Clinical trial NCT03695094
Conditions: Epilepsy
Keywords: Epilepsy Phase 1 padsevonil
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2018-09-18; Completion date: 2019-05-30
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the effect of stable coadministered oxcarbazepine (OXC), on the pharmacokinetics (PK), safety, tolerability of padsevonil (PSL) and the plasma PK of PSL metabolites, UCB1431322-000 and UCB1447499-000, in study participants with epilepsy compared with study participants co-medicated with stable doses of levetiracetam (LEV), lamotrigine (LTG) or brivaracetam (BRV) therapy.

Detailed description:

Arms: arm 1: Cohort 1 (Inducers): Study participants on stable therapy with oxcarbazepine (OXC) either as monotherapy or adjunctive to levetiracetam (LEV), lamotrigine (LTG), or brivaracetam (BRV). OXC may be used as monotherapy or in combination with 1 or more of LEV, LTG, or BRV. Padsevonil (PSL) will be dosed to steady state and the effect of background therapy on PSL pharmacokinetics will be assessed at steady state. arm 2: Cohort 2 (Neutral): Study participants on stable therapy with lamotrigine (LTG), levetiracetam (LEV), or brivaracetam (BRV). LTG or LEV may be used as monotherapy or in combination with each other. BRV may only be used in combination with LTG. LTG or LEV may be used as monotherapy or in combination with each other. BRV may only be used in combination with LTG. Padsevonil (PSL) will be dosed to steady state (4.5 days) and the effect of background therapy on PSL pharmacokinetics will be assessed at steady state.
Interventions: intervention 1: Padsevonil intervention 2: Oxcarbazepine intervention 3: Levetiracetam intervention 4: Lamotrigine intervention 5: Brivaracetam
Intervention descriptions: intervention 1: Padsevonil (PSL) will be dosed to steady state and the effect of background therapies on pharmacokinetics will be assessed intervention 2: Concomitant administration of oxcarbazepine (OXC) at therapeutic dosage intervention 3: Concomitant administration of levetiracetam (LEV) at therapeutic dosage intervention 4: Concomitant administration of lamotrigine (LTG) at therapeutic dosage intervention 5: Concomitant administration of brivaracetam (BRV) at therapeutic dosage

Protocol documents:
Prot_000.pdf: 
UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 1 of 69
PROTOCOL UP0070
A MULTICENTER, OPEN-LABEL, PARALLEL-GROUP STUDY 
IN STUDY PARTICIPANTS WITH EPILEPSY TO EVALUATE 
THE EFFECT OF OXCARBAZEPINE ON THE 
PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF 
PADSEVONIL
PHASE 1
EudraCT Number: 2018-001941-16
Sponsor:
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Protocol/Amendment number
Date
Type of amendment
Final Protocol
08 June 2018
Not applicable
Confidentia0l 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.
REDACTED 
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 2 of 69
STUDY CONTACT INFORMATION
Sponsor
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
Belgium
Principal/Coordinating Investigator
Name:
Affiliation:
Centre for Human Drug Research
Address:
Zernikedreef 8
2333 CL Leiden
The Netherlands
Phone:
Sponsor Study Physician
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest R3
B-1420 Braine-L'Alleud
Belgium
Phone:
Exploratory Project Manager (EPM)
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest R3
B-1420 Braine-L'Alleud
Belgium
Phone:
Fax:
REDACTED 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 3 of 69
Clinical Trial Biostatistician
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest
R3 1420 Braine-L’Alleud
Belgium
Phone:
Clinical Monitoring Contract Research Organization
Name:
ICON Clinical Research Limited
Address:
South County Business Park
Leopardstown
Dublin 18
Republic of Ireland
Phone:
+353 1 291 2000
Fax:
+353 1 247 6260
Quantitative Clinical Pharmacology Lead
Name:
Address:
UCB Pharma SPRL
Chemin du Foriest
B-1420 Braine l’Alleud
Belgium
Phone:
Laboratory for Pharmacokinetic Parameters
Name:
York Bioanalytical Solutions Ltd.
Address:
Cedar House
Northminster Business Park
Upper Poppleton
York YO26 6QR
United Kingdom
Phone:
+44 (0)1904 686096
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 4 of 69
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 (for interventional clinical studies)
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 5 of 69
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................10 
1 
SUMMARY.....................................................................................................................13 
2 
INTRODUCTION ...........................................................................................................14 
2.1 
Background..................................................................................................................14 
2.2 
Clinical studies and adverse event profile ...................................................................15 
2.3 
Risk assessment ...........................................................................................................16 
2.3.1 
Cardiovascular events..........................................................................................17 
2.3.2 
Psychiatric events ................................................................................................17 
2.3.3 
Interactions with other medicinal products..........................................................17 
2.3.4 
Pregnancy and lactation.......................................................................................18 
2.4 
Urgent safety measures................................................................................................18 
3 
STUDY OBJECTIVES....................................................................................................18 
3.1 
Primary objective.........................................................................................................18 
3.2 
Secondary objectives ...................................................................................................18 
3.3 
Exploratory objectives .................................................................................................18 
4 
STUDY VARIABLES.....................................................................................................19 
4.1 
Pharmacokinetic variables ...........................................................................................19 
4.1.1 
Primary pharmacokinetic variables .....................................................................19 
4.1.2 
Secondary pharmacokinetic variables .................................................................19 
4.1.3 
Other pharmacokinetic variables .........................................................................19 
4.2 
Safety variables............................................................................................................19 
4.2.1 
Secondary safety variables ..................................................................................19 
4.2.2 
Other safety variables ..........................................................................................19 
5 
STUDY DESIGN.............................................................................................................20 
5.1 
Study description .........................................................................................................20 
5.2 
Study Periods ...............................................................................................................20 
5.2.1 
Screening Period..................................................................................................20 
5.2.1.1 
Screening Visit (Day -28 to Day -2) .........................................................21 
5.2.1.2 
Baseline Visit (Day -1)..............................................................................21 
5.2.2 
Treatment Period .................................................................................................21 
5.2.3 
Safety Follow-Up Period .....................................................................................22 
5.3 
Pharmacokinetic sampling...........................................................................................22 
5.3.1 
Venous blood.......................................................................................................22 
5.3.2 
Microsamples of capillary blood .........................................................................22 
5.4 
Study duration per study participant............................................................................22 
5.5 
Planned number of study participants and sites...........................................................23 
5.6 
Anticipated regions and countries................................................................................23 
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 6 of 69
5.7 
Schedule of study assessments.....................................................................................23 
5.8 
Schematic diagram.......................................................................................................28 
5.9 
Rationale for study design and selection of dose.........................................................28 
6 
SELECTION AND WITHDRAWAL OF STUDY PARTICIPANTS ...........................29 
6.1 
Inclusion criteria ..........................................................................................................29 
6.2 
Exclusion criteria .........................................................................................................31 
6.3 
Withdrawal criteria ......................................................................................................33 
6.4 
Stopping rules ..............................................................................................................34 
6.4.1 
Individual study participants................................................................................34 
6.4.2 
All study dosing...................................................................................................34 
6.4.3 
Potential drug-induced liver injury IMP discontinuation criteria........................34 
7 
STUDY TREATMENT...................................................................................................35 
7.1 
Description of investigational medicinal product........................................................35 
7.2 
Treatment to be administered.......................................................................................35 
7.3 
Packaging.....................................................................................................................35 
7.4 
Labeling .......................................................................................................................36 
7.5 
Handling and storage requirements .............................................................................36 
7.6 
Drug accountability......................................................................................................36 
7.7 
Procedures for monitoring study participant compliance ............................................36 
7.8 
Concomitant medications/treatments...........................................................................37 
7.8.1 
Permitted concomitant treatments (medications and therapies) ..........................37 
7.8.2 
Prohibited concomitant treatments (medications and therapies) .........................37 
7.8.3 
Rescue medication...............................................................................................37 
7.8.4 
Diet, fluid, and activity control............................................................................37 
7.9 
Blinding........................................................................................................................38 
7.10 
Numbering of study participants..................................................................................38 
8 
STUDY PROCEDURES BY VISIT ...............................................................................38 
8.1 
Screening Period (Day -28 to Day -1) .........................................................................38 
8.1.1 
Screening Visit (Day -28 to Day -2)....................................................................38 
8.1.2 
Baseline Visit (Day -1) ........................................................................................39 
8.2 
Treatment Period (Day 1 to Day 12)............................................................................40 
8.2.1 
Titration Period....................................................................................................40 
8.2.1.1 
Day 1 to Day 3...........................................................................................40 
8.2.2 
Maintenance Period .............................................................................................40 
8.2.2.1 
Day 4 to Day 7...........................................................................................40 
8.2.2.2 
Day 8 (morning) ........................................................................................41 
8.2.3 
Taper Period.........................................................................................................41 
8.2.3.1 
Day 8 (evening).........................................................................................41 
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
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8.2.3.2 
Day 9 to Day 12.........................................................................................41 
8.3 
Safety Follow-Up Period .............................................................................................42 
8.3.1 
Day 13..................................................................................................................42 
8.3.2 
End of Study Visit ...............................................................................................42 
8.4 
Withdrawal Visit..........................................................................................................43 
8.5 
Unscheduled Visit........................................................................................................43 
9 
ASSESSMENT OF PHARMACOKINETIC VARIABLES...........................................43 
9.1 
Pharmacokinetic variables ...........................................................................................43 
9.2 
Pharmacokinetic sampling procedures ........................................................................43 
9.2.1 
Blood pharmacokinetic sampling scheme ...........................................................43 
9.3 
Shipment procedures....................................................................................................44 
9.4 
Communication plan....................................................................................................44 
9.5 
Bioanalytical method ...................................................................................................44 
10 ASSESSMENT OF SAFETY..........................................................................................44 
10.1 
Adverse events.............................................................................................................44 
10.1.1 
Definitions ...........................................................................................................44 
10.1.1.1 
Adverse event............................................................................................44 
10.1.1.2 
Serious adverse event ................................................................................45 
10.1.1.3 
Adverse events of special interest .............................................................46 
10.1.2 
Procedures for reporting and recording adverse events.......................................46 
10.1.2.1 
Description of adverse events....................................................................47 
10.1.2.2 
Rule for repetition of an adverse event......................................................47 
10.1.2.3 
Additional procedures for reporting serious adverse events .....................47 
10.1.3 
Follow up of adverse events ................................................................................48 
10.2 
Pregnancy.....................................................................................................................48 
10.3 
Suspected transmission of an infectious agent.............................................................49 
10.4 
Overdose of investigational medicinal product ...........................................................49 
10.5 
Safety signal detection .................................................................................................49 
10.6 
Laboratory measurements............................................................................................49 
10.6.1 
Evaluation of PDILI ............................................................................................50 
10.6.1.1 
Consultation with Medical Monitor and local hepatologist ......................53 
10.6.1.2 
Immediate action: determination of IMP discontinuation.........................53 
10.6.1.3 
Testing: identification/exclusion of alternative etiology...........................53 
10.6.1.4 
Follow-up evaluation.................................................................................55 
10.6.1.5 
Optional hepatic investigation sample collection......................................55 
10.7 
Other safety measurements..........................................................................................56 
10.7.1 
Physical examination...........................................................................................56 
10.7.2 
Vital signs ............................................................................................................56 
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 8 of 69
10.7.3 
Standard 12-lead ECG .........................................................................................57 
10.7.4 
Assessment of suicidality ....................................................................................57 
11 STUDY MANAGEMENT AND ADMINISTRATION.................................................58 
11.1 
Adherence to protocol..................................................................................................58 
11.2 
Monitoring ...................................................................................................................58 
11.2.1 
Definition of source data .....................................................................................58 
11.2.2 
Source data verification .......................................................................................59 
11.3 
Data handling...............................................................................................................59 
11.3.1 
Case Report form completion..............................................................................59 
11.3.2 
Database entry and reconciliation........................................................................59 
11.3.3 
Study Participant Screening and Enrollment log/Study Participant Identification 
Code list...............................................................................................................60 
11.4 
Termination of the study..............................................................................................60 
11.5 
Archiving and data retention........................................................................................60 
11.6 
Audit and inspection ....................................................................................................60 
11.7 
Good Clinical Practice .................................................................................................61 
12 STATISTICS ...................................................................................................................61 
12.1 
Definition of analysis sets............................................................................................61 
12.1.1 
Enrolled Set .........................................................................................................61 
12.1.2 
Full Analysis Set..................................................................................................61 
12.1.3 
Pharmacokinetic Per-Protocol Set .......................................................................61 
12.2 
General statistical considerations.................................................................................61 
12.3 
Planned pharmacokinetic analyses ..............................................................................62 
12.3.1 
Analysis of the primary pharmacokinetic variables ............................................62 
12.3.2 
Analysis of the secondary pharmacokinetic variables.........................................62 
12.3.3 
Analysis of the exploratory pharmacokinetic variables.......................................62 
12.4 
Planned safety analyses................................................................................................62 
12.4.1 
Adverse events.....................................................................................................62 
12.4.2 
Laboratory measurements....................................................................................63 
12.4.3 
Vital signs and ECGs...........................................................................................63 
12.4.4 
Assessment of suicidality ....................................................................................63 
12.4.5 
Physical examinations .........................................................................................63 
12.5 
Handling of protocol deviations...................................................................................63 
12.6 
Handling of dropouts or missing data..........................................................................64 
12.7 
Planned interim analysis and data monitoring.............................................................64 
12.8 
Determination of sample size.......................................................................................64 
13 ETHICS AND REGULATORY REQUIREMENTS......................................................64 
13.1 
Informed consent .........................................................................................................64 
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 9 of 69
13.2 
Study participant identification cards ..........................................................................65 
13.3 
Independent Ethics Committees ..................................................................................65 
13.4 
Study participant privacy.............................................................................................66 
13.5 
Protocol amendments...................................................................................................66 
14 FINANCE, INSURANCE, AND PUBLICATION.........................................................66 
15 REFERENCES ................................................................................................................66 
16 DECLARATION AND SIGNATURE OF INVESTIGATOR .......................................68 
17 SPONSOR DECLARATION ..........................................................................................69 
LIST OF TABLES
Table 5-1: 
Schedule of study assessments.........................................................................24 
Table 7-1: 
Padsevonil administration................................................................................35 
Table 9-1: 
Irrelevant time deviations for PK sampling.....................................................44 
Table 10-1: 
Anticipated SAEs for the epilepsy population.................................................46 
Table 10-2: 
Laboratory measurements................................................................................50 
Table 10-3: 
Required investigations and follow up for PDILI............................................52 
Table 10-4: 
PDILI laboratory measurements......................................................................54 
Table 10-5: 
PDILI information to be collected ...................................................................55 
LIST OF FIGURES
Figure 5-1: Schematic diagram................................................................................................28 
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 10 of 69
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
bid
twice daily
BMI
body mass index
BP
blood pressure
BRV
brivaracetam
BZD
benzodiazepine
cBZR
central benzodiazepine receptor
CDMS
clinical data management system
CI
confidence interval
CNS
central nervous system
CPMP
Committee for Proprietary Medicinal Products
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
CYP
cytochrome P450
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic Case Report form
EOS
End of Study
EPM
Exploratory Project Manager
ES
Enrolled Set
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
Full Analysis Set
GABAA
gamma-aminobutyric acid type A
GCP
Good Clinical Practice
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 11 of 69
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HCV-Ab
hepatitis C antibody
HIV-1/2Ab
human immunodeficiency virus-1/2 antibody
HLA
human leukocyte antigen
IB
Investigator’s Brochure
ICF
Informed Consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
IMP
investigational medicinal product
IPD
important protocol deviation
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LEV
levetiracetam
LTG
lamotrigine
MedDRA
Medical Dictionary for Regulatory Activities
MHD
Mono Hydroxy Derivate
NCA
noncompartmental analysis
OTC
over the counter
OXC
oxcarbazepine
PD
pharmacodynamics(s)
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 for heart rate
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RR
respiratory rate
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 12 of 69
SAE
serious adverse event
SBP
systolic blood pressure
SD
standard deviation
SFU
Safety Follow-Up
SOC
System Organ Class
SOP
Standard Operating Procedure
SV2
synaptic vesicle protein 2
ULN
upper limit of normal
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 13 of 69
1
SUMMARY
Padsevonil (PSL; previously known as UCB0942) is a novel chemical entity with selective dual 
synaptic vesicle protein 2 (SV2) and central benzodiazepine receptor (cBZR) site affinity. It is 
currently being investigated for the treatment of focal-onset seizures in adult patients with 
drug-resistant epilepsy.
Many antiepileptic drugs (AEDs) are associated with drug-drug interactions. Preclinical data 
indicate that PSL metabolism is mediated mainly by cytochrome P450 (CYP)3A4 with minor 
involvement of CYP2C19. Consequently, PSL exposure may be altered by CYP3A4 inhibitors 
and inducers. It has already been demonstrated that concomitant administration of a strong
CYP3A4 inducer (carbamazepine) significantly reduces exposure to PSL (UP0002).
UP0070 is a Phase 1, multicenter, open-label study in study participants with epilepsy, designed 
to evaluate the pharmacokinetic (PK) interaction between PSL and oxcarbazepine (OXC), a 
common AED that is known to have CYP3A4 induction potential (Spina et al, 1996), and could 
therefore have a negative impact on the efficacy of PSL if exposure is reduced significantly as a 
result.
The primary objective of UP0070 is to evaluate the effect of stable coadministered OXC (as 
monotherapy or adjunctive therapy) on the PK of PSL in study participants with epilepsy
compared with study participants co-medicated with stable doses of levetiracetam (LEV), 
lamotrigine (LTG), or brivaracetam (BRV) therapy. The secondary objectives include the 
following: to evaluate the plasma concentrations of 10,11-dihydro-10-hydroxy-carbazepine 
(Mono Hydroxy Derivate [MHD]; circulating metabolite of OXC) before, during, and after 
administration of repeated doses of PSL, to evaluate the effect of stable coadministered OXC (as 
monotherapy or adjunctive therapy) on the plasma PK of PSL metabolites, 
and 
, in study participants with epilepsy compared with study participants 
co-medicated with stable doses of LEV, LTG, or BRV therapy, and to evaluate the safety and 
tolerability of PSL coadministration with stable OXC, LEV, LTG, or BRV therapy. The 
exploratory objectives include the following: to evaluate the plasma concentrations of LTG, 
LEV, and BRV before, during, and after administration of repeated doses of PSL and to evaluate 
and compare the venous blood and MITRA microsampling (dried blood) PK of PSL following 
administration of PSL study participants with epilepsy on stable coadministered OXC compared 
with study participants co-medicated with stable doses of LEV, LTG, or BRV therapy.
UP0070 is comprised of the following periods: a Screening Period; a Treatment Period, and a 
Safety Follow-Up (SFU) Period. The study participants will remain on stable OXC 
(monotherapy or adjunctive to LEV, LTG, or BRV), LTG (monotherapy or adjunctive to LEV or 
BRV), LEV (monotherapy or adjunctive to LTG), or BRV (adjunctive to LTG) throughout the 
study. The Screening Period will occur within 28 days prior to the start of the Treatment Period. 
The Treatment Period consists of 12 days of PSL treatment increasing in dose from PSL 100mg 
twice daily (bid) to 400mg bid and then tapering back to 100mg bid. The SFU Period is 
performed 7 to 9 days after the last dose of investigational medicinal product (IMP) or upon 
discontinuation of the study.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 14 of 69
2
INTRODUCTION
2.1
Background
More than 50 million people worldwide suffer from epilepsy. The prevalence in the UK is 
estimated to be 600,000 (JECUI, 2011; WHO, 2018). 
A population-based study conducted in Western Europe estimated that 22.5% of all patients had 
drug-resistant epilepsy (Picot et al, 2008). Another population-based study of active and 
drug-resistant epilepsy in northern Italy, concluded that the frequency of drug-resistant epilepsy
was 15.6% of all active epilepsies and 10.5% of incident cases (Giussani et al, 2016).
A treatment that provides a significant reduction in seizure frequency will reduce mortality 
(Laxer et al, 2014) and significantly improve quality of life (Choi et al, 2014; Baker et al, 1997) 
by increasing patients’ ability to attain basic safety, freedom from the risk of falls and injuries, 
and reach the milestones that most people take for granted: a feeling of belonging and social 
integration; the ability to form intimate relationships and a family; and having a productive and 
rewarding profession; or other means of self-realization.
Padsevonil is a novel chemical entity currently being developed clinically for the treatment of 
focal-onset seizures in adult patients with drug-resistant epilepsy. The mechanism of action for 
PSL is unique in comparison to available AEDs because it has selective affinity both for 
presynaptic SV2 proteins and for postsynaptic cBZR sites on the gamma-aminobutyric acid
type A (GABAA) receptor. At presynaptic sites, PSL binds with high affinity to all 3 subtypes of 
the human SV2 protein (ie, SV2A, SV2B, and SV2C), and at postsynaptic sites, acts as a partial 
agonist, binding with moderate affinity to the cBZR sites. Whereas SV2A ligands are 
characterized by broad-spectrum anticonvulsant activity, GABAA receptors mediate inhibitory 
neurotransmission, and their allosteric modulation by cBZR sites offers robust protection against 
seizures.
The synergistic anticonvulsive effect observed when combining LEV, an AED that binds with 
SV2A, with benzodiazepines (BZDs) in preclinical models (Kaminski et al, 2009) was the 
motivation that led to the design of PSL. In nonclinical studies, PSL administered as a 
monotherapy has shown higher efficacy than LEV combined with a BZD (diazepam) at 
matching in vivo occupancies of SV2A and cBZR, respectively. This suggests that PSL’s 
preclinical efficacy is not only due to the combination of these 2 mechanisms of action, but that a 
unique interaction of PSL with SV2 proteins may also play a role.
Padsevonil is cleared via metabolism involving the CYP pathway; the formation of the 2 major 
metabolites, 
and 
, is mainly mediated by CYP3A4, with potential involvement of CYP2C19.
Studies in patients with refractory epilepsy showed that more than 60% of patients were treated 
concomitantly with 2 or more AEDs (Johannessen and Landmark, 2010). Drug-drug interactions 
that result in alterations in the PK of AEDs can have a profound impact on tolerability, efficacy, 
and safety, and can potentially result in toxicity. It is therefore important to consider and estimate 
at an early stage the possible interactions that may occur with the concomitant use of PSL and 
other drugs.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 15 of 69
This study will evaluate the impact of an AED with known CYP3A4 inducing potential, OXC, 
on the PK of PSL in study participants with epilepsy, compared with the PK of PSL in a control 
group with coadministration of LEV, LTG, or BRV, which are not CYP-inducers.
2.2
Clinical studies and adverse event profile
As of 01 May 2018, PSL has been administered in 9 completed human Phase 1 pharmacology 
studies (N01360, N01383, N01386, UP0001, UP0002, UP0010, UP0013, UP0036, and UP0039) 
and 1 completed Phase 2 proof of concept study (EP0069). There is also 1 ongoing Phase 1
clinical pharmacology study (UP0057), 1 ongoing Phase 2 study (EP0091), 1 ongoing Phase 2
open-label extension study (EP0073), and 1 planned Phase 2 open-label extension study 
(EP0093). These studies have investigated the safety, PK, and pharmacodynamics (PD) of single 
and multiple ascending doses of PSL in both Caucasian and Japanese study participants, and the 
potential interaction of PSL with food, valproic acid, carbamazepine, and other AEDs. 
Positron-emission tomography investigations have been performed in healthy study participants 
to evaluate the GABAA receptor occupancy at 2 steady state PSL dose levels and SV2A 
occupancy at different single PSL dose levels and times postdose.
As of 06 Jun 2017, 129 healthy study participants and 20 patients with epilepsy (male and 
female) had been exposed to PSL at single doses up to 490mg (N=26 healthy study participants) 
and repeated doses up to 400mg bid for up to 12 days (N=103 healthy study participants and 
20 patients) in the 7 completed Phase 1 studies. An additional 12 and 40 healthy study 
participants were exposed to at least 1 dose of PSL in the recently completed Phase 1 studies, 
UP0036 and UP0039, respectively. In the Phase 2 proof of concept study (EP0069), 55 study 
participants were exposed at doses up to 400mg bid during the maintenance phase of the study. 
A total of 42 of the 55 study participants enrolled in the open-label extension study (EP0073) 
during which they were allowed to adjust their PSL dose.
The safety findings to date suggest that the adverse events (AEs) experienced by study 
participants receiving single and repeated doses of PSL are limited principally to central nervous 
system (CNS) effects and that these are consistent with the known pharmacology of PSL, 
ie, similar to AEs associated with other SV2A- and GABAA-targeting AEDs. The AEs tend to be 
dose-related in frequency and intensity, self-limiting, and tend to decrease in intensity over the 
first few days of dosing.
The psychiatric findings currently reported across the Phase 1 and Phase 2 studies with PSL are 
consistent with the AE profile of other AEDs, including other SV2A ligands. Acute psychiatric 
effects occurred in 3 study participants administered PSL (2 in Phase 1 and 1 in Phase 2). The 
events were transient, acute, and required admission to psychiatric care and antipsychotic 
treatment. No definite dose relationship could be determined, and the events occurred after 
variable periods of time after the first administration of PSL. Some new AEs (mainly headache 
and sleep disturbance) developed after dose discontinuation with PSL in the Phase 1 studies, 
indicating a potential withdrawal syndrome. These have been mild, transient, not dose related 
and not of clinical concern. The occurrence of these behavioral AEs highlights the need to 
consider the possibility of significant psychiatric AEs and to maintain vigilance for them.
With regard to cardiovascular effects, minor, transient, reductions in blood pressure (BP) were 
observed in the Phase 1 and Phase 2 PSL studies; however, these were not clinically meaningful 
and resolved without intervention. The degrees of reduction seen in both systolic blood pressure 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 16 of 69
(SBP) and diastolic blood pressure (DBP) are consistent with the GABAA-targeted mechanism of 
action of PSL and do not appear likely to have a clinically significant effect in therapeutic use 
(Jones et al, 1979). In regard to electrocardiogram (ECG) results, all nonclinical and clinical 
Phase 1 and Phase 2 cardiac data in totality were reviewed by an expert cardiologist consultant 
whose opinion was that “overall, there is no clear evidence that PSL is associated with any 
increase in incidence of ectopy, change in QT interval corrected for heart rate (QTc), or
clinically-significant arrhythmia in clinical trials to date.”
Echocardiographic screening of study participants at Baseline (to exclude study participants with 
valvulopathies) and ongoing echocardiographic monitoring during treatment and posttreatment 
have been implemented in the Phase 2 studies. No major findings were observed in the 
completed EP0069 study or the ongoing open-label extension study, EP0073. Cardiac 
monitoring (eg, ECGs, vital signs, echocardiograms) is planned throughout the duration of the
PSL development program in order to better understand and mitigate any risks.
In general, the safety profile of PSL has been consistent with the pharmacological properties of 
the drug and with dose-escalation studies of CNS compounds in regards to the type and severity 
of nervous system and psychiatric AEs reported, with most AEs reported as mild or moderate.
The overall safety profile during the clinical program to date, as well as preclinical and clinical 
experience with PSL, can be found in the Investigator’s Brochure (IB).
2.3
Risk assessment
Safety pharmacology studies have shown no major adverse effects on the respiratory system and 
CNS when administered orally in single-dose safety pharmacology studies (rats) and in repeat 
dose toxicity studies (rats, dogs). A slight prolongation of QTc (≤10%) was found in a 4-week 
study in dogs and a single dose telemetry study at free plasma concentrations at least 6 times 
above the mean free peak plasma concentration reached in epilepsy patients at 30mg/kg bid; 
however, it was not confirmed in a 13-week study (animals monitored by external telemetry) or a 
39-week study at doses up to 50mg/kg bid, with free plasma concentration far above those 
reached in epilepsy patients (up to 35-fold). Small, transient increases in heart rate and changes 
in arterial pressure (hypertension in rats and hypotension in dogs) occurring mainly from single 
doses are likely related to exaggerated GABAA pharmacologic activity.
Padsevonil administration was well tolerated in rats dosed up to 150mg/kg bid over 26 weeks 
and in dogs dosed up to 50mg/kg bid over 39 weeks using dose titration approach, providing 
safety margins versus human exposure at a dose of 400mg bid of 1.5 to 5 in rats and 42 in dogs. 
In rats, at higher dose levels, lower mean overall body weight gain, despite normal food 
consumption, accompanied by a decrease in bone length was observed and was considered to be 
adverse. Similar effects were not seen in female rats or in dogs.
In clinical studies, PSL had a good safety profile. There were no deaths. Adverse events 
experienced by study participants were limited principally to CNS effects and these were 
consistent with its known pharmacology, dose-related in frequency and intensity, self-limiting, 
and tended to decrease in intensity over the first few days of dosing.
The information obtained from this study will inform decisions on safe and effective doses of 
PSL to be given to study participants with epilepsy in future studies where PSL may be 
coadministered with other AEDs. The sponsor will immediately notify the Investigator and 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 17 of 69
regulatory agencies if any additional safety or toxicology information becomes available during 
the study.
2.3.1
Cardiovascular events
In the 39-week dog toxicity study, subtle cardiac microscopic findings, consisting of minimal 
valvular inflammatory cell infiltration, or minimal to slight epithelial inflammation/fibroplasia of 
the epicardium in the right atrium, were seen in the heart of one-third of treated dogs without 
dose relationship. Findings were subtle, minor, focal, and not associated with any changes in 
systemic cardiovascular parameters. They were not seen in any dog study of shorter duration.
These findings did not cause any biological or clinical consequences in the animals in this study 
and were thus not considered to be adverse. These findings were not seen in the 13-week dog 
study. This conclusion was supported after comprehensive review of the data by 5 nonclinical 
pathologists (including a cardiovascular expert pathologist). Additionally, external advice on the 
potential human implications was sought from a British Heart Foundation Professor of 
Cardiology. It was concluded that short-term exposure should not lead to any relevant 
abnormality or clinical disease, and even with long-term exposure the potential hazard and 
likelihood of an adverse pericardial or valvular effect in humans is extremely low. 
Echocardiographic monitoring of study participants in the Phase 2 proof of concept study 
(EP0069) and its open-label extension (EP0073) was undertaken, and no major findings have 
been observed to date.
Despite the occurrence of ECG findings such as ectopies (asymptomatic, not requiring clinical 
intervention), there are no current data suggesting that PSL has an adverse effect on 
cardiovascular function other than a minimal lowering effect on BP. The degrees of reduction of 
both SBP and DBP are consistent with the GABAA-targeted mechanism of action of PSL and do 
not appear likely to have a clinically significant effect in therapeutic use. As a precaution from 
preclinical and clinical findings of nonclinically significant ECG abnormalities and hypotension, 
ECGs and vitals are being assessed frequently in current clinical studies.
2.3.2
Psychiatric events
The occurrence of acute psychiatric serious adverse events (SAEs) (delirious syndrome, 
mania-like symptoms, and acute psychosis) in 3 study participants administered PSL highlights 
the need to maintain vigilance for such events. Reported acute psychiatric effects are consistent 
with adverse effects of other anticonvulsant drugs with various mechanisms of action. These 
SAEs were transient, acute, and required clinical intervention (admission to psychiatric care and 
antipsychotics). In healthy study participants, those SAEs occurred early after initiation of PSL 
done without titration; in 1 study participant, symptoms worsened upon abrupt drug 
discontinuation. Only in 1 out of 68 epileptic study participants exposed to PSL, a psychotic 
effect emerged a few weeks following dosing start after improvement in seizure control. This 
suggests a “forced normalization” phenomenon, which is described with other AEDs in resistant 
patients and is not unexpected with a potent AED (Loganathan et al, 2015; Clemens, 2005). The 
mitigation plan for acute psychiatric effects involves gradual titration and taper, known to 
improve tolerability of AEDs. 
2.3.3
Interactions with other medicinal products
The preclinical pharmacology studies indicated that the metabolism of PSL may be affected by 
extrinsic influences on the CYP3A4/CYP2C19 pathway. In order to mitigate any risk caused by 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 18 of 69
these interactions, medication or dietary ingredients that induce, inhibit, or are a substrate for the 
CYP3A4/CYP2C19 pathways are restricted. Further details are provided in Section 7.8.1 and 
Section 7.8.2.
2.3.4
Pregnancy and lactation
Padsevonil is neither teratogenic nor embryotoxic in rats and rabbits. There was no effect on 
reproductive organs, including sperm analysis, following long-term administration (up to 
26 weeks in rats and 39 weeks in dogs). Padsevonil has not been studied in pregnant or lactating 
women, and the effects of PSL on the developing embryo/fetus in humans are unknown; 
therefore it should not be administered to women of childbearing potential unless they are using 
stringent measures of birth control.
Additional details regarding risks can be found in the IB.
2.4
Urgent safety measures
In accordance with UK Law (Medicines for Human Use [Clinical Trials] as amended: SI 1031
Part 4 Section 30), the sponsor and Investigator may take appropriate urgent safety measures in 
order to protect the study participants of a clinical study against any immediate hazard to their 
health or safety. If such measures are taken, the sponsor shall immediately (no later than 3 days 
from the date the measures are taken) give written notice of the measures taken and the
circumstances giving rise to those measures to the licensing authority and the relevant ethics 
committee.
3
STUDY OBJECTIVES
3.1
Primary objective
The primary objective of this study is to evaluate the effect of stable coadministered OXC (as 
monotherapy or adjunctive therapy) on the PK of PSL in study participants with epilepsy
compared with study participants co-medicated with stable doses of LEV, LTG, or BRV therapy.
3.2
Secondary objectives
The secondary objectives of this study are to:
x Evaluate the plasma concentrations of MHD (circulating metabolite of OXC) before, during,
and after administration of repeated doses of PSL
x Evaluate the effect of stable coadministered OXC (as monotherapy or adjunctive therapy), on 
the plasma PK of PSL metabolites, 
and
, in study 
participants with epilepsy compared with study participants co-medicated with stable doses 
of LEV, LTG, or BRV therapy.
x Evaluate the safety and tolerability of PSL coadministration with stable OXC, LEV, LTG, or 
BRV therapy
3.3
Exploratory objectives
The exploratory objectives of this study are to:
x Evaluate the plasma concentrations of LTG, LEV, and BRV before, during, and after 
administration of repeated doses of PSL. (Blood samples for plasma concentrations of LEV, 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 19 of 69
LTG, and BRV samples will be collected and stored during the study; they will only be 
measured on an as-needed basis.)
x Evaluate and compare the venous blood and MITRA microsampling (dried blood) PK of PSL 
following administration of PSL in study participants with epilepsy on stable coadministered 
OXC compared with study participants co-medicated with stable doses of LEV, LTG, or 
BRV therapy.
4
STUDY VARIABLES
4.1
Pharmacokinetic variables
4.1.1
Primary pharmacokinetic variables
The primary PK variables will comprise Cmax, tmax, AUCτ, and CL/Fss obtained from the plasma 
concentration-time profiles for PSL:
x Cmax: maximum observed plasma concentration
x tmax: time of maximum concentration
x AUCτ: area under the curve over a dosing interval (12 hours)
x CL/Fss: apparent total clearance at steady-state
4.1.2
Secondary pharmacokinetic variables
The secondary PK variable will be the trough plasma concentration of MHD (OXC metabolite) 
before, during, and after dosing to steady state with PSL.
Additionally, the secondary PK variables for PSL metabolites (
 and 
) will comprise Cmax, tmax, AUCτ, and the ratio of metabolite to PSL based on 
AUCτ.
4.1.3
Other pharmacokinetic variables
The following other PK variables will be assessed during the study:
x Trough plasma concentrations of LEV, LTG, or BRV before, during, and after dosing to 
steady state with PSL
x Comparison of plasma concentrations from MITRA microsampling (dried blood) with 
venous sampling for PSL
4.2
Safety variables
4.2.1
Secondary safety variables
The following secondary safety variables will be assessed during the study:
x Incidence of AEs and SAEs
4.2.2
Other safety variables
The following other safety variables will be assessed during the study:
x Changes in vital signs (pulse rate [PR], respiratory rate [RR], SBP, and DBP)
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 20 of 69
x Changes in clinical laboratory test results (hematology, serum chemistry, and urinalysis)
x Changes in 12-lead ECG parameters
x Physical examination findings
5
STUDY DESIGN
5.1
Study description
This is a Phase 1, multicenter, open-label study in study participants with epilepsy, to evaluate 
the effect of OXC on the PK and safety and tolerability of PSL.
A total of 28 study participants will be evaluated in the following 2 groups (14 study participants 
per group):
x Group 1 (Inducers): study participants on stable therapy with OXC (at least 1200mg/day 
either as monotherapy or adjunctive to LEV, LTG, or BRV). Oxcarbazepine may be used as 
monotherapy (at least 7 study participants) or in combination with 1 or more of LEV, LTG, 
or BRV). (For adjunctive therapy, the dosing of each AED in the combination [OXC+LEV, 
OXC+BRV, or OXC+LTG] must be within the range used per label.)
x Group 2 (Neutral [control]): study participants on stable therapy with LTG (at least 
150mg/day monotherapy or adjunctive to LEV or BRV), LEV (at least 1g/day monotherapy
or adjunctive to LTG), or BRV (up to 200mg/day adjunctive to LTG). Lamotrigine or LEV 
may be used as monotherapy (at least 7 study participants) or in combination with each other. 
Brivaracetam may only be used in combination with LTG. (For adjunctive therapy, the 
dosing of each AED in the combination [LTG+LEV or LTG+BRV] must be within the range 
used per label.)
Padsevonil will be dosed to steady state (4.5 days) in both groups and the effect of background 
therapy on PSL PK will be assessed at steady state.
5.2
Study Periods
5.2.1
Screening Period
The Screening Period consists of a single Screening Visit, which will be conducted at the unit 
within 28 days prior to check-in for the Treatment Period, and a Baseline Visit, which will be 
conducted at the unit 1 day prior to the Treatment Period.
A sufficient number of study participants with epilepsy will be screened to ensure that 14 study 
participants are included in each group.
In Group 1 (study participants taking stable coadministered OXC), OXC may be used as 
monotherapy (at least 7 study participants) or in combination with 1 or more of LEV, LTG, or 
BRV). (For adjunctive therapy, the dosing of each AED in the combination [OXC+LEV, 
OXC+BRV, or OXC+LTG] must be within the range used per label.)
In Group 2 (study participants taking LTG, LEV, or BRV), LTG or LEV may be used as 
monotherapy (at least 7 study participants) or in combination with each other. Brivaracetam may 
only be used in combination with LTG. (For adjunctive therapy, the dosing of each AED in the 
combination [LTG+LEV or LTG+BRV] must be within the range used per label.)
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 21 of 69
5.2.1.1
Screening Visit (Day -28 to Day -2)
Study participants are required to sign a written Informed Consent form (ICF) prior to the 
conduct of any study-related procedure. Screening assessments will be conducted, after which 
the eligibility of study participants will be determined based on: inclusion and exclusion criteria 
(see Section 6.1 and Section 6.2, respectively); demographics; medical history; full physical 
examination (including weight and height); medication history; vital sign measurements; several 
laboratory tests (hematology, serum chemistry, urinalysis, serology screening, alcohol breath 
test, and urine toxicology screen); triplicate 12-lead ECGs; and recording of AEs/medical 
procedures. A serum pregnancy test will be performed to assess eligibility for women of 
childbearing potential.
5.2.1.2
Baseline Visit (Day -1)
At the Baseline Visit, study participants will check in at the unit the afternoon prior to the visit 
and receive a study participant Identification Card.
The following procedures/assessments will be repeated: inclusion/exclusion criteria verification; 
medical history; full physical examination; medication history; vital sign measurements; 
laboratory tests (hematology, serum chemistry, urinalysis, alcohol breath test, and urine 
toxicology screen); triplicate 12-lead ECGs; and recording of AEs/medical procedures. A urine 
pregnancy test will be performed to assess eligibility for women of childbearing potential. Study 
participants will also be assessed with the Columbia-Suicide Severity Rating Scale (C-SSRS) to 
assess suicidal risk.
Study participants can then be discharged from the unit after all procedures/assessments have 
been completed. The study participants may continue being confined to the unit at the 
Investigator’s discretion or continue the study ambulatory until the afternoon of Day 7.
5.2.2
Treatment Period
The Treatment Period consists of 3 days of dose titration (Day 1, Day 2, and Day 3), 4.5 days of 
PSL maintained at a stable dose (Days 4 through 7 and the morning of Day 8), and 4.5 days of 
dose taper (evening of Day 8 and Days 9 through 12).
The dose titration (Day 1, Day 2, and Day 3) will be initiated as follows: all study participants 
enrolled into the study will receive 1 day of PSL 100mg bid followed by 2 further days of PSL 
200mg bid. Padsevonil 400mg will then be maintained by oral administration bid on Day 4
through Day 7 and once on Day 8 in the morning. Ambulatory study participants will be 
readmitted to the unit on the afternoon of Day 7. All dosing must be observed, ie, the study 
participants must return to the unit for the predose meal and dosing morning and evening, unless 
arrangements can be made for home visits with the same requirements.
A dose taper will be initiated on the evening of Day 8, when study participants will be 
administered PSL 200mg. On Day 9 and Day 10, PSL 200mg bid will be administered. On 
Day 11 and Day 12, PSL 100mg bid will be administered. 
The following procedures/assessments will be completed: C-SSRS (for ambulatory study 
participants only on Day 1 through Day 7); prior and concomitant medication; vital sign 
measurements; triplicate 12-lead ECGs; and recording of AEs/medical procedures.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 22 of 69
5.2.3
Safety Follow-Up Period
Study participants will be discharged on Day 13 and return for an End of Study (EOS) Visit on
Day 20±1.
The SFU Period consists of discharge from the unit on Day 13 and an EOS Visit performed on
Day 20±1 or upon discontinuation of the study. Study participants will have the following 
procedures/assessments completed at the EOS Visit: C-SSRS; a full physical examination; prior 
and concomitant medication; vital sign measurements; laboratory safety (hematology, serum 
chemistry, and urinalysis); triplicate 12-lead ECGs; and recording of AEs/medical procedures. A 
urine pregnancy test will also be administered for woman of childbearing potential.
5.3
Pharmacokinetic sampling
Study participants will undergo serial blood sampling to measure plasma concentrations of PSL, 
PSL metabolites (
 and 
), and OXC metabolite (MHD), as 
well as safety monitoring. Blood samples for plasma concentrations of LEV, LTG, and BRV 
samples will be collected and stored during the study; they will only be measured on an 
as-needed basis. Pharmacokinetic analysis will be performed using both conventional plasma as 
well as contemporaneous MITRA microsampling (dried blood) of PSL to compare the 
2 methods.
5.3.1
Venous blood
Venous blood samples for PK analysis will be collected as follows:
x Padsevonil and PSL metabolites (
 and 
):
 prior to the morning dose of PSL on Day 1 through Day 7 and Day 9 through Day 13
 prior to the morning dose of PSL and 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h 
after administration of the morning dose of PSL (prior to the evening dose) on Day 8
x AEDs: trough samples prior to the morning dose of the AED(s) on Day -1, Day 1 through 
Day 13, and the EOS Visit
5.3.2
Microsamples of capillary blood
Samples for PK of PSL from a finger skin prick will be collected using the MITRA device, as 
close to the conventional PK sampling as possible, at each of the time points identified for the 
venous blood samples for Day 8 in Section 5.3.1.
5.4
Study duration per study participant
The maximum total duration of the study is 49 days (7 weeks) for each study participant, 
including the Screening Period (up to 28 days), Treatment Period (12 days), and the SFU Period 
(maximum of 9 days).
The end of the study is defined as the date of the last visit of the last study participant in the 
study.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 23 of 69
5.5
Planned number of study participants and sites
A total of 28 evaluable study participants are planned to be enrolled at a minimum of 2 sites. If a 
study participant drops out before completing the key assessments (ie, the full PK profile on 
Day 8), the study participant will be replaced.
5.6
Anticipated regions and countries
This study will be conducted in the Netherlands, Bulgaria, and Germany (and potentially other 
countries in Europe).
5.7
Schedule of study assessments
The schedule of assessments is presented in Table 5-1.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 24 of 69
Table 5-1:
Schedule of study assessments
Procedures
Screening Period
Treatment Period
SFU Period
Screening
Baseline
Titration
Maintenance
Taper
SFU Post-
treatment
EOS/ET a
Day -28
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Day -1
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Day
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Day
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Day
20 (±1)
Written Informed Consent
X
Record info on habits and lifestyle
X
Demographics & baseline 
characteristics 
X
Inclusion/Exclusion criteria verification
X
X
General medical/procedures history
X
X
Enrollment to Inducers or Neutral 
(control) Group
X
Study Participant Identification Card 
assigned
X
Psychiatric History
X
Administer C-SSRS b
X
Xc
Xc
X
X
Physical examination
X
X
X
X
Prior and concomitant medications
X
Record intake of grapefruit, starfruit, or 
pawpaw (as beverage, fruit, or 
supplements) d
X
X
X
X
Blood sample for MHD plasma level e
X
X
X
X
X
X
X
X
Pregnancy test f
X
X
X
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 25 of 69
Table 5-1:
Schedule of study assessments
Procedures
Screening Period
Treatment Period
SFU Period
Screening
Baseline
Titration
Maintenance
Taper
SFU Post-
treatment
EOS/ET a
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to Day -2
Day -1
Days
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Day
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Day
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Hematology, serum chemistry, 
urinalysis
X
X
X
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X
Vital signs g
X
X
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X
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X
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12-lead ECG g
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Xh
X
X
Xh
X
X
X
Height/weight, BMI
X
Drug/alcohol screen
X
X
Recording of adverse events/medical 
procedures
X
Admit to study center
X
X
Discharge from study center
X
X
Dispense Padsevonil i
X
X
X
X
Study drug accountability
X
Blood sample for AED trough level j
X
X
X
X
X
X
X
Blood sampling for PSL and 
metabolites PK levels
Xk
Xk
Xl
Xk
Xk
Final Disposition Determination
X
AED=antiepileptic drug; BMI=body mass index; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EOS/ET=End of Study/Early 
Termination; h=hour(s); HIV=human immunodeficiency virus; IMP=investigational medicinal product; M=Maintenance; Mono Hydroxy Derivate;
OXC=oxcarbazepine; PK=pharmacokinetic(s); PSL=Padsevonil; SFU=Safety Follow-Up; Ta=Taper; Ti=Titration
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 26 of 69
Note: Day –1 is defined as the day before Day 1. Day 1 is defined as the first day of administration.
Note: For study participants prematurely terminating or completing the study, final disposition is recorded at EOS/ET. All study participants prematurely 
terminating from the study should be encouraged to undergo final evaluation procedures, in accordance with the EOS/ET schedule, as soon as possible after the 
last dose of study drug.
Note: Study participants will be admitted to the unit on the afternoon prior to Day -1 for baseline assessments and can be discharged after the last ECG 
assessment (6h). They will be readmitted to the unit on the afternoon of Day 7 and will be discharged from the unit on Day 13 in the morning after completion 
of all procedures/assessments. During visits on Day 1 through Day 7, ambulatory study participants to will come to the unit at least 2 hours prior to the morning 
dose and remain until completion of all procedures/assessments. They should return to the unit at least 1 hour prior to the evening dose.
a The SFU assessments should be performed for any study participant who withdraws from the study 7 to 9 days after the last dose of PSL.
b At the Baseline Visit, complete the “Baseline/Screening” version of the C-SSRS. At all other visits, complete the “Since Last Visit” version of the C-SSRS.
c Only for ambulatory study participants.
d Grapefruit, starfruit, and pawpaw (as beverage, fruit, or supplements) within 72 hours before first administration of IMP, during the Treatment Period, and 
throughout the study will not be allowed. If this is the case at the start of the study, study participation may be delayed as long as it occurs within the screening 
window.
e This is only done for study participants taking OXC. If the study participant administers OXC in the morning and evening, the blood sample should be obtained 
prior to the morning dose of OXC. If the study participant administers OXC once daily, then the blood sample should be obtained just prior to the daily dose. 
At the Screening Visit, the blood sample must be collected no later than on Day -7 (with MHD reassessment, if required, no later than Day -4); other safety 
assessments including reassessments are allowed no later than Day -2.
f A serum pregnancy test will be performed at Screening for women of childbearing potential only. A urine pregnancy test will be performed at Baseline and at 
EOS/ET for women of childbearing potential only.
g Triplicate 12-lead ECGs and vital signs (after a rest of at least 5 minutes at 2- to 3-minute intervals) will be performed on Days 1 through 12, prior to the PK 
collection prior to the morning dose of PSL.
h Triplicate 12-lead ECG (after a rest of at least 5 minutes at 2- to 3-minute intervals) will be taken shortly prior to each of the following PK collection time 
points at Day 8: predose, 0.5h, 1h, 2h, 3h, 6h, and 12h post the morning dose of PSL. In addition, 1 day prior to the first dose of PSL on Day -1 (Baseline)
triplicate 12-lead ECGs will be performed after a rest of at least 5 minutes at 2- to 3-minute intervals for each of the following matching time points: predose, 
0.5h, 1h, 2h, 3h, and 6h postdose for the morning administration of PSL, and 0.5h predose for the evening administration of PSL, where dosing time is 
equivalent to the expected time of dosing on Day 8.
i Investigational medicinal product will be administered bid 12h apart each day. All study participants enrolled into the study will receive 1 day of PSL at 
100mg bid (Day 1) followed by 2 further days at 200mg bid (Day 2 and Day 3). Padsevonil 400mg will then be administered orally bid on Day 4 through Day 7
and once on Day 8 in the morning. A dose taper will be initiated on the evening of Day 8, when study participants will be administered an evening dose of 
PSL 200mg. Padsevonil 200mg bid will be administered on Day 9 and Day 10. Padsevonil 100mg bid will be administered on Day 11 and Day 12.
j Obtain blood samples for storage; measurement of the trough level of the concomitant AED will be done as needed. If the study participant administers the 
concomitant AED in the morning and evening, the blood sample should be obtained prior to the morning dose of the AED (and on applicable days, prior to the 
morning dose of PSL). If the study participant administers the concomitant AED once daily, then the blood sample should be obtained just prior to the daily 
dose (and if applicable, prior to the dose of PSL).
k Obtain blood samples (venous only) for measurement of trough levels of PSL and metabolites just prior to the morning dose of PSL on Day 1 through Day 12.
On Day 13, sampling should occur prior to discharge.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 27 of 69
l Obtain blood samples (venous and MITRA) for measurement of plasma concentration of PSL at the following times: predose (within 5min of dosing), then at 
0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h postdose. Time windows for postdose samples are as follows: ±5min for the 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, and 
4h samples; ±10min for the 6h, 8h, and 12h samples. The 12h sample must be obtained prior to the evening dose.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 28 of 69
5.8
Schematic diagram
The study schematic diagram for UP0070 is presented in Figure 5-1.
Figure 5-1: Schematic diagram
bid=twice daily; BRV=brivaracetam; LEV=levetiracetam; LTG=lamotrigine; OXC=oxcarbazepine 
PK=pharmacokinetic(s); PSL=Padsevonil; SFU=Safety Follow-Up; T=Titration
5.9
Rationale for study design and selection of dose
In an earlier study (UP0002), carbamazepine (CBZ, a strong CYP3A4 inducer) was 
demonstrated to reduce PSL exposure by >80% compared with a control group where 
coadministration of non-inducing AED drugs (LEV/LTG) had no impact on PSL exposure. 
Oxcarbazepine is a known CYP3A4 inducer with less potency compared with CBZ 
(Andreasen et al, 2007). The primary objective of this study is to evaluate the effect of stable 
coadministered OXC on the PK of repeated doses of PSL 400mg bid in study participants with 
epilepsy, compared with study participants co-medicated with stable doses of LEV, LTG, or 
BRV therapy.
The PSL dose will be 400mg bid (the maximum intended therapeutic dose and hence highest 
exposure), which demonstrates no safety concerns in the patient population and provides a
comparison with previous studies performed with this dose (UP0002).
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 29 of 69
6
SELECTION AND WITHDRAWAL OF STUDY 
PARTICIPANTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. An Independent Ethics Committee (IEC) approved written ICF is signed and dated by the 
study participant. 
2. Study participant is considered reliable and capable of adhering to the protocol (eg, able to 
understand and complete diaries), visit schedule, and medication intake according to the 
judgment of the Investigator.
3. Study participant is male or female between 18 to 64 years of age, inclusive, with a diagnosis 
of epilepsy according to the International League Against Epilepsy (ILAE) classification 
(Fisher et al, 2014).
4. Study participant is currently treated for epilepsy with stable doses of the following for at 
least 3 months:
a) Inducers Group: OXC (at least 1200mg/day as monotherapy or in combination with BRV 
[up to 200mg/day], LEV [at least 1g/day] or LTG [at least 150mg/day]); or
b) Neutral (control) Group: LTG (at least 150mg/day monotherapy or adjunctive to LEV or 
BRV), LEV (at least 1g/day monotherapy or adjunctive to LTG), or BRV (up to 
200mg/day adjunctive to LTG).
5. Study participant in the Inducers Group is taking OXC and has a trough OXC metabolite 
(MHD) plasma level in the target range (≥12.0 to ≤35.0 mcg/mL). At the Screening Visit, the 
blood sample must be collected no later than on Day -7 (with MHD reassessment, if required, 
no later than Day -4).
6. Study participant is in generally good physical and mental health, in the opinion of the 
Investigator, determined on the basis of medical history and a general clinical examination at 
the Screening Visit (ie, study participant has no current or past medical history of clinical 
significance, other than epilepsy, that would mitigate against their participation in the study).
7. Study participant has clinical laboratory test results within the local reference ranges or 
values are considered as not clinically relevant by the Investigator and approved by the UCB 
Study Physician. Laboratory parameters outside the reference ranges can be retested and if 
the retest result is within the reference range or considered as clinically not relevant the study 
participant is allowed in the study. Alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or alkaline phosphatase (ALP) should be within the normal limits. 
Liver enzymes up to 25% above the upper limit may be repeated once and should be within 
normal limits before inclusion.
8. Study participant has a body mass index (BMI) of 18 to 35kg/m², inclusive, with a body 
weight of at least 50kg (male) or 45kg (female).
9. Study participant has BP and PR within normal range in the supine position after 5 minutes 
rest (SBP: 90mmHg to 145mmHg, DBP: 40mmHg to 95mmHg, PR: 40bpm to 100bpm). 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 30 of 69
Any values outside the normal range, but considered not clinically significant by the 
Investigator, are allowed.
10. Female study participant has a negative serum pregnancy test at the Screening Visit and 
agrees to use an efficient form of contraception for the duration of the study (unless 
menopausal [defined as no menses for 12 months without an alternative medical cause]; a 
high follicle-stimulating hormone level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy). Hormonal contraception may be susceptible to an interaction with the IMP, which 
may reduce the efficacy of the contraception method. The potential for reduced efficacy of 
any hormonal contraception methods requires that a barrier method (preferably male 
condom) also be used.
Birth control methods considered as an efficient form of contraception:
 Combined (oestrogen and progestogen containing) hormonal contraception (oral, implant, 
or injectable) associated with inhibition of ovulation in combination with a barrier 
method (preferably male condom)
 Progestogen-only hormonal contraception associated with inhibition of ovulation in 
combination with a barrier method (preferably male condom)
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS) in combination with a barrier method 
(preferably male condom)
 Bilateral tubal occlusion
 Vasectomized partner
 Sexual abstinence
True abstinence is an acceptable form of contraception when this is in line with the 
preferred and usual lifestyle of the person. Periodic abstinence (eg, calendar ovulation,
symptothermal, postovulation methods), declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception.
 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action in combination with a barrier method (preferably male condom)
 Male or female condom with spermicide (ie, double barrier)
 Cap, diaphragm, or sponge with spermicide
To ensure proper birth control, females who use hormonal contraception should use an 
efficient barrier contraceptive in the 3 months following the end of the study (ie, for 
3 months after the last intake of study medication).
11. Male study participant agrees that, during the study period, when having sexual intercourse 
with a woman of childbearing potential, he will use an efficient barrier contraceptive 
(condom plus spermicide) AND that the respective partner will use an additional efficient 
contraceptive method (eg, oral pills, IUDs, IUSs, or diaphragm, and spermicide).
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 31 of 69
6.2
Exclusion criteria
Study participants are not permitted to enroll in the study if any of the following criteria is met:
1. Study participant has previously received the IMP administered in this study.
2. Study participant has participated in another study of an investigational medication (or a 
medical device) within the last 3 months before screening (or 5 half-lives, whichever is 
longer) or is currently participating in another study of an investigational medication (or a 
medical device).
3. Study participant has a known hypersensitivity to any components of the IMP as stated in 
this protocol
4. Study participant has a current or past psychiatric condition that, in the opinion of the 
Investigator, could compromise his/her safety or ability to participate in this study or a 
history of schizophrenia, or other psychotic disorder, bipolar disorder, or severe unipolar 
depression. The presence of potential psychiatric exclusion criteria will be determined based 
on the psychiatric history collected at the Screening Visit.
5. Study participant has a lifetime history of suicide attempt (including an actual attempt, 
interrupted attempt, or aborted attempt), or has had suicidal ideation in the past 6 months as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Screening/Baseline” version of the C-SSRS at the Baseline Visit.
6. Study participant has any medical condition that, in the opinion of the Investigator, could 
jeopardize or would compromise the study participant’s ability to participate in this study.
7. Study participant has a history of status epilepticus during the last year.
8. Study participant has a history or presence of drug or alcohol dependency or tests positive for 
alcohol and/or drugs at the Screening Visit or Day -1.
9. Study participant has a consumption of more than 3 units of alcohol/day in case of females, 
more than 4 units of alcohol/day in case of males.
10. Study participant smokes more than 5 cigarettes per day (or equivalent) or has done so within 
6 months prior to the Screening Visit.
11. Study participant has a consumption of more than 600mg of caffeine/day within 7 days prior 
to the Baseline Visit and does not agree to limit consumption below this limit for the duration 
of the study (200mL of coffee contains approximately 100mg of caffeine, 200mL of black 
tea approximately 30mg, and 200mL of cola approximately 20mg).
12. Study participant ingests grapefruit, starfruit, or pawpaw (as beverage, fruit, or supplements) 
within 72 hours before first administration of IMP. These fruits are not allowed during the 
Treatment Period and throughout the study.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 32 of 69
13. Study participant has either:
 >2.0x upper limit of normal (ULN) of any of the following: 
◦ 
ALT
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ALP
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 ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome).
If study participant has elevations only in total bilirubin that are >ULN and <1.5xULN, 
fractionate bilirubin to identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin 
<35%).
For randomized study participant with a baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a baseline diagnosis and/or the cause of any clinically meaningful elevation must 
be understood and recorded.
If study participant has >ULN ALT, AST, or ALP that does not meet the exclusion limit at 
screening, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing 
clinically relevant increase. In case of a clinically relevant increase, inclusion of the study 
participant must be discussed with the UCB Study Physician.
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. If out of range again, the study participant cannot be included.
14. Study participant has made a blood or plasma donation or has had a comparable blood loss 
(>400mL) within the last 3 months prior to the Screening Visit. 
15. Study participant has a history or present condition of respiratory or cardiovascular disorders, 
eg, cardiac insufficiency, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia, 
or myocardial infarction.
16. Study participant has any clinically relevant ECG finding at the Screening Visit or at 
Baseline. Study participant has an abnormality in the 12-lead ECG that, in the opinion of the 
Investigator, increases the risks associated with participating in the study. In addition, any 
study participant with any of the following findings will be excluded: (a) QT interval 
corrected for heart rate using Bazett’s formula (QTcB) or Fridericia’s formula (QTcF) 
>450ms in 2 of 3 ECG recordings; (b) other conduction abnormalities (defined as PR interval 
≥220ms); (c) irregular rhythms other than sinus arrhythmia or occasional, rare 
supraventricular or rare ventricular ectopic beats. In case of an out of range result, 1 repeat 
will be allowed. If out of range again, the study participant cannot be included.
17. Study participant has a history of unexplained syncope or a family history of sudden death 
due to long QT syndrome.
18. Study participant tests positive for human immunodeficiency virus-1/2 antibody 
(HIV-1/2Ab), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab).
19. Female study participant tests positive for pregnancy, plans to get pregnant during the 
participation in the study, or is breastfeeding.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 33 of 69
20. Study participant has received any prescription or nonprescription medicines, including 
enzyme inhibitors or inducers, over the counter (OTC) remedies, herbal and dietary 
supplements (including St. John’s Wort), or vitamins up to 2 weeks or 5 half-lives of the 
respective drug (whichever is longer) before the first administration of IMP and during the 
clinical part of the study, unless required to treat an AE. This does not include allowed AEDs 
per the protocol, oral contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal 
hormone replacement therapy or implants, patches, or IUDs/IUSs delivering progesterone 
(for female study participants).
6.3
Withdrawal criteria
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care.
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 would interfere with his/her continued participation.
2. Study participant is noncompliant with the study procedures or medications in the opinion of 
the Investigator.
3. Study participant takes prohibited concomitant medications as defined in this protocol.
4. Study participant withdraws his/her consent.
5. 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. Subject has active suicidal ideation without specific plan as indicated by a positive response 
(“Yes”) to Question 4 of the “Since Last Visit” version of the C-SSRS. The study participant
should be referred immediately to a mental healthcare professional and may be withdrawn 
from the study based upon the Investigator’s judgment of benefit/risk of continuing the study 
participant in the study/on IMP.
Subject 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.
8. Refer to Section 6.4.3 for withdrawal criteria in relation to potential drug-induced liver injury 
(PDILI).
Investigators should attempt to obtain information on study participants in the case of 
withdrawal. For study participants considered as lost to follow up, the Investigator should make 
an effort (at least 1 phone call and 1 written message to the study participant), and document 
his/her effort (date and summary of the phone call and copy of the written message in the source 
documents), to complete the final evaluation. All results of these evaluations and observations, 
together with a narrative description of the reason(s) for removing the study participant, must be 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 34 of 69
recorded in the source documents. The eCRF (electronic Case Report form) must document the 
primary reason for withdrawal.
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a study participant in advance.
6.4
Stopping rules
6.4.1
Individual study participants
Should a study participant experience an AE meeting any of the following criteria, then IMP 
dosing in that individual will be suspended: 
x possibly drug-related SAE
x severe, possibly drug-related AE or new laboratory or other finding of Common 
Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 lasting longer than 12 hours
(ie, still present at the time of the next scheduled dose)
x moderate, possibly drug-related AE or new laboratory parameter abnormality or other finding 
of Grade ≥2 lasting for longer than 72 hours
x any AE considered severe enough by the Investigator to pose a significant threat to the study 
participant’s safety
Dosing will remain suspended in that study participant until the Investigator and UCB Study 
Physician have met to consider whether or not dosing may be resumed, based on the evolution of 
the event and any relevant clinical or laboratory findings.
6.4.2
All study dosing
Dosing of all study participants in the study will be suspended if:
x Two or more study participants meet 1 or more of the individual stopping criteria due to AEs 
in the same System Organ Class (SOC) classification or laboratory parameter class and 
(following assessment by the UCB Study Physician and Investigator) are not permitted to 
resume dosing.
x Despite the above study stopping criterion not being met, a pattern of suitably concerning 
AEs, laboratory test abnormalities, or other findings is identified that, in the opinion of the 
Investigator and/or UCB Study Physician, indicates that continued dosing is not justifiable 
under the current protocol on safety grounds.
Once dosing has been suspended in the study, as a whole, it will not be resumed prior to 
submission of an amended protocol and approval by the appropriate Regulatory Authority and 
Ethics Committee.
6.4.3
Potential drug-induced liver injury IMP discontinuation criteria
Study participants with PDILI must be assessed to determine if IMP must be discontinued. In 
addition, all concomitant medications and herbal supplements that are not medically necessary 
should also be discontinued.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 35 of 69
The PDILI criterion below requires immediate and permanent discontinuation of IMP:
x Study participants with ≥3xULN ALT or AST
Evaluation of PDILI must be initiated as described in Section 10.6.1. If study participants are 
unable to comply with the applicable monitoring schedule, IMP must be discontinued 
immediately.
Investigators should attempt to obtain information on study participants in the case of IMP 
discontinuation to complete the final evaluation. Study participants with PDILI should not be 
withdrawn from the study until investigation and monitoring are complete. All results of these 
evaluations and observations, as well as the reason(s) for IMP discontinuation and study 
participant withdrawal (if applicable), must be recorded in the source documents. The eCRF 
must document the primary reason for IMP discontinuation
7
STUDY TREATMENT
7.1
Description of investigational medicinal product
Padsevonil (100mg tablets) will be supplied by UCB.
7.2
Treatment to be administered
Padsevonil will be administered orally with 8oz (240mL) water, 30 minutes after a light or 
standard meal for the morning dose and 30 minutes after a standard meal for the evening dose,
according to Table 7-1.
Table 7-1:
Padsevonil administration
Day
Morning dose
Evening dose
1 (Ti1)
100mg
100mg
2 (Ti2)
200mg
200mg
3 (Ti3)
200mg
200mg
4-7 (M1-M4)
400mg
400mg
8 (M5/Ta1)
400mg
200mg
9 (Ta2)
200mg
200mg
10 (Ta3)
200mg
200mg
11 (Ta4)
100mg
100mg
12 (Ta5)
100mg
100mg
M=Maintenance; Ta=Taper; Ti=Titration
Treatments will be administered in an open-label fashion. Study participants will continue to take 
OXC, LTG, LEV, or BRV as per their usual regimen. 
7.3
Packaging
Padsevonil tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 36 of 69
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Council for
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements.
7.5
Handling and storage requirements
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the Investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label.
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room,
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval.
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual.
The Investigator (or designee) will instruct the study participant to store the IMP following the 
instructions on the label.
7.6
Drug accountability
A Drug Accountability form will be used to record IMP 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 IMP 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 IMP 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 IMP 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 IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedures (SOPs) or returned to UCB (or designee). Investigational medicinal product intended 
for the study cannot be used for any other purpose than that described in this protocol.
7.7
Procedures for monitoring study participant compliance
Administration of PSL will be performed under the supervision of the Investigator (or designee), 
and the Investigator (or designee) will check the study participant’s hands and the oral cavity 
immediately after dosing to confirm ingestion of the IMP. All dosing must be observed, ie, the 
study participants must return to the unit for the predose meal and dosing morning and evening, 
unless arrangements can be made for home visits with the same requirements. Compliance will 
be monitored by drug accountability and by drug assay (using the drug concentration in the 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 37 of 69
blood). Compliance with the IMP is defined as consumption by the study participant that 
conforms 100% with the planned dosage.
Drug administration/consumption will be recorded and any discrepancies with the dosing 
regimen must be explained. 
7.8
Concomitant medications/treatments
7.8.1
Permitted concomitant treatments (medications and therapies)
Study participants will continue to take a minimum of OXC (at least 1200mg/day), BRV (up to 
200mg/day), LTG (at least 150mg/day), or LEV (at least 1g/day) as per their usual regimen.
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 6h to 8h, not exceeding 2g/day, and with a total of no more than 5g over 7 days.
x Ibuprofen
x Inhaled corticosteroids for seasonal rhinitis
7.8.2
Prohibited concomitant treatments (medications and therapies)
With the exception of permitted concomitant treatments listed above all 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.
7.8.3
Rescue medication
There are no absolute restrictions on the use of concomitant medications to “rescue” study 
participants whose seizure control significantly deteriorates during the course of the study. While 
the objectives of the study should be protected as much as possible through observance of the 
restrictions detailed in Section 7.8.2, the well-being of the study participant will always take 
priority, and study participants should be managed as deemed appropriate by the Investigator. If 
use of any prohibited medications is anticipated, this should be discussed with the UCB Study 
Physician first, wherever possible.
7.8.4
Diet, fluid, and activity control
During the Treatment Period, study participants will complete a light meal 30min prior to each 
morning dose of IMP, and a standard meal 30min prior to each evening dose of IMP.
Study participants should keep their usual diet (besides the restrictions for the study) necessary 
for the maintenance of good health; excessive food consumption should be avoided. Study 
participants should refrain from heavy physical exertion (eg, vigorous exercise) from 3 days 
prior to (first) confinement and during the study.
Study participants should not consume more than 3 units alcohol/day (females) and 4 units 
alcohol/day (males), or more than 600mg of caffeine/day (200mL of coffee contains 
approximately 100mg of caffeine, 200mL of black tea approximately 30mg, and 200mL of cola 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 38 of 69
approximately 20mg) from 48 hours prior to each administration of PSL and until the final PK 
plasma sampling of the Treatment Period.
Grapefruit, starfruit, and pawpaw (as beverage, fruit, or supplements) within 72 hours before first
administration of IMP, during the Treatment Period, and throughout the study will not be 
allowed. If this is the case at start of study, study participation may be delayed as long as it 
occurs within the screening window.
Study participants must refrain from donating blood or plasma during the course of the study 
(except for the samples taken for the purpose of the study) and should refrain from donating 
blood or plasma for at least 3 months prior to the Screening Visit and until 2 months after the end 
of the study.
Water will be available ad libitum except for between 1 hour before and 2 hours after dosing. A 
total of 240mL of water will be given to each study participant at the time of administration of 
IMP.
7.9
Blinding
UP0070 is an open-label study; thus there will be no blinding.
7.10
Numbering of study participants
Each study participant will receive a unique 5-digit number assigned at Screening that serves as 
the study participant identifier throughout the study. If the study participant withdraws or is 
withdrawn from the study, this number will not be reassigned to another study participant.
8
STUDY PROCEDURES BY VISIT
8.1
Screening Period (Day -28 to Day -1)
8.1.1
Screening Visit (Day -28 to Day -2)
The Screening Visit will be conducted at the unit within 28 days prior to the first day of 
treatment. The following procedures/assessments will be performed:
x Written Informed Consent
x Demographics, habits, and lifestyle
x Inclusion/exclusion criteria verification
x General medical/psychiatric/procedures history
x Full physical examination, including height and weight
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, DBP, and oral temperature)
x Triplicate 12-lead ECGs (prior to collection of PK samples)
x Blood samples (venous) for trough PK analysis (prior to OXC morning dose):
 MHD plasma level (only for study participants taking OXC)
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 39 of 69
x Blood and urine samples for the following clinical laboratory tests will be collected:
 Serum pregnancy test (for women of childbearing potential only)
 Hematology, serum chemistry, and urinalysis
 Serology screening
 Urine drug screen
x Alcohol breath test
x Recording of AEs/medical procedures
8.1.2
Baseline Visit (Day -1)
Study participants will check in to the unit on the afternoon prior to this visit and will be 
assigned their Study Participant Identification Card. The following procedures/assessments will 
be performed before discharge: 
x Inclusion/exclusion criteria verification
x General medical/procedures history
x Enrollment to Inducers or Neutral (control) Group
x Dispense Study Participant Identification Card
x C-SSRS (“Baseline/Screening” version of the C-SSRS)
x Full physical examination
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, DBP, and oral temperature)
x Triplicate 12-lead ECGs
 Morning: approximately 0.5h prior to the expected time of the morning dose on Day 8,
and 0.5h, 1h, 2h, 3h, and 6h after the expected time of the morning dose on Day 8
 Evening: approximately 0.5h prior to the expected time of the evening dose on Day 8
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
x Blood and urine samples for the following clinical laboratory tests will be collected:
 Hematology, serum chemistry, and urinalysis
 Urine pregnancy test (for women of childbearing potential only)
 Urine drug screen
x Alcohol breath test
x Recording of AEs/medical procedures
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 40 of 69
8.2
Treatment Period (Day 1 to Day 12)
8.2.1
Titration Period
8.2.1.1
Day 1 to Day 3
Study participants may continue being confined to the unit at the Investigator’s discretion or 
continue the study ambulatory until the afternoon of Day 7. All dosing must be observed, ie, the 
study participants must return to the unit for the predose meal and dosing morning and evening, 
unless arrangements can be made for home visits with the same requirements. All study 
participants enrolled into the study will receive PSL 100mg bid on Day 1 and PSL 200mg bid on 
Day 2 and Day 3. The following procedures/assessments will be performed:
x C-SSRS for ambulatory study participants only (“Since Last Visit” version of the C-SSRS)
x Record intake of grapefruit, starfruit, or pawpaw
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, and DBP)
x Triplicate 12-lead ECGs (shortly prior to collection of PK samples)
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
x Blood samples (venous) for trough PK analysis (prior to PSL morning dose):
 PSL and metabolites (
and 
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x Dispense PSL
x Recording of AEs/medical procedures
8.2.2
Maintenance Period
8.2.2.1
Day 4 to Day 7
Study participants will receive PSL 400mg bid and will check in to the unit on the afternoon of 
Day 7. The following procedures/assessments will be performed:
x C-SSRS for ambulatory study participants only (“Since Last Visit” version of the C-SSRS)
x Record intake of grapefruit, starfruit, or pawpaw
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, and DBP)
x Triplicate 12-lead ECGs (shortly prior to collection of PK sample)
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 41 of 69
x Blood samples (venous) for trough PK analysis (prior to PSL morning dose):
 PSL and metabolites (
 and 
) levels
x Dispense PSL
x Recording of AEs/medical procedures
8.2.2.2
Day 8 (morning)
Study participants will receive PSL 400mg in the morning. The following 
procedures/assessments will be performed:
x Record intake of grapefruit, starfruit, or pawpaw
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, and DBP)
x Triplicate 12-lead ECGs
 Approximately 0.5h prior to PSL morning dose, and 0.5h, 1h, 2h, 3h, and 6h after the 
morning dose 
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
x Blood samples (venous and MITRA) for PK analysis (relative to PSL morning dose):
 PSL and metabolites (
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(predose [within 5 minutes of dosing], 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h 
[to be obtained prior to evening dose])
x Dispense PSL
x Recording of AEs/medical procedures
8.2.3
Taper Period
8.2.3.1
Day 8 (evening)
Study participants will receive PSL 200mg in the evening. The following 
procedures/assessments will be performed:
x Triplicate 12-lead ECGs (shortly prior to PSL evening dose)
x Dispense PSL
8.2.3.2
Day 9 to Day 12
Study participants will receive PSL 200mg bid on Day 9 and Day 10. Study participants will 
receive PSL 100mg bid on Day 11 and Day 12. All study participants must be confined to the 
unit for the entire Taper Period. The following procedures/assessments will be performed:
x Record intake of grapefruit, starfruit, or pawpaw
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 42 of 69
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, and DBP)
x Triplicate 12-lead ECGs (shortly prior to collection of PK samples)
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
x Blood samples (venous) for trough PK analysis (prior to PSL morning dose):
 PSL and metabolites (
 and 
) levels
x Dispense PSL
x Recording of AEs/medical procedures
8.3
Safety Follow-Up Period
8.3.1
Day 13
The following procedures/assessments will be performed prior to discharge:
x C-SSRS (“Since Last Visit” version of the C-SSRS)
x Full physical examination
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, and DBP)
x Triplicate 12-lead ECGs (shortly prior to collection of PK samples)
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
x Blood samples (venous) for trough PK analysis:
 PSL and metabolites (
 and 
) levels
x Blood and urine samples for the following clinical laboratory tests will be collected:
 Hematology, serum chemistry, and urinalysis
x Recording of AEs/medical procedures
8.3.2
End of Study Visit
The following procedures/assessments will be performed 7 to 9 days after last dose of PSL or 
upon discontinuation of the study (EOS Visit):
x C-SSRS (“Since Last Visit” version of the C-SSRS)
x Full physical examination
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 43 of 69
x Prior and concomitant medications
x Vital signs (including PR, RR, SBP, DBP, and oral temperature)
x Triplicate 12-lead ECGs (prior to collection of PK samples)
x Blood samples (venous) for trough PK analysis (prior to AED morning dose):
 MHD plasma level (only for study participants taking OXC)
 AED trough level (for storage)
x Blood and urine samples for the following clinical laboratory tests will be collected:
 Urine pregnancy test (for women of childbearing potential only)
 Hematology, serum chemistry, and urinalysis
x Recording of AEs/medical procedures
8.4
Withdrawal Visit
Study participants who withdraw from the study for any reason after the first dose, but prior to 
Day 13, will be asked to return to the unit to complete an Early Termination Visit 
(7 days ± 1 day, postdose). The same assessments as for the EOS Visit (see Section 8.3.2) will be 
performed. Study participants who withdraw between enrollment and first dose will be followed 
up only at the discretion of the Investigator.
8.5
Unscheduled Visit
At the Investigator’s discretion, an Unscheduled Visit may be completed at any time during the 
study if deemed necessary for the study participant’s safety and wellbeing. The assessments to be 
conducted during an Unscheduled Visit will be based on the Investigator’s judgement.
9
ASSESSMENT OF PHARMACOKINETIC VARIABLES
9.1
Pharmacokinetic variables
The PK variables are described in detail in Section 4.1. Calculations of PK variables will be 
made with Phoenix® WinNonlin® (version 6.3 or higher) using actual sampling times. The linear 
trapezoidal method will be used to calculate the AUC parameters. For details of PK analyses, 
refer to Section 12.3.1.
9.2
Pharmacokinetic sampling procedures
Study participants are requested to provide blood samples for measurement of PSL levels using 
the VAMS technology on the MITRA microsampling device.
9.2.1
Blood pharmacokinetic sampling scheme
Serial blood samples for PK analysis of PSL (venous and MITRA) and its metabolites 
(
 and 
; venous only) will be collected as described in 
Section 5.3 and Table 5-1.
The total blood volume collected for the study will not exceed 500mL per study participant.
Exact sampling times will be recorded in the eCRF.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 44 of 69
All sample handling procedures, including the time of each sample collection, the start and stop 
time of centrifugation and placement into frozen storage (at the end of the sample workup), and 
the date of transfer or shipment of the samples to the responsible analyst will be documented in 
detail.
Time deviations from scheduled sampling times will be discussed at the Data Review Meeting.
Full details of sample handling and processing are provided in the Laboratory Manual.
The maximum deviations from scheduled sampling times considered irrelevant for PK are 
defined in Table 9-1.
Table 9-1:
Irrelevant time deviations for PK sampling
PK blood sampling times
Deviation from scheduled time considered irrelevant
0 hours (predose)
Within 60 minutes 
0.25 to 4 hours
5 minutes
6 to 12 hours
10 minutes
PK=pharmacokinetic
9.3
Shipment procedures
Details of the PK samples labelling and shipment procedures will be provided in the Laboratory 
Manual.
9.4
Communication plan
A communication plan dedicated to PK laboratory activities (at the least) will be established in a 
separate document.
9.5
Bioanalytical method
Plasma concentrations of PSL, PSL metabolites (
 and 
), and 
AEDs will be determined with validated bioanalytical methods. Blood concentrations of PSL 
collected by MITRA devices will be determined with a validated bioanalytical method.
10
ASSESSMENT OF SAFETY
10.1
Adverse events
10.1.1
Definitions
10.1.1.1
Adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation study participant 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF), including any pretreatment and posttreatment periods required by the 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 45 of 69
protocol, must be reported in the eCRF even if no IMP was taken but specific study procedures 
were conducted. This includes all AEs not present prior to the initial visit and all AEs that 
recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the study participant’s history or the Baseline Period. 
10.1.1.2
Serious adverse event
Once it is determined that a study participant experienced an AE, the seriousness of the AE must 
be determined. An SAE must meet 1 or more of the following criteria:
x Death
x Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.)
x Significant or persistent disability/incapacity
x Congenital anomaly/birth defect (including that occurring in a fetus)
x Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or study participant and may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the definition of serious
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 10.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.)
x Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
study participant has a condition recorded on his/her medical history and later has a 
preplanned surgery for this condition, it is not appropriate to record the surgery or 
hospitalization as an SAE, since there is no AE upon which to assess the serious criteria. 
Please note that, if the pre-existing condition has worsened or manifested in an unusual or 
uncharacteristic manner, this would then qualify as an AE and, if necessary, the seriousness 
of the event would need to be determined.)
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 46 of 69
10.1.1.2.1
Anticipated serious adverse events
The following anticipated SAEs are anticipated to occur in the epilepsy population at some 
frequency that is independent of drug exposure (Table 10-1)
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 10.1.2.3.
Table 10-1: Anticipated SAEs for the epilepsy population
MedDRA SOC
MedDRA Preferred Term
Congenital and hereditary disorders
Teratogenicity
General disorders and administration site conditions
Sudden unexplained death in epilepsy
Injury, poisoning, and procedural complication
Fall 
a
, fracture a, injury a
Nervous system disorders
Cluster seizures, convulsion, incontinence a,
memory impairment, status epilepticus
Pregnancy, puerperium, and perinatal disorders
Abortion spontaneous
Psychiatric disorders
Abnormal behavior, acute psychosis, anxiety, 
cognitive disorder, confusional state, psychotic 
behavior, sleep disorder and disturbances
Reproductive system and breast disorders
Impotence, menstrual disorder
MedDRA=Medical Dictionary for Regulatory Activities, Version 19.1; SAE=serious adverse event; SOC=System 
Organ Class
a Events are anticipated when occurring in the context of seizure, but not classified in MedDRA primary SOC.
10.1.1.3
Adverse events of special interest
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. No AEs of special interest have been identified for 
PSL to date, with the exception of potential Hy’s Law cases, as described below.
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow-up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
study participant.
10.1.2
Procedures for reporting and recording adverse events
The study participant will be given the opportunity to report AEs spontaneously. A general 
prompt will also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 47 of 69
10.1.2.1
Description of adverse events
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the study participant’s 
own words on his/her own records (eg, diary card) and the corresponding medical terminology 
should be clarified in the source documentation.
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) 
are described in the eCRF Completion Guidelines.
10.1.2.2
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:
x The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”
x The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one
10.1.2.3
Additional procedures for reporting serious adverse events
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The Investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE Report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database.
An Investigator SAE Report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English.
It is important for the Investigator, when completing the SAE Report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE Report form.
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each study participant, and to also inform participating 
study participants of the need to inform the Investigator of any SAE within this period. Serious 
AEs that the Investigator thinks may be associated with the IMP must be reported to UCB 
regardless of the time between the event and the end of the study.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 48 of 69
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the IB.
10.1.3
Follow up of adverse events
An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the study participant is lost to follow up. 
This follow-up requirement applies to AEs, SAEs, and AEs of special interest; further details 
regarding follow up of PDILI events is provided in Section 10.6.1.4.
If an AE is ongoing at the end of the study for a study participant, follow up should be provided 
until resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that 
it is clinically significant, or until the study participant is lost to follow up. If no follow up is 
provided, the Investigator must provide a justification. The follow up will usually be continued 
for 30 days after the study participant has discontinued his/her IMP.
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time.
10.2
Pregnancy
If an Investigator is notified that a study participant has become pregnant after the first intake of 
any IMP, the Investigator must immediately notify UCB’s PS department by providing the 
completed Pregnancy Report and Outcome form (for contact details see Serious Adverse Event 
reporting information at the beginning of this protocol). The study participant should be 
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 immediately stop the intake of the IMP.
x The study participant should return for an EOS Visit 7 to 9 days after the study participant 
has discontinued her IMP.
The Investigator must inform the study participant of information currently known about 
potential risks and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the study participant is lost to follow up and/or refuses to give information, written 
documentation of attempts to contact the study participant needs to be provided by the 
Investigator and filed at the site. UCB’s PS department is the primary contact for any questions 
related to the data collection for the pregnancy, eventual birth, and follow up.
In cases where the partner of a male study participant enrolled in a clinical study becomes 
pregnant, the Investigator or designee is asked to contact the study participant to request consent 
of the partner via the Partner Pregnancy Consent form that has been approved by the responsible 
IEC and should be available in the Investigator site file. In case of questions about the consent 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 49 of 69
process, the Investigator may contact the UCB/contract research organization (CRO) contract 
monitor for the study. The Investigator will complete the Pregnancy Report and Outcome form 
and send it to UCB’s PS department (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol) only after the partner has agreed that additional 
information can be captured and has provided the signed Partner Pregnancy Consent form. 
UCB’s PS department is also the primary contact for any questions related to the data collection 
for the partner pregnancy, eventual birth, and follow up.
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion (elective or 
spontaneous), unintended pregnancy after hormonal contraceptive failure (if the hormonal 
contraceptive was correctly used), ectopic pregnancy, fetal demise, or any congenital 
anomaly/birth defect of the baby. Those SAEs must be additionally reported using the 
Investigator SAE Report form.
10.3
Suspected transmission of an infectious agent
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
10.4
Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt).
10.5
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 IMP so that Investigators, clinical study participants, regulatory 
authorities, and IECs will be informed appropriately and as early as possible.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative.
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study.
10.6
Laboratory measurements
Blood and urine samples will be taken for clinical laboratory assessments at the time points 
specified in Table 5-1.
A urine drug screen and alcohol breath test will be performed at the Screening Visit (Day -28 to
Day -2) and before study participants are admitted to the unit on Day -1. Serology will be 
performed at the Screening Visit to assess study participant eligibility. A serum pregnancy test 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 50 of 69
will be administered at the Screening Visit. A urine pregnancy test will be administered at 
Baseline and the EOS Visit.
Laboratory safety measurements will be performed after a fasting period of at least 4 hours only 
at the Screening Visit. Clinical laboratory parameters to be measured are presented in 
Table 10-2.
Sampling time and last AED intake should be recorded in the eCRF.
Table 10-2: Laboratory measurements
Hematology
Hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, platelets, 
total white blood cell count, and differential consisting of absolute counts and 
percentages of the following leukocyte types: neutrophils, lymphocytes, monocytes,
eosinophils, and basophils
Serum chemistry
Sodium, potassium, calcium, inorganic phosphorus, fasting glucose, urea, 
creatinine, total bilirubin (conjugated bilirubin when total bilirubin is outside the 
reference range), total protein, albumin, ALT, AST, and ALP
Viral serology 
(only at Screening 
Visit)
HIV-1/2Ab, HBsAg, and HCV-Ab
Pregnancy
Serum pregnancy test at the Screening Visit
Hormone tests
Follicle-stimulating hormone (at Screening only to confirm postmenopausal status 
in female study participants)
Urinalysis
Specific gravity, pH, glucose, protein, blood, leukocytes, nitrite, ketones, bilirubin, 
urobilinogen (with dipstick)
If protein or blood or leukocytes are abnormal (positive), a microscopic 
examination of the sediment will be performed.
Drug screen
Amphetamines/methamphetamines, benzodiazepines, barbiturates, cocaine, 
cannabis, methadone, tricyclic antidepressants, and opiates
ALT=alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; HBsAg=hepatitis B
surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibodies
10.6.1
Evaluation of PDILI
The PDILI IMP discontinuation criteria for this study are provided in Section 6.4.3, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that meets the criterion for potential Hy’s Law must be 
reported as an AE of special interest (see Section 10.1.1.3), and, if applicable, also reported as an 
SAE (see Section 10.1.1.2).
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 10-3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 10.6.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 51 of 69
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 10.6.1.4).
The results of all monitoring, including laboratory testing and other testing, should be made
available to the study site and sponsor.
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but
appropriate medical action must not be delayed waiting for the repeat result.
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages.
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the Investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative.
When IMP is stopped due to PDILI (as described in Section 6.4.3), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings.
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur.
Table 10-3 summarizes the approach to investigate PDILI.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 52 of 69
Table 10-3: Required investigations and follow up for PDILI
Laboratory value
Symptoms a of 
hepatitis or 
hypersensitivity
Consultation requirements
ALT or 
AST
Total 
bilirubin
Required testing
Continued evaluation
Requires immediate and permanent IMP discontinuation
≥3xULN
<2xULN
No
Medical Monitor must be notified 
within 24 hours (eg, by laboratory 
alert) and study participant 
discussed with Medical Monitor 
ASAP.
Must have repeat liver 
chemistry values and 
additional testing 
completed ASAP (see 
Section 10.6.1.3);
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HCP.
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normalize, stabilize, or 
return to within baseline 
values. b
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NA
Yes
Hepatology consult. c
Medical Monitor must be notified 
within 24 hours (eg, by laboratory 
alert) and study participant 
discussed with Medical Monitor 
ASAP.
Monitoring of liver 
chemistry values required 
at least twice per week 
until values normalize, 
stabilize, or return to 
within baseline values. b
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≥2xULN d
NA
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; 
IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal
a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause).
b Unless an alternative monitoring schedule is agreed by the Investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
Investigator in consultation with the hepatologist (as applicable) and UCB responsible physician, as needed.
c Details provided in Section 10.6.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
d If the study participant also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 53 of 69
10.6.1.1
Consultation with Medical Monitor and local hepatologist 
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the study participant must be discussed with the Medical 
Monitor as soon as possible. If required, the study participant must also be discussed with the 
local hepatologist. The local hepatologist is the expert usually consulted by the treating physician 
for assessment and management of potential hepatic disease. This would usually be a 
hepatologist, but may be a gastroenterologist. If determined necessary, this discussion should be 
followed by a full hepatology assessment (see Section 10.6.1.3) and SAE report (if applicable).
10.6.1.2
Immediate action: determination of IMP discontinuation
All PDILI events require immediate action, testing, and monitoring. 
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and requires permanent IMP discontinuation (see Section 6.4.3 and Table 10-3
for details).
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. The Investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any medically 
required concomitant medication known to be hepatotoxic to a suitable alternative.
10.6.1.3
Testing: identification/exclusion of alternative etiology
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 10-4 (laboratory measurements) and Table 10-5 (additional information). Results of the 
laboratory measurements and information collected are to be submitted to the sponsor on the 
corresponding eCRF. If the medical history of the study participant indicates a requirement for 
other assessments not included below, these additional assessments should be completed and 
submitted, as applicable.
All blood samples should be stored, if possible. If tests are done locally for more rapid results, a 
concurrent sample must also be sent to the central laboratory.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 54 of 69
The following measurements are to be assessed:
Table 10-4: PDILI laboratory measurements 
Virology-
related
Hepatitis A IgM antibody
HBsAg
Hepatitis E IgM antibody
HBcAb-IgM
Hepatitis C RNA
Cytomegalovirus IgM antibody
Epstein-Barr viral capsid antigen IgM antibody (if unavailable, obtain heterophile 
antibody or monospot testing)
Immunology
Anti-nuclear antibody (qualitative and quantitative)
Anti-smooth muscle antibody (qualitative and quantitative)
Type 1 anti-liver kidney microsomal antibodies (qualitative and quantitative)
Hematology
Eosinophil count
Urinalysis
Toxicology screen
Chemistry
Amylase
If total bilirubin ≥1.5xULN, obtain fractionated bilirubin to obtain % direct bilirubin
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation
Additional
Prothrombin time/INR a
Serum pregnancy test
PK sample
ALT=alanine aminotransferase; CPK=creatine phosphokinase; HBcAb-IgM=hepatitis B core antibody-IgM; 
HBsAg=hepatitis B surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury; PK=pharmacokinetic; RNA=ribonucleic acid; 
ULN=upper limit of normal
a Measured only for study participants with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis 
or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 55 of 69
The following additional information is to be collected:
Table 10-5: PDILI information to be collected 
New or updated information
Concomitant prescription and over-the-counter medications (eg, acetaminophen, herbal remedies, 
vitamins); dosages and dates should be included.
Pertinent medical history, including the following:
x 
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty liver 
disease”)
x 
Adverse reactions to drugs
x 
Allergies
x 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)
x 
Recent travel 
x 
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, should 
not be used as an explanation for significant AST and/or ALT elevations.)
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash)
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function
Alcohol and illicit drug use
Results of liver imaging or liver biopsy, if done
Results of any specialist or hepatology consult, if done
Any postmortem/pathology reports
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury
10.6.1.4
Follow-up evaluation
Potential drug-induced liver injury events require follow-up monitoring as described in
Table 10-3. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to baseline. Determination of stabilization is at the discretion of the Investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed.
10.6.1.5
Optional hepatic investigation sample collection
If a study participant is undergoing further investigation for PDILI and has consented to 
retrospective genetic analysis per local regulations, the study participant’s blood sample will be 
shipped to a secure storage facility. The blood sample will be retained in the UCB Hepatic 
Investigation Biobank to solely support retrospective genetic analyses associated with an adverse 
therapeutic response to PSL.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 56 of 69
Genetic analyses of deoxyribonucleic acid isolated from the blood will be contracted by UCB to 
specialized third-party laboratories and analysis will be limited to:
x Uridine 5′-diphospho-glucuronosyltransferase loci − the loci responsible for Gilbert’s 
syndrome (hyperbilirubinemia)
x Human leukocyte antigen (HLA) loci − for example, HLA-B5701 that has been associated 
with abacavir- and flucloxacillin-induced liver injury
x Absorption, distribution, metabolism, and excretion gene loci associated with abnormal PK
Genetic analysis of samples may be performed immediately, on a per-study basis, or as part of 
combined analyses across multiple studies belonging to the same clinical development program. 
As a result, samples will be retained for 15 years unless clinical development of the IMP is 
terminated, at which point all samples will be destroyed. The results determined using clinically 
approved diagnostic tests will be made available to the Investigator upon request.
Study participants may request at any time that their sample be removed from the UCB Hepatic 
Investigation Biobank and destroyed, though data from analyses already performed will remain 
on file. All samples, associated materials, and data will be kept securely by UCB and its agents. 
A sample destruction request should be made in writing to the Investigator who will notify the 
UCB Biorepository Manager (Global Exploratory Development, UCB, Slough, SL1 3WE, 
United Kingdom).
10.7
Other safety measurements
Other safety measurements will include physical examinations, vital signs, 12-lead ECGs, and 
assessment of suicidality.
If deemed necessary by the Investigator, eg, in case of a suspicious AE, the Investigator can 
initiate additional/unscheduled laboratory testing, vital signs, ECGs, or other assessments for 
safety evaluation during the study.
10.7.1
Physical examination
Full physical examinations will be performed at the time points specified in Table 5-1. Full 
physical examinations will include cardiac and respiratory function via auscultation and review 
of the following body systems: general appearance; ear, nose, and throat; eyes; hair and skin; 
respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological; and mental 
status.
Height (study participant without shoes, and height rounded to the nearest 0.5cm) and body 
weight (study participant in underwear or light clothing, without shoes and rounded to the 
nearest 0.1kg) will be recorded at the Screening Visit and BMI will be derived (weight (kg)/ 
[height (m)]²).
10.7.2
Vital signs
Vital signs (PR, RR, SBP, DBP, and oral temperature) will be recorded at the time points shown 
in Table 5-1.
For the purposes of assessing the inclusion criterion, at the Screening Visit and the 
Baseline Visit, BP measurements will be performed in both supine and standing positions 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 57 of 69
according to the following procedure: Measure supine BP after the study participant has been 
lying down for 10 minutes, then ask the study participant to stand up and record the standing BP 
after 1 minute and 3 minutes. At all time points after the Baseline Visit, BP will only be 
measured in the supine position, ie, there will be no assessment for orthostatic hypotension.
By decision of the sponsor and the Investigator, the time points specified in Table 5-1 may be 
modified based on preliminary safety and PK assessments from previous doses tested in the 
study.
10.7.3
Standard 12-lead ECG
Triplicate standard 12-lead ECGs (RR interval, PR interval, QRS interval, QT, QTcB, and 
QTcF) will be recorded at times specified in Table 5-1, according to the following procedure: 
study participant lies in a supine position for ≥5 minutes; then a 12-lead ECG will be recorded in 
the same position. All ECG recordings will be performed in triplicate at 2- to 3-minute intervals. 
Electrocardiograms will be recorded at a speed of 25mm/s and with a calibration of 1cm/mV.
The purpose of the enhanced ECG monitoring procedures in this study is to match the observed 
ECG parameters with the contemporaneous plasma levels of PSL as closely as possible, at key 
time points during Day -1 (no exposure) and Day 8 (anticipated peak exposure). This will 
support an evaluation of any relationship between exposure to PSL and changes in key ECG 
parameters, most particularly QT intervals.
As specified in Table 5-1, a Baseline ECG series will be performed on Day -1. On this day, 
triplicate standard 12-lead ECGs will be performed for each of the following time points, 
intended to match as closely as possible the timing of the PK sampling series planned for Day 8:
0h, 30min, 1h, 2h, 3h, 6h and the pre-evening dose PK sample. On Day 8, a matching series of 
ECGs will be performed predose, 30min, 1h, 2h, 3h, and 6h after the morning dose of PSL, and 
approximately 30min before the evening dose, as close as possible to the time of the pre-evening 
dose PK sample. On Day 1 through Day 12, except Day 8, the triplicate standard 12-lead ECG 
will be performed prior to the morning dose of PSL, again timed to match as closely as possible 
to the time of the predose PK sample being taken. Care should be taken to record the timing of 
each ECG and PK sample as accurately as possible, to enable the precise evaluation of their 
temporal relationship.
By decision of the sponsor and the Investigator, the time points specified in Table 5-1 may be 
modified based on preliminary safety and PK assessments from the study.
The Investigator or designee will determine whether the results of the ECG are normal or 
abnormal. All important abnormalities should be reported. The original ECG tracing will be 
signed or initialed, and dated by the Investigator or designee, and will be retained at the clinical 
site as part of the Investigator’s Site File. The original electronic file of all ECG tracings will be 
transferred to UCB on completion of the study, or earlier, if required.
10.7.4
Assessment of suicidality
The C-SSRS will be completed at the scheduled time points presented in Table 5-1.
Suicidality will be assessed by trained study personnel using the C-SSRS (Posner et al, 2011). 
This scale will be used for screening as well as to assess suicidal ideation and behavior that may 
occur during the study. The Investigator’s decision about study participant continuation in the 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 58 of 69
study or study participant withdrawal from the study if the study participant has a positive 
response to the CSSRS Question 4, should be based on the benefit/risk balance for continuation 
or discontinuation of study treatment in view of the individual study participant circumstances, 
condition, attained efficacy, causality, alternative risk management options, etc.
If an additional visit (or unscheduled visit) is conducted due to safety or efficacy reasons, a 
C-SSRS assessment will be performed with the study participant during the visit. If an additional 
visit (or unscheduled visit) is conducted for reasons other than safety or efficacy concerns 
(eg, replacement of lost medication, repeated collection of a laboratory specimen due to 
collection or analysis issues), a C-SSRS will not be required at these visits.
Details of the case must be documented by the Investigator (Investigator or designee, not site 
staff conducting the C-SSRS) and provided to UCB via the SAE reporting process.
11
STUDY MANAGEMENT AND ADMINISTRATION
11.1
Adherence to protocol
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study participants from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IEC, or 
sponsor.
After implementation of such measure, the Investigator must notify the EPM of the sponsor 
within 24 hours and follow any local regulatory requirements.
11.2
Monitoring
Monitoring of the study will be delegated by UCB to a CRO. The CRO will monitor the study to 
meet the CRO’s monitoring SOPs, ICH-GCP guideline, and applicable regulatory requirements, 
and to ensure that study initiation, conduct, and closure are adequate.
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IEC review, and regulatory inspection(s).
The Investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records.
11.2.1
Definition of source data
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 59 of 69
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, or video, 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).
11.2.2
Source data verification
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, study participant files, recordings from automated instruments, tracings 
[ECG], x-ray films, laboratory notes). All data reported on the eCRF should be supported by 
source documents, unless otherwise specified in Section 11.2.1.
11.3
Data handling
11.3.1
Case Report form completion
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports.
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change.
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator.
The Investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the eCRF Completion Guidelines.
11.3.2
Database entry and reconciliation
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. Case Report form data are entered into the clinical database using independent, 
double-data entry, with the exception of comment fields, which are verified by a second person. 
The data are entered into the electronic CRFs once and are subsequently verified if the study is 
performed using electronic data capture.
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 60 of 69
11.3.3
Study Participant Screening and Enrollment log/Study Participant 
Identification Code list
The study participant’s screening and enrollment will be recorded in the Study Participant 
Screening and Enrollment Log.
The Investigator will keep a Study Participant Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each study participant.
The study participant’s consent and enrollment in the study must be recorded in the study 
participant’s medical record. These data should identify the study and document the dates of the 
study participant’s participation.
11.4
Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IEC should also be informed and provided with reason(s) for the termination 
or suspension by the sponsor or by the Investigator/institution, as specified by the applicable 
regulatory requirement(s). In addition, arrangements will be made for the return of all unused 
IMP/investigational device and other material in accordance with UCB procedures for the study.
11.5
Archiving and data retention
The Investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP/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 (Committee for Proprietary Medicinal 
Products [CPMP]/ICH/135/95, 2002 {Section 4.9.5}). The Investigator will contact UCB for 
authorization prior to the destruction of any study records or in the event of accidental loss or 
destruction of any study records. The Investigator will also notify UCB should he/she relocate or 
move the study-related files to a location other than that specified in the sponsor’s trial master 
file.
11.6
Audit and inspection
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 61 of 69
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
study participants enrolled have been protected, that enrolled study participants (ie, signing 
consent and undergoing study procedures) are appropriate for the study, and that all data relevant 
for the evaluation of the IMP/investigational device have been processed and reported in 
compliance with the planned arrangements, the protocol, investigational site, and IEC SOPs, ICH 
GCP, and applicable regulatory requirements.
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee).
11.7
Good Clinical Practice
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study.
12
STATISTICS
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan.
12.1
Definition of analysis sets
12.1.1
Enrolled Set
The Enrolled Set (ES) consists of all study participants who have signed the ICF.
12.1.2
Full Analysis Set
The Full Analysis Set (FAS) consists of all study participants who have signed the ICF form and 
received IMP. Analysis of this set will be according to the treatment the study participants 
actually received.
All safety analyses will be performed using the FAS. All safety variables will be summarized by 
treatment.
12.1.3
Pharmacokinetic Per-Protocol Set
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the FAS, consisting of those study 
participants who had no important protocol deviations (IPDs) affecting the PK parameters and 
for whom a sufficient number of samples are available to determine at least 1 PK parameter. The 
reasons for exclusion of study participants from the PK-PPS analysis set will be listed.
Data from study participants who experienced emesis during the course of the study might be 
excluded from the statistical analysis, depending on the time relative to the PK sampling and the
frequency of the event.
12.2
General statistical considerations
Summary statistics will be provided for all safety and Baseline/demographic variables. The 
datasets will follow the UCB analysis data model (ADaM) data specifications. All analyses will 
be performed using SAS® version 9.4 or later (SAS Institute, Cary, NC, USA). The PK 
noncompartmental analysis (NCA) will be performed using Pharsight Phoenix WinNonlin 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 62 of 69
version 6.3 (or higher). Categorical endpoints will be summarized using number of participants, 
frequency, and percentages. Missing data will not be imputed. For continuous variables, 
descriptive statistics (number of available observations, mean, median, standard deviation [SD], 
minimum, and maximum will be tabulated).
Baseline characteristics (gender, age, weight, height, BMI, body surface area) for the FAS will 
be summarized descriptively. Disease baseline characteristics will be also summarized for the 
FAS, including AED characteristics (name, dosage, frequency).
12.3
Planned pharmacokinetic analyses 
12.3.1
Analysis of the primary pharmacokinetic variables
Pharmacokinetics will be determined using the PK-PPS.
Pharmacokinetic parameters of PSL (Cmax, tmax, AUCτ, and CL/Fss) and metabolites 
(
 and 
; Cmax, tmax, AUCτ, and metabolite:parent ratio) will be 
estimated using NCA with Pharsight Phoenix® WinNonlin® v6.3 (or higher) software.
The individual plasma concentrations of venous PSL and its metabolites (
 and 
), and PK parameters of PSL and metabolites will be summarized by treatment 
group using descriptive statistics (number of observations [n], geometric mean, lower and upper 
95% confidence intervals [CI], geometric coefficient of variation [CV], arithmetic mean, SD, 
CV, median, minimum and maximum value) and graphical displays.
Pharmacokinetic parameters (Cmax, AUCτ) of PSL will be compared between the 2 treatment 
groups (Group 1 [Inducers] vs Group 2 [Neutral {control}]) using analysis of variance 
(ANOVA) on the log-transformed parameters and estimation of geometric ratio of PK 
parameters between the 2 groups with their 90% CI will be provided.
12.3.2
Analysis of the secondary pharmacokinetic variables
The individual plasma concentrations of PSL metabolites and PK parameters of PSL metabolites 
will be summarized by treatment group using descriptive statistics and graphical displays. 
Pharmacokinetic parameters (Cmax, AUCτ) of PSL metabolites will be compared between the 
2 treatment groups (Group 1 [Inducers] vs Group 2 [Neutral {control}]) using ANOVA on the 
log-transformed parameters and estimation of geometric ratio of PK parameters between the 
2 groups with their 90% CI will be provided.
12.3.3
Analysis of the exploratory pharmacokinetic variables
The PSL concentrations and PK parameters obtained from MITRA microsampling method will 
be summarized as those obtained from the venous sampling method (see Section 12.3.1) and 
compared with those of the conventional venous sampling method using descriptive analysis 
(tables with summary statistics and graphs).
12.4
Planned safety analyses
12.4.1
Adverse events
All safety analyses will be performed using the study participants in the FAS.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 63 of 69
All AEs will be coded using the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA®) and characterized as pretreatment and treatment-emergent according to 
the intake of PSL. A listing will be provided for the pretreatment and TEAEs.
The occurrence and incidence of AEs will be summarized by MedDRA SOC, Preferred Term, by 
group, and by characterization according to the intake of PSL (pretreatment or 
treatment-emergent). The occurrence and incidence of AEs will also be summarized by intensity 
and relationship to PSL. Adverse events leading to discontinuation and SAEs will also be 
summarized by group and by characterization according to the intake of PSL.
12.4.2
Laboratory measurements
Laboratory variables and changes from Baseline (Day -1) will be summarized at each time point 
by group. Shift tables from Baseline to each post-Baseline time point will be presented. Values 
outside the reference range will be flagged in the listings. The out-of-normal range values will be 
displayed.
12.4.3
Vital signs and ECGs
Vital sign variables (PR, RR, SBP, and DBP) and changes from Baseline (predose on Day 1) will 
be summarized at each time point by group. Frequency tables of values outside the normal 
ranges will be produced by treatment group and time point.
Electrocardiograms will be recorded 3 times at each time point. The individual mean at each time 
point will be calculated as raw parameters for descriptive analysis. The 12-lead ECG parameters 
(RR interval, PR interval, QRS interval, QT, QTcB, and QTcF) and change from Baseline 
(time-matched Baseline on Day -1) will be descriptively summarized at each time point by 
group. Baseline per time (0h, 0.5h, 1h, 2h, 3h, 6h) at Day -1 is defined as the value of the 
corresponding time-matched measurements of the ECG parameters. Frequency tables of values 
outside the normal ranges will be produced by group and time point.
12.4.4
Assessment of suicidality
The C-SSRS data will be listed by group.
12.4.5
Physical examinations
Physical examination abnormalities will be listed by group.
12.5
Handling of protocol deviations
Important protocol deviations are deviations from the protocol that potentially could have a 
meaningful impact on the primary objective of the study. The criteria for identifying such 
protocol deviations will be defined within the relevant protocol deviation specification 
document, which is part of the data cleaning plan. The IPDs will be reviewed as part of the 
ongoing data cleaning process and data evaluation. After all data have been 
verified/coded/entered into a database, a data evaluation meeting will be performed. The purpose 
of this review will be to check all protocol deviations and the quality of the data. The review will 
also help guide the decision how to manage problems in the study participants’ data 
(eg, withdrawals, dropouts, and protocol deviations).
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08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 64 of 69
Accepted deviations from theoretical time points will be described in the appropriate documents 
and included in the Study Master File. After the data review, resolution of all issues, and 
documentation of all decisions, the database will be locked.
12.6
Handling of dropouts or missing data
The methods for handling dropouts and missing data will be described in the Statistical Analysis 
Plan.
12.7
Planned interim analysis and data monitoring
There is no interim analysis planned for this study.
12.8
Determination of sample size
Considering the primary objective, and based on UP0002 (with PSL 400mg bid), the intersubject 
CV of AUCτ was estimated to be 50% (PSL).
Using an intersubject CV of 50%, a total sample size of 28 study participants (14 study 
participants per group) provides approximately 92% power for the detection of a 43% decrease 
in AUCτ of PSL with OXC vs without OXC (1.75-fold change: ratio of larger mean vs lower 
mean) at a significance level of α=0.05 (one-tailed test). Sample size computation was performed 
using Nquery Advisor® version 7.0.
A total of 28 adult study participants with epilepsy (14 study participants in Group 1 [Inducers] 
and 14 study participants in Group 2 [Neutral {control}]) are planned for enrollment in this 
study. This is deemed sufficient to meet the defined objectives.
13
ETHICS AND REGULATORY REQUIREMENTS
13.1
Informed consent
Study participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the study participant in both oral and written form by the 
Investigator (or designee). Each study participant will have the opportunity to discuss the study 
and its alternatives with the Investigator.
Prior to participation in the study, the ICF should be signed and personally dated by the study 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The study participant or his/her legal 
representative must receive a copy of the signed and dated ICF. As part of the consent process, 
each study participant must consent to direct access to his/her medical records for study-related 
monitoring, auditing, IEC review, and regulatory inspection.
If the ICF is amended during the study, the Investigator (or the sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IEC and use of the amended form.
The study participant may withdraw his/her consent to participate in the study at any time. A 
study participant is considered as enrolled in the study when he/she has signed the ICF. An eCRF 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 65 of 69
must not be started, nor may any study specific procedure be performed for a given study 
participant, without having obtained his/her written consent to participate in the study.
13.2
Study participant identification cards
Upon signing the Informed Consent and Assent form (as applicable), the study participant or 
legal representative will be provided with a study participant identification card in the language 
of the study participant. The Investigator will fill in the study participant identifying information 
and medical emergency contact information. The Investigator will instruct the study participant 
to keep the card with him/her at all times.
13.3
Independent Ethics Committees
The study will be conducted under the auspices of an IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration
of Helsinki.
The Investigator/UCB will ensure that an appropriately constituted IEC that complies with the 
requirements of the current ICH-GCP version or applicable country-specific regulations will be 
responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, 
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 IEC 
for its review and approval.
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IEC for the protocol.
The Investigator will also promptly report to the IEC all changes in the study, all unanticipated 
problems involving risks to human study participants or others, and any protocol deviations, to 
eliminate immediate hazards to study participants.
The Investigator will not make any changes in the study or study conduct without IEC approval, 
except where necessary to eliminate apparent immediate hazards to the study participants. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IEC as 
allowed.
As part of the IEC requirements for continuing review of approved studies, the Investigator will 
be responsible for submitting periodic progress reports to the IEC (based on IEC requirements), 
at intervals appropriate to the degree of study participant risk involved, but no less than once per 
year. The Investigator should provide a final report to the IEC following study completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IEC will also be informed by the Investigator or the sponsor, as specified by the 
applicable regulatory requirements in each concerned country. Where applicable, Investigators 
are to provide the sponsor (or its representative) with evidence of such IEC notification.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 66 of 69
13.4
Study participant privacy
UCB staff (or designee) will affirm and uphold the study participant’s confidentiality. 
Throughout this study, all data forwarded to UCB (or designee) will be identified only by the 
study participant number assigned at Screening.
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
study participant’s primary medical records that directly concerns this study (including, but not 
limited to, laboratory test result reports, ECG reports, admission/discharge summaries for 
hospital admissions occurring during a study participant’s study participation, and autopsy 
reports for deaths occurring during the study).
13.5
Protocol amendments
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective.
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IEC, and the regulatory authorities (if required), prior to being 
implemented.
14
FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable.
15
REFERENCES
Andreasen AH, Brøsen K, Damkier P. A comparative pharmacokinetic study in healthy 
volunteers of the effect of carbamazepine and oxcarbazepine on CYP3A4. Epilepsia. 
2007;48(3):490-6.
Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a 
European study. Epilepsia. 1997;38(3):353-62.
Choi H, Hamberger MJ, Munger Clary H, Loeb R, Onchiri FM, Baker G, et al. 
Seizure frequency and patient-centered outcome assessment in epilepsy. Epilepsia. 
2014;55(8):1205-12.
Clemens B. Forced normalisation precipitated by lamotrigine. Seizure. 2005;14(7):485-9.
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official 
report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-82.
Giussani G, Canelli V, Bianchi E, Franchi C, Nobili A, Erba G, Beghi E. A population-based 
study of active and drug-resistant epilepsies in Northern Italy. Epilepsy Behav. 2016;55:30-7.
Johannessen SI, Landmark CJ. Antiepileptic drug interactions – principles and clinical 
implications. Curr Neuropharmacol. 2010;8(3):254-67.
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 67 of 69
Jones DJ, Stehling LC, Zauder HL. Cardiovascular responses to diazepam and midazolam 
maleate in the dog. Anesthesiology. 1979;51:430-34.
Kaminski RM, Matagne A, Patsalos PN, Klitgaard H. Benefit of combination therapy in 
epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia. 
2009 Mar;50(3):387-97.
Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of 
refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.
Loganathan MA, Enja M, Lippmann S. Forced normalization: epilepsy and psychosis
interaction. Innov Clin Neurosci. 2015;12(5-6):38-41.
Picot MC, Baldy-Moulinier M, Daurès JP, Dujols P, Crespel A. The prevalence of epilepsy and 
pharmacoresistant epilepsy in adults: A population-based study in a Western European country. 
Epilepsia. 2008;49:1230–38.
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.
Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with 
carbamazepine. An update. Clin Pharmacokinet. 1996;31(3):198-214.
The Joint Epilepsy Council of the UK and Ireland. Epilepsy prevalence, incidence and other 
statistics. 2011.
World Health Organization. Epilepsy. Available from: 
http://www.who.int/mediacentre/factsheets/fs999/en/ [Accessed 23 May 2018].
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 68 of 69
16
DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements.
I will ensure that all subInvestigators and other staff members read and understand all aspects of
this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB.
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract.
Investigator:
Printed name
Date/Signature
REDACTED COPY 
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UCB
08 June 2018
Clinical Study Protocol
Padsevonil
UP0070
Confidential
Page 69 of 69
17
SPONSOR DECLARATION
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Approval Signatures
Name:
up0070-protocol
Version:
1. 0
Document Number:
CLIN-000121011
Title:
UP0070 Study Protocol
Approved Date:
12 Jun 2018
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Jun-2018 08:19:36 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Jun-2018 08:39:58 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Jun-2018 19:00:34 GMT+0000
DACTED 
REDA
DA
OPY
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SAP_001.pdf: 
UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 1 of 36
FINAL ANALYSIS
STATISTICAL ANALYSIS PLAN 
Study: UP0070
Product: Padsevonil



A MULTICENTER, OPEN-LABEL, PARALLEL-GROUP STUDY
IN STUDY PARTICIPANTS WITH EPILEPSY TO EVALUATE
THE EFFECT OF OXCARBAZEPINE ON THE
PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF 
PADSEVONIL




Confidentiality Statement
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, 
published, or otherwise used without the express permission of UCB.
SAP/Amendment Number
Date
SAP Version 1.0
26 Oct 2018
REDACTED COPY
ON
ON
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201
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NE
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 2 of 36
TABLE OF CONTENTS
LIST OF ABBREVIATIONS....................................................................................................5 
1 
INTRODUCTION .............................................................................................................8 
2 
PROTOCOL SUMMARY.................................................................................................8 
2.1 Study objectives.................................................................................................................8 
2.1.1 
Primary objective...................................................................................................8 
2.1.2 
Secondary objectives .............................................................................................8 
2.1.3 
Exploratory objectives...........................................................................................9 
2.2 Study variables...................................................................................................................9 
2.2.1 
Pharmacokinetic variables.....................................................................................9 
2.2.1.1 
Primary pharmacokinetic variables.............................................................9 
2.2.1.2 
Secondary pharmacokinetic variables.........................................................9 
2.2.1.3 
Other pharmacokinetic variables.................................................................9 
2.2.2 
Safety variables......................................................................................................9 
2.2.2.1 
Secondary safety variables ..........................................................................9 
2.2.2.2 
Other safety variables..................................................................................9 
2.3 Study design and conduct ................................................................................................10 
2.4 Determination of sample size...........................................................................................12 
3 
DATA ANALYSIS CONSIDERATIONS......................................................................12 
3.1 General presentation of summaries and analyses ............................................................12 
3.2 General study level definitions ........................................................................................14 
3.2.1 
Relative day .........................................................................................................14 
3.2.2 
Study periods .......................................................................................................14 
3.3 Definition of Baseline values...........................................................................................15 
3.4 Protocol deviations...........................................................................................................16 
3.5 Analysis sets.....................................................................................................................16 
3.5.1 
Enrolled Set .........................................................................................................16 
3.5.2 
Full Analysis Set..................................................................................................17 
3.5.3 
Pharmacokinetic-Per Protocol Set .......................................................................17 
3.6 Treatment assignment and treatment group.....................................................................17 
3.7 Center pooling strategy....................................................................................................18 
3.8 Coding dictionaries ..........................................................................................................18 
3.9 Changes to protocol-defined analyses..............................................................................18 
4 
STATISTICAL/ANALYTICAL ISSUES.......................................................................18 
4.1 Adjustments for covariates...............................................................................................18 
4.2 Handling of dropouts or missing data..............................................................................18 
4.2.1 
Pharmacokinetics.................................................................................................18 
4.2.2 
Safety laboratory data..........................................................................................19 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 3 of 36
4.2.3 
Electrocardiogram data........................................................................................19 
4.2.4 
Dates and times....................................................................................................19 
4.3 Handling of repeated and unscheduled measurements ....................................................21 
4.4 Handling of measurements obtained at the early withdrawal visit ..................................21 
4.5 Interim analyses and data monitoring..............................................................................21 
4.6 Multicenter studies...........................................................................................................21 
4.7 Multiple comparisons/multiplicity...................................................................................22 
4.8 Use of an efficacy subset of subjects ...............................................................................22 
4.9 Active-control studies intended to show equivalence......................................................22 
4.10 Examination of subgroups ...............................................................................................22 
5 
STUDY POPULATION CHARACTERISTICS.............................................................22 
5.1 Subject disposition...........................................................................................................22 
5.2 Protocol deviations...........................................................................................................23 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................23 
6.1 Demographics ..................................................................................................................23 
6.2 Other Baseline characteristics..........................................................................................24 
6.3 Medical history and concomitant diseases.......................................................................24 
6.4 Prior and concomitant medications..................................................................................24 
6.4.1 
Prior medication definition..................................................................................24 
6.4.2 
Concomitant medication definition .....................................................................24 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE...............................................24 
8 
EFFICACY ANALYSES ................................................................................................25 
9 
PHARMACOKINETICS.................................................................................................25 
9.1 Analysis of the primary pharmacokinetic variables.........................................................25 
9.2 Analysis of secondary pharmacokinetic variables...........................................................26 
9.3 Analysis of other pharmacokinetic variables...................................................................26 
10 SAFETY ANALYSES.....................................................................................................27 
10.1 Extent of exposure ...........................................................................................................27 
10.2 Adverse events.................................................................................................................28 
10.3 Clinical laboratory evaluations ........................................................................................29 
10.4 Vital signs, physical findings, and other observations related to safety ..........................31 
10.4.1 
Vital signs ............................................................................................................31 
10.4.2 
Electrocardiograms..............................................................................................31 
10.4.3 
Other safety variables ..........................................................................................32 
10.4.3.1 
Physical examination.................................................................................32 
10.4.3.2 
Columbia-Suicide Severity Rating Scale ..................................................33 
11 OTHER ANALYSES ......................................................................................................33 
12 REFERENCES ................................................................................................................34 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 4 of 36
13 APPENDICES .................................................................................................................35 
REDACTED COPY 
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26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 5 of 36
LIST OF ABBREVIATIONS
AE(s)
adverse event(s)
AED
antiepileptic drug
ALT
alanine aminotransferase
ALQ
above the limit of quantification
AST
aspartate aminotransferase
AUCτ
area under the curve over a dosing interval (12 hrs)
BID
twice daily
BLQ
below the limit of quantification
BMI
body mass index
BRV
brivaracetam
CI
confidence interval
CL/Fss
apparent total clearance at steady-state
Cmax
maximum observed plasma concentration
CRF
case report form
CRU
clinical research unit
CSR
clinical study report
CV
coefficient of variation
C-SSRS
Columbia-Suicide Severity Rating Scale
DEM
data evaluation meeting
ECG
electrocardiogram
EOS
End of Study
ES
Enrolled set
EudraCT
European Union Drug Regulating Authorities 
Clinical Trials
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 6 of 36
FAS
Full Analysis Set
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
LEV
levetiracetam
LLOQ
lower limit of quantification
LTG
lamotrigine
MedDRA
Medical Dictionary for Regulatory Activities
MHD
Mono Hydroxy Derivate
MW
Molecular Weight
n
number of subjects
number of available observations
OXC
oxcarbazepine
PK-PPS
Pharmacokinetic-Per Protocol Set
PK
Pharmacokinetic(s)
PR
pulse rate
PSL
padsevonil
PT
preferred term
QTcF
QT corrected for heart rate using Fridericia’s 
formula
RR
respiratory rate
SAE(s)
serious adverse event(s)
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 7 of 36
SAP
statistical analysis plan
SD
standard deviation
SFU
Safety Follow-up
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures and listings
tmax
time to maximum concentration
ULN
upper limit of normal
vs.
versus
WHODD
World Health Organization Drug Dictionary
REDACTED COPY 
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n Drug
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 8 of 36
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 UP0070. 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 Final protocol, dated 08 June 2018
Unless specified in the sections below, the study will be analyzed as described in the most recent 
version of the protocol. If a future protocol amendment necessitates a substantial change to the 
statistical analysis of the study data, this SAP will be amended accordingly. In addition, if
analysis definitions must be modified or updated prior to database lock, a SAP amendment will 
be required. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the CSR together with the 
associated rationale.
The content of this SAP is compatible with the International Council for Harmonisation 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips et al, 2003).
UCB is the Sponsor and ICON PLC is the Contract Research Organization (CRO) for this study.
2
PROTOCOL SUMMARY
2.1
Study objectives
2.1.1
Primary objective
The primary objective of this study is to evaluate the effect of stable coadministered 
oxcarbazepine (OXC) (as monotherapy or adjunctive therapy) on the pharmacokinetics (PK) of 
padsevonil (PSL) in study participants with epilepsy compared with study participants co-
medicated with stable doses of levetiracetam (LEV), lamotrigine (LTG), or brivaracetam (BRV) 
therapy.
2.1.2
Secondary objectives
The secondary objectives of this study are to:
x Evaluate the plasma concentrations of 10,11-dihydro-10-hydroxy-carbazepine (Mono
Hydroxy Derivate [MHD]; circulating metabolite of OXC) before, during and after 
administration of repeated doses of PSL.
x Evaluate the effect of stable coadministered OXC (as monotherapy or adjunctive therapy) on
the plasma PK of PSL metabolites, 
 and 
, in study
participants with epilepsy compared with study participants co-medicated with stable doses
of LEV, LTG or BRV therapy.
x Evaluate the safety and tolerability of PSL coadministered with stable OXC, LEV, LTG, or 
BRV therapy.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 9 of 36
2.1.3
Exploratory objectives
The exploratory objectives of this study are to:
x Evaluate the plasma concentrations of LTG, LEV and BRV before, during and after 
administration of repeated doses of PSL. (Blood samples for plasma concentrations of LEV, 
LTG and BRV will be collected and stored during the study; they will only be measured on 
an as-needed basis.)
x Evaluate and compare the venous blood and MITRA microsampling (dried blood) PK of PSL 
following administration of PSL in study participants with epilepsy on stable coadministered 
OXC compared with study participants co-medicated with stable doses of LEV, LTG or BRV 
therapy.
2.2
Study variables
2.2.1
Pharmacokinetic variables
2.2.1.1
Primary pharmacokinetic variables
The primary PK variables will be Cmax, tmax, AUCτ and CL/Fss obtained from the plasma
concentration-time profiles for PSL:
x Cmax: maximum observed plasma concentration
x tmax: time of maximum concentration
x AUCτ: area under the curve over a dosing interval (12 hours)
x CL/Fss: apparent total clearance at steady-state 
2.2.1.2
Secondary pharmacokinetic variables
The secondary PK variable will be the trough plasma concentration of MHD (OXC metabolite)
before, during and after dosing to steady state with PSL.
Additionally, secondary PK variables for PSL metabolites (
 and
) will be Cmax, tmax, AUCτ, and the ratio of metabolite to PSL based on AUCτ .
2.2.1.3
Other pharmacokinetic variables
The following other PK variables will be assessed during the study:
x Trough plasma concentrations of LEV, LTG or BRV before, during and after dosing to
steady state with PSL
x 
Plasma concentrations of PSL and metabolites in venous plasma and whole blood from 
MITRA microsampling (dried blood).
2.2.2
Safety variables
2.2.2.1
Secondary safety variables
The following secondary safety variables will be assessed during the study:
x Incidence of Adverse events (AEs) and Serious adverse events (SAEs)
2.2.2.2
Other safety variables
The following other safety variables will be assessed during the study:
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 10 of 36
x Changes in vital signs (pulse rate (PR), respiratory rate (RR), systolic blood pressure (SBP) 
and diastolic blood pressure (DBP))
x Changes in clinical laboratory test results (hematology, serum chemistry and urinalysis)
x Changes in 12-lead electrocardiogram (ECG) parameters
x Physical examination findings
2.3
Study design and conduct
This is a Phase 1, multicenter, open-label drug-drug interaction study in study participants with 
epilepsy, to evaluate the effect of OXC on the PK and safety and tolerability of PSL in 2
groups of 14 study participants each. A total of 28 participants will be evaluated in the following 
2 groups: 
x Group 1 (Inducers): study participants on stable therapy with OXC (at least 1200mg/day
either as monotherapy or adjunctive to LEV, LTG, or BRV). Oxcarbazepine may be used as
monotherapy (at least 7 study participants) or in combination with 1 or more of LEV, LTG,
or BRV. (For adjunctive therapy, the dosing of each AED in the combination [OXC+LEV,
OXC+BRV, or OXC+LTG] must be within the range used per label.) 
x Group 2 (Neutral [control]): study participants on stable therapy with LTG (at least
150mg/day monotherapy or adjunctive to LEV or BRV), LEV (at least 1g/day monotherapy
or adjunctive to LTG), or BRV (up to 200mg/day adjunctive to LTG). Lamotrigine or LEV
may be used as monotherapy (at least 7 study participants) or in combination with each 
other. Brivaracetam may only be used in combination with LTG. (For adjunctive therapy, 
the dosing of each AED in the combination [LTG+LEV or LTG+BRV] must be within the 
range used per label.) 
Padsevonil will be dosed to steady state (4.5 days) in both groups and the effect of background
therapy on PSL PK will be assessed at steady state. 
This study is planned to be conducted at sites in the Netherlands, Bulgaria and Germany (and 
potentially other countries in Europe).
The total duration of the study per study participant will be approximately 49 days (7 weeks)
with a maximum of 12 days treatment period.
The end of the study is defined as the date of the last visit of the last study participant in the
study.
The study consists of 3 periods: up to 28 days for the Screening Period, 12 days for Treatment 
Period and up to 9 days for the Safety Follow-up (SFU) Period.
The Screening Period consists of a single Screening Visit, which will be conducted within 28 
days prior to check-in for Treatment Period, and a Baseline Visit, which will be conducted one
day prior to Treatment Period. A sufficient number of study participants with epilepsy will be 
screened to ensure that 14 study participants are included in each group.
The Treatment Period consists of 3 days of dose titration (Day 1, Day 2, and Day 3), 4.5 days of
PSL maintained at a stable dose (Days 4 through 7 and the morning of Day 8), and 4.5 days of
dose taper (evening of Day 8 and Days 9 through 12).
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 11 of 36
The dose titration will start with an initial PSL dose of 100mg, twice daily (BID) on Day 1
followed by 200mg BID for the following 2 days (Day 2 and Day 3). PSL 400mg will then be 
maintained by oral administration BID on Day 4 through 7 and one dose on the morning of Day 
8.
A dose taper will be initiated on the evening of Day 8, when study participants will be
administered PSL 200mg. On Day 9 and Day 10, PSL 200mg BID will be administered. On
Day 11 and Day 12, PSL 100mg BID will be administered.
The SFU Period consists of an End of Study (EOS) Visit performed on Day 20 ± 1 after 
discharged on Day 13 or upon discontinuation of the study (SFU period maximum of 9 days).
The study schematic diagram for UP0070 is presented in
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 12 of 36
Figure 2‒1.
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 13 of 36
Figure 2‒1: Schematic diagram
bid=twice daily; BRV=brivaracetam; LEV=levetiracetam; LTG=lamotrigine; OXC=oxcarbazepine
PK=pharmacokinetic(s); PSL=padsevonil; SFU=Safety Follow-Up; T=Titration.
2.4
Determination of sample size
Considering the primary objective, and based on Study UP0002 (with PSL 400mg BID), the 
intersubject CV of AUCτ was estimated to be 50% (PSL).
Using an intersubject CV of 50%, a power of 92% for the detection of a 43% decrease in AUCτ 
of PSL with OXC vs. without OXC (1.75-fold change: ratio of larger mean vs. lower mean) at a 
significance level of α=0.05 (one-tailed test), the sample size calculation results in a total sample 
size of 28 study participants (14 study participants per groups). The sample size computation was 
performed using Nquery Advisor® version 7.0.
A total of 28 adult study participants with epilepsy (14 study participants in Group 1 [Inducers]
and 14 study participants in Group 2 [Neutral {control}]) are planned for enrolment in this study. 
3
DATA ANALYSIS CONSIDERATIONS
3.1
General presentation of summaries and analyses
Statistical evaluation will be performed by ICON PLC. The datasets will follow the UCB 
analysis data model (ADaM) data specifications.
All analyses will be performed using SAS version 9.4 or higher (SAS Institute, Cary, North 
Carolina, United States). The PK noncompartmental analysis (NCA) will be performed using 
Phoenix WinNonlin®v6.3 or higher (Certara L.P., Princeton, NJ, USA) for pharmacokinetics 
parameters estimation.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 14 of 36
Continuous variables will be summarized by treatment group, visit and timepoint (where 
applicable) including number of subjects (n), mean, standard deviation (SD), median, minimum, 
maximum and 95% confidence intervals (CI) for the mean where stated in the SAP. Geometric 
coefficient of variation (geoCV), geometric mean and 95% confidence interval (CI) for the 
geometric mean will also be presented in the descriptive statistics for the PK concentration data
for PSL and its metabolites (
 and 
), and PK parameters of 
PSL and metabolites. In all outputs the confidence limits will be restricted to the possible values 
that the variable can take.
Categorical variables will be summarized by treatment group, visit and time point (where 
applicable) with frequency counts and percentages. 
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
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 subjects in the respective analysis set and treatment group.
The MITRA samples will be obtained for Padsevonil and its metabolites only whereas venous 
plasma samples will be obtained for Padsevonil, its metabolites and the other antiepileptic drugs.
When reporting descriptive statistics, the following rules will apply in general except for PK 
concentration data (plasma and blood [MITRA] PK) of PSL and PSL metabolites
(
 and 
):
x n will be an integer
x Mean (arithmetic and geometric), SD and median will use 1 decimal place more, or 1 
significant figure more – depending on the reporting format of the original data – than the 
original data
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 subjects have data at a given time point, then only n=0 will be presented. If n<3, then 
only the n, minimum and maximum will be presented. If n=3, then only n, minimum, median
and maximum will be presented. The other descriptive statistics will be left blank.
When reporting individual values and descriptive statistics for PK concentration data (plasma 
and blood [MITRA] PK of PSL and PSL metabolites,
 and 
), the following rules will apply regarding rounding and precision:
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 15 of 36
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 SD.
The 95% CI for the geometric mean will use 1 decimal place more, or 1 significant figure 
more – depending on the reporting format of the original data – than the value around which 
the confidence interval is constructed
x Geometric CV will be reported as a percentage to 1 decimal place
When reporting individual values and descriptive statistics for PK parameters (plasma and blood 
[MITRA] PK of PSL and PSL metabolites (
 and 
), and 
parent to metabolite ratio) 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 SD and to 3 for the others
Data listings containing all documented data and all derived data will be generated.
3.2
General study level definitions
3.2.1
Relative day
The relative day of an event will be derived with the date of first dose of investigational 
medicinal product (IMP), here PSL as reference. 
Relative days for an event or measurement occurring before the date of first dose are calculated 
as follows:
ܴ݈݁ܽݐ݅ݒ݁ܦܽݕൌܧݒ݁݊ݐܦܽݐ݁െܦܽݐ݁݋݂ܨ݅ݎݏݐܦ݋ݏ݁
The relative day for an event or measurement occurring on the date of first dose is 1. The relative 
day for an event or measurement occurring on or after the reference date to the date of the last 
dose will be calculated as follows:
ܴ݈݁ܽݐ݅ݒ݁ܦܽݕൌሺܧݒ݁݊ݐܦܽݐ݁െܦܽݐ݁݋݂ܦ݋ݏ݅݊݃ሻ൅ͳ
For events or measurements occurring after the date of last dose, relative day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows:
ܴ݈݁ܽݐ݅ݒ݁ܦܽݕൌ൅ሺܧݒ݁݊ݐܦܽݐ݁െܦܽݐ݁݋݂ܮܽݏݐܦ݋ݏ݁ሻ
There is no relative Day 0. Relative day will not be calculated for partial dates in cases where 
relative day is shown in a subject data listing. In such cases, relative day should be presented as 
‘--‘ in the relevant subject data listing.
3.2.2
Study periods
For each subject completing the study, the expected maximum duration of participation will be 
approximately 49 days with a maximum of 12 days exposure to investigational product, and will 
consist of the following periods:
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 16 of 36
x Screening Period (Day -28 to Day -2)
The Screening Period consists of a single Screening Visit, which will be conducted at the unit 
within 28 days prior to check-in for Treatment Period, and a Baseline Visit, which will be 
conducted at the clinical research unit (CRU) 1 day prior to Treatment Period. Study 
participants will check-in at the CRU on Day -1.
x Treatment Period (Day 1 to Day 12)
The Treatment Period consists of 3 days of dose titration (Day 1, Day 2, and Day 3), 4.5 days 
of PSL maintained at a stable dose (Days 4 through 7 and the morning of Day 8), and 
4.5 days of dose taper (evening of Day 8 and Days 9 through 12). Details are given in Table 
3-2.
x The SFU Period consists of an End of Study (EOS) Visit performed on Day 20 ± 1 after 
discharged on Day 13 or upon discontinuation of the study.
The end of the study is defined as the date of the last visit of the last subject in the study.
3.3
Definition of Baseline values
In general, Baseline will be the last non-missing value prior to dosing. Scheduled or unscheduled 
measurements can be used as the Baseline value.
Measurement-specific Baseline timepoints are presented in Table 3‒1.
Table 3‒1:
Definition of Baseline
Measurement
Definition of Baseline
x 
Hematology, serum 
chemistry, urinalysis
Baseline or if missing the Screening value
x 
Vital signs
Predose of treatment period.
Treatment Period predose Day 1 or if missing Day -1.  If Day -1 is 
missing the Screening value will be used. 
Otherwise baseline = Day -1 predose
x 
ECG
Time matched baseline at Day-1 at predose, 0.5h, 1h, 2h, 3h and 6h post
morning dose of PSL on Day 1 and 0.5h predose of evening dose of 
PSL.
x 
C-SSRS
Separate baseline questionnaire for C-SSRS. 
ECG=electrocardiogram; C-SSRS= Columbia-Suicide Severity Rating Scale
If a measurement is repeated at Baseline or a given treatment period and is obtained prior to
dosing in that treatment group, then the last available measurement will be used as the Baseline 
value.
12-lead ECG will be measured in triplicate with a 2 to 3-minute interval between replicates.
Mean of the last three measurements predose will be taken as the baseline; if less than three 
replicates are available predose, the mean of the available replicates (predose) will be taken as 
the baseline. Time matched predose values are defined as the Baseline value (see Table 3‒1).
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 17 of 36
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:
ܲ݋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 the key safety and PK outcomes for an individual 
subject. The criteria for identifying such protocol deviations will be defined within the protocol 
deviation specifications document. 
Important protocol deviations will include the following categories:
x Inclusion/exclusion criteria deviations
x Administration of prohibited concomitant medications
x Deviations relating to withdrawal criteria
x Visit schedule deviations
x Study drug administration deviations (including incorrect treatment received, handling and 
storage deviations and incorrect dosage received) and any vomiting episode(s) (that could 
impact PK concentrations)
x Procedural noncompliance
x Missing data 
All IPDs will be reviewed as part of the ongoing data cleaning process and data evaluation. After 
all data have been verified/coded/entered into a database, a data evaluation meeting (DEM) will 
be performed. 
At least one DEM will be performed at the following time:
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, define the analysis 
sets, and check the quality of the data. The reviews will also help decide how to manage 
problems in the subjects’ data (eg, missing values, withdrawals and protocol deviations).
Accepted deviations from scheduled time points will be described in the appropriate documents 
and included in the Study Master File. After the pre-analysis review, resolution of all issues, and 
documentation of all decisions (including inclusion into each of the analysis sets) at the final 
DEM, the database will be locked.
3.5
Analysis sets
3.5.1
Enrolled Set
The Enrolled Set (ES) consists of all study participants who have signed the Informed Consent 
form (ICF).
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 18 of 36
3.5.2
Full Analysis Set
The Full Analysis Set (FAS) consists of all study participants who have signed the ICF and 
received at least 1 dose of investigational medicinal product (IMP). Analysis of this set will be 
according to the treatment the study participants actually received. All safety analyses will be 
performed using the FAS. All safety variables will be summarized by treatment.
Adverse Events will be displayed for all subjects including SF.
3.5.3
Pharmacokinetic-Per Protocol Set
The Pharmacokinetic-Per Protocol Set (PK-PPS) is a subset of the FAS, consisting of study 
participants who had no IPD affecting the PK parameters and for whom a sufficient number of 
samples are available to determine at least one PK parameter.
All PK analyses will be performed using the PK-PPS.
3.6
Treatment assignment and treatment group
All study participants will complete the different fixed-doses or combination multiple-dose 
treatments as per antiepileptic drugs (AEDs) treatment schedule including at least 7 days of 
monotherapy with AEDs. Padsevonil will be administered orally with 8oz (240 mL) water, 30 
minutes after a light or standard meal for the morning dose and 30 minutes after a standard meal 
for the evening dose, according to Table 3-2. Listings will be presented by subject and treatment
group (screening, treatment period and SFU). Summaries will be presented by treatment group
(Group 1 (Inducer) and Group 2 (Neutral [control])), unless stated otherwise.
x PSL + OXC
Group 1 (Inducer)
PSL
Group 2 (Neutral [control])
PK summaries will be presented as follows:
x PSL
Treatment Period and SFU
x PSL + OXC
Treatment Period and SFU
x LEV, LTG, BRV
Screening, treatment period and SFU.
Table 3‒2: Padsevonil administration
Day
Morning dose
Evening dose
1 (Ti1)
100mg
100mg
2 (Ti2)
200mg
200mg
3 (Ti3)
200mg
200mg
4-7 (M1-M4)
400mg
400mg
8 (M5/Ta1)
400mg
200mg
9 (Ta2)
200mg
200mg
10 (Ta3)
200mg
200mg
11 (Ta4)
100mg
100mg
12 (Ta5)
100mg
100mg
Abbreviations: M=Maintenance; Ta=Taper; Ti=Titration
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 19 of 36
3.7
Center pooling strategy
The data from the different centers will be pooled. The statistical analyses will not be performed by 
center.
3.8
Coding dictionaries
Adverse events and medical history will be coded using the latest available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®) (Version v 21.0). Medications will be 
coded according to the World Health Organization Drug Dictionary (WHODD) (Version 
SEP/2017). Medical procedures will not be coded.
3.9
Changes to protocol-defined analyses
The protocol states that MITRA dried blood microsampling method will be compared to those of 
the plasma conventional venous sampling method using descriptive analysis (tables with 
summary statistics and graphs). Nonetheless, as described in Section 9.3, the exploratory analysis 
will also be described using linear mixed effects model.
4
STATISTICAL/ANALYTICAL ISSUES
4.1
Adjustments for covariates
Not applicable.
4.2
Handling of dropouts or missing data
In general, there will be no imputation of missing data unless otherwise stated below.
Missing data will be handled as described in the sections below for safety laboratory and PK 
results. No other imputations will be performed. 
4.2.1
Pharmacokinetics
The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geometric CV) is 0.Measurements of PK concentrations that are below the limit of 
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 SD 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 
“LLOQ/2” for linear scale plots.
The following rules will apply for PK data listings and summaries:
x Values below the LLOQ will be reported as “(BLQ)” in the listings
x Descriptive statistics of plasma and dried blood concentrations will be calculated if more 
than 2/3rd of individual data points are quantifiable (>=LLOQ) at the given time-point. 
Values that are BLQ will be replaced by the numerical value of the LLOQ/2 in this instance. 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 20 of 36
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.
x For tmax, only N, median, minimum and maximum will be displayed into the summary 
statistics, 
x For plasma concentrations, all BLQ values occurring prior to tmax will be replaced by 
“LLOQ/2”, except for embedded BLQ values (between two measurable data points) which 
will be treated as missing. Post-tmax, BLQ values will be treated as missing. The 
Pharmacokinetic analysis will be performed in accordance to the Guideline on performing 
NCA analysis dated 08 Nov 2017. 
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 “LLOQ/2” for 
linear scale plots.
x If no subjects 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 SD is the standard 
deviation from the log-transformed data:
Geometric CV (%) = sqrt[(exp (SD^2) – 1)] x 100
4.2.2
Safety laboratory data
The rules for handling values that are BLQ or above the limit of quantification (ALQ) in the
safety laboratory data will be the same as those described for PK data in Section 4.2.1.
4.2.3
Electrocardiogram data
For the 12-lead ECG data, all calculations of changes from Baseline and descriptive statistics 
will be based on the mean of the triplicate assessments at each timepoint. In the event that there 
are not 3 available measurements at a given timepoint, the mean will be calculated based on the 
number of measurements for which data are provided.
4.2.4
Dates and times
Partial dates may be imputed for the following reasons:
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
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 21 of 36
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 
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 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 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 22 of 36
Table 4-1:
Calculation rules for duration of adverse events
Data availability
Onset 
date/time
Outcome 
date/time
Calculation rules
Start day and time 
missing
--/--
D2/T2
Duration = [(D2 – D0)*24 + (T2 – T0)]/24 d
For a subject in the FAS, D0 and T0 are the date 
and time of first administration of study 
medication and for screen failures, D0 is the date 
of the screening visit and T0 = 00:00h
End day and time 
missing 
D1/T1
--/--
If the stop date is missing, duration will not be 
calculated.
Start and end date 
missing
--/--
--/--
If the stop date is missing, duration will not be 
calculated.
FAS=full analysis set; PSL=padsevonil.
4.3
Handling of repeated and unscheduled measurements
All repeated and unscheduled measurements will be presented in the data listings, where 
applicable. The following general rules will apply to all repeated and unscheduled 
measurements:
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 Early Withdrawal (EW) visit will be assigned
to the EOS Visit (Section 4.4) and analyzed accordingly as an EOS Visit.
4.4
Handling of measurements obtained at the early withdrawal 
visit
Study participants who withdraw early from the study for any reason, including those withdrawn 
from study medication, will be asked to return for the EOS Visit 7 to 9 days after last intake of 
study medication and will then enter the SFU Period and will undergo the same assessments 
performed at the EOS Visit.
4.5
Interim analyses and data monitoring
Not applicable.
4.6
Multicenter studies
This study is planned to be conducted at sites in Netherlands, Bulgaria and Germany (and 
potentially other countries in Europe). However, there is no plan to explore sites effect in the 
analysis.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 23 of 36
4.7
Multiple comparisons/multiplicity
Not applicable.
4.8
Use of an efficacy subset of subjects
Not applicable.
4.9
Active-control studies intended to show equivalence
Not applicable.
4.10
Examination of subgroups
Not applicable.
5
STUDY POPULATION CHARACTERISTICS
5.1
Subject disposition
The number of participants who were enrolled into the study, participants who completed or 
prematurely discontinued the study, as well as the reason for discontinuation will be summarized 
for all participants, based on the ES. A participant who completed the study is defined as a study 
participant who completed all visits up to and including the SFU.
The number and percentage of study participants who discontinued due to AEs will be 
summarized separately for all study participants, based on the ES. This will be used for European 
Union Drug Regulating Authorities Clinical Trials (EudraCT) reporting.
The number and percentage of study participants included in each of the analysis sets will be 
summarized for all participants and for each treatment group based on the ES. Percentages will
be calculated based on the ES for the purpose of this summary.
Screen failure reasons will be summarized for the ES. A listing of subjects who did not meet 
study eligibility criteria will also be presented for the ES.
In addition, the following listings will be presented:
x Subject disposition (ES)
x Study discontinuation (FAS)
x Visit dates (FAS)
x Subject analysis sets (ES)
The listing of subject disposition will include the date of informed consent, date and time of first
and last dose of study medication, date of premature termination and primary reason (if 
applicable) and date of final contact.
The listing of study discontinuation will include the reason for discontinuation and the number of 
days on study medication.
The number of days on study medication will be calculated as follows:
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 24 of 36
ܰݑܾ݉݁ݎ݋݂ܦܽݕݏ݋݊ݏݐݑ݀ݕ݉݁݀݅ܿܽݐ݅݋݊
ൌሺܦܽݐ݁݋݂ܮܽݏݐܦ݋ݏ݁ܴ݁ܿ݁݅ݒ݁݀െܦܽݐ݁݋݂ܨ݅ݎݏݐܦ݋ݏ݁ܴ݁ܿ݁݅ݒ݁݀ሻ൅ͳ
5.2
Protocol deviations
Important protocol deviations will be identified and classified by the deviation types in the IPD 
document.
A listing of all IPDs identified at the DEM will be presented for all subjects based on the FAS
and will include the deviation type and description. The number and percentage of subjects in the 
FAS with IPDs will be summarized for all subjects, for each treatment period and for each 
deviation type. The denominator for the percentages will be the number of subjects in the FAS.
6
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
6.1
Demographics
A by-subject (study participant) listing of demographics will be presented based on the ES. This 
will include the date of birth, age (in years), sex, race, ethnicity, height (in cm), weight (in kg) 
body mass index (BMI, in kg/m2). The body weight will be the measurement obtained at 
Screening.
Body mass index (kg/m2) is calculated based on the height (in m) and the weight (in kg) using 
the following formula:
BMI (kg/m2) = weight (kg)/[height (m)]2
The BMI will be reported to 1 decimal place.
All demographic characteristics (except for date of birth) will be summarized for all participants
based on the FAS. The summary of age will include descriptive statistics and categorical 
summaries, the latter based on requirements for European Union Drug Regulating Authorities 
Clinical Trials (EudraCT) and clinicaltrials.gov reporting.
For the EudraCT reporting, the categories will include:
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
Disease baseline characteristics will be also summarized for the FAS, including AED 
characteristics (name, dosage, frequency).
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 25 of 36
6.2
Other Baseline characteristics
Lifestyle information (alcohol, tobacco, illicit drug use and caffeinated beverage use), C-SSRS 
and Epilepsy characteristics (duration of epilepsy, seizure clusters history, status epilepticus 
history, seizure types) at Baseline will be listed and summarized for all participants in the FAS.
6.3
Medical history and concomitant diseases
Medical history will be listed and summarized (in an incidence table) for the FAS for all 
participants, by MedDRA system organ class (SOC) and preferred term (PT). The reported term 
will be included in the listing. The summary will include the number and percentage of study 
participant, and will be sorted alphabetically by SOC and by descending incidence of PT within 
each SOC, based on the ‘All Subjects’ column. 
Procedure history will be listed separately by the procedure reported term based on the FAS. 
Concomitant medical procedures occurring during the study will be listed for the FAS.
6.4
Prior and concomitant medications
Prior and concomitant medications will be listed and summarized separately for AED and non 
AED medications, for all participants in the FAS, by WHODD Anatomical Main Group [Level 1 
term text], Pharmacological Subgroup [Level 3 term text] and PT. The reported term will be 
included in the listing. Separate tabulations will be presented for prior medications and 
concomitant medications. Prior medications which continued into the treatment period will also 
be classified as concomitant and will be included in both summaries. Concomitant medications 
will be described for all participants and for each treatment group based on the FAS.
All tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term within 
Level 1 and decreasing frequency of PT in the ‘All Subjects’ column.
6.4.1
Prior medication definition
Prior medications include any medications that started prior to the date of first dose of PSL. This
includes medications that started prior to the first dose of PSL and continued after.
6.4.2
Concomitant medication definition
Concomitant medications are medications taken at least one day in common with the study IMP 
(after first dosing with PSL) and/or during the Safety Follow-Up Period. 
If a medication is started prior to PSL administration and stopped after, that medication will be 
classified as both prior and concomitant.
Any medications with missing dates and/or times will be handled as described in Section 4.2.4 to
classify them as prior or concomitant.
7
MEASUREMENTS OF TREATMENT COMPLIANCE
Administration of PSL will be performed under the supervision of the Investigator (or designee) 
and the Investigator (or designee) will check the study participant’s hands and the oral cavity 
immediately after dosing to confirm ingestion of the study medication. Compliance will be 
monitored by drug accountability and by drug assay for PSL (using the drug concentration in the 
blood/plasma). Compliance with the study medication is defined as consumption by the study 
participant that confirms 100% with the planned dosage.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 26 of 36
Drug administration/consumption will be recorded and any discrepancies with the dosing 
regimen will be explained. Dosing deviations will be included in the listing of IPDs where 
applicable.
No formal calculations of compliance will be presented as all study medication is administered 
on site.
8
EFFICACY ANALYSES
Not applicable.
9
PHARMACOKINETICS
The calculation of the PK parameters of PSL and its metabolites (
and 
 for both plasma conventional venous and MITRA dried blood) will be 
performed by the Quantitative Clinical Development Department, ICON PLC. All PK TFLs will 
be produced by ICON PLC SAS programming (Early Phase).
Pharmacokinetic concentrations and PK parameters will be summarized by treatment i.e. PSL 
with OXC (Group 1) and without OXC (Group 2), using the PK-PPS and listed on the FAS by 
treatment and study participants. Figures of summaries will be based on the PK-PPS and figures 
of individual concentrations will be based on the FAS.
Pharmacokinetic parameters of PSL and metabolites (
and
for both plasma conventional venous and MITRA dried blood) will be calculated using the actual 
blood sampling times.
9.1
Analysis of the primary pharmacokinetic variables
Individual plasma concentrations of PSL (from conventional venous sampling and MITRA 
microsampling) will be listed by treatment group and will include the actual and nominal 
sampling times and the deviation between them. All deviations will be calculated relative to the 
first dose of study medication. Any samples that are obtained outside the tolerance window 
permitted at the specified time point will be discussed at the DEM and any possible exclusion 
from analysis will be documented accordingly. The primary PK variables in plasma used for PSL
and metabolites (
 and 
) are: Cmax, tmax, and AUCτ. In 
addition, CL/Fss will be evaluated for PSL only. Cmax and tmax will be determined from the 
observed concentration and time data. When two or more identical peak concentrations are 
observed, tmax will be defined as the time of the first occurrence. AUCW will be computed using 
the linear trapezoidal rule.
The PK plasma and dried blood concentrations and the primary PK parameters of PSL and its 
metabolites from plasma and dried blood will be summarized by treatment group and nominal 
sampling times using descriptive statistics (number of available observations [n], arithmetic
mean, median, SD, minimum, maximum, geometric mean, geometric CV and 95% CI for the 
geometric mean [assuming lognormally distributed data]). Values below the LLOQ will be 
reported with a clear sign (flag variable in the dataset) indicating that they were below the 
LLOQ.
Individual participant concentration-time profiles of PSL, from conventional venous sampling 
and MITRA microsampling will be displayed graphically in linear and semi-logarithmic scale.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 27 of 36
Combined individual (spaghetti) plots will be displayed by treatment group with all participants
overlaid on the same plot (linear and semi-logarithmic scale).
Geometric mean profiles of plasma concentrations for PSL over time will be presented, with all 
treatment group overlaid on the same plot, in both linear and semi-logarithmic scale. For the 
linear scale plot only, the lower and upper 95% confidence interval (CI) for the geometric mean 
will be displayed.
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times.
The primary comparison of interest is the similarity of plasma PK parameters (Cmax and AUCτ)
for PSL between treatment group with OXC (Treatment Group 1) and PSL without OXC
(Treatment Group 2). Pharmacokinetic parameters (Cmax and AUCτ) of PSL will be compared 
between the 2 treatment groups (Group 1 [Inducers] vs. Group 2 [Neutral {control}]) using 
analysis of variance (ANOVA) with treatment group fitted as fixed effects. Point estimates for 
the ratio of geometric means with and without OXC (Group 1 [Inducers] vs Group 2 [Neutral 
{control}])) and the respective 2-sided 90% CIs will be computed using the least squares means 
and the root mean squares of error from the mixed effects model, based on the log-transformed 
data with subsequent exponential transformation. Additional exploratory analyses may be 
conducted using subgroups of the 2 treatment groups (monotherapy subgroups, adjunctive 
subgroups).
9.2
Analysis of secondary pharmacokinetic variables
Pharmacokinetic parameters (Cmax, AUCτ) of PSL metabolites will be compared between the
2 treatment groups (Group 1 [Inducers] vs Group 2 [Neutral {control}]) using analysis of 
variance (ANOVA) on the log-transformed parameters.
The ANOVA model described in Section 9.1 will be applied for the PK variables (Cmax, and
AUCτ ) for the two PSL metabolites (
and 
) in plasma
(conventional venous sampling). Point estimates for the ratio of geometric means and the 
respective 2-sided 90% CIs will be computed using the least squares means and the root mean 
squares of error from the mixed effects model, based on the log-transformed data with 
subsequent exponential transformation for the same comparisons than those described in Section 
9.1.
Additionally, Cmax, tmax, AUCτ, for PSL metabolites (
 and
) and the ratio of metabolite to PSL based on AUCτ will be summarized descriptively. 
Metabolite to parent ratios will be corrected for molecular weight. The molecular weight (MW) 
of PSL is 432.8, the MW of metabolite 
is 419, the MW of metabolite 
 is 433. All secondary variables including trough plasma concentration of 
MHD (OXC metabolite) before, during, and after dosing to steady state with PSL will also be 
listed.
9.3
Analysis of other pharmacokinetic variables
The other PK parameters and their analysis are the following:
x The blood concentrations and blood PK variables for PSL and its metabolite based on the 
MITRA microsampling will be summarized and plotted as described in Section 9.1.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 28 of 36
x The PSL concentrations and PK parameters obtained from MITRA microsampling method 
will be summarized as those obtained from the venous sampling method and compared with 
those of the conventional venous sampling method using descriptive analysis (tables with 
summary statistics and graphs).
x As exploratory analysis, point estimates for the ratio of geometric means for the PK 
parameters Cmax, and AUCτ for PSL based on the MITRA microsampling compared to the 
plasma conventional venous sampling along with the 2-sided 90% CIs will be computed 
using the least squares means and the root mean squares of error from a specific linear mixed
effects model, based on of the log-transformed data with subsequent exponential 
transformation for the following: 
◦ 
Overall: conventional venous compared to MITRA
x Scatter plots of the MITRA dried blood concentrations versus venous plasma concentrations 
for PSL and its metabolite will be presented. The correlation between two measurements 
(conventional vs. MITRA) of PSL and its metabolites concentration will be evaluated using 
linear regression, considering conventional sample concentration as independent variable and 
MITRA sample concentration as dependent variable. Furthermore a Bland-Altman plot of the
differences in concentration between MITRA dried blood and venous plasma vs. true 
measurement (average of MITRA dried blood with venous plasma) concentrations for PSL 
and its metabolite including regression line and its 90% confidence intervals will be 
presented for the log transformed data.
x The predose trough concentrations for both plasma conventional venous and MITRA dried 
blood sampling methods will be listed separately. The trough PSL concentrations will be 
summarized by treatment group and day. Geometric mean along with their 95% CI for the 
trough concentrations will be plotted against time.
x Trough plasma concentrations of LEV, LTG, or BRV before, during, and after dosing to 
steady state with PSL
10
SAFETY ANALYSES
All safety summaries and listings will be performed using the FAS. Unless stated otherwise, all 
summaries including figures will be presented by treatment group (Group 1 and Group 2) as 
detailed in the shells for figures (Table 13-1)Table 13-1. Summaries for continuous variables by 
timepoint will be based on the averaged value across the treatment group. Categorical variables 
will be summarized according to the actual group (no pooling). 
10.1
Extent of exposure
All study medication administration details will be listed by treatment group and study 
participant. The listing will include the date and time of administration of the morning and 
evening dose, depending on the treatment group, (either PSL and/ or OXC) and total daily dose
of both medications.
Exposure data will be listed only.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 29 of 36
10.2
Adverse events
All AEs will be coded using the MedDRA® and characterized as pre-treatment and treatment-
emergent according to the intake of the study medication. Adverse events with a start date prior 
to the first dose of study medication will be defined as pre-treatment AEs. A treatment-emergent 
AE (TEAE) is defined as any AE with a start date/time on or after the first dose of study 
medication or any unresolved event already present before administration of study medication 
that worsens in intensity following exposure to the treatment. Where dates are missing or 
partially missing, AEs will be assumed to be treatment-emergent, unless there is clear evidence 
to suggest that the AE started prior to the first dose of study medication. Missing or partially 
missing dates for AEs will be handled as described in Section 4.2.4.
Adverse events will be attributed to the treatment group in which they start. Thus, all AEs 
starting after the first intake of PSL through Day 12 will be attributed to Treatment group AEs
and AE starting more than 168 hours post last dose of PSL will be attributed to the SFU period.
All AEs will be recorded in the Case Report form (CRF) from the time of informed consent until 
study completion or termination. All AEs will be coded (see Section 3.8) and categorized by 
intensity (mild/moderate/severe) and relationship (related/not related) to study drug PSL as 
judged by the Investigator.
The number and percentage of participants who experience TEAEs will be summarized by 
MedDRA SOC, PT, by treatment group and by characterization according to the intake of PSL.  
The occurrence and incidence of AEs will also be summarized by intensity and relationship to 
PSL. Adverse events leading to discontinuation and SAEs will also be summarized by treatment 
group and by characterization according to the intake of PSL.
Summaries of TEAEs will include the following:
x Incidence of TEAEs (overview including number and percentage of subjects with any 
TEAEs, serious TEAEs, discontinuations due to TEAEs, drug-related TEAEs, severe TEAEs 
and TEAEs leading to death; event counts will also be included)
x Incidence of TEAEs
x Incidence of serious TEAEs
x Incidence of non-serious TEAEs
x Incidence of TEAEs by relationship
x Incidence of TEAEs by maximum relationship
x Incidence of TEAEs by maximum intensity
x Incidence of fatal TEAEs by relationship
x Incidence of non-serious TEAEs by relationship
x Incidence of serious TEAEs by relationship
Summary tables will contain counts of study participant, percentages of study participants in
parentheses and the number of events where applicable. A participant who has multiple events in 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 30 of 36
the same SOC and PT during a given treatment will be counted only once in the participant
counts for that treatment group but all events will be included.
In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Participants who experience the same event multiple times will be included in 
the most related category for tabulations by maximum relationship. Events with missing 
relationship will be considered as ‘Related’ but recorded as missing in the listings. 
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in 
the listings.
Adverse event summaries will be ordered alphabetically by SOC and decreasing frequency of PT 
within SOC in the group column for tables including event counts. For tables including only 
number and percentage of study participants, summaries will be ordered alphabetically by SOC 
and decreasing incidence of PT within SOC in the group column.
A listing for all AEs will be presented by study participant, treatment group and will include the 
onset date/time and outcome date/time of the event (including relative days), the AE duration 
(derived), time to onset (derived), pattern of event, intensity, relationship, action taken and 
outcome. In addition, the listing will flag AEs that led to discontinuation, TEAEs and SAEs.
10.3
Clinical laboratory evaluations
Laboratory data (clinical chemistry, hematology and urinalysis) and changes from Baseline (if 
applicable) for numeric variables will be listed by study participants, parameter, treatment group
and timepoint. Any laboratory measurements that are BLQ or ALQ will be handled as described 
in Section 4.2.2. Values outside the reference range for numeric variables will be flagged in the 
listings and in addition, will be listed separately. The reference ranges will also be reported in the 
listings. 
A separate listing will present the 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 Alkaline phosphatase ≥2xULN
x Total bilirubin increase ≥2xULN
The listing will display only group and time points for which at least one of the above criteria 
was fulfilled for a given subject, and will display all results obtained in that group or at time 
point for the specified variables.
A summary of participants who meet the criteria for potential drug-induced liver injury (PDILI) 
will be presented together with any additional relevant data collected, if applicable.
Clinical chemistry and hematology parameters will be summarized by treatment group and time
point for both absolute values and changes from Baseline.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 31 of 36
Laboratory variables will be grouped according to the laboratory function panel (Table 10-1) and 
categorized as normal, high or low, if applicable, based on the reference range supplied by the 
analytical laboratory. For selected variables that are identified in Table 10-1 the change in 
category from Baseline will be presented in shift table at all post-Baseline time points.
Any additional laboratory variables not included in the outputs described previously will be 
listed separately. These will include the following:
x Serology
x Alcohol breath test
x Serum pregnancy test (for women of childbearing potential)
x Urine toxicology screen
Figures of mean and mean change from Baseline may be presented for selected laboratory 
variables that will be identified at the DEM. Figures will be presented with all treatment periods
overlaid on the same plot.
Table 10-1: Laboratory measurements
Laboratory assessment
Parameters
Hematology
Hemoglobina, hematocrit, red blood cell counta, mean 
corpuscular volume, plateletsa, total white blood cell count, 
and differential consisting of absolute counts and percentages 
of the following leukocyte types: neutrophilsa, lymphocytesa,
monocytes, eosinophils, and basophils
Biochemistry
Sodium, potassium, calcium, inorganic phosphorous, glucose 
(fasting, only at Screening), ureaa, creatininea, total bilirubin 
(conjugated bilirubin when total bilirubin is outside the 
reference range), total protein, albumin, ALTa, ASTa, and 
ALPa
Viral serology (only at Screening 
Visit)
HIV-1/2Ab, HBsAg and HCV-Ab
Pregnancy (only at Screening Visit)
Serum pregnancy test 
Hormone tests (only at Screening 
Visit)
Follicle-stimulating hormone (to confirm postmenopausal 
status in female study participants)
Urinalysis
Specific gravity, pH, glucose, protein, blood, leukocytes, 
nitrite, ketones, bilirubin, urobilinogen (with dipstick)
If protein, blood, or leukocytes are abnormal (positive), a 
microscopic examination of the sediment will be performed.
Drug screen
Amphetamines/methamphetamines, benzodiazepines, 
barbiturates, cocaine, cannabis, methadone, tricyclic 
antidepressants and opiates
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 32 of 36
Laboratory assessment
Parameters
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBsAG=hepatitis 
B surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibodies; 
SFU=Safety Follow-Up
a Shift tables will be presented for these variables
10.4
Vital signs, physical findings, and other observations related to 
safety
10.4.1
Vital signs
The following vital signs measurements will be obtained with the study participants resting in the 
supine position for 10 minutes at all timepoint after the Baseline Visit:
x Systolic and diastolic blood pressure
x Pulse rate
x Oral body temperature
x Respiratory rate
A by- participant listing of all vital sign measurements and change from Baseline will be 
presented by treatment group and timepoint.
Descriptive statistics will be reported for all vital sign measurements. Measured values and 
changes from Baseline will be summarized by vital signs variables and timepoint for each 
treatment group.
The number and percentage of study participants with treatment-emergent markedly abnormal 
(TEMA)/potentially clinically significant (PCS) vital sign values as calculated by the criteria 
outlined in Table 10‒2 will be summarized by treatment group at each timepoint.
Table 10‒2: TEMA/PCS criteria for vital signs
Variable
Unit
Low
a
Higha
Systolic blood pressure
mmHg
Value <90 and ≥20 decrease 
from Baseline
Value >140 and ≥20 increase 
from Baseline
Diastolic blood pressure
mmHg
Value <50 and ≥15 decrease 
from Baseline
Value >90 and ≥15 increase 
from Baseline
Pulse rate
bpm
Value <45 and ≥15 decrease 
from Baseline
Value >90 and ≥15 increase 
from Baseline
bpm=beats per minute; PCS=potentially clinically significant; TEMA=treatment-emergent markedly abnormal.
a Both conditions must be satisfied for a measurement to be considered potentially clinically significant.
10.4.2
Electrocardiograms 
12-lead ECG will be recorded 3 times at each time point. The individual mean at each time point 
will be calculated as raw parameters for descriptive analysis. The individual mean and change 
from baseline (time-matched Baseline on Day -1 of each treatment, when applicable) will be 
summarized using descriptive statistics by treatment group at each time point.
All standard 12-lead ECG recordings will be taken in triplicate with the subject resting in the 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 33 of 36
supine position for at least 5 minutes. The following ECG parameters will be reported:
x PR interval 
x QT interval
x QRS interval
x RR 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- participant listings. The listing will also include the change from Baseline (time-matched
Baseline day of each treatment group, where applicable), based on the mean of the triplicate 
measurements at each timepoint, and will be presented by treatment group and timepoint.
Measured values and changes from time-matched Baseline will be summarized by treatment 
group, at each timepoint and by ECG variable (based on the mean of the triplicate values at each 
timepoint). The mean change for ECG parameter will also be displayed graphically.
The following cut-points in QTcF (observed data and change from time-matched Baseline),
based on the mean of the triplicate data, will be summarized categorically (number and 
percentage of participants) by treatment group at each timepoint.
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 timepoint will be handled as described in 
Section 4.2.3.
10.4.3
Other safety variables
10.4.3.1
Physical examination
Subjects with abnormalities in the physical examination will be listed including details of the 
abnormality.
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 34 of 36
10.4.3.2
Columbia-Suicide Severity Rating Scale
Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al, 2011) data will be listed.
Module of the questionnaire, time point, question and the associated response will be listed for 
all the visit days where this questionnaire is collected.
11
OTHER ANALYSES 
A listing of comments will be presented.
REDACTED COPY 
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UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 35 of 36
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
REDACTED COPY 
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thereof. 


UCB
26 Oct 2018
Statistical Analysis Plan
Padsevonil
UP0070
Confidential
Page 36 of 36
13
APPENDICES
Table 13-1: Breakdown of treatment groups reported into the TFLs by study 
assessment data
Treatment
Group 1
(Inducers)
Group 2
(Neutral 
[control])
All subjects
Subject disposition
X
X
X
Protocol deviations
X
X
Demographics
X
Medical history
X
Lifestyle
X
Prior medications
X
Concomitant medications
X
X
X
Adverse Events
X
X
Laboratory tests
X
X
Other safety continuous measurements (vital 
signs, ECG)
X
X
Safety categorical results (laboratory shift 
tables, PDILI)
X
X
PK plasma and dried blood for PSL and 
metabolites
X
X
ECG=electrocardiogram; EOS=end of study; PK=pharmacokinetic; PSL=Padsevonil; SFU=Safety Follow-up.
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Approval Signatures
Name:
UP0070-SAP-v1.0_26OCT2018
Version:
1. 0
Document Number:
CLIN-000127368
Title:
UP0070 Statistical Analysis Plan
Approved Date:
06 Nov 2018
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 26-Oct-2018 15:38:56 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 29-Oct-2018 09:13:27 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 06-Nov-2018 16:18:37 GMT+0000
DACTED 
REDA
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OPY
App
App
CO
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