 
the study 
Edited text regarding the replacement of 
study participants who are withdrawn from 
the study 
To align with other 
padsevonil protocols 
Section 8.2 Plasma protein 
binding 
Edited text 
To clarify the 
reporting of data for 
plasma protein binding 
of PSL and its 
metabolites 
Section 10.2 Appendix 2: 
Clinical laboratory tests 
Edited hematology laboratory assessments 
to include absolute reticulocyte counts 
instead of % reticulocytes 
Correction 
Section 10.4.2 Contraception 
guidance 
Edited text to the following: male study 
participants must refrain from donating 
sperm for the duration of the study and for 
7 days after the final dose of study 
medication 
For consistency with 
Section 5.2 
 
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11 
REFERENCES 
Clemens B. Forced normalisation precipitated by lamotrigine. Seizure. 2005;14(7):485-9. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Food and Drug Administration. Guidance for Industry. E7 studies in support of special 
populations; geriatrics; questions and answers. Center for Drug Evaluation and Research, Center 
for Biologics Evaluation and Research, 02/2012. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose and acute 
liver failure. Drug Metab Dispos 2009;37:1779-84. 
Janz R, Südhof TC. SV2C is a synaptic vesicle protein with an unusually restricted localization: 
anatomy of a synaptic vesicle protein family. Neuroscience. 1999;94:1279-90. 
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in 
epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia. 
2009 Mar;50(3):387-97. 
Klitgaard H, Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert 
Opinion on Drug Discovery 2007;2(11):1537-45. 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI. A new equation to 
estimate glomerular filtration rate. Ann Intern Med. 2009;150(9): 604-12. 
Loganathan MA, Enja M, Lippmann S. Forced normalization: epilepsy and psychosis 
interaction. Innov Clin Neurosci. 2015;12(5-6):38-41. 
Motika PV, Spencer DC. Treatment of epilepsy in the elderly. Curr Neurol Neurosci Rep 
2016;16:96. 
Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and 
pharmacokinetics. Acta Neurol Scand. 2008;118:69-86. 
Wan QF, Zhou ZY, Thakur P, Vila A, Sherry DM, Janz R, et al. SV2 acts via presynaptic 
calcium to regulate neurotransmitter release. Neuron. 2010;66:884-95. 
World Health Organization. Epilepsy. Available from: 
http://www.who.int/mediacentre/factsheets/fs999/en/ [Accessed 23 May 2018]. 
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SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
UP0053-protocol-amend-1
Version:
1. 0
Document Number:
CLIN-000134995
Title:
PSL PK Elderly Phase 1
Approved Date:
31 May 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 29-May-2019 16:29:06 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 29-May-2019 18:00:48 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 30-May-2019 10:05:40 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 31-May-2019 12:50:39 GMT+0000
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SAP_001.pdf: 
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Page 1 of 41 
 
STATISTICAL ANALYSIS PLAN  
Study: UP0053 
Product: Padsevonil 
 
 
 
AN OPEN-LABEL, PARALLEL-GROUP, PHARMACOKINETIC, 
SAFETY AND TOLERABILITY STUDY 
OF SINGLE AND MULTIPLE ORAL ADMINISTRATIONS OF 
PADSEVONIL IN ADULTS AND ELDERLY STUDY 
PARTICIPANTS 
 
 
 
 
 
 
 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
SAP/Amendment Number Date 
SAP Version 1.0 
18 Sep 2019 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 8 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 Study objectives ................................................................................................................. 8 
2.1.1 
Primary objective ................................................................................................... 8 
2.1.2 
Secondary objectives ............................................................................................. 8 
2.1.3 
Other objectives ..................................................................................................... 8 
2.2 Study variables ................................................................................................................... 9 
2.2.1 
Pharmacokinetic variables ..................................................................................... 9 
2.2.1.1 
Primary pharmacokinetic variables ............................................................. 9 
2.2.1.2 
Secondary pharmacokinetic variables ......................................................... 9 
2.2.1.3 
Other pharmacokinetic variables ................................................................. 9 
2.2.2 
Safety variables .................................................................................................... 10 
2.2.2.1 
Secondary safety variables ........................................................................ 10 
2.2.2.2 
Other safety variables ................................................................................ 10 
2.3 Study design and conduct ................................................................................................ 11 
2.4 Determination of sample size ........................................................................................... 16 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 16 
3.1 General presentation of summaries and analyses ............................................................ 16 
3.2 General study level definitions ........................................................................................ 18 
3.2.1 
Relative day ......................................................................................................... 18 
3.2.2 
Study periods ....................................................................................................... 18 
3.3 Definition of Baseline values ........................................................................................... 19 
3.4 Protocol deviations ........................................................................................................... 19 
3.5 Analysis sets ..................................................................................................................... 20 
3.5.1 
All Study Participants .......................................................................................... 20 
3.5.2 
Full Analysis Set .................................................................................................. 20 
3.5.3 
Pharmacokinetic-Per Protocol Set ....................................................................... 20 
3.6 Treatment assignment ...................................................................................................... 20 
3.7 Center pooling strategy .................................................................................................... 22 
3.8 Coding dictionaries .......................................................................................................... 22 
3.9 Changes to protocol-defined analyses.............................................................................. 22 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 22 
4.1 Adjustments for covariates............................................................................................... 22 
4.2 Handling of dropouts or missing data .............................................................................. 22 
4.2.1 
Pharmacokinetics ................................................................................................. 22 
4.2.2 
Safety laboratory data .......................................................................................... 23 
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4.2.3 
Electrocardiogram data ........................................................................................ 23 
4.2.4 
Dates and times .................................................................................................... 24 
4.3 Handling of repeated and unscheduled measurements .................................................... 25 
4.4 Handling of measurements obtained at the early withdrawal visit .................................. 26 
4.5 Interim analyses and data monitoring .............................................................................. 26 
4.6 Multicenter studies ........................................................................................................... 26 
4.7 Multiple comparisons/multiplicity ................................................................................... 26 
4.8 Use of an efficacy subset of participants ......................................................................... 26 
4.9 Active-control studies intended to show equivalence ...................................................... 26 
4.10 Examination of subgroups ............................................................................................... 26 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 27 
5.1 Participant disposition ...................................................................................................... 27 
5.2 Protocol deviations ........................................................................................................... 27 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 28 
6.1 Demographics .................................................................................................................. 28 
6.2 Other Baseline characteristics .......................................................................................... 28 
6.3 Medical history, procedure history and concomitant medical procedures....................... 29 
6.4 Prior and concomitant medications .................................................................................. 29 
6.4.1 
Prior medication definition .................................................................................. 29 
6.4.2 
Concomitant medication definition ..................................................................... 29 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 30 
8 
EFFICACY ANALYSES ................................................................................................ 30 
9 
PHARMACOKINETICS ................................................................................................. 30 
9.1 Analysis of the primary pharmacokinetic variables ......................................................... 30 
9.2 Analysis of secondary pharmacokinetic variables ........................................................... 31 
9.3 Analysis of other pharmacokinetic variables ................................................................... 32 
10 SAFETY ANALYSES ..................................................................................................... 32 
10.1 Extent of exposure ........................................................................................................... 32 
10.2 Adverse events ................................................................................................................. 32 
10.3 Clinical laboratory evaluations ........................................................................................ 34 
10.4 Vital signs, physical findings, and other observations related to safety .......................... 36 
10.4.1 
Vital signs ............................................................................................................ 36 
10.4.2 
Electrocardiograms .............................................................................................. 37 
10.4.3 
Other safety variables .......................................................................................... 38 
10.4.3.1 
Physical examination ................................................................................. 38 
10.4.3.2 
Columbia-Suicide Severity Rating Scale .................................................. 38 
11 OTHER ANALYSES ...................................................................................................... 38 
12 REFERENCES ................................................................................................................ 39 
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13 APPENDICES ................................................................................................................. 40 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 41 
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 LIST OF ABBREVIATIONS 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ALQ 
above the limit of quantification 
AST 
aspartate aminotransferase 
AUCτ 
area under the curve over a dosing interval  
BID 
twice daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CL/F 
apparent total clearance 
CL/Fss 
apparent total clearance at steady-state 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRU 
clinical research unit 
CSR 
clinical study report 
CV 
coefficient of variation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
EOS 
End of Study 
EOT 
End of Treatment 
EudraCT 
European Union Drug Regulating Authorities 
Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
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fe 
Fraction of the dose excreted unchanged 
femet 
Fraction of the dose excreted as the metabolite 
FU 
Follow-up 
geoCV 
geometric coefficient of variation 
ICF 
Informed Consent form 
ICH 
International Council on Harmonisation 
IMP 
investigational medicinal product 
IPD 
important protocol deviation 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MD 
Multiple dose 
MHD 
Mono Hydroxy Derivate 
MW 
Molecular Weight 
n 
number of participants 
number of available observations 
NCA 
Noncompartmental analysis 
PK-PPS 
Pharmacokinetic-Per Protocol Set 
PK 
Pharmacokinetic(s) 
PR 
pulse rate 
PSL 
padsevonil 
PT 
preferred term 
QTcF 
QT corrected for heart rate using Fridericia’s 
formula 
RR 
respiratory rate 
SAE(s) 
serious adverse event(s) 
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SAP 
statistical analysis plan 
SD 
Single dose  
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures and listings 
tmax 
time to maximum concentration 
ULN 
upper limit of normal 
WHODD 
World Health Organization Drug Dictionary 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of UP0053. It also defines the summary tables, figures 
and listings (TFLs) to be included in the final clinical study report (CSR) according to the 
protocol. 
This SAP is based on the following documents: 
 Final protocol, including the protocol amendment 1 dated 29 May 2019 and the original 
protocol dated 07 May 2019.  
 The protocol clarification memos dated 11 June 2019 and 11 September 2019. 
Unless specified in the sections below, the study will be analyzed as described in the most recent 
version of the protocol. If a future protocol amendment necessitates a substantial change to the 
statistical analysis of the study data, this SAP will be amended accordingly. In addition, if 
analysis definitions must be modified or updated prior to database lock, a SAP amendment will 
be required. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the CSR together with the 
associated rationale. 
The content of this SAP is compatible with the International Council for Harmonisation 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips et al, 2003). 
UCB is the Sponsor and ICON PLC is the Contract Research Organization (CRO) for this study. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective of this study is to evaluate the plasma pharmacokinetics (PK) of 
Padsevonil (PSL) in adult and elderly study participants.   
2.1.2 
Secondary objectives 
The secondary objectives of this study are to: 
 Evaluate the urine PK of Padsevonil in adult and elderly study participants. 
 Evaluate the safety and tolerability of Padsevonil in adult and elderly study participants (AE 
specific endpoints). 
2.1.3 
Other objectives 
The other objectives of this study are to: 
 Evaluate the plasma PK of Padsevonil and two of its metabolites 
 
) in adult and elderly study participants: 
 Evaluate the urine PK of Padsevonil and two of its metabolites 
 
 in adult and elderly study participants: 
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 Evaluate the relationship between creatinine clearance and hepatic function tests and the PK 
of Padvesonil and two of this metabolites 
 
) in adult and elderly study participants: 
 Further evaluate the safety and tolerability of Padsevonil in adult and elderly study 
participants (Laboratory, vital signs, ECG and PE related endpoints). 
2.2 
Study variables 
2.2.1 
Pharmacokinetic variables 
2.2.1.1 
Primary pharmacokinetic variables 
The primary PK variables will be Cmax, AUC0-t and AUC for the single dose and Cmax,ss and 
AUCτ for the multiple dose obtained from the plasma concentration-time profiles for PSL: 
 Cmax: maximum observed plasma concentration 
 AUC0-t: area under the curve from time 0 to the last quantifiable concentration  
 AUC: Area under the curve from time 0 to infinity  
 Cmax,ss: maximum observed plasma concentration at steady-state 
 AUCτ: area under the curve over a dosing interval 
2.2.1.2 
Secondary pharmacokinetic variables 
The secondary PK variables will be the amount of PSL and its metabolites excreted in urine and 
the metabolic ratio of amount excreted in urine. 
 Ae: Cumulative amount of PSL or its metabolite excreted in urine 
 MRAe: Metabolic Ae ratio 
2.2.1.3 
Other pharmacokinetic variables 
The following other PK variables for PSL and the two metabolites of PSL will be assessed 
during the study (single dose and multiple dose): 
For the plasma PK of PSL: 
Bound and unbound plasma concentration of PSL in two samples 
Single Dose: 
 CL/F: apparent total clearance  
Multiple Dose 
 CL/Fss: apparent total clearance at steady-state  
For the plasma PK of the two metabolites of PSL: 
Single Dose: 
 Cmax: maximum observed plasma concentration 
 AUC0-t: area under the curve from time 0 to the last quantifiable concentration 
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 AUC: Area under the curve from time 0 to infinity 
Multiple Dose 
 Cmax,ss: maximum observed plasma concentration at steady-state 
 AUCτ: area under the curve over a dosing interval 
For the plasma PK of PSL and the two metabolites of PSL: 
 Ctrough: Measured concentration at the end of a dosing interval at steady state 
 tmax: time of Cmax or Cmax,ss  
 t1/2: Terminal elimination half-life 
 t1/2,ss: Terminal elimination half-life at steady-state 
 AUC0-12: area under the curve from time 0 to 12h after a single PSL dose 
 MRAUCτ: Metabolic ratio for AUCτ 
 MRCmax,ss: Metabolic ratio for Cmax,ss 
For the urine PK 
 
CLR: Renal clearance of PSL 
 
fe : Fraction of the dose excreted unchanged 
 
femet: Fraction of the dose excreted as the metabolite 
2.2.2 
Safety variables 
2.2.2.1 
Secondary safety variables 
The following secondary safety variables will be assessed during the study: 
 Incidence of Treatment Emergent Adverse Events (TEAEs)  
 Incidence of Serious Adverse Events (SAEs) and  
 Incidence of TEAEs leading to discontinuation. 
2.2.2.2 
Other safety variables 
The following other safety variables will be assessed during the study: 
 Changes in safety laboratory data (hematology, clinical chemistry and urinalysis) 
 Changes in vital signs (pulse rate (PR), systolic and diastolic blood pressure (BP), respiratory 
rate (RR) and body temperature) 
 Changes in 12-lead electrocardiogram (ECG) assessment 
 Physical examination findings 
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2.3 
Study design and conduct 
This is a Phase 1, open-label study to evaluate the effect of age on the PK, safety, and 
tolerability of oral PSL in 2 cohorts of at least 10 adult (18 to 64 years, inclusive) study 
participants (Cohort A) and 18 elderly (≥65 years) study participants (Cohort B). 
 
The study utilizes a single dose (SD) and a multiple dose (MD) design. Period 1A is the SD 
Period and consists of a single dose of PSL followed by a Washout Period. Period 1B is the 
MD Period and consists of PSL up-titration, maintenance, and tapering during the 
Treatment Period, followed by a Washout Period. Both adult and elderly study participants 
will take part in the SD and MD Periods. 
 
The total study duration for each study participant is up to 28 days for Screening plus 22 
days from Day 1 through the EOS/EOT Visit (up to 50 days in total). 
 
The study consists of Screening, a Baseline Visit, Treatment Period, and Follow-up Period 
(End-of-Study/End-of-Treatment [EOS/EOT] Visit). 
 
Screening will be conducted at the study site(s) 3 to 28 days prior to check-in to the study 
site. Eligible study participants in the 2 age cohorts will be matched per gender for body 
weight if feasible, i.e., the elderly study participants will be recruited first, and per gender, 
matched for body weight with adult study participants. Individual cases will be discussed 
with the Sponsor as needed. In each age cohort, there will be a homogenous repartition 
between male and female study participants, with at least 3 participants in each gender. To 
allow for an investigation of potential age-dependent effects, the elderly study participant 
cohort will also preferably include the following categories: at least 3 males and 3 females 
from ≥65 to 74 years old, and at least 3 males and 3 females ≥75 years old. 
 
Study participants will check into the study site on Day -1 for the Baseline Visit and 
will undergo assessments as specified in the Schedule of Activities (Table 2‒1). 
 
The Treatment Period consists of Period 1A (PSL SD administration) on Days 1 to 7 and 
Period 1B (PSL MD administration) on Days 8 to 21. 
 
In Period 1A, study participants will receive a single oral dose of 200mg PSL on Day 1, 
at approximately 8:00am, 30 minutes after a light meal. No study drug will be 
administered on Days 2 to 7; assessments will be conducted during this time as specified 
in the Schedule of Activities (Table 2‒1). Days 2 to 7 are designated as a 6-day washout. 
 
In Period 1B, study participants will receive multiple oral doses of PSL as follows (note: twice 
daily [BID] dosing is achieved with a morning [approximately 8:00am] and evening 
[approximately 8:00pm] dose): 
 
    Day 8: 50mg PSL BID 
 
    Day 9: 100mg PSL BID 
 
    Days 10 to 12: 200mg PSL BID 
 
    Day 13: A morning dose of 200mg PSL and an evening dose of 100mg PSL 
 
    Days 14 and 15: 100mg PSL BID 
 
    Day 16: 50mg PSL BID 
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    Days 17 to 21: no PSL administration; 5-day washout 
 
Throughout the study, plasma and urine samples for PK analysis and safety evaluations will 
be obtained according to the Schedule of Activities (Table 2‒1). Adverse events and 
concomitant medications will be recorded throughout the study. Liver function parameters 
and creatinine clearance will be assessed in each study participant. These parameters are 
influenced by age; therefore, the acceptance ranges for these tests are wider for the elderly 
study participants. 
 
On Day 22, study participants will complete the EOS/EOT Visit procedures as specified in the 
Schedule of Activities (Table 2‒1). 
 
Dropouts may be replaced at the discretion of the Investigator and Sponsor 
 
 
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Table 2‒1 
Schedule of activities 
 
Study Period/Visit 
Scr 
BL 
Visit 
Treatment Period 
Follow-up 
Period 
Period 1A (SD) 
Period 1B (MD) 
EOS/ 
EOT Visit 
Study Day(s) 
-28 
-1 
1 
2 
3 
4 
5-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-21 
22 
to -3 
Washout 
Washout 
Procedures 
Written Informed Consent 
X 
Demographics & baseline characteristics 
X 
X 
Inclusion/exclusion criteria verification 
X 
X 
General medical/procedures history 
X 
X 
Study Participant Identification Card 
 
X 
assigned 
Suicidality risk evaluation (C-SRSS) a 
X 
X 
 
X 
 
X 
 
X 
Physical examination b 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Psychiatric and Mental Status 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test d 
X 
X 
 
X 
Hematology, serum chemistry, urinalysis e 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serology (HIV, Hep B & C) 
X 
12-lead ECG f 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine and cotinine drug screen, alcohol 
X 
X 
 
X 
breath test 
Recording of AEs /medical procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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Study Period/Visit 
Scr 
BL 
Visi
t
Treatment Period 
Follow-up 
Period 
Period 1A (SD) 
Period 1B (MD) 
EOS/ 
EOT Visit 
Study Day(s) 
-28 
-1 
1 
2 
3 
4 
5-7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17-21 
22 
to -3 
Washout 
Washout 
Procedures 
Admit to study center 
X g 
Xg 
Discharge from study center 
Xg 
Xg 
X 
Administer PSL 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for PSL PK levels h 
 
X 
X 
X 
X 
 
X 
Additional blood sampling for PPB i 
 
X 
Urine collection for PSL PK j 
 
X 
X 
X 
X 
 
X 
Final disposition determination k 
X 
AE=adverse event; BID=twice daily; BL=Baseline; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EOS=End-of-Study; 
EOT=End-of-Treatment; Hep=hepatitis; HIV=human immunodeficiency virus; MD=multiple dose; PK=pharmacokinetic(s); PPB=plasma protein binding; 
PSL=padsevonil; Scr=screening; SD=single dose; tmax=time to maximum plasma concentration 
a  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. 
b  At Screening, Baseline (Day -1) and Day 8, a full physical examination will be performed. On all other days a physical examination is performed, it will be a 
short physical examination (see Section 8.3.4 of the study protocol). 
c   Vital signs will be performed before each morning dose of PSL; if feasible; vital sign evaluations will follow the same schedule as ECGs. Blood pressure and 
pulse measurements should be preceded by at least 5 minutes of rest for the study participant in a quiet setting without distractions (eg, television, cell phones). 
d  Serum pregnancy test will be performed for females of childbearing potential at Screening. Urine pregnancy testing will be performed at all other time points 
indicated. 
e   For safety laboratory evaluations that occur on a dosing day, these will be performed before the morning dose/PK sample collection. 
f   A 12-lead ECG will be performed after a rest of at least 5 minutes. All ECG recordings will be performed in triplicate at 2 to 3 minute intervals at Screening, 
Baseline (Day -1), predose and 3 hours after the morning dose on each PSL dosing day and EOS/EOT Visit.
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g  Study participants will be confined to the study site starting at Baseline (Day -1) and may be discharged on the morning of Day 5 after the assessments are 
complete, per the discretion of the Investigator. Study participants discharged on Day 5 will be readmitted to the study site on the evening of Day 7. If the 
Investigator deems it acceptable, study participants may be discharged the morning of Day 17. 
h  PK plasma samples will be taken at the following time points: (a) Period 1A (single dose): predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48, 
and 72 hours postdose (14 samples); (b) Period 1B (multiple doses): predose (morning dose), and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, and 12h after the morning 
dose (11 samples). 
i   Two blood samples will be collected after multiple doses at steady state (Day 13 predose and 1.5h postdose[(~tmax]) for PPB. 
j   After the morning urine void and collection of a predose sample (no more than 60 minutes before dosing), PK urine collection will be performed at regular 
intervals on Days 1, 2, 3, and 4 at the following time points: 0 to <12h; 12 to <24h, 24 to <48h, and 48 to <72h after the single dose (4 samples). On Day 13, 
PK urine collection will be performed 0 to 12h after the 200mg PSL morning dose (1 sample). 
k  For study participants prematurely terminating or completing the study, final disposition is recorded at the EOS/EOT Visit. All study participants prematurely 
terminating from the study should be encouraged to undergo final evaluation procedures, in accordance with the EOS/EOT Visit schedule, as soon as possible 
after the last dose of study medication. 
 
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2.4 
Determination of sample size 
No formal sample size computation has been performed for this study. This PK study will be 
a study of limited size conducted under SD and steady-state conditions to look for sizable 
differences between adult (18 to 64 years of age) and elderly (≥65 years of age) study 
participants. A total of 28 study participants (10 study participants of age 18 to 64 years and 
18 study participants of age ≥65 years) is planned. 
 
A sample size of 9 study participants in each age group will have 97% power to detect a fold 
change in means (expected ratio) of 2.0, assuming that the coefficient of variation is 40% using 
a 2 group t-test with a 0.05 1-sided significance level. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical evaluation will be performed by ICON PLC and supervised by the Early Development 
Statistics Department of UCB. The datasets will follow the UCB analysis data model (ADaM) 
data specifications. All statistical analyses will be performed using SAS® Version 9.4 or later 
(SAS Institute, Cary, NC, USA). 
The PK noncompartmental analysis (NCA) will be performed using Phoenix WinNonlin®v6.3 or 
higher (Certara L.P., Princeton, NJ, USA) for PK parameter estimation using actual doses 
administered and the actual sampling times relative to time of dose administration. 
Categorical endpoints will be summarized using number of study participants (n), frequency, 
and percentages. Missing data will not be imputed. Individual plasma and urine concentration 
and PK parameters will be presented using 3 significant digits. 
When reporting relative frequencies or other percentage values, the following rules apply: 
 For values where all study participants fulfill certain criteria, the percentage value will be 
displayed as 100 
 For values where the absolute frequency is zero, there will be no percentage displayed 
 All other percentage displays will use 1 decimal place 
Percentages displayed based on continuous data (e.g. percentage changes from baseline) will be 
displayed to 1 decimal place. Unless otherwise stated, the denominator for the percentages will 
be based on the number of participants in the respective analysis set. 
 
Continuous variables will be summarized by visit and time point (where applicable) including 
number of study participants (n), mean, median, standard deviation (sd), minimum, maximum. 
Geometric coefficient of variation (geoCV), geometric mean and 95% confidence interval (CI) 
for the geometric mean will also be presented in the descriptive statistics for the plasma 
concentration and PK parameters for PSL and two metabolites of PSL 
 
]). In all outputs the confidence limits will be 
restricted to the possible values that the variable can take. 
 
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When reporting descriptive statistics, the following rules will apply in general except for PK 
concentration data (plasma and urine PK) of PSL and two metabolites of PSL
 
: 
 n will be an integer 
 Mean (arithmetic and geometric), standard deviation and median will use 1 decimal place 
more, or 1 significant figure more – depending on the reporting format of the original data – 
than the original data 
 Confidence intervals will use 1 decimal place more, or 1 significant figure more – depending 
on the reporting format of the original data – than the value around which the confidence 
interval is constructed 
 Coefficient of variation (CV) will be reported as a percentage to 1 decimal place 
 Minimum and maximum will be reported using the same number of decimal places or 
significant figures as the original value 
 If no participants have data at a given time point, then only n=0 will be presented. If n<3, 
then only the n, minimum and maximum will be presented. If n=3, then only n, minimum, 
median and maximum will be presented. The other descriptive statistics will be left blank. 
When reporting individual values and descriptive statistics for PK concentration data (plasma 
and urine PK of PSL and two metabolites of PSL, 
 
), the following rules will apply regarding rounding and precision: 
 Individual values for PK concentration data will be reported to the same level of precision as 
received from the bioanalytical laboratory 
 Descriptive statistics for PK concentration data will be reported to the same level of precision 
as the individual data for the minimum and maximum, and to 1 additional decimal place or 1 
additional significant figure– depending on the reporting format of the original data with a 
maximum of 3 significant digits - for the mean (arithmetic and geometric), median and 
standard deviation. The 95% CI for the geometric mean will use 1 decimal place more, or 1 
significant figure more – depending on the reporting format of the original data – than the 
value around which the confidence interval is constructed 
 Geometric CV will be reported as a percentage to 1 decimal place 
When reporting individual values and descriptive statistics for PK parameters (plasma and urine 
PK of PSL and two  metabolites of PSL 
 
, and parent to metabolite ratio) the following rules will apply with regard to 
rounding and precision: 
 Individual values for PK parameters will be reported to 3 significant figures 
 Descriptive statistics for PK parameters should be rounded to 4 significant figures for the 
mean, median and standard deviation and to 3 for the others 
Data listings containing all documented data and all derived data will be generated and presented 
by age group (Adults (18-64 years) and Elderly (>=65 years)). 
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3.2 
General study level definitions 
3.2.1 
Relative day 
The relative day of an event will be derived with the date of first dose of investigational 
medicinal product (IMP), here PSL as reference.  
Relative days for an event or measurement occurring before the date of first dose of each 
treatment period are calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= 𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑖𝑛 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 
The relative day for an event or measurement occurring on the date of first dose of each 
treatment period is 1. The relative day for an event or measurement occurring on or after the 
reference date to the date of the last dose in the treatment period will be calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= (𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑖𝑛 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑) + 1  
For events or measurements occurring after the date of last dose, relative day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= + (𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑖𝑛 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑) 
There is no relative Day 0. Relative day will not be calculated for partial dates in cases where 
relative day is shown in a participant data listing. In such cases, relative day should be presented 
as ‘--‘ in the relevant participant data listing. 
3.2.2 
Study periods 
For each participant completing the study, the expected maximum duration of participation will 
be approximately 50 days with a maximum of 10 days exposure to investigational product, and 
will consist of the following periods: 
 Screening Period (Day -28 to Day -3)  
The Screening Period consists of a single Screening Visit, which will be conducted at the unit 
within 28 days prior to check-in for Treatment Period, and a Baseline Visit, which will be 
conducted at the clinical research unit (CRU) 1 day prior to Treatment Period. Study 
participants will check-in at the CRU on Day -1. 
 Treatment Period 1A (PSL SD administration) (Day 1 to Day 7) 
In Period 1A study participants will receive a single oral dose of 200mg PSL on Day 1, at 
approximately 8:00am, 30 minutes after a light meal has finished. No study drug will be 
administered on Days 2 to 7; assessments will be conducted during this time as specified in 
the Schedule of Activities (Table 2‒1). Days 2 to 7 are designated as a 6-day washout. 
 Treatment Period 1B (PSL MD administration) (Day 8 to Day 21) 
In the Period 1B study participants will receive multiple oral PSL doses on Days 8 to 16, 
followed by a 5-day washout (Days 17 to 21). Padsevonil will be administered BID, with 
one dose in the morning [approximately 8:00am] and one dose in the evening 
[approximately 8:00pm]. The specific PSL dosing schedule is as follows: 
 
    Day 8: 50mg PSL BID 
 
    Day 9: 100mg PSL BID 
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    Days 10 to 12: 200mg PSL BID 
 
    Day 13: A morning dose of 200mg PSL and an evening dose of 100mg PSL 
 
    Days 14 and 15: 100mg PSL BID 
 
    Day 16: 50mg PSL BID 
 
    Days 17 to 21: no PSL administration; 5-day washout 
 The Follow-Up Period consists of an End of Treatment (EOT) /End of Study (EOS) Visit 
performed on Day 22 after discharge or upon discontinuation of the study.  
The end of the study is defined as the date of the last visit of the last participant in the study. 
3.3 
Definition of Baseline values 
Baseline will be the last non-missing value prior to first PSL dosing in each period (Period 1A 
(SD) and Period 1B (MD)). Scheduled or unscheduled measurements can be used as the Baseline 
value. 
If a measurement is repeated at Baseline or a given treatment period and is obtained prior to 
dosing, then the last available measurement will be used as the Baseline value. 
12-lead ECG will be measured in triplicate. The mean of the last three predose measurements 
will be taken as the baseline; if less than three predose replicates are available, the mean of the 
available predose replicates will be taken as the baseline.  
The change from Baseline to any subsequent post-Baseline visit will be calculated as the simple 
difference between that post-Baseline visit’s value and the Baseline visit value, as below:   
𝐶ℎ𝑎𝑛𝑔𝑒_𝑓𝑟𝑜𝑚_𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒= 𝑃𝑜𝑠𝑡 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 −𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 
3.4 
Protocol deviations 
Important protocol deviations (IPD) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on the primary PK outcome for an individual 
study participant. Study participants with an important protocol deviation will be excluded from 
the FAS. Study participants will be excluded from FAS only when there is documented evidence 
that they received no treatment. Study participants may be excluded from the PK Per Protocol 
Set (PK-PPS) if they had an important protocol deviation affecting the PK parameters. 
 
The criteria for identifying protocol deviations and the classification of protocol deviations will 
be captured in the Important Protocol Deviations document. 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.After all data have been 
verified/coded/entered into a database, a data evaluation meeting (DEM) will be held.  
At least one DEM will be performed at the following time: 
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 Prior to the final analysis after all data have been verified/coded/entered into the database 
Additional DEMs may be conducted as deemed necessary. 
The purpose of these DEM reviews will be to review all protocol deviations, determine whether 
the deviations are considered important or not important, define the analysis sets, and check the 
quality of the data. The reviews will also help decide how to manage problems in the 
participants’ data (e.g., missing values, withdrawals and protocol deviations).  
Accepted deviations from scheduled time points will be described in the appropriate documents 
and included in the Study Master File. After the pre-analysis review, resolution of all issues, and 
documentation of all decisions (including inclusion into each of the analysis sets) at the final 
DEM, the database will be locked. 
3.5 
Analysis sets 
3.5.1 
All Study Participants 
All Study Participants consist of all study participants who have signed the Informed Consent 
form (ICF).  
3.5.2 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all study participants who have signed the ICF and 
received at least one dose of investigational medicinal product (IMP). Analysis of this set will be 
according to the treatment the study participants actually received. All safety analyses will be 
performed using the FAS. 
3.5.3 
Pharmacokinetic-Per Protocol Set 
The Pharmacokinetic-Per Protocol Set (PK-PPS) is a subset of the FAS, consisting of those study 
participants who had no important protocol deviations affecting the PK parameters and had a 
sufficient number of samples available to determine at least one PK parameter. 
All PK analyses will be performed using the PK-PPS. 
3.6 
Treatment assignment 
 
Tables will be presented by age group (Adults (18-64 years) or Elderly (>= 65 years)) and 
overall. Listings will be presented by age group and study period as described in Section 3.2.2.  
PK summaries will be presented for PSL and two metabolites of PSL during the treatment 
periods (SD and MD)  
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Table 3‒2: Padsevonil administration 
 
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3.7 
Center pooling strategy 
The data will come from one center. The statistical analyses will not be performed by center. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using the latest available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®) Medications will be coded according 
to the latest version of the World Health Organization Drug Dictionary (WHODD) (Version 
SEP/2017). Medical procedures will not be coded. 
3.9 
Changes to protocol-defined analyses 
 Changes in the analysis of PK variables (section 1.1 of the protocol):  
o The analysis of CL/Fss (apparent total clearance at steady-state) will be conducted only 
for PSL and not for the two metabolites of PSL (as planned in protocol section 1.1). 
o The variable MRCmax,ss (Metabolic ratio for Cmax,ss) will be analysed  for PSL and two 
metabolites of PSL instead of the variable MRCmax (Metabolic ratio for Cmax). 
 Change in the name of an analysis datasets (section 9.1 of the protocol). 
o The “Enrolled Set” will be renamed as the “All Study Participants” analysis set in the 
SAP and will include all study participants who sign the informed consent form.  
 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
In general, there will be no imputation of missing data unless otherwise stated below. 
Missing data will be handled as described in the sections below for safety laboratory and PK 
results. No other imputations will be performed.  
4.2.1 
Pharmacokinetics  
The 95% CI lower and 95% CI upper should be left blank if the standard deviation (or 
equivalently, the geometric CV) is 0. Measurements of PK concentrations that are below the 
limit of quantification (BLQ) and which are occurring prior to tmax will be imputed with half of 
the lower limit of quantification (LLOQ/2), except for embedded BLQ values (between two 
measurable data points) which will be treated as missing, for the purpose of calculating the 
geometric mean and its 95% CI, the geometric CV, the arithmetic mean and standard deviation 
for summaries and figures. Post-tmax, BLQ values will be treated as missing. Descriptive statistics 
of concentrations will be calculated if at least 2/3rd of the individual data points are quantifiable 
(≥LLOQ).  
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For all individual PK concentration figures any concentrations that are BLQ will be regarded as 
missing, with the exception of predose BLQ measurements which will be imputed with zero (to 
capture lag-time) for linear scale plots. 
The following rules will apply for PK data listings: 
 Values below the LLOQ will be reported as “(BLQ)” in the listings 
The following rules will apply for PK summaries: 
 Descriptive statistics of plasma concentrations will be calculated if more than 2/3rd of 
individual data points are quantifiable (>=LLOQ) at the given time-point. However, if n<3, 
then only n, minimum and maximum will be presented, and the median will also be 
presented if n=3. The other descriptive statistics will be left blank. 
 For tmax, t1/2, and t1/2ss only N, median, minimum and maximum will be displayed into the 
summary statistics,  
 For plasma concentration summaries, all BLQ values will be replaced by “LLOQ/2 and 
missing values will be excluded.  
 When the mean value includes one or more replaced BLQ values then a footnote will be 
included to say “contains one or more BLQ value replaced by half the LLOQ value”.  
 For the individual figures, any concentrations that are BLQ will be regarded as missing, with 
the exception of predose BLQ measurements which will be imputed with zero for linear scale 
plots. 
 If no participants have data, only n=0 will be presented. The other descriptive statistics will 
be left blank. 
 The geometric CV will be calculated using the following formula where SDlog is the standard 
deviation from the log-transformed data: 
Geometric CV (%) = sqrt[(exp (SDlog^2) – 1)] x 100 
 The PK analysis will be performed in accordance to the Guideline on performing NCA 
analysis dated 08 Nov 2017, and BLQ values will be treated as stated in this document for 
the NCA analysis.  
 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ or above the limit of quantification (ALQ) in the 
safety laboratory data will be the same as those described for PK data in Section 4.2.1.  
4.2.3 
Electrocardiogram data 
For the 12-lead ECG data, all calculations of changes from Baseline and descriptive statistics 
will be based on the mean of the triplicate assessments at each time point. In the event that there 
are not 3 available measurements at a given time point, the mean will be calculated based on the 
number of measurements for which data are provided. 
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4.2.4 
Dates and times 
Partial dates may be imputed for the following reasons: 
 Classification of AEs as treatment-emergent  
 Classification of medications as prior or concomitant  
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial start dates: 
 If only the month and year are specified and the month and year of the first dose of study 
medication is not the same as the month and year of the start date then use the 1st of the 
month, or the date of screening if this is later (if the latter imputation results in an end date 
that is earlier than the start date, then use the 1st of the month). If time is missing this will be 
imputed as 00:00h 
 If only the month and year are specified and the month and year of the first dose of study 
medication is the same as the month and year of the start date, then the date of the first dose 
of study medication will be used. If this results in an imputed start date that is after the 
specified end date, then use the 1st of the month, or the date of screening if this is later (if the 
latter imputation results in an end date that is earlier than the start date, then use the 1st of the 
month). If the imputed date is the date of dosing then time will be imputed as the start time of 
the dosing (i.e., event will be regarded as treatment-emergent) 
 If only the year is specified, and the year of the first dose of study medication is not the same 
as the year of the start date then January 01 will be used. If time is missing this will be 
imputed as 00:00h 
 If only the year is specified, and the year of the first dose of study medication is the same as 
the year of the start date, then the date of the first dose of study medication will be used. If 
this results in an imputed start date that is after the specified end date, then January 01, or the 
date of screening if this is later will be used (if the latter imputation results in an end date that 
is earlier than the start date, then January 01 will be used). If the imputed date is the date of 
first dose of study medication then time will be imputed as the start time of the study 
medication intake (i.e., event will be regarded as treatment-emergent) 
The following rules will be applied to partial stop dates: 
 If only the month and year are specified, then use the last day of the month 
 If only the year is specified, then use December 31 of the known year 
 If the stop date is completely unknown, do not impute the stop date 
Missing or partially missing dates and/or times will be imputed as described in Table 3-1:
 
Calculation rules for duration of adverse eventsTable 3-1 for the calculation of duration of 
each AE. Adverse event duration is computed in and reported in day and time format: xx d 
hh:mm. 
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Table 3-1: 
Calculation rules for duration of adverse events 
Data availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Complete data 
D1/T1 
D2/T2 
Duration = [(D2 – D1)*24 + (T2 – T1)]/24 d 
End time missing 
D1/T1 
D2/-- 
End time is substituted by time 23:59h (=23.98 in 
decimal format) 
Duration = <[(D2 – D1)*24 + (23.98 – T1)]/24 d 
Start time missing 
D1/-- 
D2/T2 
Onset time is substituted by time 00:00h 
Duration = <[(D2 – D1)*24 + T2]/24 d 
Start and end time 
missing  
D1/-- 
D2/-- 
Duration = <D2 – D1 + 1 
Start day and time 
missing 
--/-- 
D2/T2 
Duration = [(D2 – D0)*24 + (T2 – T0)]/24 d 
For a participant in the FAS, D0 and T0 are the 
date and time of first administration of study 
medication and for screen failures, D0 is the date 
of the screening visit and T0 = 00:00h 
End day and time 
missing  
D1/T1 
--/-- 
If the stop date is missing, duration will not be 
calculated. 
Start and end date 
missing 
--/-- 
--/-- 
If the stop date is missing, duration will not be 
calculated. 
FAS=full analysis set; PSL=padsevonil. 
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. The following general rules will apply to all repeated and unscheduled 
measurements: 
 For repeated measurements obtained prior to the first dose of study medication the latest 
value (which may be scheduled or unscheduled) will be used in the calculation of the 
descriptive statistics 
 For repeated measurements obtained at the designated Baseline visit, the latest value (which 
may be scheduled or unscheduled) will be defined as the Baseline provided that this occurred 
prior to the first dose of study medication 
 Unscheduled and repeated measurements will not be used in the descriptive statistics at time 
points after first dose of study medication 
 Unscheduled measurements performed for the End-of-Study/End-of-Treatment (EOT) visit 
will be assigned to the EOS/EOT Visit (Section 4.4) and analyzed accordingly as an 
EOS/EOT Visit. 
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4.4 
Handling of measurements obtained at the early withdrawal 
visit 
Study participants who withdraw early from the study for any reason, including those withdrawn 
from study medication, will be asked to return for the EOS Visit as soon as possible after the last 
dose of study medication. 
4.5 
Interim analyses and data monitoring 
Not applicable. 
4.6 
Multicenter studies 
This study is planned to be conducted at one site. Thus, there is no plan to explore sites effect in 
the analysis. 
4.7 
Multiple comparisons/multiplicity 
Not applicable. 
4.8 
Use of an efficacy subset of participants 
Not applicable. 
4.9 
Active-control studies intended to show equivalence 
Not applicable. 
4.10 
Examination of subgroups 
If PK effects by age group or gender are observed (i.e., between adult and elderly study 
participants) and if there are at least 5 participants within each subgroup category within the 
elderly age groups or gender groups based on the related subgroup analysis, then subgroup 
analyses may be performed.  
An ANOVA with age group as the fixed effect and the primary PK parameters as the dependent 
variable will be performed. If the age group fixed effect is significant for at least one primary PK 
parameter at alpha = 0.1 significance level, then a subgroup analysis based on age group (≥65 to 
74 years old and ≥75 years old) will be performed within the elderly cohort.  
Similarly, an ANOVA with age group and gender as the fixed effects and the primary PK 
parameters as the dependent variable will be performed. If the gender fixed effect is significant 
for at least one primary PK parameter at alpha = 0.1 significance level, then a subgroup analysis 
based on gender (male and female) will be performed within both the adult and elderly cohorts. 
 
 
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5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Participant disposition 
The number of participants who signed the informed consent, participants who completed or 
prematurely discontinued the study, as well as the reason for discontinuation will be summarized 
for all participants, based on the All Study Participants . A participant who completed the study 
is defined as a study participant who completed all visits up to and including the EOT/EOS visit 
(in the Follow-up Period).  
The number and percentage of study participants who discontinued due to AEs will be 
summarized separately for all study participants and per age group (adults and elderly).  
The number and percentage of study participants included in each of the analysis sets will be 
summarized for all participants based on the All Study Participants. Percentages will be 
calculated based on the All Participants Set for the purpose of this summary. 
Screening failure reasons will be listed for the All Study Participants. A listing of participants 
who did not meet study eligibility criteria will also be presented for the All Study Participants. 
In addition, the following listings will be presented: 
 Participant disposition (All Study Participants) 
 Study discontinuation (FAS) 
 Visit dates (FAS) 
 Participant analysis sets (All Study Participants) 
The listing of participant disposition will include the date of informed consent, date and time of 
first and last dose of study medication, date of premature termination and primary reason (if 
applicable) and date of final contact. 
The listing of study discontinuation will include the reason for discontinuation and the number of 
days on study medication during the Period 1B (MD). During the Period 1A (SD), there was one 
day of study medication. 
The number of days on study medication during the Period 1B (MD) will be calculated as 
follows: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐷𝑎𝑦𝑠 𝑜𝑛 𝑠𝑡𝑢𝑑𝑦 𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 (𝑃𝑒𝑟𝑖𝑜𝑑 1𝐵)
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑
−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑀𝐵) + 1 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types in the IPD 
document (see also section 3.4). 
A listing of all IPDs identified at the DEM will be presented for all participants based on the 
FAS and will include the deviation type and description. The number and percentage of 
participants in the FAS with IPDs will be summarized for all participants, per treatment period 
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(Period 1A, Period 1B, and whole treatment period) and for each deviation type. The 
denominator for the percentages will be the number of participants in the FAS. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
A by-participant (study participant) listing of demographics will be presented based on the ES. 
This will include the year of birth, age (in years), sex, race, ethnicity, country, height (in cm), 
weight (in kg) body mass index (BMI, in kg/m2). The body weight will be the measurement 
obtained at Screening. Body mass index (kg/m2) is documented in the CRF.  
All demographic characteristics (except for year of birth) will be summarized for all participants 
based on the FAS. The summary of age will include descriptive statistics and categorical 
summaries, the latter based on requirements for European Union Drug Regulating Authorities 
Clinical Trials (EudraCT) and clinicaltrials.gov reporting. 
For the EudraCT reporting, the categories will include: 
 18 to <65 years 
 65 to <85 years 
 ≥85 years 
For clinicaltrials.gov reporting, the categories will include: 
 ≤18 years 
 19 to <65 years 
 ≥65 years 
Additionally, the categories will include: 
 18 to <65 years 
 65 to <75 years 
 ≥75 years 
Characteristics on experience of medical or psychiatric condition and on experience of 
procedures or surgeries will be also summarized for the FAS. 
6.2 
Other Baseline characteristics 
Lifestyle information (alcohol, tobacco, caffeinated beverage and illicit drug use), psychiatric 
and mental status (orientation, attention, memory, mood and calculus) and suicidality risk 
evaluation (C-SSRS) at Baseline will be listed and summarized for all participants in the FAS.  
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6.3 
Medical history, procedure history and concomitant medical 
procedures 
Medical history will be listed and summarized (in an incidence table) for the FAS for all 
participants, by MedDRA system organ class (SOC) and preferred term (PT). The reported term 
will be included in the listing. The summary will include the number and percentage of study 
participants, and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the ‘All Participants’ column.  
Procedure history (procedures or surgeries prior to study entry) will be listed separately by the 
procedure reported term based on the FAS.  
Concomitant medical procedures occurring during the study will be listed for the FAS. 
6.4 
Prior and concomitant medications 
Prior and concomitant medications (Period 1A (SD), Period 1B (MD) and overall) will be listed 
and summarized for all participants in the FAS, by WHODD Anatomical Main Group [Level 1 
term text], Pharmacological Subgroup [Level 3 term text] and PT. The reported term will be 
included in the listing. Separate tabulations will be presented for prior medications and 
concomitant medications (Period 1A (SD), Period 1B (MD) and overall). Prior medications 
which continued into the treatment period will also be classified as concomitant and will be 
included in both summaries. Concomitant medications (Period 1A (SD), Period 1B (MD) and 
overall) will be described for all participants and by age group based on the FAS. 
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in the ‘All Participants’ column. 
6.4.1 
Prior medication definition 
Prior medications include any medications that started prior to the date of first dose of PSL. This 
includes medications that started prior to the first dose of PSL and continued after. 
6.4.2 
Concomitant medication definition 
SD-Concomitant medications are medications taken anytime during Period 1A (SD) (Day 1 to 
Day 7).  
MD-Concomitant medications are medications taken anytime during Period 1B (MD) and 
through the Follow-Up Period (Day 8 to Day 22).  
If a medication is started prior to PSL administration and stopped after the first PSL 
administration (SD period), then that medication will be classified as both prior and SD-
concomitant medication. If this medication is stopped during the Period 1B (MD) or later, then 
that medication will also be classified as prior, SD-concomitant and MD-concomitant 
medication. 
Any medications with missing dates and/or times will be handled as described in Section 4.2.4 to 
classify them as prior or concomitant. 
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7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
The Investigator (or designee) is responsible for retaining all used, unused, and partially 
used containers of study medication until returned or destroyed. 
A Drug Accountability form will be used to record study medication dispensing and return 
information on a by-participant basis. Compliance with the study medication is defined as 
consumption by the study participant that confirms 100% with the planned dosage. 
Drug administration/consumption will be recorded and any discrepancies with the dosing 
regimen will be explained. Dosing deviations will be included in the listing of IPDs where 
applicable. 
No formal calculations of compliance will be presented as all study medication is administered 
on site. 
8 
EFFICACY ANALYSES 
Not applicable. 
9 
PHARMACOKINETICS 
The calculation of the PK parameters of PSL and two of its metabolites 
 
) will be performed by the Pharmacokinetic Pharmacodynamic Modeling and 
Simulation Department, ICON PLC. All PK TFLs will be produced by ICON PLC SAS 
programming (Early Phase). 
Pharmacokinetic concentrations and PK parameters will be summarized using the PK-PPS and 
listed on the FAS by study participants. Figures of summaries will be based on the PK-PPS and 
figures of individual concentrations will be based on the FAS. 
Pharmacokinetic parameters of PSL and two metabolites of PSL 
 
 will be computed using the actual sampling time points.  
The plasma concentration-time profiles, urine amounts, and PK parameters of PSL and two 
metabolites of PSL 
 will be summarized by age group (adult 
[18-64 years] and elderly study participants [≥65 years]) and treatment period using descriptive 
statistics. 
If PK effects by age group or gender as described in Section 4.10 observed, then the analysis of 
the primary PK variables will be repeated for subgroups within the adult and elderly cohorts.  
Individual plasma PSL concentration-time profiles along with the individual plasma 
concentration-time profiles of the two metabolites of PSL 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.  
9.1 
Analysis of the primary pharmacokinetic variables 
Individual plasma concentrations of PSL will be listed and will include the actual and nominal 
sampling times and the deviation between them. All deviations will be calculated relative to the 
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last dose of study medication (on Day 1 for Period 1A (SD) and on Day 16 for Period 1B (MD)). 
Any samples that are obtained outside the tolerance window permitted at the specified time point 
will be discussed at the DEM and any possible exclusion from analysis will be documented 
accordingly. The primary PK variables in plasma used for PSL are: Cmax, AUC0-t , AUC for the 
single dose (Period 1A) and Cmax,ss, and AUCτ for the multiple dose (Period 1B). Cmax and Cmax,ss 
will be determined from the observed concentration and time data. AUC, AUC and AUC0-t will be 
computed using the linear up/log down trapezoidal rule. 
 
The PK plasma concentrations and the primary PK parameters of PSL and its metabolites will be 
summarized by nominal sampling times using descriptive statistics (number of available 
observations [n], arithmetic mean, median, standard deviation, minimum, maximum, geometric 
mean, geometric CV and 95% CI for the geometric mean [assuming log-normally distributed 
data]). Values below the LLOQ will be reported with a clear sign (flag variable in the dataset) 
indicating that they were below the LLOQ. 
Individual participant concentration-time profiles of PSL and its metabolites will be displayed 
graphically in linear and semi-logarithmic scale. Combined individual (spaghetti) plots will be 
displayed by age group and analyte with all participants overlaid on the same plot (linear and 
semi-logarithmic scale). 
Geometric mean profiles of plasma concentrations for PSL over time will be presented, with all 
treatment group overlaid on the same plot, in both linear and semi-logarithmic scale. For the 
linear scale plot only, the lower and upper 95% confidence interval (CI) for the geometric mean 
will be displayed.  
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times. 
For the single dose (Period 1A) and multiple dose (Period 1B)) periods of the study, primary PK 
parameters (Single dose Cmax, AUC0-t, AUC and multiple dose: Cmax,ss, AUCτ  ) will be assessed 
in adults and elderly study participants with analysis of variance (ANOVA). Point estimates for 
the ratio of geometric means between adults and elderly study participants (and per category, if 
deemed necessary), 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. Inter-participant variability on PK parameters will be 
derived from these analyses. 
9.2 
Analysis of secondary pharmacokinetic variables 
The secondary PK variables are the amount excreted and metabolic ratio of amount excreted, 
measured in the urine PK of PSL and its metabolites. These PK variables along with urine 
concentrations and urine volume will be summarized for PSL and its metabolites by nominal 
sampling times using descriptive statistics (number of available observations [n], arithmetic 
mean, median, standard deviation, minimum, maximum, geometric mean, geometric CV and 
95% CI for the geometric mean [assuming lognormally distributed data]). Values below the 
LLOQ will be reported with a clear sign (flag variable in the dataset) indicating that they were 
below the LLOQ. 
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9.3 
Analysis of other pharmacokinetic variables 
The other PK parameters and their analysis are the following: 
 The relationship between PK parameters (AUCt, AUC, AUC0-t, CL/F , CLR and t1/2) of PSL 
and two metabolites of PSL and creatinine clearance, age (numerical), hepatic laboratory 
parameters (e.g., bilirubin, ALT, and AST) will be evaluated. The relationship will be 
displayed graphically using scatterplots, and the correlation between the PK parameter and 
the hepatic function test or age will be evaluated using linear regression, considering the PK 
parameter as the dependent variable and the hepatic function test or age as the independent 
variable.  
 The point estimate and the 95% CI for the median differences for tmax between the adult and 
elderly cohorts will be computed according to the Hodges-Lehmann method.  
 
10 
SAFETY ANALYSES 
All safety summaries and listings will be performed using the FAS. All safety variables will be 
summarized by the age group (adult and elderly study participants) and Treatment Period (SD, 
MD, and overall). Unless stated otherwise, all summaries including figures will be presented as 
detailed in the shells for figures. Summaries for continuous variables by time points will be 
based on the averaged value. Categorical variables will be summarized.  
10.1 
Extent of exposure 
All study medication administration details will be listed by study participant. The listing will 
include the date and time of administration of the morning and evening dose and total daily dose 
of medication.  
Exposure data will be listed only. 
10.2 
Adverse events 
All AEs will be coded using the MedDRA® and characterized as pre-treatment, SD-treatment-
emergent and MD-treatment-emergent according to the intake of the study medication. 
 Adverse events with a start date prior to the first dose of study medication will be 
defined as pre-treatment AEs. 
 SD-treatment-emergent AE (SD-TEAE) is defined as any AE with a start date/time on or 
after the first dose of study medication and until Day 7 (last Day of Period 1A) or any 
unresolved event already present before administration of study medication that worsens 
in intensity following exposure to the SD-treatment.  
 MD-treatment-emergent AE (MD-TEAE) is defined as any AE with a start date/time on 
or after the first dose of study medication during the Period 1 B (usually on Day 8) and 
until 168 hours after the last PSL intake or any unresolved event already present before 
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administration of study medication during Period 1B that worsens in intensity following 
exposure to the  MD-treatment.  
Where dates are missing or partially missing, AEs will be assumed to be SD-treatment-emergent 
and MD-treatment-emergent, unless there is clear evidence to suggest that the AE started prior to 
the first dose of study medication. Missing or partially missing dates for AEs will be handled as 
described in Section 4.2.4. 
All AEs starting after the first intake of PSL through Day 7 will be attributed to SD-Treatment 
Emergent AEs; all AEs starting (strict) after Day 7 (the first PSL intake during Period 1B  is 
foressen on Day 8) through Day 22 will be attributed to MD-Treatment Emergent AEs and AE 
starting more than 168 hours post last dose of PSL will be attributed to the FU period. 
All AEs will be recorded in the Case Report form (CRF) from the time of informed consent until 
study completion or termination. All AEs will be coded (see Section 3.8) and categorized by 
intensity (mild/moderate/severe) and relationship (related/not related) to study drug PSL as 
judged by the Investigator. 
The number and percentage of participants who experience SD-TEAEs and MD-TEAEs will be 
summarized by MedDRA SOC, PT. The occurrence and incidence of AEs will also be 
summarized by intensity and relationship to PSL. Adverse events leading to discontinuation and 
SAEs will also be summarized.  
Summaries of TEAEs (SD-TEAEs and MD-TEAEs) will include the following: 
 Incidence of TEAEs (overview including number and percentage of participants with any 
TEAEs, serious TEAEs, TEAESI, discontinuations due to TEAEs, drug-related TEAEs, 
severe TEAEs, all deaths (AEs leading to death regardless of treatment emergence) and 
TEAEs leading to death; event counts will also be included) 
 Incidence of TEAEs 
 Incidence of TEAE of special interest 
 Incidence of TEAEs by relationship 
 Incidence of TEAEs by maximum relationship 
 Incidence of TEAEs by intensity 
 Incidence of TEAEs by maximum intensity 
 Incidence of non-serious TEAEs above reporting threshold of 5% of participants 
 Incidence of non-serious TEAEs above reporting threshold of 5% of participants by 
relationship 
Summary tables will contain counts of study participants, percentages of study participants in 
parentheses and the number of events where applicable. A participant who has multiple events in 
the same SOC and PT will be counted only once in the participant counts but all events will be 
included. 
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In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Participants who experience the same event multiple times will be included in 
the most related category for tabulations by maximum relationship. Events with missing 
relationship will be considered as ‘Related’ but recorded as missing in the listings.  
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in 
the listings. 
Incidence of Non-Serious TEAEs above reporting threshold of 5% of participants and incidence 
of Non-Serious TEAEs above reporting threshold of 5% of participants by relationship will be 
reported by system organ class and preferred term. 
Adverse event summaries will be ordered alphabetically by SOC and decreasing frequency of PT 
within SOC in the group column for tables including event counts. For tables including only 
number and percentage of study participants, summaries will be ordered alphabetically by SOC 
and decreasing incidence of PT within SOC in the group column.A listing for all AEs will be 
presented by study participant and will include the onset date/time and outcome date/time of the 
event (including relative days), the AE duration (derived), time to onset (derived), pattern of 
event, intensity, relationship, action taken and outcome. In addition, the listing will flag AEs that 
led to discontinuation, TEAEs, AESIs and SAEs. 
10.3 
Clinical laboratory evaluations 
Laboratory data (clinical chemistry, hematology and urinalysis) and changes from Baseline 
(if applicable) will be summarized by descriptive statistics at each time point by age group 
and Treatment Period. Shift tables from Baseline to each post-Baseline time point will be 
presented by Treatment Period. Any laboratory measurements that are BLQ or ALQ will be 
handled as described in Section 4.2.2. Values outside the reference range for numeric 
variables will be flagged in the listings and in addition, will be listed separately. The 
reference ranges will also be reported in the listings.  
A separate listing will present the study participant who meets one or more of the following 
criteria at any time point: 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase ≥3x upper 
limit of normal (ULN) 
 Total bilirubin increase ≥2xULN 
 Alkaline phosphatase ≥2xULN 
The listing will display only time points for which at least one of the above criteria was fulfilled 
for a given study participant, and will display all results obtained i at time point for the specified 
variables. 
A summary of participants who meet the criteria for potential drug-induced liver injury (PDILI) 
will be presented together with any additional relevant data collected, if applicable. 
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Clinical chemistry and hematology parameters will be summarized by time point for both 
absolute values and changes from Baseline.  
Laboratory variables will be grouped according to the laboratory function panel (Table 10-1) and 
categorized as normal, high or low, if applicable, based on the reference range supplied by the 
analytical laboratory. For selected variables that are identified in Table 10-1 the change in 
category from Baseline will be presented in a shift table at all post-Baseline time points. 
Any additional laboratory variables not included in the outputs described previously will be 
listed separately. These will include the following: 
 Serology 
 Alcohol breath test 
 Serum pregnancy test (for women of childbearing potential) 
 Urine drug screen 
Figures of mean and mean change from Baseline may be presented for selected laboratory 
variables that will be identified at the DEM. Figures will be presented with all treatment periods 
included on the same plot. 
Table 10-1: Laboratory measurements 
Laboratory assessment 
Parameters 
Hematology 
Hemoglobina, hematocrit, red blood cell counta, mean 
corpuscular volume, platelets counta, red blood cell indices 
consisting of mean corpuscular volume, mean corpuscular 
hemoglobin and reticulocytes, total white blood cell count, 
and differential consisting of absolute counts and percentages 
of the following leukocyte types: neutrophilsa, lymphocytesa, 
monocytes, eosinophils, and basophils 
Biochemistry 
Sodium, potassium, calcium, glucose, blood urea nitrogena, 
creatininea, total and direct bilirubin (conjugated bilirubin 
when total bilirubin is outside the reference range), total 
protein, albumin, ALTa, ASTa, and ALPa 
Viral serology (only at Screening 
Visit) 
HIV 1 and 2 Ab, HBsAg and HCV-Ab 
Pregnancy (only at Screening Visit) 
Serum pregnancy test (hCG) 
Hormone tests (only at Screening 
Visit) 
Follicle-stimulating hormone and estradiol (to confirm 
postmenopausal status in female study participants) 
Urinalysis 
Specific gravity, pH, glucose, protein, blood, leukocytes, 
nitrite, ketones, bilirubin, urobilinogen (with dipstick) 
If protein, blood, or leukocytes are abnormal (positive), a 
microscopic examination of the sediment will be performed. 
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Laboratory assessment 
Parameters 
Drug screen 
Amphetamines/methamphetamines, benzodiazepines, 
barbiturates, cocaine, cannabis, methadone, tricyclic 
antidepressants and opiates 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBsAG=hepatitis 
B surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibodies; 
SFU=Safety Follow-Up 
a Shift tables will be presented for these variables 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
The following vital signs measurements will be obtained with the study participants resting in the 
supine position for 5 minutes at all time points after the Baseline Visit: 
 Systolic and diastolic blood pressure 
 Pulse rate 
 Respiratory rate 
 Oral or aural body temperature 
A by- participant listing of all vital sign measurements and change from Baseline will be 
presented at each time point.  
Descriptive statistics will be reported for all vital sign measurements. Vital sign variables and 
changes from Baseline (pre-dose of each Treatment Period) will be summarized by descriptive 
statistics at each time point by age group and Treatment Period. 
Figures of mean and mean change from Baseline will be displayed. 
The number and percentage of study participants with treatment-emergent markedly abnormal 
(TEMA)/potentially clinically significant (PCS) vital sign values as calculated by the criteria 
outlined in Table 10‒2 will be summarized by the following age groups at each time point: 
Adults (18-64 years), Elderly (>=65-74 years), and Elderly (>= 75 years) 
Table 10‒2: TEMA/PCS criteria for vital signs 
Variable 
Unit 
Lowa 
Higha 
Systolic blood pressure 
mmHg 
Value <90 and ≥20 decrease 
from Baseline 
Value >140 and ≥20 increase 
from Baseline 
Diastolic blood pressure 
mmHg 
Value <50 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase 
from Baseline 
Pulse rate 
bpm 
Value <45 and ≥15 decrease 
from Baseline 
Value >90 and ≥15 increase 
from Baseline 
bpm=beats per minute; PCS=potentially clinically significant; TEMA=treatment-emergent markedly abnormal. 
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a Both conditions must be satisfied for a measurement to be considered potentially clinically significant. 
10.4.2 
Electrocardiograms  
12-lead ECG will be recorded 3 times at each time point. The individual mean at each time point 
will be calculated as raw parameters for descriptive analysis. The individual mean and change 
from baseline (time-matched Baseline on Day -1, when applicable) will be summarized using 
descriptive statistics by age group and treatment period at each time point. 
All standard 12-lead ECG recordings will be taken in triplicate with the participant resting in the 
supine position for at least ≥5 minutes. The following ECG parameters will be reported: 
 PR interval  
 QT interval 
 QRS interval 
 QTc interval (QT corrected for heart rate using Fridericia’s formula [QTcF]) 
 Heart rate  
If available in the database, the QT corrected for heart rate using Bazett’s formula (QTcB) will 
also be included in the listings and tabulations. 
The individual measurements and the mean of the triplicate measurements will be reported in the 
by- participant listings. The listing will also include the change from Baseline (time-matched 
Baseline day of each treatment group, where applicable), based on the mean of the triplicate 
measurements at each time point, and will be presented by time point. 
Measured values and changes from time-matched Baseline will be summarized at each time 
point and by ECG variable (based on the mean of the triplicate values at each time point). The 
mean change for ECG parameter will also be displayed graphically.  
The following cut-points in QTcF (observed data and change from time-matched Baseline), 
based on the mean of the triplicate data, will be summarized categorically (number and 
percentage of participants) at each time point. 
For observed data: 
 <450 msec 
 ≥450 to <480 msec 
 ≥480 to <500 msec 
 ≥500 msec 
Absolute change from Baseline in QTcF: 
 <30 msec 
 ≥30 to <60 msec 
 ≥60 msec 
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All ECG findings for the individual triplicate measurements will be listed separately. 
Any incomplete triplicate measurements at a given time point will be handled as described in 
Section 4.2.3. 
Figures of mean and mean change from Baseline will be displayed. 
 
10.4.3 
Other safety variables 
10.4.3.1 
Physical examination 
Participants with abnormalities in the physical examination will be listed including details of the 
abnormality. 
10.4.3.2 
Columbia-Suicide Severity Rating Scale 
Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al, 2011) data will be listed. 
Module of the questionnaire, time point, question and the associated response will be listed for 
all the visit days where this questionnaire is collected. 
11 
OTHER ANALYSES  
A listing of comments will be presented.  
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12 
REFERENCES 
Phillips, A. and Haudiquet, V. (2003), ICH E9 guideline ‘Statistical principles for clinical trials’: 
a case study. Statist. Med., 22: 1-11. doi:10.1002/sim.1328 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77. 
UCB Global Exploratory Development Guideline on performing NCA analysis. Version 1.0 – 
08/NOV/2017 
 
 
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13 
APPENDICES 
Table 13-1: Breakdown of treatment periods reported into the TFLs by study 
assessment data 
Treatment 
Period 1A 
(SD) 
Period 1B 
(MD) 
All 
participants 
Participant disposition 
 
 
X 
Protocol deviations 
 
 
X 
Demographics 
 
 
X 
Medical history 
 
 
X 
Lifestyle 
 
 
X 
Prior medications 
 
 
X 
Concomitant medications 
X 
X 
X 
Adverse Events 
X 
X 
X 
Laboratory tests 
X 
X 
X 
Other safety continuous measurements (vital 
signs, ECG) 
X 
X 
X 
Safety categorical results (laboratory shift 
tables, PDILI) 
X 
X 
X 
PK plasma and urine for PSL and 
metabolites 
X 
X 
X 
ECG=electrocardiogram; MD=multiple dose; PK=pharmacokinetic; PSL=Padsevonil; SD=single dose. 
 
 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
 
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Approval Signatures
Name:
UP0053-SAP-v1.0_18Sep2019
Version:
1. 0
Document Number:
CLIN-000141170
Title:
UP0053 Statistical Analysis Plan Version 1.0
Approved Date:
20 Sep 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Qualified Person
Date of Signature: 18-Sep-2019 22:47:14 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 20-Sep-2019 14:03:30 GMT+0000
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