Clinical trial NCT03480243
Conditions: Pharmacokinetics
Keywords: Padsevonil
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2018-03-27; Completion date: 2018-08-02
Enrollment: 28 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate and compare the Pharmacokinetics (PK) of concomitant administration of Padsevonil (PSL) in the presence and absence of erythromycin in healthy study participants.

Detailed description:

Arms: arm 1: Treatment Period 1 (Day 1 to Day 11):

* Padsevonil 100 mg twice daily (bid) on Day 1 to Day 4
* Padsevonil 100 mg single dose on Day 5
* 1 week of wash-out (from evening of Day 5 to Day 11)

Treatment Period 2 (Day 12 to 22):

* Padsevonil 100 mg twice daily (bid) on Day 12 to Day 15
* Padsevonil 100 mg single dose on Day 16
* 1 week of wash-out (from evening of Day 16 to Day 22)

Treatment Period 3 (Day 23 to Day 38):

* Erythromycin 500 mg twice daily (bid) on Day 23 to Day 25
* Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32
* Padsevonil 100 mg single dose on Day 33
* Erythromycin 500 mg twice daily (bid) on Day 33 to Day 36
* Erythromycin 500 mg single dose on Day 37
Interventions: intervention 1: Padsevonil (UCB0942) intervention 2: Erythromycin
Intervention descriptions: intervention 1: * Pharmaceutical Form: film-coated tablet
* Route of Administration: Oral use intervention 2: * Pharmaceutical Form: film-coated tablet
* Route of Administration: Oral use

Protocol documents:
Prot_000.pdf: 
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PROTOCOL UP0057
AN OPEN-LABEL, FIXED-SEQUENCE STUDY IN HEALTHY 
STUDY PARTICIPANTS TO EVALUATE THE EFFECT OF 
COADMINISTERED ERYTHROMYCIN ON THE 
PHARMACOKINETICS AND SAFETY OF PADSEVONIL
PHASE 1
EudraCT Number: 2017-004694-13
Sponsor:
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Protocol/Amendment number
Date
Type of amendment
Final Protocol
26 Jan 2018
Not applicable
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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STUDY CONTACT INFORMATION
Sponsor
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
Belgium
Principal/Coordinating Investigator
Name:
, MBBS JCPTGP MPhil ALS-registered
Affiliation:
Hammersmith Medicines Research
Address:
Cumberland Avenue
London
NW10 7EW
United Kingdom
Phone:
 
24-hour on call 
physician:
Sponsor Study Physician
Name:
Address:
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
Belgium
Phone:
Exploratory Project Manager
Name:
Address:
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
Belgium
Phone:
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Clinical Trial Biostatistician
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest
R3 1420 Braine-L’Alleud
Belgium
Phone:
Clinical Monitoring Contract Research Organization
Name:
PAREXEL International (IRL) Limited
Address:
70 Sir John Rogerson’s Quay
Dublin 2
Ireland
Phone:
+353 1 473 9500
Quantitative Clinical Pharmacology Lead
Name:
 
Address:
UCB Pharma SPRL
Chemin du Foriest
B-1420 Braine l’Alleud
Belgium
Phone:
Laboratory for PK parameters
Name:
York Bioanalytical Solutions 
Address:
Cedar House
Northminster Business Park
Upper Poppleton
York YO26 6QR
United Kingdom
Phone:
+44 (0) 1904 686060
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Laboratory for safety laboratory parameters
Name:
Address:
Hammersmith Medicines Research, Laboratory
Cumberland Avenue
London
NW10 7EW
United Kingdom
Phone:
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SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 24 21
Email
Global: DSICT@ucb.com (for interventional clinical studies)
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................11
1
SUMMARY.....................................................................................................................13
2
INTRODUCTION ...........................................................................................................13
2.1 Background......................................................................................................................13
2.2 Clinical studies and adverse event profile .......................................................................14
2.3 Risk assessment ...............................................................................................................16
2.4 Urgent safety measures....................................................................................................17
3
STUDY OBJECTIVES....................................................................................................18
3.1 Primary objective.............................................................................................................18
3.2 Secondary objectives .......................................................................................................18
3.3 Exploratory objectives .....................................................................................................18
4
STUDY VARIABLES.....................................................................................................18
4.1 Pharmacokinetic variables ...............................................................................................18
4.1.1
Primary pharmacokinetic variables .....................................................................18
4.1.2
Secondary pharmacokinetic variables .................................................................18
4.1.3
Other pharmacokinetic variables .........................................................................19
4.2 Safety variables................................................................................................................19
4.2.1
Secondary safety variables ..................................................................................19
4.2.2
Other safety variables ..........................................................................................19
5
STUDY DESIGN.............................................................................................................20
5.1 Study description .............................................................................................................20
5.2 Study periods ...................................................................................................................20
5.2.1
Screening Period..................................................................................................20
5.2.1.1
Screening Visit (Day -28 to Day -2) .........................................................20
5.2.1.2
Baseline Visit (Day -2 to Day -1)..............................................................20
5.2.2
Treatment Periods................................................................................................20
5.2.2.1
Treatment Period 1 and Treatment Period 2 (Day 1 to Day 11 and Day 12 
to Day 22)..................................................................................................21
5.2.2.2
Treatment Period 3 (Day 23 to Day 38)....................................................21
5.2.3
Safety Follow-Up Period .....................................................................................22
5.3 Pharmacokinetic sampling...............................................................................................22
5.3.1
Venous blood.......................................................................................................22
5.3.2
Microsamples of capillary blood .........................................................................23
5.3.3
Urine ....................................................................................................................23
5.4 Study duration per study participant................................................................................23
5.5 Planned number of study participants and sites...............................................................23
5.6 Anticipated region and country........................................................................................23
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5.7 Schedule of study assessments.........................................................................................23
5.8 Schematic diagram...........................................................................................................29
5.9 Rationale for study design and selection of dose.............................................................31
6
SELECTION AND WITHDRAWAL OF STUDY PARTICIPANTS ...........................31
6.1 Inclusion criteria ..............................................................................................................31
6.2 Exclusion criteria .............................................................................................................33
6.3 Withdrawal criteria ..........................................................................................................35
6.4 Stopping rules ..................................................................................................................36
6.4.1
Potential drug-induced liver injury investigational medicinal product 
discontinuation criteria ........................................................................................36
7
STUDY TREATMENTS.................................................................................................37
7.1 Description of investigational medicinal products ..........................................................37
7.2 Treatments to be administered.........................................................................................37
7.3 Packaging.........................................................................................................................37
7.4 Labeling ...........................................................................................................................37
7.5 Handling and storage requirements..................................................................................37
7.6 Drug accountability..........................................................................................................37
7.7 Procedures for monitoring study participant compliance ................................................38
7.8 Concomitant medications/treatments...............................................................................38
7.8.1
Permitted concomitant treatments (medications and therapies) ..........................38
7.8.2
Prohibited concomitant treatments (medications and therapies).........................38
7.8.3
Diet, fluid, and activity control............................................................................38
7.9 Blinding............................................................................................................................39
7.10 Numbering of study participants......................................................................................39
8
STUDY PROCEDURES BY VISIT ...............................................................................39
8.1 Screening Period (Day -28 to Day -1) .............................................................................39
8.1.1
Screening Visit (Day -28 to Day -2)....................................................................39
8.1.2
Baseline Visit (Day -2 to Day -1)........................................................................40
8.2 Treatment Period 1 (Day 1 to Day 5) and Treatment Period 2 (Day 12 to Day 16)........41
8.2.1
Day 1 (Treatment Period 1) and Day 12 (Treatment Period 2) ...........................41
8.2.2
Day 2 to Day 3 (Treatment Period 1) and Day 13 to Day 14 (Treatment Period 2)42
8.2.3
Day 4 (Treatment Period 1) and Day 15 (Treatment Period 2) ...........................42
8.2.4
Day 5 (Treatment Period 1) and Day 16 (Treatment Period 2) ...........................42
8.3 Wash Out (Day 6 to Day 11 for Treatment Period 1; Day 17 to Day 22 for Treatment 
Period 2)...........................................................................................................................43
8.3.1
Day 6 (Treatment Period 1) and Day 17 (Treatment Period 2) ...........................43
8.3.2
Day 7 (Treatment Period 1) and Day 18 (Treatment Period 2) ...........................44
8.3.3
Day 8 (Treatment Period 1) and Day 19 (Treatment Period 2) ...........................44
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8.3.4
Day 9 to Day 10 (Treatment Period 1) and Day 20 to Day 22 (Treatment 
Period 2)...............................................................................................................44
8.3.5
Day 10 (Treatment Period 1) and Day 21 (Treatment Period 2) .........................44
8.4 Treatment Period 3 (Day 23 to Day 37)...........................................................................45
8.4.1
Treatment Period 3a (Day 23 to Day 25).............................................................45
8.4.1.1
Day 23 to Day 25.......................................................................................45
8.4.2
Treatment Period 3b (Day 26 to Day 33) ............................................................45
8.4.2.1
Day 26 .......................................................................................................46
8.4.2.2
Day 27 to Day 32.......................................................................................46
8.4.2.3
Day 33 .......................................................................................................47
8.4.3
Treatment Period 3c (Day 34 to Day 38).............................................................47
8.4.3.1
Day 34 to Day 37.......................................................................................47
8.4.3.2
Day 38 .......................................................................................................48
8.5 Safety Follow-Up Period (7 to 10 days from final dose).................................................48
8.5.1
End of Study Visit (Day 44, Day 45, Day 46, or Day 47)...................................48
8.6 Withdrawal Visit..............................................................................................................49
8.7 Unscheduled visit.............................................................................................................49
9
ASSESSMENT OF PHARMACOKINETIC VARIABLES...........................................49
9.1 Pharmacokinetic variables ...............................................................................................49
9.2 Pharmacokinetic sampling procedures ............................................................................49
9.2.1
Blood pharmacokinetic sampling scheme ...........................................................49
9.2.2
Urine pharmacokinetic sampling scheme............................................................50
9.3 Shipment procedures........................................................................................................50
9.4 Communication plan........................................................................................................50
9.5 Bioanalytical method .......................................................................................................50
10
ASSESSMENT OF SAFETY..........................................................................................50
10.1 Adverse events.................................................................................................................50
10.1.1
Definitions ...........................................................................................................50
10.1.1.1
Adverse event............................................................................................50
10.1.1.2
Serious adverse event ................................................................................51
10.1.1.3
Adverse events of special interest .............................................................52
10.1.2
Procedures for reporting and recording adverse events.......................................52
10.1.2.1
Description of adverse events....................................................................52
10.1.2.2
Rule for repetition of an adverse event......................................................52
10.1.2.3
Additional procedures for reporting serious adverse events .....................52
10.1.3
Follow up of adverse events ................................................................................53
10.1.4
Pregnancy ............................................................................................................53
10.1.5
Suspected transmission of an infectious agent via a medicinal product..............54
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10.1.6
Overdose of investigational medicinal product ...................................................55
10.1.7
Safety signal detection.........................................................................................55
10.2 Laboratory measurements................................................................................................55
10.2.1
Evaluation of potential drug-induced liver injury................................................56
10.2.1.1
Consultation with Medical Monitor and local hepatologist ......................59
10.2.1.2
Immediate action: determination of investigational medicinal product 
discontinuation ..........................................................................................59
10.2.1.3
Testing: identification/exclusion of alternative etiology...........................59
10.2.1.4
Follow-up evaluation.................................................................................61
10.2.1.5
Optional hepatic investigation sample collection......................................61
10.3 Other safety measurements..............................................................................................62
10.3.1
Physical examination...........................................................................................62
10.3.2
Vital signs ............................................................................................................62
10.3.3
Standard 12-lead electrocardiogram....................................................................63
10.3.4
Assessment of suicidality ....................................................................................63
11
STUDY MANAGEMENT AND ADMINISTRATION.................................................64
11.1 Adherence to protocol......................................................................................................64
11.2 Monitoring .......................................................................................................................64
11.2.1
Definition of source data .....................................................................................64
11.2.2
Source data verification .......................................................................................65
11.3 Data handling...................................................................................................................65
11.3.1
Case Report form completion..............................................................................65
11.3.2
Database entry and reconciliation........................................................................65
11.3.3
Study Participant Screening and Enrollment log/Study Participant Identification 
Code list...............................................................................................................65
11.4 Termination of the study..................................................................................................66
11.5 Archiving and data retention............................................................................................66
11.6 Audit and inspection ........................................................................................................66
11.7 Good Clinical Practice .....................................................................................................66
12
STATISTICS ...................................................................................................................67
12.1 Definition of analysis sets................................................................................................67
12.1.1
Enrolled Set .........................................................................................................67
12.1.2
Full Analysis Set..................................................................................................67
12.1.3
Pharmacokinetic Per-Protocol Set .......................................................................67
12.2 General statistical considerations.....................................................................................67
12.3 Planned pharmacokinetic and other analyses ..................................................................67
12.3.1
Analysis of the primary pharmacokinetic variables ............................................67
12.3.2
Safety analyses.....................................................................................................68
12.4 Handling of protocol deviations.......................................................................................69
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12.5 Handling of dropouts or missing data..............................................................................69
12.6 Planned interim analysis and data monitoring.................................................................69
12.7 Determination of sample size...........................................................................................69
13
ETHICS AND REGULATORY REQUIREMENTS......................................................69
13.1 Informed consent .............................................................................................................69
13.2 Study participant identification cards ..............................................................................70
13.3 Independent Ethics Committee........................................................................................70
13.4 Study participant privacy.................................................................................................71
13.5 Protocol amendments.......................................................................................................71
14
FINANCE, INSURANCE, AND PUBLICATION.........................................................71
15
REFERENCES ................................................................................................................71
16
DECLARATION AND SIGNATURE OF INVESTIGATOR .......................................73
17
SPONSOR DECLARATION ..........................................................................................74
LIST OF TABLES
Table 5-1:
Schedule of assessments ..................................................................................24
Table 9‒1:
Irrelevant time deviations for PK sampling.....................................................50
Table 10-1:
Laboratory measurements................................................................................56
Table 10‒2:
Required investigations and follow up for PDILI............................................58
Table 10‒3:
PDILI laboratory measurements......................................................................60
Table 10‒4:
PDILI information to be collected...................................................................61
LIST OF FIGURES
Figure 5‒1:
Schematic diagram...........................................................................................30
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LIST OF ABBREVIATIONS
ADaM
analysis data model
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AR
adverse reaction
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
BZD
benzodiazepine
cBZR
central benzodiazepine receptor
CDMS
clinical data management system
CI
confidence interval
CNS
central nervous system
CPMP
Committee for Proprietary Medicinal Products
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale 
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic Case Report form
ES
Enrolled Set
EOS
End of Study
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
Full Analysis Set
GABAA
gamma-aminobutyric acid type A
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HCV-Ab
hepatitis C virus antibody
HIV
human immunodeficiency virus
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IB
Investigator’s Brochure
ICF
Informed Consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
IMP
investigational medicinal product
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LEV
levetiracetam
LLOQ
lower limit of quantification
MHRA
Medicines and Healthcare products Regulatory Agency
NCA
noncompartmental analysis
OLE
open-label extension
OTC
over-the-counter
PD
pharmacodynamics(s)
PDILI
potential drug-induced liver injury
PET
positron-emission tomography
PI
Principal Investigator
PK
pharmacokinetic(s)
PK-PPS
Pharmacokinetic Per-Protocol Set
PS
Patient Safety
PSL
Padsevonil
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
REC
Research Ethics Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SFU
Safety Follow-up
SOP
Standard Operating Procedure
SV2
synaptic vesicle 2
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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1
SUMMARY
Padsevonil (PSL, previously known as UCB0942) is a novel chemical entity with selective dual 
synaptic vesicle protein 2 (SV2) and central benzodiazepine receptor (cBZR) site affinity. It is 
currently being proposed initially for the treatment of focal-onset seizures in adult patients with 
drug-resistant epilepsy.
Many antiepileptic drugs (AEDs) are associated with drug-drug interactions (DDIs). Preclinical 
data indicate that PSL metabolism is mediated mainly by cytochrome P450 (CYP) 3A4 with 
minor involvement of CYP2C19. Consequently, PSL exposure may be altered by CYP3A4 
inhibitors. It has already been demonstrated that concomitant administration of a strong CYP3A4 
inducer (carbamazepine, UP0002) significantly reduces exposure to PSL.
UP0057 is a Phase 1, open-label, fixed-sequence study in healthy study participants to evaluate 
the effect of a coadministered moderate CYP3A4 inhibitor (erythromycin) on the 
pharmacokinetics (PK) and safety of PSL.
The primary objective of UP0057 is to evaluate and compare the plasma PK of PSL in the 
presence and absence of erythromycin in healthy study participants. The secondary objectives 
include the following in healthy study participants: to assess safety and tolerability of PSL in the 
presence and absence of erythromycin; to evaluate and compare the plasma PK of PSL
metabolites in the presence and absence of erythromycin; and to assess and compare the urine 
PK of PSL and its metabolites in the presence and absence of erythromycin. The exploratory
objectives are to estimate the inter- and intra-study participant variability in the plasma PK of 
PSL and its metabolites, to evaluate and compare the venous blood and MITRA microsampling 
PK of PSL and its metabolite in the presence and absence of erythromycin, and to archive blood 
samples for genotyping of drug metabolizing enzymes and biomarkers.
UP0057 is comprised of the following periods: a Screening Period; 3 Treatment Periods, and a 
Safety Follow-Up (SFU) Period. The Screening Period will occur within 28 days prior to the 
start of Treatment Period 1. Treatment Period 1 and Treatment Period 2 each consist of 5 days of 
PSL treatment followed by 1-week of wash-out. Treatment Period 3 consists of erythromycin
only for 3 days (Treatment Period 3a), erythromycin and PSL for 8 days (Treatment Period 3b), 
and erythromycin only for 4 days (Treatment Period 3c). The SFU Period is performed 7 to 
10 days after the last dose of investigational medicinal product (IMP) or upon discontinuation of 
the study. 
2
INTRODUCTION
2.1
Background
The International League Against Epilepsy (ILAE) defines drug resistance as failure of adequate 
studies of 2 tolerated and appropriately chosen AEDs either as monotherapy or in combination to 
achieve sustained seizure freedom (ILAE Classification of Epileptic Seizures, 1981). In the US, 
there are 3 million adults with active epilepsy (Zack and Kobau, 2017). Assuming epilepsy with 
focal-onset seizures in 60% of patients and resistance to AEDs in 20% to 40% of patients in the 
US, approximately 360,000 to 720,000 adult patients with active epilepsy in the US suffer from 
drug-resistant epilepsy (Giussani et al, 2016; Kwan and Sander, 2004; Semah et al, 1998). It is 
this drug-resistant epilepsy population that represents the greatest burden of disease for 
individuals, physicians, and the healthcare system.
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A treatment that provides a significant reduction in seizure frequency will reduce mortality 
(Laxer et al, 2014) and significantly improve quality of life (Choi et al, 2014; Baker et al, 1997) 
by increasing patients’ ability to attain basic safety, freedom from the risk of falls and injuries, 
and reach the milestones that most people take for granted: a feeling of belonging and social 
integration; the ability to form intimate relationships and a family; and having a productive and 
rewarding profession; or other means of self-realization.
Padsevonil is a novel chemical entity currently being developed clinically for the treatment of 
focal-onset seizures in adult patients with drug-resistant epilepsy. The mechanism of action for 
PSL is unique in comparison to available AEDs because it has selective affinity both for 
presynaptic SV2 proteins and for postsynaptic cBZR sites on the gamma-aminobutyric acid type 
A (GABAA) receptor. At presynaptic sites, PSL binds with high affinity to all 3 subtypes of the 
human SV2 protein (ie, SV2A, SV2B, and SV2C), and at postsynaptic sites, acts as a partial 
agonist, binding with moderate affinity to the cBZR sites. Whereas SV2A ligands are 
characterized by broad-spectrum anticonvulsant activity, GABAA receptors mediate inhibitory 
neurotransmission, and their allosteric modulation by cBZR sites offers robust protection against 
seizures.
The synergistic anticonvulsive effect observed when combining levetiracetam (LEV), an AED 
that binds with SV2A, with benzodiazepines (BZDs) in preclinical models 
(Kaminski et al, 2009) was the motivation that led to the design of PSL. In nonclinical studies, 
PSL administered as a monotherapy has shown higher efficacy than LEV combined with a BZD 
(diazepam) at matching in vivo occupancies of SV2A and cBZR, respectively. This suggests that 
PSL’s preclinical efficacy is not only due to the combination of these 2 mechanisms of action, 
but that a unique interaction of PSL with SV2 proteins may also play a role.
Padsevonil is cleared via metabolism involving the CYP pathway; the formation of the 2 major 
metabolites,
and 
 
, is mainly mediated by CYP3A4, with potential involvement of CYP2C19. 
Padsevonil was also found to be a weak mechanism-based inhibitor of CYP2C19. It has been 
observed that PSL clearance decreased following repeated oral administration, probably as a 
result of the auto-inhibition of CYP2C19. Consequently, CYP3A4 is assumed to be the main 
enzyme involved in the metabolism of PSL at steady-state.
Recent studies in patients with refractory epilepsy showed that more than 60% of patients were 
treated concomitantly with 2 or more AEDs (Johannessen and Landmark, 2010). Drug-drug 
interactions that result in alterations in the PK of AEDs can have a profound impact on 
tolerability, efficacy, and safety, and can potentially result in toxicity. It is therefore important to 
consider and estimate at an early stage the possible interactions that may occur with the 
concomitant use of PSL and other drugs.
This study will evaluate the impact of a moderate CYP3A4 inhibitor, erythromycin, on the PK, 
safety, and tolerability of PSL and its metabolites 
in 
healthy study participants.
2.2
Clinical studies and adverse event profile
As of 01 December 2017, PSL has been administered in 7 completed human Phase 1
pharmacology studies (N01360, N01383, N01386, UP0001, UP0002, UP0010, and UP0013) and 
1 completed Phase 2 proof of concept study (EP0069). There are also 2 ongoing Phase 1 clinical 
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pharmacology studies (UP0036 and UP0039) and 1 ongoing Phase 2 open-label extension study
(EP0073). These studies have investigated the safety, PK, and pharmacodynamics (PD) of single
and multiple ascending doses of PSL, and the potential interaction of PSL with food, valproic 
acid, carbamazepine, and other AEDs. Position-emission tomography (PET) investigations have 
been performed to evaluate the GABAA receptor occupancy at 2 steady state PSL dose levels and 
SV2A occupancy at different single PSL dose levels and times postdose in healthy study 
participants.
In the PSL Phase 1 program completed thus far, 129 healthy study participants and 20 study 
participants with epilepsy (male and female) have been exposed to PSL at single doses up to 
490mg (26 healthy study participants) and repeated doses up to 400mg bid for up to 12 days 
(103 healthy study participants and 20 study participants). In EP0069, 55 study participants were 
exposed to repeated doses of PSL up to 400mg bid during the maintenance phase of the study. A 
total of 42 of the 55 study participants in EP0069 have enrolled in EP0073, during which they 
are allowed to adjust their PSL dose.
The safety findings to date suggest that the adverse events (AEs) experienced by study 
participants receiving single and repeated doses of PSL are limited principally to central nervous 
system (CNS) effects and that these are consistent with the known pharmacology of PSL, 
ie, similar to AEs produced by SV2A- and GABAA-targeting AEDs. 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.
The psychiatric findings currently reported across the Phase 1 and Phase 2 studies with PSL are 
consistent with the AE profile of other AEDs, including other SV2A ligands. Acute psychiatric 
effects occurred in 3 study participants administered PSL (2 in Phase 1 and 1 in Phase 2). The 
events were transient, acute, and required admission to psychiatric care and antipsychotics. No 
definite dose relationship could be determined, and the events occurred after variable periods of 
time after the first administration of PSL. The occurrence of these behavioral AEs highlights the 
need to consider the possibility of significant psychiatric AEs and to maintain vigilance for them. 
With regard to cardiovascular effects, minor, transient, reductions in blood pressure (BP) were 
observed in the Phase 1 and Phase 2 PSL studies; however, these were not clinically meaningful 
and resolved without intervention. The degrees of reduction seen in both systolic and diastolic 
BP 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 (Jones et al, 1979). In regard to 
electrocardiogram (ECG) results, all nonclinical and clinical Phase 1 and Phase 2 cardiac data in 
totality were reviewed by an expert cardiologist consultant whose opinion was that “overall, 
there is no clear evidence that PSL is associated with any increase in incidence of ectopy, change 
in QT interval corrected for heart rate changes (QTc), or clinically-significant arrhythmia in 
clinical trials to date”. Echocardiographic screening of study participants at Baseline (to exclude 
study participants with valvulopathies) and ongoing echocardiographic monitoring during 
treatment and posttreatment has been implemented in the Phase 2 studies. No major findings 
were observed in the completed EP0069 study or the ongoing open-label extension study, 
EP0073. Cardiac monitoring (eg, ECGs, vital signs, echocardiograms) is planned throughout the 
duration of the PSL development program in order to better understand and mitigate any risks.
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In general, the safety profile of PSL has been consistent with the pharmacological properties of 
the drug and with dose-escalation studies of CNS compounds in regards to the type and severity 
of nervous system and psychiatric AEs reported, with most AEs reported as mild or moderate.
The overall safety profile during the clinical program to date, as well as preclinical and clinical 
experience with PSL, can be found in the Investigator’s Brochure (IB).
2.3
Risk assessment 
Padsevonil is mainly metabolized via CYP3A4. Safety pharmacology studies have shown no 
major adverse effects on the respiratory and central nervous systems when administered orally in 
single-dose safety pharmacology studies (rats) and in repeat dose toxicity studies (rats, dogs). A 
slight prolongation of QTc was found in a 4-week study in dogs at 30mg/kg bid; however, it was 
not confirmed in a 13-week study (animals monitored by external telemetry) or a 39-week study 
at doses up to 50mg/kg bid, with free plasma concentration far above those reached in healthy 
study participants. Small, transient increases in heart rate and changes in arterial pressure 
(hypertension in rats and hypotension in dogs) occurring mainly from single doses are likely 
related to exaggerated GABAA pharmacologic activity.
In the 39-week dog toxicity study, subtle cardiac microscopic findings, consisting of minimal 
valvular inflammatory cell infiltration, or minimal to slight epithelial inflammation/fibroplasia of 
the epicardium in the right atrium, were seen in the heart of one-third of treated dogs without 
dose relationship. These findings were not seen in the 13-week study. Findings were subtle, 
focal, and not associated with any clinically significant cardiovascular changes. These findings 
did not cause any biological or clinical consequences in the animals in this study and were thus 
not considered to be adverse. This conclusion was supported after comprehensive review of the 
data by 5 nonclinical pathologists (including a cardiovascular expert pathologist). Additionally, 
external advice on the potential human implications was sought from a British Heart Foundation 
Professor of Cardiology. It was concluded that short-term exposure should not lead to any 
relevant abnormality or clinical disease, and even with long-term exposure the potential hazard 
and likelihood of an adverse pericardial or valvular effect in humans is extremely low.
Padsevonil is neither teratogenic nor embryotoxic in rats and rabbits. There was no effect on 
reproductive organs, including sperm analysis, following long-term administration (up to
26 weeks in rats and 39 weeks in dogs).
The preclinical pharmacology studies indicated that the metabolism of PSL may be affected by 
extrinsic influences on the CYP3A4/CYP2C19 pathway. In order to mitigate any risk caused by 
these interactions, medication or dietary ingredients that induce, inhibit, or are a substrate for the 
CYP3A4/CYP2C19 pathways are restricted. Further details are provided in Section 7.8.2 and 
Section 7.8.3, respectively.
In clinical trials, PSL had a good safety profile. There were no deaths. Adverse events 
experienced by study participants receiving single and repeated doses of PSL were limited 
principally to CNS effects and that these were consistent with its known pharmacology. Adverse 
events were dose-related in frequency and intensity, self-limiting, and tended to decrease in 
intensity over the first few days of dosing. Some new AEs (mainly headache and sleep 
disturbance) developed after dose discontinuation with PSL in the Phase 1 studies, indicating a 
potential withdrawal syndrome. These have been mild, transient, not dose-related and not of 
clinical concern.
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The occurrence of acute psychiatric serious adverse events (SAEs) (delirious syndrome, 
mania-like symptoms, and acute psychosis) in 3 study participants administered PSL highlights 
the need to maintain vigilance for such events. Reported acute psychiatric effects are consistent 
with adverse effects of other anticonvulsant drugs with various mechanisms of action. These 
SAEs were transient, acute, and required clinical intervention (admission to psychiatric care and 
antipsychotics). In healthy study participants, those SAEs occurred early after initiation of PSL
done without titration; in 1 study participant, symptoms worsened upon abrupt drug 
discontinuation. Only in 1 out of 68 epileptic study participants exposed to PSL, a psychotic 
effect emerged a few weeks following dosing start after improvement in seizure control. This 
suggests a “forced normalization” phenomenon, which is described with other AEDs in resistant 
patients and is not unexpected with a potent AED (Loganathan et al, 2015; Clemens, 2005). The 
mitigation plan for acute psychiatric effects involves gradual titration and taper, known to 
improve tolerability of AEDs. 
Despite the occurrence of ECG findings such as ectopies (asymptomatic, not requiring clinical 
intervention), there are no current data suggesting that PSL has an adverse effect on 
cardiovascular function other than a minimal lowering effect on BP. The degrees of reduction of 
both supine blood pressure (SBP) and diastolic blood pressure (DBP) are consistent with the 
GABAA-targeted mechanism of action of PSL and do not appear likely to have a clinically 
significant effect in therapeutic use. As a precaution from preclinical and clinical findings of 
non-clinically significant ECG abnormalities and hypotension, ECGs and vitals are being 
assessed frequently in current clinical studies. 
There is no benefit for healthy study participants to participate in this study. However, the 
information obtained from this study will inform decisions on safe and effective doses of PSL to 
be given to epileptic study participants in future studies. The Sponsor will immediately notify the 
Principal Investigator (PI) and regulatory agencies if any additional safety or toxicology 
information becomes available during the study.
2.4
Urgent safety measures
In accordance with UK Law (Medicines for Human Use [Clinical Trials] as amended: SI 1031 
Part 4 Section 30), the Sponsor and Investigator may take appropriate urgent safety measures in 
order to protect the study participants of a clinical study against any immediate hazard to their 
health or safety. If such measures are taken, the Sponsor shall immediately (no later than 3 days 
from the date the measures are taken) give written notice of the measures taken and the 
circumstances giving rise to those measures to the licensing authority and the relevant ethics 
committee.
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3
STUDY OBJECTIVES
3.1
Primary objective
The primary objective of this study is to evaluate and compare the PK of PSL in the presence and 
absence of erythromycin in healthy study participants.
3.2
Secondary objectives
The secondary objectives of this study are to: 

Assess the safety and tolerability of PSL in the presence and absence of erythromycin in 
healthy study participants

Evaluate and compare the plasma PK of PSL metabolites,
 
in the presence and absence of erythromycin in healthy study participants

Assess and compare the urine PK of PSL and its metabolites
 
and 
) in the presence and 
absence of erythromycin in healthy study participants
3.3
Exploratory objectives
The exploratory objectives of this study are to:

Estimate the inter- and intra-study participant variability in the plasma PK of PSL and its 
metabolites following administration of PSL in the presence and absence of erythromycin

Evaluate and compare the venous blood and MITRA microsampling (dried blood) PK of PSL
and its metabolite
following administration of PSL in the presence 
and absence of erythromycin

Archive blood samples for genotyping of drug metabolizing enzymes and biomarkers 
4
STUDY VARIABLES
4.1
Pharmacokinetic variables
4.1.1
Primary pharmacokinetic variables
The primary PK variables will comprise Cmax and AUC(0-12) following a single dose and Cmax,ss
and AUCτ following multiple doses of PSL in plasma:

Cmax: maximum observed plasma concentration

AUC(0-12): area under the plasma concentration-time curve from time zero to 12 hours

Cmax,ss: maximum observed steady-state plasma concentration

AUCτ: area under the curve over a dosing interval (12 hours)
4.1.2
Secondary pharmacokinetic variables
The secondary PK variables for PSL will comprise tmax, and Cmin following single dose and tmax, 
t½,ss, λz, Ctrough, and CL/Fss following multiple doses, Cmax, AUC(0-12), Cmax,ss, and AUCτ for PSL
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metabolites
, and the metabolite-to-parent ratios for 
Cmax, AUC(0-12), and AUCτ in plasma: 

tmax: time of maximum concentration

Cmin: minimum observed plasma concentration

t½,ss: apparent terminal elimination half-life at steady-state

λz: apparent elimination rate constant

Ctrough: predose observed plasma concentration

CL/Fss: apparent total clearance at steady-state
Additionally, the secondary PK variables for PSL and its metabolites 
 
 will comprise CLr, Ae, fe, and CLform in urine 
following a single dose and multiple doses:

CLr: renal clearance of PSL and its metabolites 
 

Ae: cumulative amount of PSL or metabolites excreted into the urine

fe: fraction of PSL or metabolites excreted into the urine

CLform: formation clearance of metabolites
4.1.3
Other pharmacokinetic variables
The following other PK variables will be assessed during the study:

Inter- and intra-study participant coefficients of variation (variability) in PK parameters for 
PSL and its metabolites

Pharmacokinetic parameter (and profile) data derived from venous blood with MITRA (dried 
blood) microsampling for PSL and its metabolite (only 
)
4.2
Safety variables
4.2.1
Secondary safety variables
The following secondary safety variables will be assessed during the study:

Incidence of AEs and SAEs
4.2.2
Other safety variables
The following other safety variables will be assessed during the study:

Changes in vital signs (pulse rate, BP, respiratory rate, and body temperature)

Changes in safety laboratory data (hematology, clinical chemistry, and urinalysis)

Changes in 12-lead ECG assessments

Physical examination (including neurological examination) findings
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5
STUDY DESIGN
5.1
Study description
This is a Phase 1, open-label, DDI study designed to evaluate the effect of erythromycin on the 
PK and safety of PSL and its metabolites in a single cohort of 28 healthy study participants. The 
study uses a fixed-sequence multiple-dose design per recommendation for best practice 
(Liu et al, 2016).
The study consists of 5 periods: a Screening Period, 3 Treatment Periods, and a SFU Period (see 
Figure 5‒1 for a schematic diagram).
5.2
Study periods
5.2.1
Screening Period
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 1, and a Baseline Visit, which will be 
conducted at the unit 1 day prior to Treatment Period 1.
5.2.1.1
Screening Visit (Day -28 to Day -2)
Study participants are required to sign a written Informed Consent form (ICF) prior to the 
conduct of any study-related procedure. Screening assessments will be conducted, after which 
the eligibility of study participants will be determined based on: inclusion and exclusion criteria 
(see Section 6.1 and Section 6.2, respectively); demographics (including weight and height);
medical history; full physical examination; medication history; vital sign measurements; several 
laboratory tests (hematology, serum chemistry, urinalysis, serology screening, alcohol breath 
test, cotinine test, and urine toxicology screen); triplicate 12-lead ECGs; and recording of 
AEs/medical procedures. A serum pregnancy test will be performed to assess eligibility for 
women of childbearing potential.
Study participants will also be assessed with the Columbia-Suicide Severity Rating Scale 
(C-SSRS) to assess suicidal risk.
5.2.1.2
Baseline Visit (Day -2 to Day -1)
At the Baseline Visit, study participants will check-in at the unit on Day -2 and receive a study 
participant Identification Card.
The following procedures/assessments will be repeated on Day -2: inclusion/exclusion criteria 
verification; demographics; medical history; C-SSRS; full physical examination; medication 
history; vital sign measurements; laboratory tests (hematology, chemistry profile, urinalysis, 
alcohol breath test, cotinine test, and urine toxicology screen); triplicate 12-lead ECGs; and 
recording of AEs/medical procedures. For women of childbearing potential, a serum pregnancy 
test will be performed.
Study participants will undergo the triplicate 12-lead ECG run-in on Day -1.
5.2.2
Treatment Periods
The study consists of a total of 3 Treatment Periods consisting of administration of PSL and/or 
erythromycin; Treatment Period 1 and Treatment Period 2 will be followed by a wash-out. For 
each Treatment Period, study participants will check into the unit 2 days prior to the first dosing 
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of PSL or erythromycin (Day -2, Day 10, and Day 21 for Treatment Period 1, Treatment 
Period 2, and Treatment Period 3b, respectively). Study participants will be discharged from the 
unit after the last urine sample for PK analysis is collected for each Treatment Period.
The full list of assessments to be performed at each visit is presented in Table 5-1.
During each check-in at the unit 2 days prior to PSL administration, the following 
procedures/assessments will be conducted: C-SSRS; a full physical examination; vital sign 
measurements; laboratory tests (chemistry, hematology, urinalysis, and alcohol breath, cotinine, 
and urine drug tests), and triplicate 12-lead ECGs.
For women of childbearing potential, a serum pregnancy test will be administered on Day 21 in 
Treatment Period 3a.
Administration of PSL 100mg bid during each treatment period will occur once in the morning, 
between 7AM and 10AM, and once in the evening, after the 12h postdose blood sample has been 
collected. Every effort should be made to ensure each study participant is dosed at the same 
times during the entire study. On each day of treatment, each dose will be given 30min after 
completion of a meal (see Section 7.8.3 for more details).
Adverse events will be recorded throughout the study. The Investigator will ensure that 
provisions are made for the study participants to contact the study site in case of AEs during the 
wash-out for Treatment Period 1 and Treatment Period 2. Such reporting of AEs and the 
Investigator’s response will be accurately documented, and the UCB Study Physician will be 
notified immediately. The Investigator will also ensure clear instructions are provided on 
prohibited concomitant foods and medications (see Section 7.8.2).
5.2.2.1
Treatment Period 1 and Treatment Period 2 (Day 1 to Day 11 and 
Day 12 to Day 22)
Treatment Period 1 and Treatment Period 2 each consist of 5 days of treatment, followed by 
1 week of wash-out.
During Treatment Period 1 and Treatment Period 2, study participants will receive PSL 100mg 
bid for 4 days (Day 1 to Day 4 and Day 12 to Day 15). On the fifth day (Day 5 and Day 16), 
100mg of PSL will be given as a single dose in the morning. Study participants then enter 
1 week of wash-out (from the evening of Day 5 to Day 11 and evening of Day 16 to Day 22).
Predose and postdose blood (venous and MITRA) and urine samples will be collected for PK 
analysis throughout the study (more details are provided in Section 5.3).
On Day 7 and Day 18, during the wash-out period, study participants will be discharged at the 
Investigator’s discretion. Study participants may continue being confined to the unit at the 
Investigator’s discretion. Study participants will check back into the unit on Day 10 and Day 21. 
Study participants will undergo the triplicate 12-lead ECG run-in on Day 11 and Day 22.
Study participants will be asked about the occurrence of AEs at check- in on Day 10, and via 
telephone contact on Day 20.
5.2.2.2
Treatment Period 3 (Day 23 to Day 38)
Treatment Period 3 consists of 2 erythromycin only periods (Treatment Period 3a and Treatment 
Period 3c) and a combined PSL/erythromycin treatment period (Treatment Period 3b). Study 
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participants will receive erythromycin at the same time PSL was administered in 
Treatment Period 1 and Treatment Period 2; erythromycin and PSL will be administered 
concurrently in Treatment Period 3b (see Section 5.2.2).
5.2.2.2.1
Treatment Period 3a (Day 23 to Day 25)
Study participants will receive erythromycin 500mg bid administered in the morning and in the 
evening.
5.2.2.2.2
Treatment Period 3b (Day 26 to Day 33)
Study participants will remain confined to the unit throughout Treatment Period 3b. 
Coadministration of PSL (100mg bid) and erythromycin (500mg bid) will begin on Day 26. 
Combination therapy will last for 8 days (Day 26 to Day 33). On Day 33, study participants will 
only receive a single dose of PSL 100mg in the morning, in addition to erythromycin 500mg bid.
Predose and postdose blood (venous and MITRA) and urine samples will be collected for PK 
analysis throughout the coadministration period (ie, Treatment Period 3b; see Section 5.3 for 
more details).
5.2.2.2.3
Treatment Period 3c (Day 34 to Day 38)
Study participants remain confined to the unit at the beginning of Treatment Period 3c. Study 
participants will receive erythromycin 500mg bid for the next 4 days (Day 34 to Day 37).
Study participants will be discharged on Day 38 at the Investigator’s discretion if no serious 
safety issues occur.
5.2.3
Safety Follow-Up Period
The SFU Period consists of an End of Study (EOS) Visit performed 7 to 10 days after the final
dose of erythromycin (Day 44 to Day 47) or upon discontinuation of the study. Study 
participants will have the following assessments completed at the EOS Visit: C-SSRS; a full 
physical examination; medication history; vital sign measurements; laboratory safety 
(hematology, chemistry, and urinalysis); triplicate 12-lead ECGs; and recording of AEs/medical 
procedures. A serum pregnancy test will also be administered for woman of childbearing 
potential.
5.3
Pharmacokinetic sampling
Full details regarding the collection of venous blood, microsamples of capillary blood, and urine, 
as well as samples to evaluate erythromycin levels and explore biomarkers, will be available in 
the Laboratory Manual.
5.3.1
Venous blood
Venous blood samples for PK analysis will be performed as follows:

Predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h post first dose of 
PSL during each Treatment Period (Day 1, Day 12, and Day 26)

Predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 
72h post last dose of PSL during Treatment Period 1 (Day 5) and Treatment Period 2
(Day 16)
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
Predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 
72h, 96h, and 120h post last dose of PSL during Treatment Period 3b (on the morning of 
Day 33)
Additional PK trough samples will be taken immediately prior to each morning dose of PSL 
during Treatment Period 1 (Day 2 through Day 4) and Treatment Period 2 (Day 13 through 
Day 15) and each morning combination dose during Treatment Period 3b (Day 27 through 
Day 33).
5.3.2
Microsamples of capillary blood
Samples from a finger skin prick will also be collected using the MITRA device at each of the 
time points identified for the venous blood samples in Section 5.3.1.
5.3.3
Urine
Urine samples for PK analysis will be collected as follows:

Within 1h predose and 0h to 12h post first dose of PSL during each Treatment Period (Day 1, 
Day 12, and Day 26)

0h to 12h, 12h to 24h, and 24h to 48h post last PSL dose during Treatment Period 1 (Day 5) 
and Treatment Period 2 (Day 16)

0h to 12h, 12h to 24h, 24h to 48h, 48h to 72h, and 72h to 96h post last dose of PSL during 
Treatment Period 3b (Day 33)
Urine aliquots will be taken and stored from timed urine collections described above and in 
Table 5-1. Each collection period will be completed with a full urine void. Additionally, each 
study participant will be required to void prior to the IMP dose and an aliquot will be taken as 
baseline. Full details of urine collection will be available in the Laboratory Manual.
5.4
Study duration per study participant
The total duration of study per study participant will be approximately 75 days with a maximum 
of 18 days exposure to PSL.
The end of the study is defined as the date of the last visit of the last study participant in the 
study.
5.5
Planned number of study participants and sites
A total of 28 study participants are planned to be enrolled at 1 site.
5.6
Anticipated region and country
This study will be conducted in the United Kingdom.
5.7
Schedule of study assessments
The schedule of assessments is presented in Table 5-1.
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Table 5-1:
Schedule of assessments
Assessments/ 
procedures
Screening Period
Treatment Period
SFU Period
Screen.
BL
1 and 2
3a
3b
3c
EOS
Days
Days
Days
Day
-28 to -2
-2 
to -1 a
1 b
2-3
4
5
6-11
23-25
26
27-31
32
33
34-38
44, 45, 46, 
or 47 c
12
13-14
15
16
17-22
Written Informed 
Consent
X
Inclusion/exclusion 
criteria verification
X
X
Demographics, habits, 
and lifestyle
X
X
General 
medical/psychiatric/ 
procedures history
X
X
Study participant
identification card 
assigned
X
Admit to unit d
X
X
X
Discharge from unit e
X
X
C-SSRS f
X
X
X
X
X
X
X
X
X
X
Full physical 
examination g
X
X
X
X
X
Abbreviated physical 
examination h
X
X
X
X
X
X
X
X
Prior and concomitant 
medications i
X
X
X
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Table 5-1:
Schedule of assessments
Assessments/ 
procedures
Screening Period
Treatment Period
SFU Period
Screen.
BL
1 and 2
3a
3b
3c
EOS
Days
Days
Days
Day
-28 to -2
-2 
to -1 a
1 b
2-3
4
5
6-11
23-25
26
27-31
32
33
34-38
44, 45, 46, 
or 47 c
12
13-14
15
16
17-22
Vital signs j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test k
X
X
X
X
X
Telephone contact
X l
Hematology, serum 
chemistry, urinalysis m
X
X
X
X
X
X
X
X
X
Serology (HIV, Hep B, 
and Hep C)
X
Sample collection for 
exploratory genotype or 
biomarker analysis n
X
X
X
12-lead ECG o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine and cotinine drug 
screen, alcohol breath 
test k
X
X
X
Recording of 
AEs/medical procedures
X
X
X
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Table 5-1:
Schedule of assessments
Assessments/ 
procedures
Screening Period
Treatment Period
SFU Period
Screen.
BL
1 and 2
3a
3b
3c
EOS
Days
Days
Days
Day
-28 to -2
-2 
to -1 a
1 b
2-3
4
5
6-11
23-25
26
27-31
32
33
34-38
44, 45, 46, 
or 47 c
12
13-14
15
16
17-22
Administer 
PSL 100mg
am
X
X
X
X
X
X
X
X
pm
X
X
X
X
X
X
Administer 
erythromycin 
500mg
am
X
X
X
X
X
X p
pm
X
X
X
X
X
X n
Study drug 
accountability
X
Blood sampling for PSL 
and metabolites PK 
levels
X q
X r
Urine collection for PSL 
and metabolites PK 
levels
X s
X t
Final Disposition 
Determination
X u
a The BL is defined as the 2 day period (D-2 and D-1) before D1. Day -1 is defined as 1 day before D1.
bD1 is defined as the first day of IMP administration.
c The EOS Visit will occur 7 to 10 days after the final dose of IMP is administered. The same assessments performed at the EOS Visit will be performed for a 
Withdrawal Visit, if applicable.
d Study participants will be confined to the unit beginning in the afternoon 2 days before the first PSL or erythromycin administration of each treatment period 
(D-2, D10, and D21).
e Study participants will be discharged from the unit after the last urine sample collection during each treatment period (D7, D18, and D38), at the Investigator’s 
discretion.
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f The C-SSRS will be done at Screening, when study participants are admitted to the unit (D-2, D10, and D21), before study participants are discharged from the 
unit (D7, D18, and D38), throughout Treatment Period 3b (Day 26 to Day 33), on D34 and D37 of Treatment Period 3c, and at the EOS Visit.
g A full physical examination will be performed at Screening, when study participants are admitted to the unit (D-2, D10, and D21), when study participants are 
discharged from the unit (D7, D18, and D38), and at the EOS Visit. During each treatment period, the full physical examination will be performed prior to each 
morning dosing of PSL and/or erythromycin.
h An abbreviated physical examination will be performed prior to each first PSL administration (D1, D12, and D26) of each treatment period, on D5 of 
Treatment Period 1, on D16 of Treatment Period 2, and on D24 through D37 during Treatment Period 3.
i Prior and concomitant medications will be recorded prior to morning dosing.
j Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral temperature) will be performed at Screening, when study participants are 
admitted to the unit (D-2, D10, and D21), before each morning dose of PSL and/or erythromycin throughout each treatment period, on D38, and at EOS.
k In addition to the Screening Visit, a serum pregnancy test (for women of childbearing potential only) and drug screen will be administered when study 
participants are admitted to the unit (D-2, D10, and D21). Additional serum pregnancy tests (for women of childbearing potential only) will be administered on 
D37 and at the SFU Visit.
l A telephone contact to verify any AE or concomitant treatment will occur on D9 and D20.
m Laboratory safety (hematology, chemistry, and urinalysis) will be performed after a fasting period of at least 4h only at Screening. Laboratory safety 
(non-fasting) will be performed prior to admission to the unit during each treatment period (D-1, D10, and D21), and prior to morning dosing on D4 during 
Treatment Period 1, on D15 during Treatment Period 2, and on D26, D30, D33, and D37 during Treatment Period 3, and at EOS.
n Genotype sample collection for potential exploratory analysis to be collected at predose on D1. Biomarker sample collection for potential exploratory analysis 
to be collected at predose on D1 and D12 and at 48h postdose on D1 and D12 (i.e., D3 and D14), as well as at 2h postdose on D5 and D16.
o Triplicate 12-lead ECGs will be performed after a rest of at least 5 minutes at 2- to 3-minute intervals for each of the following time points: the Screening Visit; 
D-1; D11; D38; the EOS Visit; predose, 1h, 2h, 3h and 6h postdose for each morning dose of PSL and/or erythromycin during each treatment period; and 0.5h 
predose for each evening dose of PSL and/or erythromycin during each treatment period. In addition, one day prior to first dose of PSL or erythromycin in 
Treatment Periods 1, 2 and 3 (that is, on D-1, D10, D22 and D25), triplicate 12-lead ECGs will be performed after a rest of at least 5 minutes at 2- to 3-minute 
intervals for each of the following matching time points: predose, 1h, 2h, 3h and 6h postdose for the morning administration of PSL and/or erythromycin, and 
0.5h predose for the evening administration of PSL and/or erythromycin, where dosing time is equivalent to the expected time of dosing on the subsequent day 
(the triplicate 12-lead ECG run-in day).
p Erythromycin will not be administered on D38.
q Blood samples (venous and MITRA) for PK analysis will be collected relative to the morning dose as follows: predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 
2h, 3h, 4h, 6h, 8h, and 12h postdose on D1 and D12; and predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 72h post 
last morning dose of PSL on D5 and D16. Additional PK trough samples will be taken immediately prior to each morning dose on D2 to D4
(Treatment Period 1) and D13 to D15 (Treatment Period 2). 
r Blood samples (venous and MITRA) for PK analysis will be collected relative to the morning dose as follows: predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 
2h, 3h, 4h, 6h, 8h, and 12h postdose on D26; and predose and 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, and
120h post last dose of PSL on D33. Additional PK trough samples will be taken immediately prior to each morning dose on D27 to D33 (Treatment Period 3b).
s Urine collection for PK analysis will be collected relative to the morning dose as follows: ≤1h predose and 0h to 12h post first dose on D1 and D12; and 0h to 
12h, 12h to 24h, and 24h to 48h post last PSL morning dose on D5 and D16.
t Urine collection for PK analysis will be collected relative to the morning dose as follows: ≤1h predose and 0h to 12h post first dose on D26; and 0h to 12h, 12h 
to 24h, 24h to 48h, 48h to 72h, and 72h to 96h post last dose of PSL on D33.
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u For study participants prematurely terminating or completing the study, final disposition is 7 to 10 days from final IMP dose (EOS). All study participants 
prematurely terminating from the study should be encouraged to undergo final evaluation procedures, in accordance with the EOS schedule, as soon as possible 
after the final dose of IMP.
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5.8
Schematic diagram
The study schematic diagram for UP0057 is presented in Figure 5‒1.
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Figure 5‒1: Schematic diagram
bid=twice daily; IMP=investigational medicinal product; PK=pharmacokinetic(s); PSL=padsevonil; SFU=Safety Follow-Up
a On the last day of Treatment Period 1, Treatment Period 2, and Treatment Period 3b, PSL will only be administered once in the morning.
b First and last PSL dose.
c Only after last PSL dose.
d Only after first PSL dose.
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5.9
Rationale for study design and selection of dose
Padsevonil is being administered at a dose of 100mg bid to evaluate and compare the plasma and 
urine PK, as well as the safety and tolerability profile, of PSL in the presence and absence of 
erythromycin. The plasma and urine PK of the known metabolites of PSL will also be evaluated 
and compared in the presence and absence of erythromycin. This dose has been selected to 
ensure that safety margins are not exceeded following administration of PSL with a CYP3A4 
inhibitor and that the effect of CYP2C19 auto-inhibition on PSL metabolism is achieved in 
addition to the overall effect of CYP3A4 inhibition. In addition, 100mg is 1 of the doses planned 
to be investigated in the dose-ranging study, EP0091. Erythromycin given at a dose of 500mg 
bid is expected to increase exposure to PSL by approximately 3.7-fold (SimCYP simulations).
6
SELECTION AND WITHDRAWAL OF STUDY 
PARTICIPANTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met: 
1. Study participant is informed and given ample time and opportunity to think about his/her
participation and has signed and dated the written ICF approved by an Independent Ethics 
Committee (IEC).
2. Study participant is considered reliable and capable of adhering to the protocol and visit 
schedule according to the judgment of the investigator.
3. Study participant is male or female and between 18 and 55 years of age (inclusive).
4. Study participant is of a body weight of at least 50kg for males and 45kg for females, as 
determined by a body mass index (BMI) between 18 and 30kg/m2.
5. Study participant is in good physical and mental health as determined on the basis of the 
medical history and general physical examination (ie, study participant has no current or past 
medical history of clinical significance).
6. Female study participants use an efficient form of contraception for the duration of the study 
(unless menopausal [defined as no menses for 12 months without an alternative medical 
cause]; a high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy). Hormonal contraception may be susceptible to an interaction with the 
IMP, which may reduce the efficacy of the contraception method. The potential for reduced 
efficacy of any hormonal contraception methods requires that a barrier method (preferably 
male condom) also be used.
Birth control methods considered as an efficient form of contraception:

Combined (oestrogen and progestogen containing) hormonal contraception (oral, implant, 
or injectable) associated with inhibition of ovulation in combination with a barrier 
method (preferably male condom)

Progestogen-only hormonal contraception associated with inhibition of ovulation in 
combination with a barrier method (preferably male condom)
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
Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) in combination with a barrier method 
(preferably male condom)

Bilateral tubal occlusion

Vasectomized partner

Sexual abstinence
True abstinence is an acceptable form of contraception when this is in line with the 
preferred and usual lifestyle of the person. Periodic abstinence (eg, calendar ovulation,
symptothermal, postovulation methods), declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception.

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action in combination with a barrier method (preferably male condom)

Male or female condom with spermicide (ie, double barrier)

Cap, diaphragm, or sponge with spermicide
To ensure proper birth control, females who use hormonal contraception should use an 
efficient barrier contraceptive in the 3 months following the end of the study (ie, for 
3 months after the last intake of study medication).
7. Study participant has clinical laboratory test results within the local reference ranges or 
values are considered as not clinically relevant by the investigator and approved by the UCB 
Study Physician. Lab parameters outside the reference ranges can be retested and if the retest 
result is within the reference range or considered as clinically not relevant the study 
participant will be allowed in the study. Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or alkaline phosphatase (ALP) should be within the normal limits. 
Liver enzymes up to 25% above the upper limit may be repeated once and should be within 
normal limits before inclusion. 
8. Study participant has BP and pulse rate within normal range in supine position after 
10 minutes of rest (SBP: 90 to 140mmHg, DBP: 40 to 90mmHg, pulse rate: 40 to 100bpm). 
In case of an out of range result, 1 repeat will be allowed. If out of range again, the study 
participant cannot be included.
9. Male study participant agrees that, during the study period, when having sexual intercourse 
with a woman of childbearing potential, he will use an efficient barrier contraceptive 
(condom plus spermicide) AND that the respective partner will use an additional efficient 
contraceptive method (eg, oral pills, IUDs, or diaphragm, and spermicide).
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6.2
Exclusion criteria
Study participants are not permitted to enroll in the study if any of the following criteria is met:
1. Study participant has previously received IMP in this study.
2. Study participant has participated in another study of an IMP (or a medical device) within the 
previous 3 months before Screening (or within 5 half-lives for the IMP, whichever is longer) 
or is currently participating in another study of an IMP (or a medical device).
3. Study participant has a history of drug or alcohol dependency within the previous 6 months 
or tests positive for alcohol (breath test) and/or drugs of abuse (urine test) at the Screening 
Visit.
4. Study participant has a current or past psychiatric condition that, in the opinion of the 
Investigator, could compromise his/her safety or ability to participate in this study or a 
history of schizophrenia, or other psychotic disorder, bipolar disorder, or severe unipolar 
depression. The presence of potential psychiatric exclusion criteria will be determined based 
on the psychiatric history collected at Screening.
5. Study participant has a lifetime history of suicide attempt (including an 
 
), or 
 as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Screening/Baseline” version of the C-SSRS at Screening.
6. Study participant has any medical condition that, in the opinion of the Investigator, could 
jeopardize or would compromise the study participant’s ability to participate in this study.
7. Study participant has a known hypersensitivity to any components of the IMP as stated in 
this protocol. 
8. Study participant has made a blood or plasma donation or has had a comparable blood loss 
(>400mL) within the last 3 months prior to the Screening Visit.
9. Study participant has a consumption of more than 3 units of alcohol/day in case of females, 
more than 4 units of alcohol/day in case of males.
10. Study participant smokes more than 5 cigarettes per day (or equivalent) or has done so within 
6 months prior to the Screening Visit.
11. Study participant has a consumption of more than 600mg of caffeine/day (200mL of coffee 
contains approximately 100mg of caffeine, 200mL of black tea approximately 30mg, and 
200mL of cola approximately 20mg). 
12. Study participant has a diet, which deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the investigator (eg, vegetarians or vegans). 
13. Study participant is taking any concomitant medication currently or within 2 weeks prior to 
the first day of dosing with the exception of paracetamol (acetaminophen) which is allowed 
to be taken orally up to 1000mg per dose (up to 2000mg per day). 
14. Study participant has received any prescription or nonprescription medicines, including 
enzyme inhibitors or inducers, over-the-counter (OTC) remedies, herbal and dietary 
supplements (including St. John’s Wort), vitamins up to 2 weeks or 5 half-lives of the 
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respective drug (whichever is longer) before the first administration of IMP and during the 
clinical part of the study, unless required to treat an AE. This does not include oral 
contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal hormone replacement 
therapy or implants, patches, or IUDs/IUSs delivering progesterone (for female study 
participants). 
15. Study participant tests positive for human immunodeficiency virus 1/2 antibodies 
(HIV-1/2-Ab), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (HCV-Ab). 
16. Study participant has > upper limit of normal (ULN) of any of the following: ALT, AST, 
ALP, or total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If study 
participant has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate 
bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%). To 
be enrolled, study participants must have ALT, AST, or ALP values within the ULN.
17. Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. If out of range again, the study participant cannot be included.
18. Study participant has clinically relevant out-of-range values for hematology, and clinical 
chemistry, or urinalysis variables at the Screening Visit. 
19. Study participant has any clinically significant abnormal physical examination and vital signs 
at the Screening Visit or confinement. 
20. Study participant has any clinically relevant ECG finding at the Screening Visit or 
confinement. Study participant has an abnormality in the 12-lead ECG that, in the opinion of 
the investigator, increases the risks associated with participating in the study. In addition, any 
study participant with any of the following findings will be excluded: (a) QT interval 
corrected for heart rate using Bazett’s formula (QTcB) or Fridericia’s formula (QTcF)
>450ms in 2 of 3 ECG recordings; (b) other conduction abnormalities (defined as PR interval 
≥220ms); (c) irregular rhythms other than sinus arrhythmia or occasional, rare 
supraventricular or rare ventricular ectopic beats. In case of an out of range result, 1 repeat 
will be allowed. If out of range again, the study participant cannot be included.
21. Study participant performs heavy physical exertion less than 3 days before confinement.
22. Study participant has a history within the last 5 years or present condition of malignancy, 
with the exception of basal cell carcinoma. 
23. Study participant ingests grapefruit (as beverage, fruit, or supplements) within 72 hours 
before each administration of IMP. If this is the case at the start of the study, study 
participants may be rescreened. 
24. Female study participant tests positive for pregnancy, plans to get pregnant during the 
participation in the study, or who is breastfeeding.
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6.3
Withdrawal criteria
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care.
Study participants must be withdrawn from the study if any of the following events occur:
1. Study participant develops a clinically relevant medical condition (or laboratory parameter) 
that, in the opinion of the Investigator, jeopardizes or compromises the study participant’s
ability to participate in this study or makes it unsafe to continue (for example a psychiatric 
event).
2. Study participant withdraws his/her consent.
3. The Sponsor or a regulatory agency requests withdrawal of the study participant.
4. An ECG shows an absolute QTcF value >500ms or >60ms prolongation above Baseline 
(defined as the mean of triplicate ECG taken at predose on Day 1, Day 12, Day 23 or 
Day 26) in 1 or more ECG recordings.
5. Study participant develops second- or third-degree atrioventricular block or another clinically 
relevant change in ECG results as determined by the Investigator.
6. Refer to Section 6.4.1 for withdrawal criteria in relation to potential drug-induced liver injury 
(PDILI).
7. Study participant tests positive for pregnancy at any point during the study.
Study participants may be withdrawn from the study if any of the following events occur:
8. Study participant is noncompliant with the study procedures or IMP in the opinion of the 
Investigator.
9. Study participant takes prohibited concomitant medications as defined in this protocol.
If the withdrawal occurs following dosing with IMP, the study participant will be asked to return 
for the EOS Visit 7 to 10 days after last intake of IMP.
The Investigator should attempt to obtain information on study participants in the case of 
withdrawal or discontinuation. For study participants considered as lost to follow up, the 
Investigator should make an effort (at least 1 phone call and 1 written message to the study 
participant), and document his/her effort (date and summary of the phone call and copy of the 
written message in the source documents), to complete the final evaluation. All results of these 
evaluations and observations, together with a narrative description of the reason(s) for removing 
the study participant, must be recorded in the source documents. The electronic Case Report 
form (eCRF) must document the primary reason for withdrawal or discontinuation.
Investigators should contact the Sponsor Study Physician, whenever possible, to discuss the 
withdrawal of a study participant in advance.
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6.4
Stopping rules
Dosing should be stopped in case of:

A serious adverse reaction (AR) (ie, an SAE considered at least possibly related to the IMP 
administration) in 1 study participant

Any severe nonserious AR (ie, severe nonserious AEs considered as, at least, possibly related 
to the IMP administration) in 2 study participants
In the event that the stopping criteria are reached, the Investigator will ensure all necessary 
actions at the site are taken to prevent further administration of IMP to any study participant. 
Subsequently an internal UCB safety review meeting (Safety Monitoring Committee) will be 
organized.
If, following the internal safety review, it is appropriate to continue the study with or without 
dose adaptations, potential additional safety assessments, or changes in design, a substantial 
amendment will be submitted to the Medicines and Healthcare products Regulatory Agency 
(MHRA) and Research Ethics Committee (REC). The study will not restart until the amendment
has been approved by the MHRA and REC.
6.4.1
Potential drug-induced liver injury investigational medicinal product
discontinuation criteria
Study participants with PDILI must be assessed to determine if IMP must be discontinued. In 
addition, all concomitant medications and herbal supplements that are not medically necessary 
should also be discontinued. 
The PDILI criterion below requires immediate and permanent discontinuation of IMP: 

Study participants with ≥3xULN ALT or AST
Evaluation of PDILI must be initiated as described in Section 10.2.1. If study participants are 
unable to comply with the applicable monitoring schedule, IMP must be discontinued 
immediately.
Investigators should attempt to obtain information on study participants in the case of IMP 
discontinuation to complete the final evaluation. Study participants with PDILI should not be 
withdrawn from the study until investigation and monitoring are complete. All results of these
evaluations and observations, as well as the reason(s) for IMP discontinuation and study 
participant withdrawal (if applicable), must be recorded in the source documents. The eCRF 
must document the primary reason for IMP discontinuation.
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7
STUDY TREATMENTS
7.1
Description of investigational medicinal products
Padsevonil (25mg tablets) will be supplied by UCB.
Erythromycin (500mg tablets) will be supplied by the study site.
7.2
Treatments to be administered
Padsevonil 100mg (as 4 tablets of 25mg) and/or erythromycin 500mg tablets will be 
administered orally with 8oz (240mL) water, 30min after a light or standard meal (more details 
are provided in Section 7.8.3).
Treatments will be administered in an open-label fashion. Study participants will be dosed in an 
upright position and should remain semi-recumbent until 4 hours afterwards.
7.3
Packaging
Padsevonil tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations.
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Council for
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements.
7.5
Handling and storage requirements
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the Investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label.
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval.
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual.
7.6
Drug accountability
A Drug Accountability form will be used to record IMP dispensing information on a by-study 
participant basis and will serve as source documentation during the course of the study. Details 
of any IMP lost, damaged (due to breakage or wastage), not used, partially used, or disposed of 
at the study site must also be recorded on the appropriate forms. All supplies and pharmacy 
documentation must be made available throughout the study for UCB (or designee) to review.
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until destroyed.
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee.
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The Investigator must ensure that the IMP is used only in accordance with the protocol.
Periodically, and/or after completion of the clinical period of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and 
destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedures (SOPs). Investigational medicinal product intended for the study cannot be used for 
any other purpose than that described in this protocol.
More information regarding IMP destruction is provided in the IMP Handling Manual.
7.7
Procedures for monitoring study participant compliance
Administration of PSL or erythromycin will be performed under the supervision of the 
Investigator (or designee), and the Investigator (or designee) will check the study participant’s
hands and the oral cavity immediately after dosing to confirm ingestion of the IMP. Compliance 
will be monitored by drug accountability and by drug assay (using the drug concentration in the 
blood). Compliance with the IMP is defined as consumption by the study participant that 
conforms 100% with the planned dosage.
Drug administration/consumption will be recorded and any discrepancies with the dosing 
regimen must be explained.
7.8
Concomitant medications/treatments
7.8.1
Permitted concomitant treatments (medications and therapies)
The use of concomitant medications during this study should be avoided, unless necessary to 
treat AEs or approved on a case by case basis prior to enrollment (eg, hormonal contraceptives) 
The use of any concomitant medications should be approved by the Sponsor in advance, in 
writing, when possible. 
7.8.2
Prohibited concomitant treatments (medications and therapies)
With the exception of paracetamol up to 1000mg per dose (up to 2000mg per day), all 
prescription or nonprescription medicines are prohibited within 2 weeks prior to the first day of 
dosing. This includes enzyme inhibitors or inducers (eg, strong inhibitors or inducers of 
CYP3A4 or CYP2C19), OTC remedies, vitamins, and herbal and dietary supplements (including 
St. John’s Wort) that are prohibited within 2 weeks or 5 half-lives of the respective drug 
(whichever is longer) before first administration of IMP and during the clinical part of the study, 
unless required to treat an AE. This does not include oral contraceptives not exceeding 30μg 
ethinyl estradiol or postmenopausal hormone replacement therapy or implants, patches, or 
IUDs/IUSs delivering progesterone (for female study participants). Drugs of unknown half-lives 
are prohibited within 2 weeks before administration of IMP 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.
7.8.3
Diet, fluid, and activity control
During each treatment period, study participants will complete a light meal 30min prior to each 
morning dose of IMP, and a standard meal 30min prior to each evening dose of IMP. On the 
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ECG run-in days where study participants do not receive IMP (that is, Day -1, Day 11, and 
Day 22, see Section 10.3.3), study participants will receive a light meal in the morning and a 
standard meal in the afternoon and evening at approximately the same time as it is expected to be 
given on the subsequent dosing days.
Study participants should keep their usual diet (besides the restrictions for the study) necessary 
for the maintenance of good health; excessive food consumption should be avoided. Study 
participants should refrain from heavy physical exertion (eg, vigorous exercise) from 3 days 
prior to (first) confinement and during the study.
Study participants should not consume more than 3 units alcohol/day (females) and 4 units 
alcohol/day (males), or 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) from 48 hours prior to each administration of PSL and until the final PK 
plasma sampling of each dosing period.
Grapefruit (as beverage, fruit, or supplements) within 72 hours before each administration of 
IMP will not be allowed. If this is the case at start of study, study participants may be rescreened.
Study participants must refrain from donating blood or plasma during the course of the study 
(except for the samples taken for the purpose of the study) and should refrain from donating 
blood or plasma for at least 3 months prior to the Screening Visit and until 2 months after the end 
of the study.
Water will be available ad libitum except for between 1 hour before and 2 hours after dosing. A 
total of 240mL of water will be given to each study participant at the time of administration of 
IMP.
7.9
Blinding
UP0057 is an open-label study; thus, there will be no blinding.
7.10
Numbering of study participants
Each study participant will receive a unique 5-digit number assigned at Screening that serves as 
the study participant identifier throughout the study. If the study participant withdraws or is 
withdrawn from the study, this number will not be reassigned to another study participant.
8
STUDY PROCEDURES BY VISIT
8.1
Screening Period (Day -28 to Day -1)
8.1.1
Screening Visit (Day -28 to Day -2)
The Screening Visit will be conducted at the unit within 28 days prior to check-in for 
Treatment Period 1. The following procedures/assessments will be performed:

Written Informed Consent

Inclusion/exclusion criteria verification

Demographics, habits, and lifestyle

General medical/psychiatric/procedures history
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
C-SSRS (Baseline)

Full physical examination

Prior and concomitant medications

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature)

Blood and urine samples for the following clinical laboratory tests will be collected:

Serum pregnancy test (for women of childbearing potential only)

Hematology, serum chemistry, and urinalysis

Serology screening

Urine and cotinine drug screen

Alcohol breath test

Triplicate 12-lead ECGs

Recording of AEs/medical procedures
8.1.2
Baseline Visit (Day -2 to Day -1)
Study participants will check into the unit 2 days prior to dosing and will be assigned their study 
participant identification card. The following procedures/assessments will be performed on 
Day -2: 

Inclusion/exclusion criteria verification

Demographics, habits, and lifestyle

General medical/psychiatric/procedures history

C-SSRS

Full physical examination

Prior and concomitant medications

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature)

Blood and urine samples for the following clinical laboratory tests will be collected:

Serum pregnancy test (for women of childbearing potential only)

Hematology, serum chemistry, and urinalysis

Urine and cotinine drug screen

Alcohol breath test

Triplicate 12-lead ECGs

Recording of AEs/medical procedures
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The following procedures/assessments will be performed on Day -1:

Triplicate 12-lead ECGs (run-in day):

Morning: Predose, 1h, 2h, 3h, and 6h postdose (where dosing time is equivalent to the 
expected time of dosing on the subsequent day)

Evening: approximately 0.5h predose (where dosing time is equivalent to the expected 
time of dosing on the subsequent day)
8.2
Treatment Period 1 (Day 1 to Day 5) and Treatment Period 2
(Day 12 to Day 16)
Study participants will check into the unit on Day -2 in Treatment Period 1 and Day 10 in 
Treatment Period 2, 2 days prior to the first dosing of PSL (Day 1 for Treatment Period 1 and 
Day 12 for Treatment Period 2).
All morning doses will be administered between 7AM and 10AM, 30min after completion of a 
light meal. When applicable, evening doses will be administered after the 12h postdose blood 
sample has been collected, 30min after completion of a standard meal. Every effort should be 
made to ensure each study participant is dosed at the same times during the entire study.
8.2.1
Day 1 (Treatment Period 1) and Day 12 (Treatment Period 2)
Study participants will receive PSL 100mg bid. The following procedures/assessments will be 
performed:

Abbreviated physical examination prior to morning dosing

Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Genotype (predose)

Biomarker sample (predose)

Blood samples (venous and MITRA) for PK analysis (relative to morning dosing)

Predose

Postdose: 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h

Urine samples for PK analysis (relative to morning dosing)

Predose (≤1h before dosing)

Postdose: 0 to 12h

Triplicate 12-lead ECGs

Morning dose: Predose, 1h, 2h, 3h, and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
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8.2.2
Day 2 to Day 3 (Treatment Period 1) and Day 13 to Day 14 
(Treatment Period 2)
Study participants will receive PSL 100mg bid. The following procedures/assessments will be 
performed:

Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Biomarker sample on Day 3 and Day 14 (at 48h postdose Day 1)

Blood samples for PK trough analysis will be collected immediately prior to morning dosing

Triplicate 12-lead ECGs

Morning dose: Predose,1h, 2h, 3h, and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.2.3
Day 4 (Treatment Period 1) and Day 15 (Treatment Period 2)
Study participants will receive PSL 100mg bid. The following procedures/assessments will be 
performed:

Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Blood and urine samples for the following clinical laboratory tests will be collected prior to 
morning dosing:

Hematology, serum chemistry, and urinalysis

Blood samples for PK trough analysis will be collected prior to morning dosing

Triplicate 12-lead ECGs

Morning dose: Predose, 1h, 2h, 3h and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.2.4
Day 5 (Treatment Period 1) and Day 16 (Treatment Period 2)
Study participants will receive PSL 100mg once in the morning. The following 
procedures/assessments will be performed:

Abbreviated physical examination

Prior and concomitant medications recorded prior to morning dosing
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
Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Biomarker sample: 2h postdose

Blood samples (venous and MITRA) for PK analysis

Predose

Postdose: 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, and 
72h

Urine samples for PK analysis

Postdose: 0 to 12h, 12h to 24h, and 24h to 48h

Triplicate 12-lead ECGs

Morning dose: Predose, 1h, 2h, 3h, and 6h postdose 

Recording of AEs/medical procedures
8.3
Wash Out (Day 6 to Day 11 for Treatment Period 1; Day 17 to 
Day 22 for Treatment Period 2)
After the procedures and assessments are completed following the morning dose on Day 5, study 
participants enter a 1-week wash-out period.
Study participants will check-in to the unit on Day 10 and Day 21 and undergo the following 
procedures/assessments on Day 11 and Day 22:

Triplicate 12-lead ECGs (run-in day):

Morning: Predose, 1h, 2h, 3h, and 6h postdose (where dosing time is equivalent to the 
expected time of dosing on the subsequent day)

Evening: approximately 0.5h predose (where dosing time is equivalent to the expected 
time of dosing on the subsequent day)
8.3.1
Day 6 (Treatment Period 1) and Day 17 (Treatment Period 2)
Study participants will remain at the unit and receive the following procedures/assessments:

Prior and concomitant medications

Blood samples (venous and MITRA) for PK analysis (24h and 36h after dosing on Day 5 and 
Day 16, see Section 8.2.4)

Urine samples for PK analysis (24h to 48h after dosing on Day 5 and Day 16, see 
Section 8.2.4)

Recording of AEs/medical procedures
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8.3.2
Day 7 (Treatment Period 1) and Day 18 (Treatment Period 2)
After the following procedures and assessments, study participants will be discharged from the 
unit, provided there are no clinically significant safety issues that require extended supervision in 
the opinion of the PI:

C-SSRS

Full physical examination

Prior and concomitant medications

Blood samples (venous and MITRA) for PK analysis (48h after dosing on Day 5 and Day 16, 
see Section 8.2.4)

Urine samples for PK analysis (24h to 48h after dosing on Day 5 and Day 16, see 
Section 8.2.4)

Recording of AEs/medical procedures
8.3.3
Day 8 (Treatment Period 1) and Day 19 (Treatment Period 2)
Study participants will return to the unit for the following procedures/assessments:

Prior and concomitant medications

Blood (venous and MITRA) for PK analysis (72h after dosing on Day 5 and Day 16, see 
Section 8.2.4)

Recording of AEs/medical procedures
8.3.4
Day 9 to Day 10 (Treatment Period 1) and Day 20 to Day 22 
(Treatment Period 2)
Study participants will check back into the unit on Day 10 and Day 21. Study participants will be 
asked about the occurrence of AEs at check-in on Day 10, and via telephone contact on Day 20.
8.3.5
Day 10 (Treatment Period 1) and Day 21 (Treatment Period 2)
Study participants will check into the unit of Day 10 and Day 21, 2 days prior to receiving the 
first dose in Treatment Period 2 (on Day 12) and Treatment Period 3 (Day 23). The following 
procedures/assessments will be performed on Day 10 and Day 21: 

C-SSRS

Full physical examination

Prior and concomitant medications

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature)

Blood and urine samples for the following clinical laboratory tests will be collected:

Serum pregnancy test (for women of childbearing potential only)

Hematology, serum chemistry, and urinalysis
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
Urine and cotinine drug screen

Alcohol breath test

Triplicate 12-lead ECGs

Recording of AEs/medical procedures
Study participants will undergo the triplicate 12-lead ECG run-in on Day 11 and Day 22
(see Section 8.3).
8.4
Treatment Period 3 (Day 23 to Day 37)
Study participants will check into the unit on Day 21, 2 days prior to receiving the first dose of 
erythromycin on Day 23 in Treatment Period 3. Study participants will undergo the triplicate 12-
lead ECG run-in on Day 22 (see Section 8.3). Treatment Period 3 consists of 2 erythromycin 
only periods (Treatment Period 3a and Treatment Period 3c) and a combined PSL/erythromycin
treatment period (Treatment Period 3b).
All morning doses will be administered between 7AM and 10AM, 30min after completion of a 
light meal. When applicable, evening doses will be administered after the 12h postdose blood 
sample has been collected, 30min after completion of a standard meal. Every effort should be 
made to ensure each study participant is dosed at the same times during the entire study.
8.4.1
Treatment Period 3a (Day 23 to Day 25)
Study participants will receive erythromycin 500mg bid administered in the morning and in the 
evening.
8.4.1.1
Day 23 to Day 25
The following procedures/assessments will be performed:

Prior and concomitant medications recorded prior to morning dosing

Abbreviated physical exam prior to morning dosing 

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Triplicate 12-lead ECGs

Morning dose: Predose, 1h, 2h, 3h and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.4.2
Treatment Period 3b (Day 26 to Day 33)
Study participants will be confined to the unit for the duration of Treatment Period 3b. 
Padsevonil 100mg bid will be coadministered with erythromycin 500mg bid on Day 26 to 
Day 32 during Treatment Period 3b. On Day 33, PSL 100mg will be coadministered with 
erythromycin 500mg in the morning, and only erythromycin 500mg will be administered in the 
evening.
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8.4.2.1
Day 26
The following procedures/assessments will be performed:

C-SSRS prior to morning dosing

Abbreviated physical exam prior to morning dosing

Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Blood and urine samples for the following clinical laboratory tests will be collected prior to 
morning dosing:

Hematology, serum chemistry, and urinalysis

Blood samples (venous and MITRA) for PK analysis (relative to morning dosing)

Predose

Postdose: 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h

Urine samples for PK analysis (relative to morning dosing)

Predose (≤1h before dosing)

Postdose: 0 to 12h

Triplicate 12-lead ECGs

Morning dose: Predose,1h, 2h, 3h and 6h postdose

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.4.2.2
Day 27 to Day 32
The following procedures/assessments will be performed:

C-SSRS prior to morning dosing

Abbreviated physical examination prior to morning dosing

Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Blood and urine samples for the following clinical laboratory tests will be collected (on 
Day 30 only):

Hematology, serum chemistry, and urinalysis

Blood samples for PK trough analysis will be collected prior to morning dosing

Urine samples for PK analysis (relative to morning dosing; see Section 8.4.2.1)
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
Triplicate 12-lead ECGs

Morning dose: Predose,1h, 2h, 3h, and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.4.2.3
Day 33
The following procedures/assessments will be performed:

C-SSRS prior to morning dosing

Abbreviated physical examination prior to morning dosing

Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Blood and urine samples for the following clinical laboratory tests will be collected:

Hematology, serum chemistry, and urinalysis

Blood samples (venous and MITRA) for PK analysis (relative to morning dosing)

Predose

Post last morning combination dose: 0.25h, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 6h, 
8h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, and 120h

Urine samples for PK analysis (relative to morning dosing)

Post last morning combination dose: 0 to 12h, 12h to 24h, 24h to 48h, 48h to 72h, and 
72h to 96h

Triplicate 12-lead ECGs

Morning dose: Predose, 1h, 2h, 3h, and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.4.3
Treatment Period 3c (Day 34 to Day 38)
Study participants will be confined to the unit until Day 37 during Treatment Period 3c. During 
Treatment Period 3c, study participants will receive only erythromycin 500mg bid from Day 34 
to Day 37. On Day 38, study participants will be discharged from the unit after completing the 
procedures and assessments.
8.4.3.1
Day 34 to Day 37
The following procedures/assessments will be performed:

C-SSRS prior to morning dosing (Day 34 and Day 37 only)

Abbreviated physical exam prior to morning dosing
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
Prior and concomitant medications recorded prior to morning dosing

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature) prior to morning dosing

Blood and urine samples for the following clinical laboratory tests will be collected (on 
Day 37 only):

Serum pregnancy test (for women of childbearing potential only)

Hematology, serum chemistry, and urinalysis

Blood (venous and MITRA) and urine samples for PK analysis (see Section 8.4.2.3)

Triplicate 12-lead ECGs

Morning dose: Predose, 1h, 2h, 3h and 6h postdose 

Evening dose: approximately 0.5h predose

Recording of AEs/medical procedures
8.4.3.2
Day 38
The following procedures/assessments will be performed prior to discharge:

Prior and concomitant medications

C-SSRS

Full physical exam

Prior and concomitant medications

Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature)

Triplicate 12-lead ECGs

Blood samples (venous and MITRA) for PK analysis (see Section 8.4.2.3)

Recording of AEs/medical procedures
After the procedures and assessments, study participants will be discharged from the unit 
provided there are no clinically significant safety issues that require extended supervision in the 
opinion of the Investigator.
8.5
Safety Follow-Up Period (7 to 10 days from final dose)
8.5.1
End of Study Visit (Day 44, Day 45, Day 46, or Day 47)
The following procedures/assessments will be performed 7 to 10 days after last dose of 
erythromycin or upon discontinuation of the study (EOS Visit):

C-SSRS

Full physical examination

Prior and concomitant medications
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
Vital signs (including systolic and diastolic BP, pulse rate, respiration rate, and oral 
temperature)

Blood and urine samples for the following clinical laboratory tests will be collected:

Serum pregnancy test (for women of childbearing potential)

Hematology, serum chemistry, and urinalysis

Triplicate 12-lead ECGs

Recording of AEs/medical procedures
8.6
Withdrawal Visit
Study participants who withdraw from the study for any reason after the first dose, but prior to 
the SFU Visit, will be asked to return to the unit to complete a Withdrawal Visit 
(7 days ± 2 days, postdose). The same assessments as for the EOS Visit (see Section 8.5) will be 
performed. Study participants who withdraw between enrollment and first dose will be followed 
up only at the discretion of the Investigator. 
8.7
Unscheduled visit
At the Investigator’s discretion, an Unscheduled Visit may be completed at any time during the 
study if deemed necessary for the study participant’s safety and wellbeing. The assessments to be 
conducted during an Unscheduled Visit will be based on the Investigator’s judgement.
9
ASSESSMENT OF PHARMACOKINETIC VARIABLES
9.1
Pharmacokinetic variables
The PK variables are described in detail in Section 4.1. Calculations of PK variables will be 
made with Phoenix WinNonlin (version 6.3 or higher) using actual sampling times. The linear 
trapezoidal method will be used to calculate the AUC parameters. For details of PK analyses, 
refer to Section 12.3.
Detailed information on the collection, storage, preparation, and shipping of samples will be 
presented in a bioanalytical report.
9.2
Pharmacokinetic sampling procedures
Study participants are requested to provide blood samples for measurement of PSL levels using 
the VAMS technology on the MITRA microsampling device.
9.2.1
Blood pharmacokinetic sampling scheme
Serial blood samples for PK analysis of PSL and its metabolites (venous and MITRA) will be 
collected as described in Section 5.3 and Table 5-1.
The total blood volume collected for the study will not exceed 500mL per study participant.
Exact sampling times will be recorded in the eCRF.
All sample handling procedures, including the time of each sample collection, the start and stop 
time of centrifugation and placement into frozen storage (at the end of the sample workup), and 
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the date of transfer or shipment of the samples to the responsible analyst will be documented in 
detail.
Time deviations from scheduled sampling times will be discussed at the Data Review Meeting.
Full details of sample handling and processing are provided in the Laboratory Manual.
The maximum deviations from scheduled sampling times considered irrelevant for PK are 
defined in Table 9‒1.
Table 9‒1:
Irrelevant time deviations for PK sampling
PK blood sampling times
Deviation from scheduled time considered irrelevant
0 hours (predose)
Within 60 minutes 
0.25 to 1.5 hours
2 minutes
2 to 8 hours
5 minutes
12 hours
15 minutes
24 to 48 hours
60 minutes
PK=pharmacokinetic
9.2.2
Urine pharmacokinetic sampling scheme
Full details of urine collection will be available in the Laboratory Manual.
All aliquots will be stored pending potential assay for parent and metabolites depending on the 
outcome of the blood PK analysis.
9.3
Shipment procedures
Details of the PK samples labelling and shipment procedures will be provided in the Laboratory 
Manual.
9.4
Communication plan
A communication plan dedicated to PK laboratory activities (at the least) will be established in a 
separate document.
9.5
Bioanalytical method
Plasma concentration of PSL and metabolites will be determined with a validated bioanalytical 
method. Plasma and blood concentration of parent PSL collected by MITRA devices 
respectively will be determined with a scientific validated bioanalytical method.
10
ASSESSMENT OF SAFETY
10.1
Adverse events
10.1.1
Definitions
10.1.1.1
Adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation study participant
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
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abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that 
recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the study participant’s history or Screening Period.
10.1.1.2
Serious adverse event
Once it is determined that a study participant experienced an AE, the seriousness of the AE must 
be determined. An SAE must meet 1 or more of the following criteria:

Death

Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.)

Significant or persistent disability/incapacity

Congenital anomaly/birth defect (including that occurring in a fetus)

Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or study participant and may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the definition of serious
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 10.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.)

Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
study participant has a condition recorded on his/her medical history and later has a 
preplanned surgery for this condition, it is not appropriate to record the surgery or 
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hospitalization as an SAE, since there is no AE upon which to assess the serious criteria. 
Please note that, if the pre-existing condition has worsened or manifested in an unusual or 
uncharacteristic manner, this would then qualify as an AE and, if necessary, the seriousness 
of the event would need to be determined).
10.1.1.2.1
Anticipated serious adverse events
No SAEs are anticipated to occur in the population studied in this protocol. 
10.1.1.3
Adverse events of special interest
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. No AEs of special interest have been identified for 
PSL to date, with the exception of potential Hy’s Law as described below.
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow-up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
study participant.
10.1.2
Procedures for reporting and recording adverse events
The study participant will be given the opportunity to report AEs spontaneously. A general 
prompt will also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
10.1.2.1
Description of adverse events
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the study participant’s 
own words on his/her own records (eg, diary card) and the corresponding medical terminology 
should be clarified in the source documentation.
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) 
are described in the eCRF Completion Guidelines.
10.1.2.2
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:

The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”

The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one
10.1.2.3
Additional procedures for reporting serious adverse events
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
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section at the front of the protocol). The Investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database.
An Investigator SAE report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English. 
It is important for the Investigator, when completing the SAE report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE report form.
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each study participant, and to also inform participating 
study participants of the need to inform the Investigator of any SAE within this period. Serious 
AEs that the Investigator thinks may be associated with the IMP must be reported to UCB 
regardless of the time between the event and the end of the study.
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the IB.
10.1.3
Follow up of adverse events
An AE should be followed until it has resolved, has a stable sequelae, the Investigator
determines that it is no longer clinically significant, or the study participant is lost to follow up. 
This follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events is provided in Section 10.2.1.4.
If an AE is ongoing at the end of the study for a study participant, follow up should be provided 
until resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that 
it is clinically significant, or until the study participant is lost to follow up. If no follow up is 
provided, the Investigator must provide a justification. The follow up will usually be continued 
for 30 days after the study participant has discontinued his/her IMP.
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time.
10.1.4
Pregnancy
If an Investigator is notified that a study participant has become pregnant after the first intake of 
any IMP, the Investigator must immediately notify UCB’s PS department by providing the 
completed Pregnancy Report and Outcome form (for contact details see Serious Adverse Event 
reporting information at the beginning of this protocol). The study participant should be 
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withdrawn from the study as soon as pregnancy is known (by positive pregnancy test), and the 
following should be completed:

The study participant should immediately stop the intake of the IMP.

The study participant should return for an EOS Visit 7 to 10 days after the study participant 
has discontinued her IMP.
The Investigator must inform the study participant of information currently known about 
potential risks and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the study participant is lost to follow up and/or refuses to give information, written 
documentation of attempts to contact the study participant needs to be provided by the 
Investigator and filed at the site. UCB’s PS department is the primary contact for any questions 
related to the data collection for the pregnancy, eventual birth, and follow up.
In cases where the partner of a male study participant enrolled in a clinical study becomes 
pregnant, the Investigator or designee is asked to contact the study participant to request consent 
of the partner via the Partner Pregnancy Consent form that has been approved by the responsible 
IEC and should be available in the Investigator site file. In case of questions about the consent 
process, the Investigator may contact Parexel/Hammersmith Medicines Research contract 
monitor for the study. The Investigator will complete the Pregnancy Report and Outcome form 
and send it to UCB’s PS department (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol) only after the partner has agreed that additional 
information can be captured and has provided the signed Partner Pregnancy Consent form.
UCB’s PS department is also the primary contact for any questions related to the data collection 
for the partner pregnancy, eventual birth, and follow up.
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form.
10.1.5
Suspected transmission of an infectious agent via a medicinal 
product
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
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10.1.6
Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt).
10.1.7
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 IMP so that Investigators, clinical study participants, regulatory 
authorities, and IECs will be informed appropriately and as early as possible.
The Sponsor Study Physician or medically qualified designee/equivalent will conduct an 
ongoing review of SAEs and perform ongoing SAE reconciliations in collaboration with the PS
representative.
As appropriate for the stage of development and accumulated experience with the IMP, 
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.
10.2
Laboratory measurements
Blood and urine samples will be taken for clinical laboratory assessments at the time points 
specified in Table 5-1.
A urine drug screen, cotinine urine screen, and alcohol breath test will be performed at the 
Screening Visit (Day -28 to Day -2) and before study participants are admitted to the unit on 
Day -2, Day 10, and Day 21. Serology will be performed at the Screening Visit to assess study 
participant eligibility. A serum pregnancy test will be performed at the Screening Visit, Day -2, 
Day 10, Day 21, Day 37, and the SFU Visit.
Laboratory safety measurements will be performed after a fasting period of at least 4 hours only 
at the Screening Visit. Clinical laboratory parameters to be measured are presented in
Table 10-1.
Sampling time and last AED intake should be recorded in the eCRF.
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Table 10-1: Laboratory measurements
Laboratory assessment
Parameters
Hematology
Hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, 
platelets, total white blood cell count, and differential consisting of absolute 
counts and percentages of the following leukocyte types: neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils
Biochemistry
Sodium, potassium, calcium, inorganic phosphorous, glucose (fasting, only at 
Screening), urea, creatinine, total bilirubin (conjugated bilirubin when total 
bilirubin is outside the reference range), total protein, albumin, ALT, AST, 
and ALP
Viral serology (only at 
Screening Visit)
HIV-1/2Ab, HBsAg, and HCV-Ab
Pregnancy
Serum pregnancy test 
Urinalysis
Specific gravity, pH, glucose (fasting, only at Screening), protein, blood, 
leukocytes, nitrite, ketones, bilirubin, urobilinogen (with dipstick)
If protein, blood, or leukocytes are abnormal (positive), a microscopic 
examination of the sediment will be performed.
Drug screen
Amphetamines/methamphetamines, benzodiazepines, barbiturates, cocaine, 
cannabis, methadone, tricyclic antidepressants, and opiates
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBsAG=hepatitis B 
surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibodies; 
SFU=Safety Follow-Up
10.2.1
Evaluation of potential drug-induced liver injury
The PDILI IMP discontinuation criteria for this study are provided in Section 6.4.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and Sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 10.1.1.3), and, if applicable, also reported as an
SAE (see Section 10.1.1.2).
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 10‒2 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.2.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 10.2.1.4). 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor.
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result.
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When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the Investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative.
When IMP is stopped due to PDILI (as described in Section 6.4.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings.
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur.
The table below summarizes the approach to investigate PDILI.
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Table 10‒2: Required investigations and follow up for PDILI
Laboratory value
ALT or 
AST
Total 
bilirubin
Symptoms a of hepatitis 
or hypersensitivity
Consultation requirements
Required testing
Continued evaluation
Requires immediate and permanent IMP discontinuation
≥3xULN
<2xULN
No
Medical Monitor must be notified 
within 24 hours (eg, by laboratory
alert) and study participant
discussed with Medical Monitor 
ASAP.
Must have repeat liver 
chemistry values and 
additional testing 
completed ASAP (see 
Section 10.2.1.3); 
recommended to occur 
within 24 hours at 
Phase 1 unit or with 
HCP.
Monitoring of liver 
chemistry values required 
once per week until values 
normalize, stabilize, or 
return to within Baseline
values. b
≥3xULN
NA
Yes
Hepatology consult. c
Medical Monitor must be notified 
within 24 hours (eg, by laboratory
alert) and study participant
discussed with Medical Monitor 
ASAP.
Monitoring of liver 
chemistry values required 
at least twice per week 
until values normalize, 
stabilize, or return to 
within Baseline values. b
≥3xULN 
≥2xULN
d
NA
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause).
b Unless an alternative monitoring schedule is agreed by the Investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
Investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed.
c Details provided in Section 10.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d If the study participant also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor.
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10.2.1.1
Consultation with Medical Monitor and local hepatologist 
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the study participant must be discussed with the Medical 
Monitor as soon as possible. If required, the study participant must also be discussed with the 
local hepatologist. The local hepatologist is the expert usually consulted by the treating physician 
for assessment and management of potential hepatic disease. This would usually be a 
hepatologist, but may be a gastroenterologist. If determined necessary, this discussion should be 
followed by a full hepatology assessment (see Section 10.2.1.3) and SAE report (if applicable).
10.2.1.2
Immediate action: determination of investigational medicinal product
discontinuation
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and requires permanent IMP discontinuation (see Section 6.4.1 and Table 10‒2
for details). 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The Investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative.
10.2.1.3
Testing: identification/exclusion of alternative etiology
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 10‒3 (laboratory measurements) and Table 10‒4 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the Sponsor on the 
corresponding eCRF. If the medical history of the study participant indicates a requirement for 
other assessments not included below, these additional assessments should be completed and 
submitted, as applicable.
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The following measurements are to be assessed:
Table 10‒3: PDILI laboratory measurements
Virology-
related
Hepatitis A IgM antibody
HBsAg
Hepatitis E IgM antibody
HBcAb-IgM
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing)
Immunology
Anti-nuclear antibody (qualitative and quantitative)
Anti-smooth muscle antibody (qualitative and quantitative)
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative)
Hematology
Eosinophil count
Urinalysis
Toxicology screen
Chemistry
Amylase
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation
Additional
Prothrombin time/INR
a
Serum pregnancy test
PK sample
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic acid; 
ULN=upper limit of normal
a Measured only for study participants with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis 
or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause).
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The following additional information is to be collected:
Table 10‒4: PDILI information to be collected
New or updated information
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included.
Pertinent medical history, including the following:

History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”)

Adverse reactions to drugs

Allergies

Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)

Recent travel 

Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.)
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash)
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function
Alcohol and illicit drug use
Results of liver imaging or liver biopsy, if done
Results of any specialist or hepatology consult, if done
Any postmortem/pathology reports
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury
10.2.1.4
Follow-up evaluation
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 10‒2. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the Investigator in
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed.
10.2.1.5
Optional hepatic investigation sample collection
If a study participant is undergoing further investigation for PDILI and has consented to 
retrospective genetic analysis per local regulations, the study participant’s blood sample will be 
shipped to a secure storage facility. The blood sample will be retained in the UCB Hepatic 
Investigation Biobank to solely support retrospective genetic analyses associated with an adverse 
therapeutic response to PSL.
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Genetic analyses of deoxyribonucleic acid isolated from the blood will be contracted by UCB to 
specialized third-party laboratories and analysis will be limited to:

Uridine 5′-diphospho-glucuronosyltransferase loci −the loci responsible for Gilbert’s 
syndrome (hyperbilirubinemia)

Human leukocyte antigen (HLA) loci −for example, HLA-B5701 that has been associated 
with abacavir- and flucloxacillin-induced liver injury

Absorption, distribution, metabolism, and excretion gene loci associated with abnormal 
pharmacokinetics
Genetic analysis of samples may be performed immediately, on a per-study basis, or as part of 
combined analyses across multiple studies belonging to the same clinical development program. 
As a result, samples will be retained for 15 years unless clinical development of the IMP is 
terminated, at which point all samples will be destroyed. The results determined using clinically 
approved diagnostic tests will be made available to the Investigator upon request.
Study participants may request at any time that their sample be removed from the UCB Hepatic 
Investigation Biobank and destroyed, though data from analyses already performed will remain 
on file. All samples, associated materials, and data will be kept securely by UCB and its agents. 
A sample destruction request should be made in writing to the Investigator who will notify the 
UCB Biorepository Manager (Global Exploratory Development, UCB, Slough, SL1 3WE, 
United Kingdom).
10.3
Other safety measurements
10.3.1
Physical examination
Full physical examinations will be performed at the time points specified in Table 5-1. Full 
physical examinations will include cardiac and respiratory function via auscultation and review 
of the following body systems: general appearance; ear, nose, and throat; eyes; hair and skin; 
respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological; and mental 
status.
Abbreviated physical examinations will be performed at the time points specified in Table 5-1. 
These abbreviated physical examinations will include a review of the following body systems: 
general appearance; skin; respiratory; cardiovascular; gastrointestinal; hepatic; and mental status.
Height (study participant without shoes, and height rounded to the nearest 0.5cm) and body 
weight (study participant in underwear or light clothing, without shoes and rounded to the 
nearest 0.1kg) will be recorded at the Screening Visit and BMI will be derived (weight 
(kg)/[height (m)]²). 
10.3.2
Vital signs
Vital signs (pulse rate, BP, respiratory rate, and body temperature) will be recorded at the time 
points shown in Table 5-1.
For the purposes of assessing the inclusion criterion, at the Screening Visit and the 
Baseline Visit, BP measurements will be performed in both supine and standing positions 
according to the following procedure: Measure supine BP after the study participant has been 
lying down for 10 minutes, then ask the study participant to stand up and record the standing BP 
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after 1 minute and 3 minutes. At all time points after the Screening Visit, BP will only be 
measured in the supine position, ie, there will be no assessment for orthostatic hypotension.
By decision of the Sponsor and the Investigator, the time points specified in Table 5-1 may be 
modified based on preliminary safety and PK assessments from previous doses tested in the 
study.
10.3.3
Standard 12-lead electrocardiogram
Triplicate standard 12-lead ECGs (RR interval, PR interval, QRS interval, QT, QTcB, and 
QTcF) will be recorded at times specified in Table 5-1, according to the following procedure: 
study participant lies in a supine position for ≥5 minutes; then a 12-lead ECG will be recorded in 
the same position. All ECG recordings will be performed in triplicate at 2- to 3-minute intervals. 
Electrocardiograms will be recorded at a speed of 25mm/s and with a calibration of 1cm/mV.
The times specified in Table 5-1 include a series of ‘triplicate 12-lead ECG run-in days’ to be 
performed 1 day prior to first PSL or erythromycin dose in Treatment Periods 1, 2, and 3 (that is, 
Day -1, Day 11, Day 22, and Day 25). On these days, triplicate standard 12-lead ECGs will be 
performed for each of the following matching time points: predose, 1h, 2h, 3h, and 6h postdose 
for the morning administration of PSL and/or erythromycin, and 0.5h predose for the evening 
administration of PSL and/or erythromycin. 
By decision of the Sponsor and the Investigator, the time points specified in Table 5-1 may be 
modified based on preliminary safety and PK assessments from previous doses tested in the 
study.
The Investigator or designee will determine whether the results of the ECG are normal or 
abnormal. All important abnormalities should be reported. The original ECG tracing will be 
signed or initialled, and dated by the Investigator or designee, and will be retained at the clinical 
site as part of the Investigator’s Site File. The original electronic file of the ECG tracing will be 
transferred to UCB and will remain available at least until the approval of the clinical study 
report.
10.3.4
Assessment of suicidality
The C-SSRS will be completed at the scheduled time points presented in Table 5-1.
Suicidality will be assessed by trained study personnel using the C-SSRS (Posner et al, 2011). 
This scale will be used for screening as well as to assess suicidal ideation and behavior that may 
occur during the study. The Investigator’s decision about study participant continuation in the 
study or study participant withdrawal from the study if the study participant has a positive 
response to the CSSRS Question 4, should be based on the benefit/risk balance for continuation 
or discontinuation of study treatment in view of the individual study participant circumstances, 
condition, attained efficacy, causality, alternative risk management options, etc. 
If an additional visit (or unscheduled visit) is conducted due to safety or efficacy reasons, a 
C-SSRS assessment will be performed with the study participant during the visit. If an additional 
visit (or unscheduled visit) is conducted for reasons other than safety or efficacy concerns 
(eg, replacement of lost medication, repeated collection of a laboratory specimen due to 
collection or analysis issues), a C-SSRS will not be required at these visits.
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Details of the case must be documented by the Investigator (PI or designee, not site staff 
conducting the C-SSRS) and provided to UCB via the SAE reporting process.
11
STUDY MANAGEMENT AND ADMINISTRATION 
11.1
Adherence to protocol
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study participants from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IEC, or 
Sponsor.
After implementation of such measure, the Investigator must notify the Exploratory Project 
Manager of the Sponsor within 24 hours and follow any local regulatory requirements.
11.2
Monitoring
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring SOPs, ICH-GCP 
guideline, and applicable regulatory requirements, and to ensure that study initiation, conduct, 
and closure are adequate. Monitoring of the study may be delegated by UCB to a CRO or a 
contract monitor.
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IEC review, and regulatory inspection(s).
The Investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records.
11.2.1
Definition of source data
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes).
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Source documents should be kept in a secure, limited access area.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the study participant’s source documents. 
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.
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Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee).
11.2.2
Source data verification
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, study participant files, recordings from automated instruments, tracings 
[ECG], x-ray films, laboratory notes). All data reported on the eCRF should be supported by 
source documents, unless otherwise specified in Section 11.2.1.
11.3
Data handling
11.3.1
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.
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator.
The Investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the eCRF Completion Guidelines.
11.3.2
Database entry and reconciliation
Electronic Case Report forms/external electronic data will be entered/loaded into a validated 
electronic database using a clinical data management system (CDMS). Computerized data 
cleaning checks will be used in addition to manual review to check for discrepancies and to 
ensure consistency of the data. Case Report form data are entered into the clinical database using 
independent, double-data entry, with the exception of comment fields, which are verified by a 
second person. The data are entered into the eCRFs once and are subsequently verified if the 
study is performed using electronic data capture.
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed.
11.3.3
Study Participant Screening and Enrollment log/Study Participant 
Identification Code list
The study participant’s screening and enrollment will be recorded in the Study Participant
Screening and Enrollment Log.
The Investigator will keep a Study Participant Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each study participant.
The study participant’s consent and enrollment in the study must be recorded in the study 
participant’s medical record. These data should identify the study and document the dates of the 
study participant’s participation.
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11.4
Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IEC should also be informed and provided with reason(s) for the termination 
or suspension by the Sponsor or by the Investigator/institution, as specified by the applicable 
regulatory requirement(s). In addition, arrangements will be made for the return of all unused 
IMP and other material in accordance with UCB procedures for the study.
11.5
Archiving and data retention
The Investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (Committee for Proprietary Medicinal Products [CPMP]/ICH/135/95, 2002 
[Section 4.9.5]). The Investigator will contact UCB for authorization prior to the destruction of 
any study records or in the event of accidental loss or destruction of any study records. The 
Investigator will also notify UCB should he/she relocate or move the study-related files to a 
location other than that specified in the Sponsor’s Study Master File.
11.6
Audit and inspection
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and wellbeing of the 
study participants enrolled have been protected, that enrolled study participants (ie, signing 
consent and undergoing study procedures) are appropriate for the study, and that all data relevant 
for the evaluation of the IMP have been processed and reported in compliance with the planned 
arrangements, the protocol, investigational site, and IEC SOPs, ICH GCP, and applicable 
regulatory requirements.
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee).
11.7
Good Clinical Practice
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action 
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by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study.
12
STATISTICS
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP).
12.1
Definition of analysis sets
12.1.1
Enrolled Set
The Enrolled Set (ES) consists of all study participants who have signed the ICF.
12.1.2
Full Analysis Set
The Full Analysis Set (FAS) consists of all study participants who have signed the ICF form and 
received IMP. Analysis of this set will be according to the treatment the study participants 
actually received.
All safety analyses will be performed using the FAS. All safety variables will be summarized by 
treatment (PSL alone, erythromycin alone, PSL+erythromycin, and the SFU).
12.1.3
Pharmacokinetic Per-Protocol Set
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the FAS, consisting of those study 
participants who had no important protocol deviations affecting the PK parameters and for whom 
a sufficient number of samples are available to determine at least 1 PK parameter.
12.2
General statistical considerations
Summary statistics will be provided for all safety and Baseline/demographic variables. The 
datasets will follow the UCB analysis data model (ADaM) data specifications. All 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 Pharsight Phoenix® WinNonlin®
v6.3 (or higher). Categorical endpoints will be summarized using number of participants, 
frequency, and percentages. Missing data will not be imputed. For continuous variables,
descriptive statistics (number of available observations, mean, median, standard deviation [SD], 
minimum, and maximum will be tabulated. 
12.3
Planned pharmacokinetic and other analyses
12.3.1
Analysis of the primary pharmacokinetic variables
Pharmacokinetics will be determined using the PK-PPS.
Pharmacokinetic parameters of PSL and metabolites will be calculated by using the actual blood 
sampling time points.
The plasma concentration time profiles (and urine amounts) and PK parameters of PSL and 
metabolites will be summarized by treatment periods using descriptive statistics (number of 
available observations, arithmetic mean, SD, geometric mean, coefficient of variation of the 
geometric mean, median, minimum, and maximum). Values below the lower limit of 
quantification (LLOQ) will be reported with a clear sign indicating that they were below the 
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LLOQ. Descriptive statistics of concentrations will be calculated if at least two-thirds of the 
individual data points are quantifiable (≥LLOQ).
Individual plasma PSL and metabolites concentration time profiles will be displayed graphically 
on a linear-linear scale and semi-logarithmic scale (including spaghetti plots). Geometric mean 
plasma concentrations-time curves including 95% confidence intervals (CIs) will be displayed by 
treatment period (without/with erythromycin).
The similarity of PK parameters for PSL and its metabolites (Cmax, AUC(0-12),Cmax,ss, and AUCτ) 
between periods with erythromycin and without erythromycin will be assessed within the 
analysis of variance (ANOVA) using data from the 3 treatment periods as follows: point 
estimates for the ratio of geometric means between with and without erythromycin and the 
respective 2-sided 90% CIs will be computed using the least squares means and the root mean 
squares of error from the ANOVA of the log-transformed data with subsequent exponential 
transformation. Inter-study participant and intra-study participant variability on PK parameters 
for PSL and its metabolites will be derived from these analyses. Ping pong plots will be 
displayed.
The PSL concentrations and PK parameters obtained from MITRA microsampling method will 
be compared to those of the conventional venous sampling method using descriptive analysis 
(tables with summary statistics and graphs).
12.3.2
Safety analyses
All safety analyses will be performed using the study participants in the FAS.
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) and 
characterized as pre-treatment and treatment-emergent according to the intake of the IMP. 
The occurrence and incidence of treatment-emergent adverse events (TEAEs) will be 
summarized by MedDRA system organ class and preferred term, by treatment periods, by 
treatment, and by treatment within treatment periods (for Treatment Period 3b). The occurrence 
and incidence of TEAEs will also be summarized by intensity and by relationship to the IMP as 
judged by the Investigator. Adverse events leading to discontinuation and SAEs will also be 
summarized. 
Laboratory variables and changes from Baseline (during the Screening Period) will be 
summarized by descriptive statistics at each time point by treatment periods. Shift tables from 
Baseline to each post-Baseline time point will be presented by treatment periods. Values outside 
the reference range will be flagged in the listings. Any PDILI events will be listed.
Vital sign variables (BP, PR, oral body temperature, and respiration rate) and changes from 
Baseline (predose of each treatment period) will be summarized by descriptive statistics at each 
time point by treatment periods.
Electrocardiograms will be recorded 3 times at each time point. The individual mean at each time 
point will be calculated as raw parameters for descriptive analysis. The individual mean and 
change from baseline (time-matched Baseline day of each treatment period, when applicable)
will be summarized by descriptive statistics at each time point by treatment periods.
Physical examination abnormalities and C-SSRS data will be listed.
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12.4
Handling of protocol deviations
Important protocol deviations (IPDs) are deviations from the protocol that potentially could have 
a meaningful impact on the primary objective of the study. The criteria for identifying such 
protocol deviations will be defined within the relevant protocol deviation specification 
document, which is part of the data cleaning plan. The IPDs will be reviewed as part of the 
ongoing data cleaning process and data evaluation. After all data have been 
verified/coded/entered into a database, a data evaluation meeting (DEM) will be performed. The 
purpose of this review will be to check all protocol deviations and the quality of the data. The 
review will also help guide the decision how to manage problems in the study participants’ data 
(eg, withdrawals, dropouts, and protocol deviations).
Accepted deviations from theoretical time points will be described in the appropriate documents 
and included in the Study Master File. After the data review, resolution of all issues, and 
documentation of all decisions, the database will be locked.
12.5
Handling of dropouts or missing data
The methods for handling dropouts and missing data will be described in the SAP.
12.6
Planned interim analysis and data monitoring
There is no interim analysis planned for this study.
12.7
Determination of sample size
Using SimCYP simulations data, a sample size of 20 healthy study participants is needed to 
assess the PK interaction between PSL and erythromycin, and to estimate the mean PSL AUCτ
ratio of with/without erythromycin of 3.2 with a half-width of the CI of 0.75.
This sample size has been evaluated with a conditional probability of 80%, assuming an 
inter-participant coefficient of variation of 140%, correlation of 0.5, 2-sided and α = 0.05.
A sufficient number of healthy study participants (up to 28) will be selected to have 
20 completed study participants.
13
ETHICS AND REGULATORY REQUIREMENTS
13.1
Informed consent
Study participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the study participant in both oral and written form by the 
Investigator (or designee). Each study participant will have the opportunity to discuss the study 
and its alternatives with the Investigator.
Prior to participation in the study, the ICF should be signed and personally dated by the study 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The study participant or his/her legal 
representative must receive a copy of the signed and dated ICF. As part of the consent process, 
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each study participant must consent to direct access to his/her medical records for study-related 
monitoring, auditing, 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.
13.2
Study participant identification cards
Upon signing the Informed Consent and Assent form (as applicable), the study participant or 
legal representative will be provided with a study participant identification card in the language 
of the study participant. The Investigator will fill in the study participant identifying information 
and medical emergency contact information. The Investigator will instruct the study participant
to keep the card with him/her at all times.
13.3
Independent Ethics Committee
The study will be conducted under the auspices of an IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki.
The Investigator/UCB will ensure that an appropriately constituted IEC that complies with the 
requirements of the current ICH-GCP version or applicable country-specific regulations will be 
responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, IB, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other study 
participant-related documents to be used for the study to the 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 human study participants or others, and any protocol deviations, to 
eliminate immediate hazards to study participants.
The Investigator will not make any changes in the study or study conduct without IEC approval, 
except where necessary to eliminate apparent immediate hazards to the study participants. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the 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 study 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. 
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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.
13.4
Study participant privacy
UCB staff (or designee) will affirm and uphold the study participant’s confidentiality. 
Throughout this study, all data forwarded to UCB (or designee) will be identified only by the 
study participant number assigned at Screening.
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
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).
13.5
Protocol amendments
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective.
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IEC, and the regulatory authorities (if required), prior to being 
implemented.
14
FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable.
15
REFERENCES
Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a 
European study. Epilepsia. 1997;38(3):353-62.
Choi H, Hamberger MJ, Munger Clary H, Loeb R, Onchiri FM, Baker G, et al. 
Seizure frequency and patient-centered outcome assessment in epilepsy. Epilepsia. 
2014;55(8):1205-12.
Clemens B. Forced normalisation precipitated by lamotrigine. Seizure. 2005;14(7):485-9.
Commission on Classification and Terminology of the ILAE. Proposal for revised clinical and 
electroencephalographic classification of epileptic seizures. Epilepsia. 1981;22(4);489-501.
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Giussani G, Canelli V, Bianchi E, Erba G, Franchi C, Nobili A, et al. Long-term prognosis of 
epilepsy, prognostic patterns and drug resistance: a population-based study. Eur J Neurol. 
2016;23(7):1218-27.
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Johannessen SI, Landmark, CJ. Antiepileptic drug interactions – principles and clinical 
implications. Curr Neuropharmacol. 2010;8(3):254-67.
Jones DJ, Stehling LC, Zauder HL. Cardiovascular responses to diazepam and midazolam 
maleate in the dog. Anesthesiology. 1979;51:430-34.
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in 
epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia. 
2009 Mar;50(3):387-97.
Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol 
Neurosurg Psychiatry. 2004;75(10):1376-81.
Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of 
refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. Best practices for the use of 
itraconazole as a replacement for ketoconazole in drug-drug interaction studies. J Clin 
Pharmacol. 2016;56(2):143-51.
Loganathan MA, Enja M, Lippmann S. Forced normalization: epilepsy and psychosis 
interaction. Innov Clin Neurosci. 2015;12(5-6):38-41.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77.
Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, et al. Is the underlying 
cause of epilepsy a major prognostic factor for recurrence? Neurology. 1998;51(5):1256-62.
Zack MM, Kobau R. National and state of the numbers of adults and children with active 
epilepsy-United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66:821-5.
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16
DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements.
I will ensure that all subInvestigators and other staff members read and understand all aspects of 
this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB.
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract.
Investigator:
Printed name
Date/Signature
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17
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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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Approval Date 
(dd-mon-yyyy 
(HH:mm)) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An open-label, fixed-sequence study in healthy study participants to
evaluate the effect of coadministered erythromycin on the PK and
safety of PSL
Clinical Approval
26-Jan-2018 11:51 GMT+01
Clinical Approval
26-Jan-2018 12:03 GMT+01
Clinical Approval
26-Jan-2018 12:14 GMT+01
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SAP_001.pdf: 
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21 Mar 2019 
Statistical Analysis Plan 
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Page 1 of 37 
 
STATISTICAL ANALYSIS PLAN  
Study: UP0057 
Product: Padsevonil 
AN OPEN-LABEL, FIXED-SEQUENCE STUDY IN HEALTHY STUDY PARTICIPANTS 
TO EVALUATE THE EFFECT OF COADMINISTERED ERYTHROMYCIN ON THE 
PHARMACOKINETICS AND SAFETY OF PADSEVONIL 
SAP/Amendment Number Date 
Final SAP 
15 May 2018 
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 .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 8 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 Study objectives ................................................................................................................. 8 
2.1.1 
Primary objective ................................................................................................... 8 
2.1.2 
Secondary objectives ............................................................................................. 8 
2.1.3 
Exploratory objectives ........................................................................................... 8 
2.2 Study variables ................................................................................................................... 9 
2.2.1 
Pharmacokinetic variables ..................................................................................... 9 
2.2.1.1 
Primary pharmacokinetic variables ............................................................. 9 
2.2.1.2 
Secondary pharmacokinetic variables ......................................................... 9 
2.2.1.3 
Other pharmacokinetic variables ............................................................... 10 
2.2.2 
Safety variables .................................................................................................... 10 
2.2.2.1 
Secondary safety variables ........................................................................ 10 
2.2.2.2 
Other safety variables ................................................................................ 10 
2.3 Study design and conduct ................................................................................................ 10 
2.4 Determination of sample size ........................................................................................... 12 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 12 
3.1 General presentation of summaries and analyses ............................................................ 12 
3.2 General study level definitions ........................................................................................ 13 
3.2.1 
Relative day ......................................................................................................... 13 
3.2.2 
Study periods ....................................................................................................... 14 
3.3 Definition of Baseline values ........................................................................................... 15 
3.4 Protocol deviations ........................................................................................................... 16 
3.5 Analysis sets ..................................................................................................................... 17 
3.5.1 
Enrolled Set ......................................................................................................... 17 
3.5.2 
Full Analysis Set .................................................................................................. 17 
3.5.3 
Pharmacokinetic-Per Protocol Set ....................................................................... 17 
3.6 Treatment assignment and treatment group ..................................................................... 17 
3.7 Center pooling strategy .................................................................................................... 18 
3.8 Coding dictionaries .......................................................................................................... 18 
3.9 Changes to protocol-defined analyses.............................................................................. 18 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 18 
4.1 Adjustments for covariates............................................................................................... 18 
4.2 Handling of dropouts or missing data .............................................................................. 18 
4.2.1 
Pharmacokinetics ................................................................................................. 18 
4.2.2 
Safety laboratory data .......................................................................................... 19 
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4.2.3 
Electrocardiogram data ........................................................................................ 19 
4.2.4 
Dates and times .................................................................................................... 19 
4.3 Handling of repeated and unscheduled measurements .................................................... 21 
4.4 Handling of measurements obtained at the early withdrawal visit .................................. 21 
4.5 Interim analyses and data monitoring .............................................................................. 22 
4.6 Multicenter studies ........................................................................................................... 22 
4.7 Multiple comparisons/multiplicity ................................................................................... 22 
4.8 Use of an efficacy subset of subjects ............................................................................... 22 
4.9 Active-control studies intended to show equivalence ...................................................... 22 
4.10 Examination of subgroups ............................................................................................... 22 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 22 
5.1 Subject disposition ........................................................................................................... 22 
5.2 Protocol deviations ........................................................................................................... 23 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 23 
6.1 Demographics .................................................................................................................. 23 
6.2 Other Baseline characteristics .......................................................................................... 24 
6.3 Medical history and concomitant diseases ....................................................................... 24 
6.4 Prior and concomitant medications .................................................................................. 24 
6.4.1 
Prior medication definition .................................................................................. 24 
6.4.2 
Concomitant medication definition ..................................................................... 24 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 24 
8 
EFFICACY ANALYSES ................................................................................................ 25 
9 
PHARMACOKINETICS ................................................................................................. 25 
9.1 Analysis of the primary pharmacokinetic variables ......................................................... 25 
9.2 Analysis of secondary pharmacokinetic variables ........................................................... 26 
9.3 Analysis of other pharmacokinetic variables ................................................................... 27 
10 SAFETY ANALYSES ..................................................................................................... 28 
10.1 Extent of exposure ........................................................................................................... 28 
10.2 Adverse events ................................................................................................................. 28 
10.3 Clinical laboratory evaluations ........................................................................................ 30 
10.4 Vital signs, physical findings, and other observations related to safety .......................... 31 
10.4.1 
Vital signs ............................................................................................................ 31 
10.4.2 
Electrocardiograms .............................................................................................. 32 
10.4.3 
Other safety variables .......................................................................................... 33 
10.4.3.1 
Physical examination ................................................................................. 33 
10.4.3.2 
Columbia-Suicide Severity Rating Scale .................................................. 33 
11 OTHER ANALYSES ...................................................................................................... 33 
12 REFERENCES ................................................................................................................ 34 
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13 APPENDICES ................................................................................................................. 35 
13.1 Breakdown of treatment periods reported into the TFLs by study assessment data ........ 35 
14 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN ................................. 36 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 37 
 
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LIST OF ABBREVIATIONS 
ADaM 
analysis data model 
Ae 
cumulative amount of padsevonil or metabolites 
excreted into the urine 
AE(s) 
adverse event(s) 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ALQ 
above the limit of quantification 
AST 
aspartate aminotransferase 
AUCτ 
area under the curve over a dosing interval (12 hrs) 
AUC(0-12) 
area under the plasma concentration-time curve 
from time zero to 12 hrs  
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CLform 
formation clearance of metabolites 
CL/Fss 
apparent total clearance at steady-state 
CLr 
renal clearance of padsevonil and its metabolites 
Cmax 
maximum observed plasma concentration 
Cmax,ss 
maximum observed steady-state plasma 
concentration 
Cmin 
minimum observed plasma concentration 
Ctrough 
predose observed plasma concentration 
CRF 
Case Report form 
CRO 
Contract Research Organization 
CSR 
clinical study report 
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CV 
coefficient of variation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DEM 
data evaluation meeting 
DDI 
drug-drug interaction 
ECG 
electrocardiogram 
EOS 
End of Study 
ES 
Enrolled set 
EudraCT 
European Union Drug Regulating Authorities 
Clinical Trials 
EW 
early withdrawal 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
fe 
fraction of padsevonil excreted into the urine 
geoCV 
geometric coefficient of variation 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C virus antibody 
HIV-1/2Ab 
human immunodeficiency virus-1/2 antibodies 
ICF 
Informed Consent form 
ICH 
International Council on Harmonisation 
IMP 
investigational medicinal product 
IPD 
important protocol deviation 
λz 
apparent elimination rate constant 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MW 
molecular weight 
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n 
number of subjects 
number of available observations 
NCS 
noncompartmental analysis 
PCS 
potentially clinically significant 
PDILI 
potential drug-induced liver injury 
PK-PPS 
Pharmacokinetic-Per Protocol Set 
PK 
Pharmacokinetic(s) 
PSL 
Padsevonil 
PT 
preferred term 
QTcB 
QT corrected for heart rate using Bazett’s formula 
QTcF 
QT corrected for heart rate using Fridericia’s 
formula 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SFU 
Safety Follow-up 
SOC 
system organ class 
t½,ss 
apparent terminal elimination half-life at steady-
state 
TEAE 
treatment-emergent adverse event 
TEMA 
treatment-emergent markedly abnormal 
TFLs 
tables, figures and listings 
tmax 
time to maximum concentration 
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 UP0057. 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, and assumes familiarity with, the following documents: 
 Final protocol, dated 26 January 2018 
Unless specified in the sections below, the study will be analyzed as described in the most recent 
version of the protocol. If a future protocol amendment necessitates a substantial change to the 
statistical analysis of the study data, this SAP will be amended accordingly. In addition, if 
analysis definitions must be modified or updated prior to database lock, a SAP amendment will 
be required. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the CSR together with the 
associated rationale. 
The content of this SAP is compatible with the International Council for Harmonisation 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips, A. et al. 2003). 
UCB is the Sponsor and PAREXEL is the Contract Research Organization (CRO) for this study. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective is to evaluate and compare the pharmacokinetics (PK) of padsevonil (PSL) in 
the presence and absence of erythromycin in healthy study participants.   
2.1.2 
Secondary objectives 
The secondary objectives are to: 
 Assess the safety and tolerability of PSL in the presence and absence of erythromycin in 
healthy study participants 
 Evaluate and compare the plasma PK of PSL metabolites, 
 
 in the presence and absence of erythromycin in healthy study participants 
 Assess and compare the urine PK of PSL and its metabolites 
 
 and 
) in the presence and 
absence of erythromycin in healthy study participants 
2.1.3 
Exploratory objectives 
The exploratory objectives are to: 
 Estimate the inter- and intra-study participant variability in the plasma PK of PSL and its 
metabolites following administration of PSL in the presence and absence of erythromycin 
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 Evaluate and compare the venous blood and MITRA dried blood microsampling (dried 
blood) PK of PSL and its metabolite (
 only) following administration of 
PSL in the presence and absence of erythromycin 
 Archive blood samples for genotyping of drug metabolizing enzymes and biomarkers 
2.2 
Study variables 
2.2.1 
Pharmacokinetic variables 
2.2.1.1 
Primary pharmacokinetic variables 
The primary PK variables will comprise Cmax and AUC(0-12) following a single dose and Cmax,ss 
and AUCτ following multiple doses of PSL in plasma: 
 Cmax: maximum observed plasma concentration 
 AUC(0-12): area under the plasma concentration-time curve from time zero to 12 hours 
 Cmax,ss: maximum observed steady-state plasma concentration 
 AUCτ: area under the curve over a dosing interval (12 hours) 
2.2.1.2 
Secondary pharmacokinetic variables 
The secondary PK variables for PSL will comprise tmax, and Cmin following single dose and tmax, 
t½,ss, λz, Ctrough, and CL/Fss following multiple doses, Cmax, AUC(0-12), Cmax,ss, and AUCτ for PSL 
metabolites 
), and the metabolite-to-parent ratios for 
Cmax, AUC(0-12), and AUCτ in plasma: 
 tmax: time of maximum concentration 
 Cmin: minimum observed plasma concentration 
 t½,ss: apparent terminal elimination half-life at steady-state. The terminal half-life should be 
determined over a time interval equal to at least 2 x t½, using at least 3 datapoints. If the time 
interval is less than 2 x t½, the terminal half-life and all derived parameters (e.g. CL/Fss) 
should be flagged. 
 λz: apparent elimination rate constant 
 Ctrough: predose observed plasma concentration 
 CL/Fss: apparent total clearance at steady-state (for parent drug only). 
 Metabolite-to-parent ratios calculated as: Cmax metabolite divided by Cmax of parent following 
a single dose, Cmax,ss metabolite divided by Cmax,ss of parent following multiple dosing. 
AUC(0-12) metabolite divided by AUC(0-12) parent following a single dose, AUCτ metabolite 
divided by AUCτ parent following multiple dosing. 
Additionally, the secondary PK variables for PSL and its metabolites (
 
, and 
) will comprise CLr, Ae, fe, and CLform in urine 
following a single dose and multiple doses: 
 CLr: renal clearance of PSL and its metabolites (only 
 and 
) calculated as Ae/AUC(0-12) and Ae/AUCτ for single and multiple dosing 
respectively. 
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 Ae: cumulative amount of PSL or metabolites excreted into the urine 
 fe: fraction of PSL or metabolites excreted into the urine calculated as Ae/Dose for PSL and 
as (Ae,met/Dose) x (molecular weight(MW)parent/MWmetabolite) where the MW of PSL is 
432.8, the MW of metabolite 
 is 419, the MW of metabolite 
 is 433 and the MW of metabolite 
 is 595. 
 CLform: formation clearance of metabolites calculated as (Ae,met/AUC(0-12),parent) x 
(MWparent/MWmetabolite). 
2.2.1.3 
Other pharmacokinetic variables 
The following other PK variables will be assessed during the study: 
 Inter- and intra-study participant coefficients of variation (variability) in PK parameters for 
PSL and its metabolites 
 The same PK parameters as listed in Sections 2.2.1.1and 2.2.1.2 for plasma data will be  
derived from venous blood with MITRA (dried blood) microsampling for PSL and its 
metabolite (only 
) 
2.2.2 
Safety variables 
2.2.2.1 
Secondary safety variables 
The following secondary safety variables will be assessed during the study: 
 Incidence of Adverse events (AEs) and Serious adverse events (SAEs) 
2.2.2.2 
Other safety variables 
The following other safety variables will be assessed during the study: 
 Changes in vital signs (pulse rate, blood pressure, respiratory rate, and body temperature) 
 Changes in safety laboratory data (hematology, clinical chemistry, and urinalysis) 
 Changes in 12-lead electrocardiogram (ECG) assessments 
 Physical examination (including neurological examination) findings 
2.3 
Study design and conduct 
This is a Phase 1, open-label, drug-drug interaction (DDI) study designed to evaluate the effect 
of erythromycin on the PK and safety of PSL and its metabolites in a single cohort of 28 healthy 
study participants. The study uses a fixed-sequence multiple-dose design per recommendation 
for best practice (Liu et al, 2016).  This study is planned to be conducted at a single site in the 
United Kingdom. 
The total duration of study per study participant will be approximately 75 days with a maximum 
of 18 days exposure to PSL. 
The end of the study is defined as the date of the last visit of the last study participant in the 
study. 
The study consists of 5 periods: A Screening Period, 3 Treatment Periods, and a Safety 
Follow-up (SFU) Period. 
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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 1, and a Baseline Visit, which will be 
conducted at the unit 1 day prior to Treatment Period 1. 
Treatment Period 1 and Treatment Period 2 each consist of 5 days of treatment, followed by 1 
week of wash-out. 
During Treatment Period 1 and Treatment Period 2, study participants will receive PSL 100mg 
bid for 4 days (Day 1 to Day 4 and Day 12 to Day 15). On the fifth day (Day 5 and Day 16), 
100mg of PSL will be given as a single dose in the morning. Study participants then enter 1 
week of wash-out (from the evening of Day 5 to Day 11 and evening of Day 16 to Day 22). 
Treatment Period 3 consists of 2 erythromycin-only periods (Treatment Period 3a 500mg bid for 
3 days and Treatment Period 3c 500mg bid for 4 days) and a combined PSL 100mg 
bid/erythromycin 500mg bid treatment period (Treatment Period 3b) for 8 days.. Erythromycin 
and PSL will be administered concurrently in Treatment Period 3b. 
The SFU Period consists of an End of Study (EOS) Visit performed 7 to 10 days after the final 
dose of erythromycin (Day 44 to Day 47) or upon discontinuation of the study. 
The study schematic diagram for UP0057 is presented in Figure 2‒1. 
Figure 2‒1: Schematic diagram 
 
bid=twice daily; IMP=investigational medicinal product; PK=pharmacokinetic(s); PSL=padsevonil; SFU=Safety 
Follow-Up 
a On the last day of Period 1, Period 2, and Period 3b, PSL will only be administered once in the morning. 
b First and last PSL dose. 
c Only after last PSL dose. 
d Only after first PSL dose. 
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2.4 
Determination of sample size 
Using SimCYP simulations data, a sample size of 20 healthy study participants is needed to 
assess the PK interaction between PSL and erythromycin, and to estimate the mean PSL AUCτ 
ratio of with/without erythromycin of 3.2 with a half-width of the confidence interval (CI) of 
0.75. 
This sample size has been evaluated with a conditional probability of 80%, assuming an 
inter-participant coefficient of variation of 140%, correlation of 0.5, 2-sided and α=0.05. 
A sufficient number of healthy study participants (up to 28) will be enrolled to have 
20 completed study participants. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical evaluation will be performed by PAREXEL. The datasets will follow the UCB 
analysis data model (ADaM) data specifications. 
All analyses will be performed using SAS version 9.4 or higher (SAS Institute, Cary, North 
Carolina, United States). The PK noncompartmental analysis (NCA) will be performed using 
Phoenix WinNonlin®v6.3 (or higher). 
Continuous variables will be summarized by treatment period, visit and timepoint (where 
applicable) including number of subjects (n), mean, standard deviation (SD), median, minimum, 
maximum and confidence intervals for the mean where stated in the SAP. 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 for PSL and its 
metabolites (
 for both plasma conventional venous and MITRA dried blood 
sampling and 
 for venous sampling only). In all outputs the confidence limits 
will be restricted to the possible values that the variable can take. 
Categorical variables will be summarized by treatment period, visit and timepoint (where 
applicable) with frequency counts and percentages.  
When reporting relative frequencies or other percentage values, the following rules apply: 
 For values where all subjects fulfill certain criteria, the percentage value will be displayed as 
100 
 For values where the absolute frequency is zero, there will be no percentage displayed 
 All other percentage displays will use 1 decimal place 
Percentages displayed based on continuous data (eg, percentage changes from baseline) will be 
displayed to 1 decimal place. Unless otherwise stated, the denominator for the percentages will 
be based on the number of subjects in the respective analysis set and treatment period. 
When reporting descriptive statistics, the following rules will apply in general (except for PK 
concentration data (plasma and blood [MITRA] PK of PSL and PSL metabolites, 
): 
 n will be an integer 
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 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 subjects have data at a given timepoint, then only n=0 will be presented. If n<3, then 
only the n, minimum and maximum will be presented. If n=3, then only n, minimum, median 
and maximum will be presented. The other descriptive statistics will be left blank. 
When reporting individual values and descriptive statistics for PK concentration data (plasma 
and blood [MITRA] PK of PSL and PSL metabolites, 
), the following rules will apply regarding rounding and precision: 
 Individual values for PK concentration data will be reported to the same level of precision as 
received from the bioanalytical laboratory 
 Descriptive statistics for PK concentration data will be reported to the same level of precision 
as the individual data for the minimum and maximum, and to 1 additional decimal place or 1 
additional significant figure– depending on the reporting format of the original data with a 
maximum of 3 significant digits - for the mean (arithmetic and geometric), median and SD. 
The 95% CI for the geometric mean will use 1 decimal place more, or 1 significant figure 
more – depending on the reporting format of the original data – than the value around which 
the confidence interval is constructed 
 Geometric CV will be reported as a percentage to 1 decimal place 
When reporting individual values and descriptive statistics for PK parameters (plasma and blood 
[MITRA] PK of PSL and PSL metabolites, 
), the 
following rules will apply with regard to rounding and precision: 
 Individual values for PK parameters will be reported to 3 significant figures 
 Descriptive statistics for PK parameters should be rounded to 4 significant figures for the 
mean, median and SD and to 3 for the others 
Data listings containing all documented data and all derived data will be generated. 
3.2 
General study level definitions 
3.2.1 
Relative day 
The relative day of an event will be derived with the date of first dose of investigational 
medicinal product (IMP), here PSL as reference.  
Relative days for an event or measurement occurring before the date of first dose are calculated 
as follows: 
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𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= 𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 
The relative day for an event or measurement occurring on the date of first dose is 1.  The 
relative day for an event or measurement occurring on or after the reference date to the date of 
the last dose will be calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= (𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐷𝑜𝑠𝑖𝑛𝑔) + 1  
For events or measurements occurring after the date of last dose, relative day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows: 
𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝐷𝑎𝑦= + (𝐸𝑣𝑒𝑛𝑡 𝐷𝑎𝑡𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒) 
There is no relative Day 0. Relative day will not be calculated for partial dates in cases where 
relative day is shown in a subject data listing. In such cases, relative day should be presented as 
‘--‘ in the relevant subject data listing. 
3.2.2 
Study periods 
For each subject completing the study, the expected maximum duration of participation will be 
approximately 75 days with a maximum of 18 days exposure to PSL, and will consist of the 
following periods: 
 Screening 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 1, and a Baseline Visit, which will be 
conducted at the unit 1 day prior to Treatment Period 1.  Study participants will check-in at 
the unit on Day -2. 
 Treatment Periods  1 and 2 (Day 1 to Day 11 and Day 12 to Day 22) 
Treatment Period 1 and Treatment Period 2 each consist of 5 days of treatment, followed by 
1 week of wash-out.  During Treatment Period 1 and Treatment Period 2, study participants 
will receive PSL 100mg bid for 4 days (Day 1 to Day 4 and Day 12 to Day 15). On the fifth 
day (Day 5 and Day 16), 100mg of PSL will be given as a single dose in the morning. Study 
participants then enter 1 week of wash-out (from the evening of Day 5 to Day 11 and evening 
of Day 16 to Day 22). 
 Treatment Period 3 (Day 23 to Day 38) 
Treatment Period 3 consists of 2 erythromycin only periods (Treatment Period 3a and 
Treatment Period 3c) and a combined PSL/erythromycin treatment period (Treatment Period 
3b). Study participants will receive erythromycin at the same clock-time PSL was 
administered in Treatment Period 1 and Treatment Period 2; erythromycin and PSL will be 
administered concurrently in Treatment Period 3b 
 Treatment Period 3a (Day 23 to 25) 
Study participants will receive erythromycin 500mg bid administered in the morning and 
in the evening. 
 Treatment Period 3b (Day 26 to 33) 
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Co-administration of PSL (100mg bid) and erythromycin (500mg bid) will begin on Day 
26. Combination therapy will last for 8 days (Day 26 to Day 33). On Day 33, study 
participants will only receive a single dose of PSL 100mg in the morning, in addition to 
erythromycin 500mg bid. 
 Treatment Period 3c (Day 34 to 38) 
Study participants remain confined to the unit at the beginning of Treatment Period 3c. 
Study participants will receive erythromycin 500mg bid for the next 4 days (Day 34 to 
Day 37). Study participants will be discharged on Day 38 at the Investigator’s discretion 
if no serious safety issues occur. 
 The SFU Period, EOS visit (Day 44 to 47) 
The SFU Period consists of EOS Visit performed 7 to 10 days after the final dose of 
erythromycin or upon discontinuation of the study.  
The end of the study is defined as the date of the last visit of the last subject in the study. 
3.3 
Definition of Baseline values 
In general, Baseline will be the last non-missing value prior to dosing. Scheduled or unscheduled 
measurements can be used as the Baseline value. 
Measurement-specific Baseline timepoints are presented in Table 3‒1.  
Table 3‒1: 
Definition of Baseline 
Measurement 
Definition of Baseline 
 
Hematology, serum 
chemistry, urinalysis 
Baseline or if missing the Screening value 
 
Vital signs 
 
Predose for each treatment period.  
Treatment Period 1          predose Day 1 or if missing Day -1.  If  Day -1 
is missing the Screening value will be used.  
Treatment Period 2          predose Day 12 or if missing predose Day 1 
Treatment Period 3          predose Day 23 or if missing predose 
Treatment Period 1 value 
 
Otherwise baseline = day -1 predose 
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Measurement 
Definition of Baseline 
 
ECG  
Time-matched predose for each treatment period.  
Treatment Period 1    Day-1    Morning:   predose, 1h, 2h, 3h, 6h similar 
“postdose” ; Evening: 0.5h “postdose”  
Treatment Period 2    Day 11 Morning:   predose, 1h, 2h, 3h, 6h similar 
“postdose” ; Evening: 0.5h “postdose”   
Treatment Period 3a    Day 22: Morning:   predose, 1h, 2h, 3h, 6h 
similar “postdose” ; Evening: 0.5h “postdose”  
Treatment Period 3b    Day 25: Morning:   predose, 1h,2h,3h, 6h similar 
“postdose” ; Evening: 0.5h “postdose”        
Treatment Period 3c    Day 33: Morning:   predose, 1h,2h,3h, 6h similar 
“postdose” ; Evening: 0.5h “postdose”        
 
Otherwise baseline = day -1 predose 
ECG=electrocardiogram; SFU=Safety Follow-Up. 
If a measurement is repeated at Baseline or a given treatment period and is obtained prior to 
dosing in that period, then the last available measurement will be used as the Baseline value.   
12-lead ECG will be measured in triplicate with a 1-minute interval between replicates.  Mean of 
the last three measurements predose will be taken as the baseline; if less than three replicates are 
available predose, the mean of the available replicates (predose) will be taken as the baseline.  
Time matched predose values are defined as the Baseline value (see Table 3-1). 
The change from Baseline to any subsequent post-Baseline visit will be calculated as the simple 
difference between that post-Baseline visit’s value and the Baseline value, as below:   
𝑃𝑜𝑠𝑡−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 −𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 
The percentage change from Baseline to any subsequent post-Baseline visit will be calculated as 
follows: 
100 𝑥(𝑃𝑜𝑠𝑡−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒)/(𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒) 
For 12-lead ECG, time-matched differences will only be calculated for the change from 
Baseline. 
3.4 
Protocol deviations 
Important protocol deviations (IPD) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or the key safety and PK outcomes for an individual 
subject. The criteria for identifying such protocol deviations will be defined within the protocol 
deviation specifications document.  
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 
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 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  
All IPDs will be reviewed as part of the ongoing data cleaning process and data evaluation. After 
all data have been verified/coded/entered into a database, a data evaluation meeting (DEM) will 
be performed.  
At least one DEM will be performed at the following time: 
 Prior to the final analysis after all data have been verified/coded/entered into the database 
Additional DEMs may be conducted as deemed necessary. 
The purpose of these DEM reviews will be to review all protocol deviations, define the analysis 
sets, and check the quality of the data. The reviews will also help decide how to manage 
problems in the 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 
Enrolled Set 
The Enrolled Set (ES) consists of all study participants who have signed the Informed Consent 
form (ICF).  
3.5.2 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all study participants who have signed the ICF and 
received at least 1 dose of PSL. Analysis of this set will be according to the treatment the study 
participants actually received. 
3.5.3 
Pharmacokinetic-Per Protocol Set 
The Pharmacokinetic-Per Protocol Set (PK-PPS) is a subset of the FAS, consisting of study 
participants who had no IPD affecting the PK parameters and for whom a sufficient number of 
samples are available to determine at least 1 PK parameter. 
3.6 
Treatment assignment and treatment group 
All subjects will complete the identical fixed-sequence multiple-dose treatments. Listings will be 
presented by subject and treatment period (Screening, Treatment Periods 1, 2, 3a, 3b and 3c, and 
SFU). Summaries will be presented by treatment (PSL, erythromycin, PSL + erythromycin and 
SFU), unless stated otherwise. 
 PSL 
Treatment Period 1 and 2 (pooled data) 
 Erythromycin 
Treatment Period 3a and 3c (pooled data) 
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 PSL + Erythromycin 
Treatment Period 3b 
 SFU 
 
Adverse events summaries will be presented by treatment within treatment periods as follows: 
 Period 1 and 2: PSL 
 
 Period 3a: Erythromycin (pre-PSL)  
 Period 3b: PSL + Erythromycin 
 Period 3c: Erythromycin (post-PSL) 
 SFU 
PK summaries will be presented as follows: 
 PSL: Period 1 
 
 PSL: Period 2 
 
 PSL + Erythromycin: Period 3b 
3.7 
Center pooling strategy 
Not applicable, this is a single center study. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using the latest available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®). Medications will be coded according 
to the World Health Organization Drug Dictionary (WHODD). Medical procedures will not be 
coded. 
3.9 
Changes to protocol-defined analyses 
The protocol states that MITRA dried blood microsampling method will be compared to those of 
the plasma conventional venous sampling method using descriptive analysis (tables with 
summary statistics and graphs). Nonetheless, as described in Section 9.3, the exploratory analysis 
will also be described using linear mixed effects model. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable. 
4.2 
Handling of dropouts or missing data 
In general, there will be no imputation of missing data unless otherwise stated below. 
Missing data will be handled as described in the sections below for safety laboratory and PK 
results. No other imputations will be performed.  
4.2.1 
Pharmacokinetics  
The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geometric CV) is 0. Measurements of PK concentrations that are below the limit of 
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quantification (BLQ) will be imputed with half of the lower limit of quantification (LLOQ) for 
the purpose of calculating the geometric mean and its 95% CI, the geometric CV, the arithmetic 
mean and SD for summaries and figures. Descriptive statistics of concentrations will be 
calculated if at least 2/3rd of the individual data points are quantifiable (≥LLOQ).  
For all individual PK concentration figures any concentrations that are BLQ will be regarded as 
missing, with the exception of predose BLQ values (linear scale only) which will be imputed as 
zero. 
The following rules will apply for PK data listings and summaries: 
 Values below the LLOQ will be reported as (BLQ) in the listings 
 Descriptive statistics of plasma concentrations will be calculated if at most 1/3rd of the 
individual data points are missing or are not quantifiable (<LLOQ) at the given time-point. 
Values that are BLQ will be replaced by the numerical value of the LLOQ/2 in this instance. 
However, if n<3, then only n, minimum and maximum will be presented, and the median will 
also be presented if n=3. The other descriptive statistics will be left blank. 
 For plasma concentrations, all BLQ values occurring prior to Cmax will be replaced by “0”, 
except for embedded BLQ values (between two measurable data points) which will be 
treated as missing. Post-Cmax BLQ values will be treated as missing. The Pharmacokinetic 
analysis will be performed in accordance to the User guide for Clinical Pharmacokinetics 
Modeling and Simulation version8 issued by UCB. 
 For the individual figures, any concentrations that are BLQ will be regarded as missing, with 
the exception of predose BLQ measurements on Day 1, Day 12 and Day 23 for the treatment 
periods 1, 2 and 3 respectively, which will be imputed with zero for linear scale plots. 
 If no subjects have data, only n=0 will be presented. The other descriptive statistics will be 
left blank. 
 The 95% CI for the geometric mean should be left blank if the SD (or equivalently, the 
geoCV) is 0. 
 The geometric CV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data: 
Geometric CV (%) = sqrt[(exp (SD^2) – 1)] x 100 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ or above the limit of quantification (ALQ) in the 
safety laboratory data will be the same as those described for PK data in Section 4.2.1.  
4.2.3 
Electrocardiogram data 
For the 12-lead ECG data, all calculations of changes from Baseline and descriptive statistics 
will be based on the mean of the triplicate assessments at each timepoint. In the event that there 
are not 3 available measurements at a given timepoint, the mean will be calculated based on the 
number of measurements for which data are provided. 
4.2.4 
Dates and times 
Partial dates may be imputed for the following reasons: 
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 Classification of AEs as treatment-emergent 
 Classification of medications as prior or concomitant 
Imputed dates will not be shown in the listings; all dates will be displayed as reported in the 
database. 
The following rules will be applied for partial start dates: 
 If only the month and year are specified and the month and year of the first dose of study 
medication is not the same as the month and year of the start date then use the 1st of the 
month, or the date of screening if this is later (if the latter imputation results in an end date 
that is earlier than the start date, then use the 1st of the month). If time is missing this will be 
imputed as 00:00 h 
 If only the month and year are specified and the month and year of the first dose of study 
medication is the same as the month and year of the start date, then 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 (ie, event will be regarded as treatment-emergent) 
 If only the year is specified, and the year of the first dose of study medication is not the same 
as the year of the start date then January 01 will be used. If time is missing this will be 
imputed as 00:00 h 
 If only the year is specified, and the year of the first dose of study medication is the same as 
the year of the start date, then the date of the first dose of study medication will be used. If 
this results in an imputed start date that is after the specified end date, then January 01, or the 
date of screening if this is later will be used (if the latter imputation results in an end date that 
is earlier than the start date, then January 01 will be used). If the imputed date is the date of 
first dose of study medication then time will be imputed as the start time of the study 
medication intake (ie, event will be regarded as treatment-emergent) 
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 4-1 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 4-1: 
Calculation rules for duration of adverse events 
Data availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
Complete data 
D1/T1 
D2/T2 
Duration = [(D2 – D1)*24 + (T2 – T1)]/24 d 
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Table 4-1: 
Calculation rules for duration of adverse events 
Data availability 
Onset 
date/time 
Outcome 
date/time 
Calculation rules 
End time missing 
D1/T1 
D2/-- 
End time is substituted by time 23:59h (=23.98 in 
decimal format) 
Duration = <[(D2 – D1)*24 + (23.98 – T1)]/24 d 
Start time missing 
D1/-- 
D2/T2 
Onset time is substituted by time 00:00h 
Duration = <[(D2 – D1)*24 + T2]/24 d 
Start and end time 
missing  
D1/-- 
D2/-- 
Duration = <D2 – D1 + 1 
Start day and time 
missing 
--/-- 
D2/T2 
Duration = [(D2 – D0)*24 + (T2 – T0)]/24 d 
For a subject in the FAS, D0 and T0 are the date 
and time of first administration of study 
medication and for screen failures, D0 is the date 
of the screening visit and T0 = 00:00h 
End day and time 
missing  
D1/T1 
--/-- 
If the stop date is missing, duration will not be 
calculated. 
Start and end date 
missing 
--/-- 
--/-- 
If the stop date is missing, duration will not be 
calculated. 
FAS=full analysis set; PSL=Padsevonil. 
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. The following general rules will apply to all repeated and unscheduled 
measurements: 
 For repeated measurements obtained prior to the first dose of study medication, the latest 
value (which may be scheduled or unscheduled) will be used in the calculation of the 
descriptive statistics 
 For repeated measurements obtained at the designated Baseline visit, the latest value (which 
may be scheduled or unscheduled) will be defined as the Baseline provided that this occurred 
prior to the first dose of study medication 
 Unscheduled and repeated measurements will not be used in the descriptive statistics at time 
points after first dose of study medication 
 Unscheduled measurements performed for the Early Withdrawal (EW) visit will be assigned 
to the EOS visit (Section 4.4) and analyzed accordingly as an EOS visit. 
4.4 
Handling of measurements obtained at the early withdrawal 
visit 
Subjects who withdraw early from the study for any reason, including those withdrawn from 
study medication, will be asked to return for the EOS Visit 7 to 10 days after last intake of study 
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medication and will then enter the SFU Period and will undergo the same assessments performed 
at the EOS Visit. 
4.5 
Interim analyses and data monitoring 
Not applicable, there is no interim analysis and no data monitoring planned for this study. 
4.6 
Multicenter studies 
Not applicable, this is a single center study. 
4.7 
Multiple comparisons/multiplicity 
Not applicable. 
4.8 
Use of an efficacy subset of subjects 
Not applicable. 
4.9 
Active-control studies intended to show equivalence 
Not applicable. 
4.10 
Examination of subgroups 
Not applicable. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
The number of subjects who were enrolled into the study, subjects who completed or 
prematurely discontinued the study, as well as the reason for discontinuation, will be 
summarized for all subjects, based on the FAS. A subject who completed the study is defined as 
a subject who completed all visits up to and including the SFU.  
The number and percentage of subjects who discontinued due to AEs will be summarized 
separately for all subjects, based on the FAS. This will be used for European Union Drug 
Regulating Authorities Clinical Trials (EudraCT) reporting. 
The number and percentage of subjects included in each of the analysis sets will be summarized 
for all subjects and for each treatment period based on the ES. Percentages will be calculated 
based on the FAS for the purpose of this summary. 
Screen failure reasons will be summarized for the ES. A listing of subjects who did not meet 
study eligibility criteria will also be presented for the ES. 
In addition, the following listings will be presented: 
 Subject disposition (ES) 
 Study discontinuation (FAS) 
 Visit dates (FAS) 
 Subject analysis sets (ES) 
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The listing of subject disposition will include the date of informed consent, date and time of first 
and last dose of study medication, date of premature termination and primary reason (if 
applicable) and date of final contact. 
The listing of study discontinuation will include the reason for discontinuation and the number of 
days on study medication. 
The number of days on study medicationwill be calculated as follows: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐷𝑎𝑦𝑠 𝑜𝑛 study medication
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑) + 1 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types in the IPD 
document. 
A listing of all IPDs identified at the DEM will be presented for all subjects based on the FAS 
and will include the deviation type and description. The number and percentage of subjects in the 
FAS with IPDs will be summarized for all subjects and for each treatment period for each 
deviation type. The denominator for the percentages will be the number of subjects in the FAS. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
A by-subject listing of demographics will be presented based on the ES. This will include the 
date of birth, age (in years), sex, race, ethnicity, height (in cm), weight (in kg) and body mass 
index (BMI). The body weight will be the measurement obtained at Screening. 
Body mass index in kg/m2 is calculated based on the height (in m) and the weight (in kg) using 
the following formula: 
BMI (kg/m2) = weight (kg)/[height (m)]2 
The BMI will be reported to 1 decimal place. 
All demographic characteristics (except for date of birth) will be summarized by for all subjects 
based on the FAS. The summary of age will include descriptive statistics and categorical 
summaries, the latter based on requirements for European Union Drug Regulating Authorities 
Clinical Trials (EudraCT) and clinicaltrials.gov reporting. 
For the EudraCT reporting, the categories will include: 
 18 to <65 years 
 65 to <85 years 
 ≥85 years 
For clinicaltrials.gov reporting, the categories will include: 
 ≤18 years 
 19 to <65 years 
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 ≥65 years 
6.2 
Other Baseline characteristics 
Lifestyle information (alcohol, tobacco, illicit drug use and caffeinated beverage use) will be 
listed and summarized for all subjects in the FAS. 
6.3 
Medical history and concomitant diseases 
Medical history will be listed and summarized (in an incidence table) for the FAS for all 
subjects, by MedDRA system organ class (SOC) and preferred term (PT). The reported term will 
be included in the listing. The summary will include the number and percentage of subjects, and 
will be sorted alphabetically by SOC and by descending incidence of PT within each SOC, based 
on the ‘All Subjects’ column.  
Procedure history will be listed separately by the procedure reported term based on the FAS. 
Concomitant medical procedures occurring during the study will be listed for the FAS. 
6.4 
Prior and concomitant medications 
Prior and concomitant medications will be listed and summarized for all subjects in the FAS, by 
WHODD Anatomical Main Group [Level 1 term text], Pharmacological Subgroup [Level 3 term 
text] and PT. The reported term will be included in the listing. Separate tabulations will be 
presented for prior medications and concomitant medications. Prior medications which continued 
into the treatment period will also be classified as concomitant and will be included in both 
summaries. Concomitant medications will be described for all subjects and for each treatment 
period based on the FAS. 
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in the ‘All Subjects’ column. 
6.4.1 
Prior medication definition 
Prior medications include any medications that started prior to the date of first dose of PSL. This 
includes medications that started prior to the first dose of PSL and continued after. 
6.4.2 
Concomitant medication definition 
Concomitant medications are medications taken at least one day in common with the study IMP 
(after dosing with PSL) and/or the Safety Follow-Up Period.  
If a medication is started prior to PSL administration and stopped after, that medication will be 
classified as both prior and concomitant 
Any medications with missing dates and/or times will be handled as described in Section 4.2.4 to 
classify them as prior or concomitant. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Administration of PSL or erythromycin will be performed under the supervision of the 
Investigator (or designee), and the Investigator (or designee) will check the study participant’s 
hands and the oral cavity immediately after dosing to confirm ingestion of the study medication. 
Compliance will be monitored by drug accountability and by drug assay for PSL (using the drug 
concentration in the blood/plasma). Compliance with the study medication is defined as 
consumption by the study participant that confirms 100% with the planned dosage. 
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Drug administration/consumption will be recorded and any discrepancies with the dosing 
regimen will be explained. Dosing deviations will be included in the listing of IPDs where 
applicable. 
No formal calculations of compliance will be presented as all study medication is administered 
on site. 
8 
EFFICACY ANALYSES 
Not applicable. 
9 
PHARMACOKINETICS 
The calculation of the PK parameters of PSL and its metabolites (
for both 
plasma conventional venous and MITRA dries blood and 
 for venous sampling 
only) will be performed by the Quantitative Clinical Development Department, PAREXEL. All 
PK TFLs will be produced by PAREXEL Biostatistics (Early Phase). 
Pharmacokinetic concentrations and PK parameters will be summarized by treatment ie PSL 
with (Period 3b) and without erythromycin (Periods 1 and 2 separately), using the PK-PPS and 
listed on the FAS by treatment and subject. Figures of summaries will be based on the PK-PPS 
and figures of individual concentrations will be based on the FAS. 
Pharmacokinetic parameters of PSL and metabolites (
 for both plasma 
conventional venous and MITRA dried blood and 
 for venous sampling only) 
will be calculated using the actual blood sampling times.  
9.1 
Analysis of the primary pharmacokinetic variables 
Individual plasma concentrations of PSL (from conventional venous sampling) will be listed by 
treatment period (PSL: Period 1; PSL: Period 2; PSL+ Erythromycin: Period 3b) and will include 
the actual and nominal sampling times and the deviation between them. All deviations will be 
calculated relative to the first dose of study medication in that period. Any samples that are 
obtained outside the tolerance window permitted at the specified time point will be discussed at 
the DEM and any possible exclusion from analysis will be documented accordingly. The primary 
PK variables in plasma are: Cmax and AUC(0-12) following a single dose and Cmax,ss and AUCτ 
following multiple doses of PSL. 
 
The PK plasma concentrations and primary PK parameters of PSL will be summarized by 
treatment period and nominal sampling times using descriptive statistics (number of available 
observations (n), arithmetic mean, median, SD, minimum, maximum, geometric mean, 
geometric CV and 95% CI for the geometric mean (assuming lognormally distributed data)).  
Values below the LLOQ will be reported with a clear sign indicating that they were below the 
LLOQ. 
Individual subject concentration-time profiles of PSL will be displayed graphically in linear and 
semi-logarithmic scale. Combined individual (spaghetti) plots will be displayed by treatment 
period with all subjects overlaid on the same plot (linear and semi-logarithmic scale). 
Geometric mean profiles of plasma concentrations for PSL over time will be presented, with all 
treatment periods overlaid on the same plot, in both linear and semi-logarithmic scale. For the 
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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 primary comparison of interest is the similarity of plasma PK parameters (Cmax, AUC(0-12), 
Cmax,ss, and AUCτ) for PSL between treatment periods with erythromycin (Treatment Period 3b) 
and PSL without erythromycin (treatment periods 1 and 2).  This will be assessed using a linear 
mixed effects model with treatment periods (1, 2 and 3b, comparing with vs without 
erythromycin periods) fitted as fixed effects and subject fitted as a random effect. The mixed 
effects model will be using Kenward-Rodgers degrees of freedom. Point estimates for the ratio 
of geometric means with and without erythromycin (Period 3b compared to periods 1 and 2) and 
the respective 2 sided 90% CIs will be computed using the least squares means and the root 
mean squares of error from the mixed effects model, based on of the log-transformed data with 
subsequent exponential transformation. In addition point estimates for the ratio of geometric 
means and the respective 2 sided 90% CIs will be presented for the following comparisons: 
 Treatment Period 1 (PSL) compared to Treatment Period 3b (PSL + erythromycin) 
 Treatment Period 2 (PSL) compared to Treatment Period 3b (PSL + erythromycin) 
Treatment Period 1 (PSL) compared to Treatment Period 2 (PSL) Ping pong plots will be 
displayed for each of the PK parameters (Cmax, AUC(0-12), Cmax,ss, and AUCτ) against treatment of 
PSL with (Treatment Period 3b) and without erythromycin (treatment periods 1 and 2, 
separately). 
9.2 
Analysis of secondary pharmacokinetic variables 
The secondary PK variables in plasma for PSL are:  tmax, and Cmin following single dose and tmax, 
t½,ss, λz, Ctrough, and CL/Fss following multiple doses, Cmax, AUC(0-12), Cmax,ss, and AUCτ for PSL 
metabolites (
), and the metabolite-to-parent ratios for 
Cmax, AUC(0-12), and AUCτ. 
Additionally, the secondary PK variables in urine for PSL and its metabolites 
(
 and 
) are: CLr, Ae, fe, and CLform in 
urine following a single dose and multiple doses. 
Urine amount, time profiles and PK parameters of PSL and metabolites in urine will be 
summarized and plotted as described in Section 9.1. Urine concentration and amount excreted 
will be listed for PSL and the three metabolites. 
Each of the secondary PK variables, for PSL and its metabolites in plasma, will be summarised 
by treatment period using the same descriptive statistics as for the plasma concentrations and PK 
variables in Section 9.1, and plotted in a similar manner. 
The mixed effect model described in Section 9.1 will be applied for the PK variables Cmax, 
AUC(0-12), Cmax,ss, and AUCτ for the two PSL metabolites (
) in plasma (conventional venous of sampling).  Point estimates for the ratio of geometric 
means and the respective 2 sided 90% CIs will be computed using the least squares means and 
the root mean squares of error from the mixed effects model, based on of the log-transformed 
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data with subsequent exponential transformation for the same comparisons than those described 
in Section 9.1. 
9.3 
Analysis of other pharmacokinetic variables 
The other PK variables and their analysis are the followings: 
 Inter- and intra-study participant coefficients of variation (variability) in PK parameters Cmax, 
AUC(0-12), Cmax,ss, and AUCτ for PSL and its metabolites 
Inter-study subject and intra-study subject variability on the PK parameters for PSL and its 
metabolites will be estimated from the mixed effects analysis described in Section 9.1.  The 
point estimate (CV%) and 2-sided 90% CI for the inter-subject variability will be derived 
from the subject effect of the variance covariance matrix, and for the intra-subject variability, 
the point estimate (CV%) and 2-sided 90% CI will be derived from the residual effect of the 
variance-covariance matrix. 
 Pharmacokinetic parameters Cmax, AUC(0-12), Cmax,ss, and AUCτ (and profile) data derived 
from MITRA dried blood concentration for PSL and its metabolite (only 
)  
 The blood concentrations and blood PK variables for PSL and its metabolite based on the 
MITRA microsampling will be summarised and plotted as described in Section 9.1. 
 As exploratory analysis, point estimates for the ratio of geometric means for the PK 
parameters Cmax, AUC(0-12), Cmax,ss, and AUCτ for PSL based on the MITRA dried blood 
microsampling compared to the plasma conventional venous sampling along with the 2 sided 
90% CIs will be computed using the least squares means and the root mean squares of error 
from a specific linear mixed effects model, based on of the log-transformed data with 
subsequent exponential transformation for the following periods:  
◦ 
Overall: conventional venous compared to MITRA 
◦ 
Period 1: conventional venous compared to MITRA 
◦ 
Period 2: conventional venous compared to MITRA 
◦ 
Period 3b: conventional venous compared to MITRA 
 Scatter plots of the MITRA dried blood concentrations versus venous plasma concentrations 
for PSL and its metabolite will be presented.  Furthermore a linear regression plot of the 
MITRA dried blood concentrations and venous plasma concentrations for PSL and its 
metabolite including the regression lines for the mean along with 90% confidence intervals 
will be presented for the log data. 
 The predose trough concentrations for both plasma conventional venous and MITRA dried 
blood sampling methods obtained the Days 2 to 4, 13 to 15, and 27 to 33 will be listed 
separately. The trough PSL concentrations will be summarized by treatment period and day. 
Geometric mean along with their 95% CI for the trough concentrations will be plotted against 
time, with the 3 treatment periods overlaid in one figure (one plot for each sampling method). 
 Erythromycin plasma concentrations may be listed if blood samples are bioanalyzed for 
erythromycin assessment. 
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10 
SAFETY ANALYSES 
All safety summaries and listings will be performed using the FAS. Unless stated otherwise, all 
summaries including figures will be by treatment period (Period 1 and Period 2 pooled, Period 
3b, Period 3a and Period 3c pooled and EOS/SFU) as detailed in Table 13.1. Summaries for 
continuous variables by timepoint will be based on the averaged value across the pooled periods. 
Categorical variables will be summarized according to the actual period (no pooling).  
10.1 
Extent of exposure 
All study medication administration details will be listed by treatment period and subject. The 
listing will include the date and time of administration of the morning and evening dose, 
depending on the treatment period, of either PSL and or erythromycin and total daily dose of 
both medications.  
Exposure data will be listed only. 
10.2 
Adverse events 
All AEs will be coded using the MedDRA® and characterized as pre-treatment and treatment-
emergent according to the intake of the study medication.  Adverse events with a start date prior 
to the first dose of study medication will be defined as pre-treatment AEs. 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. Where dates are missing or 
partially missing, AEs will be assumed to be treatment-emergent, unless there is clear evidence 
to suggest that the AE started prior to the first dose of study medication. Missing or partially 
missing dates for AEs will be handled as described in Section 4.2.4. 
Adverse events will be attributed to the treatment period in which they start. Thus, all AEs 
starting after the first intake of PSL through Day 11 (before PSL on Day 12) will be attributed to 
Treatment Period 1 including the washout period Day 6 through Day 11.  Likewise, all AEs 
starting after PSL on Day 12 until prior to erythromycin on Day 23 will be attributed to 
Treatment Period 2 including the washout period Day 17 through Day 22. There is no washout 
period between the Treatment Periods 3a, 3b and 3c.  Adverse events with a start date after first 
dose of erythromycin in Treatment Period 3a until prior to the first dose of either PSL or 
erythromycin dose in Treatment Period 3b will be attributed to Treatment Period 3a and likewise 
for 3b and 3c.  In Treatment Period 3c any AE starting more than 168 hours post last dose of 
erythromycin will be attributed to the SFU period. 
All AEs will be recorded in the Case Report form (CRF) from the time of informed consent until 
study completion or termination. All AEs will be coded (see Section 3.8) and categorized by 
intensity (mild/moderate/severe) and relationship (related/not related) as judged by the 
Investigator. 
The number and percentage of subjects who experience TEAEs will be summarized by 
MedDRA SOC, PT, treatment period (Period 1 and Period 2 pooled, Period 3a, Period 3b, Period 
3c and EOS/SFU)  and treatment within treatment period (see Section 3.6). Summaries of 
TEAEs will include the following: 
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 Incidence of TEAEs (overview including number and percentage of subjects with any 
TEAEs, serious TEAEs, discontinuations due to TEAEs, drug-related TEAEs, severe TEAEs 
and TEAEs leading to death; event counts will also be included) 
 Incidence of TEAEs 
 Incidence of serious TEAEs 
 Incidence of non-serious TEAEs 
 Incidence of TEAEs by relationship 
 Incidence of TEAEs by maximum relationship 
 Incidence of TEAEs by maximum intensity 
 Incidence of fatal TEAEs by relationship 
 Incidence of non-serious TEAEs by relationship 
 Incidence of serious TEAEs by relationship 
 Incidence of non-serious TEAEs above threshold of 5% of subjects in any treatment 
 Incidence of non-serious TEAEs above threshold of 5% of subjects in any treatment by 
relationship 
Summary tables will contain counts of subjects, percentages of subjects in parentheses and the 
number of events where applicable. A subject who has multiple events in the same SOC and PT 
during a given treatment period will be counted only once in the subject counts for that treatment 
period but all events will be included. 
In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Subjects who experience the same event multiple times will be included in 
the most related category for tabulations by maximum relationship. Events with missing 
relationship will be considered as ‘Related’ but recorded as missing in the listings.  
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Subjects 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 and decreasing frequency of PT 
within SOC in the ‘PSL+erythromycin’ column for tables including event counts. For tables 
including only number and percentage of subjects, summaries will be ordered alphabetically by 
SOC and decreasing incidence of PT within SOC in the ‘PSL+erythromycin’ column. 
A listing for all AEs will be presented by subject, treatment period and will include the onset 
date/time and outcome date/time of the event (including relative days), the AE duration 
(derived), time to onset (derived), pattern of event, intensity, relationship, action taken and 
outcome. In addition, the listing will flag AEs that led to discontinuation, TEAEs and SAEs. 
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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 subject, parameter, treatment period and 
timepoint. Any laboratory measurements that are BLQ or ALQ will be handled as described in 
Section 4.2.2. Values outside the reference range for numeric variables will be flagged in the 
listings and in addition, will be listed separately. The reference ranges will also be reported in the 
listings.  
A separate listing will present the subjects who meet one or more of the following criteria at any 
treatment period or time point: 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase ≥3x upper 
limit of normal (ULN) 
 Alkaline phosphatase ≥2xULN 
 Total bilirubin increase ≥2xULN 
The listing will display only treatment periods and time points for which at least one of the above 
criteria was fulfilled for a given subject, and will display all results obtained at that treatment 
period or time point for the specified variables. 
A summary of subjects who meet the criteria for potential drug-induced liver injury (PDILI) will 
be presented together with any additional relevant data collected, if applicable. 
Clinical chemistry and hematology parameters will be summarized by treatment period and 
timepoint for both absolute values and changes from Baseline.  
Laboratory variables will be grouped according to the laboratory function panel (Table 10.1) and 
categorized as normal, high or low, if applicable, based on the reference range supplied by the 
analytical laboratory. For selected variables that are identified in Table 10.1 the change in 
category from Baseline will be presented in shift tables at all post-Baseline timepoints. 
Any additional laboratory variables not included in the outputs described previously will be 
listed separately. These will include the following: 
 Serology 
 Alcohol and cotinine drug screening, alcohol breath test 
 Serum pregnancy test  
Figures of mean and mean change from Baseline may be presented for selected laboratory 
variables that will be identified at the DEM. Figures will be presented with all treatment periods 
overlaid on the same plot. 
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Table 10.1: Laboratory measurements 
Laboratory assessment 
Parameters 
Hematology 
Hemoglobina, hematocrit, red blood cell counta, mean 
corpuscular volume, plateletsa, total white blood cell count, 
and differential consisting of absolute counts and percentages 
of the following leukocyte types: neutrophilsa, lymphocytesa, 
monocytes, eosinophils, and basophils 
Biochemistry 
Sodium, potassium, calcium, inorganic phosphorous, glucose 
(fasting, only at Screening), ureaa, creatininea, total bilirubin 
(conjugated bilirubin when total bilirubin is outside the 
reference range), total protein, albumin, ALTa, ASTa, and 
ALPa 
Viral serology (only at Screening 
Visit) 
HIV-1/2Ab, HBsAg and HCV-Ab 
Pregnancy 
Serum pregnancy test  
Urinalysis 
Specific gravity, pH, glucose (fasting, only at Screening), 
protein, blood, leukocytes, nitrite, ketones, bilirubin, 
urobilinogen (with dipstick) 
If protein, blood, or leukocytes are abnormal (positive), a 
microscopic examination of the sediment will be performed. 
Drug screen 
Amphetamines/methamphetamines, benzodiazepines, 
barbiturates, cocaine, cannabis, methadone, tricyclic 
antidepressants and opiates 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBsAG=hepatitis 
B surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibodies; 
SFU=Safety Follow-Up 
a Shift tables will be presented for these variables 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
The following vital signs measurements will be obtained with the subject resting in the supine 
position for 10 minutes: 
 Systolic and diastolic blood pressure 
 Pulse rate 
 Oral body temperature 
 Respiratory rate 
A by-subject listing of all vital sign measurements and change from Baseline will be presented 
by treatment period and timepoint.  
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Descriptive statistics will be reported for all vital sign measurements. Measured values and 
changes from Baseline will be summarized by vital signs variables and timepoint for each 
treatment period.  
Figures of mean change from Baseline will be presented for each variable. Figures will be 
presented with all treatment periods overlaid on the same plot. 
The number and percentage of subjects with treatment-emergent markedly abnormal 
(TEMA)/potentially clinically significant (PCS) vital sign values as calculated by the criteria 
outlined in Table 10‒2 will be summarized by treatment period at each timepoint and overall. 
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  
12-lead ECG will be recorded 3 times at each time point. The individual mean at each time point 
will be calculated as raw parameters for descriptive analysis. The individual mean and change 
from baseline (time-matched Baseline day of each treatment period, when applicable) will be 
summarized using descriptive statistics by treatment period at each time point. 
All standard 12-lead ECG recordings will be taken in triplicate with the subject resting in the 
supine position for at least 10 minutes. The following ECG parameters will be reported: 
 PR interval  
 QT interval 
 QRS interval 
 RR interval 
 QTc interval (QT corrected for heart rate using Fridericia’s formula [QTcF]) 
 Heart rate  
If available in the database, the QT corrected for heart rate using Bazett’s formula (QTcB) will 
also be included in the listings and tabulations. 
The individual measurements and the mean of the triplicate measurements will be reported in the 
by-subject listings. The listing will also include the change from Baseline (time-matched 
Baseline day of each treatment period, when applicable), based on the mean of the triplicate 
measurements at each timepoint, and will be presented by treatment period and timepoint. 
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Measured values and changes from time-matched Baseline will be summarized by treatment 
period and at each timepoint and by ECG variable (based on the mean of the triplicate values at 
each timepoint). The summaries will include the 2-sided 95% CIs. Mean change from time-
matched Baseline in QTcF will be summarized and plotted over time. Figures will be presented 
with all treatment periods overlaid on the same plot. 
The following cut-points in QTcF (observed data and change from time-matched Baseline), 
based on the mean of the triplicate data, will be summarized categorically (number and 
percentage of subjects) by treatment period at each timepoint. 
For observed data: 
 <450msec 
 ≥450 to <480msec 
 ≥480 to <500msec 
 ≥500msec 
Absolute change from Baseline in QTcF: 
 <30msec 
 ≥30 to <60msec 
 ≥60 msec 
All ECG findings for the individual triplicate measurements will be listed separately. 
Any incomplete triplicate measurements at a given timepoint will be handled as described in 
Section 4.2.3. 
10.4.3 
Other safety variables 
10.4.3.1 
Physical examination 
Subjects with abnormalities in the physical examination will be listed including details of the 
abnormality. 
10.4.3.2 
Columbia-Suicide Severity Rating Scale 
Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al, 2011) data will be listed. 
Module of the questionnaire, time point, question and the associated response will be listed for 
all the visits days where this questionnaire is collected. 
11 
OTHER ANALYSES  
A listing of comments will be presented.  
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12 
REFERENCES 
Phillips, A. and Haudiquet, V. (2003), ICH E9 guideline ‘Statistical principles for clinical trials’: 
a case study. Statist. Med., 22: 1-11. doi:10.1002/sim.1328 
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. Best practices for the use of 
itraconazole as a replacement for ketoconazole in drug-drug interaction studies. J Clin 
Pharmacol. 2016;56 (2):143-51 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77. 
UCB GLOBAL EXPLORATORY DEVELOPMENT PHARMACOMETRICS User Guide for 
Clinical Pharmacokinetics Modeling & Simulation. Version 8.0 – 04/JUL/12 
 
.
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13 
APPENDICES 
13.1 
Breakdown of treatment periods reported into the TFLs by study assessment data 
Table 13.1: Breakdown of treatment periods reported into the TFLs by study assessment data 
Treatment 
PSL 
PSL 
Erythromycin 
pre 
PSL + 
Erythromycin 
Erythromycin 
post 
EOS/ 
SFU 
All 
subjects 
Study Period 
Period 
1 
Period 
2 
Period 
1 + 2 
Period 3a 
Period 3b 
Period 3c 
 
 
Subject disposition 
X 
X 
 
X 
X 
X 
X 
 
Protocol deviations 
X 
X 
 
X 
X 
X 
X 
 
Demographics 
 
 
 
 
 
 
 
X 
Medical history 
 
 
 
 
 
 
 
X 
Lifestyle 
 
 
 
 
 
 
 
X 
Prior/ 
concomitant medications 
 
 
 
 
 
 
 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
 
Laboratory tests 
X 
X 
 
 
X 
X 
X 
 
Other safety continuous 
measurements (vital signs, 
ECG) 
X 
X 
 
X 
X 
X 
X 
 
Safety categorical results 
(laboratory shift tables, PDILI) 
X 
X 
 
 
X 
X 
 
 
PK plasma and urine for PSL 
and metabolites 
X 
X 
 
 
 
X 
 
 
 
ECG=electrocardiogram; EOS=end of study; PK=pharmacokinetic; PSL=Padsevonil; SFU=Safety Follow-up. 
Note: Period refers to the treatment period.   
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14 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN  
Not Applicable 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the SAP 
or amended SAP is released for execution. 
 
 
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