Clinical trial NCT04131517
Conditions: Healthy Female Participants
Keywords: Padsevonil Contraceptives Healthy female participants
Sponsor: UCB Biopharma SRL
Start date: 2019-10-23; Completion date: 2020-05-22
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of the study is to investigate the effect of steady-state padsevonil on the pharmacokinetic of a single dose oral contraceptive.

Detailed description:

Arms: arm 1: Participants will receive oral contraceptive in Period 2 of Sequence A and Period 1 of Sequence B of Part 1 and Part 2. arm 2: Participants will receive padsevonil + oral contraceptive in Period 1 of Sequence A and Period 2 of Sequence B of Part 1 and Part 2.
Interventions: intervention 1: Padsevonil intervention 2: Microgynon 30®
Intervention descriptions: intervention 1: Study Medication: Padsevonil Dosage formulation: Oral tablets; 400 mg BID (Part 1) and 200 mg BID (Part 2) intervention 2: Study Medication: Microgynon 30® Dosage formulation: Oral tablets Dose: Ethinyl estradiol 30 µg + levonorgestrel 150 µg

Protocol documents:
Prot_000.pdf: 
UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 1 of 91
AN OPEN-LABEL, RANDOMIZED, TWO-WAY CROSSOVER 
STUDY TO INVESTIGATE THE POTENTIAL 
PHARMACOKINETIC INTERACTION OF PADSEVONIL WITH 
ORAL CONTRACEPTIVES IN HEALTHY FEMALE 
PARTICIPANTS 
PROTOCOL UP0035 AMENDMENT 2 
PHASE 1 
Short title: 
A pharmacokinetic, safety, and tolerability study of the interaction of padsevonil and oral 
contraceptives in healthy female participants.
Sponsor:
UCB Biopharma SRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Regulatory agency identifying number(s): 
IND Number:
135622
EudraCT Number
2019-002194-54
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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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 2 of 91
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History
Document
Date
Type of amendment
Protocol Amendment 2
25 Feb 2020
Substantial
Protocol Amendment 1
10 Oct 2019
Substantial
Original Protocol
01 Aug 2019
Not applicable
Amendment 2 (25 Feb 2020)  
Overall Rationale for the Amendment 
The study was temporarily placed on hold after the protocol-defined criteria were met
(Section 7.2) ie, 2 severe adverse events (AEs) were reported in 2 study participants. Protocol 
Amendment 2 is to restart the study and includes a reduction in the dose of padsevonil (PSL) 
from 400mg BID to 200mg BID.
During the study, a group of 14 study participants experienced central nervous system (CNS) 
AEs that were expected in type, but which in some study participants were less well tolerated 
than by study participants dosed at the same 400mg BID level in other ongoing healthy volunteer 
studies. In 1 study participant, these AEs (Verbatim Terms: 
) were 
transiently of severe intensity on the 8th day of dosing at 400mg BID, while another 
study participant experienced withdrawal effects that were also of severe intensity over the first 
2 days following completion of the taper. No study participants were prematurely withdrawn 
from the study.
The PSL dose of 400mg BID in UP0035 is one that has been well tolerated in ongoing studies in 
epilepsy patients, where more extended titration and tapering schedules are followed. Compared 
with other clinical pharmacology studies with PSL, the duration of treatment in this study is
considerably longer, and it is likely that this contributed to the persistent AEs. 
It has been decided to reduce the maximum PSL dose level from 400mg BID to 200mg BID and 
reduce the duration of dosing from 19 days to 11 days for subsequent study participants (through 
significant shortening of titration and taper period). The total exposure (cumulative PSL dose in 
mg) will be significantly reduced and similar to other ongoing clinical pharmacology studies. 
This is expected to reduce the AE burden on study participants and to reduce the likelihood of 
withdrawals. It is the evaluation of the Sponsor that the data collected in the study to date, 
coupled with the data generated following this reduction will still enable attainment of the 
drug-drug interaction (DDI) objectives of the study. As an additional safety precaution, the 
Safety Follow-up Period in the newly added Part 2 has also been extended from a maximum of 
10 to a maximum of 14 days from last dose of study medication after each Treatment Sequence.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 3 of 91
Section # and Name
Description of Change
Brief Rationale
Title page
Sponsor name has been updated from 
SPRL to SRL.
Belgium has recently 
adopted a new Code of 
Companies and 
Associations, resulting in a 
mandatory change of the 
name of the legal form of 
the entity “société privée à 
responsabilité limitée”, 
abbreviated “SPRL”, to 
“société à responsabilité 
limitée”, abbreviated 
“SRL”. This change does 
not involve any change to 
the legal form itself, and the 
company name, company 
number and VAT number 
of UCB Biopharma remain 
the same.
Section 1.1.4 and Section 3, 
Objectives and endpoints
-Where PSL dose is specified as 
400mg BID in the objective, 200mg 
BID has also been added. 
-Secondary endpoint, “Incidence of AEs 
and SAEs” has been revised to 
“Incidence of TEAEs and SAEs”. 
-200mg BID will be the 
maximum PSL dose 
evaluated in Part 2 of the 
study. 
-Clarification.
Section 1.1.5 and Section 3,
Overall design and Section 4, 
Study design
Part 2 has been added and described. 
The original design has now been 
designated Part 1. The number of 
study participants who have completed 
Part 1 at the time of its closure and 
replacement with Part 2 has been 
specified. The timing of the SFU visit in 
Part 1 has been corrected. The Part 2
description includes the key elements of 
a reduction in PSL treatment duration 
and extension of the SFU Period. The 
number of study participants planned in 
Part 2 has been specified. 
For Part 2, see overall 
rationale for the 
amendment. The SFU Day 
range for Part 1 was 
corrected so that it is 
consistent with the text in 
Section 1.1.7, Treatment 
groups and duration, which 
states, the SFU Visit should 
occur no sooner than 
7 days, and at a maximum 
of 10 days following the 
final dose of study 
medication.
Section 1.2, Schema
A study schematic for Part 2 (Table 1-3) 
has been added. The original schema 
(Table 1-2) has been retitled as Part 1
treatment sequences, and SFU Day has 
been corrected.
See overall rationale for the 
amendment. The SFU/EOS 
day for Part 1 was corrected 
for reason previously 
provided.
Section 1.3, Schedule of 
Activities
Schedules of study activities for Part 2,
Treatment Sequence A (Table 1-6) and 
See overall rationale for the 
amendment. 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 4 of 91
Section # and Name
Description of Change
Brief Rationale
Part 2, Treatment Sequence B (Table 1-
7) have been added. The original 
Schedules have been retitled to specify 
that they apply to Part 1.
Section 1.3.1.1, Table 1-4,
Schedule of activities –
Part 1 Treatment Sequence A
-EOS/SFU/EDV Day corrected
-General 
medical/medications/procedures 
history added to Baseline, Day -1
-Several assessments moved from Day 
34 to Day 33 (1 day prior to OC dosing
for the OC-only Period)
-Row for Discharge added
-Discharge at start of Washout extended 
by 1 day at discretion of PI (Footnote i
added). 
-Footnote h clarified to specify 
collection only of Mitra™ samples (not 
venous blood samples). 
Clarification.
Section 1.3.1.2, Table 1-5,
Schedule of activities –
Part 1 Treatment Sequence B
-EOS/SFU/EDV Day corrected
-General 
medical/medications/procedures 
history added to Baseline, Day -1
-Several assessments moved from 
Day 18 to Day 17 (one day prior to 
PSL dosing in the PSL+OC Period)
-Footnote e removed from 12-lead ECG 
assessment on Day 30.
-Footnote e was corrected. Deleted 
Day 30 and added Day 29. 
-Physical examination, labs, and ECG 
added to Day 36.
-Row for Discharge added. 
-Discharge added to Day 3
-Discharge at start of SFU Period 
extended by 1 day at discretion of PI 
(Footnote i added). 
-Footnote c clarified. No physical exam 
on Days 24 to 28. 
-Footnotes pertaining to PK sampling 
have been revised to remove 
redundancy and to remove PSL sample 
at 36h.
-Footnote h (Previously footnote i) 
clarified to specify only the collection 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 5 of 91
Section # and Name
Description of Change
Brief Rationale
of Mitra™ samples (not venous blood 
samples). 
Section 2.3, Benefit/risk 
assessment
The benefit/risk assessment has been 
revised. 
The revision was needed to 
account for the TEAEs 
which triggered study hold 
and the addition of Part 2,
with its essential features of 
a reduction in duration of 
PSL dosing and an 
extended SFU Period. 
Section 4.2, Scientific 
rationale for study design
Revisions have been made that are 
necessitated by the reduction of the 
maximum PSL dose from 400mg BID in 
Part 1 to 200mg BID in Part 2.
See overall rationale for the 
amendment.
Section 4.3, Justification for 
dose
Justification has been provided for 
reduction of the maximum PSL dose 
from 400mg BID in Part 1 to 200mg 
BID in Part 2, including UCB’s
assessment that the objective to explore 
the potential DDI between PSL and OC 
will not be compromised by the dose 
reduction.
See overall rational for the 
amendment. 
Section 5.2, Exclusion 
criterion 7
-Specified that the criterion pertains to 
Screening. 
-Added that if blood pressure results on
Baseline (Day -1) are deemed 
clinically significant by the principal 
investigator or designee, the study 
participant will not be included.
Correction/clarification.
Section 5.2, Exclusion 
criterion 14
Specified that the C-SSRS completed at 
Baseline (Day -1) is the “Since Last 
Visit” version.
Clarification. 
Section 5.3.1, Meals and 
dietary restrictions; Section 
6.1, Treatments administered
Specified that on PK sampling days, 
study participants should remain 
semi-recumbent until 4 hours after the 
morning dose of PSL. 
Clarification. 
Section 6.3, Measures to 
minimize bias: 
randomization and blinding
Deleted reference to “code break 
envelopes” and “sealed envelopes.” 
Inclusion of this text was an 
oversight. This is an open-
label study.
Section 6.5.1, Permitted 
concomitant treatments 
(medications and therapies)
The example of “hormonal 
contraceptives” as a concomitant 
medication that could be taken if 
approved on a case-by-case basis prior 
to enrollment has been deleted. 
It is not an appropriate 
example, because study 
participants can’t take OCs 
apart from study OCs. 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 6 of 91
Section # and Name
Description of Change
Brief Rationale
Section 7.1.2, QTc stopping 
criteria
Signs for QTc and QTc change from 
baseline corrected from > to ≥. 
Correction.
Section 7.2, Criteria for study 
hold due to adverse events
-The severe nonserious adverse reaction 
criterion has been revised to specify 
that the criterion is triggered by 
occurrence in 2 study participants in 
Part 1 or Part 2 of the study. 
-Specified that tapering of PSL doses 
and the completion of the OC-only 
TreatmentPperiod in Sequence A will 
be allowed. 
This is necessitated by the 
stoppage of Part 1 and the 
division of the study into 
2 parts. It will ensure that 
Part 2 study participants 
receive the same degree of 
protection as those in 
Part 1.
Section 8.1.1, Mitra™
Revisions have been made to specify the 
target number of study participants in 
each part from which Mitra™ samples 
will be collected. 
Additional Mitra™samples 
are required to fulfill the 
objective.
Section 8.10, Samples for 
PSL bioanalytical method 
cross-validation
Minor revisions have been made to 
wording and to the name of the report.
Clarification. 
Section 9.3, Planned 
pharmacokinetic analyses
-Specified that PK analyses will be 
performed and reported for each study 
part.
-The criteria for lack of clinically 
significant interaction between PSL 
and OC have been further specified. 
-Study days for which PK parameters 
will be compared have been specified 
for Part 2.
-This is necessitated by the 
addition of Part 2.
-This is to allow more 
flexibility in the 
interpretation the clinical 
significance of the PK 
interaction. 
-This is necessitated by the 
addition of Part 2, which 
does not match Part 1 in 
terms of treatment days
(due to shortening of PSL 
treatment duration).
Section 9.4, Planned safety 
analyses
-Specified that safety variables will be 
listed and summarized by study part. 
-Specified that safety variables will be 
listed and summarized for PSL 
treatment alone, ie, prior to 
administration of OC in the PSL+OC 
Period.
-This is necessitated by the 
addition of Part 2.
-This was not previously 
specified. 
Section 9.9, Determination of 
sample size
This has been revised to account for 
discontinuation of Part 1 before the 
planned 20 study participants were 
enrolled and to describe the power 
This was necessitated by 
the addition of Part 2.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 7 of 91
Section # and Name
Description of Change
Brief Rationale
associated with the planned 26 study 
participants in Part 2.
Section 10.2, Appendix 2: 
Clinical Laboratory Tests
and Section 10.4.2.2, 
Pregnancy testing
Revised to reflect that all pregnancy 
tests in the study are serum pregnancy 
tests rather than urine pregnancy tests.
Clarifications to the 
nonapplicable text of 
standard protocol template 
appendices.
Section 10.10, Appendix 10: 
Abbreviations and 
trademarks
New abbreviations have been added. 
Standard procedure. 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BID=twice daily; 
C-SSRS=Columbia Suicide Severity Rating Scale; EDV=Early Discontinuation Visit; EOS=End of Study; 
h=hour(s); OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; QTc=QT interval corrected for heart 
rate; SFU=Safety Follow-up; TM=registered trade mark; VAT=value added tax 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 8 of 91
SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 24 21
Email
Global: DS_ICT@ucb.com
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 9 of 91
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE......................................2 
SERIOUS ADVERSE EVENT REPORTING..........................................................................8 
1 
PROTOCOL SUMMARY...............................................................................................13 
1.1 Synopsis ...........................................................................................................................13 
1.1.1 
Protocol title: .......................................................................................................13 
1.1.2 
Short title: ............................................................................................................13 
1.1.3 
Rationale:.............................................................................................................13 
1.1.4 
Objectives and endpoints.....................................................................................13 
1.1.5 
Overall design......................................................................................................14 
1.1.6 
Number of study participants...............................................................................16 
1.1.7 
Treatment groups and duration............................................................................16 
1.2 Schema.............................................................................................................................17 
1.3 Schedule of Activities......................................................................................................20 
1.3.1 
Part 1....................................................................................................................21 
1.3.1.1 
Part 1 Sequence A .....................................................................................21 
1.3.1.2 
Part 1 Sequence B......................................................................................24 
1.3.2 
Part 2....................................................................................................................27 
1.3.2.1 
Part 2 Sequence A .....................................................................................27 
1.3.2.2 
Part 2 Sequence B......................................................................................30 
2 
INTRODUCTION ...........................................................................................................33 
2.1 Study rationale .................................................................................................................33 
2.2 Background......................................................................................................................33 
2.3 Benefit/risk assessment....................................................................................................34 
3 
OBJECTIVES AND ENDPOINTS .................................................................................36 
4 
STUDY DESIGN.............................................................................................................37 
4.1 Overall design ..................................................................................................................37 
4.2 Scientific rationale for study design.................................................................................38 
4.3 Justification for dose........................................................................................................39 
4.4 End of study definition.....................................................................................................40 
5 
STUDY POPULATION ..................................................................................................40 
5.1 Inclusion criteria ..............................................................................................................40 
5.2 Exclusion criteria .............................................................................................................41 
5.3 Lifestyle restrictions.........................................................................................................44 
5.3.1 
Meals and dietary restrictions..............................................................................44 
5.3.2 
Caffeine, alcohol, and tobacco.............................................................................44 
5.3.3 
Activity ................................................................................................................45 
5.4 Screen failures..................................................................................................................45 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 10 of 91
5.4.1 
Rescreening..........................................................................................................45 
6 
STUDY TREATMENTS.................................................................................................45 
6.1 Treatments administered..................................................................................................45 
6.2 Preparation, handling, storage, and accountability requirements ....................................46 
6.2.1 
Drug accountability .............................................................................................47 
6.3 Measures to minimize bias: randomization and blinding ................................................47 
6.3.1 
Procedures for maintaining and breaking the treatment blind.............................48 
6.3.1.1 
Maintenance of study medication blind ....................................................48 
6.3.1.2 
Breaking the study medication blind in an emergency situation...............48 
6.4 Treatment compliance......................................................................................................48 
6.5 Concomitant medication(s)/treatment(s)..........................................................................48 
6.5.1 
Permitted concomitant treatments (medications and therapies) ..........................48 
6.5.2 
Prohibited concomitant treatments (medications and therapies) .........................49 
6.5.3 
Rescue medication...............................................................................................49 
6.6 Dose modification............................................................................................................49 
6.7 Treatment after the end of the study ................................................................................49 
7 
DISCONTINUATION OF STUDY MEDICATION AND STUDY PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................................49 
7.1 Discontinuation of study medication ...............................................................................49 
7.1.1 
Liver chemistry stopping criteria.........................................................................50 
7.1.2 
QTc stopping criteria ...........................................................................................50 
7.2 Criteria for study hold due to adverse events...................................................................51 
7.3 Study participant discontinuation/withdrawal from the study.........................................51 
7.4 Lost to follow-up..............................................................................................................53 
8 
STUDY ASSESSMENTS AND PROCEDURES...........................................................54 
8.1 Pharmacokinetics .............................................................................................................54 
8.1.1 
Mitra™..................................................................................................................55 
8.2 Pharmacodynamics ..........................................................................................................55 
8.3 Safety assessments...........................................................................................................55 
8.3.1 
Physical examination...........................................................................................55 
8.3.2 
Vital signs ............................................................................................................56 
8.3.3 
Electrocardiograms..............................................................................................56 
8.3.4 
Clinical safety laboratory assessments ................................................................56 
8.3.5 
Suicidal risk monitoring ......................................................................................57 
8.3.6 
Psychiatric and Mental Status..............................................................................57 
8.4 Adverse events.................................................................................................................57 
8.4.1 
Time period and frequency for collecting AE and SAE information..................57 
8.4.2 
Method of detecting AEs and SAEs ....................................................................58 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 11 of 91
8.4.3 
Follow-up of AEs and SAEs................................................................................58 
8.4.4 
Regulatory reporting requirements for SAEs ......................................................58 
8.4.5 
Pregnancy ............................................................................................................59 
8.4.6 
Adverse events of special interest........................................................................59 
8.5 Safety signal detection .....................................................................................................59 
8.6 Efficacy assessments........................................................................................................60 
8.7 Treatment of overdose .....................................................................................................60 
8.8 Genetics............................................................................................................................60 
8.9 Biomarkers.......................................................................................................................60 
8.10 Samples for PSL bioanalytical method cross-validation .................................................60 
9 
STATISTICAL CONSIDERATIONS.............................................................................60 
9.1 Definition of analysis sets................................................................................................60 
9.2 General statistical considerations.....................................................................................61 
9.3 Planned pharmacokinetic analyses ..................................................................................61 
9.4 Planned safety analyses....................................................................................................62 
9.5 Planned efficacy/outcome analyses .................................................................................62 
9.6 Handling of protocol deviations.......................................................................................62 
9.7 Handling of dropouts or missing data..............................................................................63 
9.8 Planned interim analysis and data monitoring.................................................................63 
9.9 Determination of sample size...........................................................................................63 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS...64 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations.............................64 
10.1.1 
Regulatory and ethical considerations.................................................................64 
10.1.2 
Financial disclosure .............................................................................................64 
10.1.3 
Informed consent process ....................................................................................65 
10.1.4 
Data protection.....................................................................................................65 
10.1.5 
Committees structure...........................................................................................65 
10.1.6 
Data quality assurance .........................................................................................66 
10.1.6.1 
Case Report form completion....................................................................66 
10.1.6.2 
Apps...........................................................................................................66 
10.1.7 
Source documents................................................................................................67 
10.1.8 
Study and site closure ..........................................................................................67 
10.1.9 
Publication policy................................................................................................67 
10.2 Appendix 2: Clinical Laboratory Tests............................................................................68 
10.3 Appendix 3: Adverse events – definitions and procedures for recording, evaluating, 
follow-up, and reporting ..................................................................................................70 
10.3.1 
Definition of AE ..................................................................................................70 
10.3.2 
Definition of SAE................................................................................................71 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 12 of 91
10.3.3 
Recording and follow-up of AE and/or SAE.......................................................72 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information .............75 
10.4.1 
Definitions ...........................................................................................................75 
10.4.1.1 
Woman of childbearing potential..............................................................75 
10.4.2 
Contraception guidance .......................................................................................75 
10.4.2.1 
Male participants .......................................................................................75 
10.4.2.2 
Pregnancy testing ......................................................................................75 
10.4.2.3 
Collection of pregnancy information.........................................................75 
10.5 Appendix 5: Genetics.......................................................................................................77 
10.6 Appendix 6: Liver safety–suggested actions and follow-up assessments........................78 
10.7 Appendix 7: Medical device incidents – definition and procedures for recording, 
evaluating, follow-up, and reporting................................................................................82 
10.8 Appendix 8: Rapid alert procedures ................................................................................83 
10.9 Appendix 9: Country-specific requirements....................................................................84 
10.10 
Appendix 10: Abbreviations and trademarks ........................................................85 
10.11 
Appendix 11: Protocol Amendment History .........................................................87 
11 REFERENCES ................................................................................................................89 
SPONSOR DECLARATION..................................................................................................91 
LIST OF TABLES 
Table 1-1: 
Objectives and endpoints .................................................................................13 
Table 1-2: 
Part 1 treatment sequences...............................................................................18 
Table 1-3: 
Part 2 treatment sequences...............................................................................19 
Table 1-4: 
Schedule of activities- Part 1 Treatment Sequence A......................................21 
Table 1-5: 
Schedule of activities- Part 1 Treatment Sequence B......................................24 
Table 1-6: 
Schedule of activities- Part 2 Treatment Sequence A......................................27 
Table 1-7: 
Schedule of activities- Part 2 Treatment Sequence B......................................30 
Table 3-1: 
Objectives and endpoints .................................................................................36 
Table 6-1: 
Study medications administered ......................................................................46 
Table 8‒1: 
Irrelevant time deviations for PK sampling.....................................................55 
Table 10-1: 
Highly Effective Contraceptive Methods ........................................................76 
Table 10-2: 
Phase I liver chemistry stopping criteria and follow-up assessments..............79 
LIST OF FIGURES 
Figure 7-1: 
Liver chemistry stopping algorithm.................................................................50 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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Page 13 of 91
1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
1.1.1 
Protocol title: 
An open-label, randomized, two-way crossover study to investigate the potential 
pharmacokinetic interaction of padsevonil with oral contraceptives in healthy female 
participants.
1.1.2 
Short title: 
A pharmacokinetic, safety, and tolerability study of the interaction of padsevonil with oral 
contraceptives in healthy female participants.
1.1.3 
Rationale: 
Padsevonil is currently being investigated for the treatment of focal onset seizures in adult 
patients with drug-resistant epilepsy. Preclinical investigations (NCD2151, NCD2356), which 
used cryopreserved human hepatocytes, showed that PSL was a weak CYP3A4 inducer. These in 
vitro findings were confirmed in a clinical drug-drug interaction (DDI) study (UP0013) with 
midazolam, a sensitive CYP3A4 probe substrate, which showed that PSL given at 
400mg twice daily (BID) over 6 days, reduced the oral exposure of midazolam by 44%. Oral 
contraceptives (OC), usually in the form of fixed combinations of estrogen and progestin 
steroids, are metabolized at the gut and hepatic level (via oxidation by CYP3A4) 
(Zhang et al, 2018). Therefore, there is potential for PSL to decrease the exposure of OC, and 
thus impair their effectiveness.
This study aims to evaluate the effect of the likely impact of coadministration of PSL on the 
exposure of ethinylestradiol (EE) and levonorgestrel (LN). The outcome of this study will be 
used to inform labeling regarding the use of PSL in combination with OC.
1.1.4 
Objectives and endpoints 
Table 1-1: 
Objectives and endpoints 
Objectives
Endpoints
Primary
x To investigate the effect of steady-state 
PSL (400mg BID or 200mg BID) on the 
PK of a single dose oral contraceptive 
containing EE 30μg and LN 150μg.
 Cmax and AUC of EE and LN
Secondary
x To evaluate the safety and tolerability of 
PSL in healthy female study participants.
 Incidence of TEAEs and SAEs
x To evaluate the effect of single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL.
 Cmax(ss) and AUCτ of PSL
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 14 of 91
Table 1-1: 
Objectives and endpoints 
Objectives
Endpoints
Other
x To evaluate the safety and tolerability of 
PSL in healthy female study participants.
 Changes in vital signs (oral or aural 
temperature, pulse rate, respiratory 
rate, and BP)
 Changes in safety laboratory data 
(hematology, clinical chemistry, and 
urinalysis)
 Changes in 12-lead ECG assessments
 Physical and neurological examination 
findings
x To evaluate the effect of a single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL.
 
CLss/F, Cmin, tmax, t1/2 of PSL
x To evaluate the effect of a single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL 
metabolites
 AUCτ and Cmax,ss, tmax, t1/2ss, Ctrough,
and metabolic ratios of AUCτ and 
Cmax,ss
x To investigate the effect of steady-state 
PSL (400mg BID or 200 mg BID) on the 
PK of a single-dose oral contraceptive 
containing EE 30μg and LN 150μg
 Tmax, AUC(0-t), t1/2,and CL/F of EE and 
LN
x To collect and store blood samples for 
genotyping of drug metabolizing enzymes 
and/or transporters. (if needed)
 Potential genotyping of 
study participants for specific genes 
related to drug metabolizing enzymes 
and/or transporters.
x To collect venous plasma and blood 
samples (Mitra™) for cross-validation of 
PSL bioanalytical method 
 Cross validation of PSL bioanalytical 
method.
BP=blood pressure; ECG=electrocardiogram; EE=ethinylestradiol; LN= levonorgestrel PK=pharmacokinetic; 
PSL=padsevonil; SAE=serious adverse event; TEAE=treatment-emergent adverse event
1.1.5 
Overall design 
This is a Phase 1, open label, randomized, 2-way cross-over study to investigate the potential 
pharmacokinetic (PK) interaction of PSL with OC in healthy female study participants.
Prior to Protocol Amendment 2, the intention was to screen a sufficient number of 
study participants to ensure that 20 study participants would be included in each treatment 
sequence shown in Table 1-2. This pair of treatment sequences has now been designated as 
Part 1, necessitated by the introduction of a new pair of treatment sequences at the new, lower 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 15 of 91
dose level, termed Part 2, for new study participants that will be enrolled under the amended 
protocol. At the time of Amendment 2, 14 study participants completed Part 1 and were dosed 
with PSL 400mg BID (7 study participants in Sequence A and 7 study participants in 
Sequence B). In Part 2, a sufficient number of study participants will be screened to ensure that 
13 study participants are included in each treatment sequence.
Each Part of the study (1 and 2) consists of a Screening Visit, 2 Treatment Periods with at least a 
14-day washout between periods, and a Safety Follow-up (SFU) Visit that will occur no sooner 
than 7 days, and at a maximum of 10 days (Part 1) or 14 days (Part 2) following the final dose of 
study medication. 
Study participants who provide written informed consent will be screened during the 28-day 
period from Day -29 to Day -2. Study participants who meet all inclusion and none of the 
exclusion criteria will check into the clinic on Day -1 (Baseline, the day prior to Day 1, the first 
day of the first Treatment Period, and will be randomized into one of the 2 treatment sequences: 
Treatment Sequence A or Treatment Sequence B (see Section 1.3, Schedules of activities).
Each study participant will be dosed with OC and OC+PSL during the 2 Treatment Periods in 
either Treatment Sequence A or Treatment Sequence B. If the study participant is randomized to 
Treatment Sequence A, they will receive OC+PSL during the first Treatment Period followed by 
OC alone during second Treatment Period. If the study participant is randomized to 
Treatment Sequence B, they will receive OC alone during the first Treatment Period followed by 
OC+PSL during the second Treatment Period. There will be a Washout Period of at least 14 days 
between treatments within each sequence (see Section 1.2, Schema).
Part 1
Sequence A
Study participants enrolled in the Treatment Sequence A group will start with up-titration of PSL 
with increasing repeated BID doses to reach a steady-state dose level of PSL 400mg BID. Once 
at steady-state, on the morning of Day 13, study participants will receive a single dose of OC in 
addition to PSL 400mg BID. From Day 15 to Day 19, PSL will be tapered from a dose of 
400mg BID to 100mg BID. On Day 20, study participants will start the 14-day Washout Period. 
On Day 34, a single dose of OC will be administered followed by 2 days of PK measurements. 
An SFU Visit will occur between Day 41 to Day 44.
Sequence B
Study participants enrolled in the Treatment Sequence B group will start with the single dose of 
OC on the morning of Day 1 followed by 2 days of PK measurements and will then start the
14-day Washout Period. At the end of the Washout Period, the Treatment Sequence B group will 
start with up-titration of PSL treatment with increasing repeated BID doses to reach a steady-
state dose level of PSL 400mg BID. Once at steady-state, on the morning of Day 30,
study participants will receive a single dose of OC in addition to PSL 400mg BID. From 
Day 32 to Day 36, PSL will be tapered from a dose of 400mg BID to 100mg BID. All
study participants will complete an SFU Visit between Day 43 and Day 46. 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 16 of 91
Part 2
Protocol Amendment 2 introduces Part 2 (Schematic shown in Table 1-3) in which 
26 study participants are planned to be enrolled, due to the stop of Part 1 after the completion of 
14 study participants.
Sequence A
All study participants enrolled in Part 2, Treatment Sequence A, will be administered 
PSL 100mg BID on Day 1, with titration to 200mg BID for Day 2 to Day 10. A single dose of 
OC is administered on the morning of Day 9, at which time PSL is at steady state. 
Pharmacokinetic assessments will be collected according to the Schedule of Activities. To taper, 
100mg BID of PSL will be given on Day 11. Starting on Day 12, the study participants will then 
complete a Washout Period for 14 days followed by a return to the clinic on Day 25 for the 
OC-only dosing on Day 26. Pharmacokinetic samples will be collected on Days 26, 27, and 28. 
An SFU Visit will occur between Day 33 and Day 40.
Sequence B
All study participants enrolled in Part 2, Treatment Sequence B, will be administered a single 
dose of OC on the morning of Day 1 followed by PK assessments that day and the next 2 days. 
The study participants will then complete a 14-day Washout Period followed by a return to the 
clinic for the OC+PSL dosing from Day 18 to Day 28 (OC to be administered on Day 26, at
which time PSL is at steady state). Study participants will be administered PSL 100mg BID on 
Day 18, with titration to 200mg BID for Day 19 to Day 27. To taper, 100mg BID of PSL will be 
given on Day 28. An SFU Visit will occur between Day 35 and Day 42.
1.1.6 
Number of study participants 
Forty evaluable study participants will be enrolled overall. A total of 14 evaluable 
study participants (7 study participants in each sequence) have completed Part 1 with 
PSL 400mg BID dosing. For Part 2 with PSL 200mg BID dosing, a total of 26 evaluable 
study participants is planned (13 study participants in each sequence).
Study participants who are withdrawn may be replaced following discussion between the 
Investigator and Sponsor.
1.1.7 
Treatment groups and duration 
In Part 1, the maximum total duration of the study is approximately 75 days for each 
study participant, including the Screening Period (up to 28 days), a 36-day Treatment Period 
including a 14-day Washout Period, and a SFU Visit (the SFU Visit should occur no sooner than
7 days, and at a maximum of 10 days following the final dose of study medication). 
Study participants in Part 1 (either sequence) will be treated with PSL (maximum dose of 400mg 
BID) for a total of 19 days. 
In Part 2, the maximum total duration of the study is approximately 70 days for each 
study participant, including the Screening Period (up to 28 days), a 28-day Treatment Period, 
including a 14-day Washout Period, and a SFU Visit (the SFU Visit should occur no sooner than 
7 days, and at a maximum of 14 days following the final dose of study medication). 
Study participants in Part 2 (either sequence) will be treated with PSL (maximum dose of 200mg 
BID) for 11 days, a reduction of 8 days compared with Part 1.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 17 of 91
1.2 
Schema 
Detailed schematic diagrams of the Part 1 and Part 2 treatment sequences are provided in 
Table 1-2 and Table 1-3.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 18 of 91
Table 1-2: 
Part 1 treatment sequences  
Part 1 Treatment Sequence A
PSL+OC
Washout 
(14 Days)
OC
SFU/
EOS
Day
1
2 to 3
4 to 5
6 to 12
13
14
15 to 16
17 to 18
19
20 to 33
34
35
36
41 to 44
OC Dose
OC SD
OC 
SD
PSL Dose
(mg)
100 BID
200 BID
300 BID
400 BID
400 BID
400 BID
300 BID
200 BID
100 BID
PK 
Sampling
PK 
(Day 2
only)a
PK
(Day 4
only) a
PK
(Days 6, 
8, 10, and 
12)
PK
PK
PK
(Day 15
only)
PK
PK
PK
Part 1 Treatment Sequence B
OC
Washout 
(14 
Days)
PSL+OC
SFU/
EOS
Day
1
2
3
4 to 17
18
19 to 20
21 to 22
23 to 29
30
31
32 to 33
34 to 35
36
43 to 46
OC Dose
OC 
SD
OC SD
PSL 
Dose(mg)
100 BID
200 BID
300 BID
400 BID
400 BID
400 BID
300 BID
200 BID
100 BID
PK 
Sampling
PK
PK
PK
PK 
(Day 19
only) a
PK 
(Day 21
only) a
PK 
(Days 23, 
25, 27, 
and 29)
PK
PK
PK
(Day 32)
BID=twice daily; EOS=End of Study; OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SD=single dose; SFU=Safety Follow-up
a Pharmacokinetic samples must be taken before morning dose of PSL.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 19 of 91
Table 1-3: 
Part 2 treatment sequences 
Part 2 Treatment Sequence A
PSL+OC
Washout 
(14 Days)
OC
SFU/
EOS
Day
1
2 to 8
9
10
11
12 to 25
26
27
28
33 to 40
OC Dose
OC SD
OC SD
PSL Dose (mg)
100 BID
200 BID
200 BID
200 BID
100 BID
PK Sampling
PK (Days 2, 4, 6, 8 only) 
a
PK
PK
PK
PK
PK
PK
Part 2 Treatment Sequence B
OC
Washout 
(14 Days)
PSL+OC
SFU/
EOS
Day
1
2
3
4 to 17
18
19 to 25
26
27
28
35 to 42
OC Dose
OC SD
OC SD
PSL Dose 
(mg)
100 BID
200 BID
200 BID
200 BID
100 BID
PK Sampling
PK
PK
PK
PK (Day 19, 21, 23, 25 only) 
a
PK
PK
PK
BID=twice daily; EOS=End of Study; OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SD=single dose; SFU=Safety Follow-up
a Information on sampling time is provided in the Schedule of Activities Table.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 20 of 91
1.3 
Schedule of Activities 
The Schedules of Activities for Part 1, Treatment Sequences A and B are presented in Table 1-4
and Table 1-5, respectively.
The Schedules of Activities for Part 2, Treatment Sequences A and B are presented in Table 1-6
and Table 1-7, respectively.
COPY 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 21 of 91
1.3.1 
Part 1 
1.3.1.1 
Part 1 Sequence A 
Table 1-4: 
Schedule of activities- Part 1 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ 
SFU/
EDVa
Day
-29 to -2
-1
1
2 to 3 4 to 5
6 to 12
13
14
15 to 1
6
17 to 18
19
20 to 33
34
35
36
41 to 44
Written informed 
consent
X
Demographics and 
baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
General medical 
/medications/ 
procedures history
X
X
X (D33)
Suicidality Risk 
Assessment (C-SSRS)b
X
X
X (D33)
X
Psychiatric and mental 
status evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X (D33)
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D33)
Hematology, clinical 
chemistry, urinalysis
X
X
X
X (D33)
X
Serology (HIV, HBsAg 
HEV, syphilis, and 
HCV-Ab)
X
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 22 of 91
Table 1-4: 
Schedule of activities- Part 1 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ 
SFU/
EDVa
Day
-29 to -2
-1
1
2 to 3 4 to 5
6 to 12
13
14
15 to 1
6
17 to 18
19
20 to 33
34
35
36
41 to 44
12-lead ECG
X
X
X
Xe
Xe
Xe
X
X
X
X
Urine and cotinine drug 
screen, and alcohol 
breath test
X
X
X (D33)
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X
X
X
X
X
X
X (D33)
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing enzymes 
and/or transporters
X
Admit to clinic
X
X (D33)
Administer PSL
X
X
X
X
X
X
X
X
X
Administer OC
X
X
Blood sampling for PSL 
PK levels
Xf
Xf
Xf
Xf
Xf
Xf
Blood sampling for OC 
PK levels 
Xg
Xg
Xg
Xg
Xg
Xg
Blood sampling for 
cross-validationh
X
Discharge
X (D20 or 
D21)i
X
C-SSRS=Columbia Suicide Severity Rating Scale; EOS=End of Study; EDV=Early Discontinuation Visit; ECG=electrocardiogram; h=hour(s);
HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus; 
OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 23 of 91
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months), followed by the “Since 
Last Visit” version at subsequent visits.
c At Screening, Baseline (Day -1), Day 6, and Day 12, a full physical examination will be performed. On all other days a physical examination is performed, it
will be a brief physical examination (Section 8.3.1). On Days 7 to 11, physical examination will not be performed. 
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions), pulse rate, 
respiratory rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood 
pressure measurement.
e ECG will be completed on Days 2, 4, 6, and 12 only of multiple day periods during Treatment Sequence A.
f During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 2, Day 4, Day 6, Day 8 and Day 10. 
Additional blood sampling for PK analysis will be taken on Day 12 (PSL PK) before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 
6h, 8h, 12h postdose and on Day 13 (PSL and OC PK) before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 
12h, 24h (before morning PSL dose on Day 14), and 48h (before morning PSL dose on Day 15) postdose.
g During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 13 (before OC+PSL morning dose) and after PSL and OC 
morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 14), 36h (Day 14), and 48h (Day 15) postdose. During the single-dose OC period, PK 
blood samples will be taken on Day 34 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 35), 36h (Day 35), and 48h (Day 36) postdose.
h Mitra ™ (finger prick) blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 12 only for selected study participants. See Section 8.1.1 for details 
about selection.
i The study participant can be discharged on Day 20 or Day 21, at the discretion of the principal investigator. 
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 24 of 91
1.3.1.2 
Part 1 Sequence B 
Table 1-5: 
Schedule of activities- Part 1 Treatment Sequence B 
Screening
Baseline
OC
Washout 
(14 Days)
PSL+OC
EOS/ 
SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 20
21 to 
22
23 to 
29
30
31
32 to 
33
34 to 
35
36
43 to 46
Written informed 
consent
X
Demographics and 
baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
X
General medical 
/medications/ 
procedures history
X
X
X (D17)
Suicidality Risk 
Assessment (C-SSRS)b
X
X
X (D17)
X
Psychiatric and mental 
status evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D17)
Hematology, clinical 
chemistry, urinalysis
X
X
X (D17)
X
X
Serology (HIV, HbsAg, 
HEV, syphilis, and 
HCV-Ab)
X
12-lead ECG
X
X
X
X
Xe
Xe
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X
X
X
X
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 25 of 91
Table 1-5: 
Schedule of activities- Part 1 Treatment Sequence B 
Screening
Baseline
OC
Washout 
(14 Days)
PSL+OC
EOS/ 
SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 20
21 to 
22
23 to 
29
30
31
32 to 
33
34 to 
35
36
43 to 46
Urine and cotinine drug 
screen, and alcohol 
breath test
X
X
X (D17)
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X(D17)
X
X
X
X
X
X
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing enzymes 
and/or transporters
X
Admit to clinic
X
X (D17)
Administer PSL
X
X
X
X
X
X
X
X
X
Administer OC
X
X
Blood sampling for PSL 
PK levels
Xf
Xf
X f
Xf
Xf
Xf
Blood sampling for OC 
PK levels
Xg
Xg Xg
Xg
Xg
Xg
Blood sampling for 
cross-validationh
X
Discharge
X
X (D37 
or D38)i
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EDV= Early Discontinuation Visit; EOS=End of Study; h=hour(s); 
HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus;
OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 26 of 91
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months), followed by the “Since 
Last Visit” version at subsequent visits.
c At Screening, Baseline (Day -1), Day 23, and Day 29, a full physical examination will be performed. On all other days a physical examination is performed, it
will be a brief physical examination (Section 8.3.1). On days 24-28, physical examination will not be performed. 
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions.), pulse rate, 
respiratory rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood 
pressure measurement.
e ECG will be completed on Days 19, 21, 23, and 29 only of multiple day periods during Treatment Sequence B.
f During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 19, Day 21, Day 23, Day 25, and Day 27. 
Additional blood sampling for PK analysis will be taken on Day 29 (PSL PK) before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 
6h, 8h, 12h postdose and on Day 30 (PSL PK) before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h 
postdose. In addition, blood samples will be obtained prior to the morning dose on Day 31 and prior to the morning dose on Day 32.
g During the single-dose OC period, PK blood samples will be taken on Day 1 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day2), 36h 
(Day 2), and 48h (Day 3) postdose. During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 30 (before OC+PSL morning 
dose) and after PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 31), 36h (Day 31), and 48h (Day 32) postdose.
h Mitra ™ (finger prick) blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 29 only. See Section 8.1.1 for details about selection.
i The study participant can be discharged on Day 37 or Day 38, at the discretion of the principal investigator.
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 27 of 91
1.3.2 
Part 2 
1.3.2.1 
Part 2 Sequence A 
Table 1-6: 
Schedule of activities- Part 2 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ SFU/
EDVa
Day
-29 to -2
-1
1
2 to 8
9
10
11
12 to 25
26
27
28
33 to 40
Written informed consent
X
Demographics and 
baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
General medical 
/medications/ procedures 
history
X
X
X (D25)
Suicidality Risk 
Assessment (C-SSRS)b
X
X
X(D25)
X
Psychiatric and mental 
status evaluation 
X
X
Xh
Xh
Xh
Xh
Xh
X
Physical examinationc
X
X
X
X
X
X (D25)
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D25)
Hematology, clinical 
chemistry, urinalysis
X
X
X
X (D25)
X
Serology (HIV, HBsAg 
HEV, syphilis, and 
HCV-Ab)
X
12-lead ECG
X
X
X
Xe
X
X
X
X
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 28 of 91
Table 1-6: 
Schedule of activities- Part 2 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ SFU/
EDVa
Day
-29 to -2
-1
1
2 to 8
9
10
11
12 to 25
26
27
28
33 to 40
Urine and cotinine drug 
screen, and alcohol 
breath test
X
X
X (D25)
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X
X
X (D25)
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing enzymes 
and/or transporters
X
Admit to clinic
X
X (D25)
Administer PSL
X
X
X
X
X
Administer OC
X
X
Blood sampling for PSL 
PK levels
Xf
Xf
Xf
Xf
Blood sampling for OC 
PK levels 
Xg
Xg
Xg
Xg
Xg
Xg
Blood sampling for 
cross-validationj
X
Discharge
X (D12 or D13)i
X
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EOS=End of Study; h=hour(s);
HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus; OC=oral 
contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 29 of 91
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months), followed by the “Since 
Last Visit” version at subsequent visits.
c At Screening, Baseline (Day -1), and Day 8, a full physical examination will be performed. On all other days a physical examination is performed, it will be a 
brief physical examination (Section 8.3.1). On days 2-7, physical examination will not be performed. 
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions), pulse rate, 
respiratory rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood 
pressure measurement.
e ECG will be completed on Days 2, and 8 only of multiple day periods during Treatment Sequence A.
f During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 2, Day 4, and Day 6. Additional blood 
sampling for PK analysis will be taken on Day 8  before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h postdose and on 
Day 9  before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (before morning PSL dose on Day 10), 
and 48h (before morning PSL dose on Day 11) postdose.
g During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 9 (before OC+PSL morning dose) and after PSL and OC morning 
dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, In addition, blood samples will be obtained prior to the morning dose on Day 10, 36h (Day 10), and 48h 
(Day 11) postdose. During the single-dose OC period, PK blood samples will be taken on Day 26 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 
24h (Day 27), 36h (Day 27), and 48h (Day 28) postdose.
h Psychiatric and mental status evaluation will be done pre-dose. 
i The study participant can be discharged on Day 12 or Day 13, at the discretion of the principal investigator.
j Mitra ™ (finger prick) and venous blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 8 only for selected study participants. See Section 8.1.1
for details about selection.
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 30 of 91
1.3.2.2 
Part 2 Sequence B 
Table 1-7: 
Schedule of activities- Part 2 Treatment Sequence B 
Screening
Baseline
OC
Washout 
(14 Days)
PSL+OC
EOS/ SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 25
26
27
28
35 to 42
Written informed 
consent
X
Demographics and 
baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
X
General medical 
/medications/ 
procedures history
X
X
X (D17)
Suicidality Risk 
Assessment (C-SSRS)b
X
X
X (D17)
X
Psychiatric and mental 
status evaluation 
X
X
Xf
Xf
Xf
Xf
Xf
X
Physical examinationc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D17)
Hematology, clinical 
chemistry, urinalysis
X
X
X(D17)
X
X
Serology (HIV, HbsAg, 
HEV, syphilis, and 
HCV-Ab)
X
12-lead ECG
X
X
X
X
Xe
X
X
X
X
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2


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 31 of 91
Table 1-7: 
Schedule of activities- Part 2 Treatment Sequence B 
Screening
Baseline
OC
Washout 
(14 Days)
PSL+OC
EOS/ SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 25
26
27
28
35 to 42
Urine and cotinine drug 
screen, and alcohol 
breath test
X
X
X(D17)
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X (D17)
X
X
X
X
X
X
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genotyping of drug 
metabolizing enzymes 
and/or transporters
X
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X
X (D17)
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X
X
X
X
X
Administer OC
X
X
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PK levels
X g
Xg
Xg
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PK levels
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X
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X
X (D29 or 
D30)i
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EOS=End of Study; h=hour(s); 
HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus; OC=oral 
contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months) followed by the “Since 
Last Visit” version at subsequent visits.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 32 of 91
c At Screening, Baseline (Day -1), and Day 25, a full physical examination will be performed. On all other days a physical examination is performed, it will be a 
brief physical examination (Section 8.3.1). On Days 19-24, physical examination will not be performed. 
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions.), pulse rate, 
respiratory rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood 
pressure measurement.
e ECG will be completed on Days 19, and 25 only of multiple day periods during Treatment Sequence B.
f Psychiatric and mental evaluation will be done pre-dose. 
g During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 19, Day 21,and Day 23. Additional blood 
sampling for PK analysis will be taken on Day 25  before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h postdose and 
on Day 26 before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 27), and 48h (Day28) postdose.
h During the single-dose OC period, PK blood samples will be taken on Day 1 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,  24h (Day 2), 36h 
(Day 2), and 48h (Day 3) postdose. During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 26 (before OC+PSL morning 
dose) and after PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 27), 36h (Day 27), and 48h (Day 28) postdose.
i The study participant can be discharged on Day 29 or Day 30, at the discretion of the principal investigator.
j Mitra ™ (finger prick) and venous blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 25 only for selected study participants. See 
Section 8.1.1 for details about selection.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 33 of 91
2 
INTRODUCTION 
2.1 
Study rationale 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic vesicle protein 2 
(SV2) isoforms and postsynaptic central benzodiazepine receptor cBZR sites on the GABAA
receptor that has shown compelling, broad-range efficacy in several preclinical models of 
epilepsy conducted by UCB. Padsevonil is currently being investigated for the treatment of focal 
onset seizures in adult patients with treatment-resistant epilepsy. Preclinical investigations 
(NCD2151, NCD2356), which used cryopreserved human hepatocytes, showed that PSL was a 
weak CYP3A4 inducer. These in vitro findings were confirmed in the clinical DDI study with 
midazolam, a sensitive CYP3A4 probe substrate (UP0013). Indeed, this study showed that PSL 
given at 400mg BID reduced the oral exposure of midazolam by 44%.
Oral contraceptives, usually in the form of fixed combinations of estrogen and progestin steroids, 
are metabolized via oxidation by CYP3A4 at the gut and hepatic level (Zhang et al, 2018). 
Strong CYP3A4 inducers like rifampin, carbamazepine, and phenytoin, which have very large 
impact on oral midazolam exposure (>80% exposure reduction), reduced the exposure of EE to a 
lesser extent (38% to 66%) (Backman et al, 1996). The smaller effect size of EE compared with 
oral midazolam to CYP3A4 inducers is most likely due to the multiple elimination pathways of 
EE which may be less inducible than CYP3A4. As a weak inducer of CYP3A4, it is expected 
that the effect of PSL on EE exposure will be less than that observed for oral midazolam. A 
fit-for-purpose physiologically-based PK model aiming at predicting the DDI between PSL and 
EE showed that a weak DDI (16% decrease of EE AUC) may occur at a PSL dose of 400mg 
BID.
Therefore, UP0035 aims to evaluate the impact of coadministration of PSL on the exposure of 
EE and LN. The outcome of this study will be used to inform labeling regarding the use of PSL 
in combination with OC.
2.2 
Background 
More than 50 million people worldwide suffer from epilepsy (World Health Organization, 2018). 
An imbalance between excitatory and inhibitory neurotransmission is widely recognized as a key 
factor leading to epilepsy. Consequently, drugs currently used in the treatment of epilepsy aim to 
restore this balance. In fact, most of the current anti-epileptic drugs (AEDs) modulate neuronal 
transmission by either blocking voltage-gated sodium channels or acting on inhibitory/excitatory 
receptors located at the postsynaptic level.
The GABAA receptor mediates the bulk of inhibitory neurotransmissions in the brain. Allosteric 
modulation of inhibitory GABAA receptors by the cBZR site offers robust protection against 
seizures (Riss et al, 2008). However, their clinical use as AEDs is limited due to an unfavorable 
side effect profile (eg, drowsiness, ataxia, amnesia, paradoxical aggression), as well as the 
development of tolerance to anticonvulsant effects.
Compounds binding to SV2A proteins on synaptic vesicles are characterized by broad-spectrum 
efficacy against both generalized and partial seizures in preclinical models, and this protective 
activity strongly correlates with their binding affinity (Kaminski et al, 2008). The function of 
SV2B and SV2C subtypes is not well established, but they share a high degree of sequence 
homology to SV2A and localization within synaptic vesicles (Wan et al, 2010; 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 34 of 91
Janz and Südhof, 1999). Levetiracetam (LEV), exemplifying a SV2A-related mechanism of 
action, displays prominent clinical efficacy in patients with different forms of epilepsy 
(Klitgaard and Verdru, 2007).
Compounds with dual activity at SV2A and GABAA receptors are expected to have superior 
efficacy to those drugs working through only one of these mechanisms. Preclinical data in 
animal models of epilepsy support this assumption with compelling synergistic interaction 
observed between LEV and AEDs with GABAergic mechanisms of action 
(Kaminski et al, 2009). This synergistic interaction was particularly pronounced when 
combinations of LEV and benzodiazepines were tested and a significant increase in the 
anticonvulsant potency of these drugs was observed associated with a higher therapeutic index.
Padsevonil is a novel chemical entity with selective affinity for both presynaptic SV2 proteins 
and postsynaptic cBZR sites on the GABAA receptor. At presynaptic sites, PSL binds with high 
affinity to all 3 subtypes of the SV2 protein (ie, SV2A, SV2B, and SV2C), and with moderate 
affinity to postsynaptic cBZR sites. Pharmacological results obtained in rodent models of either 
partial or generalized seizures in humans show that PSL provides potent and efficacious seizure 
suppression, suggesting a broad-spectrum profile. Furthermore, PSL revealed potent and 
efficacious seizure suppression in models of drug-refractory epilepsy, suggesting superior 
efficacy against seizures refractory to currently used AEDs. Specifically, in the rat amygdala
kindling model, a model of refractory focal epilepsy, PSL was the only compound that produced 
seizure freedom at doses that can be administered in humans. Valproate, brivaracetam, 
clonazepam, diazepam, and phenobarbital only produced seizure freedom at plasma exposures 
that exceeded the maximum human exposures multiple times over. Padsevonil is not associated 
with loss of anticonvulsant efficacy after repeated administration in mice, suggesting reduced 
potential for the development of tolerance. Because of its unique properties, PSL is currently 
being proposed as adjunctive therapy in the treatment of focal-onset seizures in adult patients 
with drug-resistant epilepsy.
2.3 
Benefit/risk assessment 
Overall, the AE profile of PSL in clinical pharmacology studies is consistent with the 
pharmacological activity of the product, and, as expected, in the context of early dose escalation 
studies in healthy study participants. The safety findings to date suggest that the AEs 
experienced by study participants receiving single and repeated doses of PSL are limited 
principally to CNS effects. The AEs tend to be dose related in frequency and intensity, 
self-limiting, and tend to decrease in intensity over the first few days of dosing.
As described in the Investigator’s Brochure, the overall safety for the Phase 1 studies was 
generally good at doses up to 400mg BID administration. As of the cut-off date of 06 Dec 2019,
there have been 2 serious adverse events (delirium and mania) and no deaths during the studies. 
Of the treatment emergent adverse events (TEAEs) occurring in 247 healthy study participants 
and 79 study participants with epilepsy exposed to PSL, 3 study participants reported 47 severe 
TEAEs, with the most prevalent being somnolence, fatigue and balance disorder. The severe 
psychiatric AEs that have occurred in Phase 1 and Phase 2 studies were delirium, depressed 
mood, and insomnia. These severe psychiatric adverse events were transient, and the symptoms 
resolved after withdrawal of PSL. The possibility of acute psychiatric AEs highlights the need to 
maintain vigilance for such effects and to monitor for any psychiatric/mood/behavioral signs in 
studies with healthy study participants and in studies with epilepsy patients.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 35 of 91
Acute psychiatric events of transiently severe intensity were observed in 2 healthy study 
participants in UP0035. Such events are considered to be part of the identified risks of acute 
psychiatric incidents per the Safety Risk Management Strategy; ie, it is not unexpected for this 
type of event to occur, especially with repeated dosing at 400mg BID. The Safety Risk 
Management Strategy already considers that:
x Psychiatric and behavioral symptoms may require dose reduction or discontinuation.
x Study participants should be withdrawn if they develop psychiatric/mood/behavioral signs or 
disturbances that are ‘clinically concerning’ or that worsen over time. 
x Clinically significant psychiatric AEs will lead to prompt withdrawal from studies. 
x Monitoring for psychiatric AEs will be performed throughout the study and increased 
vigilance observed during dose titration and dose tapering, in addition to monitoring for 
withdrawal symptoms during dose taper of investigational medicinal product (IMP).
Unless compelled by objective-specific regulatory guidance, the clinical pharmacology studies 
have routinely used lower doses (ie, 200mg or 100mg) due to the poorer tolerability in healthy 
study participants as compared to epilepsy patients. However, in UP0035, such regulatory 
guidance was followed in order to evaluate the highest dose for potential effects of PSL on oral 
contraceptives. In addition, the dosing needed to be slightly longer versus other clinical 
pharmacology studies due to the time required for any induction of metabolizing enzymes by 
PSL to take place. The findings from this study will provide important information as to whether 
coadministration of PSL reduces exposure to EE and LN in women of child-bearing potential 
with epilepsy. 
The nature, frequency and severity of the AEs are similar to those observed in earlier clinical 
pharmacology studies, even though some specific measures (titration and tapering) were utilized 
in this study to try to improve tolerability. This provides further evidence that healthy 
study participants do not tolerate repeated dosing of PSL at 400mg BID as well as epilepsy 
patients. It is currently unknown if a longer titration and tapering period would result in a better 
tolerability in healthy participants; nevertheless, this is not feasible for Phase 1 studies.  
With respect to cardiovascular health, despite the occurrence of several ECG findings (including 
different types of ectopy) both in healthy study participants and study participants with epilepsy, 
an independent expert cardiologist reviewed data from Phase 1 and Phase 2 studies (EP0069 and 
EP0073) and determined that none of these findings were assessed as being likely to be related to 
PSL. No clinically significant echocardiographic findings (only minor/trace or Grade 1 findings) 
were observed in EP0069 and EP0073, and all echocardiograms were assessed as normal. There 
are currently no clinical data to suggest that the drug has an adverse effect on cardiovascular 
function other than a minimal lowering effect on blood pressure. The degrees of reduction seen 
in both systolic blood pressure and diastolic blood pressure are consistent with the 
GABA-A-targeted mechanism of action of PSL and do not appear likely to have a clinically 
significant effect in therapeutic use. As a precaution, and in view of the nonclinical 
histopathological cardiac findings, echocardiogram screening of study participants at Baseline 
and ongoing echocardiogram monitoring during treatment and posttreatment have been 
implemented in the studies that have a >3-week treatment duration. To date, no clinically 
significant echocardiogram findings (only minor/trace or Grade 1 findings) have been observed.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 36 of 91
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of PSL may be found in the Investigator’s Brochure. The current Investigator’s 
Brochure reflects the safety profile of PSL as it is known and may change with the accumulation 
of additional data.
The study participants included in this study will receive no medical benefit from participation. 
The risks from taking part in the study will be minimized through the use of appropriate dose 
levels and duration of dosing, selection of appropriate study participants defined by the 
inclusion/exclusion criteria, and safety monitoring.
3 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints for this study are presented in Table 3-1.
Table 3-1: 
Objectives and endpoints 
Objectives
Endpoints
Primary
x To investigate the effect of steady-state 
PSL (400mg BID or 200mg BID) on the 
PK of a single dose oral contraceptive 
containing EE 30μg and LN 150μg.
 Cmax and AUC of EE and LN
Secondary
x To evaluate the safety and tolerability of 
PSL in healthy female study participants.
 Incidence of TEAEs and SAEs
x To evaluate the effect of single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL.
 Cmax(ss) and AUCτ of PSL
Other
x To evaluate the safety and tolerability of 
PSL in healthy female study participants.
 Changes in vital signs (oral or aural 
temperature, pulse rate, respiratory 
rate, and BP)
 Changes in safety laboratory data 
(hematology, clinical chemistry, and 
urinalysis)
 Changes in 12-lead ECG assessments
 Physical and neurological examination 
findings
x To evaluate the effect of a single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL.
 
CLss/F, Cmin, tmax, t1/2 of PSL
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 37 of 91
x To evaluate the effect of a single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL 
metabolites
 AUCτ and Cmax,ss, tmax, t1/2ss, Ctrough,
and metabolic ratios of AUCτ and 
Cmax,ss
x To investigate the effect of steady-state 
PSL on the PK of a single-dose oral 
contraceptive containing EE 30μg and LN 
150μg
 Tmax, AUC(0-t), t1/2,and CL/F of EE and 
LN
x To collect and store blood samples for 
genotyping of drug metabolizing enzymes 
and/or transporters. (if needed)
 Potential genotyping of 
study participants for specific genes 
related to drug metabolizing enzymes 
and/or transporters.
x To collect venous plasma and blood 
samples (Mitra™) for cross-validation of 
PSL bioanalytical method 
 Cross validation of PSL bioanalytical
method.
BP=blood pressure; ECG=electrocardiogram; EE=ethinylestradiol; LN= levonorgestrel PK=pharmacokinetic; 
PSL=padsevonil; SAE=serious adverse event; TEAE=treatment-emergent adverse event
4 
STUDY DESIGN 
4.1 
Overall design 
This is a Phase 1, open label, randomized, two-way cross-over study to investigate the potential 
PK interaction of PSL with OC in healthy female study participants. The designs of Part 1 and 
Part 2 are shown in Table 1-2 and Table 1-3.
A study participant who provides written informed consent will be screened within 28 days 
before the first Treatment Period. Each Part of the study (Part 1 and Part 2) consists of a 
Screening Period, 2 Treatment Periods, a Washout Period, and a Safety-Follow-Up (SFU) Period 
of 7 to 10 days (Part 1) or 7 to 14 days (Part 2).
Study participants who meet all inclusion criteria and none of the exclusion criteria will check 
into the clinic the day prior to the first day of the first Treatment Period and will be randomized 
into one of the treatment sequences: Treatment Sequence A or Treatment Sequence B.
The Treatment Periods will consist of a single dose of OC or a dose of OC combined with 
multiple doses of PSL for a time period. The OC Treatment Periods are separated by a 
Washout Period lasting at least 14 days.
Part 1
Sequence A
In Part 1, study participants enrolled in Treatment Sequence A will be administered PSL BID 
(up-titration to steady-state [400mg BID]) from Day 1 to Day 5, followed by a steady-state 
period from Day 6 to Day 12 with a single dose of OC administered on the morning of Day 13.
A taper of PSL will occur from Day 15 to Day 19. Starting on Day 20, the study participants will 
then complete a Washout Period for 14 days followed by a return to the clinic for the OC-only 
dosing on Day 34. Pharmacokinetic samples will be collected on the days shown in Table 1-2,
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 38 of 91
Treatment Sequence A. An SFU Visit will occur between Day 41 and Day 44. All assessments, 
including PK sampling, are shown in the Schedule of Activities (Part 1, Treatment Sequence A, 
Table 1-4).
Sequence B
Study participants enrolled in Treatment Sequence B will be administered a single dose of OC on 
the morning of Day 1 followed by PK assessments that day and the next 2 days. The 
study participants will then complete a 14-day Washout Period followed by a return to the clinic 
for the OC+PSL dosing from Day 18 to Day 36 (OC to be administered on Day 30).
Pharmacokinetic samples will be collected on the days shown in Table 1-2,
Treatment Sequence B. Study Participants will be administered PSL BID (up-titration to 
steady-state) from Day 18 to Day 22 followed by a maintenance period from Day 23 to Day 31.
A taper of PSL will occur from Day 32 to Day 36. An SFU Visit will occur between Day 43 and 
Day 46. All assessments, including PK sampling, are shown in the Schedule of Activities (Part 1,
Treatment Sequence B, Table 1-5.
Part 2
Sequence A
In Part 2, all study participants enrolled in Treatment Sequence A will be administered PSL 
100mg BID on Day 1, with titration to 200mg BID for Day 2 to Day 8. A single dose of OC is 
administered on the morning of Day 9, at which time PSL is at steady-state. To taper, 100mg 
BID of PSL will be given on Day 11. Starting on Day 12, the study participants will then 
complete a Washout Period for 14 days followed by a return to the clinic for the OC-only Period
on Day 25 (OC dosing on Day 26). Pharmacokinetic samples will be collected on the days 
shown in Table 1-3, Treatment Sequence A. An SFU Visit will occur between Day 33 and 
Day 40. All assessments, including PK sampling, are shown in the Schedule of Activities (Part 2,
Treatment Sequence A, Table 1-6.
Sequence B
All study participants enrolled in Treatment Sequence B will be administered a single dose of 
OC on the morning of Day 1 followed by PK assessments that day and the next 2 days. The 
study participants will then complete a 14-day Washout Period followed by a return to the clinic 
for the OC+PSL dosing from Day 18 to Day 28 (OC to be administered on Day 26, at which 
time PSL is at steady state). Pharmacokinetic samples will be collected on the days shown in 
Table 1-3, Treatment Sequence B. Study participants will be administered PSL 100mg BID on 
Day 18, with titration to 200mg BID for Day 19 to Day 27. To taper, 100mg BID of PSL will be 
given on Day 28. An SFU Visit will occur between Day 35 and Day 42. All assessments, 
including PK sampling, are shown in the Schedule of Activities (Part 2, Treatment Sequence B, 
Table 1-7.
4.2 
Scientific rationale for study design 
The potential interaction between PSL and OC will be assessed with a two-way cross-over study 
design, which is deemed appropriate to reach the goal of the study.
In Part 1, PSL will be up-titrated from 100mg to 400mg BID over 5 days and, in Part 2, from 
100mg BID to 200mg BID in 1 day to increase tolerability as demonstrated in previous clinical 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 39 of 91
pharmacology studies. Afterwards, a steady-state period of 7 days will take place before subjects 
receive OC. This 7-day steady-state period will ensure that the potential CYP3A4 induction 
(mediated by PSL) is close to its maximum level and will be appropriate to evaluate the effect on 
OC. After OC administration, PSL will be tapered.
The washout period between the 2 treatment periods has a duration of 14 days mainly to ensure 
that CYP3A4 enzyme activity is back to baseline.
Since the risk of DDI between OC and PSL is predicted to be low (PSL 400mg BID) or not 
clinically relevant (PSL 200mg BID) and to reduce the burden of continuous administration of 
PSL (over 2 menstrual cycles) at the MTD in healthy female study participants, the DDI 
potential of PSL will be assessed on a single dose of the chosen OC. Therefore, EE and LN PK 
parameters (Cmax and AUC) will be used as primary endpoints and bioequivalence criteria will be 
applied for defining clinical relevance of the DDI (
). This PK-based 
approach has been used widely to assess DDI between OC and many drugs (Menon et al, 2016; 
Mohamed et al, 2018; Hurst et al, 2016; Crawford et al, 1990; Mildvan et al, 2002).
This study design will also allow evaluation of the effect of single dose OC on the steady-state 
PK of PSL and its metabolites.
Single dose OC is deemed appropriate to investigate the potential effect of EE/LN on PSL as 
there is no accumulation described with EE (Kuhnz et al, 1994). Though LN is known to 
accumulate (2 to 3-fold) following repeated administration (Kuhnz et al, 1994), there have been 
no CYP3A4/2C19 inhibition effects described in the literature (Palovaara et al, 2003); therefore, 
no DDI mediated by LN is expected.
4.3 
Justification for dose 
In Part 1, the rationale for the dose selected for this study is a balance between the desire to use 
the highest possible dose of PSL (as required by regulatory guidance) and the need to protect the 
safety and comfort of study participants. On this basis, the dose of 400mg BID (already 
identified as the MTD in earlier studies) was seen as the optimal dose for these purposes. A dose 
of 400mg BID is also potentially the highest dose currently planned for inclusion in the New 
Drug Application/Marketing Authorization Application (NDA/MAA).
However, although the CNS adverse events reported were similar to those seen in previous 
clinical trials with PSL, their overall impact has been more troublesome in some participants 
than in others receiving the same dose levels (PSL 400mg BID). Given that 14 study participants 
have already completed the study at 400mg BID (which will provide appropriate information on 
the DDI risk between OC and PSL at the highest anticipated dose to be included in the 
NDA/MAA), it seems appropriate to reduce the maximum dose administered in Part 2 to 200mg 
BID. As a consequence, treatment duration will be decreased from 19 days to 11 days (through 
reduction of the titration and taper period) and the total exposure of PSL (cumulative dose in mg) 
will be significantly reduced and will be similar to other ongoing clinical pharmacology studies.  
This is anticipated to reduce the AE burden on study participants but still permit adequate 
exploration of the potential DDI between PSL and OC at this dose, which is also potentially to be 
included in the NDA/MAA. 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 40 of 91
4.4 
End of study definition 
A study participant is considered to have completed the study if she has completed all periods of 
the study including the last scheduled procedure shown in the Schedules of Activities (Part 1,
Treatment Sequence A, Table 1-4 and Treatment Sequence B, Table 1-5; Part 2,
Treatment Sequence A, Table 1-6 and Treatment Sequence B, Table 1-7).
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule 
of Activities for the last study participant.
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply:
Age 
1. Participant must be aged 18 years of age or greater, at the time of signing the informed 
consent.
Sex 
2. Participant must be a premenopausal female with no indication of abnormal or 
gestational/lactational hypothalamic-pituitary-ovarian function. Menopause will be defined 
for the purpose of this study as amenorrhea of ≥12 months for which no other reason has 
been identified. 
Type of participant and disease characteristics 
3. Participant must not be pregnant (see Appendix 4; Section 10.4) or breastfeeding. Participant 
must agree to use an effective form of contraception (other than hormonal methods) for the 
duration of the Treatment Period and for at least 90 days (or 5 terminal half-lives) after the 
last dose of study medication.
4. Participant must be in good physical and mental health as determined by medical evaluation 
including medical history, physical examination, laboratory tests, and cardiac monitoring.
Weight 
5. Participant must have body weight of at least 45kg and body mass index within the range 
18 to 30 kg/m2 (inclusive).
Informed consent 
6. Participant must be capable of giving signed informed consent as described in Appendix 1
(Section 10.1), which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.
7. Participant must be considered reliable and capable of adhering to the protocol, according to 
the judgment of the Investigator, and must be capable of communicating satisfactorily with 
the Investigator.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 41 of 91
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or compromise the study participant’s ability to participate in this study, 
such as a history of schizophrenia, or other psychotic disorder, bipolar disorder, or severe 
unipolar depression. The presence of potential psychiatric exclusionary conditions will be 
determined based on the psychiatric history collected at Screening Visit. 
2. Participant has a history of discontinued use of OC for medical reasons.
3. Participant has any medical reason that would contraindicate the administration of OC (per 
label).
4. Participant has used any of the following within the specified time period prior to first dose 
of study medication:
a) OC or oral hormone replacement therapy within prior 30 days
b) Implanted hormonal contraceptives within prior 6 months
c) Injectable contraceptives within prior 12 months
d) Topical controlled-delivery contraceptives within prior 3 months
e) Hormone-releasing intrauterine devices (‘coils’) within prior 3 months.
5. Participant has other relevant gynecological disorders (such as premature ovarian failure or 
endometriosis).
6. Participant has a known hypersensitivity to any components of the study medication as stated 
in this protocol. Participant has sensitivity to any of the study interventions, or components 
thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates 
participation in the study. 
7. Participant has abnormal BP according to the following:
Participants must have blood pressure and pulse rate within normal range in the supine 
position after 5 minutes rest (SBP: 90mmHg to 145mmHg; DBP: 40mmHg to 95mmHg; PR: 
40bpm to 100bpm) at Screening 
Any values marginally (ie, no more than 5mmHg) outside the normal range but considered 
not clinically significant by the Investigator are allowed. In the case of an out-of-range result, 
1 repeat will be allowed. If the readings are out of range again, the study participant will not 
be included. On Day –1, if the results are deemed clinically significant by the principal 
investigator or designee, the study participant will not be included.
8. Participant has had lymphoma, leukemia, or any malignancy within the past 5 years except 
for basal cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years.
9. Participant is unable to tolerate oral medication or has a history of gastric bypass surgery.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 42 of 91
10. Participant has gastrointestinal disease with the potential to influence absorption, including 
motility disorders.
11. Participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, 
isoniazid, phenytoin, rifampicin, etc.) within 2 months prior to dosing. In case of uncertainty, 
the UCB Study Physician should be consulted.
12. Participant has a history of chronic alcohol or drug abuse within the previous 6 months. A 
pre-study drug/alcohol screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids, and benzodiazepines) is conducted to aid evaluation of this criterion. 
A participant with a positive finding on the drug screen may still be enrolled at the discretion 
of the Investigator if a plausible clinical explanation exists (eg, prior or concomitant 
medication use).
13. Participant has a history or presence of cardiovascular (eg, cardiac insufficiency, coronary 
heart disease, hypertension, arrhythmia, tachyarrhythmia, or myocardial infarction), 
respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or elimination of 
drugs; constituting a risk when taking the study medication; or interfering with the 
interpretation of data.
Suicidality 
14. Participant has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has had suicidal ideation in the past 6 months as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the “Screening/Baseline” 
version of the C-SSRS at Screening or “Since Last Visit” version at Baseline (Day -1).
Prior/concomitant therapy 
15. 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), or vitamins up to 2 weeks or 5 half-lives of the respective drug 
(whichever is longer) before the first administration of study medication and during the 
clinical part of the study, unless required to treat an AE. This does not include medications 
listed in Section 6.5.1.
Prior/concurrent clinical study experience 
16. Participant has participated in another study of a study medication within the previous 
1 month (or 5 half-lives, whichever is longer) prior to Screening, or is currently participating 
in another study of a study medication, or has participated in >4 studies of a study medication 
within the past year or has previously been assigned to treatment in a study of the medication 
under investigation in this study.
Diagnostic assessments 
17. Study participant has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or 
alkaline phosphatase (ALP) >1.0x upper limit of normal (ULN).
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 43 of 91
18. Study participant has bilirubin >1.0xULN (isolated bilirubin <1.5xULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%).
19. Study participant has current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome).
20. Participant has any clinically relevant ECG finding at the Screening Visit or at Baseline 
(Day -1) that, in the opinion of the Investigator, increases the risks associated with 
participating in the study. In addition, any study participant with any of the following 
findings will be excluded: (a) QT interval corrected for heart rate using Bazett’s formula 
(QTcB) or Fridericia’s formula (QTcF) >450ms in 2 of 3 ECG recordings; (b) other 
conduction abnormalities (defined as PR interval ≥220ms); (c) irregular rhythms other than 
sinus arrhythmia or occasional, rare supraventricular or rare ventricular ectopic beats. In case 
of an out-of-range result, 1 repeat will be allowed. If the result is out-of-range again, the 
study participant cannot be included.
NOTE A: The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), or Fridericia’s formula (QTcF). It is either machine-read or manually 
over-read.
NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In other 
words, several different formulas cannot be used to calculate the QTc for an individual
participant and then the lowest QTc value used to include or discontinue the participant.
21. Participant has a history of unexplained syncope or a family history of sudden death due to 
long QT syndrome.
22. Participant tests positive for human immunodeficiency virus-1/2 antibody (human 
immunovirus-1/2Ab) at Screening or within 3 months prior to the first dose of study 
medication.
23. Participant tests positive for Hepatitis B surface antigen, or HCV-Ab at Screening or within 
3 months prior to the first dose of study medication.
NOTE: Participants with positive HCV-Ab due to prior resolved disease can be enrolled if a 
confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained. The HCV RNA 
testing is optional and participants with negative HCV-Ab test are not required to also 
undergo Hepatitis C RNA testing.
Other exclusions 
24. Participant is, in the judgement of the Investigator, likely to be nonreliable or noncompliant 
or uncooperative during the study.
25. Participant has made a blood or plasma donation or has had a comparable blood loss 
(>450mL) within the last 30 days prior to Screening. Blood donation during the study is not 
permitted.
26. Participant has received blood or plasma derivatives within the 6 months preceding 
Screening.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 44 of 91
27. 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).
28. Participant smokes more than 5 cigarettes per day (or equivalent) or has done so within
6 months prior to the Screening Visit. Smoking within 48 hours prior to CNS assessments is 
prohibited.
29. Participant ingests grapefruit, passion fruit, or pawpaw (as beverage, fruit, or supplements) 
within 72 hours before each administration of study medication. If this is the case at the start 
of the study, study participants may be rescreened.
30. Female participant tests positive for pregnancy, plans to get pregnant during participation in 
the study, or is breastfeeding.
31. Study participant has a diet that deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the Investigator.
32. Study participant has undergone sudden and/or extreme changes in exercise levels for 
2 weeks prior to Screening Visit.
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
x Study participants will complete a light meal 30 minutes prior to each morning dose of PSL 
and will complete a standard meal 30 minutes prior to the evening dose. The standardized 
meal composition and timing should be consistent for all days the participant is on study. On 
days when PK assessments will be taken, study participants will complete a standardized 
meal (same macronutrients will be administered for minimizing covariates) in the afternoon 
and evening.
x Padsevonil will be administered orally with 8oz (240mL) water. Between 1h predose and 
2h postdose, the total intake of beverages should be limited to 100mL. On PK sampling days, 
study participants must be dosed in an upright position and must remain semi-recumbent 
until 4 hours after the morning dose of PSL (apart from when required to do otherwise for 
study assessments such as vital signs, ECGs, etc).
x The study participant must not ingest grapefruit, starfruit, and pawpaw (as beverage, fruit, or 
supplements) within 72h before the study medication administration. These fruits are not 
allowed during the Treatment Period and throughout the study.
5.3.2 
Caffeine, alcohol, and tobacco 
x During each dosing session, participants will abstain from ingesting caffeine- or
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 48 hours before 
the start of dosing until after collection of the final PK sample.
x During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK sample.
x Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 45 of 91
5.3.3 
Activity 
x Participants will abstain from strenuous exercise for 24 hours before each blood collection 
for clinical laboratory tests and during the study. Participants may participate in light 
recreational activities during the study (eg, watching television, reading).
5.4 
Screen failures 
Screen failures are defined as study participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure study participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
5.4.1 
Rescreening 
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened. Study participants may be rescreened under conditions such as the following:
x Study participant ingests grapefruit (as beverage, fruit, or supplements) within 72 hours
before first administration of study medication.
x If a study participant does not meet the exclusion criteria at Screening or on Day -1 due to an 
out-of-range laboratory result or a minor illness, she can be rescreened once at the discretion 
of the Investigator. Provided all inclusion criteria are met at the second screening, the 
study participant can be included.
Study participants may be included if the repeat values for the laboratory screening criteria are 
within normal ranges and/or if repeat values show normalization of the out-of-range safety 
laboratory values, and/or after the study participant makes a complete recovery from the mild or 
moderate illness, and if all other screening criteria are met.
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation; if the results are out of range again, the study participant cannot be 
included.
Rescreened study participants will be assigned a new participant number.
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or
medical device(s) intended to be administered to a study participant according to the study 
protocol.
6.1 
Treatments administered 
A summary of the study treatments administered is provided in Table 6-1. Treatments will be 
administered in an open-label fashion and study participants will be dosed in an upright position.
On PK sampling days, study participants must remain semi-recumbent until 4 hours after the 
morning dose of PSL (apart from when required to do otherwise for study assessments such as 
vital signs, ECGs, etc).
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 46 of 91
Table 6-1: 
Study medications administered 
Study Medication Name:
Padsevonil
Dosage formulation:
Tablets
Unit dose strength(s)/Dosage level(s):
100mg tablets for BID dosing
Route of Administration:
Oral
Dosing instructions:
All treatments will be administered orally with 8oz 
(240mL) water. The use of beverages between 1h predose 
and 2h postdose should be limited to a maximum of 100mL 
(in order to keep groups comparable with respect to period 
of dosing). Study participants will complete a light meal 
30 minutes prior to each morning dose of PSL and will 
complete a standard meal 30 minutes prior to the evening 
dose of PSL.
Treatments will be administered in an open-label fashion. 
Study participants will be dosed in an upright position. On 
PK sampling days, study participants must remain semi-
recumbent until 4 hours after the morning dose of PSL 
(apart from when required to do otherwise for study 
assessments such as vital signs, ECGs, etc).
Packaging and Labeling
Padsevonil tablets are manufactured, packaged, and labeled 
according to Good Manufacturing Practice guidelines and 
applicable laws and regulations.
Manufacturer
UCB
Study Medication Name:
Single dose Microgynon 30® (ethinyl estradiol 
30μg+levonorgestrel 150μg)
Dosage formulation:
Tablets
Unit dose strength(s):
(ethinyl estradiol 30μg+levonorgestrel 150μg)
Route of Administration:
Oral
Dosing instructions:
Dosing instructions are provided in the UP0035 IMP 
Handling Manual (IMP Instructions for Handling).
Packaging and Labeling
Tablets are manufactured, packaged, and labeled according 
to Good Manufacturing Practice guidelines and applicable 
laws and regulations
Manufacturer
Bayer
IMP=investigational medicinal product; PSL=padsevonil
6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medications received and any discrepancies are reported 
and resolved before use of the study medication.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 47 of 91
Only participants enrolled in the study may receive study medication and only authorized site 
staff may supply or administer study medication. All study medication must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study medication accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the UP0035 IMP Handling Manual.
Further guidance and information for the final disposition of unused study medication are 
provided in the UP0035 IMP Handling Manual.
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record study medication dispensing and return 
information on a by-study participant basis and will serve as source documentation during the 
course of the study. Details of any study medication lost, damaged (due to breakage or wastage), 
not used, partially used, disposed of at the study site, or returned to the Sponsor or designee must 
also be recorded on the appropriate forms. All supplies and pharmacy documentation must be 
made available throughout the study for UCB (or designee) to review.
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of study medication until returned or destroyed.
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee.
The Investigator must ensure that the study medication is used only in accordance with the 
protocol.
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB standard operating 
procedures or returned to UCB (or designee). Investigational medicinal product intended for the 
study cannot be used for any other purpose than that described in this protocol.
6.3 
Measures to minimize bias: randomization and blinding 
This study is an open-label study; therefore, no study personnel or study participants will be 
blinded.
A contract research organization (CRO; ie, ICON) randomization biostatistician will create the 
program to generate the randomization code. A dummy randomization schedule will be prepared 
by the randomization biostatistician (a cross-over 2x2 scheme with 2 treatment sequences) and 
reviewed by the Clinical Study Biostatistician in order to ensure that the code meets the study 
requirements.
After finalization of the dummy code, the randomization program will be run with a different 
seed number to create the final randomization list; the final list will be generated and will be 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 48 of 91
reviewed by a quality control randomization biostatistician. The treatment assignment will be 
random.
Copies of the randomization lists will be sent before the start of the study in a secure fashion 
directly from the contracted CRO to:
x Sponsor Patient Safety staff for SAE reporting 
x Bioanalytical staff (to identify samples to be measured)
x A member of pharmacy involved in IMP preparation and dispensing
x The Clinical Study Biostatistician/Statistical Programmer
In addition, staff involved in the analysis of PK data, such as a representative from the UCB 
Clinical Pharmacology/Modeling and Simulation team and a monitor, will have access to the 
data during the study.
Once the Investigator determines that the study participant is eligible for the study, and before 
IMP administration, a central person in charge of issuing the randomization numbers will 
manually allocate a randomization number to the study participant and communicate the 
randomization assignment to the Site Pharmacist. Each specific randomization number will be 
linked to the treatment allocation on the randomization schedule, which will be dispensed by the 
site pharmacist. The randomization numbers will also be recorded in the eCRF.
Each study participant will receive a 5-digit study participant number, from a range of numbers 
supplied by UCB Clinical Data Operations, Technology, and Standards, assigned at Screening 
that will serve as the study participant identifier throughout the study. The study participant 
number will be required in all communication between the Investigator/designee.
6.3.1 
Procedures for maintaining and breaking the treatment blind 
6.3.1.1 
Maintenance of study medication blind 
This is not applicable as this is an open-label study.
6.3.1.2 
Breaking the study medication blind in an emergency situation 
This is not applicable as this is an open-label study.
6.4 
Treatment compliance 
Study participant compliance will be ensured by the administration of study medication by 
designated site personnel. Drug accountability must be recorded on the Drug Accountability 
form.
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The use of concomitant medications during this study should be avoided unless necessary to treat 
AEs or unless approved on a case-by-case basis prior to enrollment. The use of any concomitant 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 49 of 91
medications should be approved by the Sponsor in advance, in writing, when possible. The 
following concomitant medications are permitted during the study:
x Paracetamol for the treatment of mild symptoms (eg, headache or other pain), given at most 
every 6 hours to 8 hours, not exceeding 2g/day, and with a total of no more than 5g over 
7 days
x Ibuprofen
x Inhaled corticosteroids for seasonal rhinitis
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
With the exception of permitted concomitant treatments listed in Section 6.5.1, prescription or 
nonprescription medicines, including OTC remedies and herbal and dietary supplements 
(including St John’s Wort), are prohibited within 14 days or 5 half-lives (whichever is longer) 
before administration of PSL and during the Treatment Period, unless required to treat an AE. 
Drugs of unknown half-life are prohibited within 14 days before administration of PSL and 
during the Treatment Period, unless required to treat an AE. The use of any inducers or inhibitors 
of CYP2C19 or CYP3A4 is prohibited.
Combined (estrogen and progestogen containing) hormonal contraception and progesterone only 
hormonal contraceptive methods are not permitted in this study (Section 10.4).
6.5.3 
Rescue medication 
Not applicable.
6.6 
Dose modification 
No PSL dose modifications are permitted during the study for an individual study participant.
6.7 
Treatment after the end of the study 
There are no plans for continued study participant care or treatment after the end of the study.
7 
DISCONTINUATION OF STUDY MEDICATION AND 
STUDY PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Study medication will be stopped if the study participant develops a medical condition, 
laboratory abnormality, ECG change, or other finding that, in the opinion of the Investigator, 
compromises the study participant’s ability to participate or safety.
In all cases the study participant should be followed until the condition has resolved as agreed by 
the Investigator and the UCB Study Physician. Study participants withdrawn from the study 
should complete PSL tapering. Investigators should contact the UCB Study Physician, in 
advance whenever possible, to discuss the withdrawal of a study participant and the appropriate 
schedule of tapering under the circumstances. No restart will be allowed.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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Page 50 of 91
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study medication for abnormal liver function should be considered by the 
Investigator when a study participant meets 1 of the conditions outlined in Figure 7-1 or if the 
Investigator believes that it is in best interest of the study participant.
Study medication will be discontinued immediately and permanently for a study participant if 
liver chemistry stopping criteria are met.
Figure 7-1: Liver chemistry stopping algorithm 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal
Liver safety–suggested actions and follow-up assessments for potential drug-induced liver injury 
(PDILI) are provided in Appendix 6 (Section 10.6).
7.1.2 
QTc stopping criteria 
A study participant who meets any of the bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from the study.
x QTc ≥500msec
x Change from baseline: QTc ≥60msec
If a clinically significant finding is identified (including, but not limited to, changes from 
Baseline in QTcB or QTcF after enrollment), the Investigator or qualified designee will 
determine if the study participant can continue in the study and if any change in study participant 
management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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Page 51 of 91
See the Schedules of Activities (Part 1, Treatment Sequence A, Table 1-4 and 
Treatment Sequence B, Table 1-5; Part 2, Treatment Sequence A, Table 1-6 and 
Treatment Sequence B, Table 1-7) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.2 
Criteria for study hold due to adverse events 
In recognition of the advanced status of the development program for PSL, the following study 
hold/stopping rules will apply to this study:
x A serious adverse reaction (SAR) (ie, an SAE considered at least possibly related to the study 
medication) in 1 study participant;
x A severe nonserious adverse reaction (ie, severe nonserious AEs considered at least possibly 
related to the study medication administration) in 2 study participants in a single part of the 
study (Part 1 or Part 2), independent of within or not within the same SOC.
If either stopping criterion is met, the trial will be put on temporary halt. However, tapering of 
PSL doses, and completion of the OC-only treatment period in Sequence A will be allowed. In 
the event that either or both of the stopping criteria are met, a safety review will be immediately 
initiated. The safety review will be conducted by an internal, study-specific Safety Monitoring 
Committee comprised of the Investigator and appropriate members of the UCB Study Team 
(such as Study Physician, Safety Physician, Clinical Project Manager, Clinical Pharmacologist), 
as quickly as possible, to review the available data and determine whether it is appropriate to 
continue dosing at the next scheduled dosing point. This will take the form of a risk/benefit 
evaluation from the perspective of the individual study participants. In making this evaluation, 
account will be taken of the potential risks of sudden discontinuation of study medication, 
particularly in participants who may be taking higher dose levels, and whether or not a tapering 
period, and its duration/speed, should be undertaken.
The Safety Monitoring Committee will also decide whether it is appropriate to continue the study 
with or without dose adaptations, additional safety assessments, or other changes in design. In 
case of any temporary halt of the study, further dosing in the study will be suspended while a 
substantial amendment is submitted to the Country(ies) Health Authority and Research Ethics 
Committee(s) and the study will not restart until that amendment has been approved.
Detailed procedures for reporting SAEs and other safety events which may meet study 
hold/stopping criteria are provided in Appendix 3 (see Section 10.3).
7.3 
Study participant discontinuation/withdrawal from the study 
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care.
A study participant may withdraw from the study at any time at her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons.
If the study participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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Page 52 of 91
If a study participant withdraws from the study, she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.
Upon early termination/withdrawal, the study participant will be administered tapering doses of 
the study medication and will complete SFU Visit assessments following the last dose of study 
medication. In all cases, such withdrawals and the degree of tapering should be discussed first 
with the UCB Study Physician, wherever possible.
See the Schedules of Activities (Part 1, Treatment Sequence A, Table 1-4 and 
Treatment Sequence B, Table 1-5; Part 2, Treatment Sequence A, Table 1-6 and 
Treatment Sequence B, Table 1-7) for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations to be completed.
Study participants should be withdrawn from the study if any of the following events occur:
1. Study participant develops a clinically relevant medical condition (physical or psychiatric) 
that, in the opinion of the Investigator, jeopardizes or compromises the study participant’s 
ability to participate in the study or makes it unsafe to continue.
2. Study participant is noncompliant with the study procedures or medications in the opinion of 
the Investigator.
3. Study participant takes prohibited concomitant medications as defined in this protocol.
4. Study participant withdraws her consent.
5. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test.
6. The Sponsor or a regulatory agency requests withdrawal of the study participant.
7. Study participant has changes in the ECG results that are regarded as clinically significant 
and/or that worsen over time.
8. Study participant has an ECG that shows an absolute value for QTcB or QTcF ≥500ms or 
≥60ms above Baseline.
9. Study participant develops a second- or third-degree atrioventricular block or another 
clinically relevant change in ECG results as determined by the Investigator.
10. Study participant has active suicidal ideation without a specific plan as indicated by a 
positive response (“Yes”) to Question 4 of the “Since Last Visit” version of the C-SSRS. The 
study participant should be referred immediately to a mental healthcare professional and may 
be withdrawn from the study based upon the Investigator’s judgement of the benefit/risk of 
continuing the study participant in the study on PSL.
11. Study participant has active suicidal ideation with a specific plan as indicated by a positive 
response (“Yes”) to Question 5 of the “Since Last Visit” version of the C-SSRS. The study 
participant should be referred immediately to a mental healthcare professional and must be 
withdrawn from the study.
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Clinical Study Protocol
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UP0035
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Page 53 of 91
12. Study participant is suspected of having a serious multiorgan hypersensitivity reaction. 
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
Sponsor by the Investigator using the following algorithm:
 An AE or laboratory value (as defined below) suggestive of internal organ involvement 
including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, 
pancreatitis, myositis, arthritis, or hematologic system involvement combined with at 
least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia.
 Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia:
◦ 
Eosinophils percentage ≥10%
◦ 
Eosinophils absolute ≥0.5G/L
◦ 
Neutrophils absolute <1.5G/L
◦ 
Platelets absolute ≤100G/L
Investigators should attempt to obtain follow-up information on study participants in the case of 
withdrawal.
Study participants withdrawn from the study should complete the Taper Period described in the 
PSL+OC portion of the study. Investigators should contact the UCB Study Physician, whenever 
possible, to discuss the withdrawal of a study participant in advance.
Study participants who are withdrawn will be replaced at the discretion of the Investigator and 
Sponsor.
7.4 
Lost to follow-up 
A participant will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a study participant fails to return to the clinic for a 
required study visit:
x The site must attempt to contact the study participant and reschedule the missed visit as soon 
as possible, counsel the study participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the study participant wishes to and/or should continue 
in the study.
x Before a study participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the study participant (at least 1 phone call and 1 
written message to the study participant) and document his/her effort (date and summary of 
the phone call and copy of the written message in the source documents), to complete the 
final evaluation. All results of these evaluations and observations, together with a narrative 
description of the reason(s) for considering the study participant lost to follow-up, must be 
recorded in the source documents. The electronic Case Report Form (eCRF) must document 
the primary reason for withdrawal.
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Clinical Study Protocol
Padsevonil
UP0035
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Page 54 of 91
Should the study participant continue to be unreachable, she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up documented in the eCRF.
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedules of Activities  (Part 1,
Treatment Sequence A, Table 1-4 and Treatment Sequence B, Table 1-5; Part 2,
Treatment Sequence A, Table 1-6 and Treatment Sequence B, Table 1-7). Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the UCB Study Physician immediately upon 
occurrence or awareness to determine if the study participant should continue or discontinue 
study medication.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
study participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all study participants screened and confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the study participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the appropriate Schedule of Activities.
The maximum amount of blood collected from each study participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 500mL per study 
participant. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1 
Pharmacokinetics 
Whole blood will be collected for measurement of plasma concentrations of PSL as specified in 
the Schedule of Activities. Additional samples may be collected at additional time points during 
the study if warranted and agreed upon between the Investigator and the Sponsor.
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample and each dose of OC or 
PSL administered will be recorded. Plasma samples will be collected for measurement of plasma 
concentrations and to evaluate the PK of PSL, EE, and LN as specified in the appropriate 
Schedule of Activities.
Samples collected for analyses of PSL plasma concentration may also be used to evaluate safety 
aspects related to concerns arising during or after the study.
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files but will not constitute a protocol amendment. The institutional review board 
(IRB)/independent ethics committee (IEC) will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the ICF.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 55 of 91
Instructions and additional details regarding PK sampling are provided in the Laboratory 
Manual.
The maximum deviations from scheduled sampling times considered irrelevant for PK are 
defined in Table 8‒1.
Table 8‒1: Irrelevant time deviations for PK sampling 
PK blood sampling times
Deviation from scheduled time considered irrelevant
0 hours (predose)
Within 60 minutes 
0.25 to 1.5 hours
2 minutes
2 to 8 hours
5 minutes
12 hours
15 minutes
24 to 48 hours
60 minutes
PK=pharmacokinetic
8.1.1 
Mitra™ 
As described in Schedule of Activities, Mitra™samples will be collected for cross-validation of 
PSL bioanalytical method. These additional samples will be taken on a limited number of 
study participants (ideally, at least 9 from each study part) who will agree and consent for the 
additional blood sampling for this study objective. However, a lower number of study 
participants may be allowed at the discretion of the principal investigator and sponsor. 
8.2 
Pharmacodynamics 
Not applicable.
8.3 
Safety assessments 
The safety and tolerability of multiple doses of PSL will be monitored by evaluation of AEs, 
vital signs (oral or aural body temperature, PR, respiratory rate [RR], BP), 12-lead ECG 
parameters, physical examination findings, and clinical laboratory test results. Planned time 
points for all safety assessments are provided in the Schedule of Activities.
8.3.1 
Physical examination 
Physical examinations will be performed at the time points specified in Schedule of Activities. A 
complete physical examination will include, at a minimum, general appearance; ear, nose, and 
throat; eyes, hair, and skin; abdomen; assessments of the Cardiovascular, Respiratory, 
Gastrointestinal Neurological, Musculoskeletal, and Hepatic systems; and mental status. Height 
and weight will also be measured and recorded at Screening only.
A brief physical examination will be conducted only as needed. A brief physical examination 
will include, at a minimum, assessments of general appearance, skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).
Clinically relevant findings or worsening of previous findings will be recorded as AEs.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 56 of 91
8.3.2 
Vital signs 
Oral or aural temperature, PR, RR, and BP will be assessed. Whichever method of temperature 
measurement is used should be used for all evaluations for that study participant, and ideally 
across all study participants.
Blood pressure and pulse measurements will be assessed in a supine position with a completely 
automated device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
study participant in a quiet setting without distractions (eg, television, cell phones).
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
1 BP measurement.
8.3.3 
Electrocardiograms 
Triplicate 12-lead ECGs will be obtained as outlined in the Schedule of Activities using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Section 7 for QTc withdrawal criteria and any additional QTc readings that 
may be necessary.
All ECG recordings should be taken with the study participant resting in the supine position for 
at least 5 minutes before the recording.
Three individual ECG tracings should be obtained as closely as possible in succession, but no 
more than 2 minutes apart. The full set of triplicates should be completed in less than 4 minutes.
8.3.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
Schedule of Activities for the timing and frequency.
The Investigator must review the laboratory reports, document these reviews, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are laboratory findings that changed considerably or that increased in 
frequency or intensity more than expected as compared with the clinical profile known to the 
Investigator from the study participant’s history or Screening Visit.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or at the SFU Visit should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or UCB Study Physician.
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the UCB Study Physician notified.
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the Laboratory Manual or equivalent document and the Schedule 
of Activities.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 57 of 91
clinically significant by the Investigator (eg, SAE or AE), then the results must be recorded in 
the eCRF.
8.3.5 
Suicidal risk monitoring 
Padsevonil is considered to be an AED. Suicidal ideation and behavior have been reported in 
patients treated with antiepileptic agents in several indications. A meta-analysis of randomized 
placebo-controlled studies of AEDs has also shown a small increased risk of suicidal ideation 
and behavior. The mechanism of this risk is not known and the available data do not exclude the 
possibility of an increased risk for PSL.
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia University 
Medical Center, 2008). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. All study participants will complete the 
“Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months), 
followed by the “Since Last Visit” version at the visits indicated on the Schedule of Activities.
Study participants being treated with PSL should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior. Families and 
caregivers of study participants being treated with PSL should be instructed to monitor 
study participants for the emergence of unusual changes in behavior, as well as the emergence of 
suicidal ideation and behavior, and to report such symptoms immediately to the Investigator. 
Consideration should be given to discontinuing PSL in study participants who experience signs 
of suicidal ideation or behavior.
8.3.6 
Psychiatric and Mental Status 
The psychiatric and mental status of study participants will be closely monitored. Assessment of 
specific domains of psychiatric and cognitive symptoms will be performed by a staff member 
trained in the identification of psychiatric symptoms. The Psychiatric and Mental Status 
assessment will be performed according to the Schedule of Activities. The parameters that will 
be evaluated cover orientation, attention, memory, mood, calculus, behavior, and thinking or 
feeling. These parameters will be assessed as normal or abnormal and then determined whether 
clinically significant. If present and abnormal, psychiatric symptoms, mental impairment, and 
behavioral problems will be assessed as to whether they are clinically significant.
8.4 
Adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
Adverse events will be reported by the study participant.
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study medication or study procedures, or that caused 
the study participant to discontinue PSL or UP0035 (see Section 7).
8.4.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF and at the time points specified 
in the Schedule of Activities.
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UP0035
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Medical occurrences that begin before the start of study medication, but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the study 
medication), up to 30 days from the end of the study for each study participant, and to also 
inform study participants of the need to inform the Investigator of any SAE within this period. 
Serious AEs that the Investigator thinks may be associated with the study medication must be 
reported to UCB regardless of the time between the event and the end of the study.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
8.4.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the study participant is the preferred method to inquire about 
AE occurrences.
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
study participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 8.4.6), will be followed until resolution, stabilization, the Investigator 
determines that it is no longer clinically significant, the event is otherwise explained, or the 
study participant is lost to follow-up (as defined in Section 7.4). Further information on follow-
up procedures is given in Appendix 3 (Section 10.3).
8.4.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of study participants and the safety of a 
study medication under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study medication under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary.
An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review the document 
and file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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8.4.5 
Pregnancy 
Details of all pregnancies will be collected after the start of study medication and until up to 
30 days after the birth for any significant medical issues. In certain circumstances, UCB may 
request that follow-up is continued for a period up to 12 months. If the study participant is lost to 
follow-up and/or refuses to give information, written documentation of attempts to contact the 
study participant needs to be provided by the Investigator and filed at the site. UCB’s PS 
department is the primary contact for any questions related to the data collection for the 
pregnancy, eventual birth, and follow-up.
If a pregnancy is reported, the Investigator must immediately inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
Section 10.4).
The study participant should be withdrawn from the study as soon as pregnancy is known (by 
positive pregnancy test), and the following should be completed:
x The study participant should return for the EOS Visit.
x The study participant should immediately stop the intake of the study medication or be 
down-titrated as instructed at the EOS Visit.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs.
8.4.6 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. No AEs of special interest have been identified for 
PSL to date, with the exception of potential Hy’s Law as described below.
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to be concluded). Follow-up information should then be 
reported if an alternative etiology is identified during investigation and monitoring of the 
study participant.
8.5 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect, as early as possible, any 
safety concern(s) related to the study medication so that Investigators, study participants, 
regulatory authorities, and IRBs/IECs can be informed appropriately.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the UCB 
PS representative.
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory or ECG results) for which data will be periodically reviewed 
during the course of the study.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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Page 60 of 91
8.6 
Efficacy assessments 
Not applicable.
8.7 
Treatment of overdose 
For this study, any dose of PSL greater than that prescribed in the protocol will be considered an 
overdose. Overdose events are only considered AEs or SAEs if there are associated clinical signs 
and/or symptoms or if the act of taking the excess study medication itself is an AE or SAE 
(eg, suicide attempt).
UCB does not recommend specific treatment for an overdose. Padsevonil will not be 
self-administered by the study participant.
In the event of an overdose, the Investigator should:
1. Contact the UCB Study Physician immediately.
2. Closely monitor the study participant for any AE/SAE and laboratory abnormalities until 
study medication can no longer be detected systemically (at least 3 days).
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
medication if requested by the UCB Study Physician (determined on a case-by-case basis).
4. Document the quantity of the excess dose, as well as the duration of the overdose, in the 
eCRF.
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
UCB Study Physician based on the clinical evaluation of the study participant.
8.8 
Genetics 
Archived blood samples for genotyping of drug metabolizing enzymes and/or transporters will 
be collected as specified in the Schedule of Activities.
8.9 
Biomarkers 
Not applicable.
8.10 
Samples for PSL bioanalytical method cross-validation 
Mitra™and venous blood samples will be collected as specified in the Schedule of Activities. 
The bioanalytical results from these samples will not be reported in the clinical study report. 
They will be included in the bioanalytical cross validation report.
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). Deviations in analyses from the final SAP will be documented in the 
clinical study report.
9.1 
Definition of analysis sets 
The following are the defined analysis sets:
x Enrolled Set (ES): All study participants who have signed the ICF.
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Clinical Study Protocol
Padsevonil
UP0035
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Page 61 of 91
x Safety Set (SS): All study participants who received at least one dose of study medication.
x Pharmacokinetic Per Protocol Set (PK-PPS): the PK-PPS is a subset of the SS, consisting of 
those study participants who had no important protocol deviations affecting the PK of EE, 
LN, or PSL and its metabolites and for whom at least one measurable concentration exists.
9.2 
General statistical considerations 
Statistical evaluation will be performed by the Sponsor or designee and supervised by the Early 
Development Statistics Department of UCB. All statistical analyses will be performed using 
SAS® Version 9.4 or later (SAS Institute, Cary, NC, USA).
For continuous variables, summary statistics will include number of study participants, mean, 
median, standard deviation, minimum, and maximum (geometric mean and geometric coefficient 
of variation [CV] for plasma concentrations and PK parameters). Categorical endpoints will be 
summarized using number of study participants, frequency, and percentages. Missing data will 
not be imputed. Individual plasma concentration and PK parameters will be presented using 
three significant digits.
If not otherwise stated, Baseline will be the last assessment prior to dosing. Measurement of 
specific Baseline values will be described in the SAP.
9.3 
Planned pharmacokinetic analyses 
All PK analyses will be performed using the PK-PPS. Pharmacokinetic parameters of EE, LN, 
PSL, and PSL metabolites (eg, Cmax, tmax, AUC or AUC0-t or AUCτ, t1/2 or CL/F) will be 
estimated using noncompartmental analysis with Pharsight Phoenix® WinNonlin® v6.3 (or 
higher) software. Pharmacokinetic analyses will be performed and reported for each study part 
(Part 1 and Part 2).
The individual time-plasma concentrations of EE, LN, PSL, PSL metabolites, and PK parameters 
of EE, LN, PSL and PSL metabolites will be summarized by treatment using descriptive 
statistics (number of observations, geometric mean, lower and upper 95% confidence intervals 
[CI], geometric coefficient of variation [CV], arithmetic mean, standard deviation [SD] and CV, 
median, and minimum and maximum value) and graphical displays.
Ethinylestradiol/levonorgestrel primary PK parameters will be compared between treatments 
using analysis of variance for a cross-over design (treatment, period, sequence as fixed effects, 
and subject within sequence as random effect) on the log-transformed parameters and estimation 
of the geometric mean ratio of PK parameters between groups with their 90% CI will be 
provided.
Lack of PSL effect on EE/LN will be concluded if the 90% CI of the geometric mean ratio 
between treatment PSL+EE/LN and treatment EE/LN of the least squares means for the 
log-transformed AUC, and Cmax is within the bioequivalence acceptance range of 80% to 125%.
If the 90% CI is slightly broader than the BE criteria, individual AUC and Cmax geometric 
means ratios will be assessed with the aim of achieving >0.7 (less than a 30% decrease OC 
exposure in the presence of PSL) to declare a lack of a clinically significant PK interaction.
Pharmacokinetic parameters (Cmax,ss, AUCτ) of PSL and its metabolites will be compared 
between days with OC [Part 1: Day 13 for Treatment Sequence A and Day 30 for Treatment 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
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Page 62 of 91
Sequence B; Part 2: Day 9 for Treatment Sequence A and Day 26 for Treatment Sequence B] 
and without OC [Part 1: Day 12 for Treatment Sequence A and Day 29 for Treatment 
Sequence B; Part 2: Day 8 for Treatment Sequence A and Day 25 for Treatment Sequence B] 
using analysis of variance on the log-transformed parameters and estimation of geometric ratio 
of PK parameters between days with their 90% CI will be provided.
The relationship between individual AUC ratio (with and without PSL) of EE and LN, and the 
exposure to PSL (AUCτ) will be assessed by scatterplots and linear regression analyses 
(log-transformed and also untransformed data).
The estimated slope with 95% CI will be computed. In absence of interaction, intercept and slope 
will be equal to 0.
9.4 
Planned safety analyses 
All safety analyses will be performed using the SS. All safety variables will be listed and 
summarized by study part and treatment (OC with PSL, OC alone, and PSL alone when 
applicable) and time point, when applicable.
All AEs will be coded using the Medical Dictionary for Regulatory Activities and characterized 
as pretreatment and treatment-emergent according to the intake of the study medications (PSL, 
OC). All AE data will be listed by study participant number, visit, treatment, and time. The 
listings will include the following data pertaining to the AEs: start and end dates with relative 
days to study medication administration, duration, intensity, seriousness, relationship to study 
medication, action taken, and final outcome.
x The occurrence and incidence of AEs will be summarized by treatment according to the 
intake of PSL (pretreatment or treatment-emergent) and by intensity or relationship to PSL.
x Safety laboratory measurements, vital signs, and 12-lead ECGs parameters will be tabulated 
using descriptive statistics. Laboratory values outside the reference range will be flagged in 
the listings. Any PDILI events will be listed.
x Assessment of suicidality will be listed.
x Physical and neurological examinations abnormalities will be listed.
9.5 
Planned efficacy/outcome analyses 
Efficacy is not being evaluated in this study.
9.6 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary PK outcome for an individual 
study participant. Furthermore, study participants will be excluded from the SS only when there 
is documented evidence that they received no treatment. The criteria for identifying important 
protocol deviations and the classification of important protocol deviations will be defined within 
the relevant protocol deviation specification document, which is part of the study Data Cleaning 
Plan. To the extent feasible, rules for identifying protocol deviations will be defined without 
review of the data and without consideration of the frequency of occurrence of such deviations. 
Whenever possible, criteria for identifying important protocol deviations will be implemented 
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 63 of 91
algorithmically to ensure consistency in the classification of important protocol deviations across 
all study participants.
Important protocol deviations will be reviewed as part of an ongoing process prior to database 
lock to confirm exclusion from analysis sets.
9.7 
Handling of dropouts or missing data 
The method for handling dropouts will be described in the SAP.
Data of study participants prematurely terminating the study will be used to the maximum 
possible extent. No procedures for replacing missing data are intended. If a Baseline value is 
missing or not reliable, the last value before administration of study medication will serve as 
Baseline.
9.8 
Planned interim analysis and data monitoring 
No interim analysis or data monitoring are planned in this study.
9.9 
Determination of sample size 
Lack of PK interaction in this study will be concluded if 90% confidence intervals for both AUC 
and Cmax geometric means ratios (with/without PSL) of LN and EE are included in the 
80% to 125% bioequivalence range.
In a previous OC interaction study conducted by UCB with brivaracetam (N01282), an 
intra-subject coefficient of variation of 10% for AUCτ for both EE and LN (including Cmax) and 
16% for Cmax was observed for EE.
Provided that the ratio of the expected means for test (with PSL) and reference (without PSL) is 
included in the range [0.90, 1.10] and for a type-I error of 0.05 and an intra-subject coefficient of 
variation of 16%, a total sample size of 34 study participants should allow at least 90% power for 
the assessment of lack of interaction (or 26 study participants for 80% power).
A total of 40 study participants will be randomized: Part 1 (PSL 400mg BID) will include 
14 study participants and will allow a good estimate of the different ratios of PK parameters. 
Part 2 (PSL 200mg BID) will include 26 study participants (13 study participants in each 
sequence). Assuming no drop-outs, a decrease of 10% in PK parameters of OC and intrasubject 
coefficient of variation of 16%, this will allow 80% power for assessing lack of PK interaction.
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Clinical Study Protocol
Padsevonil
UP0035
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Page 64 of 91
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
International Council on Harmonisation-Good Clinical Practice (ICH-GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki.
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, 
Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), advertisement (if 
applicable), and all other study participant-related documents to be used for the study to the 
IRB/IEC for its review and approval.
Before initiating a study, the Investigator will have written and dated full approval from the
responsible IRB/IEC for the protocol.
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to study participants or others, and any protocol 
deviations, to eliminate immediate hazards to study participants.
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the 
study participants. For minor changes to a previously approved protocol during the period 
covered by the original approval, it may be possible for the Investigator to obtain an expedited 
review by the IRB/IEC as allowed.
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of study participant risk involved, but no less 
than once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide UCB (or its representative) with evidence of such IRB/IEC 
notification.
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements.
Finance and insurance are addressed in the Investigator and/or clinical research organization 
agreements, as applicable.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 65 of 91
10.1.3 
Informed consent process 
Study participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the study participant in both oral and written form by the 
Investigator (or designee). Each study participant will have the opportunity to discuss the study 
and its alternatives with the Investigator.
Prior to participation in the study, the ICF should be signed and personally dated by the 
study participant, or her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The study participant or her legal representative 
must receive a copy of the signed and dated ICF. As part of the consent process, each study 
participant must consent to direct access to her medical records for study-related monitoring, 
auditing, IRB/IEC review, and regulatory inspection.
If the ICF is amended during the study, the Investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form.
The study participant may withdraw her consent to participate in the study at any time. A study 
participant is considered as enrolled in the study when 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 her written consent to participate in the study.
10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the study participant’s confidentiality. 
Throughout this study, all data forwarded to UCB (or designee) will be identified only by the 
study participant number assigned at Screening. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, and representatives of regulatory authorities will be allowed to review that portion of 
the study participant’s primary medical records that directly concerns this study (including, but 
not limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a study participant’s study participation, and autopsy 
reports for deaths occurring during the study).
The study participant must be informed that her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the study participant.
The study participant must be informed that her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, or by inspectors from regulatory authorities.
10.1.5 
Committees structure 
A Safety Monitoring Committee will always comprise the Investigator, the Sponsor’s medical 
representative, the scientific lead, and a PK expert where appropriate. Other experts may be 
included in this group or consulted at the discretion of the Sponsor.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 66 of 91
10.1.6 
Data quality assurance 
All study participant data relating to the study will be recorded on the eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of study participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH-GCP, and all applicable regulatory requirements.
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study medication/investigational device. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or by an agreement with UCB (CPMP/ICH/135/95, 2002 
[Section 4.9.5]). The Investigator will contact UCB for authorization prior to the destruction of 
any study records or in the event of accidental loss or destruction of any study records. The 
Investigator will also notify UCB should he/she relocate or move the study-related files to a 
location other than that specified in the Sponsor’s trial master file.
10.1.6.1 
Case Report form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
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.
10.1.6.2 
Apps 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 67 of 91
10.1.7 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments
(such as removable self-stick notes).
Source documents are original records in which raw data are first recorded. These may include 
clinic records, charts, laboratory results, printouts, pharmacy records, ECG or other printouts, or 
completed scales, for example. Source documents should be kept in a secure, limited access area.
Source documents that are computer-generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the study participant’s source documents. 
The Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent.
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee).
10.1.8 
Study and site closure 
The Sponsor/designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:
x Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines
x Inadequate recruitment of study participants by the Investigator
x Discontinuation of further study medication development
10.1.9 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments.
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 68 of 91
10.2 
Appendix 2: Clinical Laboratory Tests 
x The tests detailed in the table below will be performed by a local laboratory.
x Protocol-specific requirements for inclusion or exclusion of study participants are detailed in 
Section 5.1 and Section 5.2 of this protocol.
x Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocyte count
WBC Count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
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Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
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(SGOT)
Total and 
direct 
bilirubin
Creatinine
Sodium
Alanine Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose
Calcium
Alkaline phosphatase
Routine 
Urinalysisb
x Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte by dipstick. If protein or blood or 
leukocytes are abnormal (positive), a microscopic examination of the 
sediment will be performed.
Other 
Screening 
Tests
x Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids, and benzodiazepines)
x Alcohol breath test
x Pregnancy test: Serum human chorionic gonadotropin (hCG) test (as 
needed for women of childbearing potential)
x Serology (HIV 1 and 2 Ab, HBsAg, HCV-Ab, syphilis; hepatitis E RNA)
The results of each test must be entered into the eCRF.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 69 of 91
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Section 10.6. All events of ALT ≥3×ULN) and bilirubin ≥2×ULN 
(>35% direct bilirubin) or ALT≥3×ULN and international normalized ratio (INR) >1.5, if INR measured, may 
indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).
b Serum pregnancy testing (not urine) will be standard for this protocol.
Investigators must document their review of each laboratory safety report.
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 70 of 91
10.3 
Appendix 3: Adverse events – definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1 
Definition of AE 
AE Definition
x An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study medication, whether or not considered related 
to the study medication.
x NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study medication.
Events Meeting the AE Definition
x Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgement of the Investigator (ie, not related to progression of underlying 
disease).
x Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
x New condition detected or diagnosed after study medication administration even though it 
may have been present before the start of the study.
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
medication or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition
x Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.
x The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition.
x Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
x Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 71 of 91
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity
x The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
x This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
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f. 
Important medical events
x Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include, but are not limited to, potential Hy’s Law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 72 of 91
10.3.3 
Recording and follow-up of AE and/or SAE 
AE and SAE Recording
x When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
x The Investigator will then record all relevant AE/SAE information in the eCRF.
x It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to UCB in lieu of completion of the UCB AE/SAE eCRF page.
x There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to UCB.
x The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:
x Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
x Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
x Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
x An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE may 
be either serious or not serious, depending on whether these criteria are also met).
The National Cancer Institute Common Terminology Criteria for Adverse Events should be 
used as a supportive standardization instrument to evaluate AEs and SAEs, but the final 
intensity grading by the Investigator must be mild, moderate, or severe.
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 73 of 91
Assessment of Causality
x The Investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE.
x A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
x The Investigator will use clinical judgment to determine the relationship.
x Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study medication 
administration, will be considered and investigated.
x The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
x For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
x There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to UCB. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to UCB.
x The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
x The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs
x The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
x An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the participant is lost to follow-up.
This follow-up requirement applies to AEs, SAEs, and AEs of special interest.
x If a participant dies during participation in the study or during a recognized follow-up
period, the Investigator will provide UCB with a copy of any post-mortem findings 
including histopathology.
x New or updated information will be recorded in the originally completed eCRF.
x The Investigator will submit any updated SAE data to UCB within 24 hours of receipt of 
the information. 
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Reporting of SAEs
SAE Reporting to UCB via an Electronic Data Collection Tool
x The primary mechanism for reporting an SAE to UCB will be the electronic data collection 
tool.
x If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).
x The site will enter the SAE data into the electronic system as soon as it becomes available.
x After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.
x If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the UCB Study Physician by telephone.
x Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT REPORTING. 
SAE Reporting to UCB via Paper CRF
x Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the UCB Study Physician.
x In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service.
x Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
x Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT REPORTING.
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10.4 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information 
10.4.1 
Definitions 
10.4.1.1 
Woman of childbearing potential 
In general, a woman is considered fertile following menarche and until becoming 
post-menopausal unless permanently sterile (see below).
In this study, the only women considered to be of non-childbearing potential who are eligible for 
inclusion are:
1. Premenopausal females with 1 of the following:
 Documented hysterectomy
 Documented bilateral salpingectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
10.4.2 
Contraception guidance 
10.4.2.1 
Male participants 
Not applicable.
10.4.2.2 
Pregnancy testing 
x WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test.
x Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
x Serum beta human chorionic gonadotropin (HCG) pregnancy testing will be performed at all
timepoints mentioned in the Schedule of activities.
x The result must be negative prior to dosing the study participant.
10.4.2.3 
Collection of pregnancy information 
10.4.2.3.1 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10-1.
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Table 10-1: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
x Combined (estrogen and progestogen containing) hormonal contraception and progesterone 
only hormonal contraceptive methods are not permitted in this study.
Highly Effective Methods That Are User Independent
x Intrauterine device (IUD)
x Bilateral tubal occlusion
x Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.
x Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study medication. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
10.4.2.3.2 
Male participants with partners who become pregnant 
Not applicable.
10.4.2.3.3 
Female participants who become pregnant 
x The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, the follow-up will be at least 30 days (or up to 
12 months) after the delivery date. Any termination of pregnancy will be reported, regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to the study medication by the 
Investigator will be reported to the Sponsor as described in Section 8.4.5. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting.
x Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
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10.5 
Appendix 5: Genetics 
Genetics are not evaluated in this study; however, a blood sample will be taken for potential 
genotyping of metabolizing enzymes and/or drug transporters. Genotyping samples will be 
destroyed once the clinical study report has been finalized, approximately 1 year after the end of 
the study.
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10.6 
Appendix 6: Liver safety–suggested actions and follow-up 
assessments 
Participants with PDILI must be assessed to determine if study medication must be discontinued. 
In addition, all concomitant medications and herbal supplements that are not medically necessary 
should be discontinued.
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete a final evaluation.
Study participants with PDILI should not be withdrawn from the study until investigation and 
monitoring are complete. All results of these evaluations and observations, as well as the 
reason(s) for study medication discontinuation and/or participant withdrawal (if applicable), 
must be recorded in the source documents. The eCRF must document the primary reason for 
discontinuation of study medication.
A specific monitoring plan must be agreed between the UCB Study Physician and the 
Investigator for study participants who have ALT >5 ULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values).
Phase 1 liver chemistry stopping criteria are designed to assure participant safety and to evaluate 
liver event etiology (Table 10-2).
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Table 10-2: Phase I liver chemistry stopping criteria and follow-up 
assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT ≥3xULN AND bilirubin t2xULN (>35% direct bilirubin) OR international 
normalized ratio (INR) >1.5, report as a serious adverse event (SAE).a,b
See additional actions and follow-up assessments listed below.
Suggested Actions and Follow-up Assessments
Actions
Follow-Up Assessments
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x Report the event to the UCB within 24 hours.
x Complete the liver event eCRF, and complete 
an SAE data collection tool if the event also 
met the criteria for an SAE.b
x Perform liver chemistry follow-up assessments. 
x Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return to 
baseline (see MONITORING).
MONITORING:
If ALT t3xULN AND bilirubin t2xULN or INR 
>1.5:
x Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin) and perform liver event 
follow-up assessments within 24 hours.
x Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to baseline.
x A specialist or hepatology consultation is 
recommended.
If ALT ≥3xULN AND bilirubin <2xULN and INR 
≤1.5:
x Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver chemistry follow-up assessments 
within 24 to 72 hours.
x Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to baseline.
x Viral hepatitis serology.c
x Obtain INR and recheck with each 
liver chemistry assessment until the
transaminases values show 
downward trend.
x Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH).
x Fractionate bilirubin, if total 
bilirubin t2xULN.
x Obtain complete blood count with 
differential to assess eosinophilia.
x Record the appearance or worsening 
of clinical symptoms of liver injury 
or hypersensitivity on the AE eCRF.
x Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, and 
other over-the-counter medications) 
on the concomitant medications 
eCRF.
x Record alcohol use on the liver event 
alcohol intake eCRF.
If ALT ≥3xULN AND bilirubin t2xULN 
or INR >1.5:
x Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total IgG or gamma 
globulins.
x Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James et al, 2009].) 
NOTE: Not required in China.
x Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) and/or liver biopsy to 
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evaluate liver disease; complete liver 
imaging and/or liver biopsy eCRFs.
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing 
is unavailable, record the absence/presence of detectable urinary bilirubin on dipstick, which is indicative of 
direct bilirubin elevations suggesting liver injury.
b All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR >1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis). The INR measurement is not required, and the stated threshold value will not apply to 
participants receiving anticoagulants.
c Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HCV-Ab; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody.
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10.7 
Appendix 7: Medical device incidents – definition and 
procedures for recording, evaluating, follow-up, and reporting 
Not applicable.
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10.8 
Appendix 8: Rapid alert procedures 
Not applicable.
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10.9 
Appendix 9: Country-specific requirements 
Not applicable.
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10.10 
Appendix 10: Abbreviations and trademarks 
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
BID
twice per day
BP
blood pressure
cBZR
central benzodiazepine receptor
CI
confidence interval
CNS
central nervous system
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
CV
coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic Case Report form
EE
ethinylestradiol
ES
enrolled set
FDA
Food and Drug Administration
GABA
gamma-aminobutyric acid
GCP
Good Clinical Practice
HCG
human chorionic gonadotropin
HCV-Ab
hepatitis C antibody
HIV
human immunovirus
IB
Investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
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IMP
investigational medicinal product
IRB
Institutional Review Board
LEV
levetiracetam
LFT
liver function test
LN
levonorgestrel
MTD
maximum tolerated dose
NDA
New Drug Application
OC
oral contraceptive
OTC
over-the-counter
PDILI
potential drug-induced liver injury
PK
pharmacokinetic(s)
PK-PPS
Pharmacokinetic Per Protocol Set
PR
pulse rate
PS
Patient Safety
PSL
Padsevonil
QTc
QT interval corrected
QTcB
QT interval corrected for Bazett’s formula
QTcF
QT interval corrected for Fridericia’s formula
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SFU
Safety Follow-up
SS
safety set
SV2
synaptic vesicle protein 2
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WOCBP
women of childbearing potential
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10.11 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 1: 10 Oct 2019
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The protocol has been amended to comply with changes requested by the Medicines and 
Healthcare products Regulatory Agency (MHRA). Changes were made in the exclusion criteria 
to set the upper limit of acceptable range of total bilirubin test results and to clarify language 
regarding liver function tests (absolute rule for liver function test parameters). Changes were 
made in Section 7.2 (Criteria for study hold due to adverse events) to comply with MHRA 
requirement to align with European Medicines Agency Guidance on risk mitigation in first-in-
human and early clinical trials, and to add an additional electrocardiogram (ECG) measurement 
at Day 14 (for Treatment Sequence A) and Day 31 (for Treatment Sequence B).
Section # and Name
Description of Change
Brief Rationale
Section 1.2 Treatment 
Sequences
Day of oral contraceptive administration 
was changed from Day 31 to Day 30 in 
Treatment Sequence B to align with the 
rest of the protocol.
Correction
Section 1.3 Schedule of 
activities
An additional ECG measurement at 
Day 14 (for Treatment Sequence A) and 
Day 31 (for Treatment Sequence B) were 
added to the schedule of activities.
Add an additional 
ECG assessment
Section 1.3 Schedule of 
activities
Physical exam and blood sampling for 
cross-validation in Treatment Sequence B 
have been changed from Day 30 to Days 
23 to 29 to align with the assessment days 
described in Treatment Sequence A.
Correction to align 
schedule of activities 
between Treatment 
Sequence A and 
Treatment 
Sequence B.
Section 1.3 Schedule of 
activities
Administer OC and blood sampling for OC 
PK level were changed from Day 31 to 
Day 30. Footnotes g, h, and i were 
updated to correct the days blood samples 
are to be collected.
Correction to align 
schedule of activities 
between Treatment 
Sequence A and 
Treatment 
Sequence B.
Section 5.2-Exclusion Criteria
Language specifying an adult cohort in 
exclusion criterion #7 has been removed 
for clarification purposes, as all 
participants in this study are adults. 
Changed exclusion criterion #18 to 
include that isolated bilirubin must be 
<1.5xULN instead of >1xULN. The 
Update exclusion 
criteria
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Section # and Name
Description of Change
Brief Rationale
exception of asymptomatic gallstones was 
removed from exclusion criterion #19.
Section 5.2-Exclusion Criteria
Exclusion criterion #19 had the note 
removed regarding liver function test 
values above the ULN and repeat tests that 
could be performed in such situations. 
Language regarding retesting of 
participants with out-of-range laboratory 
values remains elsewhere in the protocol 
including Section 5.4.1 (Rescreening).
Update exclusion 
criteria
Section 7.2 Criteria for study 
hold due to adverse events
The criteria have been amended to align 
with the EMA Guidance on risk mitigation 
in first-in-human and early clinical trials.
Regulatory alignment
Section 10.5 Appendix 5: 
Genetics
The language describing sample collection 
was updated for clarity.
Language clarification
Section 10.4.2.3.1 Female 
participants
Brand names of IUDs containing 
hormones were removed.
Correction
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11 
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Impaired Renal Function-Study Design, Data Analysis, and Impact on Dosing and Labeling, 
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Janz R, Südhof TC. SV2C is a synaptic vesicle protein with an unusually restricted localization: 
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Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in 
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Kilpatrick CJ, Lowe AJ. Management of Epilepsy in Older People. J Pharm Pract Res. 
2002;32:110-4.
Klitgaard H, Verdru P. Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert 
Opin Drug Discov. 2007;2(11):1537-45.
Kuhnz W, Staks T, Jütting G. Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 
women during three months of treatment with a tri-step combination oral contraceptive: serum 
protein binding of levonorgestrel and influence of treatment on free and total testosterone levels 
in the serum. Contraception. 1994; 50(6):563-79.
Loganathan MA, Enja M, Lippmann S. Forced normalization: epilepsy and psychosis 
interaction. Innov Clin Neurosci. 2015;12(5-6):38-41.
Palovaara S1, Tybring G, Laine K. The effect of ethinyloestradiol and levonorgestrel on the 
CYP2C19-mediated metabolism of omeprazole in healthy female subjects. Br J Clin Pharmacol. 
2003; 56(2):232-7.
Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and 
pharmacokinetics. Acta Neurol Scand. 2008;118:69-86.
Wan QF, Zhou ZY, Thakur P, Vila A, Sherry DM, Janz R, et al. SV2 acts via presynaptic 
calcium to regulate neurotransmitter release. Neuron. 2010;66:884-95.
World Health Organization. Epilepsy. Available from: 
http://www.who.int/mediacentre/factsheets/fs999/en/ [Accessed 23 May 2018].
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 90 of 91
Zhang N, Shon J, Kim MJ, Yu C, Zhang L, Huang SM, et al. Role of CYP3A in Oral 
Contraceptives Clearance. Clin Transl Sci. 2018; 11(3):251-60.
REDACTED COPY 
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UCB
25 Feb 2020
Clinical Study Protocol
Padsevonil
UP0035
Confidential
Page 91 of 91
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Approval Signatures
Name:
up0035-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000148552
Title:
UP0035 Protocol Amendment 2
Approved Date:
27 Feb 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-Feb-2020 21:00:08 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 26-Feb-2020 10:10:33 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Feb-2020 07:59:12 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 27-Feb-2020 09:04:01 GMT+0000
DACTED 
REDA
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SAP_001.pdf: 
UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 1 of 50
 
 
STATISTICAL ANALYSIS PLAN  
Study: UP0035
Product: Padsevonil
季
季
AN OPEN-LABEL, RANDOMIZED TWO-WAY CROSSOVER 
STUDY TO INVESTIGATE THE POTENTIAL 
PHARMACOKINETIC INTERACTION OF PADSEVONIL WITH 
ORAL CONTRACEPTIVES IN HEALTHY FEMALE 
PARTICIPANTS 
季
Confidentiality Statement
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, 
published, or otherwise used without the express permission of UCB.
SAP/Amendment Number
Date
Version 1.0
28-May-2020
REDACTED
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 2 of 50
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................... 4 
1 
INTRODUCTION............................................................................................................. 7 
2 
PROTOCOL SUMMARY................................................................................................. 7 
2.1 Study objectives and endpoints ......................................................................................... 7 
2.2 Study design and conduct.................................................................................................. 8 
2.3 Determination of sample size .......................................................................................... 24 
3 
DATA ANALYSIS CONSIDERATIONS...................................................................... 24 
3.1 General presentation of summaries and analyses ............................................................ 24 
3.2 General study level definitions........................................................................................ 26 
3.2.1 
Relative day......................................................................................................... 26 
3.2.2 
Study periods....................................................................................................... 26 
3.3 Definition of Baseline values........................................................................................... 28 
3.4 Protocol deviations .......................................................................................................... 29 
3.5 Analysis sets .................................................................................................................... 29 
3.5.1 
All Study Participants.......................................................................................... 29 
3.5.2 
Safety Set (SS)..................................................................................................... 29 
3.5.3 
Pharmacokinetic Set (PKS)................................................................................. 30 
3.6 Treatment assignment...................................................................................................... 30 
3.7 Center pooling strategy.................................................................................................... 31 
3.8 Coding dictionaries.......................................................................................................... 31 
3.9 Changes to protocol-defined analyses ............................................................................. 31 
4 
STATISTICAL/ANALYTICAL ISSUES....................................................................... 32 
4.1 Adjustments for covariates .............................................................................................. 32 
4.2 Handling of dropouts or missing data.............................................................................. 32 
4.2.1 
Pharmacokinetics................................................................................................. 32 
4.2.2 
Safety laboratory data.......................................................................................... 33 
4.2.3 
Electrocardiogram data........................................................................................ 33 
4.2.4 
Dates and times ................................................................................................... 33 
4.3 Handling of repeated and unscheduled measurements.................................................... 35 
4.4 Handling of measurements obtained at the early withdrawal visit.................................. 35 
4.5 Interim analyses and data monitoring.............................................................................. 35 
4.6 Multicenter studies........................................................................................................... 35 
4.7 Multiple comparisons/multiplicity .................................................................................. 35 
4.8 Use of an efficacy subset of study participants ............................................................... 35 
4.9 Active-control studies intended to show equivalence ..................................................... 36 
4.10 Examination of subgroups............................................................................................... 36 
5 
STUDY POPULATION CHARACTERISTICS ............................................................ 36 
5.1 Study participant disposition ........................................................................................... 36 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 3 of 50
5.2 Protocol deviations .......................................................................................................... 36 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS........................ 36 
6.1 Demographics.................................................................................................................. 36 
6.2 Other Baseline characteristics.......................................................................................... 37 
6.3 Medical history, procedure history and concomitant medical procedures ...................... 37 
6.4 Prior and concomitant medications ................................................................................. 37 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE .............................................. 39 
8 
EFFICACY ANALYSES................................................................................................ 39 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS.......................................... 39 
9.1 Analysis of the primary pharmacokinetic variables ........................................................ 40 
9.2 Analysis of secondary pharmacokinetic variables........................................................... 41 
9.3 Analysis of other pharmacokinetic variables................................................................... 41 
10 SAFETY ANALYSES .................................................................................................... 41 
10.1 Extent of exposure........................................................................................................... 42 
10.2 Adverse events................................................................................................................. 42 
10.3 Clinical laboratory evaluations........................................................................................ 44 
10.4 Vital signs, physical findings, and other observations related to safety.......................... 46 
10.4.1 
Vital signs............................................................................................................ 46 
10.4.2 
Electrocardiograms.............................................................................................. 47 
10.4.3 
Other safety variables.......................................................................................... 48 
10.4.3.1 
Physical examination ................................................................................ 48 
10.4.3.2 
Columbia-Suicide Severity Rating Scale.................................................. 48 
11 OTHER ANALYSES...................................................................................................... 48 
12 REFERENCES ................................................................................................................ 49 
13 APPENDICES................................................................................................................. 50 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 4 of 50
 LIST OF ABBREVIATIONS 
AE(s)
adverse event(s)
ALT
alanine aminotransferase
ALQ
above the limit of quantification
ANOVA
analysis of variance
AST
aspartate aminotransferase
ASP
all study participants
AUC
area under the curve from time 0 to infinity
AUC0-t
area under the curve from time 0 to the last 
quantifiable concentration
AUC0-12
area under the curve from time 0 to 12h 
AUCτ
area under the curve over a dosing interval 
BID
twice daily
BLQ
below the limit of quantification
BMI
body mass index
BP
Blood pressure
CI
confidence interval
CL/F
apparent total clearance
CLSS/F
apparent total clearance at steady-state
Cmax
maximum observed plasma concentration
Cmax,ss
maximum observed plasma concentration at steady-
state
Cmin
minimum observed plasma concentration
CRF
case report form
CRU
clinical research unit
Ctrough
plasma trough concentration
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 5 of 50
CSR
clinical study report
CV
coefficient of variation
C-SSRS
Columbia-Suicide Severity Rating Scale
DEM
data evaluation meeting
DDI
Drug Drug Interaction
ECG
electrocardiogram
EDV
Early Discontinuation Visit
EE
Ethinylestradiol
EOS
End of Study
EudraCT
European Union Drug Regulating Authorities 
Clinical Trials
FDA
Food and Drug Administration
geoCV
geometric coefficient of variation
ICF
Informed Consent form
ICH
International Council on Harmonisation
IMP
investigational medicinal product
IPD
important protocol deviation
LLOQ
lower limit of quantification
LN
Levonorgestrel
MedDRA
Medical Dictionary for Regulatory Activities
MRAUCτ 
Metabolic ratio for AUCτ
MRCmax,ss
Metabolic ratio for Cmax,ss
n
number of study participants
number of available observations
NCA
Noncompartmental analysis
OC
Oral contraceptive
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 6 of 50
PDILI
Potential drug-induced liver injury
PKS
Pharmacokinetic Set
PK
Pharmacokinetic(s)
PK-PPS
Pharmacokinetic-Per Protocol Set
PR
pulse rate
PSL
Padsevonil
PT
preferred term
QTcF
QT corrected for heart rate using Fridericia’s 
formula
RR
respiratory rate
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SD
single dosing
sd
standard deviation
SFU
Safety Follow-up
SOC
system organ class
SS
Safety Set
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
TFLs
tables, figures and listings
tmax
time to maximum concentration (Cmax or Cmax,ss)
t1/2
terminal elimination half-life
t1/2,ss
terminal elimination half-life at steady state
ULN
upper limit of normal
WHODD
World Health Organization Drug Dictionary
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 7 of 50
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 UP0035. It also defines the summary tables, figures and 
listings (TFLs) to be included in the final clinical study report (CSR) according to the protocol.
This SAP is based on the following documents:
x Original Clinical Study Protocol dated 01 Aug 2019
x Clinical Study Protocol Amendment 1 dated 10 Oct 2019
x File Note with number Ward v3 (HMR code 19-009) dated 12 Dec 2019
x Clinical Study Protocol Amendment 2 dated 25 Feb 2020
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.
Following UCB’s decision to terminate the padsevonil (PSL) epilepsy project in partial onset 
seizures, the UP0035 study has been stopped and no study participants will enter study Part 2. 
Consequently, study results reporting will be restricted to study Part 1 of this SAP and a subset of 
the tables, figures, and listings will be reported in line with Clinical Trial Reporting duties 
(EUDRA-CT, ClinicalTrials.gov).
The content of this SAP is compatible with the International Council for Harmonisation 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips et al, 2003).
UCB is the Sponsor and ICON PLC is the Contract Research Organization for this study.
2 
PROTOCOL SUMMARY 
2.1 
Study objectives and endpoints 
Table 2-1: 
Objectives and endpoints 
Objectives
Endpoints
Primary
x To investigate the effect of steady-state 
PSL (400 mg twice daily (BID) or 200 mg 
BID) on the pharmacokinetics (PK) of a 
single dose oral contraceptive containing 
EE 30μg and LN 150μg.
 Cmax and AUC of EE and LN
Secondary
x To evaluate the safety and tolerability of 
PSL in healthy female study participants.
 Incidence of TEAEs and SAEs
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 8 of 50
Table 2-1: 
Objectives and endpoints 
Objectives
Endpoints
x To evaluate the effect of single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL.
 Cmax,ss and AUCτ of PSL
Other
x To evaluate the safety and tolerability of 
PSL in healthy female study participants.
 Changes in vital signs (oral or aural 
temperature, pulse rate, respiratory rate, 
and BP)
 Changes in safety laboratory data 
(hematology, clinical chemistry, and 
urinalysis)
 Changes in 12-lead ECG assessments
 Physical and neurological examination 
findings
x To evaluate the effect of a single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL.
 
CLss/F, Cmin, tmax, t1/2 of PSL
x To evaluate the effect of a single-dose oral 
contraceptive containing EE 30μg and 
LN 150μg on the steady-state PK of PSL 
metabolites
 AUCτ, Cmax,ss, tmax, t1/2ss, Ctrough, and 
metabolic ratios of AUCτ and Cmax,ss for 
PSL metabolites
x To investigate the effect of steady-state 
PSL (400 mg BID or 200 mg BID) on the 
PK of a single-dose oral contraceptive 
containing EE 30μg and LN 150μg
 Tmax, AUC(0-t), t1/2,and CL/F of EE and 
LN
x To collect and store blood samples for 
genotyping of drug metabolizing enzymes 
and/or transporters. (if needed)
 Potential genotyping of study 
participants for specific genes related to 
drug metabolizing enzymes and/or 
transporters.
x To collect venous plasma and blood 
samples (Mitra™) for cross-validation of
PSL bioanalytical method
 Cross validation of PSL bioanalytical 
method.
BP=blood pressure; ECG=electrocardiogram; EE=ethinylestradiol; LN= levonorgestrel PK=pharmacokinetic; 
PSL=padsevonil; SAE=serious adverse event; TEAE=treatment-emergent adverse event
2.2 
Study design and conduct 
This is a Phase 1, open-label, randomized, 2-way crossover study to investigate the potential 
pharmacokinetic (PK) interaction of PSL with oral contraceptive (OC) in healthy female study 
participants.
Prior to Protocol Amendment 2, the intention was to screen a sufficient number of study 
participants to ensure that 20 study participants would be included in each treatment sequence 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 9 of 50
shown in Table 2-2. This pair of treatment sequences has now been designated as Part 1, 
necessitated by the introduction of a new pair of treatment sequences at the new, lower dose level, 
termed Part 2, for new study participants that will be enrolled under the amended protocol. At the 
time of Amendment 2, 14 study participants completed Part 1 and were dosed with PSL 400mg 
BID (7 study participants in Sequence A and 7 study participants in Sequence B). In Part 2, a 
sufficient number of study participants will be screened to ensure that 13 study participants are 
included in each treatment sequence. 
Each Part of the study (1 and 2) consists of a Screening Visit, a Baseline Visit, 2 Treatment Periods 
(a PSL+OC Period and an OC alone Period) with at least a 14-day washout between periods, and a 
Safety Follow-up (SFU) Visit that will occur no sooner than 7 days, and at a maximum of 10 days 
(Part 1) or 14 days (Part 2) following the final dose of study medication. 
Study participants who provide written informed consent will be screened during the 28-day period 
from Day -29 to Day -2.  Study participants who meet all inclusion and none of the exclusion 
criteria will check into the clinic on Day -1 (Baseline, the day prior to Day 1, the first day of the 
first Treatment Period and will be randomized into one of the 2 treatment sequences: Treatment 
Sequence A or Treatment Sequence B.
Each study participant will be dosed with OC alone and OC+PSL during the 2 Treatment Periods 
in either Treatment Sequence A or Treatment Sequence B. If the study participant is randomized to 
Treatment Sequence A, they will receive OC+PSL during the first Treatment Period followed by 
OC alone during the second Treatment Period. If the study participant is randomized to Treatment 
Sequence B, they will receive OC alone during the first Treatment Period followed by OC+PSL 
during the second Treatment Period. There will be a Washout Period of at least 14 days between 
treatments within each sequence.
Forty (40) evaluable study participants will be enrolled overall. A total of 14 evaluable study 
participants (7 study participants in each sequence) have completed Part 1 with PSL 400mg BID 
dosing. For Part 2 with PSL 200mg BID dosing, a total of 26 evaluable study participants are 
planned (13 study participants in each sequence). Study participants who are withdrawn may be 
replaced following discussion between the Investigator and Sponsor.
In Part 1, the maximum total duration of the study is approximately 75 days for each study 
participant, including the Screening Period (up to 28 days), a 36-day Treatment Period including a 
Washout Period of at least 14 days, and a SFU Visit (the SFU Visit should occur no sooner than 
7 days, and at a maximum of 10 days following the final dose of study medication). Study 
participants in Part 1 (either sequence) will be treated with PSL (maximum dose of 400mg BID) 
for a total of 19 days.
In Part 2, the maximum total duration of the study is approximately 70 days for each study 
participant, including the Screening Period (up to 28 days), a 28-day Treatment Period, including a 
14-day Washout Period, and a SFU Visit (the SFU Visit should occur no sooner than 7 days, and at 
a maximum of 14 days following the final dose of study medication). Study participants in Part 2 
(either sequence) will be treated with PSL (maximum dose of 200mg BID) for 11 days, a reduction 
of 8 days compared with Part 1. 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 10 of 50
Table 2-2: 
Part 1 treatment sequences 
Part 1 Treatment Sequence A
PSL+OC
Washout 
(14 Days)
OC
SFU/
EOS
Day
1
2 to 3
4 to 5
6 to 12
13
14
15 to 16
17 to 18
19
20 to 33
34
35
36
41 to 44
OC Dose
OC SD
OC 
SD
PSL Dose
(mg)
100 BID
200 BID
300 BID
400 BID
400 BID
400 BID
300 BID
200 BID
100 BID
PK 
Sampling
PK 
(Day 2
only)a
PK
(Day 4
only) a
PK
(Days 6, 
8, 10, and 
12)
PK
PK
PK
(Day 15
only)
PK
PK
PK
Part 1 Treatment Sequence B
OC
Washout 
(14 Days)
PSL+OC
SFU/EOS
Day
1
2
3
4 to 17
18
19 to 20
21 to 22
23 to 29
30
31
32 to 33
34 to 35
36
43 to 46
OC Dose
OC 
SD
OC SD
PSL 
Dose(mg)
100 BID
200 BID
300 BID
400 BID
400 BID
400 BID
300 BID
200 BID
100 BID
PK Sampling
PK
PK
PK
PK 
(Day 19
only) a
PK 
(Day 21
only) a
PK 
(Days 23, 
25, 27, 
and 29)
PK
PK
PK
(Day 32)
BID=twice daily; EOS=End of Study; OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SD=single dose; SFU=Safety Follow-up
a Pharmacokinetic samples must be taken before morning dose of PSL.
REDACTED 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 11 of 50
Table 2-3: 
Part 2 treatment sequences 
Part 2 Treatment Sequence A
PSL+OC
Washout 
(14 Days)
OC
SFU/
EOS
Day
1
2 to 8
9
10
11
12 to 25
26
27
28
33 to 40
OC Dose
OC SD
OC SD
PSL Dose (mg)
100 BID
200 BID
200 BID
200 BID
100 BID
PK Sampling
PK (Days 2, 4, 6, 8 only) a
PK
PK
PK
PK
PK
PK
Part 2 Treatment Sequence B
OC
Washout 
(14 Days)
PSL+OC
SFU/
EOS
Day
1
2
3
4 to 17
18
19 to 25
26
27
28
35 to 42
OC Dose
OC SD
OC SD
PSL Dose (mg)
100 BID
200 BID
200 BID
200 BID
100 BID
PK Sampling
PK
PK
PK
PK (Day 19, 21, 23, 25 only) a
PK
PK
PK
BID=twice daily; EOS=End of Study; OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SD=single dose; SFU=Safety Follow-up
a Information on sampling time is provided in the Schedule of Activities Table.
REDACTED 
18
18
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26
26
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on thereof. 


UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 12 of 50
 
 
Table 2-4: 
Schedule of activities- Part 1 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ 
SFU/
EDVa
Day
-29 to -2
-1
1
2 to 
3
4 to 
5
6 to 
12
13
14
15 to 16 17 to 18
19
20 to 33
34
35
36
41 to 
44
Written informed 
consent
X
Demographics and 
baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
General medical 
/medications/ 
procedures history
X
X
X (D33)
Suicidality Risk 
Assessment 
(C-SSRS)b
X
X
X (D33)
X
Psychiatric and mental 
status evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Physical examinationc
X
X
X
X
X
X (D33)
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D33)
Hematology, clinical 
chemistry, urinalysis
X
X
X
X (D33)
X
Serology (HIV, 
HBsAg HEV, syphilis, 
and HCV-Ab)
X
12-lead ECG
X
X
X
Xe
Xe
Xe
X
X
X
X
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 13 of 50
 
 
Table 2-4: 
Schedule of activities- Part 1 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ 
SFU/
EDVa
Day
-29 to -2
-1
1
2 to 
3
4 to 
5
6 to 
12
13
14
15 to 16 17 to 18
19
20 to 33
34
35
36
41 to 
44
Urine and cotinine 
drug screen, and 
alcohol breath test
X
X
X (D33)
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X
X
X
X
X
X
X (D33)
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing enzymes 
and/or transporters
X
Admit to clinic
X
X (D33)
Administer PSL
X
X
X
X
X
X
X
X
X
Administer OC
X
X
Blood sampling for 
PSL PK levelsf
X
X
X
X
X
X
Blood sampling for 
OC PK levelsg
X
X
X
X
X
X
Blood sampling for 
cross-validationh
X
Discharge
X (D20 or 
D21)i
X
C-SSRS=Columbia Suicide Severity Rating Scale; EOS=End of Study; EDV=Early Discontinuation Visit; ECG=electrocardiogram; h=hour(s); HbsAg-Ab=HepB 
surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus; OC=oral contraceptive; 
PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
REDACTED 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 14 of 50
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months) followed by the “Since Last 
Visit” version at subsequent visits.
c At Screening, Baseline (Day -1), Day 6, and Day 12, a full physical examination will be performed. On all other days a physical examination is performed, it will be 
a brief physical examination. On Days 7 to 11, physical examination will not be performed.
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions), pulse rate, respiratory 
rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood pressure 
measurement.
e ECG will be completed on Days 2, 4, 6, and 12 only of multiple day periods during Treatment Sequence A.
f During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 2, Day 4, Day 6, Day 8 and Day 10. 
Additional blood sampling for PK analysis will be taken on Day 12 (PSL PK) before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 
8h, 12h postdose and on Day 13 (PSL and OC PK) before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h 
(before morning PSL dose on Day 14), and 48h (before morning PSL dose on Day 15) postdose.
g During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 13 (before OC+PSL morning dose) and after PSL and OC morning 
dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 14), 36h (Day 14), and 48h (Day 15) postdose. During the single-dose OC period, PK blood samples 
will be taken on Day 34 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 35), 36h (Day 35), and 48h (Day 36) postdose.
h Mitra ™ (finger prick) blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 12 only for selected study participants. 
i  The study participant can be discharged on Day 20 or Day 21, at the discretion of the principal investigator.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 15 of 50
 
 
Table 2-5: 
Schedule of activities- Part 1 Treatment Sequence B 
Screenin
g
Baselin
e
OC
Washout 
(14 Days)
PSL+OC
EOS/ 
SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 
20
21 to 
22
23 to 
29
30
31
32 to 
33
34 to 
35
36
43 to 
46
Written informed 
consent
X
Demographics and 
baseline 
characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
X
General medical 
/medications/ 
procedures history
X
X
X (D17)
Suicidality Risk 
Assessment 
(C-SSRS)b
X
X
X (D17)
X
Psychiatric and 
mental status 
evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D17)
Hematology, clinical 
chemistry, urinalysis
X
X
X (D17)
X
X
Serology (HIV, 
HbsAg, HEV, 
X
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thereof. 


UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 16 of 50
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
syphilis, and 
HCV-Ab)
12-lead ECG
X
X
X
X
Xe
Xe
Xe
X
X
X
X
Urine and cotinine 
drug screen, and 
alcohol breath test
X
X
X (D17)
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X (D17)
X
X
X
X
X
X
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing 
enzymes and/or 
transporters
X
Admit to clinic
X
X (D17)
Administer PSL
X
X
X
X
X
X
X
X
X
Administer OC
X
X
Blood sampling for 
PSL PK levelsf
Xf
Xf
Xf
Xf
Xf
Xf
Blood sampling for 
OC PK levelsg
Xg
Xg
Xg
Xg
Xg
Xg
Blood sampling for 
cross-validationh
X
Discharge
X
X
(D37 
or 
D38)i
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; h=hour(s); EDV=Early Discontinuation Visit, EOS=End of Study,
h=hour(s), HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency 
virus; OC=oral contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
EDACTED 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 17 of 50
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months) followed by the “Since Last 
Visit” version at subsequent visits.
c At Screening, Baseline (Day -1), Day 23, and Day 29, a full physical examination will be performed. On all other days a physical examination is performed, it will 
be a brief physical examination. On Days 24-28, physical examination will not be performed.
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions.), pulse rate, respiratory 
rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood pressure 
measurement.
e ECG will be completed on Days 19, 21, 23, and 29 only of multiple day periods during Treatment Sequence B.
f During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 19, Day 21, Day 23, Day 25 and Day 27. 
Additional blood sampling for PK analysis will be taken on Day 29 (PSL PK) before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 
6h, 8h, 12h postdose and on Day 30 (PSL PK) before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h postdose. 
In addition, blood samples will be obtained prior to the morning dose on Day 31 and prior to the morning dose on Day 32. 
g During the single-dose OC period, PK blood samples will be taken on Day 1 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 2), 36h (Day 2), 
and 48h (Day 3) postdose. During the OC+PSL Treatment Period blood sampling for OC PK analysis will be taken on Day 30 (before OC+PSL morning dose) and
after PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 31), 36h (Day 31) and 48h (Day 32) postdose.
h  Mitra ™ (finger prick) blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 29 only.
I  The study participant can be discharged on Day 37 or Day 38, at the discretion of the principal investigator.
REDACTED COPY
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n Da
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 18 of 50
Table 2-6: 
Schedule of activities- Part 2 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ SFU/
EDVa
Day
-29 to -2
-1
1
2 to 8
9
10
11
12 to 25
26
27
28
33 to 40
Written informed consent
X
Demographics and 
baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
General medical 
/medications/ procedures 
history
X
X
X (D25)
Suicidality Risk 
Assessment (C-SSRS)b
X
X
X(D25)
X
Psychiatric and mental 
status evaluation 
X
X
Xh
Xh
Xh
Xh
Xh
X
Physical examinationc
X
X
X
X
X
X (D25)
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D25)
Hematology, clinical 
chemistry, urinalysis
X
X
X
X (D25)
X
Serology (HIV, HBsAg 
HEV, syphilis, and 
HCV-Ab)
X
12-lead ECG
X
X
X
Xe
X
X
X
X
REDACTED 
AC
R
COPY 
PY
CO
This document cannot 
X
X
no
ca
be used 
ed
u
to 
X
support 
X
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te
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 19 of 50
Table 2-6: 
Schedule of activities- Part 2 Treatment Sequence A 
Screening
Baseline
OC+PSL
Washout 
(14 Days)
OC
EOS/ SFU/
EDVa
Day
-29 to -2
-1
1
2 to 8
9
10
11
12 to 25
26
27
28
33 to 40
Urine and cotinine drug 
screen, and alcohol breath 
test
X
X
X (D25)
Recording of adverse 
events/medical procedures
X
X
X
X
X
X
X
X (D25)
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing enzymes 
and/or transporters
X
Admit to clinic
X
X (D25)
Administer PSL
X
X
X
X
X
Administer OC
X
X
Blood sampling for PSL 
PK levels
Xf
Xf
Xf
Xf
Blood sampling for OC 
PK levels 
Xg
Xg
Xg
Xg
Xg
Xg
Blood sampling for cross-
validationj
X
Discharge
X (D12 or D13)i
X
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EOS=End of Study; h=hour(s);
HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus; OC=oral 
contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months), followed by the “Since Last 
Visit” version at subsequent visits.
REDACTED 
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thereof. 


UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 20 of 50
c At Screening, Baseline (Day -1), and Day 8, a full physical examination will be performed. On all other days a physical examination is performed, it will be a brief 
physical examination (Section 8.3.1). On days 2-7, physical examination will not be performed. 
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions), pulse rate, respiratory 
rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood pressure 
measurement.
e ECG will be completed on Days 2, and 8 only of multiple day periods during Treatment Sequence A.
f During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 2, Day 4, and Day 6. Additional blood 
sampling for PK analysis will be taken on Day 8  before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h postdose and on Day 
9  before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (before morning PSL dose on Day 10), and 48h 
(before morning PSL dose on Day 11) postdose.
g During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 9 (before OC+PSL morning dose) and after PSL and OC morning 
dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, In addition, blood samples will be obtained prior to the morning dose on Day 10, 36h (Day 10), and 48h 
(Day 11) postdose. During the single-dose OC period, PK blood samples will be taken on Day 26 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h 
(Day 27), 36h (Day 27), and 48h (Day 28) postdose.
h Psychiatric and mental status evaluation will be done pre-dose. 
i The study participant can be discharged on Day 12 or Day 13, at the discretion of the principal investigator.
j Mitra ™ (finger prick) and venous blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 8 only for selected study participants. See Section Error! 
Reference source not found. for details about selection.
REDACTED COPY
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 21 of 50
Table 2-7: 
Schedule of activities- Part 2 Treatment Sequence B 
Screening
Baseline
OC
Washout 
(14 Days)
PSL+OC
EOS/ SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 25
26
27
28
35 to 42
Written informed 
consent
X
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baseline characteristics
X
Inclusion /Exclusion 
criteria verification
X
X
X
X
General medical 
/medications/ procedures 
history
X
X
X (D17)
Suicidality Risk 
Assessment (C-SSRS)b
X
X
X (D17)
X
Psychiatric and mental 
status evaluation 
X
X
Xf
Xf
Xf
Xf
Xf
X
Physical examinationc
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X
X (D17)
Hematology, clinical 
chemistry, urinalysis
X
X
X(D17)
X
X
Serology (HIV, HbsAg, 
HEV, syphilis, and 
HCV-Ab)
X
12-lead ECG
X
X
X
X
Xe
X
X
X
X
Urine and cotinine drug 
screen, and alcohol 
breath test
X
X
X(D17)
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 22 of 50
Table 2-7: 
Schedule of activities- Part 2 Treatment Sequence B 
Screening
Baseline
OC
Washout 
(14 Days)
PSL+OC
EOS/ SFU
EDVa
Day
-29 to -2
-1
1
2
3
4 to 17
18
19 to 25
26
27
28
35 to 42
Recording of adverse 
events/medical 
procedures
X
X
X
X
X
X (D17)
X
X
X
X
X
X
Blood sampling for 
genotyping of drug 
metabolizing enzymes 
and/or transporters
X
Admit to clinic
X
X (D17)
Administer PSL
X
X
X
X
X
Administer OC
X
X
Blood sampling for PSL 
PK levels
X g
Xg
Xg
Xg
Blood sampling for OC 
PK levels
Xh Xh
Xh
Xh
Xh
Xh
Blood sampling for 
cross-validationj
X
Discharge
X
X (D29 or 
D30)i
C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EOS=End of Study; h=hour(s); 
HbsAg-Ab=HepB surface antigen antibodies; HCV-Ab=HepC virus antibodies; HEV=hepatitis E virus; HIV=human immunodeficiency virus; OC=oral 
contraceptive; PK=pharmacokinetic; PSL=padsevonil; SFU=Safety Follow-Up
a If a study participant discontinues early, SFU procedures should be completed as the EDV. Upon early termination/withdrawal, the study participant will be 
encouraged to complete SFU assessments following the last dose of study medication.
b All study participants will complete the “Screening/Baseline” version of the C-SSRS during Screening (assessing the past 6 months) followed by the “Since Last 
Visit” version at subsequent visits.
c At Screening, Baseline (Day -1), and Day 25, a full physical examination will be performed. On all other days a physical examination is performed, it will be a brief 
physical examination (Section 8.3.1). On Days 19-24, physical examination will not be performed. 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 23 of 50
d Oral or aural body temperature (temperature must be performed using the same method in any individual study participant on all occasions.), pulse rate, respiratory 
rate, and blood pressure will be assessed. Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 1 blood pressure 
measurement.
e ECG will be completed on Days 19, and 25 only of multiple day periods during Treatment Sequence B.
f Psychiatric and mental evaluation will be done pre-dose. 
g During the OC+PSL Treatment Period, trough levels of PSL will be collected on morning before PSL dosing on Day 19, Day 21,and Day 23. Additional blood 
sampling for PK analysis will be taken on Day 25  before (predose) and after PSL morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h postdose and on 
Day 26 before (predose) and after the PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 27), and 48h (Day28) postdose.
h During the single-dose OC period, PK blood samples will be taken on Day 1 at predose and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h,  24h (Day 2), 36h 
(Day 2), and 48h (Day 3) postdose. During OC+PSL Treatment Period, blood sampling for OC PK analysis will be taken on Day 26 (before OC+PSL morning 
dose) and after PSL and OC morning dose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h (Day 27), 36h (Day 27), and 48h (Day 28) postdose.
i The study participant can be discharged on Day 29 or Day 30, at the discretion of the principal investigator.
j Mitra ™ (finger prick) and venous blood samples will be taken at 0.5h, 1h, 3h, 6h, 12h postdose on Day 25 only for selected study participants. See Section Error! 
Reference source not found. for details about selection.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 24 of 50
2.3 
Determination of sample size 
Lack of PK interaction in this study will be concluded if 90% confidence intervals for both AUC 
and Cmax geometric means ratios (with/without PSL) of LN and EE are included in the 
80% to 125% bioequivalence range.
In a previous OC interaction study conducted by UCB with brivaracetam (N01282), an 
intra-subject coefficient of variation of 10% for AUCτ for both EE and LN (including Cmax) and 
16% for Cmax was observed for EE.
Provided that the ratio of the expected means for test (with PSL) and reference (without PSL) is 
included in the range [0.90, 1.10] and for a type-I error of 0.05 and an intra-subject coefficient of 
variation of 16%, a total sample size of 34 study participants should allow at least 90% power for 
the assessment of lack of interaction (or 26 study participants for 80% power).
A total of 40 study participants will be randomized: Part 1 (PSL 400mg BID) will include 14 
study participants and will allow a good estimate of the different ratios of PK parameters. Part 2 
(PSL 200mg BID) will include 26 study participants (13 study participants in each sequence). 
Assuming no drop-outs, a decrease of 10% in PK parameters of OC and intrasubject coefficient 
of variation of 16%, this will allow 80% power for assessing lack of PK interaction. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical evaluation will be performed by ICON PLC and supervised by UCB. The datasets will 
follow the UCB analysis data model (ADaM) data specifications. All statistical analyses will be
performed using SAS® Version 9.4 or later (SAS Institute, Cary, NC, USA).
Pharmacokinetic parameters will be determined by non-compartmental analysis (NCA) with
Pharsight Phoenix® WinNonlin® Build 8.0 or higher (Certara L.P., Princeton, NJ, NCA)
software. Pharmacokinetic analyses will be performed and reported for each study part. PK 
parameter estimation will use actual doses administered and the actual sampling times relative to 
time of dose administration.
Categorical endpoints will be summarized using number of study participants (n), frequency,
and percentages. Missing data will not be imputed. Individual plasma concentrations and PK
parameters will be presented using 3 significant digits.
When reporting relative frequencies or other percentage values, the following rules apply:
x For values where all study participants fulfill certain criteria, the percentage value will be 
displayed as 100
x For values where the absolute frequency is zero, there will be no percentage displayed
x All other percentage displays will use 1 decimal place
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 25 of 50
Percentages displayed based on continuous data (e.g. percentage changes from baseline) will be 
displayed to 1 decimal place. Unless otherwise stated, the denominator for the percentages will 
be based on the number of study participants in the respective analysis set.
Continuous variables will be summarized by day and time point (where applicable) including 
number of study participants (n), mean, median, standard deviation (sd), minimum and 
maximum. Geometric coefficient of variation (geoCV), geometric mean and 95% confidence 
interval (CI) for the geometric mean will also be presented in the descriptive statistics for the 
plasma concentrations and PK parameters for EE, LN, PSL and its metabolites (
 
[
] and 
). In all outputs, the confidence 
limits will be restricted to the possible values that the variable can take.
Venous plasma samples will be obtained for EE, LN, PSL and its metabolites.
When reporting descriptive statistics, the following rules will apply in general except for PK 
concentration data (plasma and blood (PK) of EE, LN, PSL and its metabolites (
 and 
):
x n will be an integer
x Mean (arithmetic and geometric), standard deviation and median will use 1 decimal place 
more, or 1 significant figure more – depending on the reporting format of the original data –
than the original data
x 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
x Coefficient of variation (CV) will be reported as a percentage to 1 decimal place
x Minimum and maximum will be reported using the same number of decimal places or 
significant figures as the original value
x If no study participants have data at a given time point, then only n=0 will be presented. If 
n<3, then only the n, minimum and maximum will be presented. If n=3, then only n, 
minimum, median and maximum will be presented. The other descriptive statistics will be 
left blank.
When reporting individual values and descriptive statistics for PK concentration data (EE, NL, 
PSL and its metabolites (
and 
), the following rules will apply regarding rounding and precision:
x Individual values for PK concentration data will be reported to the same level of precision as 
received from the bioanalytical laboratory
x Descriptive statistics for PK concentration data will be reported to the same level of precision 
as the individual data for the minimum and maximum, and to 1 additional decimal place or 1 
additional significant figure– depending on the reporting format of the original data with a 
maximum of 3 significant digits - for the mean (arithmetic and geometric), median and 
standard deviation. The 95% CI for the geometric mean will use 1 decimal place more, or 1 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 26 of 50
significant figure more – depending on the reporting format of the original data – than the 
value around which the confidence interval is constructed
x Geometric CV will be reported as a percentage to 1 decimal place
When reporting individual values and descriptive statistics for PK parameters (PK of EE, LN, 
PSL and its metabolites (
 and 
)) the following rules will apply with regard to rounding and precision:
x Individual values for PK parameters will be reported to 3 significant figures
x Descriptive statistics for PK parameters should be rounded to 4 significant figures for the 
mean, median and standard deviation and to 3 for the others
Data listings containing all documented data and all derived data will be generated and presented 
by treatment sequence (treatment sequence A and treatment sequence B) and treatment period.
3.2 
General study level definitions 
3.2.1 
Relative day 
Relative day will be calculated based on the treatment received. Therefore, three relative days are 
defined, based on treatment with OC alone, PSL alone and the combination of OC and PSL.
The relative day of an event will be derived with the date of first dose of the treatment, as 
reference. For Padsevonil, this will be Day 1 in Sequence A and Day 18 in Sequence B. For OC 
alone this will be Day 34 in Sequence A and Day 1 in Sequence B. For the combination of 
PSL+OC the first dose is given on Day 13 in Sequence A and Day 30 in Sequence B
Relative days for an event or measurement occurring before the date of first dose of treatment are 
calculated as follows:
ܴ݈݁ܽݐ݅ݒ݁ܦܽݕൌܧݒ݁݊ݐܦܽݐ݁െܦܽݐ݁݋݂ܨ݅ݎݏݐܦ݋ݏ݁݋݂ܶݎ݁ܽݐ݉݁݊ݐ
The relative day for an event or measurement occurring on the date of first treatment dose is 1.
The relative day for an event or measurement occurring on or after the date of first treatment 
dose to the date of the last dose will be calculated as follows:季
ܴ݈݁ܽݐ݅ݒ݁ܦܽݕൌሺܧݒ݁݊ݐܦܽݐ݁െܦܽݐ݁݋݂ܨ݅ݎݏݐܦ݋ݏ݁݋݂ܶݎ݁ܽݐ݉݁݊ݐሻ൅ͳ
For events or measurements occurring after the date of last treatment dose, relative day will be 
prefixed with ‘+’ in the data listings and will be calculated as follows:
ܴ݈݁ܽݐ݅ݒ݁ܦܽݕൌ൅ሺܧݒ݁݊ݐܦܽݐ݁െܦܽݐ݁݋݂ܮܽݏݐܦ݋ݏ݁݋݂ܶݎ݁ܽݐ݉݁݊ݐሻ
There is no relative Day 0. Relative day will not be calculated for partial dates in cases where 
relative day is shown in a study participant data listing. In such cases, relative day should be 
presented as ‘--‘ in the relevant study participant data listing.
3.2.2 
Study periods 
For each study participant completing Part 1, the expected maximum duration of participation 
will be approximately 75 days with a maximum of 20 days exposure to investigational product 
(19 days exposed to PSL, (with or without OC) and one day exposed to OC only).
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 27 of 50
For each study participant completing Part 2, the expected maximum duration of participation is  
approximately 70 days with a maximum of 12 days exposure to investigational product (11 days 
exposed to PSL, (with or without OC) and one day exposed to OC only). 
The various periods of the study are described below:季
x Screening/Baseline Period (Day -28 to Day -1)
The Screening Period consists of a single Screening Visit, which will be conducted at the unit 
within 28 days prior to check-in for treatment period, and a Baseline Visit, which will be 
conducted at HMR, the clinical research unit (CRU) 1 day prior to treatment period (on Day -
1). Study participants will check-in at the CRU on Day -1.
Part 1
Sequence A (Day 1 to Day 36)
In Part 1, study participants enrolled in Treatment Sequence A will be administered PSL BID 
(up-titration to steady-state [400mg BID]) from Day 1 to Day 5, followed by a maintenance 
period from Day 6 to Day 12 with a single dose of OC administered on the morning of 
Day 13. A taper of PSL will occur from Day 15 to Day 19. Starting on Day 20, the study 
participants will then complete a 14-day Washout Period followed by a return to the clinic 
for the OC-only dosing on Day 34. A SFU Visit will occur between Day 41 and Day 44. 
Treatment Sequence A consists of the “PSL+OC Period” followed by the “OC alone Period”.
Sequence B (Day 1 to Day 36)
In Part 1, study participants enrolled in Treatment Sequence B will be administered a single 
dose of OC on the morning of Day 1 followed by PK assessments that day and the next 2 
days. The study participants will then complete a 14-day Washout Period followed by a 
return to the clinic for the OC+PSL dosing from Day 18 to Day 36 (OC to be administered 
on Day 30). Study participants will be administered PSL BID (up-titration to steady-state) 
from Day 18 to Day 22 followed by a maintenance period from Day 23 to Day 31. A taper of 
PSL will occur from Day 32 to Day 36. An SFU Visit will occur between Day 43 and Day 
46.
Treatment Sequence B consists of the “OC alone Period” followed by the “PSL+OC Period”.
Part 2
Sequence A (Day 1 to Day 28)
In Part 2, all study participants enrolled in Treatment Sequence A will be administered PSL 
100mg BID on Day 1, with titration to 200mg BID for Day 2 to Day 8. A single dose of OC 
is administered on the morning of Day 9, at which time PSL is at steady-state. To taper, 
100mg BID of PSL will be given on Day 11. Starting on Day 12, the study participants will 
then complete a Washout Period for 14 days followed by a return to the clinic for the OC-
only Period on Day 25 (OC dosing on Day 26). An SFU Visit will occur between Day 33 and 
Day 40. 
Treatment Sequence A consists of the “PSL+OC Period” followed by the “OC alone Period”.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 28 of 50
Sequence B (Day 1 to Day 28)
In Part 2, all study participants enrolled in Treatment Sequence B will be administered a 
single dose of OC on the morning of Day 1 followed by PK assessments that day and the 
next 2 days. The study participants will then complete a 14-day Washout Period followed by 
a return to the clinic for the OC+PSL dosing from Day 18 to Day 28 (OC to be administered 
on Day 26, at which time PSL is at steady state). Study participants will be administered PSL 
100mg BID of PSL will be given on Day 28. An SFU Visit will occur between Day 35 and 
Day 42. 
Treatment Sequence B consists of the “OC alone Period” followed by the “PSL+OC Period”.
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule 
of Activities for the last study participant. 
3.3 
Definition of Baseline values 
In either study part, Baseline will be the last non-missing value prior to first dosing on Day 1 
(PSL dosing in Treatment Sequence A or OC dosing in Treatment Sequence B). Scheduled or 
unscheduled measurements can be used as the Baseline value.
If a measurement is repeated at Baseline and is obtained prior to dosing, then the last available 
measurement will be used as the Baseline value. If an assessment occurs on the date of dosing, 
the time must occur prior to the time of dosing. 
Variable
Baseline definition
Hematology, serum, 
chemistry, urinalysis
The baseline value is defined as the value on Day -1. If 
the baseline value is missing, the value obtained at 
Screening will be used.
Vital signs
The baseline value is defined as the last value prior to 
dosing.
ECG
12-lead ECG will be measured in triplicate. Baseline is 
the mean of the last three available measurements prior 
to dosing. If less than three replicates are available, the 
mean of the available replicates at the same visit (prior to 
dosing) will be considered as baseline.
C-SSRS
The baseline value is defined as the value from Day -1. If 
the baseline value is missing, the value obtained at 
Screening will be used.
The change from Baseline to any subsequent post-Baseline visit will be calculated as the simple 
difference between that post-Baseline visit’s value and the Baseline visit value, as below:  
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 29 of 50
ܥ݄ܽ݊݃݁݂ݎ݋݉ܤܽݏ݈݁݅݊݁ൌܲ݋ݏݐܤܽݏ݈݁݅݊݁ܸ݅ݏ݅ݐܸ݈ܽݑ݁ െܤܽݏ݈݁݅݊݁ܸ݅ݏ݅ݐܸ݈ܽݑ݁
3.4 
Protocol deviations 
Important protocol deviations (IPD) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on the primary PK outcome for an individual 
study participant. Study participants will be excluded from SS only when there is documented
evidence that they received no treatment. Study participants may be excluded from the 
Pharmacokinetic Set (PKS) if they had an important protocol deviation affecting the PK 
parameters.
The criteria for identifying protocol deviations and the classification of protocol deviations will 
be captured in the Important Protocol Deviations document. To the extent feasible, rules for 
identifying protocol deviations will be defined without review of the data and without 
consideration of the frequency of occurrence of such deviations. Whenever possible, criteria for 
identifying important protocol deviations will be implemented algorithmically to ensure 
consistency in the classification of important protocol deviations across all study participants.
Important protocol deviations will be reviewed as part of an ongoing data cleaning process prior 
to database lock to confirm exclusion from analysis sets. After all data have been 
verified/coded/entered into a database, a data evaluation meeting (DEM) will be held. 
At least one DEM will be performed at the following time:
x Prior to the final analysis after all data have been verified/coded/entered into the database
Additional DEMs may be conducted as deemed necessary.
The purpose of these DEM reviews will be to review all protocol deviations, determine whether 
the deviations are considered important or not important, define the analysis sets, and check the 
quality of the data. The reviews will also help decide how to manage problems in the study 
participants’ data (e.g., missing values, withdrawals and protocol deviations). 
Accepted deviations from scheduled time points will be described in the appropriate documents 
and included in the Study Master File. After the pre-analysis review, resolution of all issues, and 
documentation of all decisions (including inclusion into each of the analysis sets) at the final 
DEM, the database will be locked.
3.5 
Analysis sets 
3.5.1 
All Study Participants 
All Study Participants consists of all study participants who have signed the Informed Consent 
Form (ICF). 
3.5.2 
Safety Set (SS) 
The Safety Set (SS) consists of all study participants who received at least one dose of study 
medication (PSL or OC).
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 30 of 50
3.5.3 
Pharmacokinetic Set (PKS) 
The Pharmacokinetic Set (PKS) is a subset of the SS, consisting of those study participants who 
had no important protocol deviations affecting the PK parameters of EE, LN, or PSL and its 
metabolites and for whom at least one measurable concentration exists.
3.6 
Treatment assignment 
It is expected that study participants will receive treatments as per the randomized treatment 
sequence and hence the analyses will be based on the randomized treatment. If a study 
participant was randomized but not dosed in any treatment period, the study participant results 
will be reported under the randomized treatment group. For safety analyses based on the SS, 
study participants will be classified according to the medication that was actually received.
Except for PK, concomitant medications, and adverse events, tables will be presented separately 
for each study part by randomized Treatment Sequence (Sequence A: PSL+ OC followed by OC 
alone and Sequence B: OC alone followed by PSL+OC) and overall. Listings will be presented 
by study part, randomized treatment sequence, and study participant number. PK summaries will 
be presented by study part, treatment period (OC alone and OC+PSL), and analyte (EE, LN; PSL 
and its metabolites). Concomitant medication and adverse event tables will be presented 
separately for each study part by treatment (OC alone, PSL alone, and OC+PSL).
A detailed schematic diagram of the study is provided in Table 2-2 and Table 2-3.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 31 of 50
3.7 
Center pooling strategy 
The data will come from one center. The statistical analyses will not be performed by center.
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using version 22.0 of the Medical Dictionary
for Regulatory Activities (MedDRA®). Medications will be coded according to the latest version 
of the World Health Organization Drug Dictionary (WHODD) (Version SEP/2017). Medical 
procedures will not be coded.
The versions of the coding dictionaries used will be displayed in the relevant TFLs.
3.9 
Changes to protocol-defined analyses 
x Changes in the name of analysis datasets (section 9.1 of the protocol):
- 
The analysis set “Enrolled set” will be renamed as “All Study Participants” in the SAP 
and will correspond to all study participants who sign the informed consent form. 
- 
The analysis set “Pharmacokinetic Per Protocol Set (PK-PPS)” will be renamed as 
“Pharmacokinetic Set (PK Set)” in the SAP and will still correspond to the protocol 
definition of PK-PPS.
x For the purpose of the analysis of concomitant medications and adverse events 3 groups will 
be created, based on the treatment administered. The results will be presented for PSL alone, 
OC alone and the combination of PSL and OC.
x For the primary PK analysis, ping-pong plots have been added for EE and LN for Cmax, and 
AUC for OC with and without PSL.
x Ping-pong plots have also been added for Cmax,ss and AUCτ, for PSL and its two metabolites 
(
 and 
) for PSL with and 
without OC. 
x Ping-pong plots have been added for Cmax,ss, AUCτ, MRAUCτ, MRCmax,ss, CLss, t1/2,  for PSL 
(with and without OC).
x Furthermore, the relationship between MR and Cmax (with and without PSL) of EE and LN, 
and the exposure to PSL (AUCτ) will be explored.
x Ctrough and MR based on AUCτ of PSL and its two metabolites, will also be compared 
between days (with OC [Day 13 for Sequence A and Day 30 for Sequence B] and without 
OC [Day 12 for Treatment Sequence A and Day 29 for Treatment Sequence B] using 
analysis of variance on the log-transformed parameters and estimation of geometric ratio of 
PK parameters between days with their 90% CI will be provided.
x Furthermore, the relationship between individual Cmax (with and without PSL) of EE and LN 
and the exposure to PSL (AUCτ) will be assessed by scatterplots and linear regression 
analyses.
x According to the protocol, the occurrence and incidence of AEs will be summarized by 
treatment sequence according to the intake of PSL (pretreatment or treatment-emergent) and 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 32 of 50
by intensity or relationship to PSL. As the relationship to PSL alone is not documented in the 
CRF, the relationship to study medication (PSL, PSL+OC, and OC) will be analyzed. 
Consequently, the definition of TEAE will be related to treatment (PSL, PSL+OC, or OC) 
and a TEAE will be attributed to a treatment according to the start date. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable.
4.2 
Handling of dropouts or missing data 
In general, there will be no imputation of missing data unless otherwise stated below.
Missing data will be handled as described in the sections below for safety laboratory and PK 
results. No other imputations will be performed. 
4.2.1 
Pharmacokinetics  
The 95% CI lower and 95% CI upper should be left blank if the standard deviation (or 
equivalently, the geometric CV) is 0.季Measurements of PK concentrations that are below the 
limit of quantification (BLQ) and which are occurring prior to tmax will be imputed with half of 
the lower limit of quantification (LLOQ/2), except for embedded BLQ values (between two 
measurable data points) which will be treated as missing, for the purpose of calculating the 
geometric mean and its 95% CI, the geometric CV, the arithmetic mean and standard deviation 
for summaries and figures. Post-tmax, BLQ values will be treated as missing. Descriptive statistics 
of concentrations will be calculated if at least 2/3rd of the individual data points are quantifiable 
(≥LLOQ). 
For all individual PK concentration figures, any concentrations that are BLQ will be regarded as 
missing, with the exception of predose BLQ measurements which will be imputed with zero (to 
capture lag-time) for linear scale plots.
The following rules will apply for PK data listings:
x Values below the LLOQ will be reported as “(BLQ)” in the listings
The following rules will apply for PK summaries
x Descriptive statistics of plasma concentrations will be calculated if more than 2/3rd of
individual data points are quantifiable (>=LLOQ) at the given time-point. However, if n<3, 
then only n, minimum and maximum will be presented, and the median will also be 
presented if n=3. The other descriptive statistics will be left blank.季
x For tmax,only N, median, minimum and maximum will be displayed into the summary 
statistics, 季
x For plasma concentration summaries, all BLQ values will be replaced by “LLOQ/2” and 
missing values will be excluded. 季
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 33 of 50
x When the mean value includes one or more replaced BLQ values then a footnote will be 
included to say “contains one or more BLQ value replaced by half the LLOQ value”. 季
x For the individual figures, any concentrations that are BLQ will be regarded as missing, with 
the exception of predose BLQ measurements which will be imputed with zero for linear scale 
plots.
x If no study participants have data, only n=0 will be presented. The other descriptive statistics 
will be left blank.
x The geometric CV will be calculated using the following formula where SDlog is the standard 
deviation from the log-transformed data:
Geometric CV (%) = sqrt[(exp (SDlog^2) – 1)] x 100 
The PK analysis will be performed in accordance to the Guideline on performing NCA analysis 
dated 08 Nov 2017, and BLQ values will be treated as stated in this document for the NCA 
analysis. 
4.2.2 
Safety laboratory data 
The rules for handling values that are BLQ or above the limit of quantification (ALQ) in the 
safety laboratory data will be the same as those described for PK data in Section 4.2.1.
4.2.3 
Electrocardiogram data 
For the 12-lead ECG data, all calculations of changes from Baseline and descriptive statistics 
will be based on the mean of the triplicate assessments at each time point. In the event that there 
are not three available measurements at a given time point, the mean will be calculated based on 
the number of measurements for which data are provided.
4.2.4 
Dates and times 
Partial dates may be imputed for the following reasons:
x Classification of AEs as treatment-emergent 
x 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:
x If only the month and year are specified and the month and year of the first dose of study 
medication is not the same as the month and year of the start date then use the 1st of the 
month, or the date of screening if this is later (if the latter imputation results in an end date 
that is earlier than the start date, then use the 1st of the month). If time is missing this will be 
imputed as 00:00h
x 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 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 34 of 50
latter imputation results in an end date that is earlier than the start date, then use the 1st of the 
month). If the imputed date is the date of dosing then time will be imputed as the start time of 
the dosing (i.e., event will be regarded as treatment-emergent)
x If only the year is specified, and the year of the first dose of study medication is not the same 
as the year of the start date then January 01 will be used. If time is missing this will be 
imputed as 00:00h
x If only the year is specified, and the year of the first dose of study medication is the same as 
the year of the start date, then the date of the first dose of study medication will be used. If 
this results in an imputed start date that is after the specified end date, then January 01, or the 
date of screening if this is later will be used (if the latter imputation results in an end date that 
is earlier than the start date, then January 01 will be used). If the imputed date is the date of 
first dose of study medication then time will be imputed as the start time of the study 
medication intake (i.e., event will be regarded as treatment-emergent)
The following rules will be applied to partial stop dates:
x If only the month and year are specified, then use the last day of the month
x If only the year is specified, then use December 31 of the known year
x 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 . 
Calculation rules for duration of adverse events can be found in Table 4-1 and will be applied 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
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 study participant in the SS, 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
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 35 of 50
Table 4-1:
Calculation rules for duration of adverse events
Data availability
Onset 
date/time
Outcome 
date/time
Calculation rules
End day and time 
missing 
D1/T1
--/--
If the stop date is missing, duration will not be 
calculated.
Start and end date 
missing
--/--
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If the stop date is missing, duration will not be 
calculated.
4.3 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. The following general rules will apply to all repeated and unscheduled 
measurements:
x 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
x 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
x Unscheduled and repeated measurements will not be used in the descriptive statistics at time 
points after first dose of study medication
x Unscheduled measurements performed for the End of Study/Safety-Follow-Up/Early 
Discontinuation Visit (EOS/SFU/EDV) visit will be assigned to the EOS/SFU/EDV Visit
(Section 4.4) and analyzed accordingly as an EOS/SFU/EDV Visit.
4.4 
Handling of measurements obtained at the early withdrawal 
visit 
Study participants who withdraw early from the study for any reason, including those withdrawn 
from study medication, will be asked to return for the EOS/SFU/EDV Visit as soon as possible 
after the last dose of study medication.
4.5 
Interim analyses and data monitoring 
Not applicable.
4.6 
Multicenter studies 
This study is planned to be conducted at one site. Thus, there is no plan to explore sites effect in 
the analysis.
4.7 
Multiple comparisons/multiplicity 
Not applicable.
4.8 
Use of an efficacy subset of study participants 
Not applicable.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 36 of 50
4.9 
Active-control studies intended to show equivalence 
Not applicable.
4.10 
Examination of subgroups 
Not applicable
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Study participant disposition 
The number of study participants who signed the informed consent and study participants who 
were screen failures, completed or prematurely discontinued the study, as well as the reason for 
discontinuation will be summarized separately per study part for all study participants, based on 
the ASP. A study participant who completed the study is defined as a study participant who
completed all visits up to and including the EOS/SFU/EDV visit. If there is more than one 
termination due to AE, then an additional table summarizing the discontinuations due to AE will 
be produced. In case that only one subject discontinues due to AE, then this will be presented in 
a listing. The number of study participants screened, number of screen failures and primary 
reason for screen failure will be summarized based on the ASP.
The number and percentage of study participants included in each of the analysis sets will be 
summarized based on All Study Participants. Percentages will be calculated based on All Study 
Participants for the purpose of this summary.
In addition, the following listings will be presented:
x Study participant disposition (All Study Participants) - including screening failure reasons
x Study participant analysis sets (All Study Participants)
The listing of study participant disposition will include the date of informed consent, the date of 
randomization, date and time of first and last dose of PSL, date and time of first and second dose 
of OC, date of premature termination and primary reason (if applicable).
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types in the IPD 
document (see also section 3.4). A listing of all IPDs identified at the DEM will be presented by 
study part and treatment sequence for all study participants based on the SS and will include the 
deviation type and description. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
A by-study participant listing of demographics will be presented by study part, treatment 
sequence (Sequence A, Sequence B) based on All Study Participants. This will include the year 
of birth, age (in years), sex, race, ethnicity, country, height (in cm), weight (in kg) body mass 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 37 of 50
index (BMI, in kg/m2). The body weight will be the measurement obtained at Screening. Body 
mass index (kg/m2) is documented in the CRF. 
All demographic characteristics (except for year of birth) will be summarized separately for each 
study part by treatment sequence and overall (Sequence A, Sequence B and All Study 
Participants) based on the SS. 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:
x 18 to <65 years
x 65 to <85 years
x ≥85 years
For clinicaltrials.gov reporting, the categories will include:
x ≤18 years
x 19 to <65 years
x ≥65 years 
Characteristics about childbearing potential and method of birth control will be listed by study 
part and treatment sequence for study participants in the ASP.
6.2 
Other Baseline characteristics 
Lifestyle characteristics including data regarding alcohol, caffeine, and tobacco use will be 
listed.
6.3 
Medical history, procedure history and concomitant medical 
procedures 
Medical history will be listed (by study part) and summarized (in separate incidence tables per 
study part) for the SS, by MedDRA system organ class (SOC) and preferred term (PT) per 
treatment sequence and overall. The reported term will be included in the listing. The summary 
will include the number and percentage of study participants, and will be sorted alphabetically by 
SOC and by descending incidence of PT within each SOC, based on the ‘All Participants’ 
column. 
6.4 
Prior and concomitant medications 
Prior medications include any medications that started prior to the date of first dose of IMP. 
Concomitant medications are medications taken after the first dose of IMP (PSL or OC). 
Concomitant medications will be attributed to the treatment in which they start. Thus, for study 
participants in Part 1 randomized in Sequence A, any medication taken on Day 1 through Day 13 
(prior to OC intake) will be attributed to the PSL alone period; any medications taken on Day 13 
(after OC intake) through Day 34 (prior to OC intake) will be attributed to the PSL+OC period 
and any medication taken on Day 34 (after OC intake) through Day 44 will be attributed to OC 
alone. For study participants in Part 1 randomized in Sequence B, any medication taken on Day 1 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 38 of 50
through Day 18 (prior to PSL intake)  will be attributed to OC alone; any medications taken on 
Day 18 (after PSL intake) through Day 30 (prior to OC intake) will be attributed to PSL and any 
medication taken on Day 30 (after OC intake) through Day 46 will be attributed to PSL+OC. For 
study participants in Part 2 randomized in Sequence A, any medication taken on Day 1 through 
Day 9 (prior to OC intake) will be attributed to the PSL alone period; any medications taken on 
Day 9 (after OC intake) through Day 26 (prior to OC intake) will be attributed to the PSL+OC 
period and any medication taken on Day 26 (after OC intake) through Day 40 will be attributed 
to OC alone. For study participants in Part 2 randomized in Sequence B, any medication taken on 
Day 1 through Day 18 (prior to PSL intake) will be attributed to OC alone; any medications 
taken on Day 18 (after PSL intake) through Day 26 (prior to OC intake) will be attributed to PSL 
and any medication taken on Day 26 (after OC intake) through Day 42 will be attributed to
PSL+OC.
A schematic summary is given below:
Study Part
Sequence
PSL alone
PSL + OC
OC alone
1
A
Day 1 – 13 (prior 
to OC intake)
Day 13 (after OC 
intake) – 34 (prior 
to OC alone intake)
Day 34 (after OC 
intake) - 44
B
Day 18 (after PSL 
intake) – Day 30 
(prior to OC intake)
Day 30 (after OC 
intake) - 46
Day 1 – 18 (prior 
to PSL intake)
2
A
Day 1 – 9 (prior to 
OC intake)
Day 9 (after OC 
intake) – 26 (prior 
to OC intake)
Day 26 (after OC 
intake) - 40
B
Day 18 (after PSL 
intake) – 26 (prior 
to OC intake) 
Day 26 (after OC 
intake) – 42
Day 1 – 18 (prior 
to PSL intake)
If a medication started prior to IMP administration (PSL or OC) and stopped after the first IMP 
administration (PSL or OC) or stopped during the first treatment period (for Sequence A: PSL 
period; for Sequence B: OC alone period), then that medication will be classified as both prior 
and concomitant for PSL alone or OC alone period respectively (depending on the randomized 
sequence). 
If a medication starts prior to IMP administration (PSL or OC) and is stopped during the second 
treatment period (for Sequence A: PSL+OC period; for Sequence B: PSL period), then that 
medication will be classified as prior and concomitant for both treatment periods (PSL+OC and 
PSL alone). The same rule will apply for the third treatment period.
Any medications with missing dates and/or times will be handled as described in Section 4.2.4 to
classify them as prior or concomitant.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 39 of 50
Prior and concomitant medications will be listed by study part for all study participants in the SS. 
Prior and concomitant medication will be tabulated separately. The summary will be presented 
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. Tabulation for prior 
medications will be presented separately for each study part by treatment sequence; tabulation 
for concomitant medications (PSL+OC concomitant, PSL alone-concomitant and OC alone-
concomitant) will be summarized separately for each study part by treatment separately for each 
treatment sequence.
The prior medication tabulation will be sorted alphabetically by Level 1 term, alphabetical Level 
3 term within Level 1 and decreasing frequency of PT in the ‘All Participants’ column. The 
concomitant medication tabulation will be sorted alphabetically by Level 1 term, alphabetical 
Level 3 term within Level 1 and decreasing frequency of PT in the PSL+OC column.
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Administration of study medication will be performed under the supervision of the Investigator 
(or designee). Compliance will be monitored by drug accountability. A Drug Accountability
form will be used to record study medication dispensing and return information on a by-study 
participant basis. 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 AND PHARMACODYNAMICS 
The calculation of the PK parameters of EE, LN, PSL and its metabolites (
 
[
] and 
 [
]) will be performed by the 
Pharmacokinetics, Pharmacodynamics, Modeling and Simulation Department, ICON PLC. All 
PK TFLs will be produced by ICON PLC SAS programming (Early Phase) or ICON 
Biostatistics. All PK tables and figures will be produced separately for each study part. All PK 
listings will be presented by study part.
Pharmacokinetic parameters of EE, LN, PSL and its two metabolites (
will be computed using the actual sampling time 
points. 
The individual time-plasma concentrations of EE, LN, PSL, PSL metabolites, and PK parameters 
of EE, LN, PSL and PSL metabolites will be summarized by treatment (for EE and LN: OC 
alone and PSL+OC; for PSL and its two metabolites: PSL+OC and PSL alone) using descriptive 
statistics (number of observations, geometric mean, lower and upper 95% confidence intervals 
[CI], geometric coefficient of variation [CV], arithmetic mean, standard deviation [SD] and CV, 
median, and minimum and maximum value) and graphical displays. During the PSL + OC 
treatment period, two sets of PSL PK parameters will be analyzed: one set when PSL is 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 40 of 50
administered alone and the other set when PSL is administered with OC. Two sets of EE and LN 
PK parameters will be analyzed: one set during the PSL+OC treatment period and another during 
the OC alone treatment period. 
All PK sampling time deviations will be calculated relative to the last dose of study medication. 
For sequence A, it will be on Day 19 for the PSL+OC period and on Day 34 for the OC alone 
period. For sequence B, it will be on Day 1 for the OC alone period and on Day 36 for the 
PSL+OC 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. 
9.1 
Analysis of the primary pharmacokinetic variables 
The primary PK variables in plasma used for EE and LN are Cmax and AUC. Cmax and AUC will 
be determined from the observed concentration and time data. AUC will be computed using the 
linear up/log down trapezoidal rule.
The PK individual time plasma concentrations and the primary PK parameters of EE and LN will 
be summarized by treatment (PSL+OC/OC alone), using descriptive statistics (number of 
available observations [n], arithmetic mean, median, standard deviation, minimum, maximum, 
geometric mean, geometric CV and 95% CI for the geometric mean [assuming log-normally 
distributed data]). Values below the LLOQ will be reported with a clear sign (flag variable in the 
dataset) indicating that they were below the LLOQ.季
Individual study participant concentration-time profiles of EE and LN will be displayed 
graphically on both linear and semi-logarithmic scales. Spaghetti plots will be presented for all 
study participants per treatment (OC alone and PSL+OC) and analyte with all study participants 
overlaid on the same plot (linear and semi-logarithmic scale). Ping-pong plots will also be 
produced for Cmax and AUC for EE and LN (with and without PSL).
The EE/LN primary PK parameters will be compared between treatments (PSL + OC and OC 
alone) using analysis of variance for a cross-over design (treatment, period, sequence as fixed 
effects, and subject within sequence as random effect) on the log-transformed parameters and 
estimation of the geometric mean ratio of PK parameters between treatments with their 90% CI 
will be provided.
A lack of PSL effect on EE/LN will be concluded if the 90% CI of the geometric mean ratio 
between treatment PSL+OC and treatment OC alone of the least squares means for the 
log-transformed AUC, and Cmax is within the bioequivalence acceptance range of 80% to 125%.
If the 90% CI is slightly broader than the bioequivalence criteria, individual AUC and Cmax 
geometric mean ratios will be assessed with the aim of achieving >0.7 (less than a 30% decrease 
in OC exposure in the presence of PSL) to declare a lack of a clinically significant PK 
interaction.
Geometric mean profiles of plasma concentrations for EE and LN over time will be presented, 
with both treatments (PSL+ OC and OC alone) overlaid on the same plot, in both linear and 
semi-logarithmic scale. For the linear scale plot only, the lower and upper 95% confidence 
interval (CI) for the geometric mean will be displayed. 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 41 of 50
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times.
9.2 
Analysis of secondary pharmacokinetic variables 
The secondary PK variables in plasma used for PSL are Cmax,ss and AUCτ. Cmax,ss will be 
determined from the observed concentration and time data. AUCτ will be computed using the
linear up/log down trapezoidal rule.
Pharmacokinetic parameters (Cmax,ss, Ctrough, AUCτ,, metabolic ratio based on AUCτ (MRAUCτ)) of 
PSL and its two metabolites will be compared between days with OC [Part 1: Day 13 for 
Sequence A and Day 30 for Sequence B; Part 2: Day 9 for Treatment Sequence A and Day 26 
for Treatment Sequence B] and without OC [Part 1: Day 12 for Treatment Sequence A and Day 
29 for Treatment Sequence B; Part 2: Day 8 for Treatment Sequence A and Day 25 for 
Treatment Sequence B] using analysis of variance on the log-transformed parameters and 
estimation of geometric ratio of PK parameters between days with their 90% CI will be provided.
Ping-pong plots will also be produced for each study part for Cmax,ss, AUCτ, MRAUCτ, MRCmax,ss,
CLss, t1/2, for PSL (with and without OC).
The relationship between individual AUC ratio and individual Cmax (with and without PSL) of 
EE and LN, and the exposure to PSL (AUCτ) will be assessed by scatterplots and linear 
regression analyses (log-transformed and also untransformed data) presented for each study part.
The estimated slope with 95% CI will be computed. In absence of interaction, intercept and slope 
will be equal to 0.
9.3 
Analysis of other pharmacokinetic variables 
The other steady-state PK parameters for PSL are CLSS/F, Cmin, tmax and t1/2.
The other steady-state PK parameters for the two PSL metabolites 
include Cmax,ss, AUCτ, tmax, t1/2,ss, Ctrough , MRAUCτ, 
MRCmax,ss. Cmax,ss will be determined from the observed concentration and time data. AUCW will 
be computed using the linear up/log down trapezoidal rule.
The other PK parameters for EE and LN (single-dose oral contraceptive containing EE and LN) 
include tmax, AUC0-t, t1/2 and CL/F. 
The other PK parameters will be summarized by study part and treatment using descriptive 
statistics (number of available observations [n], arithmetic mean, median, standard deviation, 
minimum, maximum, geometric mean, geometric CV and 95% CI for the geometric mean 
[assuming lognormally distributed data]). tmax will only display the number of available 
observations [n], median, minimum, and maximum.
Ping-pong plots will also be produced for Cmax,ss, and AUCτ separately for each study part for the 
two PSL metabolites (
]).
10 
SAFETY ANALYSES 
All safety summaries and listings will be performed using the SS. All safety variables will be 
listed and summarized by study part, treatment sequence (Sequence A/Sequence B), treatment 
(PSL+OC / OC alone / PSL alone) and time point, when applicable.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 42 of 50
10.1 
Extent of exposure 
All study medication (OC and PSL) administration details will be listed by study part, treatment 
sequence, and study participant. The listing will include the date and time of administration of 
the morning and evening dose and total daily dose of medication. 
Exposure data will be listed only.
10.2 
Adverse events 
All AEs will be coded using the MedDRA® and characterized as pre-treatment and treatment-
emergent according to the intake of the study medications (PSL, OC). 
Adverse events with a start date prior to the first dose of study medication will be defined as pre-
treatment AEs. For sequence A, the first dose of PSL is given on Day 1. For sequence B, the first 
dose of OC is given on Day 1.
A treatment-emergent AE (TEAE) is defined as any AE with a start date/time on or after the first 
dose of study medication (OC or PSL) 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 (OC, PSL or OC+PSL) after which they start. 
Thus, in part 1, for study participants randomized in Sequence A, all AEs starting after the first 
intake of PSL through Day 13 (prior to OC intake) will be attributed to PSL, all AEs starting 
after OC intake on Day 13 through Day 34 (prior to OC intake) will be attributed to PSL+OC, 
and all AEs starting after OC intake on Day 34 though Day 41 will be attributed to OC. In part 
1, for study participants randomized in Sequence B, all AEs starting after the OC intake on Day 
1 through Day 18 (prior to PSL intake) will be attributed to OC, all AEs starting after PSL intake 
on Day 18 though Day 30 (prior to OC intake) will be attributed to PSL, and all AEs starting 
after OC intake on Day 30 through Day 43 will be attributed to OC+PSL. In part 2, for study 
participants randomized in Sequence A, all AEs starting after the first intake of PSL through Day 
9 (prior to OC intake) will be attributed to PSL, all AEs starting after OC intake on Day 9 
through Day 26 (prior to OC intake) will be attributed to PSL+OC, and all AEs starting after OC 
intake on Day 26 though Day 33 will be attributed to OC. In part 2, for study participants 
randomized in Sequence B, all AEs starting after the OC intake on Day 1 through Day 18 (prior 
to PSL intake) will be attributed to OC, all AEs starting after PSL intake on Day 18 though Day 
26 (prior to OC intake) will be attributed to PSL, and all AEs starting after OC intake on Day 26 
through Day 35 will be attributed to OC+PSL. AEs starting more than 168 hours post last dose 
of study medication will be attributed to the SFU Period. A schematic summary is shown below.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 43 of 50
Study Part
Sequence
PSL alone
PSL + OC
OC alone
SFU
1
A
Day 1 – 13 (prior 
to OC intake)
Day 13 (after OC 
intake) – 34 (prior to 
OC alone intake)
Day 34 (after 
OC intake) -
41
42+
B
Day 18 (after PSL 
intake) – Day 30 
(prior to OC intake)
Day 30 (after OC 
intake) - 43
Day 1 – 18
(prior to PSL 
intake)
44+
2
A
Day 1 – 9 (prior to 
OC intake)
Day 9 (after OC 
intake) – 26 (prior to 
OC intake)
Day 26 (after 
OC intake) -
33
34+
B
Day 18 (after PSL 
intake) – 26 (prior 
to OC intake) 
Day 26 (after OC 
intake) – 35
Day 1 – 18
(prior to PSL 
intake)
36+
All AEs will be recorded in the CRF from the time of informed consent until study completion or 
termination. All AEs will be coded (see Section 3.8) and categorized by intensity 
(mild/moderate/severe) and relationship (related/not related) to study medication (PSL, 
PSL+OC, and OC) as judged by the Investigator.
All AE data will be listed by study part, treatment sequence, study participant number, start date, 
and time. The listings will include the following data pertaining to the AEs: start and end dates 
with relative days to study medication administration, duration, intensity, seriousness, 
relationship to study medication, action taken, and final outcome.
The number and percentage of study participants who experience TEAEs will be summarized by 
MedDRA SOC, PT, treatment sequence and treatment period. 
Summaries of TEAEs will include the following:
x Overview of incidence of TEAEs (overview including number and percentage of study 
participants with any TEAEs, any serious AEs, TEAE of Special Interest, TEAEs leading to 
discontinuation, drug-related TEAEs, severe TEAEs and TEAEs leading to death; event 
counts will also be included)
x Incidence of TEAEs by maximum relationship
x Incidence of TEAEs by maximum intensity
x Incidence of non-serious TEAEs above reporting threshold of 5% of study participants
Summary tables will contain counts of study participants, percentages of study participants in 
parentheses and the number of events where applicable. A study participant who has multiple 
events in the same SOC and PT will be counted only once in the study participant counts but all 
events will be included.
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 44 of 50
In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Study participants who experience the same event multiple times will be 
included in the most related category for tabulations by maximum relationship. Events with 
missing relationship will be considered as ‘Related’ but recorded as missing in the listings. 
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Study participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in 
the listings.
Incidence of Non-Serious TEAEs above reporting threshold of 5% of study participants will be 
reported by system organ class and preferred term.
Adverse event summaries will be ordered alphabetically by SOC and decreasing frequency of PT 
within SOC in the PSL+OC column for tables including event counts. For tables including only 
number and percentage of study participants, summaries will be ordered alphabetically by SOC 
and decreasing incidence of PT within SOC in the PSL+OC column.
Listings of AEs and TEAES will include the following:
x All AEs
x Incidence of all TEAEs
x All Serious AEs
x Discontinuation due to AEs.
All listings (except incidence of all TEAEs) will be presented by study part, treatment sequence 
(Sequence A/Sequence B) study participant and treatment period (PSL+OC/OC alone) and will 
include the SOC, PT, reported term, onset date/time and outcome date/time of the event 
(including relative days), the event duration (derived), time to onset (derived), pattern of event, 
intensity, relationship, action taken, outcome and AEs that led to discontinuation. TEAEs and 
SAEs will be flagged.
The listing of incidence of all TEAEs will be presented by study part and treatment sequence and 
will include intensity, relationship, severity, number of subject reporting a least one TEAE 
within SOC/PT, number of individual occurrences of TEAEs and site-participant number.
Additional summary tables of fatal, serious and discontinuation due to TEAEs by relationship 
will be produced if more than one of these events occurs.
10.3 
Clinical laboratory evaluations 
Laboratory data (clinical chemistry, hematology and urinalysis) and changes from Baseline (if 
applicable) will be summarized by descriptive statistics at each time point separately for each 
study part by treatment sequence for both absolute values and changes from Baseline. Shift 
tables from Baseline to each post-Baseline time point will be presented separately for each 
study part by treatment sequence. Any laboratory measurements that are BLQ or ALQ will be 
handled as described in Section 4.2.2. Only values outside the reference range for numeric 
variables will be listed. The reference ranges will also be reported in the listings. 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 45 of 50
A separate listing will present the study participant who meets one or more of the following 
criteria at any time point:
x Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase ≥3x upper 
limit of normal (ULN)
x Total bilirubin increase ≥2xULN
x Alkaline phosphatase ≥2xULN
The listing will display only time points for which at least one of the above criteria was fulfilled 
for a given study participant, and will display all results obtained at time point for the specified 
variables.
A listing of study participants who meet the criteria for potential drug-induced liver injury 
(PDILI) will be presented together with any additional relevant data collected, if applicable.
Laboratory variables will be grouped according to the laboratory function panel (Table 10-1) and 
categorized as normal, high or low, if applicable, based on the reference range supplied by the 
analytical laboratory. For selected variables that are identified in Table 10-1 the change in 
category from Baseline will be presented in a shift table at all post-Baseline time points.
Any additional laboratory variables not included in the outputs described previously will be 
listed separately. These will include:
x Serology
x Alcohol breath test
x Serum pregnancy test (for women of childbearing potential)
x Urine drug screen
Table 10-1: Safety Laboratory measurements 
Laboratory
Assessments
Parameters
Hematology
Platelet Countc
RBC Indices:
MCV
MCH 
Reticulocytes
WBC Count with
Differential:
Neutrophilsc
Lymphocytesc
Monocytes
Eosinophils
Basophils
RBC Countc
Hemoglobinc
Hematocritc
Coagulation panel
INR / Prothrombin
Clinical
Chemistrya
Blood Urea Nitrogen
(BUN)c
Potassium
Aspartate Aminotransferase
(ASTc)/ Serum Glutamic-
Oxaloacetic Transaminase
(SGOT)
Total and direct
bilirubin
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 46 of 50
Creatininec
Sodium
Alanine Aminotransferase
(ALTc)/ Serum 
Glutamic-Pyruvic
Transaminase (SGPT)
Total Protein
Glucose
Calcium
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Routine
Urinalysisb
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ketones,
bilirubin,
urobilinogen, nitrite, leukocyte by dipstick. If protein or blood or leukocytes
are abnormal (positive), a microscopic examination of the sediment will be 
performed.
Other Screening
Tests
x 
Follicle-stimulating hormone (at Screening only) to confirm postmenopausal
status in female study participants
x 
Urine drug screen (to include at minimum: amphetamines, barbiturates,
cocaine, opiates, cannabinoids and benzodiazepines)
x 
Pregnancy test: Serum human chorionic gonadotropin (hCG) test (as needed
for women of childbearing potential)
x 
Serology (HIV 1 and 2 Ab, HBsAg, HCV-Ab)
The results of each test must be entered into the CRF.
a Details of liver chemistry stopping criteria and required actions and follow up assessments after liver
stopping or monitoring event are given in protocol Section 7.1.1 and protocol Section 10.6. All events
of ALT ≥3×ULN) and bilirubin ≥2×ULN (>35% direct bilirubin) or ALT≥3×ULN and INR >1.5, if
INR measured, may indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE
(excluding studies of hepatic insufficiency or cirrhosis).
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation
or IRB/IEC.
c Shift tables will be produced.
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
The following vital signs measurements will be obtained with the study participants resting in the 
supine position for 5 minutes at all time points:
x Systolic blood pressure 
x Diastolic blood pressure
x Pulse rate
x Respiratory rate
x Oral or aural body temperature
A by- study participant listing of all vital sign measurements and change from Baseline will be 
presented at each time point separately for each study part by treatment sequence. 
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Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 47 of 50
Descriptive statistics will be reported for all vital sign measurements. Vital sign variables and
changes from Baseline will be summarized by descriptive statistics at each time point separately 
for each study part by treatment sequence.
In case the treatment-emergent markedly abnormal (TEMA)/potentially clinically significant 
(PCS) criteria are fulfilled, the results will be flagged.
Table 10-2: TEMA/PCS criteria for vital signs 
Variable
Unit
Lowa
Higha
Systolic blood 
pressure
mmHg
Value <90 and ≥20 
decrease from Baseline
Value >140 and ≥20 increase 
from Baseline
Diastolic blood 
pressure
mmHg
Value <50 and ≥15 
decrease from Baseline
Value >90 and ≥15 increase 
from Baseline
Pulse rate
bpm
Value <45 and ≥15 
decrease from Baseline
Value >90 and ≥15 increase 
from Baseline
bpm=beats per minute
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 means at each time 
point will be calculated as raw parameters for descriptive analysis. The individual mean and 
change from baseline will be summarized separately for each study part using descriptive 
statistics at each time point by treatment sequence.
All standard 12-lead ECG recordings will be taken in triplicate with the participant resting in the 
supine position for at least ≥5 minutes. The following ECG parameters will be reported:
x PR interval 
x QT interval
x QRS interval
x QTc interval (QT corrected for heart rate using Fridericia’s formula [QTcF])
x 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- study participant listings. The listing will also include the change from Baseline, based on 
the mean of the triplicate measurements at each time point, and will be presented by treatment 
sequence and by time point.
Measured values and changes from Baseline will be summarized at each time point and by ECG 
variable (based on the mean of the triplicate values at each time point). The mean change for 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 48 of 50
ECG parameter will also be displayed graphically separately for each study part by treatment 
sequence. 
The following cut-points in QTcF, based on the mean of the triplicate data, will be summarized 
categorically (number and percentage of participants) at each time point.
For observed data:
x <450 msec
x ≥450 to <480 msec
x ≥480 to <500 msec
x ≥500 msec
Absolute change from Baseline in QTcF:
x <30 msec
x ≥30 to <60 msec
x ≥60 msec
All ECG findings for the individual triplicate measurements will be listed separately.
Any incomplete triplicate measurements at a given time point will be handled as described in 
Section 4.2.3.
Figures of mean change from Baseline in ECG parameters over time by treatment sequence will 
be displayed separately for each study part.
10.4.3 
Other safety variables 
10.4.3.1 
Physical examination 
Study participants with abnormalities in the physical examination will be listed by study part 
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 by 
study part only. Module of the questionnaire, time point, question and the associated response 
will be listed for all the visit days where this questionnaire is collected. The listing will be based 
on the SS. 
11 
OTHER ANALYSES  
A listing of comments will be presented. 
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UCB
28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 49 of 50
12 
REFERENCES 
Phillips, A. and Haudiquet, V. (2003), ICH E9 guideline ‘Statistical principles for clinical trials’: 
a case study. Statist. Med., 22: 1-11. doi:10.1002/sim.1328
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77.
UCB Global Exploratory Development Guideline on performing NCA analysis. Version 1.0 –
08/NOV/2017
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0 –
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28 May 2020
Statistical Analysis Plan
Padsevonil
UP0035
Confidential
Page 50 of 50
13 
APPENDICES 
Treatment
Sequence
Treatment
Overall
Study participant disposition
X
Protocol deviations
X
Demographics
X
Medical history
X
Lifestyle
X
Prior medications
X
Concomitant medications
X
X
Adverse Events
X
X
Laboratory tests
X
Other safety continuous measurements (vital 
signs, ECG)
X
Safety categorical results (laboratory shift 
tables, PDILI)
X
PK plasma for PSL and its metabolites
X
PK for EE and LN
X
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Approval Signatures
Name:
up0035-sap
Version:
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Document Number:
CLIN-000146011
Title:
up0035 - Statistical Analysis Plan
Approved Date:
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Document Approvals
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Name: 
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Date of Signature: 29-May-2020 06:16:47 GMT+0000
Approval
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Name: 
Capacity: Clinical
Date of Signature: 29-May-2020 12:12:14 GMT+0000
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This document cannot be used to support any ma
marketing 
ma
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uthorization 
n
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Nam
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application 
p
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ova
a
and any extensions or variations thereof.