Clinical trial NCT04126343
Conditions: Healthy Study Participants
Keywords: Healthy study participants Padsevonil Moxifloxacin Cardiac repolarization
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2019-10-23; Completion date: 2020-05-22
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of the study is to evaluate the effects on cardiac repolarization of high-dose padsevonil (PSL) in comparison to placebo in healthy study participants.

Detailed description:

Arms: arm 1: Study participants randomized to this arm will receive assigned doses of padsevonil twice daily. On Day 8 padsevonil will be administered in the morning, and placebo will administered in the evening. arm 2: Study participants randomized to this arm will receive placebo twice daily to maintain the blinding. arm 3: Study participants randomized to this arm will receive padsevonil-placebo twice daily. On Day 8 placebo will be administered in the morning, and moxifloxacin will administered in the evening.
Interventions: intervention 1: Padsevonil intervention 2: Moxifloxacin intervention 3: Placebo
Intervention descriptions: intervention 1: * Pharmaceutical form: Film-coated tablet
* Route of administration: Oral use
* Study participants will receive padsevonil in a pre-specified dosing sequence during the Treatment Period intervention 2: * Pharmaceutical form: Film-coated tablet
* Route of administration: Oral use
* Study participants will receive moxifloxacin once during the Treatment Period intervention 3: * Pharmaceutical form: Film-coated tablet
* Route of administration: Oral use
* Study participants will receive placebo in a pre-specified sequence during the Treatment Period to match padsevonil and maintain the blinding

Protocol documents:
Prot_000.pdf: 
UCB 
 
10 Oct 2019 
Clinical Study Protocol 
Padsevonil 
UP0050 
 
 
 
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Page 1 of 78 
A SINGLE-CENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, 3 TREATMENT PERIOD 
CROSSOVER STUDY TO ASSESS THE EFFECT OF 
PADSEVONIL ON CARDIAC REPOLARIZATION 
(QTc INTERVAL) (USING MOXIFLOXACIN AS A POSITIVE 
CONTROL) IN HEALTHY STUDY PARTICIPANTS 
 
PROTOCOL UP0050 AMENDMENT 1 
PHASE 1 
SHORT TITLE: 
 
A placebo-controlled safety and tolerability study comparing the pharmacodynamic effect of 
high-dose padsevonil on cardiac repolarization, including moxifloxacin as a positive 
pharmacologic control, in healthy study participants. 
Sponsor: 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
Eudra CT Number: 
2019-002797-31 
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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Document History 
Document 
Date 
Type of amendment 
Protocol Amendment 1 
10 Oct 2019 
Substantial 
Original Protocol 
22 Jul 2019 
Not applicable 
Amendment 1 (10 Oct 2019) 
Overall Rationale for the Amendment 
The protocol has been amended to comply with the requirement of the Medicines and Healthcare 
products Regulatory Agency (MHRA). Changes were made in the exclusion criteria to set the 
upper limit of acceptable range of total bilirubin test results and to clarify language regarding 
liver function tests (absolute rule for liver function test parameters) for alignment with regulatory 
requests in another padsevonil (PSL) protocol. Changes were made in Section 7.1.3 (Criteria for 
study hold due to adverse events) to comply with an MHRA requirement to align with European 
Medicines Agency Guidance on risk mitigation in first-in-human and early clinical trials. In 
addition, further changes have been made to correct various other typographical errors and to add 
clarifying language. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 3 Table 3-1 
Language regarding a secondary endpoint 
was removed. 
This is a correction to 
align information in 
the objective and 
endpoints section of 
the summary along 
with the information in 
the Schedule of 
activities (Table 1-1). 
Section 5.2-Exclusion Criteria 
Changed exclusion criterion #15 to include 
that isolated bilirubin must be <1.5x upper 
limit of normal (ULN) instead of >1xULN. 
Exclusion criterion #15 had the note 
removed regarding liver function test values 
above the ULN and repeat tests that could 
be performed in such situations. Language 
regarding retesting of participants with 
out-of-range laboratory values remains 
elsewhere in the protocol including 
Section 5.4.1 (Rescreening). 
Update exclusion 
criteria 
Section 5.2-Exclusion Criteria 
The exception of asymptomatic gallstones 
was removed from exclusion criterion #16. 
Update exclusion 
criteria 
Section 6.1 Table 6-1 Treatments 
administered 
The manufacturer of moxifloxacin has been 
updated from Bayer to Accord Healthcare, 
Ltd. 
Correction 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.3 Criteria for study 
hold due to adverse events 
The criteria have been amended to align 
with the European Medicines Agency 
Guidance on risk mitigation in first-in-
human and early clinical trials. 
Regulatory alignment 
Section 8.5.5 Pregnancy 
The pregnancy language was updated that 
UCB will collect pregnancy and birth 
information for up to 12 months after a 
birth. This aligns with other PSL protocols. 
Correction and 
alignment with other 
PSL protocols 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24 hour) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
Email 
Global: DS_ICT@ucb.com or DSICT.-@ucb.com 
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TABLE OF CONTENTS 
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 ................................................................................. 19 
4 
STUDY DESIGN ............................................................................................................. 22 
4.1 Overall design .................................................................................................................. 22 
4.1.1 
Screening and Baseline Periods ........................................................................... 22 
4.1.2 
Treatment Periods 1, 2, and 3 .............................................................................. 22 
4.1.3 
Washout Periods .................................................................................................. 24 
4.1.4 
Safety Follow-up Period ...................................................................................... 24 
4.2 Scientific rationale for study design................................................................................. 24 
4.3 Justification for dose ........................................................................................................ 25 
4.4 End of study definition ..................................................................................................... 25 
5 
STUDY POPULATION .................................................................................................. 25 
5.1 Inclusion criteria .............................................................................................................. 26 
5.2 Exclusion criteria ............................................................................................................. 27 
5.3 Lifestyle restrictions ......................................................................................................... 29 
5.3.1 
Meals and dietary restrictions .............................................................................. 29 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 30 
5.3.3 
Activity ................................................................................................................ 30 
5.4 Screen failures .................................................................................................................. 30 
5.4.1 
Rescreening .......................................................................................................... 31 
6 
STUDY TREATMENTS ................................................................................................. 31 
6.1 Treatments administered .................................................................................................. 31 
6.2 Preparation, handling, storage, and accountability requirements .................................... 33 
6.2.1 
Drug accountability ............................................................................................. 33 
6.3 Measures to minimize bias: randomization and blinding ................................................ 33 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 34 
6.3.1.1 
Maintenance of study treatment blind ....................................................... 34 
6.3.1.2 
Breaking the treatment blind in an emergency situation ........................... 34 
6.4 Treatment compliance ...................................................................................................... 35 
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6.5 Concomitant medications/treatments ............................................................................... 35 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 35 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 35 
6.5.3 
Rescue medication ............................................................................................... 35 
6.6 Dose modification ............................................................................................................ 36 
6.7 Treatment after the end of the study ................................................................................ 36 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 36 
7.1 Discontinuation of study medication ............................................................................... 36 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 36 
7.1.2 
QTc stopping criteria ........................................................................................... 37 
7.1.3 
Study hold/stopping rules .................................................................................... 38 
7.1.4 
Temporary discontinuation .................................................................................. 38 
7.1.5 
Rechallenge .......................................................................................................... 38 
7.2 Participant discontinuation/withdrawal from the study ................................................... 38 
7.3 Lost to follow-up .............................................................................................................. 40 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 40 
8.1 Efficacy assessments ........................................................................................................ 41 
8.2 Pharmacodynamics assessments ...................................................................................... 41 
8.2.1 
ECG/continuous Holter monitoring ..................................................................... 41 
8.3 Pharmacokinetics assessments ......................................................................................... 41 
8.4 Safety assessments ........................................................................................................... 42 
8.4.1 
Physical examination ........................................................................................... 42 
8.4.2 
Vital signs ............................................................................................................ 43 
8.4.3 
Safety 12-lead ECGs ............................................................................................ 43 
8.4.4 
Clinical safety laboratory assessments ................................................................ 43 
8.4.5 
Suicidal risk monitoring ...................................................................................... 44 
8.4.6 
Psychiatric and mental status ............................................................................... 44 
8.5 Adverse events ................................................................................................................. 45 
8.5.1 
Time period and frequency for collecting AE and SAE information .................. 45 
8.5.2 
Method of detecting AEs and SAEs .................................................................... 45 
8.5.3 
Follow-up of AEs and SAEs ................................................................................ 45 
8.5.4 
Regulatory reporting requirements for SAEs ...................................................... 46 
8.5.5 
Pregnancy ............................................................................................................ 46 
8.5.6 
AESI .................................................................................................................... 46 
8.6 Safety signal detection ..................................................................................................... 47 
8.7 Treatment of overdose ..................................................................................................... 47 
8.8 Genetics ............................................................................................................................ 47 
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8.9 Biomarkers ....................................................................................................................... 47 
8.10 Medical resource utilization and health economics ......................................................... 48 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 48 
9.1 Definition of analysis sets ................................................................................................ 48 
9.2 General statistical considerations ..................................................................................... 48 
9.3 Planned efficacy/outcome analyses ................................................................................. 48 
9.4 Planned PD analyses ........................................................................................................ 49 
9.4.1 
Analysis of the primary ECG endpoint ............................................................... 49 
9.4.2 
Analysis of the secondary ECG endpoints .......................................................... 49 
9.4.3 
Analysis of the other PD endpoints ..................................................................... 49 
9.5 Planned PK analyses ........................................................................................................ 49 
9.6 Planned safety analyses .................................................................................................... 50 
9.7 Handling of protocol deviations ....................................................................................... 50 
9.8 Handling of dropouts or missing data .............................................................................. 51 
9.9 Planned interim analysis and data monitoring ................................................................. 51 
9.10 Determination of sample size ........................................................................................... 51 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 52 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations ............................. 52 
10.1.1 
Regulatory and ethical considerations ................................................................. 52 
10.1.2 
Financial disclosure ............................................................................................. 52 
10.1.3 
Informed consent process .................................................................................... 52 
10.1.4 
Data protection ..................................................................................................... 53 
10.1.5 
Data quality assurance ......................................................................................... 53 
10.1.5.1 
Case Report Form completion ................................................................... 54 
10.1.5.2 
Apps ........................................................................................................... 54 
10.1.6 
Source documents ................................................................................................ 55 
10.1.7 
Study and site closure .......................................................................................... 55 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................ 56 
10.3 Appendix 3: Adverse Events – Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................ 58 
10.3.1 
Definition of AE .................................................................................................. 58 
10.3.2 
Definition of SAE ................................................................................................ 59 
10.3.3 
Recording and follow-up of AE and/or SAE ....................................................... 60 
10.3.4 
Reporting of SAEs ............................................................................................... 62 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ........... 63 
10.5 Appendix 5: Genetics ....................................................................................................... 67 
10.6 Appendix 6: Liver safety – Suggested Actions and Follow-up Assessments .................. 68 
10.7 Appendix 7: Medical Device Incidents – Definition and Procedures for Recording, 
Evaluating, Follow up, and Reporting ............................................................................. 70 
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10.8 Appendix 8: Rapid Alert Procedures ............................................................................... 71 
10.9 Appendix 9: Country-specific Requirements ................................................................... 72 
10.10 
Appendix 10: Abbreviations and Trademarks ....................................................... 73 
10.11 
Appendix 11: Protocol Amendment History ......................................................... 75 
11 REFERENCES ................................................................................................................ 77 
SPONSOR DECLARATION .................................................................................................. 78 
 
LIST OF TABLES 
Table 1-1: 
Schedule of activities ....................................................................................... 14 
Table 3-1: 
Objectives and endpoints ................................................................................. 20 
Table 6-1: 
Treatments administered .................................................................................. 32 
Table 8-1: 
Irrelevant time deviations for PK sampling ..................................................... 42 
Table 10-1: 
Protocol-required safety laboratory assessments ............................................. 56 
Table 10-2: 
Highly effective contraceptive methods .......................................................... 65 
Table 10-3: 
Phase I liver chemistry stopping criteria and follow-up assessments .............. 68 
 
LIST OF FIGURES 
Figure 1-1: 
UP0050 Study Design ...................................................................................... 13 
Figure 7-1: 
Liver chemistry stopping algorithm ................................................................. 37 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: 
A single-center, randomized, placebo-controlled, 3 treatment period crossover study to assess the 
effect of padsevonil on cardiac repolarization (QT interval corrected [QTc]) (using moxifloxacin 
as a positive control) in healthy study participants. 
Short title: 
A placebo-controlled safety and tolerability study comparing the pharmacodynamics (PD) effect 
of high-dose PSL on cardiac repolarization, including moxifloxacin as a positive pharmacologic 
control, in healthy study participants. 
Rationale: 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic vesicle protein 2 
(SV2) isoforms and postsynaptic central benzodiazepine receptor (cBZR) sites on the 
gamma-aminobutyric acid-A (GABAA) receptor that has shown broad-range efficacy in several 
preclinical models of epilepsy conducted by UCB. 
As is the case with all new chemical entities under development, the development program for 
PSL as an adjunctive treatment for focal-onset seizures in patients with epilepsy calls for the 
evaluation of its potential to affect cardiac repolarization, as indicated by prolongation of the 
heart rate (HR)-corrected QT interval on a standard 12-lead electrocardiogram (ECG). 
Historically, such evaluations have been performed (in compliance with International Council for 
Harmonisation [ICH] Guideline E14, 2005) in large, rigorously controlled clinical studies, across 
a wide range of target drug exposure (Cmax) levels that clearly bracket those to be anticipated in 
patients receiving the drug within the dosing regimen sought in the intended labelling. Use of 
placebo and a positive control have also usually been mandatory in such ‘Thorough’ QT (TQT) 
studies. 
However, in response to questions about the potential use of concentration-response analysis 
(‘pharmacokinetic [PK]/PD modeling’), Revision 3 of the E14 Guidance (2017) provided 
clarification that such an analysis using adequate data from standard early phase clinical studies 
could provide the necessary evidence in place of a specific TQT study, if certain technical 
requirements were met. 
UCB Pharma, having undertaken a detailed assessment of the data available from the early phase 
study program with PSL, believes those data to be sufficient to provide an acceptable evaluation 
across the Cmax range associated with the anticipated labelled doses and lower, but not at the 
higher, supratherapeutic levels usually required by E14. The purpose of this study is, therefore, 
to gather data at the highest dose anticipated in labelling, 400mg twice daily dosing (bid) (which 
is also the maximum tolerated dose [MTD] for PSL) in comparison to both placebo and a 400mg 
moxifloxacin positive control (a drug known to have a prolongation effect on the QTc interval), 
to complete the dataset required. 
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This is a Phase 1, single-center, randomized, placebo-controlled, 3 treatment period crossover 
study to assess the effect of PSL on QTc (using moxifloxacin as a positive control) in healthy 
study participants. 
Objectives and endpoints: 
Objectives 
Endpoints 
Primary 
The primary PD objective is: 
 
To evaluate the effects on cardiac 
repolarization (QTc interval) of high-dose 
PSL in comparison to placebo in healthy study 
participants 
The primary PD endpoint is: 
 
Placebo-corrected change from Baseline in QTc, 
based on Fridericia’s correction (QTcF) method 
(ΔΔQTcF) evaluated during the Target Dose 
Day of the PSL and Placebo Treatment Periods, 
using time point analysis 
Secondary 
The secondary PD objective is: 
 
To evaluate other aspects of the effects on 
cardiac function of high-dose PSL in 
comparison with placebo and moxifloxacin 
The secondary PD endpoints are: 
 
Placebo-corrected change from Baseline in 
QTcF after a single dose of moxifloxacin 
 
Placebo-corrected changes from Baseline for 
HR, PR interval, and QRS interval 
 
Frequency of treatment-emergent changes for 
T-wave morphology and U-wave presence 
 
Change from Baseline in QTcF (ΔQTcF) 
evaluated at drug-specific tmax (∆tmax) for PSL, 
, and 
possibly moxifloxacin 
The secondary PK objective is: 
 
To evaluate the plasma PK of PSL at steady 
state in healthy study participants 
The secondary PK endpoints are: 
 
Cmax,ss, tmax, and AUC, obtained from the 
plasma concentration-time profiles for PSL at 
steady state (on the Target Dose Day) 
The secondary safety objective is: 
 
To evaluate the safety and tolerability of PSL 
at the dosed level in healthy study participants 
The secondary safety endpoints are: 
 
Adverse events (AEs), serious adverse events 
(SAEs), treatment-related AEs, and AEs leading 
to discontinuation of the study 
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Objectives 
Endpoints 
Other 
The other PD objectives are: 
 
To evaluate other aspects of the effects on 
cardiac function of high-dose PSL in 
comparison with placebo and moxifloxacin 
 
To evaluate (using concentration-QT [C-QT] 
effect modeling) the relationship between QTc 
interval and the concentration of PSL and its 
metabolites 
The other PD endpoints are: 
 
Categorical outliers for HR, QTcF, PR interval, 
and QRS interval 
 
Relationship between ∆QTcF (change from 
Baseline in QTcF) and the plasma 
concentrations of PSL, 
 
 and possibly moxifloxacin 
The other PK objectives (depending on the 
outcome of PK and/or QT analyses) are: 
 
To evaluate from plasma samples the PK of 
PSL and the major metabolites of PSL 
(
 
]) 
 
To evaluate from banked plasma samples the 
PK of moxifloxacin (if needed) in healthy 
study participants 
 
To collect and store blood for potential 
absorption, distribution, metabolism, and 
excretion (ADME) genotyping (if needed) 
The other PK endpoints are: 
 
For PSL: 
 
Single dose: AUC0-12, Cmax, and tmax. 
 
Multiple dose: CLss/F and Ctrough  
 
For PSL metabolites: 
 
Single dose: AUC0-12, Cmax, tmax, and 
metabolic ratios for Cmax and AUC0-12 
 
Multiple dose: AUC, AUC0-t, Ctrough, Cmax,ss, 
tmax, and metabolic ratios for Cmax,ss and 
AUC 
 
For moxifloxacin (if needed): 
 
Single dose: AUC, AUC0-t, t½, Cmax, and tmax 
 
Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL and metabolite PK analyses) (if 
needed) 
The other safety objective is: 
 
To evaluate safety and tolerability of PSL at 
the dosed level in healthy study participants 
The other safety endpoints are: 
 
Changes from Baseline in safety laboratory data 
(hematology, clinical chemistry, and urinalysis) 
 
Changes from Baseline in vital signs (pulse rate 
[PR], respiratory rate, systolic blood pressure 
[SBP], and diastolic blood pressure [DBP]) 
 
Changes from Baseline in 12-lead ECG 
assessment 
 
Physical examination findings 
Overall design: 
This is a Phase 1, single-center, randomized, placebo-controlled, crossover study of the effects of 
high-dose PSL (400mg bid at steady state = MTD) on cardiac repolarization, including 
moxifloxacin as an open-label positive pharmacologic control in healthy study participants. 
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The study includes a Screening Period (up to 28 days), 3 Treatment Periods, 2 Washout Periods, 
and the Safety Follow-up (SFU) Period. However, this may vary according to the scheduling of 
Treatment Periods. 
Study participants who provide written informed consent will be screened within 28 days before 
the first Treatment Period. 
During each Treatment Period, each study participant will check into the clinic the day prior to 
the relevant First Dosing Day. Throughout the relevant Dosing Days, continuous Holter 
monitoring will be undertaken to provide extracted ECG records at the relevant time points 
necessary for the evaluation of QT interval effects. During the hour prior to administration of the 
first dose of each Treatment Period, 3 triplicate ECGs extracted from the Holter record will serve 
to provide a time-averaged Baseline for that Treatment Period. 
For study participants in the PSL Treatment Period, the bid doses of PSL will be titrated up 
(from PSL 100mg to 400mg) to reach steady state in time for the target dose on the ‘Target Dose 
Day’ (Day 8). For further detail on the dose titration, refer to Figure 1-1. 
During the first dosing day of each Treatment Period, Holter monitoring will take place from 
1 hour prior to the first dose of study medication until dosing (at -0.75, -0.5, and -0.25 hours), 
and a venous blood sample and vital signs will be collected at the time points specified in the 
Schedule of activities (Table 1-1). 
During the Target Dose Day for each Treatment Period (Day 8), Holter monitoring will take 
place ≥1 hour prior to the morning dose of study medication until 24 hours following the 
morning dose (and collection of the Day 9 trough PK sample), and venous blood samples and 
vital signs will be collected at the time points specified in the Schedule of activities (Table 1-1). 
On the evening of each Target Dose Day, all study participants will receive a placebo medication 
in order to protect the 18- and 24-hour PK/QT evaluations during the PSL Treatment Period. 
On Days 12, 13, and 14 of each Treatment Period, study participants will remain at the clinic for 
inpatient follow-up assessments. 
Following completion of each Treatment Period, study participants will be discharged from the 
clinic, returning on the day prior to the First Dosing Day of the next Treatment Period for 
readmission. The interval between Treatment Periods (Washout Period) will be sufficient to 
ensure a minimum of 7 days’ washout from the study medication administered during the 
previous Treatment Period. 
Following completion of the final Treatment Period, study participants will be discharged and 
return for an SFU Visit within 7 to 10 days after their discharge from the clinic. 
For further information, see the Schedule of activities (Table 1-1). 
Number of participants: 
Up to 54 eligible study participants will be randomized. 
Treatment groups and duration: 
The maximum study duration for each study participant will be up to 87 days, including 
Screening (up to 28 days), crossover dosing across 3 Treatment Periods (14 days per Treatment 
Period), 2 Washout Periods (7 days per Washout Period), and the SFU Visit (Days 21 to 24). 
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1.2 
Schema 
The study design is presented in Figure 1-1. 
Figure 1-1: UP0050 Study Design 
 
AM=morning; BID=twice daily; D=Day; MXF=moxifloxacin; PBO=placebo; PM=afternoon; PSL=padsevonil; 
T=Treatment Period 
 
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1.3 
Schedule of activities 
The schedule of activities is provided in Table 1-1. 
Table 1-1: 
Schedule of activities 
Study Period 
SCR 
Treatment Periods 1, 2, and 3 
SFU/
EOS 
Baseline 
Dosing Day 
Inpatient FU Days 
Study Day 
D -28 
to -2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
T3 
D21-
D24 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
eligibilitya 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen and 
alcohol breath 
testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to 
clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous/ 
concomitant 
medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE and 
neurological 
examinations 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Body weight/ 
heightb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric and 
mental status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1-1: 
Schedule of activities 
Study Period 
SCR 
Treatment Periods 1, 2, and 3 
SFU/
EOS 
Baseline 
Dosing Day 
Inpatient FU Days 
Study Day 
D -28 
to -2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
T3 
D21-
D24 
Suicidality risk 
assessment 
(C-SSRS)c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology, 
chemistry, urine, 
serologyd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH testf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-h Holter 
monitoringi 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Standardized 
breakfastj 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Study medication 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK sampling 
 
 
Xk 
Xl 
Xl  
Xl  
Xl  
Xl  
Xl  
Xk 
Xl  
Xl  
Xl  
Xl 
  
 
 
Sampling for 
ADME genotype 
analysis 
 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from 
clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Table 1-1: 
Schedule of activities 
Study Period 
SCR 
Treatment Periods 1, 2, and 3 
SFU/
EOS 
Baseline 
Dosing Day 
Inpatient FU Days 
Study Day 
D -28 
to -2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
T3 
D21-
D24 
AE=adverse event; BP=blood pressure; C-SSRS=Columbia Suicide Severity Rating Scale; D=day; ECG=electrocardiogram; FSH=follicle stimulating hormone; 
FU=Follow-up; h=hour; PE=physical exam; PK=pharmacokinetic; SCR=Screening Period; SFU=Safety Follow-up; T=Treatment Period 
a At the first Baseline Day (D -1) only. 
b Height will be measured only at Screening. Body weight will be measured at Screening and Baseline (D-1) for each Treatment Period. 
c Study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening or Baseline (D-1) visits, followed by the “Since Last Visit” 
version at subsequent visits. 
d Virus serology will be measured only at Screening. All laboratory blood assessments may be performed nonfasting. 
e For women of childbearing potential. Serum or urine pregnancy test will be performed at Screening, at Baseline for each Treatment Period, and at the SFU 
Visit. 
f Female study participants of nonchildbearing potential are to confirm their postmenopausal status. 
g Vital signs will be evaluated predose and 3h (± 30 minutes) postdose for each morning dose. Blood pressure measurements will be performed in both supine 
and standing positions for orthostatic measurement at Screening (supine BP after the study participant has been lying down for 5 minutes and then standing BP 
after 1 minute and 3 minutes) and in a supine position for routine BP measurements at all assessments. 
h Triplicate 12-lead ECG will be performed as immediate safety evaluations at Screening and Baseline. They will also be performed on each dosing day 
(approximately 3h [± 30 minutes] postdose), on each inpatient FU day, and at the SFU Visit. On D1 and D8 of each Treatment Period, the ECG recordings may 
be substituted with recordings from the Holter monitoring equipment, if they are immediately available for review. All 3 ECG recordings should be sufficiently 
separated so they have a different ‘minute’ on the timestamp, and all are to be performed within 4 minutes. All ECG recordings should be taken with the study 
participant resting in the supine position for ≥5 minutes before the recording. 
i Holter monitoring will be performed for 24h at Screening. On D1and D8 of each Treatment Period, Holter monitoring will commence ≥1h prior to the morning 
dose of study medication, to enable extraction of the required predose ECGs. On D1 and D8, Holter monitoring is to continue for 24h following the morning 
dose (and until after collection of the following day’s trough PK sample). 
j A standardized light breakfast will be served; to be completed approximately 30 minutes prior to each morning dose, with the exception of D1 (morning) and 
D8 (morning) of each Treatment Period, when study participants will be dosed in fasted state (and will remain fasted for at least 2h postdose). 
k On D1 and D8 of each Treatment Period, PK samples will be collected at 0.5h prior to the morning dose and at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 
12h after dosing. An additional venous blood sample will be collected 18h after the D8 morning dose (D8 afternoon, 6h postdose sample). 
l A venous blood sample will be collected at 0.5h prior to the morning dose (or at the time of the previous morning doses of study medication for days when 
dosing does not occur), for trough/ongoing PK concentration evaluation. 
m Sample will be collected prior to the first dose of study medication on D1 of Treatment Period 1. 
 
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2 
INTRODUCTION 
2.1 
Study rationale 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic SV2 isoforms 
and postsynaptic cBZR sites on the GABAA receptor that has shown broad-range efficacy in 
several preclinical models of epilepsy conducted by UCB. 
The development program for PSL as an adjunctive treatment for focal-onset seizures in patients 
with epilepsy calls for the evaluation of its potential to affect cardiac repolarization, as indicated 
by prolongation of the HR-corrected QT interval on a standard 12-lead ECG. 
Historically, such evaluations have been performed (in compliance with ICH 
Guideline E14, 2005) in large, rigorously controlled clinical studies, across a wide range of 
target drug exposure (Cmax) levels that clearly bracket those to be anticipated in patients 
receiving the drug within the dosing regimen sought in the intended labelling. 
However, in response to questions about the potential use of concentration-response analysis 
(‘PK/PD modeling’), Revision 3 of the E14 Guidance (2017) provided clarification that such an 
analysis using adequate data from standard early phase clinical studies could provide the 
necessary evidence in place of a specific TQT study, if certain technical requirements were met. 
UCB Pharma, having undertaken a detailed assessment of the data available from the early phase 
study program with PSL, believes those data to be sufficient to provide an acceptable evaluation 
across the Cmax range associated with the anticipated labelled doses and lower, but not at the 
higher, supratherapeutic levels usually required by E14. The purpose of this study is, therefore, 
to gather data at the highest dose anticipated in labelling, 400mg bid (which is also the MTD for 
PSL), in comparison to both placebo and a 400mg moxifloxacin positive control (a drug known 
to have a prolongation effect on the QTc interval), to complete the dataset required. 
This is a Phase 1, single-center, randomized, placebo-controlled, 3 treatment period crossover 
study to evaluate the effects of high-dose PSL on cardiac repolarization in healthy study 
participants. Moxifloxacin will be used as a positive pharmacologic control to allow 
demonstration of assay sensitivity. 
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 anti-epileptic drugs (AEDs) modulate neuronal 
transmission by either blocking voltage-gated sodium channels or acting on inhibitory/excitatory 
receptors located at the postsynaptic level. 
The GABAA receptor mediates the bulk of inhibitory neurotransmissions in the brain. Allosteric 
modulation of inhibitory GABAA receptors by the cBZR site offers robust protection against 
seizures (Riss et al, 2008). However, their clinical use as AEDs is limited due to an unfavorable 
side effect profile (eg, drowsiness, ataxia, amnesia, and paradoxical aggression), as well as the 
development of tolerance to anticonvulsant effects. 
Compounds binding to SV2A proteins on synaptic vesicles are characterized by broad-spectrum 
efficacy against both generalized and partial seizures in preclinical models, and this protective 
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activity strongly correlates with their binding affinity (Kaminski et al, 2008). The function of 
SV2B and SV2C subtypes is not well established, but they share a high degree of sequence 
homology to SV2A and localization within synaptic vesicles (Wan et al, 2010; Janz and 
Südhof, 1999). Levetiracetam (LEV), exemplifying an SV2A-related mechanism of action, 
displays prominent clinical efficacy in patients with different forms of epilepsy (Klitgaard and 
Verdru, 2007). 
Compounds with dual activity at SV2A and GABAA receptors are expected to have superior 
efficacy to those drugs working through only one of these mechanisms. Preclinical data in 
animal models of epilepsy support this assumption with synergistic interaction observed between 
LEV and AEDs with GABAergic mechanisms of action (Kaminski et al, 2009). This synergistic 
interaction was particularly pronounced when combinations of LEV and benzodiazepines were 
tested and a significant increase in the anticonvulsant potency of these drugs was observed 
associated with a higher therapeutic index. 
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-resistant 
epilepsy, suggesting superior efficacy against seizures resistant 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 produced seizure freedom 
only 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. 
Padsevonil is cleared via metabolism involving the cytochrome P450 (CYP) pathway; the 
formation of the major metabolites, 
 
 is mainly mediated by CYP3A4, with potential 
involvement of CYP2C19. While 
 is an inactive metabolite, the 
 metabolite has been shown to have affinity for SV2A proteins (20-fold lower 
compared with PSL). 
Because of its unique properties, PSL is currently being proposed as adjunctive therapy in the 
treatment of focal-onset seizures in adult patients with epilepsy. 
2.3 
Benefit/risk assessment 
Overall, the clinical pharmacology and clinical studies in drug-resistant epilepsy demonstrated 
the 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. 
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Reported acute psychiatric serious adverse events (SAEs) are consistent with adverse effects of 
other AEDs, including SV2A ligands. Events were transient, acute, and required admission to 
psychiatric care and medical treatment. The events in healthy study participants (n=2) occurred 
early after initiation or cessation of PSL, which was done without titration or tapering. The 
psychotic effect in an epilepsy study participant (Study EP0069) emerged after dramatic 
improvement in seizure control and electroencephalogram activity a few weeks after the start of 
PSL, suggesting a “forced normalization” (Clemens, 2005; Loganathan et al, 2015). Dose 
reduction of PSL and medical treatment resulted in complete resolution of psychosis within days, 
as the treatment with PSL continued. The occurrence of acute psychiatric effects in these 3 study 
participants administered PSL highlights the need to consider the possibility of significant 
psychiatric adverse effects and to maintain vigilance for such effects. The mitigation plan for 
acute psychiatric effects involves gradual titration and taper, which are known to improve 
tolerability of AEDs. 
After the occurrence of several ECG findings (including different types of ectopy), both in 
healthy study participants and study participants with epilepsy, an independent expert 
cardiologist reviewed data from Phase 1 and Phase 2 studies and determined that none of these 
findings were assessed as being likely to be related to PSL. No clinically significant 
echocardiographic findings (only minor/trace or Grade 1 findings) were observed in 
Studies EP0069 and EP0073, and all echocardiograms were assessed as normal. There are 
currently no clinical data to suggest that PSL has an adverse effect on cardiovascular function 
other than a minimal lowering effect on BP. The degrees of reduction seen in both SBP and DBP 
are consistent with the GABAA-targeted mechanism of action of PSL and do not appear likely to 
have a clinically significant effect in therapeutic use. As a precaution and in view of the 
nonclinical histopathological cardiac findings, echocardiogram screening of study participants at 
Baseline and ongoing echocardiogram monitoring during treatment and posttreatment have been 
implemented in 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. 
The healthy study participants included in this study will receive no medical benefit from 
participation. 
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. 
3 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints for this study are presented in Table 3-1. 
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Table 3-1: 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
The primary PD objective is: 
 To evaluate the effects on cardiac 
repolarization (QTc interval) of high-dose 
PSL in comparison to placebo in healthy 
study participants 
The primary PD endpoint is: 
 Placebo-corrected change from Baseline in 
QTc, based on Fridericia’s correction 
(QTcF) method (ΔΔQTcF) evaluated 
during the Target Dose Day of the PSL and 
placebo Treatment Periods, using time 
point analysis 
Secondary 
The secondary PD objective is: 
 To evaluate other aspects of the effects on 
cardiac function of high-dose PSL in 
comparison with placebo and moxifloxacin 
The secondary PD endpoints are: 
 Placebo-corrected change from Baseline in 
QTcF after a single dose of moxifloxacin 
 Placebo-corrected changes from Baseline 
for HR, PR interval, and QRS interval 
 Frequency of treatment-emergent changes 
for T-wave morphology and U-wave 
presence 
 Change from Baseline in QTcF (ΔQTcF) 
evaluated at drug-specific tmax (∆tmax) for 
PSL, 
 
 and possibly 
moxifloxacin 
The secondary PK objective is: 
 To evaluate the plasma PK of PSL at 
steady state in healthy study participants 
The secondary PK endpoints are: 
 Cmax,ss, tmax, and AUC, obtained from the 
plasma concentration-time profiles for PSL 
at steady state (on the Target Dose Day) 
The secondary safety objective is: 
 To evaluate the safety and tolerability of 
PSL at the dosed level in healthy study 
participants 
The secondary safety endpoints are: 
 Adverse events, SAEs, treatment-related 
AEs, and AEs leading to discontinuation of 
the study 
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Other 
The other PD objectives are: 
 To evaluate other aspects of the effects on 
cardiac function of high-dose PSL in 
comparison with placebo and moxifloxacin 
 To evaluate (using concentration-QT 
[C-QT] effect modeling) the relationship 
between QTc interval and the concentration 
of PSL and its metabolites 
The other PD endpoints are: 
 Categorical outliers for HR, QTcF, PR 
interval, and QRS interval 
 Relationship between ∆QTcF (change from 
Baseline in QTcF) and the plasma 
concentrations of PSL, 
 
, and possibly 
moxifloxacin 
The other PK objectives (depending on the 
outcome of PK and/or QT analyses) are: 
 To evaluate from plasma samples the PK of 
PSL and the major metabolites of PSL 
(
 
 
 To evaluate from banked plasma samples 
the PK of moxifloxacin (if needed) in 
healthy study participants 
 To collect and store blood for possible 
ADME genotyping (if needed) 
The other PK endpoints are: 
 For PSL: 
 Single dose: AUC0-12, Cmax, and tmax 
 Multiple dose: CLss/F and Ctrough 
 For PSL metabolites: 
 Single dose: AUC0-12, Cmax, tmax, and 
metabolic ratios for Cmax and AUC0-12 
 Multiple dose: AUC, AUC0-t, Ctrough, 
Cmax,ss, tmax, and metabolic ratios for 
Cmax,ss and AUC  
 For moxifloxacin (if needed): 
 Single dose: AUC, AUC0-t, t½, Cmax, 
and tmax 
 Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL and metabolite PK 
analyses) (if needed) 
The other safety objective is: 
 To evaluate safety and tolerability of PSL 
at the dosed level in healthy adult study 
participants 
The other safety endpoints are: 
 Changes from Baseline in safety laboratory 
data (hematology, clinical chemistry, and 
urinalysis) 
 Changes from Baseline in vital signs (PR, 
respiratory rate, SBP, and DBP) 
 Changes from Baseline in 12-lead ECG 
assessment 
 Physical examination findings 
ADME=absorption, distribution, metabolism, and excretion; AE=adverse event; C-QT=concentration-QT; 
ΔQTcF=time-matched, Baseline-subtracted QTcF; DBP=diastolic blood pressure; ECG=electrocardiogram; 
HR=heart rate; PD=pharmacodynamic; PK=pharmacokinetic; PR=pulse rate; PSL=padsevonil; QTc=QT interval 
corrected; QTcF=QT interval corrected for HR using the Fridericia method; SAE=serious adverse event; 
SBP=systolic blood pressure 
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4 
STUDY DESIGN 
4.1 
Overall design 
This is a Phase 1, single-center, randomized, placebo-controlled, crossover study to compare the 
PD effect on cardiac repolarization of high-dose PSL (400mg bid at steady state = MTD), with 
those of moxifloxacin (an open-label drug known to have a prolongation effect on the QTc 
interval) and placebo, in healthy study participants. 
The target total duration of the study is 94 days for each study participant, including the 
Screening Period (up to 28 days), crossover dosing across 3 Treatment Periods (14 days per 
Treatment Period), 2 Washout Periods (7 days per Washout Period), and the SFU Visit (within 
7 to 10 days after their discharge from the clinic). However, this may vary according to the 
scheduling of Treatment Periods. 
The study schema is presented in Section 1.2 and the Schedule of activities is presented in 
Table 1-1. 
4.1.1 
Screening and Baseline Periods 
The design uses a 3-Treatment Period crossover structure. Study participants who provide 
written informed consent will be screened within 28 days before the first Treatment Period. For 
further details regarding the assessments performed during the Screening and Baseline Periods, 
refer to the Schedule of activities (Table 1-1). 
4.1.2 
Treatment Periods 1, 2, and 3 
During each Treatment Period, each study participant will check into the site the day prior to the 
relevant First Dosing Day. Throughout the relevant Dosing Days, continuous Holter monitoring 
will be undertaken to provide extracted ECG records at the relevant time points necessary to the 
evaluation of QT interval effects. During the hour prior to administration of the first dose of each 
Treatment Period, 3 triplicate ECGs extracted from the Holter record will serve to provide a 
time-averaged Baseline for that Treatment Period. 
Subsequently, dosing with the allocated study medication will be initiated: for study participants 
in the PSL Treatment Period, the bid doses of PSL will be titrated up to reach steady state in time 
for the target dose on the ‘Target Dose Day,’ as shown in Figure 1-1. 
The randomized dosing regimen will be as follows: 
 In the PSL Treatment Period: 
 On Day 1, 100mg PSL will be administered bid, in the morning and the evening. 
 On Days 2 and 3, 200mg PSL will be administered bid, in the morning and the evening. 
 On Days 4 and 5, 300mg PSL will be administered bid, in the morning and the evening. 
 On Days 6 and 7, 400mg PSL will be administered bid, in the morning and evening. 
 On Day 8, the Target Dose Day, study participants will be fasted prior to the morning 
dose. Subsequently, 400mg PSL will be administered in the morning, and placebo will be 
administered in the evening. 
 On Day 9, 300mg PSL will be administered bid, in the morning and the evening. 
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 On Day 10, 200mg PSL will be administered bid, in the morning and the evening. 
 On Day 11, 100mg PSL will be administered bid, in the morning and the evening. 
 In the Placebo Treatment Period: 
 On Days 1 through 7, placebo to match the PSL Treatment Period doses will be 
administered bid, in the morning and the evening. 
 On Day 8, the Target Dose Day, study participants will be fasted prior to the morning 
dose. Subsequently, placebo to match 400mg PSL will be administered in the morning, 
and in the evening. 
 On Days 9 through 11, placebo to match the PSL Treatment Period doses will be 
administered bid, in the morning and the evening. 
 In the MoxifloxacinTreatment Period: 
 On Days 1 through 7, placebo to match the PSL Treatment Period doses will be 
administered bid, in the morning and the evening. 
 On Day 8, the Target Dose Day, study participants will be fasted prior to the morning 
dose. Subsequently, 400mg moxifloxacin will be administered in the morning, and 
placebo will be administered in the evening. 
 On Days 9 through 11, placebo to match the PSL Treatment Period doses will be 
administered bid, in the morning and the evening. 
On the morning of Day 1 of each Treatment Period, Holter ECG monitoring will be conducted at 
0.75, 0.5, and 0.25 hours prior to the time of first dosing with study medication and until dosing, 
and a venous blood sample for PK analysis will also be drawn 0.5 hours prior to dosing. On the 
Target Dose Day of each Treatment Period (T1D8, T2D8, and T3D8), Holter ECG monitoring 
will be conducted from 1 hour prior to the morning dose of study medication and will continue 
for 24 hours afterwards. For a full description of Day 1 and Day 8 blood sampling time points, 
refer to the Schedule of activities (Table 1-1). 
On the evening of the Target Dose Day for each Treatment Period, all study participants will 
receive placebo in order to protect the 18- and 24-hour PK/QT evaluations during the PSL 
Treatment Period. 
On Days 3 through 7 and Days 10 through 21 of each Treatment Period, a venous blood sample 
will be taken prior to the morning dose / at the time of the previous morning doses of study 
medication, for trough / ongoing PK level evaluation. The blood samples will be used to measure 
plasma concentrations of PSL, 
, and 
, and possibly 
moxifloxacin, as well as for safety monitoring. 
On Days 12, 13, and 14 of each Treatment Period, study participants will remain at the clinic for 
inpatient follow-up assessments. 
The safety and tolerability of repeated doses of PSL will be monitored throughout the study by 
evaluation of AEs, psychiatric and mental status, C-SSRS, vital signs, 12-lead ECG parameters, 
physical and neurological examination findings, and clinical laboratory test results. 
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For further information, see the Schedule of activities (Table 1-1). 
4.1.3 
Washout Periods 
Following completion of each Treatment Period, study participants will be discharged from the 
clinic, returning on the day prior to the First Dosing Day of the next Treatment Period for 
readmission. The interval between Treatment Periods (Washout Period) will be sufficient to 
ensure a minimum of 7 days’ washout from the study medication administered during the 
previous Treatment Period. 
4.1.4 
Safety Follow-up Period 
Following completion of the final Treatment Period, study participants will be discharged and 
return for an SFU Visit within 7 to 10 days after their discharge from the clinic. 
4.2 
Scientific rationale for study design 
The development program for PSL as an adjunctive treatment for focal-onset seizures in patients 
with epilepsy calls for the evaluation of its potential to affect cardiac repolarization, as indicated 
by prolongation of the HR-corrected QT interval on a standard 12-lead ECG. 
Historically, such evaluations have been performed (in compliance with ICH Guideline 
E14, 2005) in large, rigorously controlled clinical studies, across a wide range of target drug 
exposure (Cmax) levels that clearly bracket those to be anticipated in patients receiving the drug 
within the dosing regimen sought in the intended labelling. Use of placebo and a positive control 
have also usually been mandatory in such TQT studies. 
The FDA advocates use of moxifloxin as a positive control to confirm assay sensitivity in TQT 
studies. Because moxifloxin has a known QT-prolonging effect, the inclusion of moxifloxin in 
the treatment sequence will confirm that UP0050 is sensitive enough to demonstrate 
QT prolongation at thresholds of regulatory concern (FDA, Guidance for Industry, 06/2017). 
The E14 Guidance recommends that – in the absence of any logistical or ethical reasons to do 
otherwise – the most appropriate population for TQT studies is a healthy population of male and 
female study participants. 
In previous Phase 1 healthy volunteer studies, results from repeat bid PSL dosing suggest 
time-dependent inhibition of apparent clearance, with a mean exposure 1.7 times higher than 
anticipated PSL exposures and a longer time to achieve steady state. This implies that the single 
dose PK of PSL cannot be extrapolated linearly to the multiple dose scenario. Therefore, 
participants in this study will receive multiple doses of PSL, up-titrating from 100mg bid to 
400mg bid, which has been demonstrated to increase tolerability. Steady state for both PSL and 
 is achieved following 2 to 3 days of PSL treatment. 
Therefore, the assessment day (‘Target Dose Day’) will be Day 8, by which time participants in 
the PSL treatment arm will be at steady state. 
A double-blind technique will be used for PSL and its matching placebo, while a single-blind 
technique (with the PSL placebo) will be used for the moxifloxacin Treatment Period. Treatment 
sequence randomization will be undertaken using a double William’s Latin square design in 
order to accommodate the single-blind nature of the moxifloxacin treatment period. 
On the morning of Day 8, within each of the 3 treatment periods, participants will receive either 
400mg PSL, a single 400mg dose of moxifloxacin, or placebo, according to their randomization 
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allocation. The treatment duration of the positive control, a single 400mg dose of moxifloxacin 
on Day 8, is deemed sufficiently long enough to exert the expected QT-related changes. 
4.3 
Justification for dose 
Padsevonil was determined to have an MTD of 400mg bid with repeated dosing in healthy study 
participants for up to 12 days’ duration (Study N01386). Most of the AEs affected the CNS and 
were consistent with the pharmacology of PSL; these events occurred in the absence of titration 
or tapering of PSL doses. The most commonly reported AE for study participants on PSL 400mg 
bid was somnolence (100%). Other AEs that occurred more frequently at the PSL 400mg bid 
dose included amnesia, ataxia, disturbance in attention, dizziness, and headache. The incidences 
of ataxia, diplopia, dizziness, headache, and somnolence increased with increasing dose of PSL 
(100mg bid to 400mg bid), while no clear dose dependence was observed for the majority of the 
other reported AEs (most of which were mild or moderate in intensity). However, 9 study 
participants treated with PSL experienced treatment-emergent adverse events (TEAEs) of severe 
intensity. Overall, the CNS AE profile showed some evidence of a dose relationship, was 
generally self-limiting, did not pose any significant risk to study participants, and was considered 
to be clinically manageable. 
In studies conducted using titration and tapering of PSL doses, the 400mg dose of PSL is often 
associated with cognitive and motor impairment of mild to moderate intensity when administered 
as single and multiple doses to healthy study participants; therefore, PSL 400mg bid (the 
anticipated high therapeutic dose) has been selected as the high dose for this study. 
Accordingly, because the primary objective of this study is to acquire data on the relationship 
between PSL Cmax and QTc at the highest acceptable exposure level, the morning dose on the 
Target Dose Day (Day 8) of the PSL Treatment Period has been selected to be 400mg (at steady 
state), to provide an acceptable balance between the study objectives and the safety of the study 
participants. 
Evaluation of any PD effect of PSL at the anticipated Cmax levels with those of placebo and 
400mg moxifloxacin – within the context of a rigorously performed ‘Mini QT’ study – is 
expected to provide the data required to satisfy the E14 requirement for the clinical evaluation of 
QT/QTc interval prolongation risk. 
4.4 
End of study definition 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last scheduled procedure shown in the Schedule of activities (Table 1-1). 
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule 
of activities (Table 1-1) for the last study participant in the study globally. 
The maximum study duration per study participant is up to 94 days, including Screening (up to 
28 days), 3 Treatment Periods (of up to 14 days each), 2 Washout Periods (of 7 days each), and 
the SFU Visit within 7 to 10 days after their discharge from the clinic. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
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5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 55 years of age inclusive, at the time of signing the ICF. 
Type of participant and disease characteristics 
2. Participant who is overtly healthy as determined by medical evaluation including medical 
history, physical examination, laboratory tests, and cardiac monitoring. 
Note: Study participant has clinical laboratory test results within the local reference ranges or 
values that are considered as not clinically relevant by the Investigator and approved by the 
UCB Study Physician. Laboratory 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 
3. Body weight of at least 50kg (males) or 45kg (females) and body mass index (BMI) within 
the range 18 to 30kg/m2 (inclusive). 
Sex 
4. Male and/or female: 
 A male study participant must agree to use contraception as detailed in Appendix 4 
(Section 10.4) of this protocol during the Treatment Period and for at least 90 days after 
the last dose of study medication and refrain from donating sperm during this period. 
 A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 10.4]), not breastfeeding, and at least 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 medication. 
Informed consent 
5. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
6. Participant must be considered reliable and capable of adhering to the protocol, according to 
the judgment of the Investigator, and is capable of communicating satisfactorily with the 
Investigator. 
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5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study, such as a history of schizophrenia or other psychotic disorder, bipolar disorder, or 
severe unipolar depression. The presence of potential psychiatric exclusion criteria will be 
determined based on the psychiatric history collected at the Screening Visit. 
2. 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. Participant has a history of chronic alcohol or drug abuse within the previous 6 months. 
4. Participant has a positive prestudy drug/alcohol screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines). 
Note: A 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. Participant has a known hypersensitivity to any components of the study medication or 
comparative drugs as stated in this protocol or history of tendon pathology secondary to use 
of quinolone antibiotics. 
6. Participant has a history of unexplained syncope or a family history of sudden death due to 
long QT syndrome. 
7. Participant has a present condition of respiratory or cardiovascular disorders, eg, cardiac 
insufficiency, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia, or 
myocardial infarction. 
8. Abnormal BP. Note: This includes both the routine and orthostatic hypotension BP 
assessments. For routine BP, participant must have BP and PR within normal range in the 
supine position after 5 minutes of rest (SBP: 90mmHg to 140mmHg; DBP: 40mmHg to 
90mmHg; PR: 40bpm to 100bpm). Any values marginally (ie, no more than 5mmHg) outside 
the normal range but considered not clinically significant by the Investigator would be 
allowed. In case of an out of  range result, 1 repeat will be allowed. If the readings are out of 
range again, the study participant will not be included. 
9. 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 
10. 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 
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a positive response (“Yes”) to either Question 4 or Question 5 of the “Screening/Baseline” 
version of the C-SSRS at Screening. 
Prior/concomitant therapy 
11. Past or intended use of over-the-counter (OTC) 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. 
12. Participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, 
isoniazid, phenytoin, rifampicin, etc) within 2 months prior to the first dose of study 
medication. In case of uncertainty, the UCB Study Physician should be consulted. 
Prior/concurrent clinical study experience 
13. Participant has previously received PSL in this or any other study. 
14. Participant has participated in another study of a study medication (and/or an investigational 
device) within the previous 30 days or 5 half-lives (whichever is longer) or is currently 
participating in another study of a study medication (and/or an investigational device). 
Diagnostic assessments 
15. Participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or 
alkaline phosphatase (ALP) >1.0x ULN. 
Participant has bilirubin >1.0xULN (isolated bilirubin <1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
16. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the 
exception of Gilbert's syndrome). 
17. Participant has any clinically relevant ECG finding at the Screening Visit or at Baseline. 
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 participant with 
any of the following findings will be excluded: 
a. QTcF ≥450ms (on mean of triplicate ECG recordings); 
b. Other conduction abnormalities (defined as PR interval >220ms); 
c. QRS interval >109ms; 
d. Any rhythm other than sinus rhythm; 
e. Any history of Wolff-Parkinson-White Syndrome, Brugada Syndrome, unexplained 
syncope, or ventricular tachycardia; 
f. Family history of QTc prolongation or of unexplainable sudden death at <50 years of age 
In case of an out of range result, 1 repeat will be allowed. If out of range again, the 
participant cannot be included. 
NOTE A: The QTc is the QT interval corrected for HR according to Bazett’s formula 
(QTcB), QTcF, and/or another method. It is either machine-read or manually over-read. 
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NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In other words, 
several different formulas cannot be used to calculate the QTc for an individual participant 
and then the lowest QTc value used to include or discontinue the participant. 
18. Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to 
dosing. 
19. Positive hepatitis C antibody test result at Screening or within 3 months prior to starting 
study intervention. NOTE: 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. 
20. Positive human immunodeficiency virus (HIV) antibody test. 
Other exclusions 
21. Participant has made a blood or plasma donation or has had a comparable blood 
loss (>450mL) within 30 days prior to the Screening Visit. Blood donation during the study 
is not permitted. 
22. Participant has a consumption of more than 600mg of caffeine/day (200mL of coffee 
contains approximately 100mg of caffeine, 200mL of black tea approximately 30mg, and 
200mL of cola approximately 20mg). 
23. Participant smokes more than 5 cigarettes per day (or equivalent) or has done so within 
6 months prior to the Screening Visit. Smoking within 48 hours prior to CNS assessments is 
prohibited. 
24. Participant ingests grapefruit, passion fruit, or pawpaw (as beverage, fruit, or supplements) 
within 72 hours before each administration of study medication. If this is the case at the start 
of the study, participants may be rescreened. 
25. Female participant tests positive for pregnancy, plans to get pregnant during the participation 
in the study, or who is breastfeeding. 
26. Participant has a diet that deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the Investigator. 
27. Participant has undergone sudden and/or extreme changes in exercise levels for 2 weeks prior 
to the Screening Visit. 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
 Refrain from consumption of grapefruit, starfruit, and pawpaw as beverage, fruit or 
supplements) from 3 days before the start of study medication until after the final dose. 
 On Day 1 and Day 8, study participants will be in the fasted state prior to the morning dosing 
and until approximately 2 hours postdose, and the standard evening meal will be completed 
approximately 30 minutes prior to dosing. 
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 On the dosing days (other than Day 1 and Day 8), participants will consume a light meal 
approximately 30 minutes prior to each morning dose and will consume a standard meal 
approximately 30 minutes prior to each evening dose. Other meals during the day will be 
allowed, provided consistent timing and similar meal content are maintained during 
Treatment Periods. Timing may vary depending on assessements collected in close proximity 
to meal administration; however, every effort will be made to ensure a consistent meal 
schedule is adhered to during Treament Periods. On nondosing days, morning and evening 
meals will be completed approximately 30 minutes prior to dosing, and other meals (and 
content) may be consumed at the site’s discretion. 
Minor departures from the above 30 minute interval are permitted, but the following 
situations will be handled as protocol deviations: 
 No meal is consumed 
 Study medication is taken prior to commencing the meal 
 Study medication is taken >1 hour following completion of the meal 
 Padsevonil will be administered orally with 240mL (8oz) water. Between 1 hour predose and 
2 hours postdose, the total intake of beverages should be limited to 100mL. Water will be 
available ad libitum except for between 1 hour before and 2 hours after dosing. 
5.3.2 
Caffeine, alcohol, and tobacco 
 During each dosing session, 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 and/or PD sample. 
 During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK and/or PD sample. 
 Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit. 
5.3.3 
Activity 
 From Screening through the SFU Visit, participants will abstain from strenuous exercise. 
Participants may participate in light recreational activities during studies (eg, watching 
television, reading). 
5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
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5.4.1 
Rescreening 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
Study participants may be rescreened under conditions such as the following: 
 Study participant ingests grapefruit (as beverage, fruit, or supplements) within 72 hours 
before each administration of study medication. 
 If a study participant does not meet the exclusion criteria at the Screening Visit (Days -21 
to -2) or at the Baseline Visits (Day -1 of each Treatment Period) 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 participant may be included if the repeat values for the laboratory screening criteria are 
within normal ranges and/or if repeat values show normalization of the out-of-range safety 
laboratory values, and/or after the study participant makes a complete recovery from the mild 
or moderate illness, and if all other screening criteria are met. 
 Rescreened participants should be assigned the same participant number as for the initial 
screening. 
 Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes rescreening. 
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. Further guidance and information regarding study treatments are provided in the 
UP0050 Investigational Medicinal Product (IMP) Handling Manual. 
6.1 
Treatments administered 
A summary of the treatments administered is provided in Table 6-1. Further guidance or 
information is provided in the IMP Handling Manual. 
 
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Table 6-1: 
Treatments administered 
Study Treatment Name: 
PSL 
Moxifloxacin 
Placebo 
Dosage formulation: 
Tablet 
Tablet 
Tablet 
Dosage levels: 
100mg, 200mg, 300mg, and 400mg bid  
400mg 
To match PSL 100mg, 200mg, 300mg, and 
400mg bid  
Route of administration: 
Oral 
Oral 
Oral 
Dosing instructions: 
Dosing instructions are provided in the UP0050 IMP Handling Manual (IP Instruction for Handling). 
Packaging and labeling: 
Padsevonil tablets are manufactured, 
packaged, and labeled according to GMP 
guidelines and applicable laws or 
regulations. 
Moxifloxacin tablets are 
manufactured, packaged, and 
labeled according to GMP 
guidelines and applicable laws or 
regulations. 
Placebo to match PSL tablets are 
manufactured, packaged, and labeled 
according to GMP guidelines and applicable 
laws or regulations. 
Manufacturer: 
UCB 
Accord Healthcare Ltd. 
UCB  
bid=twice daily dosing; GMP=Good Manufacturing Practice; IMP=investigational medicinal product; IP=investigational product; PSL=padsevonil 
 
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6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medications received and any discrepancies are reported 
and resolved before use of the study medication. 
Only participants enrolled in the study may receive study medication, and only authorized site 
staff may supply or administer study medication. All study medications must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the UP0050 IMP Handling Manual. 
Further guidance and information for the final disposition of unused study medication are 
provided in the UP0050 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 (SOPs) or returned to UCB (or designee). Study medications 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 
A contract research organization (CRO; ie, ICON) randomization biostatistician will create the 
program to generate the randomization code and code break envelopes. The randomization 
biostatistician will be independent of the study. A dummy randomization schedule will be 
prepared by the randomization biostatistician (ICON) and reviewed by the Clinical Study 
Biostatistician in order to ensure that the code meets the study requirements. 
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After finalization of the dummy code, the randomization program will be run with a different 
seed number to create the final randomization list; the final list will be generated in a secure 
environment and will be reviewed by a quality control randomization biostatistician, also 
independent of the study. This randomization list will be retained by the unblinded 
randomization biostatistician and study pharmacist until the end of the study (ie, until after 
database lock). The treatment assignment will be random. 
Copies of the randomization lists will be sent before the start of the study in a secure fashion 
directly from the contracted CRO to: 
 Sponsor Patient Safety (PS) staff for SAE reporting (sealed envelope) 
 Bioanalytical staff (to identify samples to be measured) 
 Unblinded member of pharmacy involved in study medication preparation and dispensing 
 Independent Biostatistician/Early Statistical Programmer 
In addition, staff involved in the analysis of unblinded PK data, such as a representative from the 
UCB Clinical Pharmacology/ Modeling and Simulation team and an unblinded monitor, will 
have access to the unblinded data during the study. 
At Screening, each study participant will be assigned a unique 5-digit study participant number 
from a range of numbers supplied by UCB Clinical Data Operations, Technology, and Standards. 
Once the Investigator determines that the study participant is eligible for the study, and before 
study medication administration, a central person in charge of issuing the randomization 
numbers will manually allocate a randomization number to the study participant (one for each 
study part) and communicate the randomization assignment to the unblinded site pharmacist. 
Each specific randomization number will be linked to the treatment allocation on the 
randomization schedule, which will be dispensed by the unblinded site pharmacist. The 
randomization numbers will also be recorded in the eCRF. 
6.3.1 
Procedures for maintaining and breaking the treatment blind 
6.3.1.1 
Maintenance of study treatment blind 
All participant treatment details (treatments, Treatment Period, and treatment sequences) will be 
allocated and maintained through the use of randomization lists and code break envelopes (or 
equivalent). 
6.3.1.1.1 
PSL and matching placebo 
A site pharmacist who is not a member of the study team (has no responsibilities for study 
participant assessments) will prepare PSL or PSL placebo treatment from bulk supplies in 
accordance with the randomization schedule supplied by the ICON unblinded randomization 
statistician. 
6.3.1.2 
Breaking the treatment blind in an emergency situation 
A code break envelope (or equivalent) containing the randomization code will be printed for 
each participant in a double-blind study and must not be broken, except for emergency situations. 
The Clinical Project Manager (CPM) must be informed immediately when a code is broken, but 
should remain blinded to specific treatment information. Any unblinding of the study medication 
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performed by the Investigator must be recorded in the source documents and on the Study 
Termination eCRF page. 
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 medications/treatments 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are permitted during the study: 
 Paracetamol/acetaminophen for the treatment of mild symptoms (eg, headache or other pain), 
given at most every 6 hours to 8 hours, not exceeding 2g per day, and with a total of no more 
than 5g over 7 days. 
 Ibuprofen, not exceeding 1.2g per day. 
 Inhaled corticosteroids for seasonal rhinitis and topical corticosteroids for controlled 
dermatological conditions. 
 Oral contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal hormone 
replacement therapy or implants, patches, or intrauterine devices/intrauterine systems 
delivering progesterone (for female study participants). 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
With the exception of permitted concomitant treatments listed in Section 6.5.1, the following 
concomitant medications are prohibited during the study: 
 All prescription or nonprescription medicines, are prohibited within 2 weeks or 5 half-lives 
(whichever is longer) before administration of study medication and during the clinical part 
of the study, unless required to treat an AE. This includes all OTC remedies, vitamins, and 
herbal and dietary supplements (including St John’s Wort). 
 Hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, isoniazid, phenytoin, 
rifampicin, etc.) should not be used within 2 months prior to dosing. In case of 
uncertainty, the UCB Study Physician should be consulted. 
 Drugs of unknown half-lives are prohibited within 2 weeks before administration of study 
medication and during the clinical part of the study, unless required to treat an AE. 
If a study participant needs or takes any prohibited medication, the Investigator will (where 
possible) discuss with the Sponsor Study Physician and a decision will be made whether the 
study participant can continue in the study or must be withdrawn. 
6.5.3 
Rescue medication 
Not applicable. 
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6.6 
Dose modification 
No PSL dose modifications are permitted during the study for an individual study participant 
unless necessary to protect study participant safety or well-being. 
6.7 
Treatment after the end of the study 
There are no plans for participant 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 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 participant meets 1 of the conditions outlined for potential drug-induced 
liver injury (PDILI) outlined in Figure 7-1 or if the Investigator believes that it is in best interest 
of the study participant. 
Study medication will be discontinued immediately and permanently for a study participant if 
liver chemistry stopping criteria are met. 
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Figure 7-1: Liver chemistry stopping algorithm 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal 
Specific assessments and follow up actions for potential drug-induced liver injury are provided 
in Appendix 6 (Section 10.6). Discontinuation of study medication for abnormal liver function 
should be considered by the Investigator when a study participant meets 1 of the conditions 
outlined in the algorithm or if the Investigator believes that it is in best interest of the study 
participant. 
7.1.2 
QTc stopping criteria 
A participant who meets the bulleted criteria based on the average of triplicate ECG readings 
will be withdrawn from the study. 
 QTc >500ms 
 Change from Baseline: QTc >60ms 
See the Schedule of activities (Table 1-1) for data to be collected at the time of treatment 
discontinuation and follow up and for any further evaluations that need to be completed. 
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7.1.3 
Study hold/stopping rules 
In recognition of the advanced status of the development program for PSL, the following study 
hold/stopping rules will apply to this study: 
 A serious adverse reaction (SAR) (ie, an SAE considered at least possibly related to the study 
medication) in 1 study participant; 
 A severe nonserious adverse reaction (ie, severe nonserious AEs considered at least possibly 
related to the study medication administration) in 2 study participants in the same cohort, 
independent of within or not within the same SOC. 
If either stopping criterion is met, the study will be put on temporary halt. In the event that either 
or both of the stopping criteria are met, a safety review will be immediately initiated. The safety 
review will be conducted by an internal, study-specific Safety Monitoring Committee comprised 
of the Investigator and appropriate members of the UCB Study Team (such as Study Physician, 
Safety Physician, Clinical Project Manager, Clinical Pharmacologist), as quickly as possible, to 
review the available data and determine whether it is appropriate to continue dosing at the next 
scheduled dosing point. This will take the form of a risk/benefit evaluation from the perspective 
of the individual study participants. In making this evaluation, account will be taken of the 
potential risks of sudden discontinuation of study medication, particularly in participants who 
may be taking higher dose levels, and whether or not a tapering period, and its duration/speed, 
should be undertaken. 
The Safety Monitoring Committee will also decide whether it is appropriate to continue the study 
with or without dose adaptations, additional safety assessments, or other changes in design. In 
case of any temporary halt of the study, further dosing in the study will be suspended while a 
substantial amendment is submitted to the Country(ies) Health Authority and Research Ethics 
Committee(s) and the study will not restart until that amendment has been approved. 
Detailed procedures for reporting SAEs and other safety events which may meet study 
hold/stopping criteria are provided in Appendix 3 (see Section Section 10.3). 
7.1.4 
Temporary discontinuation 
If a participant discontinues study medication, no restart will be allowed. 
7.1.5 
Rechallenge 
No rechallenge will be permitted. 
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. 
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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 1-1) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations to be completed. 
Study participants should be withdrawn from the study if any of the following events occur: 
1. 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. Study participant is noncompliant with the study procedures or medications in the opinion of 
the Investigator. 
3. Study participant takes prohibited concomitant medications as defined in this protocol. 
4. Study participant withdraws his/her consent. 
5. The Sponsor or a regulatory agency requests withdrawal of the study participant. 
6. Study participant has changes in the ECG that are regarded as clinically significant and/or 
that worsens over time. An ECG shows an absolute value for QTcB or QTcF ≥500ms or 
≥60ms above Baseline. 
7. Study participant develops second- or third-degree atrioventricular block or another clinically 
relevant change in ECG as determined by the Investigator. 
8. Participant has active suicidal ideation without a specific plan as indicated by a positive 
response ("Yes") to Question 4 of the "Since Last Visit" version of the C-SSRS. The study 
participant should be referred immediately to a mental healthcare professional and may be 
withdrawn from the study based upon the Investigator's judgment of the benefit/risk ratio of 
continuing the study participant in the study on PSL. 
 Participant has active suicidal ideation with a specific plan as indicated by a positive 
response ("Yes") to Question 5 of the "Since Last Visit" version of the C-SSRS. The 
study participant should be referred immediately to a mental healthcare professional and 
must be withdrawn from the study. 
9. 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. 
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 Neutrophils absolute <1.5G/L. 
 Platelets absolute ≤100G/L. 
Withdrawn study particpants should follow the 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. 
Investigators should contact the UCB Study Physician, whenever possible, to discuss the 
withdrawal of a participant in advance. 
Participants withdrawn may 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 participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
 Before a study participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (at least 1 phone call and 1 written 
message to the participant), and document his/her effort (date and summary of the phone call 
and copy of the written message in the source documents), to complete the final evaluation. 
All results of these evaluations and observations, together with a narrative description of the 
reason(s) for removing the 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. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of activities (Table 1-1). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the UCB Study Physician immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
medication. 
Adherence to the study design requirements, including those specified in the Schedule of 
activities (Table 1-1), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
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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 1-1). 
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 
Efficacy assessments 
Not applicable. 
8.2 
Pharmacodynamics assessments 
8.2.1 
ECG/continuous Holter monitoring 
Pharmacodynamics will be assessed via ECG (placebo-corrected ΔQTcF). The 12-lead Holter 
and ECG equipment will be supplied and supported by ERT. All ECG data will be collected 
using a Global Instrumentation (Manlius, NY, US) M12R ECG continuous 12-lead digital 
recorder. The continuous 12-lead digital ECG data will be stored onto secure digital memory 
cards. Electrocardiograms to be used in the analyses will be selected by predetermined time 
points as defined in the Schedule of activities (Table 1-1) and will be read centrally by ERT. On 
Day 1 and Day 8 of each Treatment Period, continuous Holter monitoring will be recorded from 
≥1 hour predose until after collection of the PK sample 24 hours postdose (trough sample of the 
following day) using a M12R continuous 12-lead Holter/ECG device. Expert Precision QT will 
enable extraction of up to 10 replicate ECGs per time point. Each study participant should be 
assigned 1 M12R continuous 12-lead Holter/ECG device throughout the study. Study 
participants will remain resting in supine position and in a controlled, calm environment for 
15 minutes prior to PK sampling time. Extracted ECG records at the relevant time points will be 
used for the evaluation of QT interval effects. During the hour prior to administration of the first 
dose of each Treatment Period, up to 10 replicate ECGs extracted from the Holter record 
(at -0.75, -0.5, and -0.25 hours) will serve to provide a predose time-averaged Baseline for that 
Treatment Period (seeTable 1-1). 
The data will be analyzed using a standard ECG extraction protocol by ERT. Further detail will 
be provided in the SAP. 
8.3 
Pharmacokinetics assessments 
Whole blood will be collected for measurement of plasma concentrations of PSL, its metabolites, 
and moxifloxacin, as specified in the Schedule of activities (Table 1-1). 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. 
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Samples collected for analyses of PSL, its metabolites, and moxifloxacin plasma concentrations 
may also be used to evaluate safety aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to the 
investigative site or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files, but will not constitute a protocol amendment. The Independent Ethics 
Committee (IEC) will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF. 
Instructions and additional details regarding PK sampling are provided in the Laboratory 
Manual. 
The maximum deviations from scheduled sampling times considered irrelevant for PK are 
defined in Table 8-1. 
Table 8-1: 
Irrelevant time deviations for PK sampling 
Pharmacokinetic blood sampling times (hours) 
Deviation from scheduled time considered 
irrelevant (minutes) 
0 (predose) 
60 (prior to dosing) 
0.25 to 1.5 
2 
2 to 8 
5 
12 
15 
24 to 48 
60 
PK=pharmacokinetic 
8.4 
Safety assessments 
The safety and tolerability of single and multiple doses of PSL will be monitored by evaluation 
of AEs, clinical laboratory test results, vital signs (PR, RR, 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 1-1). 
8.4.1 
Physical examination 
Physical examinations will be performed at Screening and at the time points specified in the 
Schedule of activities (Table 1-1). 
A complete physical examination will include, at a minimum, general appearance; ear, nose, and 
throat; eyes, hair, and skin; and assessments of the Cardiovascular, Respiratory, Gastrointestinal, 
Neurological, Musculoskeletal, and Hepatic systems. Height and weight will also be measured 
and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
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The Investigator should pay special attention to clinical signs related to previous serious 
illnesses. 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
8.4.2 
Vital signs 
Body temperature, PR, respiratory rate, and BP will be assessed as outlined in the Schedule of 
activities (Table 1-1). 
Body temperature may be measured by either oral or aural route at the discretion of the site, but 
must be performed using the same method in any individual study participant on all occasions. 
Blood pressure measurements will be performed in both supine and standing positions for 
orthostatic measurement at Screening (supine BP after the study participant has been lying down 
for 5 minutes, then standing BP after 1 minute and 3 minutes), and in a supine position for 
routine BP measurements at all other 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 
participant in a quiet setting without distractions (eg, television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
1 BP measurement. Vital signs will be evaluated predose and 3 hours postdose for each morning 
dose. 
8.4.3 
Safety 12-lead ECGs 
Triplicate 12-lead ECGs will be obtained as outlined in the Schedule of activities (Table 1-1) 
using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and 
QTc intervals. 
All ECG recordings should be taken with the study participant resting in the supine position for 
≥5 minutes before the recording. 
On Day 1 and Day 8 of each Treatment Period, when Holter monitoring is in place, the ECG 
recordings may be substituted with hardcopy ECGs extracted from the Holter monitoring 
equipment, if they can be made immediately available for safety review. 
At each time point at which triplicate ECG are required for safety, all 3 recordings should be 
sufficiently separated so that they have a different ‘minute’ on the timestamp, and all are to be 
performed within 4 minutes. 
Refer to Section 7.1.2 for QTc withdrawal criteria and any additional QTc readings that may be 
necessary. 
8.4.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of activities (Table 1-1) 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 
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laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or at the SFU Visit should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or UCB Study Physician. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the Laboratory Manual and the Schedule of activities (Table 1-1). 
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
8.4.5 
Suicidal risk monitoring 
Padsevonil is considered to be an AED. Suicidal ideation and behavior have been reported in 
patients treated with antiepileptic agents in several indications. A meta-analysis of randomized 
placebo-controlled studies of AEDs has also shown a small increased risk of suicidal ideation 
and behavior. The mechanism of this risk is not known, and the available data do not exclude the 
possibility of an increased risk for PSL. 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. 
All study participants will complete the “Screening” version of the C-SSRS at the Screening 
Visit (Days -28 to -2) (assessing the past 6 months) or Baseline Visit (Day -1) for each 
Treatment Period, followed by the “Since Last Visit” version at the Day 14 Visit and the SFU 
Visit (Days 21 to 24), as indicated on the Schedule of activities (Table 1-1). 
Participants being treated with PSL should be monitored appropriately and observed closely for 
suicidal ideation and behavior or any other unusual changes in behavior. Caregivers of 
participants being treated with PSL should be instructed to monitor participants for the 
emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior, and to report such symptoms immediately to the study Investigator. Consideration 
should be given to discontinuing PSL in participants who experience signs of suicidal ideation or 
behavior. 
8.4.6 
Psychiatric and mental status 
The psychiatric and mental status of participating study participants will be closely monitored. 
Assessment of specific domains of psychiatric and cognitive symptoms will be performed by a 
staff member trained in the identification of psychiatric symptoms. All study participants will 
undergo psychiatric/mental status evaluation at Screening and at the time points indicated on the 
Schedule of activities (Table 1-1). 
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 
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then determined whether clinically significant. If present and abnormal, psychiatric symptoms, 
mental impairment, and behavioral problems will be assessed as to whether they are clinically 
significant. 
8.5 
Adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the study participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study medication or study procedures, or that caused 
the study participant to discontinue UP0050 or PSL (see Section 7). 
8.5.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF and at the time points specified 
in the Schedule of activities (Table 1-1). 
Medical occurrences that begin before the start of study medication but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported to UCB (or designee) within 24 hours, as indicated in 
Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to UCB within 
24 hours of it being available. 
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the study 
medication), up to 30 days from the end of the study for each participant, and to also inform 
study participants of the need to inform the Investigator of any SAE within this period. Serious 
AEs that the Investigator thinks may be associated with the study medication must be reported to 
UCB, regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.5.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.5.3 
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 nonserious AEs of special 
interest [AESI] [as defined in Section 8.5.6]) will be followed until resolution, stabilization, the 
Investigator determines that it is no longer clinically significant, the event is otherwise explained, 
or the study participant is lost to follow up (as defined in Section 7.3). Further information on 
follow-up procedures is given in Appendix 3 (Section 10.3). 
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8.5.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the Investigator to UCB of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of 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, 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 
according to local regulatory requirements. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from UCB will review and then file it along 
with the IB and will notify the IEC, if appropriate, according to local requirements. 
8.5.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants, will be collected after the start of study medication and until 30 days after the birth 
for any significant medical issues, but preferably up to 12 months after the birth. If the study 
participant is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the study participant needs to be provided by the Investigator and filed at the 
site. UCB’s 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 UCB within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
The participant should be withdrawn from the study as soon as pregnancy is known (by positive 
pregnancy test), and the following should be completed: 
 The participant should return for an End of Study (EOS)/End of Treatment (EOT) Visit. 
 The participant should immediately stop the intake of the study medication or be 
down-titrated as instructed at the EOS/EOT Visit. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
8.5.6 
AESI 
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, 
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must ALWAYS be reported to UCB 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 participant. 
8.6 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that Investigators, clinical study participants, 
regulatory authorities, and IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the UCB PS 
representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory, or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.7 
Treatment of overdose 
For this study, any dose of PSL greater than that prescribed in the protocol will be considered an 
overdose. Overdose events are only considered AEs or SAEs if there are associated clinical signs 
and symptoms or if the act of taking the excess study medication itself is an AE or SAE 
(eg, suicide attempt). 
UCB does not recommend any specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the UCB Study Physician immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
medication can no longer be detected systemically (at least 3 days). 
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
medication if requested by the UCB Study Physician (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the UCB Study Physician based on the clinical evaluation of the study 
participant. 
8.8 
Genetics 
Blood samples will be collected prior to the first dose of study medication on Day 1 of Treatment 
Period 1 and stored for possible ADME genotyping for drug metabolizing enzymes (depending 
on the outcome of PSL and metabolite PK analyses, if required). 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
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8.10 
Medical resource utilization and health economics 
Medical resource utilization and health economics are not evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). Deviations in analyses from the final SAP will be documented in the 
clinical study report. 
9.1 
Definition of analysis sets 
The following are the defined analysis sets: 
 Enrolled Set (ES): All study participants who have signed the ICF. 
 Randomized Set (RS): All enrolled study participants who are randomized will be included 
in the RS. 
 Safety Set (SS): All enrolled study participants who receive at least 1 dose of study 
medication. 
 Pharmacokinetic Per-Protocol Set (PK-PPS): All enrolled study participants who receive at 
least 1 dose of study medication and who have no important protocol deviations affecting the 
PK and for whom at least 1 measurable concentration is available. 
For definitions of the Pharmacodynamic Per-Protocol Set (PD-PPS) and other relevant PD 
analysis sets, refer to the SAP. 
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 (SD), minimum, and maximum (geometric mean and geometric 
coefficient of variation [CV] for plasma concentrations and PK parameters). Categorical 
endpoints will be summarized using number of study participants, frequency, and percentages. 
Missing data will not be imputed. 
If not otherwise stated, Baseline for each Treatment Period will be the last assessment prior to 
dosing. Measurement of specific Baseline values will be described in the SAP. 
9.3 
Planned efficacy/outcome analyses 
As efficacy was not evaluated in this study, there will be no primary efficacy endpoint. 
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9.4 
Planned PD analyses 
9.4.1 
Analysis of the primary ECG endpoint 
During the hour prior to administration of the first dose of each Treatment Period, up to 
10 replicate ECGs extracted from the Holter record (at -0.75, -0.5, and -0.25 hours) will serve to 
provide a predose time-averaged Baseline for that Treatment Period and use to compute change 
from Baseline QTcF (ΔQTcF). 
The primary objective of evaluating the effects on QTc interval of high-dose PSL in comparison 
to placebo will be analyzed as follows: 
 The primary analysis will be based on a by-time point analysis to evaluate the effect of PSL 
on the ΔΔQTcF at each postdose time point using the Intersection Union Test (IUT). 
Moxifloxacin will be used for confirmation of assay sensitivity. 
Further detail on the primary endpoint analysis will be provided in the SAP. 
9.4.2 
Analysis of the secondary ECG endpoints 
The secondary effects on cardiac repolarization (QTc interval) of high-dose PSL in comparison 
with placebo and moxifloxacin will be analyzed as follows: 
 The effect of PSL on placebo-corrected change from Baseline in HR, PR, and QRS (ΔΔHR, 
ΔΔPR, and ΔΔQRS) will also be evaluated using the IUT. 
 Assay sensitivity will also be evaluated using by-time point analysis of the effect on 
ΔΔQTcF of moxifloxacin using a similar model as for the primary analysis. 
 An analysis of categorical outliers will be performed for changes in HR, QTcF, PR, QRS, 
T-wave morphology and U-wave presence. 
 The ∆tmax will be evaluated using an analysis of variance (ANOVA) mixed-effect model by 
study drug (PSL 400mg bid, and moxifloxacin 400mg), with the treatment (active treatment 
and placebo) as fixed effects. A 95% one-sided confidence interval (CI) (equivalent to 90% 
two-sided CI) of the mean difference between each active treatment and placebo will be 
derived from ANOVA. 
Further detail on the secondary endpoint analyses will be provided in the SAP. 
9.4.3 
Analysis of the other PD endpoints 
Results of the other PD endpoints and analyses will be reported in either the Clinical Study 
Report or an overarching Cardiac Safety Report. 
 The relationship between plasma concentrations of PSL and its major metabolites 
 and ΔQTcF will be evaluated using a linear 
mixed-effects modeling approach (Garnett et al, 2018). 
9.5 
Planned PK analyses 
The planned PK analyses will be estimated using noncompartmental analysis (NCA) with 
Pharsight Phoenix® WinNonlin® v6.3 (or higher) software. 
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The planned secondary PK endpoints of PSL include the parameters Cmax,ss, tmax, and AUC at 
steady state (Target Dose Day [Day 8]). 
The planned other PK endpoints of PSL include the parameters AUC0-12, Cmax, and tmax (single 
dose), and CLss/F and Ctrough (multiple dose). 
The planned other PK endpoints of the major metabolites of PSL (
 
) include the parameters AUC0-12, 
Cmax, tmax, and metabolic ratios for Cmax and AUC0-12 (single dose) and AUCt, AUC0-t, CLss/F, 
Ctrough, Cmax,ss, tmax and metabolic ratios for Cmax,ss and AUC (multiple dose). 
If required, the planned other PK endpoints of moxifloxacin include the parameters AUC, 
AUC0-t, t½, Cmax, and tmax (single dose). 
The individual plasma concentrations and PK parameters of PSL, 
 
 and possibly moxifloxacin will be summarized by day (Day 1 or Day 8) 
using descriptive statistics (number of observations, geometric mean, lower and upper 95% CI, 
geometric CV, arithmetic mean, SD and CV, median, and minimum and maximum value) and 
graphical displays. 
9.6 
Planned safety analyses 
All safety analyses will be performed using the SS. All safety variables will be listed and 
summarized by each study part and treatment. 
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 
medications. All AE data will be listed by study participant number, visit, treatment, and time. 
The listings will include the following data pertaining to the AEs: start and end dates with 
relative days to study medication administration, duration, intensity, seriousness, relationship to 
study medication, action taken, and final outcome. 
The occurrence and incidence of TEAEs will be summarized by study part according to the 
intake of study medication (pretreatment or treatment-emergent) and by intensity or relationship 
to PSL. 
Safety laboratory measurements, vital signs, and 12-lead/Holter ECG parameters will be 
tabulated by Treatment Period using descriptive statistics. Laboratory values outside the 
reference range will be flagged in the listings. Any PDILI events will be listed. 
Data of assessment of suicidality (C-SSRS) will be listed. 
Physical and neurological examination abnormalities will be listed. 
9.7 
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 (or primary PD outcome) for 
an individual study participant. Study participants will be excluded from the PK-PPS (or 
PD-PPS) only when there is documented evidence that they received no treatment. The criteria 
for identifying important protocol deviations and the classification of important protocol 
deviations will be defined within the relevant protocol deviation specification document, which 
is part of the study Data Cleaning Plan. To the extent feasible, rules for identifying protocol 
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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 blinded data cleaning 
process prior to database lock to confirm exclusion from analysis sets. 
9.8 
Handling of dropouts or missing data 
The methods for handling dropouts will be described in the SAP. Data of study participants 
prematurely terminating the study will be used to the maximum possible extent. No procedures 
for replacing missing data are intended. If a Baseline value is missing or not reliable, the last 
value before administration of study medication will serve as Baseline. 
9.9 
Planned interim analysis and data monitoring 
No formal interim analyses are planned. 
9.10 
Determination of sample size 
The sample size for this study is based on the most stringent of the requirements for the test 
compound (PSL) and for the positive control (moxifloxacin). 
A sample size of up to 54 study participants was chosen to obtain 49 evaluable study participants 
who will complete the study. Assuming a 1-sided 5% significance level and a within-study 
participant SD of 8ms for ΔQTcF for all treatment groups and a true mean difference of 3ms in 
ΔQTcF between PSL and placebo, based on the calculation of the sample size for a TQT study 
(Zhang and Machado, 2008), a sample size of 49 evaluable study participants will provide a 
power of 96% to demonstrate that the upper limit of all the 2-sided 90% CIs on ΔΔQTcF will fall 
below 10ms for up to 11 postdose time points. 
Sample size calculation for assay sensitivity: Based on the calculation of the sample size for a 
TQT study (Zhang and Machado, 2008), as the test will be performed at 3 prespecified time 
points separately, a one-sided 5% significance level (with adjusted one-sided significance levels 
of 5%, 2.5%, and 1.67%) will be used in addition to a within-study participant SD of 8ms for 
ΔQTcF and a true effect of moxifloxacin of 10ms. A sample size of 49 evaluable study 
participants will provide a power of 99% to demonstrate assay sensitivity of excluding a mean 
difference of 5ms in ΔQTcF between moxifloxacin and placebo groups, ie, the lower limit of the 
2-sided 90% CI of ΔΔQTcF will exceed 5msec at least one of the 3 prespecified time points. 
To achieve a balanced design, and to allow for a few dropouts, it is planned to recruit up to 
54 study participants. 
Dropouts may be replaced at the discretion of the principal Investigator and Sponsor, depending 
on the circumstances. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IEC, as defined in local regulations, 
ICH-Good Clinical Practice (GCP), and in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IEC that complies with the 
requirements of the current ICH-GCP version or applicable country-specific regulations will be 
responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, IB, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
participant-related documents to be used for the study to the IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IEC for the protocol. 
The Investigator will also promptly report to the IEC all changes in the study, all unanticipated 
problems involving risks to participants or others, and any protocol deviations, to eliminate 
immediate hazards to participants. 
The Investigator will not make any changes in the study or study conduct without IEC approval, 
except where necessary to eliminate apparent immediate hazards to the participants. For minor 
changes to a previously approved protocol during the period covered by the original approval, it 
may be possible for the Investigator to obtain an expedited review by the IEC as allowed. 
As part of the IEC requirements for continuing review of approved studies, the Investigator will 
be responsible for submitting periodic progress reports to the IEC (based on IEC requirements), 
at intervals appropriate to the degree of participant risk involved, but no less than once per year. 
The Investigator should provide a final report to the 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 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 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 CRO 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. 
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Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee). Each 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, 
each study participant must consent to direct access to his/her medical records for study-related 
monitoring, auditing, 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 IEC and use of the amended 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 
participant number assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
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 IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Data quality assurance 
All study participant data relating to the study will be recorded on 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 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
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The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH-GCP, and all applicable regulatory requirements. 
All essential documents are to be retained by the Investigator until ≥2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or ≥2 years have elapsed since the formal 
discontinuation of clinical development of the study medication. 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. 
10.1.5.1 
Case Report Form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. Use of correction fluid is not permitted. 
Corrections made after the Investigator’s review and signature of the completed eCRF will be 
resigned and dated by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
electronic eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the electronic 
eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.1.5.2 
Apps 
Not applicable. 
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10.1.6 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, or 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
Source documents are original records in which raw data are first recorded. These may include 
clinic records, charts, laboratory results, printouts, pharmacy records, ECG or other printouts, or 
completed scales, for example. Source documents should be kept in a secure, limited access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the participant’s source documents. The 
Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.7 
Study and site closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IEC or local 
health authorities, the Sponsor's procedures, or GCP guidelines. 
 Inadequate recruitment of participants by the Investigator. 
 Discontinuation of further study medication development. 
 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 Table 10-1 below will be performed by a local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol, respectively. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Table 10-1: Protocol-required safety laboratory assessments 
Laboratory 
Assessments 
Parameters 
Hematologya 
Platelet Count 
RBC Indices: 
MCV 
MCH 
Reticulocyte count 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistrya b 
BUN 
Potassium 
AST/SGOT 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Glucose 
(nonfasting) 
Calcium 
Alkaline phosphatase 
 
Routine 
Urinalysis 
 
Specific gravity 
 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase 
 
Microscopic examination (if blood or protein is abnormal) 
 
Urine hCG pregnancy test (as needed for WOCBP) at each Baseline and the SFU 
Visitc 
Other Screening 
Tests 
 
FSH and estradiol (as needed in women of nonchildbearing potential only) 
 
Alcohol breath test and urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 
 
Serum hCG pregnancy test (as needed for WOCBP)c 
 
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) 
The results of each test must be entered into the eCRF. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; eCRF=electronic Case 
Report Form; FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic 
gonadotropin; HIV=human immunodeficiency virus; IEC=Independent Ethics Committee; INR=international 
normalized ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; 
SAE=serious adverse event; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; UL=upper limit; ULN=upper limit of normal; WBC=white blood cell; WOCBP=woman of 
childbearing potential 
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a Hematology, clinical chemistry, and urinalysis assessments will be performed nonfasting. 
b Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Section 10.6. All events of ALT ≥3XUL and bilirubin ≥2XULN 
(>35% direct bilirubin) or ALT ≥3XULN and INR >1.5, if INR measured, may indicate severe liver injury 
(possible Hy’s Law) and must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IEC. 
Serum pregnancy test will be performed at Screening. 
The Investigator must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to the investigative 
site or other blinded personnel until the study has been unblinded. 
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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 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). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Important medical events: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or malignant 
cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
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10.3.3 
Recording and follow-up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to 
UCB in lieu of completion of the UCB AE/SAE eCRF page. 
 
There may be instances when copies of medical records for certain cases are requested by UCB. 
In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to UCB. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with 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 participant is lost to follow up. This follow-up 
requirement applies to AEs, SAEs, and AESIs. 
 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide UCB with a copy of any postmortem findings including histopathology. 
 
New or updated information will be recorded in the originally completed eCRF. 
 
The Investigator will submit any updated SAE data to UCB within 24 hours of receipt of the 
information. 
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10.3.4 
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 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal. 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy. 
 Documented bilateral salpingectomy. 
 Documented bilateral oophorectomy. 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female. 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
 Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the protocol-defined time frame in Section 5.1: 
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
 Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 10-2 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition male participants must refrain from donating sperm for the duration of the study and 
for at least 90 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 at least 90 days after the final dose of study medication. 
Pregnancy testing 
 A WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test at the Screening Visit (Days -28 to -2). 
 Urine or serum pregnancy testing should be performed at Screening, each Baseline Visit 
(Day -1 of each Treatment Period) and at the SFU Visit, after the last dose of study 
medication, and as required locally. The result must be negative prior to dosing the study 
participant. 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 Should a serum pregnancy test not be available, a urine pregnancy test with a sensitivity of  
10mIU/mL will be performed at the Screening Visit (Days -28 to -2), each Baseline Visit 
(Day -1 of each Treatment Period), and at the SFU Visit. The result must be negative prior to 
dosing the study participant. 
Collection of pregnancy information 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10-2. 
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Table 10-2: Highly effective contraceptive methods 
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationb 
 
Oral 
 
Intravaginal 
 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral 
 
Injectable 
Highly effective methods that are user independent 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
 
IUD 
 
IUS 
 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study medication. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
IUD=intrauterine device; IUS=intrauterine system; WOCBP=woman of childbearing potential 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for study participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study medication, which may reduce the 
efficacy of the contraceptive method. In this case, a suitable additional barrier method of contraception 
(ie, condom) should be utilized during the treatment period and for at least 90 days, corresponding to time needed 
to eliminate study medication plus 30 days for study medications with genotoxic potential after the last dose of 
study medication. 
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 
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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. 
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 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 participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, the follow-up will 
be at least 30 days (or up to 12 months) after the delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study medication by the 
Investigator will be reported to the Sponsor as described in Section 8.5.5. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
 Any female study participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver safety – Suggested Actions and Follow-up 
Assessments 
Study participants with PDILI must be assessed to determine if study medication must be 
discontinued. In addition, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication disconintuation to complete the final evaluation. 
Study participants with PDILI should not be withdrawn from the study until investigation and 
monitoring are complete. All results of these evaluations and observations, as well as the 
reason(s) for study medication discontinuation and/or study participant withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for discontinuation of study medication. 
A specific monitoring plan must be agreed between the UCB Study Physician and the 
Investigator for study participants who have ALT >3 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 (see Table 10-3). 
Table 10-3: Phase I liver chemistry stopping criteria and follow-up assessments 
Liver chemistry stopping criteria 
ALT-absolute 
ALT≥3xULN 
If ALT ≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) OR INR >1.5, 
report as an SAEa,b 
See additional actions and follow-up assessments listed below 
Required actions and follow-up assessments 
Actions 
Follow-up assessments 
 Report the event to UCB within 24 hours 
 Complete the liver event eCRF, and complete an 
SAE data collection tool if the event also met the 
criteria for an SAEa 
 Perform liver chemistry follow-up assessments 
 Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to 
Baseline (see MONITORING) 
 Consider the need for a toxicology screening 
MONITORING: 
If ALT 3xULN AND bilirubin 2xULN or INR >1.5: 
 Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
 Viral hepatitis serologyc 
 Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend 
 Obtain blood sample for PK analysis 
as soon as possible after the most 
recent dose 
 Serum CPK and LDH 
 Fractionate bilirubin, if total bilirubin 
 2xULN 
 Obtain complete blood count with 
differential to assess eosinophilia 
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liver event follow-up assessments within 
24 hours 
 Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, or 
return to Baseline 
 A specialist or hepatology consultation is 
recommended 
If ALT ≥3xULN AND bilirubin <2xULN and INR 
≤1.5: 
 Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver chemistry follow-up assessments within 24 
to 72 hours 
 Monitor participants weekly until liver chemistry 
abnormalities resolve, stabilize, or return to 
Baseline 
 Record the appearance or worsening 
of clinical symptoms of liver injury, 
or hypersensitivity, on the AE eCRF 
 Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, and 
other OTC medications) on the 
concomitant medications eCRF 
 Record alcohol use on the liver event 
alcohol intake eCRF 
If ALT ≥3xULN AND bilirubin 2xULN 
or INR >1.5: 
 Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total IgG or gamma 
globulins 
 Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James et al, 2009].) 
NOTE: Not required in China 
 Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) and/or liver biopsy to 
evaluate liver disease; complete liver 
imaging and/or liver biopsy eCRFs 
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; 
eCRF=electronic Case Report Form; HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; 
HPLC=high performance liquid chromatography; Ig=immunoglobulin; INR=international normalized ratio; 
LDH=lactate dehydrogenase; OTC=over-the-counter; RNA=ribonucleic acid; SAE=serious adverse event; 
ULN=upper limit of normal 
a 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. 
b Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention if ALT ≥3xULN and bilirubin ≥2xULN. Additionally, if 
serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on a dipstick, which is indicative of direct bilirubin elevations suggesting liver injury. 
c Hepatitis A 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 
anti-epileptic drug 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
bid 
twice daily dosing 
cBZR 
postsynaptic central benzodiazepine receptor 
CI 
confidence interval 
CNS 
central nervous system 
CPM 
Clinical Project Manager 
C-QT 
concentration-QT 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
coefficient of variation 
CYP 
cytochrome P450 
D 
Day 
DBP 
diastolic blood pressure 
Δ 
change from Baseline 
ΔΔQTcF 
placebo-corrected change from Baseline 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EOS 
End of Study 
EOT 
End of Treatment 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FDA 
Food and Drug Administration 
GABAA 
gamma-aminobutyric acid-A 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator's Brochure 
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ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IUT 
Intersection Union Test 
LEV 
levetiracetam 
MTD 
maximum tolerated dose 
NCA 
noncompartmental analysis 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PDILI 
potential drug-induced liver injury 
PD-PPS 
Pharmacodynamic Per-Protocol Set 
PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PR 
pulse rate 
PS 
Patient Safety 
PSL 
padsevonil 
QTc 
QT interval corrected 
QTcB 
QT interval corrected for heart rate according to Bazett’s formula 
QTcF 
QT interval corrected for heart rate using the Fridericia method 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
serious adverse reaction 
SBP 
systolic blood pressure 
SD 
standard deviation 
SFU 
Safety Follow-up 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SV2 
presynaptic vesicle protein 2 
TEAE 
treatment-emergent adverse event 
TQT 
Thorough QT 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
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10.11 
Appendix 11: Protocol Amendment History 
Amendment 1 (10 Oct 2019) 
Overall Rationale for the Amendment 
The protocol has been amended to comply with the requirement of the Medicines and Healthcare 
products Regulatory Agency (MHRA). Changes were made in the exclusion criteria to set the 
upper limit of acceptable range of total bilirubin test results and to clarify language regarding 
liver function tests (absolute rule for liver function test parameters) for alignment with regulatory 
requests in another padsevonil (PSL) protocol. Changes were made in Section 7.1.3 (Criteria for 
study hold due to adverse events) to comply with an MHRA requirement to align with European 
Medicines Agency Guidance on risk mitigation in first-in-human and early clinical trials. In 
addition, further changes have been made to correct various other typographical errors and to add 
clarifying language. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 3 Table 3-1 
Language regarding a secondary endpoint 
was removed. 
This is a correction to 
align information in 
the objective and 
endpoints section of 
the summary along 
with the information in 
the Schedule of 
activities (Table 1-1). 
Section 5.2-Exclusion Criteria 
Changed exclusion criterion #15 to include 
that isolated bilirubin must be <1.5x upper 
limit of normal (ULN) instead of >1xULN. 
Exclusion criterion #15 had the note 
removed regarding liver function test values 
above the ULN and repeat tests that could 
be performed in such situations. Language 
regarding retesting of participants with 
out-of-range laboratory values remains 
elsewhere in the protocol including 
Section 5.4.1 (Rescreening).  
Update exclusion 
criteria 
Section 5.2-Exclusion Criteria 
The exception of asymptomatic gallstones 
was removed from exclusion criterion #16. 
Update exclusion 
criteria 
Section 6.1 Table 6-1 Treatments 
administered 
The manufacturer of moxifloxacin has been 
updated from Bayer to Accord Healthcare, 
Ltd. 
Correction 
Section 7.1.3 Criteria for study 
hold due to adverse events 
The criteria have been amended to align 
with the European Medicines Agency 
Guidance on risk mitigation in 
first-in-human and early clinical trials.  
Regulatory alignment 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5.5 Pregnancy 
The pregnancy language was updated that 
UCB will collect pregnancy and birth 
information for up to 12 months after a 
birth. This aligns with other PSL protocols. 
Correction and 
alignment with other 
PSL protocols 
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11 
REFERENCES 
Clemens B. Forced normalisation precipitated by lamotrigine. Seizure. 2005;14(7):485-9. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
Food and Drug Administration. Guidance for Industry. E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrythmic Drugs-Questions and 
Answers (R3), Center for Drug Evaluation and Research, Center for Biologics Evaluation and 
Research, 06/2017. 
Food and Drug Administration. Guidance for Industry. Clinical Drug Interaction Studies-Study 
Design, Data Analysis, and Clinical Implications, Center for Drug Evaluation and Research, 
Center for Biologics Evaluation and Research, 10/2017. 
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):383-97. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM, 
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, Leclercq K, Gillard M, Michel P, Kenda B, et al. SV2A protein is a 
broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure 
protection in models of both partial and generalized epilepsy. Neuropharmacology. 
2008;54:715-20. 
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in 
epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia. 2009;50(3):387-97. 
Klitgaard H, Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert 
Opin Drug Discov. 2007;2(11):1537-45. 
Loganathan MA, Enja M, Lippmann S. Forced normalization: epilepsy and psychosis 
interaction. Innov Clin Neurosci. 2015;12(5-6):38-41. 
Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and 
pharmacokinetics. Acta Neurol Scand. 2008;118:69-86. 
Wan QF, Zhou ZY, Thakur P, Vila A, Sherry DM, Janz R, Heidelberger 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]. 
Zhang J and Machado SG. Statistical issues including design and sample size calculation in 
thorough QT/QTc studies, J Biopharm Stat. 2008;18(3):451-67. 
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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:
UP0050-protocol-amendment-01
Version:
1. 0
Document Number:
CLIN-000142042
Title:
UP0050-protocol-amendment-01
Approved Date:
11 Oct 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 11-Oct-2019 07:58:51 GMT+0000
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SAP_001.pdf: 
UCB 
 
22Jan2020 
Statistical Analysis Plan 
Padsevonil 
UP0050 
 
 
 
 
Confidential 
 
Page 1 of 38 
 
  
STATISTICAL ANALYSIS PLAN  
 
Study: UP0050 
Product:  Padsevonil  
 
 
A SINGLE-CENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, 3 TREATMENT PERIOD 
CROSSOVER STUDY TO ASSESS THE EFFECT OF 
PADSEVONIL ON CARDIAC REPOLARIZATION (QTc 
INTERVAL) (USING MOXIFLOXACIN AS A POSITIVE 
CONTROL) IN HEALTHY STUDY PARTICIPANTS. 
 
 
 
 
 
SAP/Amendment Number Date 
SAP Final 1.0 
22 January 2020 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 4 
1 
INTRODUCTION ....................................................................................................... 6 
2 
PROTOCOL SUMMARY ........................................................................................... 6 
2.1 
Study objectives and endpoints .......................................................................... 6 
2.2 
Study design and conduct .................................................................................. 9 
2.3 
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 ........................................................................ 17 
3.2.1 
Relative day ........................................................................................... 17 
3.2.2 
Study periods ......................................................................................... 18 
3.3 
Definition of Baseline values ........................................................................... 18 
3.4 
Protocol deviations........................................................................................... 20 
3.5 
Analysis sets..................................................................................................... 21 
3.5.1 
All Study Participants ............................................................................ 21 
3.5.2 
Safety Set ............................................................................................... 21 
3.5.3 
Pharmacokinetic Set .............................................................................. 21 
3.5.4 
Pharmacodynamic Per-Protocol Set ...................................................... 21 
3.6 
Treatment assignment and treatment groups ................................................... 21 
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 
4.2.1.1 
PK concentrations ........................................................................ 23 
4.2.1.2 
PK parameters .............................................................................. 23 
4.2.2 
Electrocardiogram data .......................................................................... 24 
4.2.3 
Safety laboratory data ............................................................................ 24 
4.2.4 
Dates and times ...................................................................................... 24 
4.3 
Handling of repeated and unscheduled measurements .................................... 26 
4.4 
Interim analyses and data monitoring .............................................................. 26 
4.5 
Multicenter studies ........................................................................................... 26 
4.6 
Multiple comparisons/multiplicity ................................................................... 26 
4.7 
Use of an efficacy subset of participants ......................................................... 26 
4.8 
Active-control studies intended to show equivalence ...................................... 27 
4.9 
Examination of subgroups ............................................................................... 27 
5 
STUDY POPULATION CHARACTERISTICS ....................................................... 27 
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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 and concomitant diseases ....................................................... 28 
6.4 
Prior and concomitant medications .................................................................. 28 
6.4.1 
Prior medication definition .................................................................... 29 
6.4.2 
Concomitant medication definition ....................................................... 29 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ......................................... 29 
8 
EFFICACY ANALYSES .......................................................................................... 29 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .................................... 29 
9.1 
Pharmacodynamics .......................................................................................... 29 
9.2 
Pharmacokinetics ............................................................................................. 29 
9.2.1 
Analysis of secondary pharmacokinetic variables ................................. 29 
9.2.2 
Analysis of other pharmacokinetic variables ......................................... 30 
10 SAFETY ANALYSES ............................................................................................... 30 
10.1 
Extent of exposure ........................................................................................... 30 
10.2 
Adverse events ................................................................................................. 31 
10.2.1 
Adverse event of special interest (AESI) ............................................... 32 
10.3 
Clinical laboratory evaluations ........................................................................ 32 
10.4 
Vital signs, physical findings, and other observations related to safety .......... 35 
10.4.1 
Vital signs .............................................................................................. 35 
10.4.2 
Electrocardiograms ................................................................................ 35 
10.4.3 
Other safety variable(s) .......................................................................... 36 
10.4.3.1 
Physical examination ................................................................... 36 
10.4.3.2 
Columbia-Suicide Severity Rating Scale ..................................... 36 
11 OTHER ANALYSES ................................................................................................ 36 
12 REFERENCES .......................................................................................................... 37 
13 APPENDICES ........................................................................................................... 38 
 
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LIST OF ABBREVIATIONS 
 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALQ 
Above the Limit of Quantification 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
  ASPS 
All Subject Participants Set 
  AUC 
Area Under the Curve  
AUCτ 
Area Under the Curve over a dosing interval 
bid 
twice daily dosing 
BLQ 
Below the Limit of Quantification 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
Cmax,ss 
maximum observed plasma concentration at steady-state 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
ΔΔQTcF 
placebo-corrected change from baseline 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
HLGT 
High Level Group Term 
HLT 
High Level Term 
HR 
Heart Rate 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IPD 
Important Protocol Deviations 
IUT 
Intersection Union Test 
LLOQ 
Lower Limit Of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
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NCA 
Noncompartmental Analysis 
PD 
Pharmacodynamic 
PD-PPS 
Pharmacodynamic Per-Protocol Set 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Set 
PR 
Pulse Rate 
PSL 
Padsevonil 
PT 
Preferred Term 
QTc 
QT interval corrected 
QTcB 
QT interval corrected for heart rate according to Bazett’s formula 
QTcF 
QT interval corrected for heart rate using the Fridericia method 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SFU 
Safety Follow-Up 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables, Figures, Listings 
tmax 
time to maximum concentration  
TQT 
Thorough QT 
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 UP0050. 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: 
 Protocol amendment 1, dated 10 October 2019.  
 Electronic case report form (eCRF), dated 24 October 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 Harmonization/Food 
and Drug Administration E9 Guidance documents (Phillips et al, 2003).  
UCB is the Sponsor and ICON PLC is the Contract Research Organization for this study. 
 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives and endpoints 
The objectives and corresponding endpoints for this study are presented in Table 2-1. 
Table 2-1: 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
The primary PD objective is: 
 To evaluate the effects on cardiac 
repolarization (QTc interval) of 
high-dose PSL in comparison to 
placebo in healthy study participants 
The primary PD endpoint is: 
 Placebo-corrected change from Baseline 
in QTc, based on Fridericia’s correction 
(QTcF) method (ΔΔQTcF) evaluated 
during the Target Dose Day of the PSL 
and placebo Treatment Periods, using 
time point analysis 
Secondary 
The secondary PD objective is: 
 To evaluate other aspects of the effects 
on cardiac function of high-dose PSL 
The secondary PD endpoints are: 
 Placebo-corrected change from Baseline 
in QTcF after a single dose of 
moxifloxacin 
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in comparison with placebo and 
moxifloxacin 
 
 Placebo-corrected changes from Baseline 
for HR, PR interval, and QRS interval 
 Frequency of treatment-emergent changes 
for T-wave morphology and U-wave 
presence 
 Change from Baseline in QTcF (ΔQTcF) 
evaluated at drug-specific tmax (∆tmax) for 
PSL, 
, 
, and possibly 
moxifloxacin 
The secondary PK objective is: 
 To evaluate the plasma PK of PSL at 
steady state in healthy study 
participants 
The secondary PK endpoints are: 
 Cmax,ss, tmax, and AUC, obtained from the 
plasma concentration-time profiles for 
PSL at steady state (on the Target Dose 
Day) 
The secondary safety objective is: 
 To evaluate the safety and tolerability 
of PSL at the dosed level in healthy 
study participants 
The secondary safety endpoints are: 
 Adverse events, SAEs, treatment-related 
AEs, and AEs leading to discontinuation 
of the study 
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Other 
The other PD objectives are: 
 To evaluate other aspects of the effects 
on cardiac function of high-dose PSL 
in comparison with placebo and 
moxifloxacin 
 To evaluate (using concentration-QT 
[C-QT] effect modeling) the 
relationship between QTc interval and 
the concentration of PSL and its 
metabolites 
The other PD endpoints are: 
 Categorical outliers for HR, QTcF, PR 
interval, and QRS interval 
 Relationship between ∆QTcF (change 
from Baseline in QTcF) and the plasma 
concentrations of PSL, 
 
and possibly moxifloxacin 
The other PK objectives (depending on the 
outcome of PK and/or QT analyses) are: 
 To evaluate from plasma samples the 
PK of PSL and the major metabolites 
of PSL (
 
 
 
 To evaluate from banked plasma 
samples the PK of moxifloxacin (if 
needed) in healthy study participants 
 To collect and store blood for possible 
ADME genotyping (if needed) 
The other PK endpoints are: 
 For PSL: 
 Single dose: AUC0-12, Cmax, and tmax 
 Multiple dose: CLss/F and Ctrough 
 For PSL metabolites: 
 Single dose: AUC0-12, Cmax, tmax, and 
metabolic ratios for Cmax and AUC0-12 
 Multiple dose: AUC, AUC0-t, Ctrough, 
Cmax,ss, tmax, and metabolic ratios for 
Cmax,ss and AUC  
 For moxifloxacin (if needed): 
 Single dose: AUC, AUC0-t, t½, Cmax, 
and tmax 
 Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL and metabolite PK 
analyses) (if needed) 
The other safety objective is: 
 To evaluate safety and tolerability of 
PSL at the dosed level in healthy adult 
study participants 
The other safety endpoints are: 
 Changes from Baseline in safety 
laboratory data (hematology, clinical 
chemistry, and urinalysis) 
 Changes from Baseline in vital signs (PR, 
respiratory rate, SBP, and DBP) 
 Changes from Baseline in 12-lead ECG 
assessment 
 Physical examination findings 
ADME=absorption, distribution, metabolism, and excretion; AE=adverse event; C-QT=concentration-QT; 
ΔQTcF=time-matched, Baseline-subtracted QTcF; DBP=diastolic blood pressure; ECG=electrocardiogram; 
HR=heart rate; PD=pharmacodynamic; PK=pharmacokinetic; PR=pulse rate; PSL=padsevonil; QTc=QT 
interval corrected; QTcF=QT interval corrected for HR using the Fridericia method; SAE=serious adverse 
event; SBP=systolic blood pressure 
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Analysis of all endpoints except pharmacodynamics (PD) will be detailed in the current SAP. 
The analysis of PD endpoints will be conducted by ERT,  and the planned analysis will be 
detailed in a separate SAP prepared by ERT. 
 
2.2 
Study design and conduct 
This is a Phase 1, single-center, randomized, placebo-controlled, crossover study to compare 
the PD effect on cardiac repolarization of high-dose PSL (400mg bid at steady state = 
maximum tolerable dose), with those of moxifloxacin (an open-label drug known to have a 
prolongation effect on the QTc interval) and placebo, in healthy study participants.  
The target total duration of the study is 94 days for each study participant, including the 
screening period (up to 28 days), crossover dosing across 3 treatment periods (14 days per 
treatment period), 2 washout periods (7 days per washout period), and the SFU visit (within 7 
to 10 days after their discharge from the clinic). However, this may vary according to the 
scheduling of Treatment Periods. 
The study schema is presented in Figure 2.1 and the schedule of activities is presented in Table 
2-2. 
Screening and Baseline Periods 
The design uses a 3-Treatment Period crossover structure. Study participants who provide 
written informed consent will be screened within 28 days before the first Treatment Period. 
For further details regarding the assessments performed during the Screening and Baseline 
Periods, refer to the Schedule of activities (Table 2-2). 
 
Treatment Periods 1, 2, and 3 
During each Treatment Period, each study participant will check into the site the day prior to 
the relevant First Dosing Day. Throughout the relevant Dosing Days, continuous Holter 
monitoring will be undertaken to provide extracted ECG records at the relevant time points 
necessary to the evaluation of QT interval effects. During the hour prior to administration of 
the first dose of each Treatment Period, 3 triplicate ECGs extracted from the Holter record will 
serve to provide a time-averaged Baseline for that Treatment Period.  
Subsequently, dosing with the allocated study medication will be initiated: for study 
participants in the PSL Treatment Period, the bid doses of PSL will be titrated up to reach 
steady state in time for the target dose on the ‘Target Dose Day,’ as shown in Figure 2-1. 
The randomized dosing regimen will be as follows : 
In the PSL Treatment Period: 
- 
On Day 1, 100mg PSL will be administered bid, in the morning and the evening. 
- 
On Days 2 and 3, 200mg PSL will be administered bid, in the morning and the evening. 
- 
On Days 4 and 5, 300mg PSL will be administered bid, in the morning and the evening. 
- 
On Days 6 and 7, 400mg PSL will be administered bid, in the morning and evening. 
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- 
On Day 8, the Target Dose Day, study participants will be fasted prior to the morning 
dose. Subsequently, 400mg PSL will be administered in the morning, and placebo will 
be administered in the evening. 
- 
On Day 9, 300mg PSL will be administered bid, in the morning and the evening.  
- 
On Day 10, 200mg PSL will be administered bid, in the morning and the evening. 
- 
On Day 11, 100mg PSL will be administered bid, in the morning and the evening. 
In the Placebo Treatment Period: 
- 
On Days 1 through 7, placebo to match the PSL treatment period doses will be 
administered bid, in the morning and the evening. 
- 
On Day 8, the Target Dose Day, study participants will be fasted prior to the morning 
dose. Subsequently, placebo to match 400mg PSL will be administered in the morning, 
and in the evening. 
- 
On Days 9 through 11, placebo to match the PSL treatment period doses will be 
administered bid, in the morning and the evening. 
In the Moxifloxacin Treatment Period: 
- 
On Days 1 through 7, placebo to match the PSL treatment period doses will be 
administered bid, in the morning and the evening. 
- 
On Day 8, the Target Dose Day, study participants will be fasted prior to the morning 
dose. Subsequently, 400mg moxifloxacin will be administered in the morning, and 
placebo will be administered in the evening. 
- 
On Days 9 through 11, placebo to match the PSL treatment period doses will be 
administered bid, in the morning and the evening. 
On the morning of Day 1 of each treatment period, Holter ECG monitoring will be conducted 
at 0.75, 0.5, and 0.25 hours prior to the time of first dosing with study medication and until 
dosing, and a venous blood sample for PK analysis will also be drawn 0.5 hours prior to dosing. 
On the Target Dose Day of each Treatment Period (T1D8, T2D8, and T3D8), Holter ECG 
monitoring will be conducted from 1 hour prior to the morning dose of study medication and 
will continue for 24 hours after wards. For a full description of blood sampling time points, 
refer to the Schedule of activities (Table 2-2). 
On the evening of the target dose day for each treatment period, all study participants will 
receive placebo in order to protect the 18 and 24-hour PK/QT evaluations during the PSL 
treatment period. 
On Days 3 through 7 and Days 10 through 21 of each treatment period, a venous blood sample 
will be taken prior to the morning dose / at the time of the previous morning doses of study 
medication, for trough / ongoing PK level evaluation. The blood samples will be used to 
measure plasma concentrations of PSL, 
, and 
possibly moxifloxacin, as well as for safety monitoring.  
On days 12, 13, and 14 of each treatment period, study participants will remain at the clinic for 
inpatient follow-up assessments. 
The safety and tolerability of repeated doses of PSL will be monitored throughout the study by 
evaluation of AEs, psychiatric and mental status, C-SSRS, vital signs, 12-lead ECG parameters, 
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physical and neurological examination findings, and clinical laboratory test results. The details 
of assessment of parameters refer schedule of activities (Table 2-2). 
Washout Periods 
Following completion of each Treatment Period, study participants will be discharged from the 
clinic, returning on the day prior to the First Dosing Day of the next Treatment Period for 
readmission. The interval between Treatment Periods (Washout Period) will be sufficient to 
ensure a minimum of 7 days’ washout from the study medication administered during the 
previous Treatment Period. 
Safety Follow-up Period 
Following completion of the final Treatment Period, study participants will be discharged and 
return for an SFU Visit within 7 to 10 days after their discharge from the clinic. 
The study schema is presented in Figure 2-1 and the schedule of activities is presented in 
Table 2-2. 
 
 
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Figure 2-1: UP0050 Study Design 
 
AM=morning; BID=twice daily; D=Day; MXF=moxifloxacin; PBO=placebo; PM=afternoon; PSL=padsevonil; 
T=Treatment Period 
 
 
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Table 2-2: 
Schedule of activities 
Study Period 
SCR 
Treatment Periods 1, 2, and 3 
SFU/
EOS 
Baseline 
Dosing Day 
Inpatient FU Days 
Study Day 
D -28 
to -2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
T3 
D21
-
D24 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
eligibilitya 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug screen and 
alcohol breath 
testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to 
clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous/ 
concomitant 
medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE and 
neurological 
examinations 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Body weight/ 
heightb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric and 
mental status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality risk 
assessment 
(C-SSRS)c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
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Table 2-2: 
Schedule of activities 
Study Period 
SCR 
Treatment Periods 1, 2, and 3 
SFU/
EOS 
Baseline 
Dosing Day 
Inpatient FU Days 
Study Day 
D -28 
to -2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
T3 
D21
-
D24 
Hematology, 
chemistry, urine, 
serologyd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH testf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-h Holter 
monitoringi 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Standardized 
breakfastj 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Study 
medication 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK sampling 
 
 
Xk 
Xl 
Xl  
Xl  
Xl  
Xl  
Xl  
Xk 
Xl  
Xl  
Xl  
Xl 
  
 
 
Sampling for 
ADME genotype 
analysis 
 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge from 
clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Table 2-2: 
Schedule of activities 
Study Period 
SCR 
Treatment Periods 1, 2, and 3 
SFU/
EOS 
Baseline 
Dosing Day 
Inpatient FU Days 
Study Day 
D -28 
to -2 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
T3 
D21
-
D24 
AE=adverse event; BP=blood pressure; C-SSRS=Columbia Suicide Severity Rating Scale; D=day; ECG=electrocardiogram; FSH=follicle stimulating 
hormone;FU=Follow-up; h=hour; PE=physical exam; PK=pharmacokinetic; SCR=Screening Period; SFU=Safety Follow-up; T=Treatment Period 
a At the first Baseline Day (D -1) only. 
b Height will be measured only at Screening. Body weight will be measured at Screening and Baseline (D-1) for each Treatment Period. 
c Study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening or Baseline (D-1) visits, followed by the “Since Last Visit” 
version at subsequent visits. 
d Virus serology will be measured only at Screening. All laboratory blood assessments may be performed nonfasting. 
e For women of childbearing potential. Serum or urine pregnancy test will be performed at Screening, at Baseline for each Treatment Period, and at the SFU 
Visit. 
f Female study participants of nonchildbearing potential are to confirm their postmenopausal status. 
g Vital signs will be evaluated predose and 3h (± 30 minutes) postdose for each morning dose. Blood pressure measurements will be performed in both supine 
and standing positions for orthostatic measurement at Screening (supine BP after the study participant has been lying down for 5 minutes and then standing BP 
after 1 minute and 3 minutes) and in a supine position for routine BP measurements at all assessments. 
h Triplicate 12-lead ECG will be performed as immediate safety evaluations at Screening and Baseline. They will also be performed on each dosing day 
(approximately 3h [± 30 minutes] postdose), on each inpatient FU day, and at the SFU Visit. On D1 and D8 of each Treatment Period, the ECG recordings may 
be substituted with recordings from the Holter monitoring equipment, if they are immediately available for review. All 3 ECG recordings should be sufficiently 
separated so they have a different ‘minute’ on the timestamp, and all are to be performed within 4 minutes. All ECG recordings should be taken with the study 
participant resting in the supine position for ≥5 minutes before the recording. 
i Holter monitoring will be performed for 24h at Screening. On D1and D8 of each Treatment Period, Holter monitoring will commence ≥1h prior to the morning 
dose of study medication, to enable extraction of the required predose ECGs. On D1 and D8, Holter monitoring is to continue for 24h following the morning 
dose (and until after collection of the following day’s trough PK sample). 
j A standardized light breakfast will be served; to be completed approximately 30 minutes prior to each morning dose, with the exception of D1 (morning) and 
D8 (morning) of each Treatment Period, when study participants will be dosed in fasted state (and will remain fasted for at least 2h postdose). 
k On D1 and D8 of each Treatment Period, PK samples will be collected at 0.5h prior to the morning dose and at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 
12h after dosing. An additional venous blood sample will be collected 18h after the D8 morning dose (D8 afternoon, 6h postdose sample). 
l A venous blood sample will be collected at 0.5h prior to the morning dose (or at the time of the previous morning doses of study medication for days when 
dosing does not occur), for trough/ongoing PK concentration evaluation. 
m  Sample will be collected prior to the first dose of study medication on D1 of Treatment Period 1.
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2.3 
Determination of sample size 
The sample size for this study is based on the most stringent of the requirements for the test 
compound (PSL) and for the positive control (moxifloxacin). 
A sample size of up to 54 study participants was chosen to obtain 49 evaluable study 
participants who will complete the study. Assuming a 1-sided 5% significance level and a 
within-study participant standard deviation (SD) of 8ms for ΔQTcF for all treatment groups 
and a true mean difference of 3ms in ΔQTcF between PSL and placebo, based on the 
calculation of the sample size for a Thorough’ QT (TQT) study (Zhang and Machado, 2008), 
a sample size of 49 evaluable study participants will provide a power of 96% to demonstrate 
that the upper limit of all the 2-sided 90% confidence intervals (CIs) on ΔΔQTcF will fall 
below 10ms for up to 11 post dose time points. 
Sample size calculation for assay sensitivity: Based on the calculation of the sample size for a 
TQT study (Zhang and Machado, 2008), as the test will be performed at 3 pre-specified time 
points separately, a one-sided 5% significance level (with adjusted one-sided significance 
levels of 5%, 2.5%, and 1.67%) will be used in addition to a within-study participant SD of 
8ms for ΔQTcF and a true effect of moxifloxacin of 10ms. A sample size of 49 evaluable study 
participants will provide a power of 99% to demonstrate assay sensitivity of excluding a mean 
difference of 5ms in ΔQTcF between moxifloxacin and placebo groups, ie, the lower limit of 
the 2-sided 90% CI of ΔΔQTcF will exceed 5msec at least one of the 3 pre-specified time 
points. 
To achieve a balanced design, and to allow for a few dropouts, it is planned to recruit up to 54 
study participants. 
Dropouts may be replaced at the discretion of the principal Investigator and Sponsor, 
depending on the circumstances. 
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.  
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. 
 Unless otherwise stated, the denominator for the percentages will be based on the number 
of participants in the respective analysis set. 
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For continuous variables, summary statistics will include number of study participants (n), 
mean, median, SD, minimum, and 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 PK concentration data and PK parameters of PSL 
and its metabolites 
]). 
When reporting descriptive statistics, the following rules will apply in general except for PK 
concentration data (plasma and urine PK) of PSL and its metabolites: 
 n will be an integer. 
 Mean, (arithmetic and geometric),  SD 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.  
Details on the presentation of PK concentration data (plasma and urine PK) of PSL and its 
metabolites are given in section 4.2.1. 
3.2 
General study level definitions 
3.2.1 
Relative day 
The study day of an event will be derived relative to the date of first dose in treatment period 
1.  
Study days for an event or measurement occurring before the first date of drug intake are 
calculated as follows: 
Study Day = Event Date - Date of first drug intake in first treatment period 
The study day for an event or measurement occurring on the date of first drug intake is 1. The 
study day for an event or measurement occurring after the date of first drug intake will be 
calculated as follows: 
Study Day = (Event Date - Date of first drug intake in first treatment period) + 1 
There is no study Day 0. Study day will not be calculated for partial dates. In such cases, 
study day should be presented as “--”in the relevant participant data listing. 
For events or measurements occurring after the date of last dose, study day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows: 
Study Day = + (Event Date −Date of Last Dose in the last treatment period) 
Period day of an event will be derived for each treatment period with the date of first drug 
intake in that corresponding period as reference. 
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The period day for an event or measurement occurring on the date of first drug intake is 1. The 
period day for an event or measurement occurring after the date of first drug intake will be 
calculated as follows: 
Period Day = (Event Date - Date of first drug intake in that treatment period) + 1 
There is no Period Day 0. 
3.2.2 
Study periods 
The following study periods can be identified: 
Screening and Baseline Period (Day -28 to Day -1): 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 the each treatment period (on Day -1). Study participants will check-in at 
the CRU on Day -1. 
Treatment Periods 1, 2, and 3: The study is designed as a crossover dosing across 3 treatment 
periods. Each treatment period consists of 14 days. The first dosing day will be Day 1, there is 
no Day 0. The first 2 treatment periods are followed by a wash-out period. 
Washout Periods 
After completion of a treatment period, study participants will be discharged from the clinic, 
returning on the day prior to the first dosing day of the next treatment period for readmission. 
The interval between treatment periods (washout period) will be sufficient to ensure a 
minimum of 7 days’ washout from the study medication administered during the previous 
treatment period. 
Safety Follow-up Period 
After completion of the final treatment period, study participants will be discharged and return 
for a safety follow up (SFU) visit within 7 to 10 days after their discharge from the clinic. 
3.3 
Definition of Baseline values 
Unless otherwise specified, baseline for each treatment period will be the last available pre-
dose value prior to the first study drug intake in each treatment period, whether it is from 
scheduled or unscheduled measurements, ie there will be separate baseline values for each 
treatment period.  
 
 
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Treatment Periods 
Baseline value 
1 
Prior to first dose in Period 1 
2 
Prior to first dose in Period 2 
3 
Prior to first dose in Period 3 
The change from baseline to any subsequent post-baseline visit will be calculated as the 
absolute difference between that post-baseline visit’s value and the baseline visit value, as 
below:  
𝑃𝑜𝑠𝑡 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 −𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 
Measurement-specific baseline time points are presented in the table below.   
 
 
 
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Table 3‒1: 
Definition of Baseline 
 
Variable 
Baseline definition 
Hematology, serum, 
chemistry, urinalysis 
The baseline value is defined as the value from Day -1 of each treatment 
period. In case the Day -1 value of first treatment period is missing, the 
value obtained at the screening visit will be considered as baseline. If 
the day -1 value is missing for treatment period 2 and/or 3, the Day -1 
value of the first treatment period will be considered.  
Vital signs 
The baseline value is defined as the last available pre-dose value on Day 
1 of each treatment period. If the pre-dose day 1 value is missing for a 
treatment period,  the value on Day -1 of that respective treatment 
period will be used. 
ECG 
12-lead ECG will be measured in triplicate. Baseline is the mean of the 
last three measurements prior to dosing for each treatment period. If less 
than three replicates are available, the mean of the available replicates 
(prior to dosing) will be considered as baseline. 
C-SSRS 
 
The baseline value is defined as the value from Day -1 of each treatment 
period. In case the Day -1 value of first treatment period is missing, the 
value obtained at the screening visit will be considered as baseline. If 
the day -1 value is missing for treatment period 2 and/or 3, the Day -1 
value of the first treatment period will be considered. 
ECG=electrocardiogram; C-SSRS= Columbia-Suicide Severity Rating Scale 
3.4 
Protocol deviations 
Important protocol deviations (IPDs) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on the primary outcome or key secondary 
outcome for an individual study participant. The criteria for identifying important protocol 
deviations and the classification of important protocol deviations will be defined within the 
relevant protocol deviation specification document, which is part of the study data cleaning 
plan.  
Important protocol deviations will include the following categories: 
 Inclusion/exclusion criteria deviations 
 Administration of prohibited concomitant medications 
 Deviations relating to withdrawal criteria 
 Visit schedule deviations 
 Study drug administration deviations (including incorrect treatment received, handling 
and storage deviations and incorrect dosage received) and any vomiting episode(s) (that 
could impact PK concentrations) 
 Procedural noncompliance 
 Missing data  
Important protocol deviations will be reviewed as part of an ongoing blinded data cleaning 
process prior to database lock to confirm exclusion from analysis sets. 
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After all data have been verified/coded/entered into a database, a data evaluation meeting 
(DEM) will be performed. 
At least one DEM will be performed at the following time:  
 Prior to the final analysis after all data have been verified/coded/entered into the 
database. 
Additional DEMs may be conducted as deemed necessary.  
The purpose of these DEM reviews will be to review all protocol deviations, define the analysis 
sets  and check the quality of the data. The reviews will also help decide how to manage 
problems in the subjects’ data (eg,  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 Set (ASPS) consists of all study participants who have signed the 
informed consent form. This set was previously referred to as Enrolled Set in the Study 
Protocol. 
3.5.2 
Safety Set 
Safety Set (SS) defined as all study participants who receive at least 1 dose of study medication. 
3.5.3 
Pharmacokinetic Set 
Pharmacokinetic Set (PKS): All study participants who receive at least 1 dose of study 
medication and who have no important protocol deviations affecting the PK and for whom at 
least 1 measurable PK concentration is available. This set has been referred to as PK-PPS 
(Pharmacokinetic Per Protocol Set) in the protocol. 
3.5.4 
Pharmacodynamic Per-Protocol Set  
Pharmacodynamic Per-Protocol Set (PD-PPS) defined as all study participants who receive at 
least 1 dose of study medication and who have no important protocol deviations affecting the 
PD endpoint (ECG) and for whom at least 1 measurable value is available. 
3.6 
Treatment assignment and treatment groups 
It is expected that participants will receive treatments as per the randomized treatment sequence 
and hence the analyses will be based on the randomized treatment. If a participant was 
randomized but not dosed in any treatment period, the participants results will be reported 
under the randomized treatment group. 
Data collected only prior to dosing of first medication will be summarized per treatment 
sequence: 
 
 
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 Sequence ABC, ACB, BAC, BCA, CAB, CBA. 
Code 
Treatment 
A 
Padsevonil 400 mg 
B 
Placebo 
C 
Moxifloxacin 400 mg 
 
 
Data collected during each of the 3 treatment periods will be summarized per treatment. 
3.7 
Center Pooling Strategy 
Since this is a single center study this is not applicable. 
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). 
Medical procedures will not be coded. 
The versions of the coding dictionaries used will be displayed in the relevant TFLs. 
3.9 
Changes to protocol-defined analyses 
The randomized set (RS) has been deleted from the analysis sets and will no longer be used. 
All outputs which were initially planned for the RS will now be based on the SS.  
The Enrolled Set has been renamed to  All Study Participants set. 
The PKPPS set has been renamed to PKS. 
AUC0-t has been added to the pharmacokinetic analysis. 
 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No adjustments for covariates will be made. 
4.2 
Handling of dropouts or missing data 
In general, there will be no imputation of missing data.  
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.  
The geometric CV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data:  
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Geometric CV (%) =  sqrt[(exp (SD^2) –  1)] x 100 
The Pharmacokinetic analysis will be performed in accordance to the Guideline on performing 
NCA analysis dated 08 Nov 2017. 
 
4.2.1.1 
PK concentrations 
When reporting individual data in listings the following rules will apply: 
 Missing data should be reported as NV (no value). 
 Concentrations below the limit of quantification should be reported as BLQ (below 
the limit of quantification). 
 Concentrations should be listed to the same number of significant figures supplied 
by the bioanalytical laboratory. 
When reporting individual data in figures the following rules will apply: 
 BLQ values prior to Cmax should be set to 0 for purposes of plotting the figure  (to 
capture lag-time)  
 Actual sampling times should be used 
When summarising the data in tables the following rules will apply: 
 To calculate descriptive statistics, BLQ values should be set to half the LLOQ  
value and missing values should be excluded 
 When the total number of BLQ and missing values exceeds one third of the total 
then only minimum and maximum should be reported for this time point. Other 
descriptive statistics should be reported as missing (“-“). The minimum should be 
reported as “BLQ” 
 When the mean value includes one or more replaced BLQ values then a footnote 
should be included to say “contains one or more BLQ value replaced by half the 
LLOQ value” 
 A minimum of 3 values are required to calculate summary statistics. If only 2 values 
are available then these should be presented as the minimum and maximum with 
other descriptive statistics reported as missing (“-“) 
 If no participants have data, only n=0 will be presented. The other descriptive 
statistics will be left blank. 
When summarising the data in figures the following rules will apply: 
 The data plotted in the figure should match the data presented in the summary table, 
with the exception of missing values prior to Cmax which should be set to 0 in the 
figure  (to capture lag-time) 
 Geometric mean should be plotted (as opposed to arithmetic mean) due to the log-
normal distribution of concentrations.Variability should be plotted as detransformed 
SD computed on ln-transformed data 
 Nominal sampling times should be used 
 Both linear and semi-logarithmic scales should normally be presented 
 
4.2.1.2 
PK parameters 
When reporting individual data in listings the following rules will apply: 
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 Individual PK parameters should be reported to 3 significant figures. 
 If a parameter cannot be calculated it should be reported as NE (not estimable ie if 
input data is missing which prevents calculation) or NC (not calculable ie if the data 
were available but the calculation was considered unreliable) 
When summarizing the data in tables the following rules will apply: 
 Generally descriptive statistics should be calculated on individual PK parameters 
that have 9 decimal places (exceptions include tmax and tlag ie discontinuous 
variables) 
 For most PK parameters (ie for continuous variables) the following descriptive 
statistics should be calculated: mean, SD, geometric mean, CV, minimum, median 
and maximum.  For tmax and tlag (ie for discontinuous variables) only median, 
minimum and maximum should be reported 
 Descriptive statistics should be reported to 4 significant figures for the mean, 
median and standard deviation (SD) and to 3 significant figures for all others 
 If at least two thirds of the subjects have a PK parameter reported then descriptive 
statistics will be calculated, otherwise only minimum and maximum will be 
reported for this PK parameter and all other descriptive statistics will be reported as 
NE (ie not estimable) 
 A minimum of 3 values are required to calculate summary statistics. If only 2 values 
are available then these should be presented as the minimum and maximum with 
other descriptive statistics reported as missing (“-“) 
 
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”.  
The Pharmacokinetic analysis will be performed in accordance to the Guideline on performing 
NCA analysis dated 08 Nov 2017. 
4.2.2 
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. 
4.2.3 
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.  
4.2.4 
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: 
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 If only the month and year are specified and the month and year of the first dose of study 
medication is not the same as the month and year of the start date then use the 1st of the 
month, or the date of screening if this is later (if the latter imputation results in an end date 
that is earlier than the start date, then use the 1st of the month). If time is missing this will 
be imputed as 00:00h. 
 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 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. 
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 
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Table 3-1: 
Calculation rules for duration of adverse events 
Data availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Start day and time 
missing 
--/-- 
D2/T2 
Duration = [(D2 – D0)*24 + (T2 – T0)]/24 d 
For a participant in the ASPS, 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. 
 
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. Repeated measurements are defined as more than 1 measurement at same time 
point. For example, the same lab parameters were assessed twice using the same batch of blood 
samples since the first assessment had issues. The following general rules will apply to all 
repeated and unscheduled measurements: 
 Unscheduled and repeated measurements will not be used in the descriptive statistics at 
time points after first dose of study medication. For repeated measurements obtained after 
first dose of study medication, only the scheduled latest value can be used in the 
calculation of the descriptive statistics. For repeated measurements obtained prior to the 
first dose of study medication the latest value (which may be scheduled or unscheduled, 
sorting data by sampling date/time and take the last record) 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 measurements performed for the Early Withdrawal (EW) visit will be 
assigned to the EOS visit and analyzed accordingly as an EOS visit. 
4.4 
Interim analyses and data monitoring 
No formal interim analyses are planned. 
4.5 
Multicenter studies 
Not applicable as this is a single center study. 
4.6 
Multiple comparisons/multiplicity 
No adjustments for multiplicity will be made. 
4.7 
Use of an efficacy subset of participants 
As efficacy was not evaluated in this study, there will be no primary efficacy endpoint. 
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4.8 
Active-control studies intended to show equivalence 
Not applicable. 
4.9 
Examination of subgroups 
Not applicable. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Participant disposition 
The number of participants who signed the informed consent form, participants randomized, 
participants who completed or prematurely discontinued the study, as well as the reason for 
discontinuation will be summarized for all participants.. In addition, the number of participants 
who completed each treatment period will be included. 
A participant who completed a treatment period is defined as a participant who has completed 
all visits belonging to that respective treatment period. A participant who completed the study 
is defined as a participant who completed all visits up to and including the EOS/ETV visit (in 
the Follow-up Period).  
The number and percentage of participants included in each of the analysis sets will be 
summarized per treatment for all participants based on the ASPS.  
In addition, the following listings will be presented: 
 Participant disposition (ASPS). 
 Participant analysis sets (ASPS). 
 Discontinuation due to AEs (SS) 
The listing of participant disposition will include the date of informed consent, date and time 
of first and last dose of drug per treatment period and overall, date of premature termination 
and primary reason (if applicable) for termination and date of final contact. An overview on 
the reasons for screen failure will be included. 
The listing of study discontinuation will include the reason for premature study 
discontinuation, and the number of days on study medication per treatment. 
The number of days on study medication will be calculated as follows: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐷𝑎𝑦𝑠 𝑜𝑛 𝑠𝑡𝑢𝑑𝑦 𝑚𝑒𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑) + 1 
The number of days on study medication will be calculated for each of the 3 treatment 
periods. 
 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types in the IPD 
document. 
A listing of all IPDs identified at the Data Evaluation Meeting will be presented for all 
participants based on the SS and will include the deviation type and description.  
 
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6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
A by-participant (study participant) listing of demographics sorted by treatment sequence will 
be presented based on the ASPS. This will include the year of birth, age (in years), sex, race, 
ethnicity, height (in cm), baseline weight (in kg) and body mass index (BMI, in kg/m2). The 
height will be the measurement obtained at screening. Weight will be the last non-missing 
value prior to the first study drug intake at each treatment period. BMI documented in the CRF 
will be presented.  
All demographic characteristics (except for year of birth) will be summarized for all 
participants based on the ASPS and SS by treatment sequence. The summary of age will 
include descriptive statistics.  
Characteristics on experience of medical conditions will be also summarized for the SS and 
presented per treatment sequence. 
The summary of age will include descriptive statistics and 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 
6.2 
Other Baseline characteristics 
Lifestyle information (alcohol, drug abuse) for the subjects with DILI will be listed. 
6.3 
Medical history and concomitant diseases 
Medical history will be listed for the SS by MedDRA system organ class (SOC), high level 
group term (HLGT), high level term (HLT), and preferred term (PT) per treatment sequence. 
The reported term will be included in the listing. The summary will include the number and 
percentage of participants, and will be sorted alphabetically by SOC and by descending 
incidence of PT within each SOC, based on the “All Participants” column. 
 
6.4 
Prior and concomitant medications 
Prior and concomitant medications will be listed and summarized separately for all participants 
in the SS, by WHODD Anatomical Main Group [Level 1 term text], Pharmacological Subgroup 
[Level 3 term text] and PT. Prior medications will be summarized by treatment sequence and 
concomitant medication by treatment periods. The reported term will be included in the listing. 
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Separate tabulations will be presented for prior medications and concomitant medications. 
Prior medications which continued into the first treatment period will also be classified as 
concomitant and will be included in both summaries. 
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in overall column. 
6.4.1 
Prior medication definition 
Prior medications include any medications that started prior to the date of first intake of study 
drug in the first treatment period. This includes medications that started prior to the first dose 
and continued after. 
6.4.2 
Concomitant medication definition 
Concomitant medications include any medications taken from the time of first drug 
administration in the first treatment period to a later point in the study. This includes 
medications that started prior to the first dose and continued after. 
Any medication with missing dates and/or times will be handled as described in Section 4.2.4 
to classify as either prior or concomitant medication. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Study participant compliance will be ensured by the administration of study medication by 
designated site personnel. Drug administration must be recorded on the Study Medication 
Administration form. As all study drug is administered on site no formal calculations of 
compliance will be presented.  
8 
EFFICACY ANALYSES 
Not applicable 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS  
9.1 
Pharmacodynamics 
Full details on the analysis of the pharmacodynamics endpoints will be provided in a dedicated 
cardiac SAP. 
 
9.2 
Pharmacokinetics 
9.2.1 
Analysis of secondary pharmacokinetic variables 
The planned secondary PK endpoints of PSL include the parameters Cmax,ss, tmax, and AUCτ at 
steady state (Target Dose day [Day 8]). 
The PK parameters will be listed and summarized for participants who received PSL treatment  
using descriptive statistics (number of available observations [n], median, SD, minimum, 
maximum, geometric mean, geometric CV and 95% CI for the geometric mean [assuming log 
normally distributed data]) for PSL and its metabolites.  
 
 
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9.2.2 
Analysis of other pharmacokinetic variables 
The planned other PK endpoints of PSL include the parameters AUC0-12, AUC0-t, Cmax, and tmax 
(single dose), and CLss/F and Ctrough (multiple dose).  
The planned other PK endpoints of the major metabolites of PSL 
 
 include the 
parameters AUC0-12, Cmax, tmax, and metabolic ratios for Cmax and AUC0-12 (single dose) and 
AUCt, AUC0-t, CLss/F, Ctrough, Cmax,ss, tmax and metabolic ratios for Cmax,ss and AUCτ 
(multiple dose).  
If required, the planned other PK endpoints of moxifloxacin including the parameters AUC, 
AUC0-t, t½, Cmax, and tmax (single dose) will be calculated. In this case, these results will be 
reported in an addendum to the CSR. 
The individual plasma concentrations and PK parameters of PSL, 
 
, and available moxifloxacin will be summarized by day (single dose day 1 
or multiple dose, day 8) using descriptive statistics (number of available observations [n], 
median, standard deviation, minimum, maximum, geometric mean, geometric CV and 95% CI 
for the geometric mean [assuming log-normally distributed data]). In addition all data will be 
listed. 
Individual participant plasma concentration-time profiles of PSL and its metabolites will be 
displayed graphically in linear and semi-logarithmic scale. 
Combined individual (spaghetti) plasma concentration-time profiles plots will be displayed for 
PSL and its metabolites with all participants overlaid on the same plot (linear and 
semi-logarithmic scale). 
Geometric mean profiles of plasma concentrations for PSL and its metabolites over time will 
be presented, in both linear and semi-logarithmic scale for Day 1 and Day 8. For the linear 
scale plot only, the lower and upper 95% confidence interval (CI) for the geometric mean will 
be displayed. 
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots 
and will be based on scheduled times. 
The Ctrough concentration for PSL and its metabolites over time (Day 2 to 12) will be presented  
graphically. 
In addition, box plots for the PSL PK parameters Cmax, tmax and AUCτ at day 1 (100 mg) and 
day 8 (400 mg) will be provided. In these plots the PK parameter will be on the y-axis, 
whereas the timepoint (Day 1 and Day 8, respectively) will be on the x-axis. 
 
10 
SAFETY ANALYSES 
All safety listings will be performed using the SS and summarized by each treatment (PSL, 
Moxifloxacin, Placebo) and overall.  
10.1 
Extent of exposure 
All study medication administration details will be listed by study participant. The listing will 
include the fasting state, dose, number of tablets taken, date and time of administration of the 
morning and evening dose and total daily dose of medication.  
Exposure data will be listed only. 
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10.2 
Adverse events 
All AEs will be coded using the MedDRA® and categorized by intensity 
(mild/moderate/severe) 
and 
relationship 
(related/not 
related) 
as 
judged 
by 
the 
Investigator.Adverse Events will be categorized as Pre-treatment AEs, TEAEs, or Post-
Treatment Period TEAEs (PTP-TEAEs), according to the intake of study drug. A treatment-
emergent AE (TEAE) is defined as any AE with a start date/time on or after the first dose of 
study medication or any unresolved event already present before administration of study 
medication that worsens in intensity following exposure to the treatment. The following 
definition will be applied: 
Pre-treatment AE: Any AE that starts prior to the date of the first dose of study drug (in the 
first treatment period). 
TEAE: 
Any AE that starts on or after the date of the first dose of study drug and 
on or before the last date of the last treatment period (T3D14) or any 
unresolved event already present before administration of treatment that 
worsens in intensity following exposure to the treatment.  
PTP-TEAE: 
Any AE that starts after the date last inpatient FU day of the last 
treatment period i.e. occurring during the SFU Period. 
Any event occurred during washout period will be considered treatment emergent and 
attributed to the most recent treatment received (ie. the treatment of the previous period). 
Missing or partially missing dates for AEs will be handled as described in Section 4.2.4. Where 
dates are missing or partially missing, AEs will be assumed to be treatment-emergent, unless 
there is clear evidence to suggest that the AE started prior to the first dose of study medication, 
or AE started during SFU.  Adverse events will be attributed to the treatment in which they 
started. 
The number and percentage of participants who experience TEAEs will be summarized by 
MedDRA system organ class (SOC), preferred term (PT) and treatment.  
Summaries of TEAEs will include the following: 
 Incidence of TEAEs (overview including number and percentage of participants with any 
TEAEs, serious TEAEs, TEAE of special interest (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). 
The TEAEs will be summarized and tabulated at both the study participants (number and 
percentage of participants) and event (number of events) level wherever applicable: 
 TEAEs by treatment, SOC, PT, and maximum reported severity grade (mild, 
moderate, severe). 
 TEAEs by treatment, SOC, PT, and maximum relationship to study drug. 
 Non-serious TEAEs above reporting threshold of 5% by treatment, SOC, PT. 
A participant who has multiple events in the same SOC and PT will be counted only once in 
the participant counts for that treatment but all events will be included. 
In summaries including relationship, the following relationships will be summarized: “Not 
related” and “Related”. If a participant reports the same event with different relationship 
assessments, the participant is counted under  related. As such, each subject will be counted 
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once within each System Organ class and Preferred Term. 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. 
Adverse event summaries will be ordered alphabetically by SOC, within each SOC, PTs will 
be sorted by decreasing frequency of “All Participants” column for tables.  
A listing for all AEs will be presented by participant and treatment sequence. The listings will 
include the following data pertaining to the AEs: SOC, HLT, PT, reported term, start and end 
dates with relative days to study medication administration (per period), duration, intensity, 
seriousness, relationship to study medication, action taken, and final outcome. In addition, 
separate listings will be provided for the incidence of all TEAEs, SAEs and AEs leading to 
discontinuation. 
The listing of incidence of all TEAEs will be presented by treatment and will include intensity, 
relationship, seriousness, number of subject reporting a least one TEAE within SOC/PT, 
number of individual occurrences of TEAEs and site-participant number. 
 
10.2.1 
Adverse event of special interest (AESI) 
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. Potential Hy’s Law, defined as ≥3xULN  alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) with coexisting ≥2xULN total bilirubin in the 
absence of ≥2xULN alkaline phosphatase (ALP), with no alternative explanation for the 
biochemical abnormality, must ALWAYS be reported to UCB as an AESI. Follow-up 
information should then be reported if an alternative etiology is identified during investigation 
and monitoring of the participant. 
Therefore a separate listing will present the study participants who meet 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 at that time point for the 
specified variables. 
 
10.3 
Clinical laboratory evaluations 
Laboratory data (clinical chemistry, hematology and urinalysis) and changes from baseline (if 
applicable) for numeric variables will be listed by participants, parameter, treatment sequence 
and time point. Only abnormal laboratory values will be listed. In case of any abnormal value, 
all values for the respective subject on this laboratory parameter will be listed. 
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Any laboratory measurements that are BLQ or ALQ will be handled as described in 
Section 4.2.3. Values outside the reference range for numeric variables will be flagged in the 
listings and in addition, will be listed separately for each lab category (hematology, chemistry 
and urinalysis). The reference ranges will also be reported in the listings. 
Clinical chemistry, hematology, and urinalysis parameters will be summarized by treatment 
and time point for both absolute values and changes from baseline.  
Shift tables from baseline to each post-baseline time point will be presented by treatment period 
for selected hematology and chemistry parameters (see Table 10.1). 
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. 
Additionally the following laboratory variables will be listed by treatment sequence: 
 Serology 
 Urine Drug Screen 
 Alcohol detection test 
 Serum and urine pregnancy test (for women of childbearing potential) 
In addition, potential drug induced liver injury (PDILI) data will be listed by treatment 
sequence. This will include laboratory results meeting the PDILI categories as mentioned 
below: 
 ALT increase ≥3xULN or AST increase ≥3xULN 
 ALP ≥2xULN 
 Total Bilirubin increase ≥2xULN. 
The listing will display only treatments and time points for which at least one of the above 
criteria was fulfilled for a given subject, and will display all results obtained at that treatment 
or time point for the specified variables. 
A summary of participants who meet the criteria for potential drug-induced liver injury 
(PDILI) will be presented together with any additional relevant data collected, if applicable. 
 
 
 
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Table 10-1: Protocol-required safety laboratory assessments  
Laboratory 
Assessments 
Parameters 
Hematologya 
Platelet Countd  
RBC Indices: 
MCV 
MCH 
Reticulocyte count 
WBC Count with 
Differential: 
Neutrophilsd 
Lymphocytesd 
Monocytes 
Eosinophils 
Basophils 
RBC Countd 
Hemoglobind 
Hematocrit 
Clinical 
Chemistrya,b 
Blood Urea 
Nitrogen 
(BUN)d 
Potassium 
Aspartate Aminotransferase 
(ASTd)/Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinined 
Sodium 
Alanine Aminotransferase 
 (ALTd)/Serum Glutamic-
Pyruvic Transaminase (SGPT) 
Total Protein 
 
Glucose 
(nonfasting)  
Calcium 
Alkaline phosphatased 
 
Routine 
Urinalysisa 
 Specific gravity,  
 pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase. 
 Microscopic examination (if blood or protein is abnormal) 
 Urine hCG pregnancy test (as needed for woman of childbearing potential 
(WOCBP)) at each baseline and the SFU Visitc. 
Other Screening 
Tests 
 FSH and estradiol (as needed in women of nonchildbearing potential only)  
 Alcohol breath test and urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)  
 Serum hCG pregnancy test (as needed for WOCBP)c 
  Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; eCRF=electronic Case 
Report Form; FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic  
gonadotropin; HIV=human immunodeficiency virus; IEC=Independent Ethics Committee; INR=international 
normalized ratio; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; 
SAE=serious adverse event; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 
transaminase; UL=upper limit; ULN=upper limit of normal; WBC=white blood cell; WOCBP=woman of childbearing 
potential. 
a Hematology, clinical chemistry, and urinalysis assessments will be performed nonfasting.  
b Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in protocol Section 7.1.1 and Section 10.6.  
All events of ALT ≥3XUL and bilirubin ≥2XULN (>35% direct bilirubin) or ALT ≥3XULN and INR >1.5, if 
INR measured, may indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).  
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IEC. 
Serum pregnancy test will be performed at Screening 
d Shift tables will be produced. 
 
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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 participants resting in the 
supine position at all time points from the baseline visit: 
 Systolic and diastolic blood pressure (standing position at screening only) 
 Pulse rate 
 Temperature 
 Respiration rate 
A by-participant listing of all vital sign measurements and change from baseline will be 
presented by treatment sequence and time point. 
Descriptive statistics will be reported for all vital sign measurements. Vital sign variables and 
changes from baseline will be summarized by descriptive statistics at each time point by 
treatment. 
In case the TEMA/PCS criteria are fulfilled, the results will be flagged. 
 
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. 
a Both conditions must be satisfied for a measurement to be considered potentially clinically significant. 
 
 
10.4.2 
Electrocardiograms  
Safety 12-lead ECG will be recorded 3 times at each time point. The individual mean at each 
time point will be calculated as raw parameters for descriptive analysis. The individual mean 
and change from baseline will be summarized using descriptive statistics by treatment 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: 
 Heart rate  
 PR interval 
 RR Interval 
 PQ/PR interval  
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 QRS interval 
 QT Duration 
 QTcB interval (QT interval corrected for HR according to Bazett’s formula) 
 QTcF  
The individual measurements and the mean of the triplicate measurements will be reported in 
the by-participant listings. The listing will also include the change from baseline, based on the 
mean of the triplicate measurements at each time point, and will be presented by treatment 
sequence and time point. ECG findings will also be listed. 
The following cut-points in QTcF, based on the mean of the triplicate data, will be 
summarized categorically (number and percentage of participants) by treatment 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 
 
10.4.3 
Other safety variable(s) 
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) data will be listed only. 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  
No other analysis planned.  
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12 
REFERENCES 
 Columbia University Medical Center. Columbia-Suicide Severity Rating Scale 
(2008). http://www.cssrs.columbia.edu/. 
 Electronic case report form (eCRF) dated 24 October 2019. 
 Food and Drug Administration. Guidance for Industry. E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrythmic 
Drugs-Questions and Answers (R3), Center for Drug Evaluation and Research, Center 
for Biologics Evaluation and Research, 06/2017. 
 Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper 
on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):383-
97. 
 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 
 Protocol amendment 1 dated 10 October 2019.  
 
Zhang J and Machado SG. Statistical issues including design and sample size 
calculation in thorough QT/QTc studies. J Biopharm Stat. 2008;18(3):451-67 
 
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13 
APPENDICES 
Table 13-1: Breakdown of treatment group reported into the TFLs by study 
assessment data 
  
Analysis Set 
Treatment 
Sequence 
Treatment 
 
 
Table Figure Listing 
 
PSL/Moxifloxacin/ 
Placebo 
All 
Participants 
Study participant disposition 
ASPS 
  
ASPS 
 
X 
X 
Protocol deviations 
 
  
SS 
X 
 
X 
Study participant Discontinuation  
SS 
  
SS 
X 
 
X 
Participants analysis sets 
ASPS 
 
ASPS 
X 
 
X 
Demographics & Baseline 
Characteristics 
ASPS 
  
SS 
X 
 
X 
Medical history 
SS 
  
SS 
X 
 
X 
Prior medications 
SS 
  
SS 
X 
 
X 
Concomitant medications 
SS 
  
SS 
 
X 
X 
Study Drug Administration 
 
  
SS 
X 
X 
PD Parameter  
PD-PPS 
  
PD-PPS 
 
X 
X 
PK Conc. Individual 
PKS 
PK-S 
PKS 
 
X 
X 
PK Parameter 
PKS 
PKS  
PKS 
 
X 
X 
Adverse Events 
SS 
  
SS 
 
X 
X 
Lab (Hematology, Chemistry, 
Urinalysis) 
SS 
 
SS 
 
X 
X 
Lab (Virology, Serology, Alcohol) 
SS 
  
SS 
X 
X 
PDILI 
 
 
SS 
 
X 
X 
Urine sampling (pregnancy, drug screen) 
  
  
SS 
X 
X 
Vital signs 
SS 
  
SS 
 
X 
X 
12-lead ECG 
SS 
SS 
SS 
 
X 
X 
Physical Examination 
  
  
SS 
X 
  
X 
C-SSRS  
 
  
SS 
X 
 
X 
 
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Approval Signatures
Name:
up0050-sap
Version:
1. 0
Document Number:
CLIN-000148437
Title:
UP0050 Statistical Analysis Plan
Approved Date:
29 May 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 28-Jan-2020 17:03:40 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 28-May-2020 07:47:20 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 29-May-2020 19:44:58 GMT+0000
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