Double-blind, Randomized, Placebo-controlled Study of the Efficacy, Safety/Tolerability, and Pharmacokinetic Profile of UCB0942 in Adults With Highly Drug-resistant Focal Epilepsy.
Phase: PHASE2
Conditions: Highly Drug-resistant Focal Epilepsy
Sponsor: UCB Biopharma S.P.R.L.

UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 1 of 125
PROTOCOL EP0069 AMENDMENT 4.0
A DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY OF THE EFFICACY, 
SAFETY/TOLERABILITY, AND PHARMACOKINETIC 
PROFILE OF UCB0942 IN ADULT PATIENTS WITH HIGHLY 
DRUG-RESISTANT FOCAL EPILEPSY
PHASE 2A
EudraCT Number: 2014-003330-12
Sponsor:
UCB Biopharma SPRL
Allée de la Recherche 60
B-1070 Brussels
BELGIUM
Protocol/Amendment number
Date
Type of 
amendment
Final Protocol
18 Mar 2015
Not applicable
Protocol Amendment 0.1 (
27 Jul 2015
Nonsubstantial
Protocol Amendment 1.0
16 Sep 2015
Substantial
Protocol Amendment 2.0
19 Nov 2015
Substantial
Protocol Amendment 3.0
13 May 2016
Substantial
Protocol Amendment 4.0
10 Oct 2016
Nonsubstantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB.
REDACTED 
mber
mber
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 2 of 125
STUDY CONTACT INFORMATION
Sponsor
UCB Biopharma SPRL
Allée de la Recherche 60
B-1070 Brussels
BELGIUM
Coordinating Investigator
Name:
Prof. 
Affiliation:
Address:
Phone:
Coordinating Investigator 
Name:
Prof. Dr. 
Affiliation:
Address:
Phone:
Early Development Lead/New Medicines Therapeutic Area Specialist
Name:
, MD
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
Sponsor Study Physician
Name:
, MD
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 3 of 125
Exploratory Project Manager
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
Clinical Trial Biostatistician
Name:
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Phone:
Clinical Monitoring Contract Research Organization
Name:
PRA Health Sciences
Address:
Phone:
Fax:
REDACTED 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 4 of 125
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World: +32 2 386 24 21
Email
Global: DSICT@ucb.com (for interventional clinical studies)
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 5 of 125
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................10
1
SUMMARY.....................................................................................................................13
2
INTRODUCTION ...........................................................................................................14
2.1
General background...............................................................................................14
2.2
Phase 1 experience.................................................................................................16
2.2.1
Adverse event profile...................................................................................16
2.2.2
Psychiatric adverse events ...........................................................................16
2.2.3
Drug-drug interactions.................................................................................17
2.3
Rationale for this study..........................................................................................17
3
STUDY OBJECTIVES....................................................................................................17
3.1
Primary objective...................................................................................................17
3.2
Secondary objectives .............................................................................................17
3.3
Exploratory objectives ...........................................................................................17
4
STUDY VARIABLES.....................................................................................................18
4.1
Efficacy variables...................................................................................................18
4.1.1
Primary efficacy variable.............................................................................18
4.1.2
Secondary efficacy variables .......................................................................18
4.1.3
Exploratory efficacy variables.....................................................................18
4.2
Pharmacokinetic variables .....................................................................................18
4.3
Exploratory variables.............................................................................................19
4.4
Safety variables......................................................................................................20
5
STUDY DESIGN.............................................................................................................21
5.1
Study description ...................................................................................................21
5.1.1
Study duration per subject ...........................................................................23
5.1.2
Planned number of subjects and sites ..........................................................23
5.1.3
Anticipated regions and countries................................................................23
5.2
Schedule of study assessments...............................................................................24
5.3
Schematic diagram.................................................................................................34
5.4
Rationale for study design and selection of dose...................................................34
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................35
6.1
Inclusion criteria ....................................................................................................35
6.2
Exclusion criteria ...................................................................................................36
6.3
Withdrawal criteria ................................................................................................38
6.3.1
Potential drug-induced liver injury IMP discontinuation criteria................40
7
STUDY TREATMENTS.................................................................................................41
7.1
Description of investigational medicinal products ................................................41
7.2
Treatments to be administered...............................................................................41
7.2.1
Test study medication..................................................................................41
7.2.2
Reference product........................................................................................41
7.3
Packaging...............................................................................................................41
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 6 of 125
7.4
Labeling .................................................................................................................42
7.5
Handling and storage requirements .......................................................................42
7.6
Drug accountability................................................................................................42
7.7
Procedures for monitoring subject compliance......................................................43
7.8
Concomitant medications/treatments.....................................................................43
7.8.1
Permitted concomitant treatments (medications and therapies) ..................43
7.8.2
Prohibited concomitant treatments (medications and therapies) .................43
7.8.3
Rescue medication.......................................................................................43
7.9
Blinding..................................................................................................................44
7.9.1
Procedures for maintaining and breaking the treatment blind.....................44
7.9.1.1
Maintenance of study treatment blind................................................44
7.9.1.2
Breaking the treatment blind in an emergency situation....................44
7.9.1.3
Breaking the treatment blind for taper of dose during the study .......44
7.10
Randomization and numbering of subjects............................................................44
8
STUDY PROCEDURES BY VISIT ...............................................................................45
8.1
Screening and Baseline Period...............................................................................45
8.1.1
Screening (Visit 1, Day -1)..........................................................................45
8.1.2
Baseline Period (Visit 2, Day BL1 to BL14-21) .........................................46
8.2
Inpatient Period (3 weeks) .....................................................................................46
8.2.1
Titration Week (Visit 3, Day T1 to Day T7) ...............................................46
8.2.2
Maintenance-Dose Week (Visit 4, Day MD1 to Day MD7) .......................47
8.2.3
Transition-to-Outpatient Week (Visit 5, Day TTO1 to Day TTO7)............48
8.3
Outpatient Period (14 weeks).................................................................................49
8.3.1
Outpatient Maintenance Period (Visit 6 to Visit 15, Day OP1 to Day 
OP57)...........................................................................................................49
8.3.2
Taper Period (Visit 15 to Visit 17, Day OP57 to TOO14) ..........................51
8.3.3
Safety Follow-Up (Visit 18 to 20, Day SFU7, SFU14, and SFU28)...........52
8.3.4
Echocardiography follow up........................................................................52
8.4
Withdrawal Visit....................................................................................................52
8.5
Unscheduled Visit..................................................................................................53
8.6
Open-label extension study (EP0073) ...................................................................53
9
ASSESSMENT OF EFFICACY......................................................................................53
9.1
Seizure frequency...................................................................................................53
9.1.1
Video monitoring.........................................................................................54
9.2
Seizure Severity Questionnaire..............................................................................54
9.3
Quality of Life Inventory in Epilepsy-31-P...........................................................54
9.4
Diary Addendum....................................................................................................55
10
ASSESSMENT OF PK AND EXPLORATORY VARIABLES ....................................55
10.1
Pharmacokinetic parameters..................................................................................55
10.2
Exploratory parameters..........................................................................................55
10.3
Sampling procedures..............................................................................................56
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 7 of 125
10.4
Bioanalytical methods............................................................................................56
10.5
Pharmacokinetic/pharmacodynamic relationships.................................................56
11
ASSESSMENT OF SAFETY..........................................................................................56
11.1
Adverse events.......................................................................................................56
11.1.1
Definition of adverse event..........................................................................56
11.1.2
Procedures for reporting and recording adverse events...............................57
11.1.3
Description of adverse events......................................................................57
11.1.4
Follow up of adverse events ........................................................................57
11.1.5
Rule for repetition of an adverse event........................................................57
11.1.6
Pregnancy.....................................................................................................57
11.1.7
Overdose of investigational medicinal product ...........................................58
11.1.8
Safety signal detection.................................................................................58
11.1.9
Safety Review Group...................................................................................59
11.2
Serious adverse events...........................................................................................59
11.2.1
Definition of serious adverse event .............................................................59
11.2.2
Procedures for reporting serious adverse events..........................................60
11.2.3
Follow up of serious adverse events............................................................61
11.3
Adverse events of special interest..........................................................................61
11.4
Immediate reporting of adverse events..................................................................61
11.5
Anticipated serious adverse events........................................................................61
11.6
Laboratory measurements......................................................................................62
11.6.1
Evaluation of PDILI.....................................................................................62
11.6.1.1
Consultation with the Medical Monitor and local hepatologist.........66
11.6.1.2
Immediate action: determination of IMP discontinuation .................66
11.6.1.3
Testing: identification/exclusion of alternative etiology ...................66
11.6.1.4
Follow-up evaluation .........................................................................68
11.7
Other safety measurements....................................................................................68
11.7.1
Vital signs ....................................................................................................68
11.7.2
Electrocardiograms ......................................................................................68
11.7.3
Echocardiograms .........................................................................................69
11.7.4
Physical examination...................................................................................69
11.7.5
Assessment of suicidality.............................................................................69
11.7.6
Psychiatric and cognitive assessments.........................................................70
11.7.7
Withdrawal monitoring................................................................................70
12
STUDY MANAGEMENT AND ADMINISTRATION.................................................70
12.1
Adherence to protocol............................................................................................70
12.2
Monitoring .............................................................................................................70
12.2.1
Definition of source data..............................................................................70
12.2.2
Source data verification ...............................................................................71
12.3
Data handling.........................................................................................................71
12.3.1
Case Report form completion......................................................................71
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 8 of 125
12.3.2
Database entry and reconciliation................................................................71
12.3.3
Database lock...............................................................................................71
12.3.4
Subject Screening and Enrollment log/Subject Identification Code list......72
12.4
Termination of the study........................................................................................72
12.5
Archiving and data retention..................................................................................72
12.6
Audit and inspection ..............................................................................................72
12.7
Good Clinical Practice...........................................................................................73
13
STATISTICS ...................................................................................................................73
13.1
Definition of analysis sets......................................................................................73
13.2
General statistical considerations...........................................................................74
13.3
Planned efficacy analyses ......................................................................................74
13.3.1
Analysis of the primary efficacy variable....................................................74
13.3.2
Secondary efficacy analyses ........................................................................74
13.3.3
Exploratory efficacy analyses......................................................................75
13.4
Planned safety and population PK analyses...........................................................75
13.4.1
Safety analyses.............................................................................................75
13.4.2
PK analyses..................................................................................................76
13.4.2.1
Non-compartmental PK analysis .......................................................76
13.4.2.2
Population PK analysis ......................................................................76
13.4.2.3
Population PK-PD analysis................................................................76
13.5
Handling of protocol deviations.............................................................................77
13.6
Handling of dropouts or missing data....................................................................77
13.7
Planned interim analyses and data monitoring ......................................................77
13.8
Determination of sample size.................................................................................78
14
ETHICS AND REGULATORY REQUIREMENTS......................................................78
14.1
Informed consent ...................................................................................................78
14.2
Subject identification cards....................................................................................79
14.3
Subject compensation ............................................................................................79
14.4
Independent Ethics Committees ............................................................................79
14.5
Subject privacy.......................................................................................................80
14.6
Protocol amendments.............................................................................................80
15
FINANCE, INSURANCE, AND PUBLICATION.........................................................80
16
REFERENCES ................................................................................................................81
17
APPENDICES .................................................................................................................82
17.1
Protocol Amendment 1.0 .......................................................................................82
17.2
Protocol Amendment 2.0 .......................................................................................91
17.3
Protocol Amendment 3.0 .......................................................................................94
17.4
Protocol Amendment 4.0 .....................................................................................118
18
DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................122
19
DECLARATION AND SIGNATURE OF COORDINATING INVESTIGATOR 
(
).................................................................................................................123
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 9 of 125
20
DECLARATION AND SIGNATURE OF COORDINATING INVESTIGATOR......124
21
SPONSOR DECLARATION ........................................................................................125
LIST OF TABLES
Table 5‒1: Dose titration to UCB0942 400mg bid.................................................................22
Table 5‒2: Taper from UCB0942 400mg bid to UCB0942 200mg bid .................................22
Table 5‒3: Dose taper from UCB0942 400mg bid.................................................................23
Table 5-4: Schedule of study assessments .............................................................................25
Table 5‒5: Schedule of study assessments, Inpatient Period..................................................31
Table 7‒1: Description of investigational medicinal product.................................................41
Table 11‒1:
Anticipated SAEs for the epilepsy population.............................................61
Table 11‒2:
Laboratory measurements............................................................................62
Table 11‒3:
Required investigations and follow up for PDILI .......................................64
Table 11‒4:
PDILI laboratory measurements..................................................................67
Table 11‒5:
PDILI information to be collected...............................................................68
LIST OF FIGURES
Figure 5‒1: Study design..........................................................................................................34
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 10 of 125
LIST OF ABBREVIATIONS
50%RR
50% responder rate
75%RR
75% responder rate
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
BPRS
Brief Psychiatric Rating Scale
BRV
brivaracetam
BUN
blood urea nitrogen
cBZR
benzodiazepine-binding site
CDMS
clinical data management system
CI
confidence interval
CIWA-B
Clinical Institute Withdrawal Assessment-Benzodiazepines
CNS
central nervous system
CPMP
Committee for Proprietary Medicinal Products
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
CV
coefficient of variation
CYP
cytochrome P450
DAP
data analysis plan
DNA
deoxyribonucleic acid
DS
Drug Safety
ECG
electrocardiogram
eCRF
electronic Case Report form
EEG
electroencephalogram
EPM
Exploratory Project Manager
ES
Enrolled Set
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 11 of 125
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
Full Analysis Set
GABA-A
gamma-aminobutyric acid receptor type A
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HCV-Ab
hepatitis C antibody
HIV-1/2Ab
human immunodeficiency virus-1/2 antibody
ICF
Informed Consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy 
IMP
investigational medicinal product
IRT
interactive response technology
LEV
levetiracetam
MedDRA
Medical Dictionary for Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMSE
mini-mental state examination
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
NCA
non-compartmental analysis
OLE
open-label extension
PDILI
potential drug-induced liver injury
PI
Principal Investigator
PK
pharmacokinetic(s)
PPS
Per-Protocol Set
QOLIE-31-P
Quality of Life Inventory in Epilepsy-31-P
QTcB
QT interval corrected for heart rate using Bazett’s formula
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RS
Randomized Set
SAE
serious adverse event
SD
standard deviation
SFU
Safety Follow Up
SAP
Statistical Analysis Plan
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euro
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 12 of 125
SOP
Standard Operating Procedure
SRG
Safety Review Group
SS
Safety Set
SSQ
Seizure Severity Questionnaire
SV2
synaptic vesicle glycoprotein 2 (also known as SV2A)
ULN
upper limit of normal
VNS
vagus nerve stimulation
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 13 of 125
1
SUMMARY
UCB0942 is a new chemical entity with selective affinity for synaptic vesicle glycoprotein 2 
(SV2) and for the benzodiazepine-binding site (cBZR) on the gamma-aminobutyric acid 
receptor type A (GABA-A). UCB0942 has shown superior efficacy in several preclinical 
models of epilepsy.
EP0069 is a Phase 2A, double-blind, randomized, placebo-controlled, multicenter study that 
will test the potential efficacy, safety/tolerability, and pharmacokinetic (PK) profile of 
UCB0942 in adult subjects with highly drug-resistant focal epilepsy. Randomization will be 
in a 1:1 ratio. 
The primary objective of the study is to evaluate the efficacy of UCB0942 administered 
concomitantly with each subject’s current, stable antiepileptic drug (AED) regimen in 
subjects who have 4 or more focal seizures with or without secondary generalization per 
week and who have failed to achieve seizure control with ≥4 AED regimens of adequate dose 
and duration. In this protocol, unless otherwise specified, “focal seizures” refers to partial-
onset seizures of type IA1, IB, and IC, but does not include type IA2, IA3, or IA4 seizures.
The secondary objectives are to evaluate the safety and tolerability of UCB0942 and to 
evaluate the steady-state PK of UCB0942 and its metabolites.
This study consists of:
!
A 4-week prescreening Historical Baseline Period for study eligibility purposes
!
A Screening Visit followed by a 2- to 3-week postscreening Prospective Outpatient 
Baseline Period (Day BL1 to Day BL14-21)
!
A 3-week Inpatient Period which consists of:
∀
An Inpatient Titration Week (Day T1 to Day T7)
∀
An Inpatient Maintenance-Dose Week (Day MD1 to Day MD7)
∀
An Inpatient Transition-to-Outpatient Week (Day TTO1 to Day TTO7)
!
An open-label Outpatient Maintenance Period of 8 weeks (Day OP1 to Day OP57)
!
A Tapering Period of 2 weeks (Day TOO1 to Day TOO14)
!
A Safety Follow-Up (SFU) Period of 4 weeks (Day SFU1 to Day SFU28)
!
An echocardiogram during dosing and after the last dose (the SFU7 echocardiogram). 
The echocardiogram will be repeated at 6 months (±1 month) after the last dose in the 
following subjects:
∀
Subjects who complete this study but do not enter the OLE study
∀
Subjects who withdraw from the Outpatient Period 
∀
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 
echocardiogram
Titration to UCB0942 400mg bid will occur over the course of 1 week in the clinical unit. 
For subjects in the active arm, doses will be titrated to UCB0942 400mg bid during the first 
inpatient week. For subjects who initially received placebo, doses will be titrated to 
UCB0942 400mg bid during the last week of the Inpatient Period. Dose reductions will be 
allowed during titration and maintenance in the Inpatient Period, but this should be discussed 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 14 of 125
with the Sponsor Study Physician unless this is not possible due to the circumstances. 
Multiple adjustments (tapering or increase) of the dose are allowed during the Outpatient 
Maintenance Period (minimum 100mg bid and maximum 400mg bid); however, any change 
of dose in the Outpatient Maintenance Period should first be discussed with the Sponsor 
Study Physician.
The total duration for subject participation in the study will be up to 20 weeks, plus an
echocardiographic follow-up visit 6 months after the last dose of study medication. The total 
duration of exposure to UCB0942 is 13 weeks in EP0069. Subjects who experience 
substantial benefit from UCB0942 with acceptable tolerability according to the subject and 
Investigator, will have the opportunity to continue taking UCB0942 in an open-label 
extension (OLE) study. Each subject’s decision to enter the OLE study will be in 
consultation with their neurologist and taking into account the potential risks and benefits of 
continuing to take UCB0942 and the potential risks and benefits of other treatment options. 
Subjects who enter the OLE study will not have a Tapering Period at the end of the 
Outpatient Maintenance Period. The OLE study is described in a separate protocol (EP0073).
The primary efficacy measure is the 75% responder rate (75%RR, proportion of subjects who 
achieve ≥75% reduction in focal seizure frequency) during the Inpatient Period compared to 
the 2-week Prospective Outpatient Baseline Period.
Secondary efficacy variables include:
!
Median percent reduction in weekly focal seizure frequency from the Prospective
Outpatient Baseline Period to the Inpatient Period and the End of Treatment.
!
Seizure-free rate during the Inpatient Period, the last 4 weeks of the Outpatient
Maintenance Period, and at the End of Treatment.
!
The 75%RR during the last 4 weeks of the Outpatient Maintenance Period and at the End
of Treatment.
!
Percentage of seizure-free days during the Inpatient and Outpatient Periods.
The exploratory efficacy variables are detailed in Section 4.1.3.
Plasma concentrations of UCB0942, and its identified metabolites 
, will be determined from blood samples obtained in the study in order to 
investigate the PK of UCB0942 and its major metabolites.
Blood samples for deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), and 
lipidomics/proteomics/additional blood biomarkers will be collected during the study for 
exploratory biomarker studies.
The safety of participating subjects will be closely monitored. Assessment of specific 
domains of psychiatric and cognitive symptoms will be performed by a staff member trained 
in the identification of psychiatric symptoms.
Other safety variables are detailed in Section 4.4.
2
INTRODUCTION
2.1
General background
In Europe and North America there are 350,000 to 500,000 (3 to 4 million worldwide) 
patients with focal epilepsy who have not been able to achieve freedom from disabling 
seizures despite sequential and/or combination treatment with several of the available AEDs. 
Despite the introduction of 12 new AEDs over the last 2 decades, the proportion of patients 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 15 of 125
with epilepsy who are unable to achieve complete control of their seizures has only decreased 
minimally, from 36% to 34% (Brodie et al, 2012), highlighting the large unmet medical need 
and the fact that recently-developed AEDs have not been able to meet this medical need. 
Patients with focal epilepsy who have failed to achieve seizure control with 2 or more AED 
regimens are defined as drug-resistant by the International League Against Epilepsy (ILAE; 
Kwan et al, 2010). It is important to highlight that there is a continuum of degrees of drug 
resistance within the patient population classified as drug-resistant according to ILAE 
criteria. When a patient with focal epilepsy has failed to achieve seizure freedom after the 
second AED regimen, he or she has less than 10% chance of achieving complete seizure 
control with subsequent AED regimens (Steinhoff, 2014; Beyenburg et al, 2012; Chung et al, 
2010; Schiller and Najjar, 2008; Mohanraj and Brodie, 2006). The likelihood of achieving 
complete seizure control diminishes as the number of failed AED regimens increases. Thus, 
when a patient with focal epilepsy has not been able to control their seizures despite 
treatment with 5 or more AED regimens, the likelihood of achieving complete seizure control 
with another AED regimen is 1-6% (Schiller and Najjar, 2008; Mohanraj and Brodie, 2006; 
UCB internal data on lacosamide and brivaracetam [BRV]). In addition, high-seizure 
frequency also correlates with reduced likelihood of achieving seizure freedom. For instance, 
patients who have failed 3 or 4 AED regimens but who have daily seizures have only a 2% 
chance of becoming seizure free with subsequent AEDs. In this study, to ensure that subjects 
who participate have a very low likelihood of benefiting from existing treatments, we will 
combine 2 criteria to identify the target population: failure to control seizures despite 
treatment with at least 4 AED regimens and having at least 4 seizures per week on average. 
This group of patients will be referred to as having “highly drug-resistant focal epilepsy.”
Resective surgery is an option for some patients with drug-resistant focal epilepsy. The ILAE 
recommends that patients be evaluated for surgery after failing to achieve seizure freedom 
with the second AED regimen; however, in most places patients are referred for surgery only 
after failing multiple AED regimens. Therefore, the patients who in practice are evaluated for 
and undergo surgery are similar to the highly drug-resistant population as defined above. Due 
to various factors (limited number of epilepsy surgery centers, inability to localize the seizure 
focus during work-up, contraindications to surgery, etc) fewer than 1% of patients with drug-
resistant focal epilepsy undergo epilepsy surgery. Therefore, the vast majority of patients 
with highly drug-resistant focal epilepsy have no treatment options (pharmacological or 
surgical) that can provide complete seizure control or even substantial reduction in the 
number of seizures.
UCB0942 has shown superior efficacy in several preclinical models of epilepsy. UCB0942 is 
superior to levetiracetam (LEV) and BRV in 10 animal models of focal and generalized
epilepsy, indicating that it has broad antiseizure effects. In the rat amygdala kindling model –
a model of drug-resistant focal epilepsy – UCB0942 is superior to 12 other AEDs tested thus 
far: LEV, BRV, phenytoin, phenobarbital, carbamazepine, lacosamide, valproate, retigabine, 
perampanel, clobazam, diazepam, clonazepam, and the combination of LEV or BRV with 
diazepam. In this model of drug-resistant focal epilepsy, UCB0942 was the only compound 
that produced complete seizure suppression in all animals at a plasma exposure equivalent to 
the plasma exposure achieved in humans taking UCB0942 400mg bid. Other AEDs produced
seizure suppression in this model, but only at plasma exposures that are unattainable in 
humans. Based on its superior preclinical efficacy profile, UCB0942 may show efficacy in 
patients with focal epilepsy who continue to suffer from frequent seizures despite having 
attempted to achieve seizure control with multiple AED regimens (patients with highly drug-
resistant focal epilepsy).
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 16 of 125
If seizure freedom or a substantial reduction in seizure frequency could be achieved in these 
patients, their quality of life would dramatically improve, and this improvement is expected 
to outweigh the potential risks associated with the administration of UCB0942.
Preclinical experience with UCB0942 is described extensively in the Investigator’s Brochure.
2.2
Phase 1 experience
UCB0942 has completed Phase 1 development with a total of 145 subjects exposed to single 
doses up to UCB0942 490mg and multiple doses up to UCB0942 400mg bid for up to 
14 days, including 20 subjects with epilepsy at 400mg bid. There were no clinically
significant changes in laboratory tests or vital signs thought to be related to UCB0942 during 
Phase 1 development, although transient, minor reductions in systolic and diastolic blood 
pressure were seen (consistent with the known effects of benzodiazepine drugs). There were 
no clinically significant changes attributed to UCB0942 in 12-lead ECGs; however, 
4 subjects had treatment-emergent rhythm disturbances (atrial and ventricular ectopy). These 
were asymptomatic and were assessed by an external cardiologist expert in electrophysiology 
as unlikely to be related to UCB0942.
2.2.1
Adverse event profile 
The safety findings to date suggest that the adverse event (AE) profile in subjects receiving 
single and repeated doses of UCB0942 is related mostly to the central nervous system (CNS). 
At UCB0942 300mg bid and above the AEs tend to be of slightly greater severity and 
persistence than at doses below UCB0942 300mg bid. In broad terms, the AEs are consistent 
with the AEs associated with established SV2 and GABA-A targeting AEDs, and common 
CNS AEs include headache, nausea, somnolence, fatigue, dizziness, balance disorder, 
disturbance in attention, and memory impairment. Modeling of the relationship between dose 
or plasma exposure, time, and AEs showed that 1) headache, fatigue, somnolence, balance 
disorder, and disturbance in attention are dose-dependent AEs; 2) tolerance develops for 
disturbance in attention and balance disorder; 3) tolerance does not seem to develop for 
fatigue, somnolence, and headache; and 4) titration will reduce the likelihood that a subject 
experiences most of these AEs. 
2.2.2
Psychiatric adverse events
In the multiple ascending dose study, 1 healthy volunteer had a “delirious syndrome” with 
prominent psychotic symptoms, and in a subsequent Phase 1 study, 1 healthy volunteer had 
“mania-like symptoms.” Both of these AEs were classified as serious adverse events (SAEs)
because the subjects required hospitalization. After these psychiatric SAEs occurred, close 
psychiatric monitoring was implemented. Therefore, when 2 other healthy volunteers began 
to develop “hypomania” and “aggressive state,” respectively, the symptoms were discovered 
early, and discontinuation of UCB0942 prevented the development of these symptoms into 
more severe psychiatric symptoms. Based on this, it appears that close psychiatric monitoring 
during the first 2 weeks of dosing, and tapering and discontinuation of the drug in subjects 
who start to develop psychiatric AEs, will reduce the risk that subjects develop more severe 
psychiatric AEs or psychiatric SAEs. Therefore, in this study, daily psychiatric monitoring 
will be performed in all subjects for the first 2 weeks after dosing starts, and weekly 
thereafter. In addition, to further reduce the risk that participating subjects develop 
psychiatric AEs, subjects with a history of psychosis, schizophrenia, bipolar disorder, or 
severe unipolar depression will be excluded from this study. Lastly, based on the fact that 
titration has been shown to reduce the incidence of other AEs and increase the general 
tolerability of UCB0942, titration may also reduce the risk of psychiatric AEs.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 17 of 125
2.2.3
Drug-drug interactions
A drug-drug interaction study in subjects with epilepsy showed that carbamazepine – a strong 
cytochrome P450 (CYP) 3A4 inducer – reduced UCB0942 plasma exposure by >85%. 
Therefore, subjects on carbamazepine or other strong CYP3A4 inducers (eg, phenytoin, 
phenobarbital, or primidone) will not be enrolled in this study because the plasma exposure 
may be too low to produce any therapeutic benefit.
2.3
Rationale for this study
This is a Phase 2A efficacy, safety, and tolerability study.
Based on the preclinical results in 10 animal models of focal and generalized epilepsy, and 
the precedented mechanisms of action, it is almost certain that UCB0942 will have 
antiseizure effects in humans. The rationale for the current study is to test whether UCB0942 
has unprecedented efficacy in a very severe patient population, namely in subjects with focal 
epilepsy who continue to suffer from frequent, almost-daily seizures despite having attempted 
to achieve seizure control with multiple AED regimens. In this study the efficacy of 
UCB0942 400mg bid in subjects with such highly drug-resistant focal epilepsy will be 
assessed for the first time. In this protocol, “focal seizures” refers to partial-onset seizures of 
type IA1, IB, and IC, but does not include type IA2, IA3, or IA4 seizures.
Based on analysis of similar subjects in UCB’s lacosamide and BRV databases, the placebo 
response is very low (after 2 weeks of treatment <7% achieved ≥75% reduction in seizure 
frequency and <2% were seizure free, and after 12 weeks of treatment <4% maintained ≥75% 
reduction in seizure frequency and 0% were seizure free); however, the placebo arm is 
necessary to confirm that the placebo response is equally low in the current target population 
and in the setting of this study (ie, inpatient) and to avoid a false positive study due to an 
apparent seizure frequency reduction from the Prospective Outpatient Baseline Period to the 
Inpatient Treatment Period.
3
STUDY OBJECTIVES
3.1
Primary objective
The primary objective is to evaluate the efficacy of UCB0942 administered concomitantly 
with each subject’s current, stable AED regimen in subjects who have 4 or more focal 
seizures with or without secondary generalization per week and who have failed to achieve 
seizure control with ≥4 AED regimens of adequate dose and duration. 
3.2
Secondary objectives
The secondary objectives are to:
!
Evaluate the safety and tolerability of UCB0942
!
Evaluate the PK of UCB0942 and its metabolites
3.3
Exploratory objectives
The exploratory objectives are to:
!
Identify genetic polymorphisms, gene expression patterns, plasma proteins, plasma lipids,
or other plasma substances that predict or are associated with disease etiology, drug 
response, or tolerability
!
Use video recordings, when available, to explore the effect of UCB0942 on seizure type, 
seizure severity, seizure duration, and duration of the postictal period
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 18 of 125
!
To assess motivations, hopes and impact of seizures using a Diary Addendum
4
STUDY VARIABLES
4.1
Efficacy variables
4.1.1
Primary efficacy variable
Seizure frequency will be determined using subject diary cards. The subject will be instructed 
as to how to complete the diary, and the procedure for completing the diary will be identical 
during the Outpatient and Inpatient Periods.
The primary outcome measure is the 75%RR. In the active group, this is defined as the 
proportion of subjects with a 75% or greater reduction in focal seizure frequency during the 
last 2 weeks of the Inpatient Period compared to the 2-week Prospective Outpatient Baseline
Period. In the placebo group, the 75%RR is defined as the proportion of subjects with a 75% 
or greater reduction in focal seizure frequency during the first 2 weeks of the Inpatient Period 
(the 2 weeks on placebo) compared to the Prospective Outpatient Baseline Period.
4.1.2
Secondary efficacy variables
The secondary efficacy variables are:
!
Median percent reduction in weekly focal seizure frequency from the Prospective 
Outpatient Baseline Period to the Inpatient Period and the End of Treatment.
!
Seizure-free rate during the Inpatient Period, the last 4 weeks of the Outpatient 
Maintenance Period, and at the End of Treatment.
!
The 75%RR during the last 4 weeks of the Outpatient Maintenance Period and at the End 
of Treatment.
!
Percentage of seizure-free days during the Inpatient and Outpatient Periods.
4.1.3
Exploratory efficacy variables
Exploratory efficacy variables are as follows:
!
Median seizure frequency by seizure type (IA1, IB, IC) per study period: Prospective 
Outpatient Baseline, Titration Inpatient, 1-week Maintenance Inpatient, Transition to 
Outpatient, Outpatient Maintenance, and overall on-treatment period.
!
The 50% responder rate (50%RR) during the Inpatient Period and during the Outpatient 
Maintenance Period.
!
Seizure Severity Questionnaire (SSQ, Cramer et al, 2002), change from Baseline to the 
end of the Inpatient Period and the end of the Outpatient Maintenance Period.
!
Changes in average seizure severity as calculated by the percentage of seizures that are 
type IC.
!
Change from Baseline in score (subscale and total) of the Quality of Life Inventory in 
Epilepsy-31-P (QOLIE-31-P, Cramer et al, 2003)
4.2
Pharmacokinetic variables
Plasma concentrations of UCB0942, 
 will be used 
to calculate the following PK parameters:
!
AUCτ:
area under the plasma concentration-time curve over a dosing interval
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 19 of 125
!
Cmax:
maximum observed plasma concentration
!
tmax:
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!
t½:
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!
Ctrough:
measured concentration at the end of the dosing interval at steady state
4.3
Exploratory variables
!
Blood samples for DNA, mRNA, and lipidomics/proteomics/additional blood biomarkers
will be collected during the study:
∀
DNA: One tube for DNA isolation will be collected at the beginning of the Inpatient 
Period of the study. The DNA may be used to assess known variants associated with 
drug-resistant epilepsy or AED resistance and may be used for further genetic 
analyses relating to epilepsy and drug response.
∀
mRNA: One tube will be collected on the day before the first dose of 
UCB0942/placebo, and 1 tube will be collected on the last day of the Inpatient 
Maintenance-Dose Week. The mRNA samples may be used to identify gene 
expression patterns that are associated with disease etiology, that predict (Baseline 
sample), or that are associated with (posttreatment sample) drug response.
∀
Lipidomics/proteomics/additional blood biomarkers: One tube will be collected on 
the day before the first dose of UCB0942 or placebo, and 1 tube will be collected on 
the last day of the Inpatient Maintenance-Dose Week. These samples may be used for 
additional blood biomarker analysis.
All subjects will be asked to provide specific consent for these samples. Refusal to provide 
consent for the collection of samples for DNA, mRNA, and lipidomics/proteomics will not 
disqualify the subject from participating in the study.
Single archive blood samples (for potential background AED assay) will be collected at the 
start of titration, the end of the Inpatient Period, and at the end of the Outpatient Maintenance 
Period (before last dose of IMP). These samples will be collected just before the morning 
dose of IMP and stored for up to 1 year after the study ends.
!
At the discretion of the Investigator, sites may or may not perform video or 
video-electroencephalogram (EEG) monitoring during parts of the Inpatient Period or 
during the whole Inpatient Period, depending on the infrastructure of each site, to assess 
seizure type, severity, duration, and the duration of the postictal period. The video data 
will not be used to corroborate or supplement the diary data and shall not influence the 
diary seizure capture by the subject.
!
Responses to open questions in the Diary Addendum, including:
∀
Reason for participation in the study
∀
Hopes for this new treatment and fulfillment of hopes during the study
∀
Baseline and change from Baseline in the impact of seizures on the patient’s life
The subject will be instructed to leave any questions blank that he/she does not feel 
comfortable answering. 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 20 of 125
4.4
Safety variables
The safety of participating subjects will be closely monitored. Psychiatric assessment will be 
performed by a staff member trained in the identification of psychiatric symptoms, and the 
assessments will be performed using the Brief Psychiatric Rating Scale (BPRS; Overall and 
Gorham, 1962), which assesses various psychiatric domains including:
!
Changes in mood and symptoms of depression or mania
!
Changes in thinking and perception, and other symptoms of psychosis
!
Changes in behavior
Other safety variables are:
!
Adverse events reported by the subject and/or caregiver or observed by the Investigator or 
inpatient staff
!
Serious adverse events
!
Subject withdrawals or premature UCB0942 tapering due to AEs
!
Changes in clinical laboratory test parameters
!
Changes in vital sign parameters – pulse rate, blood pressure, and respiratory rate
!
Changes in 12-lead electrocardiogram (ECG) parameters
!
Changes in 2-dimensional Doppler echocardiography from Baseline to after Baseline 
(during dosing, after the last dose, and 6 months after last dose), with diastolic 
measurements as well as atrial volumes to identify any subtle valvular changes and to 
assess for pericardial effusions
!
Changes in physical examination (including body weight) and neurological examination 
findings
!
Changes in memory or cognition as assessed with the mini-mental state examination 
(MMSE; Folstein et al, 1975)
!
Changes indicative of a hypersensitivity reaction including an AE or laboratory value (as 
defined below) suggestive of internal organ involvement (including but not limited to 
hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, pancreatitis, myositis, 
arthritis, or hematologic system involvement) combined with at least 1 of the following: 
fever, rash, lymphadenopathy, or eosinophilia
∀
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia:
◦
Eosinophils % ≥10%
◦
Eosinophils absolute ≥0.5G/L
◦
Neutrophils absolute <1.5G/L
◦
Platelets ≤100G/L
◦
ALT ≥2x ULN
◦
AST ≥2x ULN
!
Any indication of withdrawal symptoms using the Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B; Busto et al, 1989)
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 21 of 125
!
Changes in suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS)
5
STUDY DESIGN
5.1
Study description
EP0069 is a Phase 2A, double-blind, randomized, placebo-controlled, multicenter study that 
will test the potential efficacy, safety/tolerability, and PK profile of UCB0942 in adult 
subjects with highly drug-resistant focal epilepsy. UCB0942 400mg bid will be administered 
as add-on to each subject’s concomitant AED regimen.
Screening assessments will be conducted after subjects have understood the risks and 
potential benefits of the study and signed the written Informed Consent form (ICF). Only 
subjects who fulfill all eligibility criteria will be enrolled.
This study consists of:
!
A 4-week prescreening Historical Baseline Period for study eligibility purposes
!
A Screening Visit followed by a 2- to 3-week postscreening Prospective Outpatient 
Baseline Period (Day BL1 to Day BL14-21)
!
A 3-week Inpatient Period, which consists of:
∀
An Inpatient Titration Week (Day T1 to Day T7)
∀
An Inpatient Maintenance-Dose Week (Day MD1 to Day MD7)
∀
An Inpatient Transition-to-Outpatient Week (Day TTO1 to Day TTO7)
!
An open-label Outpatient Maintenance Period of 8 weeks (Day OP1 to Day OP57)
!
A Tapering Period of 2 weeks (Day TOO1 to Day TOO14)
!
A Safety Follow-Up Period of 4 weeks (Day SFU1 to Day SFU28) 
!
An echocardiogram during dosing and after the last dose (the SFU7 echocardiogram). 
The echocardiogram will be repeated at 6 months (±1 month) after the last dose in the 
following subjects:
∀
Subjects who complete this study but do not enter the OLE study
∀
Subjects who withdraw from the Outpatient Period 
∀
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 
echocardiogram
UCB0942 doses for placebo subjects will be titrated to UCB0942 400mg bid during the 
Inpatient Transition-to-Outpatient Week (Day TTO1 to Day TTO7). After the Inpatient 
Period, all subjects will continue in an open-label Outpatient Maintenance Period and a final 
Tapering Period of 2 weeks (Day TOO1 to Day TOO14). Doses for subjects continuing in the 
OLE study will not be tapered but will follow the schedule of safety and efficacy assessments 
as outlined in the OLE study protocol. Safety follow up will consist of 2 required visits, 1 and 
4 weeks after the last dose of IMP (Day SFU7 and Day SFU28), and 1 optional visit 2 weeks 
after the last dose of IMP (Day SFU14). For details of the study assessments, refer to 
Table 5-4. For a general presentation of the study design refer to Figure 5‒1.
Dosing in the Inpatient Period
Titration Week (first week of the Inpatient Period
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 22 of 125
The objective of the Titration Week is to achieve the maximum UCB0942 dose of 400mg bid 
in as many of the subjects randomized to UCB0942 as possible while minimizing tolerability 
issues. During the Titration Week the dose for subjects randomized to UCB0942 will be 
titrated to UCB0942 400mg bid following the schedule in Table 5‒1. The UCB0942 dose 
will be titrated to 400mg bid in a double-blinded fashion (ie, it will also appear that subjects 
randomized to placebo are being titrated). If, in the opinion of the Investigator, the Subject 
will be unable to titrate to the maximum dose of IMP due to intolerance of a lower dose, the 
Investigator should discuss this immediately with the Sponsor Study Physician, unless the 
subject’s condition warrants immediate unblinding, and time does not allow discussion with 
the Sponsor. Unblinding may be required depending on the plan agreed upon by the 
Investigator and Sponsor Study Physician before dose tapering to UCB0942 200mg bid or 
100mg bid. If unblinding reveals that the Subject is randomized to placebo, then further 
dosing with IMP will cease until the Transition-to-Outpatient Week (third week of the 
Inpatient Period), at which time, the Subject will titrate UCB0942 according to Table 5‒1.All 
other assessments will continue as planned.
Table 5‒1:
Dose titration to UCB0942 400mg bid
Day T1a
Day T2
Day T3
Day T4
Day T5
Day T6
Day T7
Day MD1
AM
0
100mg
100mg
200mg
200mg
300mg
300mg
400mg
PM
100mg
100mg
200mg
200mg
300mg
300mg
400mg
400mg
AM=morning dose; PM=evening dose 
a In placebo-arm subjects the same schedule is used from Day TTO1 to TTO7.
Maintenance-Dose Week (second week of the Inpatient Period)
If a subject is not tolerating the maximum dose of IMP well during the 
Maintenance-Dose Week such that the Investigator believes a dose reduction is necessary, 
then then the Investigator should contact the Sponsor Study Physician to discuss the situation 
and agree upon a course of action. If a dose reduction is agreed, unblinding will be required. 
If the subject is randomized to UCB0942, the dose can be tapered from UCB0942 400mg bid
to UCB0942 200mg bid. The taper from UCB0942 400mg bid to UCB0942 200mg bid will
occur over 3 days (see Table 5‒2) Dose tapering to UCB0942 100mg bid may also be 
permitted after discussion with the Sponsor’s Study Physician. If it is revealed that the 
Subject is randomized to placebo, then further dosing with IMP will cease until the 
Transition-to-Outpatient Week (third week of the Inpatient Period), at which time, the 
Subject will titrate UCB0942 according to Table 5‒1. All other assessments will continue as 
planned.
Table 5‒2:
Taper from UCB0942 400mg bid to UCB0942 200mg bid
Taper Day 1
Taper Day 2
Taper Day 3
Taper Day 4 onwards
AM
300mg
300mg
200mg
200mg
PM
400mg
300mg
300mg
200mg
AM=morning dose; PM=evening dose
Transition-to-Outpatient Week (third week of the Inpatient Period)
The objective of the Transition-to-Outpatient Week is to achieve the maximum UCB0942 
dose of 400mg bid in as many of the subjects randomized to placebo (now switching to 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 23 of 125
UCB0942) as possible while minimizing tolerability issues. The UCB0942 dose will be 
titrated to 400mg bid in a double-blinded fashion (ie, it will also appear that subjects 
randomized to UCB0942 are being titrated) following the schedule in Table 5‒1. If, in the 
opinion of the Investigator, the Subject will be unable to titrate to the maximum dose of IMP 
due to intolerance of a lower dose, the Investigator should discuss this with the Sponsor 
Study Physician. Unblinding may be required depending on the plan agreed upon by the 
Investigator and Sponsor Study Physician.
Dosing in the Outpatient Maintenance Period and Tapering Period
During the Outpatient Maintenance Period, Subjects will continue to administer UCB0942 at 
the final Inpatient Period dose. Multiple adjustments (tapering or increase) of the dose are 
allowed during the Outpatient Maintenance Period (minimum 100mg bid and maximum 
400mg bid); however, any change of dose in the Outpatient Maintenance Period should first 
be discussed with the Sponsor Study Physician. 
At the end of the Outpatient Maintenance Period, or at the time a subject is withdrawn from 
the study, UCB0942 will be tapered following the schedule in Table 5‒3. If the subject is not 
taking a dose of UCB0942 other than 400mg bid, then the Investigator should contact the 
Sponsor Study Physician to discuss the appropriate tapering schedule.
Table 5‒3:
Dose taper from UCB0942 400mg bid
Day
TOO1 to TOO4
TOO5 to TOO8
TOO9 to TOO12
TOO13 and TOO14
AM
300mg
200mg
100mg
PM
300mg
200mg
100mg
100mg
AM=morning; PM=evening dose
In order to provide an ongoing assessment of the safety of subjects as the study progresses, a 
Safety Review Group (SRG) comprising appropriate Sponsor study team members and the 
Investigator(s) at each site will meet regularly to review appropriate safety data (see 
Section 11.1.9).
5.1.1
Study duration per subject
The total duration of the study after Screening is 20 weeks for each subject, including the 
Prospective Outpatient Baseline Period (2 to 3 weeks), the Inpatient Period (3 weeks), the 
Outpatient Period (8 weeks of treatment and 2 weeks of taper), and a SFU Period (4 weeks).
In addition, there is an echocardiography visit at 6 months after the last dose. The total 
duration of exposure to UCB0942 during this study is 13 weeks.
The end of the study is defined as the date of the last visit of the last subject in the study.
5.1.2
Planned number of subjects and sites
Subjects with highly drug-resistant focal epilepsy will be enrolled at 
 sites in order 
to provide 46 evaluable subjects, ie, 46 subjects who complete the Inpatient Period. Subjects 
who drop out before Visit 6 (eg, during the Inpatient Period) for reasons other than safety or 
tolerability will be replaced. First subject, first visit is planned for Q2 2015.
5.1.3
Anticipated regions and countries
The study is planned to be performed in The 
 
 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 24 of 125
5.2
Schedule of study assessments
The schedule of study assessments is presented in Table 5-4, and a detailed schedule of 
assessments for the Inpatient Period is presented in Table 5‒5.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 25 of 125
Table 5-4:
Schedule of study assessments
Assessments
Baseline
Period
Inpatient Period
Outpatient Period
Period
Screeninga/
Baseline
Titration
Mainte-
nance
Transition 
to 
Outpatient
Outpatient Maintenance Period
Taper/Safety Follow-Up Period
Duration
1 day
2 weeksb
1 week
1 week
1 week
8 weeks
Up to 2
weeks
4 weeks
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Study days
-1
BL1 to 
BL14/21
T1 to T7
MD1 to 
MD7
TTO1 to 
TTO7
OP
3
OP
5
OP
8
OP
15
OP
22
OP
29
OP
36
OP
43
OP
50
OP
57c
TOO
7
TOO
14
SFU
7
SFU
14d
SFU
28
(±2)
(±2) (±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2) (±2)
(±1)
(±1)
(±2)
(±2)
Written informed 
consent
X
Demographic data
X
Habits and lifestyle
X
X
General 
medical/medication/
procedures history
X
X
Review historic 
seizure count
X
Verification of 
inclusion/exclusion 
criteria
X
X
Admission to clinic
X
Discharge from 
clinic
Xe
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationf
X
X
X
X
X
X
X
X
X
X
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 26 of 125
Table 5-4:
Schedule of study assessments
Assessments
Baseline
Period
Inpatient Period
Outpatient Period
Period
Screeninga/
Baseline
Titration
Mainte-
nance
Transition 
to 
Outpatient
Outpatient Maintenance Period
Taper/Safety Follow-Up Period
Duration
1 day
2 weeksb
1 week
1 week
1 week
8 weeks
Up to 2
weeks
4 weeks
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Study days
-1
BL1 to 
BL14/21
T1 to T7
MD1 to 
MD7
TTO1 to 
TTO7
OP
3
OP
5
OP
8
OP
15
OP
22
OP
29
OP
36
OP
43
OP
50
OP
57c
TOO
7
TOO
14
SFU
7
SFU
14d
SFU
28
(±2)
(±2) (±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2) (±2)
(±1)
(±1)
(±2)
(±2)
Neurological 
examinationf
X
X
X
X
X
X
X
X
X
X
Psychiatric and 
cognitive 
assessmentsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CIWA-Bh
X
X
X
X
X
X
Vital signs (BP, 
pulse, and 
respiratory rate)i
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and 
heightj
X
X
X
X
X
X
12-lead ECGi
X
X
X
X
X
X
X
X
Echocardiogramk
X
X
X
Clinical laboratoryl
X
X
X
X
X
X
X
X
Video or video-
EEG monitoringm
X
X
X
Pregnancy testn
X
X
X
X
X
X
X
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 27 of 125
Table 5-4:
Schedule of study assessments
Assessments
Baseline
Period
Inpatient Period
Outpatient Period
Period
Screeninga/
Baseline
Titration
Mainte-
nance
Transition 
to 
Outpatient
Outpatient Maintenance Period
Taper/Safety Follow-Up Period
Duration
1 day
2 weeksb
1 week
1 week
1 week
8 weeks
Up to 2
weeks
4 weeks
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Study days
-1
BL1 to 
BL14/21
T1 to T7
MD1 to 
MD7
TTO1 to 
TTO7
OP
3
OP
5
OP
8
OP
15
OP
22
OP
29
OP
36
OP
43
OP
50
OP
57c
TOO
7
TOO
14
SFU
7
SFU
14d
SFU
28
(±2)
(±2) (±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2) (±2)
(±1)
(±1)
(±2)
(±2)
Serologyo
X
Screening for drug 
and alcohol usep
X
X
X
X
Randomizationq
X
Administration of 
IMP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sample for
UCB0942, 
 
plasma 
concentrations
Xr
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Sample for DNA
X
Sample for mRNA/ 
lipidomics/ 
proteomics
X
X
SSQ (Baseline 
version)
X
X
X
X
X
X
X
X
QOLIE-31-Pt
X
X
X
X
X
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 28 of 125
Table 5-4:
Schedule of study assessments
Assessments
Baseline
Period
Inpatient Period
Outpatient Period
Period
Screeninga/
Baseline
Titration
Mainte-
nance
Transition 
to 
Outpatient
Outpatient Maintenance Period
Taper/Safety Follow-Up Period
Duration
1 day
2 weeksb
1 week
1 week
1 week
8 weeks
Up to 2
weeks
4 weeks
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Study days
-1
BL1 to 
BL14/21
T1 to T7
MD1 to 
MD7
TTO1 to 
TTO7
OP
3
OP
5
OP
8
OP
15
OP
22
OP
29
OP
36
OP
43
OP
50
OP
57c
TOO
7
TOO
14
SFU
7
SFU
14d
SFU
28
(±2)
(±2) (±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2) (±2)
(±1)
(±1)
(±2)
(±2)
C-SSRS (Screening/
Baseline version)
X
C-SSRS (Since last 
visit)
X
X
X
X
X
X
X
Dispense IMPu
X
X
X
X
X
X
X
IMP returnv
X
X
X
X
X
Dispense/return
diary card 
X
Xw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diary Addendumx
X
1
Concomitant 
medications/ 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AED archive 
sample
X
X
X
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 29 of 125
Table 5-4:
Schedule of study assessments
Assessments
Baseline
Period
Inpatient Period
Outpatient Period
Period
Screeninga/
Baseline
Titration
Mainte-
nance
Transition 
to 
Outpatient
Outpatient Maintenance Period
Taper/Safety Follow-Up Period
Duration
1 day
2 weeksb
1 week
1 week
1 week
8 weeks
Up to 2
weeks
4 weeks
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Study days
-1
BL1 to 
BL14/21
T1 to T7
MD1 to 
MD7
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(±2) (±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2)
(±2) (±2)
(±1)
(±1)
(±2)
(±2)
AE=adverse event; AED=antiepileptic drug; BL=Baseline; BP=blood pressure; BPRS=Brief Psychiatric Rating Scale; CIWA-B=Clinical Institute Withdrawal 
Assessment-Benzodiazepines; C-SSRS=Columbia-Suicide Severity Rating Scale; DBP=diastolic blood pressure; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; EEG=electroencephalogram; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human 
immunodeficiency virus-1/2 antibody; IMP=investigational medicinal product; IRT=interactive response technology; MD=Maintenance Dose; MINI=Mini 
International Neuropsychiatric Interview; MMSE=mini-mental state examination; mRNA=messenger ribonucleic acid; OLE=open-label extension; 
OP=Outpatient; PR=pulse rate; QOLIE-31-P=Quality of Life Inventory in Epilepsy-31-P; SBP=systolic blood pressure; SFU=Safety Follow-Up Visit; 
SSQ=Seizure Severity Questionnaire; T=Titration; TOO=Taper of Outpatient; TTO=Transition to Outpatient
a If a subject fails screening, a rescreening is allowed if deemed appropriate by the Investigator.
b Baseline Period of at least 2 weeks and no more than 3 weeks.
c Day OP57 is the same day as Day TOO1.
d SFU14 is optional, only if deemed necessary by the Investigator. Additional assessments can be added if necessary.
e On Day TTO7 after completing all assessments, subjects will be discharged.
f Physical examination (complete) and neurological examination at Screening and on Days MD1, TTO7, OP22, OP57, TOO14, SFU7, SFU14 (if deemed 
necessary by the Investigator), and SFU28. Physical examination (focused, or as per center policy) and neurological examination on Day T1.
g MINI at Screening; BPRS and MMSE at every visit. During the first week after discharge psychiatric symptoms will be assessed during each visit, using the 
BPRS and MMSE, and by phone, using the BPRS only, on the other days. 
h CIWA-B will be performed before the evening dose on the last day before discharge from the inpatient unit.
i Vital signs include PR, respiratory rate, SBP, and DBP. In addition, at Day T1, MD7, and TTO7 body temperature should be measured; on Day T1 this should 
be prior to first administration of UCB0942. Obtain vital signs and a 12-lead ECG once in the morning, unless otherwise noted. 
j Height at Screening only.
k In addition to the echocardiogram during dosing and after the last dose (SFU7), the echocardiogram will be repeated at 6 months (±1 month) after the last dose 
in the following subjects: 1) Subjects who complete this study but do not enter the OLE study, 2) Subjects who withdraw from the Outpatient Period, and 3) 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 30 of 125
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 echocardiogram. Please note that the during dosing time point of Day OP22 for 
the echocardiogram has a time window of ±1 week instead of ±2 days and the Day SFU7 echocardiogram has a time window of ±1 week instead of ±1 day.
l Clinical chemistry, hematology, and urinalysis.
m At the discretion of the Investigator, sites may or may not perform video or video-EEG monitoring during parts of the Inpatient Period or during  the whole 
Inpatient Period.
n Urine or serum pregnancy test.
o Serology to include HIV-1/2Ab, HBsAg, and HCV-Ab.
p The drug screen will include amphetamines, benzodiazepines, barbiturates, cocaine, cannabinoids, methadone, opiates, and alcohol. Use of AED from one of 
the classes mentioned will be allowed if allowed by inclusion and exclusion criteria.
q Randomization on Day T1 before first IMP administration using IRT.
r Obtain blood samples for measurement of plasma concentration of UCB0942 and metabolites on Day MD1 and MD7, at the following times: predose (within 
5min of dosing), then at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h postdose. Time windows for postdose samples are as follows: ±5min for the 0.5h, 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 pm dose. 
s Obtain blood samples for measurement of trough levels of UCB0942 and metabolites just prior to the morning dose of UCB0942. If a predose sample is not 
possible prior to the morning dose a sample can be taken just prior to the evening dose of UCB0942. If no sample can be taken just prior to dosing, a postdose 
sample will be taken and the actual dosing and sampling times will be recorded. 
t The QOLIE-31-P will be completed by all subjects prior to any other study procedures at the visit. At Day T1, QOLIE-31-P will be assessed in the morning 
before randomization.
u For the Outpatient Period, medication will be dispensed on Days TTO7, OP15, OP29, OP43, and OP57.
v Medication should be presented at each visit for check on compliance.
w During the Baseline Period the subjects should be called at least once to check on the completion of the diary card.
x The subject will be instructed to leave any questions blank that he/she does not feel comfortable answering.
y Collect at Day OP57 or at Early Withdrawal. 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 31 of 125
Table 5‒5:
Schedule of study assessments, Inpatient Period
Period
Titration 
Maintenance
Transition to Outpatient
Visit
Visit 3
Visit 4
Visit 5
Study days
T1 T2
T3
T4 T5
T6 T7
MD1
MD2
MD3
MD4
MD5
MD6
MD7
TTO1 TTO2
TTO3
TTO4
TTO5
TTO6 TTO7
Admission to clinica
X
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Xb
Habits and lifestyle
X
General Medical/Medication/ 
procedures history
X
Verification of inclusion/
exclusion criteria
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical/Neurological 
examination (complete)
Xc
X
X
Psychiatric assessment 
(BPRS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cognitive assessment 
(MMSE)
X
X
X
X
X
X
X
CIWA-B
Xd
Vital signs (BP, pulse, and 
respiratory rate)e
X
X
X
X
X
X
X
X
Body temperaturef
X
X
X
Body weight
X
X
12-lead ECGe
X
X
X
X
X
X
Clinical laboratoryg
X
X
X
Video or video-EEG 
monitoringh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 32 of 125
Table 5‒5:
Schedule of study assessments, Inpatient Period
Period
Titration 
Maintenance
Transition to Outpatient
Visit
Visit 3
Visit 4
Visit 5
Study days
T1 T2
T3
T4 T5
T6 T7
MD1
MD2
MD3
MD4
MD5
MD6
MD7
TTO1 TTO2
TTO3
TTO4
TTO5
TTO6 TTO7
Screening for drugs and 
alcohol
X
Randomizationj
X
Administration of IMPk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sample for UCB0942, 
 
 plasma 
concentrations
X
X
Sample for DNA
X
Sample for mRNA
X
X
Sample for lipidomics
X
X
Sample for proteomics
X
X
SSQ (Baseline version)m
X
X
X
X
QOLIE-31-Pm
X
C-SSRS (since last visit)
X
X
X
X
Diary card completion
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IMPn
X
X
X
X
Dispense diary cardn
X
X
X
X
Diary Addendumo
X
Concomitant 
medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AED archival sample
X
X
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 33 of 125
Table 5‒5:
Schedule of study assessments, Inpatient Period
Period
Titration 
Maintenance
Transition to Outpatient
Visit
Visit 3
Visit 4
Visit 5
Study days
T1 T2
T3
T4 T5
T6 T7
MD1
MD2
MD3
MD4
MD5
MD6
MD7
TTO1 TTO2
TTO3
TTO4
TTO5
TTO6 TTO7
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BPRS=Brief Psychiatric Rating Scale; CIWA-B=Clinical Institute Withdrawal Assessment-
Benzodiazepines; C-SSRS=Columbia-Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; ECG=electrocardiogram; EEG=electroencephalogram;
IMP=investigational medicinal product; IRT=interactive response technology; MD=Maintenance Dose; MMSE=mini-mental state examination; 
mRNA=messenger ribonucleic acid; QOLIE-31-P=Quality of Life Inventory in Epilepsy-31-P; SSQ=Seizure Severity Questionnaire; T=Titration; 
TTO=Transition to Outpatient
a Admission in the morning of Day T1.
b Discharge after completion of all assessments on Day TTO7; pm dose is first outpatient dose.
c Physical examination can be focused on Day T1 if center procedures allow.
d CIWA-B will be performed before the evening dose on the last day before discharge from the inpatient unit.
e Obtain vital signs and a 12-lead ECG once in the morning, unless otherwise noted.
f Body temperature should be measured before the first dose of UCB0942 on Day T1.
g Clinical chemistry, hematology, and urinalysis.
h At the discretion of the Investigator, sites may or may not perform video or video-EEG monitoring during parts of the Inpatient Period or during the whole 
Inpatient Period.
i Urine or serum pregnancy test, female subject only.
j Randomization after completion of all assessments on Day T1 using IRT.
k First administration after randomization in the evening of Day T1 followed by bid dosing.
l Obtain blood samples for measurement of plasma concentration of UCB0942 and metabolites on Day MD1 and MD7, at the following times: predose (within 
5min of dosing), then at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h postdose. Time windows for postdose samples are as follows: ±5min for the 0.5h, 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 pm dose. 
m The QOLIE-31-P and SSQ (Baseline version) will be completed by all subjects prior to any other study procedures at the visit.
n For the Outpatient Period, after completion of all assessments on Day TTO7.
o The subject will be instructed to leave any questions blank that he/she does not feel comfortable answering.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 34 of 125
5.3
Schematic diagram
Figure 5‒1: Study design
5.4
Rationale for study design and selection of dose
This multicenter, double-blind, randomized, placebo-controlled, parallel-group study will 
assess the safety and efficacy of UCB0942 in the adjunctive treatment of seizures with or 
without secondary generalization in adult subjects with highly drug-resistant focal epilepsy, 
for the first time. The study will have an Inpatient Period to minimize the psychiatric risk to 
subjects during the titration. The Outpatient Maintenance Period is necessary to ensure that 
any efficacy observed is maintained and that subjects do not develop tolerance to UCB0942.
The dose used in this study (UCB0942 400mg bid) was chosen because it is the maximum
tolerated dose (MTD) in Phase 1 studies. This dose is expected to:
1. achieve exposures similar to those that show unprecedented efficacy in the rat amygdala 
kindling model of drug-resistant focal epilepsy,
2. achieve full and constant SV2 occupancy based on modeling predictions, and
3. achieve 10-15% occupancy of the cBZR site on the GABA-A receptor.
Based on previous experience in Phase 1, a dose titration over 1 week was chosen to 
minimize the occurrence of AEs. The titration will be performed during the Inpatient Period 
in all subjects (Section 8.2.1). If a subject does not tolerate UCB0942 400mg bid during the 
Maintenance-Dose Week or later, taper to UCB0942 200mg bid can be started by the 
Investigator.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 35 of 125
The SRG will monitor the effectiveness of these strategies in controlling AEs on an ongoing 
basis, as detailed in Section 11.1.9.
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. Subject is an adult (18 years of age or more).
2. Subject is able to understand the study and the ICF as assessed by the Investigator.
Subjects with known mental retardation (defined as IQ below 70) are not eligible to 
participate.
3. A written ICF approved by the or Independent Ethics Committee (IEC) is signed and 
dated by the subject, after the Investigator assesses whether the subject is able to 
understand the potential risks and benefits of participating in the study. A separate ICF 
should be signed and dated by the subject to allow for the optional DNA, mRNA, and 
lipidomics/proteomics/additional blood biomarker samples.
4. Subject and/or caregiver is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete diaries), visit schedule, and the medication intake 
scheme as instructed according to the judgment of the Investigator.
5. Subject is of normal weight as determined by a body mass index (BMI) between 16.0 and 
40.0kg/m2 (exclusive) and with a body weight of at least 50kg (males) or 45kg (females).
6. Subject fulfills ILAE (1989) criteria for focal epilepsy:
∀
clinical semiology should be described and fulfill criteria for focal seizures.
∀
there will have been an electroencephalogram (EEG) reading compatible with focal 
epilepsy in the last 5 years.
∀
the subject has no seizures that are not focal by the new ILAE criteria.
∀
a brain MRI (magnetic resonance imaging) or head CT (computed tomography) to be 
performed before randomization, if no such scan was performed in the last 5 years, 
and a report is available. If a scan was performed within the last 5 years but the 
epilepsy has not been stable since the last scan, a new scan should be obtained.
7. Subject has failed to achieve seizure control with ≥4 appropriately chosen AED regimens 
of adequate dose and duration, including the current treatment, as documented in medical 
records and per Investigator assessment of patient report.
8. Subject is currently treated with a stable dose of at least 1 AED for the 4 weeks prior to 
the Screening Visit (Visit 1) and throughout the duration of the Treatment Period with or 
without additional concurrent vagus nerve stimulation (VNS) or other neurostimulation 
treatments. The VNS must have been in place for at least 12 months with constant 
settings for at least 3 months and the battery life of unit anticipated to extend for the 
duration of study prior to the Screening Visit and throughout the duration of the study.
9. During the 4 weeks prior to Screening (Historical Baseline Period), subject must report to 
have had an average of at least 4 spontaneous and observable focal seizures per week 
(“focal seizures” refers to partial-onset seizures of type IA1, IB, and IC, but does not 
include type IA2, IA3, or IA4 seizures), and cannot have had any seizure-free period 
longer than 3 days (based on Investigator assessment of subject report and seizure diaries
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 36 of 125
if available). The cut-off seizure frequency (4 seizures per week) and maximum seizure-
free interval (3 days) must be maintained during the 2-week Prospective Outpatient 
Baseline Period.
10. Subject has clinical laboratory test results within the reference ranges of the laboratory or
isolated test results that are outside the specified ranges and that are deemed as not 
clinically significant by the Investigator.
11. Subject has blood pressure and heart rate within normal range in the supine position after 
5 minutes rest, or the subject has hypertension that is under partial control with a stable 
antihypertensive medication regimen but that the Investigator deems as clinically not 
significant.
12. Female subjects of nonchildbearing potential (premenarcheal, postmenopausal for at least 
2 years, bilateral oophorectomy or tubal ligation, and complete hysterectomy) are eligible. 
Female subjects of childbearing potential are eligible if they use medically accepted 
contraceptive methods. Oral or depot contraceptive treatment with at least ethinylestradiol 
30μg per intake used with an additional barrier contraception method, monogamous 
relationship with vasectomized or female partner, or double-barrier contraception are 
acceptable methods. The subject must understand the consequences and potential risks of 
inadequately protected sexual activity, be educated about and understand the proper use 
of contraceptive methods, and undertake to inform the Investigator of any potential 
change in status. Abstinence will be considered as an acceptable method of contraception 
if the Investigator can document that the subject agrees to be compliant when it is in line 
with the preferred and usual lifestyle of the subject.
13. Male subjects confirm that during the study period and for a period of 3 months after the 
final dose, when having sexual intercourse with a woman of childbearing potential, he 
will use a barrier contraceptive (eg, condom) and that the respective partner will use an 
additional contraceptive method.
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject has participated in another study of an investigational medication (or medical 
device) within the last 30 days or is currently participating in another study of an 
investigational medication (or a medical device).
2. Subject has either:
∀
>1.5x upper limit of normal (ULN) of any of the following: 
◦
alanine aminotransferase (ALT)
◦
aspartate aminotransferase (AST)
◦
alkaline phosphatase (ALP)
-OR-
∀
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). 
If subject 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%). 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 37 of 125
For randomized subjects with a baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a baseline diagnosis and/or the cause of any clinically meaningful elevation 
must be understood and recorded in the Case Report form (CRF). 
If subject 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 
subject must be discussed with the Medical Monitor.
3. Subject has a known hypersensitivity to any components of UCB0942 formulation or to 
similar drugs (LEV, BRV, or benzodiazepines), or a history of drug or other allergy that, 
in the opinion of the Investigator or UCB Study Physician, contraindicates her/his 
participation.
4. Subject has had significant blood loss or has donated or received 1 or more units (450mL) 
of blood within 30 days prior to UCB0942 administration, or has donated plasma or 
platelets within 14 days prior to UCB0942 administration for this study.
5. Subject tests positive for human immunodeficiency virus-1/2 antibody (HIV-1/2Ab), 
hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab).
6. Subject has a medical condition that, in the opinion of the Investigator, could jeopardize 
or would compromise the subject’s safety or his/her ability to participate in this study.
7. Subject 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 including a history 
of schizophrenia, schizoaffective disorder, bipolar disorder, or severe unipolar depression. 
The presence of potential psychiatric exclusion criteria will be determined based on
screening with the BPRS plus the Mini International Neuropsychiatric Interview (MINI).
8. Subject has a history of status epilepticus or has been hospitalized for status epilepticus 
within the 6-month period prior to Screening Visit.
9. Subject has had EEGs showing a pattern not consistent with a diagnosis of focal epilepsy 
(eg, generalized spike-wave).
10. Subject only has seizures that are uncountable due to clustering.
11. Subject has had pseudoseizures, conversion disorder, or other nonepileptic ictal events 
that, in the opinion of the Investigator, could be confused with seizures.
12. Subject had epilepsy surgery <1 year or an epilepsy dietary therapy initiated < 3 months 
prior to Screening.
13. Subject has taken other (non-AED) prescription, nonprescription, dietary (eg, grapefruit 
or passion fruit), or herbal products that are potent inducers or inhibitors of the CYP3A4 
pathway for 2 weeks (or 5 half-lives, whichever is longer) prior to the Baseline Visit.
14. Subject is currently treated with carbamazepine, phenytoin, primidone, or phenobarbital 
or any other drug known as a strong inducer of CYP3A4 liver enzymes.
15. Subject is taking tiagabine, felbamate, or vigabatrin.
16. Subject is taking benzodiazepines, zolpidem, zaleplon, or zopiclone >3 times per week
for any indication.
17. Subject had intolerable or serious psychiatric side effects with a previous exposure to 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 38 of 125
18. Subject has past or present substance abuse/dependence that in the opinion of the 
Investigator could threaten the subject’s safety within the study, affect the subject’s 
ability to fully participate in the study, or confound study interpretation.
19. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by 
a positive response (Yes) to either Question 4 or Question 5 of the C-SSRS at Screening.
20. Subject has a clinically significant abnormality on ECG that, in the opinion of the 
Investigator, increases the risks associated with participating in the study. In addition, any 
subject with any of the following findings will be excluded:
∀
QT corrected for heart rate using Bazett’s formula (QTcB) or QT corrected for heart 
rate using Fridericia’s formula (QTcF) interval >450ms
∀
Bundle branch blocks and other conduction abnormalities that are clinically 
significant according to the Investigator and/or with a PR interval ≥220ms
∀
Irregular rhythms other than sinus arrhythmia or occasional, rare supraventricular or 
rare ventricular ectopic beats
∀
In the judgment of the Investigator, T-wave configurations are not of sufficient 
quality for assessing QT interval duration.
21. Subject has a history of unexplained syncope or a family history of sudden death due to 
long QT syndrome.
22. Subject has a clinically significant abnormality on echocardiography at Screening or a 
history of rheumatic heart disease or other known valvular abnormalities.
23. Subjects with a history of hypersensitivity reactions or autoimmune disease.
24. Female subject who is pregnant or breastfeeding.
6.3
Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
Subject may be withdrawn by the Investigator if s/he is noncompliant with the study 
procedures or medications in a way that, in the opinion of the Investigator, may affect the 
study or the safety of the subject, or a subject is unable to manage the completion of the 
diary, or demonstrates a questionable diary.
Subjects must be withdrawn from the study if any of the following events occur:
1. Subject develops a clinically relevant medical condition (or laboratory abnormality) that, 
in the opinion of the Investigator, compromises the subject’s ability to participate or 
safety. Potential drug-induced liver injury IMP discontinuation criteria are described in 
Section 6.3.1. To monitor for hypersensitivity reactions, percent eosinophils >10% or 
absolute eosinophil count ≥0.5G/L or absolute neutrophil count <1.5G/L or absolute 
platelet count ≤100G/L, if in combination with fever, rash, lymphadenopathy, or other 
symptoms/signs suggestive of internal organ involvement (including but not limited to 
hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, pancreatitis, myositis, or 
arthritis) will lead to stopping the IMP.
2. UCB or a regulatory agency requests withdrawal of the subject.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 39 of 125
3. Subject develops psychiatric/mood/behavioral signs or disturbances (see examples in list 
below) that are clinically concerning or that worsen over time. Tapering and 
discontinuation of UCB0942 would be performed in such subjects and they would be 
referred to a mental healthcare professional.
a) Auditory or visual hallucinations
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4. Subject requires treatment with a medication that is not permitted (Section 7.8.2) and is 
not allowed after discussion with the UCB Study Physician.
5. Subject becomes pregnant.
6. 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 
subject 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 subject in the study/on study medication. If the Subject has active suicidal 
ideation with a plan as indicated by a positive response (“Yes”) to Question 5 of the 
“Since Last Visit” version of the C-SSRS, the subject should be referred immediately to a 
Mental Healthcare Professional and must be withdrawn from the study.
7. Subject has a prolongation or worsening of overall seizure duration, frequency, type, or 
pattern considered by the Investigator as persistent and serious enough to warrant 
discontinuation from the study.
In the case of withdrawal or discontinuation during the study or during the echocardiography 
follow-up period, the Investigator should attempt to obtain information on subjects. For 
subjects considered as lost to follow up, the Investigator should make an effort (at least 1 
phone call and 1 written message to the subject), 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 subject, must be recorded in the 
source documents. The electronic Case Report form (eCRF) must document the primary 
reason for withdrawal or discontinuation.
The Investigator should contact the UCB Study Physician whenever possible to discuss the 
withdrawal of a subject in advance. If this is not possible, the Investigator should contact the
UCB study physician to inform him/her about the subject withdrawal as soon as possible after 
the withdrawal. 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 40 of 125
6.3.1
Potential drug-induced liver injury IMP discontinuation criteria
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if 
IMP must be discontinued. In addition, all concomitant medications and herbal supplements 
that are not medically necessary should also be discontinued. 
The PDILI criteria below require immediate and permanent discontinuation of IMP: 
!
Subjects with either of the following:
∀
ALT or AST ≥5xULN
∀
ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of IMP:
!
Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without 
clear alternative cause), rash, or eosinophilia (ie, >5%).
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume 
IMP administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in Section 11.6.1.2.1 are followed.
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator. 
!
Subjects with ALT or AST ≥3xULN (and ≥2x baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis 
(eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness).
Evaluation of PDILI must be initiated as described in Section 11.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately.
Investigators should attempt to obtain information on subjects in the case of IMP 
discontinuation to complete the final evaluation. Subjects 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 
subject withdrawal (if applicable), must be recorded in the source documents. The CRF must 
document the primary reason for IMP discontinuation.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 41 of 125
7
STUDY TREATMENTS
7.1
Description of investigational medicinal products
The details of the active and placebo IMP are displayed in Table 7‒1.
Table 7‒1:
Description of investigational medicinal product
UCB0942
Placebo for UCB0942
Dosage form
Tablets (white, film-coated), in 
2 strengths:
-
100mg
-
200mg
100mg and 200mg tablets have 
the same size and appearance
Tablets (white, film-coated):
Provided in a size and 
appearance matching UCB0942.
Manufacturer
Batch/lot number
Will be assigned according to GMP
Expiry date
Will be assigned according to GMP
GMP=Good Manufacturing Practice
Note: For the Inpatient Period, 1 kit per treatment period and per dose will be packaged. Each kit will contain 
blister packs, each covering 1 week of treatment. For the Outpatient Period, UCB0942 tablets will be 
provided in bottles, containing 37 tablets per bottle, either 200mg tablets for subjects on UCB0942 400mg bid
or UCB0942 200mg bid, or 100mg tablets for subjects who reduce dose to UCB0942 100mg bid. The bottles 
containing 37 UCB0942 100mg tablets will be dispensed for the Taper Period.
7.2
Treatments to be administered
7.2.1
Test study medication
UCB0942 will be supplied by UCB as 100mg and 200mg tablets that are identical in 
appearance.
7.2.2
Reference product
The placebo will be provided as tablets that are identical in appearance to the tablets
containing UCB0942.
7.3
Packaging
All study medication for the double-blind Inpatient Period will be provided in blister packs 
and administered in a double-blind manner. All subjects will be instructed to take tablets 
containing either UCB0942 or placebo twice per day, approximately 12 hours apart. The
blister-packed treatment cards will each provide 7 days’ treatment of active or placebo 
UCB0942. For the open-label Outpatient Maintenance Period, tablets will be provided in 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 42 of 125
bottles, with a 2-week supply (see Table 5-4). For the Taper Period, bottles of 100mg tablets 
will be dispensed for 1-2 weeks, depending on dose from which the taper starts.
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Conference 
on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good 
Manufacturing Practice (GMP) and will include any locally required statements. If necessary, 
labels will be translated into the local language.
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.
Appropriate room temperature storage conditions must be demonstrated by completion of a 
temperature log in accordance with local requirements, including the capture of minimum 
and maximum temperatures reached over a time interval. Temperatures, including minimum 
and maximum recordings, should be documented daily on the log during the site’s days of 
operation. The IMP is to be stored according to the instructions on the label.
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Exploratory Project Manager (EPM) (or designee) before further use of the IMP.
The EPM (or designee) will transmit the out-of-range temperature (copy of the temperature 
log and duration of the out-of-range temperature, if available) to the Drug Supply 
Coordinator. Based on discussion with a UCB Quality Assurance representative, the Drug 
Supply Coordinator will then provide the EPM (or designee) with instructions for the site 
regarding use of the IMP.
The Investigator (or designee) will instruct the subject 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-subject basis and will serve as source documentation during the course of the study. 
Details of any IMP lost (due to breakage or wastage), not 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) and unused IMP containers must be reconciled and returned to UCB (or 
designee), preferably in their original package. Investigational medicinal product intended for 
the study cannot be used for any other purpose than that described in this protocol.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 43 of 125
7.7
Procedures for monitoring subject compliance
At each visit after where new IMP is dispensed and at the end of the Taper Period (Days 
OP15, OP29, OP43, OP57, and TOO14), subjects must return all unused IMP and empty IMP 
containers. Subjects will be asked to document drug intake on the subject diary throughout 
the Treatment Period. Drug accountability must be done in the subject’s presence in order to 
obtain explanations regarding discrepancies in compliance with the dosing regimen. Drug 
accountability must be recorded on the Drug Accountability form.
If a subject is found to be persistently noncompliant (defined as less than 75% or more than 
125% compliant with the dosage schedule), the Sponsor, in conjunction with the Investigator, 
will make a decision as to whether the subject should be withdrawn from the study.
Timely completion of the subject diary is essential for evaluation of safety and efficacy. A 
caregiver is allowed to help the subject with the completion of the subject diary. Subject diary 
completion will be evaluated at each visit.
7.8
Concomitant medications/treatments
7.8.1
Permitted concomitant treatments (medications and therapies)
The following concomitant medications are permitted during the study:
!
All subjects should continue using their Baseline AED regimen throughout the Inpatient 
Treatment Period. Changes in AEDs during the Outpatient Maintenance Period should be 
discussed with the UCB Study Physician on an individual and case-by-case basis.
!
Oxcarbazepine, eslicarbazepine.
!
Benzodiazepines (as a rescue medication less than or equal to 3 doses within 7 days).
!
Other medication, not mentioned as prohibited, that does not induce CYP3A4 and is
approved by the UCB Study Physician.
7.8.2
Prohibited concomitant treatments (medications and therapies)
The following concomitant medications are prohibited during the study (this is not a 
complete list of prohibited medications):
!
Carbamazepine, phenytoin, phenobarbital, primidone, or other strong CYP3A4 inducers
!
Benzodiazepines taken >3 times per week (see Section 7.8.1)
!
Zolpidem, zaleplon, or zopiclone taken >3 times per week
!
Tiagabine
!
Felbamate
!
Vigabatrin
!
Non-AED CYP3A4 inducers/inhibitors (ie, prescription drugs, nonprescription drugs, 
dietary [eg, grapefruit or passion fruit], or herbal products)
7.8.3
Rescue medication
Benzodiazepines can be used as rescue medication (less than or equal to 3 doses within 
7 days).
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 44 of 125
7.9
Blinding
This is a study with a double-blind Inpatient Period and an open-label Outpatient Period. At 
the start of the Titration Period (Day T1) subjects will be randomized to UCB0942 400mg 
bid or placebo in a 1:1 ratio.
The randomization will be stratified for the following LEV prior/current use factor to ensure 
the balance across treatment groups (Placebo, UCB0942 400mg bid):
!
use of LEV (3 levels):
1. LEV prior and current use (concomitant use of LEV at study entry)
2. LEV Prior Use Only=History of prior LEV use and must have discontinued 
4 weeks prior to study entry
3. LEV Naïve=No history of prior LEV use, and no use at study entry
7.9.1
Procedures for maintaining and breaking the treatment blind
7.9.1.1
Maintenance of study treatment blind
All subject treatment details will be allocated and maintained by the interactive response 
technology (IRT). Details of the IRT system will be addressed in a separate randomization 
schedule specification document.
7.9.1.2
Breaking the treatment blind in an emergency situation
In the event of an emergency, it will be possible to determine which treatment arm and dose 
the subject has been allocated to by contacting the IRT. All sites will be provided with details 
of how to contact the system for code breaking at the start of the study. The Medical Monitor 
or equivalent should be consulted prior to unblinding, whenever possible.
The EPM will be informed immediately via the IRT when a code is broken, but will remain 
blinded to specific treatment information. Any unblinding of the IMP performed by the 
Investigator must be recorded in the source documents and on the Study Termination eCRF 
page.
The SRG may also elect to break the blind for individual subjects as part of its review 
process, in order to better assess the significance and response to AEs of concern (see 
Section 11.1.9).
7.9.1.3
Breaking the treatment blind for taper of dose during the study
When the Investigator and Sponsor Study Physician agree that a subject cannot titrate to the 
maximum dose or that a dose reduction is necessary during the Inpatient Period (See 
Section 5.1, the blind will have to be broken, following the procedure described in Section 
7.9.1.2.
7.10
Randomization and numbering of subjects
An IRT will be used for assigning eligible subjects to a treatment regimen based on a 
predetermined production randomization and/or packaging schedule provided by the IRT 
vendor. The randomization schedule will be produced by the IRT vendor. The IRT will 
generate individual assignments for subject kits of study drug, as appropriate, according to 
the visit schedule.
To enroll a subject (Visit 1), the Investigator or designee will contact the IRT and provide 
brief details about the subject to be enrolled. Each subject will receive a 5-digit number 
assigned at Screening that serves as the subject identifier throughout the study. The subject 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 45 of 125
number will be required in all communication between the Investigator or designee and the 
IRT regarding a particular subject. Subject numbers and kit numbers will be tracked via the 
IRT. 
To randomize a subject (Visit 3), the Investigator or designee will contact the IRT and 
provide brief details about the subject to be randomized. The IRT will automatically inform 
the Investigator or designee of the subject’s randomization number. The IRT will allocate kit 
numbers to the subject based on the subject number during the course of the study.
After completion of the Inpatient Maintenance Period, doses for subjects receiving placebo 
will be titrated to the Outpatient Maintenance Dose (Day TTO 1 to TTO7). To ensure 
continued blinding all subjects will remain in the clinic for this titration period.
8
STUDY PROCEDURES BY VISIT 
Details of the study assessments to be performed at specific time points prior to and after IMP 
administration are provided in Table 5-4, and an outline of all assessments performed is 
provided in the sections below.
The total blood collection for the study will not exceed 500mL per subject.
8.1
Screening and Baseline Period
8.1.1
Screening (Visit 1, Day -1)
!
Written informed consent
!
Complete medical, medication, and procedure history recording
!
Concomitant and past AEDs
!
Review of historic seizure count (ie, in the preceding 4 weeks)
!
Review of inclusion/exclusion criteria
!
Date of birth, sex, ethnicity, and race
!
Habits and lifestyle
!
Physical examination (complete)
!
Neurological examination
!
Psychiatric and cognitive assessments (MINI, BPRS, and MMSE)
!
Vital signs (blood pressure [BP], pulse, and respiratory rate)
!
Body weight and height
!
12-lead ECG
!
Echocardiogram (this can be done on a different day but must be done before dosing with 
UCB0942)
!
Clinical laboratory (clinical chemistry, hematology, and urinalysis)
!
Urine or serum pregnancy test (female subjects only)
!
Drug and alcohol screening
!
Serology (HIV-1/2Ab, HBsAg, and HCV-Ab)
!
C-SSRS (Screening/Baseline version)
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 46 of 125
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Diary card dispense
8.1.2
Baseline Period (Visit 2, Day BL1 to BL14-21)
The Baseline Period (Day BL1 to BL14-21) will commence the day after the first day of 
Screening and will start no more than 3 weeks before entry into the clinic for the Inpatient 
Period. 
During the Baseline Period a phone call will be made to the subject to verify completion of 
the diary card and to confirm the T1 admission day.
Screening assessments that cannot be completed on the first screening visit (eg, brain imaging 
with MRI or CT and echocardiogram) can be performed at any time during the Baseline 
Period but must be completed before the first dose of UCB0942.
If a subject fails screening, a rescreening is allowed if deemed appropriate by the 
Investigator.
8.2
Inpatient Period (3 weeks)
Details of the study assessments to be performed at specific time points during the Inpatient 
Period are provided in Table 5‒5.
An outline of all assessments performed is provided in the sections below.
8.2.1
Titration Week (Visit 3, Day T1 to Day T7)
At the discretion of the Investigator, sites may or may not perform video or video-EEG 
monitoring during parts of the Inpatient Period or during the whole Inpatient Period of the 
study, depending on the infrastructure of each site, to provide objective data on seizure type, 
severity, and duration, and on the duration of the postictal period as an exploratory outcome 
measure. The following assessments will be performed at admission to the clinic on Day T1
before administration of IMP:
!
Return of diary cards and seizure count for the Prospective Outpatient Baseline Period to 
verify continued eligibility to participate in the study
!
Dispense of new diary card
!
Habits and lifestyle
!
Concomitant medication/procedures
!
Urine or serum pregnancy test (female subjects only)
!
Drug and alcohol screening
!
Review of inclusion/exclusion criteria
!
Withdrawal criteria assessment
!
Physical examination (focused)
!
Neurological examination
!
Psychiatric monitoring with BPRS
!
Cognitive monitoring with MMSE
!
Vital signs (BP, pulse, temperature, and respiratory rate)
!
Body weight
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 47 of 125
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12-lead ECG
!
Blood sample for DNA
!
Blood sample for mRNA
!
Blood sample for lipidomics/proteomics/additional biomarkers
!
Blood sample for AED (archival)
!
SSQ (Baseline version)
!
QOLIE-31-P
!
Diary Addendum (T1)
!
C-SSRS (since last visit)
!
Concomitant AEDs
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Concomitant medication/procedures
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Randomization (after all assessments have been done)
Subjects randomized to the active group will be titrated up to UCB0942 400mg bid over 
1 week, as shown in Table 5‒1. Subjects randomized to placebo will do a dummy titration. 
After all admission assessments have been completed, all subjects will be given their first 
100mg dose of IMP (or placebo) in the evening under medical supervision. During the 
double-blind part of the study, subjects in both arms will take the same number of tablets. All 
subjects will continue to record their seizures in subject diaries during the Titration Week.
During the Titration Week the following assessments will be performed as outlined in the 
schedule of assessments (Table 5‒5):
!
Return and dispense of diary card (Day T1)
!
Video or video-EEG monitoring (optional)
!
Withdrawal criteria assessment
!
Psychiatric monitoring with BPRS
!
Cognitive monitoring with MMSE (Days T4 and T7)
!
Vital signs (BP, pulse, and respiratory rate; Days T3, T5, and T7)
!
12-lead ECG (Day T4)
!
Administration of IMP and Baseline AED regimens
!
Concomitant AEDs
!
Concomitant medication/procedures
!
AEs
8.2.2
Maintenance-Dose Week (Visit 4, Day MD1 to Day MD7)
At the end of the Titration Week, subjects continue in the Maintenance-Dose Week, during 
which they will continue to record their seizures in subject diaries.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 48 of 125
During this period the following assessments will be performed as outlined in the schedule of 
assessments (Table 5‒5):
!
Return and dispense of diary card
!
Video or video-EEG monitoring (optional)
!
Withdrawal criteria assessment
!
Physical examination (complete, Day MD1)
!
Neurological examination (Day MD1)
!
Vital signs (BP, pulse, and respiratory rate; Days MD3 and MD7)
!
Body temperature (Day MD7)
!
12-lead ECG (Days MD1, MD3, and MD7)
!
Clinical laboratory (clinical chemistry, hematology, and urinalysis; Days MD1 and MD7)
!
C-SSRS (since last visit; Days MD1 and MD7)
!
Psychiatric monitoring with BPRS
!
Cognitive monitoring with MMSE (Days MD3 and MD7)
!
Administration of IMP and Baseline AED regimens
!
On Day MD1 and MD7, blood samples for measurement of plasma concentration of 
UCB0942 and metabolites at the following times: predose (within 5min of the morning 
dose), then at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h postdose. All times relative to 
morning IMP administration time.
!
Blood sample for mRNA (Day MD7)
!
Blood sample for lipidomics/proteomics/additional biomarkers (Day MD7)
!
Concomitant AEDs
!
Concomitant medication/procedures
!
AEs
!
SSQ (Baseline version) for previous week on Day MD1 and MD7
8.2.3
Transition-to-Outpatient Week (Visit 5, Day TTO1 to Day TTO7)
After the end of the Maintenance-Dose Week, subjects will continue to take IMP if this is 
well tolerated (as determined by the Investigator and the subject). If a subject in the active 
arm is not tolerating UCB0942 400mg bid well during the Maintenance-Dose Week, the dose 
can be tapered to UCB0942 200mg bid during the Transition-to-Outpatient Week before 
discharge to the Outpatient Maintenance Period. In this case, the blind will be broken. The 
taper from UCB0942 400mg bid to UCB0942 200mg bid would occur over 3 days (see 
Table 5‒2).
UCB0942 doses for subjects in the placebo arm will be titrated to UCB0942 400mg bid in the 
same way as the doses for subjects in the active arm were titrated during the Titration Week 
(Table 5‒1). If UCB0942 is well tolerated during the titration, subjects in the placebo arm 
will be discharged on UCB0942 400mg bid and followed in the Outpatient Maintenance 
Period. If a subject in the placebo arm cannot tolerate the titration up to UCB0942 400mg 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 49 of 125
bid, the blind will be broken and the subjects will remain on a tolerable dose (ie, UCB0942 
200mg bid) before starting the Outpatient Maintenance Period.
The entire Inpatient Period will be double-blind (except in cases in which the dose needs to 
be reduced or the taper cannot be completed, as described above); however, subjects and staff 
will know that at discharge all subjects are taking active compound. Therefore, the Outpatient 
Period is open-label.
During the Transition-to-Outpatient Week the following assessments will be performed as 
outlined in the schedule of assessments (Table 5‒5):
!
Return and dispense of diary card
!
Video or video-EEG monitoring (optional)
!
Withdrawal criteria assessment
!
Physical examination (complete; Day TTO7)
!
Neurological examination (Day TTO7)
!
Vital signs (BP, pulse, and respiratory rate; Days TTO4 and TTO7)
!
Body temperature (Day TTO7)
!
Body weight (Day TTO7)
!
12-lead ECG (Day TTO7)
!
Clinical laboratory (clinical chemistry, hematology, and urinalysis; Day TTO7)
!
Administration of IMP and Baseline AED regimens
!
Psychiatric monitoring with BPRS
!
Cognitive monitoring with MMSE (Days TTO4 and TTO7)
!
Withdrawal monitoring with CIWA-B (before evening dose on Day TTO6)
!
SSQ (Baseline version) (Day TTO7)
!
C-SSRS (since last visit; Day TTO7)
!
Blood sample for AED (archival; Day TTO7)
!
Concomitant AEDs
!
Concomitant medication/procedures
!
AEs
Upon release from the clinic subjects will receive IMP for 2 weeks and a diary card for the 
first week of the Outpatient Maintenance Period.
8.3
Outpatient Period (14 weeks)
8.3.1
Outpatient Maintenance Period (Visit 6 to Visit 15, Day OP1 to Day 
OP57)
All subjects will take active UCB0942 during the Outpatient Maintenance Period; however, 
they will not know whether they were taking active or placebo during the Inpatient Period. If 
well tolerated, all subjects will continue to take UCB0942 400mg bid for 8 weeks during the 
Outpatient Maintenance Period. At any time during the Outpatient Maintenance Period, if a 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 50 of 125
subject does not tolerate UCB0942 400mg bid, the Investigator can decide to taper to 
UCB0942 200mg bid as shown in Table 5‒2. During the first week of the Outpatient 
Maintenance Period, all subjects will undergo psychiatric monitoring by phone on the days 
they do not visit the clinic (Days OP1, OP2, OP4, OP6, and OP7) and in person in the clinic 
on Days OP3, OP5, and OP8. Cognitive monitoring with MMSE will take place in the clinic 
on Days OP3, OP5, and OP8. This monitoring is necessary because the subjects initially 
randomized to placebo will be discharged directly after the titration to UCB0942 400mg bid
and psychiatric AEs are most likely to occur in the first 2 weeks of UCB0942 administration.
During the Outpatient Maintenance Period subjects will visit the clinic on the following days 
(±2 days to allow for weekend interruptions):
Day OP3, OP5, OP8, OP15, OP22, OP29, OP36, OP43, OP50, and OP57.
When possible, outpatient clinic visit days will take place in the morning to allow dosing to 
take place in the clinic and collection of a predose blood sample for evaluation of trough PK 
levels at specific visits.
Dose tapering from UCB0942 400mg bid to UCB0942 200mg bid to increase tolerability 
may be implemented for each subject at any time during the 8 weeks of treatment in the 
Outpatient Maintenance Period at the discretion of the Investigator in conjunction with the 
wishes of the subject. Dose tapering to UCB0942 100mg bid may be permitted after 
discussion with the Sponsor’s Study Physician.
During this period the following assessments will be performed according to the schedule of 
assessments (Table 5-4):
!
Return and dispense of diary cards at each visit
!
Return IMP (Days OP15, OP29, OP43, and OP57)
!
Dispense IMP (Days OP15, OP29, OP43, and OP57)
!
Administration of IMP
!
Withdrawal criteria will be assessed at each visit
!
Physical examination (complete; Days OP22 and OP57)
!
Body weight (Days OP22 and OP57)
!
Neurological examination (Days OP22 and OP57)
!
Vital signs (BP, pulse, and respiratory rate; Days OP8, OP22, OP36, and OP57)
!
12-lead ECG (Days OP22 and OP57)
!
Echocardiogram (Day OP22 ±1 week)
!
Clinical laboratory (clinical chemistry, hematology, urinalysis; Days OP8, OP22, and 
OP57)
!
Drug and alcohol screening (Days 22 and OP57)
!
Urine or serum pregnancy test (females only; Days OP8, OP36, and OP57)
!
Obtain blood samples for measurement of plasma concentration of UCB0942 and  
metabolites before morning dose (Days OP3, OP5, OP8, OP15, OP22, OP29, OP36, 
OP43, OP50, and OP57)
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 51 of 125
!
Psychiatric monitoring with BPRS at the visits (Days OP3, OP5, OP8, OP15, OP22, 
OP29, OP36, OP43, OP50, and OP57) and by phone (Days OP1, OP2, OP4, OP6, and 
OP7)
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Concomitant AEDs recording
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Concomitant medication/procedures recording
!
AEs recording
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Decision to continue in the OLE study (Day OP43)
8.3.2
Taper Period (Visit 15 to Visit 17, Day OP57 to TOO14)
All subjects who do not continue into the OLE study (see Section 8.6) will undergo a Taper 
and Safety Follow-Up Period to taper off study medication over a 2-week period (Table 5‒3). 
Subjects will start their taper on Day OP57 (Visit 15) and will return for the Mid Taper Visit 
(Day TOO7) after 1 week and for the End of Taper Visit (Day TOO14) after 2 weeks. 
Changes to concomitant AED(s) are allowed during taper of UCB0942. Subjects can also 
start this taper earlier during the Outpatient Maintenance Period, if they decide to exit the 
study early.
During this period the following assessments will be performed as outlined in the schedule of 
assessments (Table 5-4):
!
Return and dispense of diary cards at each visit
!
Withdrawal criteria will be assessed at each visit
!
Administration of IMP
!
Physical examination (Day TOO14)
!
Neurological examination (Day TOO14)
!
Vital signs (BP, pulse, and respiratory rate) (Day TOO14)
!
12-lead ECG (Day TOO14)
!
Return IMP (Day TOO14)
!
SSQ (Baseline version) (Day TOO14)
!
QOLIE-31-P questionnaire (Day TOO14) 
!
Psychiatric monitoring with BPRS (Days TOO7 and TOO14)
!
Cognitive monitoring with MMSE (Days TOO7 and TOO14)
!
Withdrawal monitoring with CIWA-B (Days TOO7 and TOO14)
!
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 52 of 125
!
AED archival sample (Day TOO14)
!
Concomitant medication/procedures
!
AEs
8.3.3
Safety Follow-Up (Visit 18 to 20, Day SFU7, SFU14, and SFU28)
Two SFU visits are planned: the first SFU is planned 1 week after the end of the Taper Period
(SFU7) and a final SFU 4 weeks after the end of the Taper Period (SFU28). During these
visits the following assessments will be performed:
!
Return of diary card (Day SFU7, SFU14 [optional], and SFU28), dispense of diary card 
(Day SFU7 and SFU14 [optional])
!
Physical examination
!
Neurological examination
!
Vital signs (BP, pulse, and respiratory rate)
!
Body weight (Day SFU28)
!
12-lead ECG (Day SFU28)
!
Clinical laboratory (clinical chemistry, hematology, and urinalysis)
!
Echocardiogram after last dose and 6 months later (±1 month). For subjects who 
withdraw during the Inpatient Period and for subjects who withdraw during the 
Outpatient Period, see Section 8.4 for echocardiogram requirements following 
withdrawal. 
!
Pregnancy test (urine or serum, females only)
!
SSQ (Baseline version)
!
C-SSRS (since last visit)
!
Psychiatric monitoring with BPRS
!
Cognitive monitoring with MMSE
!
Withdrawal monitoring with CIWA-B
!
Concomitant medication/procedures
!
AEs
If deemed necessary by the Investigator 1 additional SFU visit can be planned one week after 
Day SFU7 (Day SFU14) containing those assessments deemed necessary by the Investigator.
8.3.4
Echocardiography follow up
For subjects who complete this study but do not continue in the OLE study, it is mandatory 
that they have an echocardiogram at 6 months (±1 month) after the last dose of IMP (in 
addition to the echocardiogram at Screening, during dosing, and after the last dose). 
8.4
Withdrawal Visit
In case of early withdrawal of the subject for any reason, all efforts should be taken to have a 
safety follow-up visit as described in Section 8.3.3.
If a complete SFU is not feasible, at least the following assessments will be performed:
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 53 of 125
!
Physical examination
!
Neurological examination
!
Vital signs (BP, pulse, and respiratory rate)
!
Body weight
!
12-lead ECG
!
Echocardiogram
∀
Withdrawal during the Inpatient Period: The SFU7 echocardiogram should be 
performed. If there is no abnormality, the echocardiogram does not need to be 
repeated. If there is an abnormality, the echocardiogram should be repeated at 
6 months (±1 month) after the last dose of IMP. 
∀
Withdrawal during the Outpatient Period: The SFU7 echocardiogram should be 
performed, and the echocardiogram should be repeated at 6 months (±1 month) after 
the last dose of IMP. 
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Clinical laboratory (clinical chemistry, hematology, and urinalysis)
!
Pregnancy test (urine or serum, females only)
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Diary Addendum
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8.5
Unscheduled Visit
At any time, the subject may have an unscheduled clinic visit/phone call if the Investigator or 
the subject deems it necessary.
During an Unscheduled Visit the assessments will be performed as applicable as judged by 
the Investigator
8.6
Open-label extension study (EP0073)
Subjects who experience substantial benefit from UCB0942 with acceptable tolerability may 
have the option to continue taking UCB0942 during an OLE study. The decision to enter the 
OLE study must be made by the subject in consultation with the Investigator and/or the 
subject’s caregiver. This decision must take into account the benefit experienced, the 
potential risks of long-term exposure to UCB0942, and the potential benefit and risks of other 
treatment options available. Subjects who enter the OLE study will have echocardiographic 
follow up as scheduled in the OLE study protocol and will therefore not participate in the
echocardiographic follow up described in Section 8.3.4.
9
ASSESSMENT OF EFFICACY
The efficacy variables are described in detail in Section 4.1.
9.1
Seizure frequency
At the Screening Visit, seizure count will be based on Investigator assessment of subjects’ 
reports during the 4 weeks prior to the Screening Visit, which will determine the subject’s
eligibility for the study. The minimum required historic seizure count during the 4 weeks
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 54 of 125
prior to Screening is 4 partial-onset seizures (IA1, IB, or IC according to the International 
Classification of Epileptic Seizures, 1981) per week on average with no seizure-free period 
longer than 3 days (based on Investigator assessment of subject report). During the study, 
subjects will keep diaries to record daily seizure activity from the Screening Visit until the 
end of study participation. Subjects should be reminded to bring their diaries with them to 
each clinic visit. 
The written information will be discussed with the subjects at each visit in order to ensure 
completeness and accuracy. As a result of the discussion, the Investigator will assess the 
seizures according to the ILAE codes and record the seizure types and frequency in the 
eCRF; he/she will also confirm the presence of AEs if applicable.
Subjects should be educated to complete their diary entries after each seizure or at least once 
a day (eg, when taking evening tablets). A caregiver can assist in completing the diary if 
necessary. Substantial noncompliance with diary completion (seizure recording) may result in 
subject discontinuation from the study at any time by the Investigator or the Sponsor; see 
Section 6.3.
The following seizure information will be recorded in the diary:
!
Seizure type
!
Seizure frequency
9.1.1
Video monitoring
At the discretion of the Investigator, sites may or may not perform video or video-EEG 
monitoring during part of the Inpatient Period or during the whole Inpatient Period,
depending on the infrastructure of each site, to allow exploratory analysis of seizure type, 
severity, and duration, and of the duration of the postictal period.
9.2
Seizure Severity Questionnaire
The SSQ (Cramer et al, 2002) is a review of various aspects of seizures. The person who has 
seizures may ask people who have observed the seizures (family, friends) to help answer 
some of the questions asking about events, but not about feelings. There are 10 questions in 3
sections asking about events before, during, and after typical seizures.
The subject should describe their most common type of seizure when answering the 
questions. If subjects are unsure about how to answer a question, they should give the best 
answer they can and write a comment or explanation on the side of the page. 
The Baseline SSQ will be completed according to the tabular schedule of study procedures, 
Table 5-4. The Baseline version of the SSQ will be used for all visits during which the SSQ is 
to be completed. For this study the recall period will be set to 1 week rather than the original 
4 weeks. At the very beginning of the visit, the SSQ will be provided to all subjects. The 
subject will be asked to complete the questionnaire on his/her own. Once completed, the 
subject will return the completed questionnaire to the Investigator or designee, who will 
verify that all questions have been answered. Further details about the SSQ will be covered in 
the Study Manual.
9.3
Quality of Life Inventory in Epilepsy-31-P
The QOLIE-31-P assesses subject functioning and health-related quality of life.
The QOLIE-31-P (Cramer et al, 2003) is an adaptation of the original QOLIE-31 instrument 
(Cramer et al, 1998) that includes 30 items grouped into 7 multi-item subscales (Seizure 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 55 of 125
Worry [5 items], Overall Quality of Life [2 items], Emotional Well-being [5 items], 
Energy/Fatigue [4 items], Cognitive Functioning [6 items], Medication Effects [3 items], and 
Daily Activities/Social Functioning [5 items]) and 1 health status item.
In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items assessing the 
degree of “distress” associated with the topic of each subscale (ie, distress items) and 1 item 
asking about the relative importance of each subscale topic (ie, prioritization item).
The QOLIE-31-P will be completed according to the tabular schedule of study procedures in
Table 5-4. At the very beginning of the visit, the QOLIE-31-P will be provided to all 
subjects. The subject will be asked to complete the questionnaire on his/her own. Once 
completed, the subject will return the completed questionnaire to the Investigator or designee, 
who will verify that all questions have been answered. Further details about the QOLIE-31-P 
will be covered in the Study Manual.
9.4
Diary Addendum
A Diary Addendum will be completed according to the tabular schedule of study procedures 
in Table 5-4 as well as at the Withdrawal Visit, if applicable. The Diary Addendum will 
consist of a series of open-ended questions including the following: 
!
Why did you agree to take part in this study? 
!
What are your hopes for this new treatment? 
!
What are the biggest impacts of seizures on your life currently? 
!
What was your experience like during the study?
!
Did participating in the study fulfill any of the hopes you had going into the study? 
!
How do you describe the impact of seizures on your life now? Has that changed since the 
beginning of the study? 
Subjects will be instructed to leave any question blank that he/she does not feel comfortable 
answering. 
10
ASSESSMENT OF PK AND EXPLORATORY VARIABLES
10.1
Pharmacokinetic parameters
The PK variables are described in detail in Section 4.2. Calculations of PK parameters will be 
made with Phoenix WinNonlin (version 6.2 or higher) using the actual sampling times and 
are described in Section 13.4.2. The linear trapezoidal method will be used to calculate the 
AUC parameters. 
Detailed information on the collection, storage, preparation, and shipping of samples will be 
presented in a Laboratory Manual.
10.2
Exploratory parameters
Detailed information on the collection, storage, preparation, and shipping of samples for 
DNA, mRNA, lipidomics, and proteomics analysis will be presented in a Laboratory Manual.
Results for the exploratory parameters obtained from DNA, mRNA, lipidomics, and 
proteomics analysis will be described in a separate report.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 56 of 125
10.3
Sampling procedures
Blood samples for PK and exploratory variables will be obtained at the scheduled time points 
presented in Table 5-4.
Times for PK samplings will be taken with respect to the time of the morning UCB0942 dose 
on the first and last day of the Maintenance-Dose Week, taken as Time 0=0h. Exact sampling 
times will be recorded in the eCRF. 
Predose blood samples for levels of UCB0942 and its major metabolites will be obtained 
after ECGs and vital signs but prior to dosing of the study medication at Visit 4 and Visit 5.
Predose (trough) blood samples for levels of UCB0942 and its major metabolites will be 
obtained at Visits 6 to 15. The Investigator and the subject should make a realistic effort to 
plan the visits during the Outpatient Maintenance Period before the morning or the evening 
dose of UCB0942. If a predose blood sample is not feasible for a specific visit, a postdose 
blood sample should be collected and the actual times of the dosing and sampling recorded.
For the exploratory assessments, the processing of the blood samples will be described in the 
Laboratory Manual. One sample each will be collected for the mRNA, lipidomics, and 
proteomics assay.
For the AED archival samples, processing will be described in the Laboratory Manual.
Preprinted labels will be provided by the analytical laboratory of UCB. Laboratory kits will 
be provided by UCB or a delegate.
10.4
Bioanalytical methods
Plasma concentrations of UCB0942 and metabolites 
 
 will be determined using validated bioanalytical methods.
10.5
Pharmacokinetic/pharmacodynamic relationships 
If appropriate, a population PK analysis will be performed, as described in Section 13.4.2.
If needed, exploratory exposure-response analysis will be performed to describe the 
relationship between the exposure to UCB0942 and the efficacy and/or safety variables.
11
ASSESSMENT OF SAFETY
11.1
Adverse events
11.1.1
Definition of adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
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 Informed Consent form), including any pretreatment and 
posttreatment periods required by the protocol, ie, through the end of the Taper/Safety 
Follow-up Period, 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.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 57 of 125
Signs or symptoms of the condition/disease for which the investigational product is being 
studied (ie, seizures) 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 subject’s history or the Baseline Period.
11.1.2
Procedures for reporting and recording adverse events
The subject 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.
11.1.3
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 subject’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.
11.1.4
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 subject is lost to follow up.
If an AE is ongoing at the end of the Taper/Safety Follow-up Period, 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 subject 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 subject has discontinued his/her IMP.
Adverse events should not be recorded in the eCRF after the end of the Taper/Safety Follow-
up Period.
11.1.5
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported 
with:
!
The outcome date of the first AE that is not related to the natural course of the disease 
being the same as the start date of the repeated AE, and the outcome of “worsening”
!
The AE verbatim term being the same for the first and repeated AE, so that the repeated 
AE can be easily identified as the worsening of the first one
11.1.6
Pregnancy
If an Investigator is notified that a subject has become pregnant after the first intake of any 
IMP, the Investigator must immediately notify UCB’s Drug Safety (DS) department by 
providing the completed Pregnancy Report and Outcome form (for contact details see SAE
reporting information at the beginning of this protocol). The subject should be withdrawn 
from the study as soon as pregnancy is known (by positive pregnancy test), and the following 
should be completed:
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 58 of 125
!
The subject should return for an early discontinuation visit.
!
The subject should immediately stop the intake of the IMP or be tapered as instructed at 
the early discontinuation visit. 
!
A Safety Follow-Up Visit should be scheduled 1 week after the subject has discontinued 
her IMP.
The Investigator must inform the subject 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 subject is lost to follow up and/or refuses to give information, 
written documentation of attempts to contact the subject needs to be provided by the 
Investigator and filed at the site. UCB’s DS 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 subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via 
the Partner Pregnancy Consent form that has been approved by the responsible IEC and 
should be available in the Investigator site file. In case of questions about the consent 
process, the Investigator may contact 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 DS 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 DS 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 a 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.
11.1.7
Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the Drug Accountability or Study Drug Dosing module of 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).
11.1.8
Safety signal detection
Appropriate data from the study will be reviewed on an ongoing basis to detect as early as 
possible any safety concern(s) related to the IMP so that Investigators, clinical study subjects, 
regulatory authorities, and IECs will be informed appropriately and as early as possible.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 59 of 125
The Study Physician or medically qualified designee/equivalent will conduct an ongoing 
review of AEs and (especially) any SAEs and perform ongoing SAE reconciliations in 
collaboration with the DS representative.
In addition, the SRG will conduct scheduled reviews of appropriate study data for the 
purpose of safety signal detection.
11.1.9
Safety Review Group
An SRG will be established prior to the start of the study, which will comprise, at a 
minimum, the Study Physician(s), clinical pharmacologist, DS representative, biostatistician,
Coordinating Investigator, and the 
 local Coordinating Investigator, with the intention 
of protecting the safety, health, and well-being of each participating subject. Individual 
Principal Investigators (PI, or their delegate) for each participating site will be invited when 
required. The precise membership, scope, and responsibilities of the SRG are described in the 
SRG Charter. 
The SRG will meet once the first 4 subjects have completed the Transition-to-Outpatient 
Week (Visit 6) or withdrawn from the study before Visit 6. Subsequent meetings will occur 
when the first 10 subjects, the first 16 subjects, and the first 22 subjects have completed 
Visit 6 or withdrawn from the study before Visit 6. Thereafter, SRG meetings will be held on 
an as required/ad hoc basis, in response to emerging data, and at the request of any member 
of the SRG.
The SRG will remain blinded through the first database lock (see Section 12.3.3) unless 
emergent safety information requires unblinding of individual drug allocation for optimal 
assessment and response to AEs of concern. At the time of the first database lock, the Study 
Physician(s), clinical pharmacologist, DS representative, biostatistician, and other UCB 
personnel will be unblinded as to all subjects’ treatment allocation at the beginning of the 
Inpatient Period. 
11.2
Serious adverse events
11.2.1
Definition of serious adverse event
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:
!
Death
!
Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred 
in a more severe form.)
!
Significant or persistent disability/incapacity
!
Congenital anomaly/birth defect (including that occurring in a fetus)
!
Important medical event that, based upon appropriate medical judgment, may jeopardize 
the patient or subject 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 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.)
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 60 of 125
!
Initial inpatient hospitalization or prolongation of hospitalization, except if an extension 
of the Inpatient Period is required to adjust the dose of UCB0942 before discharge
(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 subject 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.)
11.2.2
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 subject, and to also inform participating 
subjects 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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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 61 of 125
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 Investigator’s 
Brochure.
11.2.3
Follow up of serious adverse events
An SAE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
Information on SAEs obtained after clinical database lock will be captured through the DS 
database without limitation of time.
11.3
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.
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 subject.
11.4
Immediate reporting of adverse events
The following AEs must be reported immediately:
!
SAE: AE that the Investigator classifies as serious by the above definitions regardless of 
causality
!
Suspected transmission of an infectious agent via a medicinal product
11.5
Anticipated serious adverse events
The following list of Anticipated SAEs has been identified, as these SAEs are anticipated to 
occur in the epilepsy population at some frequency that is independent of drug exposure. This 
original list will remain in effect for the duration of the protocol.
This list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 11.2.2.
Table 11‒1: Anticipated SAEs for the epilepsy population
MedDRA System Organ Class
MedDRA Preferred Term
Congenital, familial and genetic disorders
Teratogenicity
General disorders and administration site 
conditions
Sudden unexplained death in epilepsy
Injury, poisoning, and procedural complication
Fall
a, fracturea, injurya
Nervous system disorders
Cluster seizures, cognitive disorder, convulsion,
incontinencea,b, status epilepticus
Pregnancy, puerperium, and perinatal disorders
Abortion spontaneous
Psychiatric disorders
Abnormal behavior, anxiety, confusional state,
psychotic behavior, sleep disorder
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
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Table 11‒1: Anticipated SAEs for the epilepsy population
MedDRA System Organ Class
MedDRA Preferred Term
Reproductive system and breast disorders
Impotence, menstrual disorder
MedDRA=Medical Dictionary for Regulatory Activities; SAE=serious adverse event; SOC=System Organ Class
a Event is considered to be anticipated when occurring in context of seizure.
b Event is not classified in MedDRA primary SOC.
11.6
Laboratory measurements
Each site will use their own local clinical laboratory. The following laboratory parameters 
will be measured:
Table 11‒2: Laboratory measurements
Hematology
Chemistry
Urinalysis
a
Basophils
ALP
Total protein
Eosinophils
Calcium
Glucose
Lymphocytes
Chloride
pH
Monocytes
Magnesium
RBC
Neutrophils
Potassium
WBC
Hematocrit
Sodium
Hemoglobin
Glucose
MCH
BUN or urea
MCHC
AST
MCV
ALT
Platelet count
Total bilirubin
RBC count
LDH
WBC count
Creatinine
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood 
cell; WBC=white blood cell
a Dipstick test only
11.6.1
Evaluation of PDILI
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI 
events must be reported as an AE and reported to the study site and sponsor within 24 hours 
of learning of their occurrence. Any PDILI event that meets the criterion for potential Hy’s 
Law must be reported as an AE of special interest (see Section 11.3), and, if applicable, also 
reported as an SAE (see Section 11.1.1).
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒3 (specific tests dependent on laboratory results and corresponding symptoms) and 
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
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Page 63 of 125
consultation with a local hepatologist (if applicable; discussed in Section 11.6.1.1). 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 on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.6.1.4). 
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 CRF 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 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 11.6.1.2.1 are met, rechallenge with IMP may be appropriate. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may 
be fatal, and must not occur.
The table below summarizes the approach to investigate PDILI.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 64 of 125
Table 11‒3: Required investigations and follow up for PDILI
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptomsa of 
hepatitis or 
hypersensitivity
Consultation 
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Actions
Testing
Evaluation
≥3xULN
≥2xULN
b
NA
Hepatology consult.c
Medical Monitor 
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within 24 hours 
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discussed with 
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ASAP.
Immediate, 
permanent IMP 
discontinuation.
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 11.6.1.3); 
recommended to 
occur at the site 
with HCP.
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values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d
≥8xULN
NA
NA
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NA
Yes
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temporary or 
permanent, IMP 
discontinuation.
≥3xULN 
(and ≥2x 
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and 
<5xULN
<2xULN
No
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met.
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 11.6.1.2).
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator).
≥5xULN 
(and ≥2x 
baseline) 
<2xULN
No
Discussion with 
Medical Monitor 
required.
Immediate, 
permanent IMP 
discontinuation.
Essential: Every 
attempt must be 
made to have 
repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
at the site with 
HCP (see 
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Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 65 of 125
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 If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor.
c Details provided in Section 11.6.1.1. 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 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
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
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Page 66 of 125
11.6.1.1
Consultation with the 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 subject must be discussed with the Medical 
Monitor as soon as possible. If required, the subject 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 11.6.1.3) and SAE report (if 
applicable).
11.6.1.2
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 ranges from continuation of IMP (followed by immediate investigation) 
to immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒3 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.
11.6.1.2.1
IMP restart/rechallenge (if applicable)
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may 
be fatal, and must not occur.
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 11‒3), but for whom an alternative diagnosis 
is confirmed, can rarely restart IMP. Rechallenge with IMP can occur only if ALL of the 
following requirements are met:
!
The results of additional testing and monitoring described in Section 11.6.1.3 and 
Section 11.6.1.4 confirm a nondrug-related cause for the abnormal hepatic laboratory 
parameters and any associated symptoms (ie, a subsequent alternative diagnosis fully 
explains the hepatic findings). 
!
No alternative treatment options are available to the subject.
!
The subject has shown clear therapeutic benefit from the IMP.
!
Subject’s ALT or AST elevations do not exceed ≥3xULN.
!
Subject’s total bilirubin is <1.5xULN.
!
Subject has no signs or symptoms of hypersensitivity. 
!
The rechallenge is approved by the UCB responsible physician and a hepatologist. The 
hepatologist must be external to UCB. It is recommended that the hepatologist be a local 
hepatology expert or the hepatologist treating the subject.
!
Subject agrees to the investigator-recommended monitoring plan.
11.6.1.3
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 
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UCB
10 Oct 2016
Clinical Study Protocol
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Page 67 of 125
in Table 11‒4 (laboratory measurements) and Table 11‒5 (additional information). Results of 
the laboratory measurements and information collected are to be submitted to the sponsor on 
the corresponding CRF. If the medical history of the subject 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.
The following measurements are to be assessed:
Table 11‒4: 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 subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause).
The following additional information is to be collected:
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
Confidential
Page 68 of 125
Table 11‒5: 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:
!
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”)
!
Adverse reactions to drugs
!
Allergies
!
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)
!
Recent travel 
!
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.)
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash)
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function
Alcohol and illicit drug use
Results of liver imaging or liver biopsy, if done
Results of any specialist or hepatology consult, if done
Any postmortem/pathology reports
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury
11.6.1.4
Follow-up evaluation
Potential drug-induced liver injury events require follow-up and monitoring as described in 
Table 11‒3. 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.
11.7
Other safety measurements
11.7.1
Vital signs
Vital signs including pulse rate, systolic BP, diastolic BP, respiratory rate, and body 
temperature (Day T1 before UCB0942 administration) will be measured in supine position, 
after 5 minutes of rest. Any clinically significant abnormality in the view of the Investigator
will be recorded as an AE.
Vital signs will be measured at the scheduled time points presented in Table 5-4.
11.7.2
Electrocardiograms
All ECG recordings will be performed with the subject resting in the supine position for at 
least 5 minutes. The 12-lead ECG recordings will be measured at the scheduled time points 
presented in Table 5-4. ECG will be recorded at a speed of 25mm/s and with a calibration of 
1cm/mV.
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
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The Investigator should review all ECG recordings and, if there are abnormalities that are 
considered clinically significant for a particular subject, then the Investigator should initiate a 
review by a specialist of all ECG data pertaining to that subject. The following ECG 
parameters will be recorded in the eCRF: heart rate, PR-interval, QRS-duration, QT-interval, 
QTcB or QTcF, and Investigator’s conclusion on ECG profile.
11.7.3
Echocardiograms
Echocardiograms will be performed during Screening, during dosing (Day OP22 ±1 week), 
and after the last dose of IMP (SFU7), as described in Table 5-4. The echocardiogram will be 
repeated at 6 months (±1 month) after the last dose in the following subjects: 
!
Subjects who complete this study but do not enter the OLE study
!
Subjects who withdraw from the Outpatient Period 
!
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 
echocardiogram
2D Doppler echocardiography will be performed with:
1. Diastolic measurements (mitral forward flow E and A waves and deceleration time)
2. Tissue Doppler on medial and lateral mitral valve annulus (S, E, and A waves)
3. Standardized views for left atrial volume measurements
Images will be recorded and stored digitally and retained if further analysis is needed. A 
complete echocardiography manual will be provided.
11.7.4
Physical examination
Physical examinations will be performed at the scheduled time points presented in Table 5-4. 
The physical examination will include general appearance; ear, nose, and throat; eyes, hair, 
and skin; respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological 
(including limb reflexes); and mental status. Findings that are considered clinically 
significant changes since the physical examination at the Screening Visit will be recorded as 
AEs.
In addition, height will be measured at the Screening Visit with the subject not wearing shoes 
and the outcome will be rounded to the nearest 0.5cm. Body weight will be measured at the 
scheduled time points presented in Table 5-4 . Body weight will be measured with the subject 
in underwear or light clothing and without wearing shoes; the outcome will be rounded to the 
nearest 0.1kg. At the Screening Visit, the BMI will be calculated (weight [kg]/[height (m)]²) 
and will be reported to 1 decimal place.
11.7.5
Assessment of suicidality
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 C-SSRS will be completed according to the tabular schedule 
of study procedures (Section 5.2). The Investigator’s decision about patient continuation in 
the study or patient withdrawal from the study if the patient 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 patient circumstances, condition, 
attained efficacy, causality, alternative risk management options, etc. Details of the case must 
be documented by the investigator (PI or investigator physician, not site staff conducting the 
CSSRS) and provided to UCB via the SAE reporting process.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 70 of 125
11.7.6
Psychiatric and cognitive assessments
The overall psychiatric condition of the subjects will be assessed at screening using the BPRS 
and the MINI questionnaire. The BPRS is a questionnaire consisting of 16 questions which 
captures the psychiatric condition of the subject. 
The MINI is a widely used psychiatric structured diagnostic interview instrument. The MINI 
is divided into modules identified by letters corresponding to diagnostic categories. Rating is 
done to the right of each question by circling either Yes or No.
The MMSE is a sensitive, valid, and reliable 30-point questionnaire that is used extensively 
in clinical and research settings to measure cognitive impairment.
Further details about all questionnaires used in this study will be covered in the Study 
Manual.
11.7.7
Withdrawal monitoring
Any symptoms of withdrawal reactions will be monitored using the CIWA-B questionnaire. 
The CIWA-B questionnaire contains 22 questions which are selected to distinguish 
withdrawal symptoms from other symptoms. Further details about this questionnaire will be 
covered in the Study Manual.
12
STUDY MANAGEMENT AND ADMINISTRATION 
12.1
Adherence to protocol
The Investigator should not deviate from the protocol. In medical emergencies, the 
Investigator may use his/her medical judgment and may remove a study participant from 
immediate hazard before notifying UCB (or its representative) and the IEC in writing 
regarding the type of emergency and the course of action taken.
12.2
Monitoring
PRA will monitor the study to meet PRA’s monitoring Standard Operating Procedures 
(SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure that study 
initiation, conduct, and closure are adequate. Monitoring of the study may be delegated by 
UCB to a CRO or a contract monitor.
The Investigator and his/her staff are expected to cooperate with PRA and to be available 
during the monitoring visits to answer questions sufficiently and to provide any missing 
information. The Investigators/institutions will permit direct access to source data/documents 
for study-related monitoring, audits, IEC review, and regulatory inspection(s).
The Investigator will allow PRA to periodically review all eCRFs and corresponding source 
documents (eg, hospital and laboratory records for each study participant). Monitoring visits 
will provide the CRO 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.
12.2.1
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
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 71 of 125
Source documents are original records in which raw data are first recorded. These may 
include hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, 
printouts, pharmacy records, care records, ECG or other printouts, completed scales, or 
quality of life questionnaires, for example. Source documents should be kept in a secure, 
limited access area.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and 
dated by the Investigator and become a permanent part of the subject’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 echocardiogram results, must be saved and stored as 
instructed by UCB (or designee).
12.2.2
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, subject 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 12.2.1.
12.3
Data handling
12.3.1
Case Report form completion
This study is performed using remote data capture. 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.
12.3.2
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. The data are entered into the eCRF once and are subsequently 
verified.
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.
12.3.3
Database lock
The database lock and unblinding may occur in a tiered approach. 
Details regarding the tiered database lock will be described in the Data Management Plan. 
Plans for analysis of data and production of tables, figures and listings will be described in 
the Statistical Analysis Plan (SAP).
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10 Oct 2016
Clinical Study Protocol
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EP0069
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Page 72 of 125
12.3.4
Subject Screening and Enrollment log/Subject Identification Code 
list
The subject’s screening and enrollment will be recorded in the Subject Screening and 
Enrollment Log.
The Investigator will keep a Subject Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each subject.
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation.
12.4
Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at 
a single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform 
the Investigators/institutions and the regulatory authority(ies) of the termination or 
suspension and the reason(s) for the termination or suspension, in accordance with applicable 
regulatory requirement(s). The IEC should also be informed and provided with reason(s) for 
the termination or suspension by the Sponsor or by the Investigator/institution, as specified 
by the applicable regulatory requirement(s). In addition, arrangements will be made for the 
return of all unused IMP and other material in accordance with UCB procedures for the 
study.
12.5
Archiving and data retention
The Investigator will maintain adequate records for the study, including eCRFs, medical 
records, laboratory results, Informed Consent documents, drug dispensing and disposition 
records, safety reports, information regarding participants who discontinued, and other 
pertinent data.
All essential documents are to be retained by the Investigator until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IMP. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirement(s) 
or by an agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The Investigator 
will contact UCB for authorization prior to the destruction of any study records or in the 
event of accidental loss or destruction of any study records. The Investigator will also notify 
UCB should he/she relocate or move the study-related files to a location other than that 
specified in the Sponsor’s study master file.
12.6
Audit and inspection
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, 
and inspections by domestic or foreign regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and well-being of 
the subjects enrolled have been protected, that enrolled subjects (ie, signing consent and 
undergoing study procedures) are appropriate for the study, and that all data relevant for the 
evaluation of the IMP have been processed and reported in compliance with the planned 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 73 of 125
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).
12.7
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.
13
STATISTICS
A description of statistical methods follows and will be described in more detail in the SAP.
13.1
Definition of analysis sets
Analysis sets will be defined as follows:
∀
The Enrolled Set (ES) will consist of all subjects who signed the ICF.
∀
The Randomized Set (RS) will consist of all enrolled subjects who were randomized.
∀
The Full Analysis Set (FAS) will consist of all randomized subjects who received at 
least 1 dose of IMP and have at least 1 post-Baseline seizure diary.
∀
The Per-Protocol Set (PPS) will consist of all subjects in the FAS Population who do 
not have a major protocol deviation impacting the primary efficacy variable.
∀
The Safety Set (SS) will consist of all randomized subjects who receive at least 1 dose 
of IMP.
All primary and secondary efficacy analyses will be carried out using the FAS.
Selected supportive efficacy analyses will be carried out using the PPS.
Safety analyses will be carried out using the SS.
All analyses will be based on randomized treatment assignment. Incorrectly-treated subjects
will be evaluated during the data evaluation meeting to assess the potential impact of such 
cases and any special analysis considerations.
The periods considered in the definition of efficacy and safety variables are the following:
!
Baseline Period consisting of 2 weeks of prospective subject diary seizure counts during 
the Prospective Outpatient Baseline Period
!
Inpatient Double-Blind Treatment Period
∀
Double-Blind Titration Week (inpatient)
∀
Maintenance-Dose Week (inpatient)
∀
Transition to Outpatient Week (inpatient)
!
Outpatient Maintenance Period
!
Last 4 weeks of Outpatient Maintenance Period
!
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10 Oct 2016
Clinical Study Protocol
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EP0069
Confidential
Page 74 of 125
13.2
General statistical considerations
Summary statistics will be provided for all efficacy, safety, and Baseline/demographic 
variables. Summary statistics will consist of frequency tables for categorical variables. For 
continuous variables, descriptive statistics (number of available observations, mean, median, 
standard deviation [SD], minimum, maximum, 25th and 75th percentiles) will be tabulated. 
Unless otherwise mentioned, statistical hypothesis tests will be one-sided at the 5% 
significance level.
13.3
Planned efficacy analyses
The efficacy variables will be analyzed as described below using the FAS.
Total seizure frequency per week (7 days) will be derived from the seizure count information 
recorded on the diary card and is defined as the number of seizures standardized to a 7-day 
period. It is computed as the number of seizures recorded (by category: total, type I, type IA1, 
IB, and IC) over the period, divided by the total number of days in that period, multiplied 
by 7.
13.3.1
Analysis of the primary efficacy variable
The primary outcome measure is the 75%RR. In the active group, this is defined as the 
proportion of subjects with a 75% or greater reduction in focal seizure frequency during the 
last 2 weeks of the Inpatient Period compared to the 2-week Prospective Outpatient Baseline
Period. In the placebo group, the 75%RR is defined as the proportion of subjects with a 75% 
or greater reduction in focal seizure frequency during the first 2 weeks of the Inpatient Period 
(the 2 weeks on placebo) compared to the Prospective Outpatient Baseline Period. The 
75%RR will be analyzed using a logistic regression with effects for treatment, for LEV use 
stratification factor, and log-transformed Baseline seizure frequency as a continuous 
covariate. Odds-ratio of UCB0942 versus placebo groups and its 95% confidence intervals
(CI) will be estimated. The primary analysis will be performed on the FAS but also on the 
PPS.
13.3.2
Secondary efficacy analyses
Median percent reduction in seizures:
The percent reduction in total and partial seizure frequency from Baseline to the 
corresponding Treatment Period will be compared between UCB0942 arm and placebo using 
a Wilcoxon-Mann-Whitney test. The Hodges-Lehmann non-parametric estimator will be used 
to estimate the median percent reduction in seizures between groups and its corresponding 
95% CI will be provided. For secondary efficacy variables using responder rate (75%RR and 
50%RR), the analysis will be conducted similarly to the primary efficacy analysis 
(Section 13.3.1). Different treatment periods will be considered (inpatient as defined in 
Section 13.3.1, outpatient, and overall).
Seizure freedom:
To be considered seizure free, a subject must not report seizures of any type and must 
complete the corresponding treatment period. The seizure freedom rate will be analyzed 
using a logistic regression with effects for treatment and log-transformed Baseline seizure 
frequency as a continuous covariate. Odds-ratio of UCB0942 versus placebo groups and its 
95% CIs will be estimated. The seizure freedom will be evaluated at the following different 
treatment times: Inpatient Period as defined in Section 13.3.1, last 4 weeks of Outpatient 
Maintenance Period.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 75 of 125
Percentage of seizure-free days:
A descriptive analysis will be performed on the percentage of seizure-free days by treatment 
group and study periods.
13.3.3
Exploratory efficacy analyses
Seizure severity:
Changes in the SSQ and average seizure severity as calculated by the percentage of seizures 
that are type IC from Baseline to the end of the Inpatient Period and the end of the Outpatient 
Maintenance Period will be analyzed.
The QOLIE-31-P (change from Baseline) will be analyzed by descriptive statistics and any 
relevant graphical displays. Relationship between QOLIE-31-P parameters and efficacy 
parameters (seizure reduction, 75%RR) will be evaluated.
Seizure frequency (continuous variable):
An analysis of covariance (ANCOVA) will be performed on the log-transformed weekly 
seizure frequency data. Specifically, ln(1+weekly seizure frequency during the Treatment 
Period) will be modeled with treatment group as factor and ln(1+weekly seizure frequency at 
Baseline) as covariate. Contrasts will be estimated to compare UCB0942 to observed placebo 
results.
All seizure frequency (Type I+II+III) and subtypes of partial seizures (Type IA, IB, IC) per 
week over the Treatment Period will be analyzed in a manner similar to the seizure 
frequency. Transformation of efficacy data could be envisaged given the data distribution. 
Different treatment periods will be considered (inpatient as defined in Section 13.3.1, 
outpatient, and overall).
Box-plots will be also displayed for the change in seizure frequency (absolute and 
percentage).
Exploratory analysis will be performed on the seizure count/SSQ data collected during the 
Tapering/Safety Follow-Up Period.
13.4
Planned safety and population PK analyses
13.4.1
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Adverse events will be summarized by MedDRA System Organ Class and 
Preferred Term. The incidence of SAEs, AEs leading to premature discontinuation or dose 
tapering, and related AEs, and the incidence of AEs by maximum intensity, will also be 
summarized.
Laboratory values, ECG data (ventricular rate, PR, QTc [using Bazett’s and Fridericia’s 
formula], and QRS), vital signs, weight, and changes from Baseline in these measures will be 
summarized by period, visit, and treatment group. Possibly clinically significant treatment-
emergent abnormalities for laboratory values, vital signs, and weight will be listed and 
summarized by period and visit for each treatment group. 
Electrocardiogram abnormalities as well as physical and neurological abnormalities will also 
be listed by period and visit. Quantitative safety parameters will be summarized descriptively 
by time point and treatment group. Categorical safety summaries will provide the number and 
percentage of subjects within each summarized category. Doppler echocardiography results 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
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Page 76 of 125
at Baseline and during and after treatment, and changes from Baseline, will be listed and 
descriptively summarized.
All C-SSRS data obtained at Baseline and subsequent visits will be reported as a listing 
ordered by subject and visit. Psychiatric and cognitive assessments (MINI, BPRS, and 
MMSE) and CIWA-B data will also be covered using listings. Moreover, hypersensitivity 
reactions data will be summarized and listed.
13.4.2
PK analyses
13.4.2.1
Non-compartmental PK analysis
Plasma concentrations of UCB0942, 
 will be 
determined from blood samples obtained in the study, during the Titration and Maintenance 
Periods in order to investigate the PK of UCB0942 and its major metabolites.
The following PK parameters will be calculated:
! AUCτ:
area under the plasma concentration-time curve over a dosing interval, as 
determined using the linear trapezoidal rule.
! Cmax:
maximum observed plasma concentration.
! tmax:
time of Cmax.
! t½:
apparent terminal elimination half-life, reported in hours, as determined via 
simple linear regression (slope = -λz) of natural log(ln) concentration vs time 
for data points in the terminal phase of the concentration-time curve. t½ is 
calculated as ln(2)/λz.
! Ctrough:
measured concentration at the end of the dosing interval at steady state.
The PK variables will be computed by non-compartmental analysis (NCA) with Phoenix 
WinNonlin (version 6.2 or higher) using the actual sampling times. The linear trapezoidal 
method will be used to calculate AUC parameters.
PK parameters of UCB0942 and its metabolites will be listed and summarized using the 
following descriptive statistics: number of observations, geometric mean, lower and upper 
95% CI, geometric coefficient of variation (CV), arithmetic mean, SD, median, and minimum 
and maximum values. Graphical outputs over time will be produced on the trough plasma 
drug concentrations.
13.4.2.2
Population PK analysis
If appropriate, a population PK analysis will be conducted to characterize the PK of 
UCB0942, including inter-individual variability, and to assess the potential effect of 
concomitant AEDs on the PK of UCB0942. The population PK analysis will be based on 
plasma concentrations obtained during the Maintenance Week of the Inpatient Period, as well 
as samples collected during the Outpatient Maintenance Period. A separate data analysis plan 
(DAP) will describe the analysis, which will be reported in a separate report.
13.4.2.3
Population PK-PD analysis
Exploratory population PK-PD analysis may be performed if needed to characterize the 
relationship between exposure to UCB0942 and the clinical and/or safety clinical outcome. A 
separate DAP will describe the analysis, which will be reported in a separate report.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
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Page 77 of 125
13.5
Handling of protocol deviations
After all lockable data have been verified/entered into a database and prior to the first 
database lock, a data evaluation meeting will take place. The purpose of the data evaluation 
will be to examine all protocol deviations, define the PPS, and to verify the quality of the 
data. The data evaluation will also help in guiding decisions on how to manage data issues on 
a case-by-case basis (eg, withdrawals, dropouts, and protocol deviations).
Accepted deviations from theoretical time points will be described in the appropriate 
documents and included in the Study Master File. After the data review, resolution of all 
issues, and documentation of all decisions, the database will be locked.
13.6
Handling of dropouts or missing data
The methods for handling dropouts will be described in the SAP.
13.7
Planned interim analyses and data monitoring
An interim analysis will be performed if needed for purposes of planning and designing of 
future studies. If performed, this analysis will be conducted when at least 75% of patients 
have been randomized and completed through the Inpatient Period (completed through 
Visit 5).
All subjects who have completed through Visit 5 at the time of the data snapshot will be 
included in the interim analysis.
All statistical analyses will be described in detail in the interim SAP.
For the interim analysis, the primary efficacy variable (75%RR) will be analyzed using the 
methods described for the primary efficacy analysis. In addition, seizure-free rate, 50%RR, 
and percent reduction in focal seizure frequency will be analyzed as described for the 
secondary/exploratory analyses.
The 75%RR, Seizure-free rate, and 50%RR variables may also be analyzed using Bayesian 
logistic regression. If Bayesian analysis is performed, the percent reduction in focal seizure 
frequency from the Baseline will be estimated using Bayesian analysis of variance (ANOVA) 
and/or ANCOVA. For these analyses, posterior medians, 95% credible intervals for the 
treatment effect, and additional posterior probabilities will be presented. Non informative and 
informative priors will be considered, and sensitivity to different prior settings will be 
assessed. Other efficacy variables may also be analyzed in the Bayesian framework.
The following safety data will also be presented: 
!
Treatment emergent AEs
!
AEs leading to drop-out or withdrawal
!
SAEs
!
Laboratory assessments out of normal range
!
BPRS
The study will not be terminated early for either efficacy or futility based on the results of 
this interim analysis and therefore, an alpha penalty of 0.001 to be assessed on the primary 
efficacy analysis is considered appropriate.  
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10 Oct 2016
Clinical Study Protocol
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EP0069
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Page 78 of 125
The study is not expected to be stopped due to safety reasons during this interim analysis, 
since there are ongoing quarterly Safety Review Group meetings already planned for this 
purpose. Therefore, no criteria for evaluation of early stopping due to safety are included.  
An unblinded team will be established at both the Sponsor and CRO and will include the 
following roles (all unblinded): Data Manager, Statistician, Statistical Programmer, and 
Project Lead. All staff involved in the conduct of the study, including staff at UCB, the CRO, 
participating vendors, and the participating sites will remain blinded to individual treatment 
identity and will not be informed of the results of the interim analysis until final unblinding. 
13.8
Determination of sample size
This is an exploratory pilot study to obtain a first evaluation of the efficacy (estimate and 
variability) of UCB0942 in this specific refractory population. The planned sample size was 
evaluated based on placebo results obtained in similar refractory epileptic populations from
BRV and lacosamide Phase 3 studies in add-on partial epilepsy, and the desired effect was 
based on a doubling of the effect of lacosamide and BRV in subjects in the current target 
population.
For the primary efficacy variable, the 75%RR in the placebo group from these historical 
studies was estimated to be less than 5%. The response on UCB0942 was expected to be 
36.5% in order to provide clear differentiation from lacosamide and BRV in this patient 
population. 
Based on a 2-group Fisher's exact one-sided test with a ratio active:placebo of 1:1, the 
required number of subjects is 23 in each arm to detect a significant difference between the 
2 groups with a power of 80% and a false positive rate of 5%.
14
ETHICS AND REGULATORY REQUIREMENTS
14.1
Informed consent
Subject’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 subject in both oral and written form by the Investigator 
(or designee). Each subject will have the opportunity to discuss the study and its alternatives 
with the Investigator.
Prior to participation in the study, the written ICF should be signed and personally dated by 
the subject, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The subject or his/her legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, each subject 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 subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent form. An
eCRF must not be started, nor may any study specific procedure be performed for a given 
subject, without having obtained his/her written consent to participate in the study.
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10 Oct 2016
Clinical Study Protocol
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EP0069
Confidential
Page 79 of 125
14.2
Subject identification cards
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the 
subject. The Investigator will fill in the subject identifying information and medical 
emergency contact information. The Investigator will instruct the subject to keep the card 
with him/her at all times.
14.3
Subject compensation
In addition to reimbursement of incurred expenses (eg, travel), subjects will be financially 
compensated for the burden and inconvenience of spending time at the inpatient unit as this is 
an unusual requirement for participants in clinical studies. The amount of compensation will 
be country-specific and approved by the local ethics committee.
14.4
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, 
Informed Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if 
applicable), advertisement (if applicable), and all other subject-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 subjects or others, and any protocol 
deviations, to eliminate immediate hazards to subjects.
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 subjects. 
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 subject 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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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 80 of 125
14.5
Subject privacy
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject 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 subject’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 subject’s study participation, and autopsy reports 
for deaths occurring during the study).
14.6
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 IECs, and the regulatory authorities (if required), prior to 
being implemented.
15
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.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 81 of 125
16
REFERENCES
Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern nonenzyme-
inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis. Epilepsia.
2012;53(3):512-20.
Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in 
newly diagnosed epilepsy. Neurology. 2012;78(20):1548-54.
Busto UE, Sykora K, Sellers EM. A clinical scale to assess benzodiazepine withdrawal. J 
Clin Psychopharmacol. 1989;9(6):412-6
Chung S, Ben-Menachem E, Sperling MR, Rosenfeld W, Fountain NB, Benbadis S, et al.
Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical 
trials. CNS Drugs. 2010;24(12):1041-54.
Commission on Classification and Terminology of the International League Against 
Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia. 1981;22:489-501.
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Cramer JA, Baker GA, Jacoby A. Development of a new seizure severity questionnaire: 
initial reliability and validity testing. Epilepsy Res. 2002;48:187-97.
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. 
Epilepsia. 1998;39(1):81-8.
Cramer JA, Van Hammée G, N132 Study Group. Maintenance of improvement in health-
related quality of life during long-term treatment with levetiracetam. Epilepsy Behav. 
2003;4(2):118-23.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-98.
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al.
Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the 
ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-77.
Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment 
schedules. Eur J Neurol. 2006;13(3):277-82.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychological Reports.
1962:10:799-812.
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.
Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment 
history. Neurology. 2008;70(1):54-65.
Steinhoff BJ. Efficacy of perampanel: a review of pooled data. Epilepsia. 2014;55 Suppl 1:
9-12.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 82 of 125
17
APPENDICES
17.1
Protocol Amendment 1.0
Rationale for the amendment
The addition of an echocardiogram during dosing was made as a result of comments from the 
Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und 
Medizinprodukte). They have requested the addition of an echocardiogram during dosing. 
This echocardiogram has been added at Day OP22. In addition, the following changes were 
made:
-
It has been clarified that either urine or serum pregnancy tests can be used for all 
visits. 
-
It has been pointed out that the decision to continue in the OLE will occur at
Day OP43. 
-
Clarification on the procedure for dose reduction in cases of poor tolerability of 
UCB0942 400mg bid (ie, reduction to UCB0942 200mg bid and in some cases to 
UCB0942 100mg bid).
-
The withdrawal criteria for elevated transaminases have been reworded as the 
previous description was not clear.
Modifications and changes
Specific changes
Change #1
Section 1 SUMMARY, bullet #7
!
An echocardiogram at the end of the study and at 6 months after the final dose
Has been changed to:
!
An echocardiogram during dosing, after the last dose, and at 6 months after the final dose
Change #2
Section 1 SUMMARY, paragraph 6
Titration to UCB0942 400mg bid will occur over the course of 1 week in the clinical unit. For 
subjects in the active arm, doses will be titrated to UCB0942 400mg bid during the first 
inpatient week. For subjects who initially received placebo, doses will be titrated to 
UCB0942 400mg bid during the last week of the Inpatient Period. For subjects in the active 
arm who do not tolerate UCB0942 400mg bid, during the third week of the Inpatient Period, 
the dose can be tapered to UCB0942 200mg bid before starting the Outpatient Maintenance 
Period. Similarly, for subjects in the placebo group the dose can be tapered to a tolerable dose 
during the Outpatient Maintenance Period. All subjects will stay in the clinical unit for a total 
of 3 weeks and will then be discharged for an 8-week Outpatient Maintenance Period.
Has been changed to:
Titration to UCB0942 400mg bid will occur over the course of 1 week in the clinical unit. For 
subjects in the active arm, doses will be titrated to UCB0942 400mg bid during the first 
inpatient week. For subjects who initially received placebo, doses will be titrated to 
UCB0942 400mg bid during the last week of the Inpatient Period. For subjects in the active 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
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Page 83 of 125
arm who do not tolerate UCB0942 400mg bid, during the third week of the Inpatient Period, 
the dose can be tapered to UCB0942 200mg bid before starting the Outpatient Maintenance 
Period. Similarly, for subjects in the placebo group the dose can be tapered to UCB0942 
200mg bid during the Outpatient Maintenance Period. Dose tapering to UCB0942 100mg bid 
may be permitted after discussion with the Sponsor’s Study Physician. All subjects will stay 
in the clinical unit for a total of 3 weeks and will then be discharged for an 8-week Outpatient 
Maintenance Period.
Change #3
Section 4.1.3 Exploratory efficacy variables, bullet #4
!
Change in time to recovery from Baseline to the end of the Inpatient Period and the end 
of the Outpatient Maintenance Period (derived from the SSQ, see Section 9.2).
Has been deleted
Change #4
Section 4.4 Safety variables, bullet #10
!
Changes in 2-dimensional Doppler echocardiography from Baseline to after treatment 
(end of dosing and 6 months after last dose), with diastolic measurements as well as atrial 
volumes to identify any subtle valvular changes and to assess for pericardial effusions
Has been changed to:
!
Changes in 2-dimensional Doppler echocardiography from Baseline to after Baseline 
(during dosing, after the last dose, and 6 months after last dose), with diastolic 
measurements as well as atrial volumes to identify any subtle valvular changes and to 
assess for pericardial effusions
Change #5
Section 5.1 Study description, bullet #7
!
An echocardiogram at the end of the study and at 6 months after the last dose
Has been changed to:
!
An echocardiogram during dosing, after the last dose, and at 6 months after the last dose
Change #6
Section 5.1 Study description, paragraph 6
If a subject is not tolerating UCB0942 400mg bid well, the dose can be tapered to UCB0942 
200mg bid. The taper from UCB0942 400mg bid to UCB0942 200mg bid will occur over 
3 days (see Table 5‒2) and will require unblinding of the subject if this occurs during the 
Inpatient Period.
Has been changed to:
If a subject is not tolerating UCB0942 400mg bid well, the dose can be tapered to UCB0942 
200mg bid. The taper from UCB0942 400mg bid to UCB0942 200mg bid will occur over 
3 days (see Table 5‒2) and will require unblinding of the subject if this occurs during the 
Inpatient Period. Dose tapering to UCB0942 100mg bid may be permitted after discussion 
with the Sponsor’s Study Physician.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 84 of 125
Change #7
Section 5.1.2 Planned number of subjects and sites
Subjects with highly drug-resistant focal epilepsy will be enrolled at up to 10 
 sites 
in order to provide 46 evaluable subjects, ie, 46 subjects who complete the Inpatient Period.
Subjects who drop out before Visit 6 (eg, during the Inpatient Period) for reasons other than 
safety or tolerability will be replaced. First subject, first visit is planned for Q2 2015.
Has been changed to:
Subjects with highly drug-resistant focal epilepsy will be enrolled at 
 sites in order 
to provide 46 evaluable subjects, ie, 46 subjects who complete the Inpatient Period. Subjects 
who drop out before Visit 6 (eg, during the Inpatient Period) for reasons other than safety or 
tolerability will be replaced. First subject, first visit is planned for Q2 2015.
Change #8
Section 5.2 Schedule of study assessments
In the schedule of study assessments (Table 5-4), an “X” has been added at Day OP22 for 
echocardiogram. 
Change #9
Section 5.2 Schedule of study assessments, Table 5-4, footnote j:
j In addition to the echocardiogram after the last dose, for subjects who do not continue in the 
OLE study, an echocardiogram at 6 months after the last dose will also be performed.
Has been changed to:
j In addition to the echocardiogram during dosing and after the last dose, for subjects who do 
not continue in the OLE study, an echocardiogram at 6 months after the last dose will also be 
performed. Please note that the during dosing time point of Day OP22 for the 
echocardiogram has a time window of ±1 week instead of ±2 days.
Change #10
Section 5.2 Schedule of study assessments, Table 5-4, footnote l:
l Serum pregnancy test at Screening and admission (Day T1); urine pregnancy test at all other 
occasions.
Has been changed to:
l Urine or serum pregnancy test.
Change #11
Section 5.2 Schedule of study assessments, Table 5-5, footnote h:
h Serum pregnancy test, female subject only.
Has been changed to:
h Urine or serum pregnancy test, female subject only.
Change #12
Section 5.3 Schematic diagram
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 85 of 125
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 86 of 125
Change #13
Section 6.3 Withdrawal criteria, criterion #1
Subject develops a clinically relevant medical condition (or laboratory abnormality) that, in 
the opinion of the Investigator, compromises the subject’s ability to participate or safety. In 
the case of transaminase (AST, ALT, or both) levels at least 3 times the upper limit of normal 
(ULN) to less than 5 times the ULN, in the presence of normal total bilirubin, the laboratory 
tests will be repeated within a few days. If the repeat testing confirms the abnormality (ie, 
transaminases are at least 3 times the ULN to less than 5 times the ULN with normal 
bilirubin), then weekly monitoring of liver function tests should continue until resolved (ie, 
less than 3 times the ULN or stable condition). The Investigator is to decide whether or not to 
stop the investigational medicinal product (IMP). To monitor for hypersensitivity reactions, 
percent eosinophils >10% or absolute eosinophil count ≥0.5G/L or absolute neutrophil count 
<1.5G/L or absolute platelet count ≤100G/L, if in combination with fever, rash, 
lymphadenopathy, or other symptoms/signs suggestive of internal organ involvement 
(including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, 
pancreatitis, myositis, or arthritis) will lead to stopping the IMP.
Has been changed to:
Subject develops a clinically relevant medical condition (or laboratory abnormality) that, in 
the opinion of the Investigator, compromises the subject’s ability to participate or safety. In 
the case of transaminase (AST, ALT, or both) levels at least 3 times the upper limit of normal 
(ULN) in the presence of normal total bilirubin, the laboratory tests will be repeated within a 
few days. If the repeat testing confirms the abnormality, then weekly monitoring of liver 
function tests should continue until resolved (ie, less than 3 times the ULN or stable 
condition). The Investigator is to decide whether or not to stop the investigational medicinal 
product (IMP). To monitor for hypersensitivity reactions, percent eosinophils >10% or 
absolute eosinophil count ≥0.5G/L or absolute neutrophil count <1.5G/L or absolute platelet 
count ≤100G/L, if in combination with fever, rash, lymphadenopathy, or other 
symptoms/signs suggestive of internal organ involvement (including but not limited to 
hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, pancreatitis, myositis, or 
arthritis) will lead to stopping the IMP.
Change #14
Section 7.1 Description of investigational medicinal products, Table 7-1, 
Note
For the Inpatient Period, 1 kit per treatment period and per dose will be packaged. Each kit 
will contain blister packs, each covering 1 week of treatment. For the Outpatient Period, 
UCB0942 tablets will be provided in bottles, containing 40 tablets per bottle, either 200mg 
tablets for subjects on UCB0942 400mg bid, or 100mg tablets for subjects who reduce dose 
to UCB0942 200mg bid. The bottles containing 40 UCB0942 100mg tablets will be 
dispensed for the Taper Period.
Has been changed to:
For the Inpatient Period, 1 kit per treatment period and per dose will be packaged. Each kit 
will contain blister packs, each covering 1 week of treatment. For the Outpatient Period, 
UCB0942 tablets will be provided in bottles, containing 37 tablets per bottle, either 200mg 
tablets for subjects on UCB0942 400mg bid, or 100mg tablets for subjects who reduce dose 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 87 of 125
to UCB0942 200mg bid. The bottles containing 37 UCB0942 100mg tablets will be 
dispensed for the Taper Period.
Change #15
Section 7.9.1.3 Breaking the treatment blind for taper of dose during the 
study
If the IMP is not tolerated during the Inpatient Period by an individual subject, the dose can 
be tapered to the last tolerated dose. This is only permitted if the subject has great difficulty 
tolerating the IMP and the Investigator does not think that tolerability will improve. When it 
is decided to reduce the dose, the blind will have to be broken, following the procedure 
described in Section 7.9.1.2.
Has been changed to:
If the IMP is not tolerated during the Inpatient Period by an individual subject, the dose can 
be tapered to UCB0942 200mg bid. This is only permitted if the subject has great difficulty 
tolerating the IMP and the Investigator does not think that tolerability will improve. When it 
is decided to reduce the dose, the blind will have to be broken, following the procedure 
described in Section 7.9.1.2.
Change #16
Section 8.1.1 Screening (Visit 1, Day -1), bullet #16
!
Serum pregnancy test (female subjects only)
Has been changed to:
!
Urine or serum pregnancy test (female subjects only)
Change #17
Section 8.2.1 Titration Week (Visit 3, Day T1 to Day T7), bullet #5
!
Serum pregnancy test (female subjects only)
Has been changed to:
!
Urine or serum pregnancy test (female subjects only)
Change #18
Section 8.3.1 Outpatient Maintenance Period (Visit 6 to Visit 15, Day OP1 
to Day OP57), paragraph 4
Further dose tapering may be implemented for each subject during the 8 weeks of treatment 
in the Outpatient Maintenance Period at the discretion of the Investigator in conjunction with 
the wishes of the subject.
Has been changed to:
Dose tapering from UCB0942 400mg bid to UCB0942 200mg bid to increase tolerability 
may be implemented for each subject at any time during the 8 weeks of treatment in the 
Outpatient Maintenance Period at the discretion of the Investigator in conjunction with the 
wishes of the subject. Dose tapering to UCB0942 100mg bid may be permitted after 
discussion with the Sponsor’s Study Physician.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 88 of 125
And the following bullet point has been added:
!
Echocardiogram (Day OP22 ±1 week)
Change #19
Section 8.3.1 Outpatient Maintenance Period (Visit 6 to Visit 15, Day OP1 
to Day OP57), BULLET #13
!
Urine pregnancy test (females only; Days OP8, OP36, and OP57)
Has been changed to:
!
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And the following bullet point has been added:
!
Decision to continue in the OLE study (Day OP43)
Change #20
Section 8.3.3 Safety Follow-Up (Visit 18 to 20, Day SFU7, SFU14, and 
SFU28), BULLET #9
!
Pregnancy test (urine, females only)
Has been changed to:
!
Pregnancy test (urine or serum, females only)
Change #21
Section 8.3.4 Echocardiography follow up
For subjects who do not continue in the OLE study, it is mandatory that they have an 
echocardiogram at 6 months (±1 month) after the last dose of IMP (in addition to the 
echocardiogram at the end of the study). 
Has been changed to:
For subjects who do not continue in the OLE study, it is mandatory that they have an 
echocardiogram at 6 months (±1 month) after the last dose of IMP (in addition to the 
echocardiogram at Screening, during dosing, and after the last dose). 
Change #22
Section 8.4 Withdrawal Visit, bullet #18
!
Pregnancy test (serum, females only)
Has been changed to:
!
Pregnancy test (urine or serum, females only)
Change #23
Section 8.6 Open-label extension study (EP0073)
Subjects who experience substantial benefit from UCB0942 with acceptable tolerability will 
have the option to continue taking UCB0942 during an OLE study. The decision to enter the 
OLE study must be made by the subject in consultation with the Investigator and/or the 
subject’s habitual epilepsy provider (the neurologist who treats the subject outside of the 
study), and this decision must take into account the benefit experienced, the potential risks of 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 89 of 125
long-term exposure to UCB0942, and the potential benefit and risks of other treatment 
options available that have not been tried. Subjects who enter the OLE study will have 
echocardiographic follow up as scheduled in the OLE study protocol and will therefore not 
participate in the echocardiographic follow up described in Section 8.3.4.
Has been changed to:
Subjects who experience substantial benefit from UCB0942 with acceptable tolerability may 
have the option to continue taking UCB0942 during an OLE study. The decision to enter the 
OLE study must be made by the subject in consultation with the Investigator and/or the 
subject’s caregiver. This decision must take into account the benefit experienced, the 
potential risks of long-term exposure to UCB0942, and the potential benefit and risks of other 
treatment options available. Subjects who enter the OLE study will have echocardiographic 
follow up as scheduled in the OLE study protocol and will therefore not participate in the 
echocardiographic follow up described in Section 8.3.4.
Change #24
Section 9.2 Seizure Severity Questionnaire, paragraph 3
The SSQ will be competed according to the tabular schedule of study procedures, Table 5-4.
For this study the recall period will be set to 1 week rather than the original 4 weeks. At the 
very beginning of the visit, the SSQ will be provided to all subjects. The subject will be asked 
to complete the questionnaire on his/her own. Once completed, the subject will return the 
completed questionnaire to the Investigator or designee, who will verify that all questions 
have been answered. Further details about the SSQ will be covered in the Study Manual.
Has been changed to:
The SSQ will be completed according to the tabular schedule of study procedures, Table 5-4.
For this study the recall period will be set to 1 week rather than the original 4 weeks. At the 
very beginning of the visit, the SSQ will be provided to all subjects. The subject will be asked 
to complete the questionnaire on his/her own. Once completed, the subject will return the 
completed questionnaire to the Investigator or designee, who will verify that all questions 
have been answered. Further details about the SSQ will be covered in the Study Manual.
Change #25
Section 11.7.3 Echocardiograms, paragraph 1
Echocardiograms will be performed during Screening, after the last dose of IMP, and at 
6 months after the last dose of IMP, as described in Table 5-4.
Has been changed to:
Echocardiograms will be performed during Screening, during dosing (Day OP22 ±1 week), 
after the last dose of IMP, and at 6 months after the last dose of IMP, as described in 
Table 5-4.
Change #26
Section 13.3.3 Exploratory efficacy analyses, paragraph 1
Changes in the SSQ, time to recovery, and average seizure severity as calculated by the 
percentage of seizures that are type IC from Baseline to the end of the Inpatient Period and 
the end of the Outpatient Maintenance Period will be analyzed.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 90 of 125
Has been changed to:
Changes in the SSQ and average seizure severity as calculated by the percentage of seizures 
that are type IC from Baseline to the end of the Inpatient Period and the end of the Outpatient 
Maintenance Period will be analyzed.
Change #27
Section 13.4.1 Safety analyses, paragraph 3
Electrocardiogram abnormalities as well as physical and neurological abnormalities will also 
be listed by period and visit. Quantitative safety parameters will be summarized descriptively 
by time point and treatment group. Categorical safety summaries will provide the number and 
percentage of subjects within each summarized category. Doppler echocardiography results 
at Baseline and after treatment, and changes from Baseline, will be listed and descriptively 
summarized.
Has been changed to:
Electrocardiogram abnormalities as well as physical and neurological abnormalities will also 
be listed by period and visit. Quantitative safety parameters will be summarized descriptively 
by time point and treatment group. Categorical safety summaries will provide the number and 
percentage of subjects within each summarized category. Doppler echocardiography results 
at Baseline and during and after treatment, and changes from Baseline, will be listed and 
descriptively summarized.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 91 of 125
17.2
Protocol Amendment 2.0
Rationale for the amendment
The protocol describes the use of video monitoring during the Inpatient Period. The video 
monitoring is an exploratory endpoint, and the data will be used to assess the difference 
between seizure diaries (the primary endpoint) and seizures detected with video. The 
intention of the protocol language was to let sites perform video monitoring according to their 
usual clinical practice; however, the language in the first version was not sufficiently clear to 
convey this flexibility. The purpose of this amendment is to make the video monitoring 
language in the protocol more flexible so that sites/Investigators can perform this according 
to their usual practice. This new language will also allow video-EEG monitoring as some 
sites do not perform video-only monitoring. 
A second change was the wording of the drug misuse exclusion criterion. As is customary in 
most UCB protocols, exclusion for drug misuse is only applicable if the Investigator deems 
that study participation is either a risk to the subject or that the drug misuse could confound 
the outcomes measured in the study. The wording of this exclusion criterion was changed to 
match that of other UCB studies.
In addition, the possibility of rescreening screening failures was added.
Modifications and changes
Specific changes
Change #1
Section 3.3 Exploratory objectives, bullet #2
Use video recordings to explore the effect of UCB0942 on seizure type, seizure severity, 
seizure duration, and duration of the postictal period
Has been changed to:
Use video recordings, when available, to explore the effect of UCB0942 on seizure type, 
seizure severity, seizure duration, and duration of the postictal period
Change #2
Section 4.3, Exploratory variables, paragraph 4
During the Inpatient Period, there will be video monitoring of subjects in their rooms (and in 
other areas depending on the infrastructure of each site) to assess seizure type, severity, 
duration, and the duration of the postictal period.
Has been changed to:
At the discretion of the Investigator, sites may or may not perform video or 
video- electroencephalogram (EEG) monitoring during parts of the Inpatient Period or during 
the whole Inpatient Period, depending on the infrastructure of each site, to assess seizure 
type, severity, duration, and the duration of the postictal period.
Change #3
Section 5.2 Schedule of study assessments, Table 5-4, footnote a:
If a subject fails screening, a rescreening is allowed if deemed appropriate by the 
Investigator.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 92 of 125
Has been added, subsequent footnotes have been renumbered 
accordingly
Change #4
Section 5.2 Schedule of study assessments, Table 5-4:
Video monitoring in subject rooms
Has been changed to:
Video or video-EEG monitoringm
Change #5
Section 5.2 Schedule of study assessments, Table 5-4:
EEG=electroencephalogram;
Has been added
Change #6
Section 5.2 Schedule of study assessments, Table 5-4, footnote m:
At the discretion of the Investigator, sites may or may not perform video or video-EEG 
monitoring during parts of the Inpatient Period or during the whole Inpatient Period.
Has been added, subsequent footnotes have been renumbered 
accordingly
Change #7
Section 5.2 Schedule of study assessments, Table 5-5:
Video monitoring in subject rooms
Has been changed to:
Video or video-EEG monitoringh
Change #8
Section 5.2 Schedule of study assessments, Table 5-5:
EEG=electroencephalogram;
Has been added
Changes #9
Section 5.2 Schedule of study assessments, Table 5-5, footnote h:
At the discretion of the Investigator, sites may or may not perform video or video-EEG 
monitoring during parts of the Inpatient Period or during the whole Inpatient Period.
Has been added, subsequent footnotes have been renumbered 
accordingly
Change #10
Section 6.2 Exclusion criteria, criterion #18
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 93 of 125
18. Subject has a history in the last 5 years of drug or alcohol dependency or tests positive for 
drugs of abuse or alcohol during Screening.
Has been changed to:
18. Subject has past or present substance abuse/dependence that in the opinion of the 
Investigator could threaten the subject’s safety within the study, affect the subject’s 
ability to fully participate in the study, or confound study interpretation.
Change #11
Section 8.1.2 Baseline Period (Visit 2, Day BL1 to BL14-21)
If a subject fails screening, a rescreening is allowed if deemed appropriate by the 
Investigator.
Has been added
Change #12
Section 8.2.1 Titration Week (Visit 3, Day T1 to Day T7)
During the Inpatient Period of the study, all subjects will be monitored by video in their 
bedrooms (and at some sites in other areas) to provide objective data on seizure type, 
severity, and duration, and on the duration of the postictal period as an exploratory outcome 
measure.
Has been changed to:
At the discretion of the Investigator, sites may or may not perform video or video-EEG 
monitoring during parts of the Inpatient Period or during the whole Inpatient Period of the 
study, depending on the infrastructure of each site, to provide objective data on seizure type, 
severity, and duration, and on the duration of the postictal period as an exploratory outcome
measure.
Change #13
Section 8.2.1 Titration Week (Visit 3, Day T1 to Day T7)
!
Video seizure monitoring in subject rooms
Has been changed to:
!
Video or video-EEG monitoring (optional)
Change #14
Section 8.2.2 Maintenance-Dose Week (Visit 4, Day MD1 to Day MD7)
At the end of the Titration Week, subjects continue in the Maintenance-Dose Week, during 
which they will continue to record their seizures in subject diaries and will continue to be 
video-monitored in their bedrooms.
Has been changed to:
At the end of the Titration Week, subjects continue in the Maintenance-Dose Week, during 
which they will continue to record their seizures in subject diaries.
Change #15
Section 8.2.2 Maintenance-Dose Week (Visit 4, Day MD1 to Day MD7)
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 94 of 125
!
Video monitoring in subject rooms
Has been changed to:
!
Video or video-EEG monitoring (optional) 
Change #16
Section 8.2.3
Transition-to-Outpatient Week (Visit 5, Day TTO1 to Day 
TTO7)
!
Video monitoring
Has been changed to:
!
Video or video-EEG monitoring (optional)
Change #17
Section 9.1.1
Video monitoring
During all inpatient periods, there will be continuous video monitoring in subjects’ rooms 
(and at some sites in other areas) to allow exploratory analysis of seizure type, severity, and 
duration, and of the duration of the postictal period.
Has been changed to:
At the discretion of the Investigator, sites may or may not perform video or video-EEG
monitoring during part of the Inpatient Period or during the whole Inpatient Period, 
depending on the infrastructure of each site, to allow exploratory analysis of seizure type, 
severity, and duration, and of the duration of the postictal period.
17.3
Protocol Amendment 3.0
Rationale for the Amendment
The primary reason for Amendment 3 is to add and describe an optional interim analysis for 
purposes of planning and designing of future studies. 
Other reasons for the amendment include the following: 
!
To add an exploratory objective, variable and associated assessment (diary 
addendum). Note that this was already part of the study, but not clearly described in 
the protocol.
!
To clarify procedures for dosing when there is intolerance to study medication during 
the Inpatient Period
!
To allow and specify flexibility in dosing during the Outpatient Maintenance Period
!
To further specify which Subjects require an echocardiogram at 6 months after the 
last dose of study medication
!
To expand the range of BMIs allowed for inclusion in the study
!
To revise procedures for assessment of suicidality using the C-SSRS (specifically, the 
C-SSRS withdrawal criterion) in line with revision to sop-ai-015774, Version 2.0,
which became effective on 01 Apr 2016. 
!
To update the protocol information pertaining to potential drug-induced liver injury 
(exclusion criteria, withdrawal criteria, adverse events of special interest, and 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 95 of 125
assessments) based on new standard language which is being applied across all 
protocols at UCB. Note that these additions do not reflect a change in the known 
safety of the compound. 
!
To revise study personnel and make other administrative changes 
Modifications and changes
Specific changes
Change #1
Coordinating Investigator 
Name:
Dr. 
Affiliation:
Address:
Phone:
+
Has been changed to: 
Coordinating Investigator 
Name:
Prof. Dr. 
Affiliation:
Address:
Phone:
Change #2
Study Contact Information, Early Development Lead/New Medicines 
Therapeutic Area Specialist
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 96 of 125
Has been changed to: 
Name:
, MD
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
Change #3
Study Contact Information, Sponsor Study Physician
Name:
Address:
UCB Celltech, UK Registered Branch of UCB Pharma SA
208 Bath Road, Slough
Berkshire, SL1 3WE
UNITED KINGDOM
Phone:
Has been changed to: 
Name:
, MD
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
Change #4
Sponsor Contact Information, Clinical Trial Biostatistician
Name:
Address:
UCB Biopharma SPRL
Chemin du Foriest
B-1420 Braine-l'Alleud
BELGIUM
Phone:
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 97 of 125
Has been changed to: 
Name:
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Phone:
Change #5
List Of Abbreviations
Have been added: 
ANOVA
analysis of variance
PDILI
potential drug-induced liver injury
SAP
Statistical Analysis Plan
Change #6
Section 1 SUMMARY, bullet #7
!
An echocardiogram during dosing, after the last dose, and at 6 months after the final dose
Has been changed to: 
!
An echocardiogram during dosing and after the last dose (the SFU7 echocardiogram). 
The echocardiogram will be repeated at 6 months (±1 month) after the last dose in the 
following subjects:
∀
Subjects who complete this study but do not enter the OLE study
∀
Subjects who withdraw from the Outpatient Period 
∀
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 
echocardiogram
Change #7
Section 3.3 Exploratory objectives
Added the following exploratory objective: 
!
To assess motivations, hopes and impact of seizures using a Diary Addendum
Change #8
Section 4.3 Exploratory variables
Added the following exploratory variable: 
!
Responses to open questions in the Diary Addendum, including: 
∀
Reason for participation in the study
∀
Hopes for this new treatment and fulfillment of hopes during the study
∀
Baseline and change from Baseline in the impact of seizures on the patient’s life
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 98 of 125
The subject will be instructed to leave any questions blank that he/she does not feel 
comfortable answering.
Change #9
Section 5.1 Study description, bullet #7
!
An echocardiogram during dosing, after the last dose, and at 6 months after the last dose
Has been changed to: 
!
An echocardiogram during dosing and after the last dose (the SFU7 echocardiogram). 
The echocardiogram will be repeated at 6 months (±1 month) after the last dose in the 
following subjects:
∀
Subjects who complete this study but do not enter the OLE study
∀
Subjects who withdraw from the Outpatient Period 
∀
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 
echocardiogram
Change #10
Section 5.1 Study description, paragraph immediately following bulleted 
list (bolded text has been deleted)
UCB0942 doses for placebo subjects will be titrated to UCB0942 400mg bid during the 
Inpatient Transition-to-Outpatient Week (Day TTO1 to Day TTO7). After the Inpatient 
Period, all subjects will continue in an open-label Outpatient Maintenance Period and a final 
Tapering Period of 2 weeks (Day TOO1 to Day TOO14). Doses for subjects continuing in the 
OLE study will not be tapered but will follow the schedule of safety and efficacy assessments 
as outlined in the OLE study protocol. Safety follow up will consist of 2 required visits, 1 and 
4 weeks after the last dose of IMP (Day SFU7 and Day SFU28), and 1 optional visit 2 weeks 
after the last dose of IMP (Day SFU14). In addition, all subjects who do not enter the 
OLE study will have an echocardiogram 6 months after the last dose of IMP. For details 
of the study assessments, refer to Table 5-4. For a general presentation of the study design 
refer to Figure 5-1.
Has been changed to: 
UCB0942 doses for placebo subjects will be titrated to UCB0942 400mg bid during the 
Inpatient Transition-to-Outpatient Week (Day TTO1 to Day TTO7). After the Inpatient 
Period, all subjects will continue in an open-label Outpatient Maintenance Period and a final 
Tapering Period of 2 weeks (Day TOO1 to Day TOO14). Doses for subjects continuing in the 
OLE study will not be tapered but will follow the schedule of safety and efficacy assessments 
as outlined in the OLE study protocol. Safety follow up will consist of 2 required visits, 1 and 
4 weeks after the last dose of IMP (Day SFU7 and Day SFU28), and 1 optional visit 2 weeks 
after the last dose of IMP (Day SFU14). For details of the study assessments, refer to Table 
5-4. For a general presentation of the study design refer to Figure 5-1.
Change #11
Section 5.1 Study description, starting at second paragraph following 
the bulleted list
During the Titration Week the dose for subjects randomized to UCB0942 will be titrated to 
UCB0942 400mg bid following the schedule in Table 5-1. Subjects randomized to placebo 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 99 of 125
will follow the same schedule during the Transition-to-Outpatient Week. The entire Inpatient 
Period will be double-blind.
Table 5-1:
Dose titration to UCB0942 400mg bid
Day T1a
Day T2
Day T3
Day T4
Day T5
Day T6
Day T7
Day MD1
AM
0
100mg
100mg
200mg
200mg
300mg
300mg
400mg
PM
100mg
100mg
200mg
200mg
300mg
300mg
400mg
400mg
AM=morning dose; PM=evening dose 
a In placebo-arm subjects the same schedule is used from Day TTO1 to TTO7.
If a subject is not tolerating UCB0942 400mg bid well, the dose can be tapered to UCB0942 
200mg bid. The taper from UCB0942 400mg bid to UCB0942 200mg bid will occur over 
3 days (see Table 5-1) and will require unblinding of the subject if this occurs during the 
Inpatient Period. Dose tapering to UCB0942 100mg bid may be permitted after discussion 
with the Sponsor’s Study Physician.
Table 5-2:
Taper from UCB0942 400mg bid to UCB0942 200mg bid
Day TTO1
Day TTO2
Day TTO3
Day TTO4 onwards
AM
300mg
300mg
200mg
200mg
PM
400mg
300mg
300mg
200mg
AM=morning dose; PM=evening dose
At the end of the Outpatient Maintenance Period, or at the time a subject is withdrawn from 
the study, UCB0942 will be tapered following the schedule in Table 5-3.
Table 5-3:
Dose taper from UCB0942 400mg bid
Day
TOO1 to TOO4
TOO5 to TOO8
TOO9 to TOO12
TOO13 and TOO14
AM
300mg
200mg
100mg
PM
300mg
200mg
100mg
100mg
AM=morning; PM=evening dose
In order to provide an ongoing assessment of the safety of subjects as the study progresses, a 
Safety Review Group (SRG) comprising appropriate Sponsor study team members and the 
Investigator(s) at each site will meet regularly to review appropriate safety data (see 
Section 11.1.9).
Has been changed to: 
Dosing in the Inpatient Period
Titration Week (first week of the Inpatient Period
The objective of the Titration Week is to achieve the maximum UCB0942 dose of 400mg bid 
in as many of the subjects randomized to UCB0942 as possible while minimizing tolerability 
issues. During the Titration Week the dose for subjects randomized to UCB0942 will be 
titrated to UCB0942 400mg bid following the schedule in Table 5-1. The UCB0942 dose will 
be titrated to 400mg bid in a double-blinded fashion (ie, it will also appear that subjects 
randomized to placebo are being titrated). If, in the opinion of the Investigator, the Subject 
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 100 of 125
will be unable to titrate to the maximum dose of IMP due to intolerance of a lower dose, the 
Investigator should discuss this immediately with the Sponsor Study Physician, unless the 
subject’s condition warrants immediate unblinding, and time does not allow discussion with 
the Sponsor. Unblinding may be required depending on the plan agreed upon by the 
Investigator and Sponsor Study Physician before dose tapering to UCB0942 200mg bid or 
100mg bid. If unblinding reveals that the Subject is randomized to placebo, then further 
dosing with IMP will cease until the Transition-to-Outpatient Week (third week of the 
Inpatient Period), at which time, the Subject will titrate UCB0942 according to Table 5-1.All 
other assessments will continue as planned.
Table 5-1:
Dose titration to UCB0942 400mg bid
Day T1a
Day T2
Day T3
Day T4
Day T5
Day T6
Day T7
Day MD1
AM
0
100mg
100mg
200mg
200mg
300mg
300mg
400mg
PM
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100mg
200mg
200mg
300mg
300mg
400mg
400mg
AM=morning dose; PM=evening dose 
a In placebo-arm subjects the same schedule is used from Day TTO1 to TTO7.
Maintenance-Dose Week (second week of the Inpatient Period)
If a subject is not tolerating the maximum dose of IMP well during the 
Maintenance-Dose Week such that the Investigator believes a dose reduction is necessary, 
then then the Investigator should contact the Sponsor Study Physician to discuss the situation 
and agree upon a course of action. If a dose reduction is agreed, unblinding will be required. 
If the subject is randomized to UCB0942, the dose can be tapered from UCB0942 400mg bid 
to UCB0942 200mg bid. The taper from UCB0942 400mg bid to UCB0942 200mg bid will 
occur over 3 days (see Table 5-2) Dose tapering to UCB0942 100mg bid may also be 
permitted after discussion with the Sponsor’s Study Physician. If it is revealed that the 
Subject is randomized to placebo, then further dosing with IMP will cease until the 
Transition-to-Outpatient Week (third week of the Inpatient Period), at which time, the 
Subject will titrate UCB0942 according to Table 5-1. All other assessments will continue as 
planned.
Table 5-2:
Taper from UCB0942 400mg bid to UCB0942 200mg bid
Taper Day 1
Taper Day 2
Taper Day 3
Taper Day 4 onwards
AM
300mg
300mg
200mg
200mg
PM
400mg
300mg
300mg
200mg
AM=morning dose; PM=evening dose
Transition-to-Outpatient Week (third week of the Inpatient Period)
The objective of the Transition-to-Outpatient Week is to achieve the maximum UCB0942 
dose of 400mg bid in as many of the subjects randomized to placebo (now switching to 
UCB0942) as possible while minimizing tolerability issues. The UCB0942 dose will be 
titrated to 400mg bid in a double-blinded fashion (ie, it will also appear that subjects 
randomized to UCB0942 are being titrated) following the schedule in Table 5-1. If, in the 
opinion of the Investigator, the Subject will be unable to titrate to the maximum dose of IMP 
due to intolerance of a lower dose, the Investigator should discuss this with the Sponsor 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 101 of 125
Study Physician. Unblinding may be required depending on the plan agreed upon by the 
Investigator and Sponsor Study Physician.
Dosing in the Outpatient Maintenance Period and Tapering Period
During the Outpatient Maintenance Period, Subjects will continue to administer UCB0942 at 
the final Inpatient Period dose. Multiple adjustments (tapering or increase) of the dose are 
allowed during the Outpatient Maintenance Period (minimum 100mg bid and maximum 
400mg bid); however, any change of dose in the Outpatient Maintenance Period should first 
be discussed with the Sponsor Study Physician. 
At the end of the Outpatient Maintenance Period, or at the time a subject is withdrawn from 
the study, UCB0942 will be tapered following the schedule in Table 5-3. If the subject is not 
taking a dose of UCB0942 other than 400mg bid, then the Investigator should contact the 
Sponsor Study Physician to discuss the appropriate tapering schedule.
Table 5-3:
Dose taper from UCB0942 400mg bid
Day
TOO1 to TOO4
TOO5 to TOO8
TOO9 to TOO12
TOO13 and TOO14
AM
300mg
200mg
100mg
PM
300mg
200mg
100mg
100mg
AM=morning; PM=evening dose
In order to provide an ongoing assessment of the safety of subjects as the study progresses, a 
Safety Review Group (SRG) comprising appropriate Sponsor study team members and the 
Investigator(s) at each site will meet regularly to review appropriate safety data (see 
Section 11.1.9).
Change #12
Section 5.2 Schedule of study assessments, Table 5-4
Added the following assessment: 
Diary Addendum has been added. This is completed at V3 and V15. 
Change #13
Section 5.2 Schedule of study assessments, Table 5-4, footnote k
In addition to the echocardiogram during dosing and after the last dose, for subjects who do
not continue in the OLE study, an echocardiogram at 6 months after the last dose will also be 
performed. Please note that the during dosing time point of Day OP22 for the 
echocardiogram has a time window of ±1 week instead of ±2 days.
Has been changed to: 
In addition to the echocardiogram during dosing and after the last dose (SFU7), the 
echocardiogram will be repeated at 6 months (±1 month) after the last dose in the following 
subjects: 1) Subjects who complete this study but do not enter the OLE study, 2) Subjects 
who withdraw from the Outpatient Period, and 3) Subjects who withdraw from the Inpatient 
Period and have an abnormal SFU7 echocardiogram. Please note that the during dosing time 
point of Day OP22 for the echocardiogram has a time window of ±1 week instead of ±2 days
and the Day SFU7 echocardiogram has a time window of ±1 week instead of ±1 day.
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10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 102 of 125
Change #14
Section 5.2 Schedule of study assessments, Table 5-4, new footnote x
Added the following footnote x (pertaining to the Diary Addendum): 
The subject will be instructed to leave any questions blank that he/she does not feel 
comfortable answering
Change #15
Section 5.2 Schedule of study assessments, Table 5-4, new footnote y
Added the following footnote y (pertaining to the Diary Addendum): 
Collect at Day OP57 or at Early Withdrawal.
Change #16
Section 5.2 Schedule of study assessments, Inpatient Period Table 5-5
Added the following assessment: 
Diary Addendum has been added. This is completed at V3, Study Day T1. 
Change #17
Section 5.2 Schedule of study assessments, Inpatient Period Table 5-5, 
new footnote o
Added the following footnote o (pertaining to the Diary Addendum): 
The subject will be instructed to leave any questions blank that he/she does not feel 
comfortable answering. 
Change #18
Section 6.1 Inclusion criteria, Inclusion Criterion #5 (changes bolded)
Subject is of normal weight as determined by a body mass index (BMI) between 18.0 and 
35.0kg/m2 (exclusive), with a body weight of at least 50kg (males) or 45kg (females).
Has been changed to: 
Subject is of normal weight as determined by a body mass index (BMI) between 16.0 and 
40.0kg/m2 (exclusive) and with a body weight of at least 50kg (males) or 45kg (females).
Change #19
Section 6.2 Exclusion criteria, Exclusion Criterion #2
Subject has a history of liver disease, including but not limited to, stable (on repeat testing) 
elevation of liver enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST] >1.5 times the upper limit of laboratory reference ranges or alkaline phosphatase 
[ALP] >2 times the upper limit of laboratory reference range).
Has been changed to: 
Subject has either:
∀
>1.5x upper limit of normal (ULN) of any of the following: 
◦
alanine aminotransferase (ALT)
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 103 of 125
◦
aspartate aminotransferase (AST)
◦
alkaline phosphatase (ALP)
-OR-
∀
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). 
If subject 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 subjects with a baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a baseline diagnosis and/or the cause of any clinically meaningful elevation 
must be understood and recorded in the Case Report form (CRF). 
If subject 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 
subject must be discussed with the Medical Monitor. 
Change #20 Exclusion criteria, Exclusion Criterion #14 (changes bolded)
Subject is currently treated with carbamazepine, phenytoin, primidone, or phenobarbital or 
any other drug known to induce CYP3A4 liver enzymes.
Has been changed to: 
Subject is currently treated with carbamazepine, phenytoin, primidone, or phenobarbital or 
any other drug known as a strong inducer of CYP3A4 liver enzymes.
Change #21
Section 6.3 Withdrawal criteria, Withdrawal Criterion #1
Subject develops a clinically relevant medical condition (or laboratory abnormality) that, in 
the opinion of the Investigator, compromises the subject’s ability to participate or safety. In 
the case of transaminase (AST, ALT, or both) levels at least 3 times the upper limit of normal 
(ULN) in the presence of normal total bilirubin, the laboratory tests will be repeated within a 
few days. If the repeat testing confirms the abnormality, then weekly monitoring of liver 
function tests should continue until resolved (ie, less than 3 times the ULN or stable 
condition). The Investigator is to decide whether or not to stop the investigational medicinal 
product (IMP). To monitor for hypersensitivity reactions, percent eosinophils >10% or 
absolute eosinophil count ≥0.5G/L or absolute neutrophil count <1.5G/L or absolute platelet 
count ≤100G/L, if in combination with fever, rash, lymphadenopathy, or other 
symptoms/signs suggestive of internal organ involvement (including but not limited to 
hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, pancreatitis, myositis, or 
arthritis) will lead to stopping the IMP.
Has been changed to: 
Subject develops a clinically relevant medical condition (or laboratory abnormality) that, in 
the opinion of the Investigator, compromises the subject’s ability to participate or safety. 
Potential drug-induced liver injury IMP discontinuation criteria are described in Section
6.3.1. To monitor for hypersensitivity reactions, percent eosinophils >10% or absolute 
eosinophil count ≥0.5G/L or absolute neutrophil count <1.5G/L or absolute platelet count 
≤100G/L, if in combination with fever, rash, lymphadenopathy, or other symptoms/signs 
suggestive of internal organ involvement (including but not limited to hepatitis, nephritis, 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 104 of 125
pneumonitis, carditis, colitis, encephalitis, pancreatitis, myositis, or arthritis) will lead to 
stopping the IMP.
Change #22
Section 6.3 Withdrawal criteria, Withdrawal Criterion #6
Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (Yes) to either Question 4 or Question 5 of the C-SSRS at Screening. 
Subjects may be withdrawn from the study if the following event occurs: for subject who did 
not complete a C-SSRS at Screening, subject had actual suicidal ideation prior to study entry 
or since study initiation as indicated by a positive response (Yes) to either Question 4 or 
Question 5 of the “Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
immediately refer the subject to a Mental Healthcare Professional and use clinical judgment 
as to whether to withdraw the subject from the study.
Has been changed to: 
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 subject 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 subject in the 
study/on study medication. If the Subject has active suicidal ideation with a plan as indicated 
by a positive response (“Yes”) to Question 5 of the “Since Last Visit” version of the C-SSRS, 
the subject should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study.
Change #23
Section 6.3 Withdrawal criteria
Added the following Withdrawal Criterion #7:
Subject has a prolongation or worsening of overall seizure duration, frequency, type, or 
pattern considered by the Investigator as persistent and serious enough to warrant 
discontinuation from the study.
Change #24
Section 6.3 Withdrawal criteria, paragraph immediately above Section 
6.3.1
The Investigator should contact the UCB Study Physician whenever possible to discuss the 
withdrawal of a subject in advance.
Has been changed to:
The Investigator should contact the UCB Study Physician whenever possible to discuss the 
withdrawal of a subject in advance. If this is not possible, the Investigator should contact the 
UCB study physician to inform him/her about the subject withdrawal as soon as possible after 
the withdrawal.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 105 of 125
Change #25
Section 6.3 Withdrawal criteria
Added Section 6.3.1 Potential drug-induced liver injury IMP 
discontinuation criteria: 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if 
IMP must be discontinued. In addition, all concomitant medications and herbal supplements 
that are not medically necessary should also be discontinued. 
The PDILI criteria below require immediate and permanent discontinuation of IMP: 
!
Subjects with either of the following:
∀
ALT or AST ≥5xULN
∀
ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of IMP:
!
Subjects with ALT or AST ≥3xULN who exhibit temporally associated symptoms of 
hepatitis or hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness. Hypersensitivity symptoms include fever (without 
clear alternative cause), rash, or eosinophilia (ie, >5%).
If a nondrug-related cause for the symptoms can be confirmed, these subjects may resume 
IMP administration after discussion with the responsible UCB physician, but only when the 
requirements for rechallenge with IMP as provided in Section 11.6.1.2.1 are followed.
The PDILI criterion below allows for subjects to continue on IMP at the discretion of the 
investigator. 
!
Subjects with ALT or AST ≥3xULN (and ≥2x baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis 
(eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness).
Evaluation of PDILI must be initiated as described in Section 11.6.1. If subjects are unable to 
comply with the applicable monitoring schedule, IMP must be discontinued immediately.
Investigators should attempt to obtain information on subjects in the case of IMP 
discontinuation to complete the final evaluation. Subjects 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 
subject withdrawal (if applicable), must be recorded in the source documents. The CRF must 
document the primary reason for IMP discontinuation.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 106 of 125
Change #26
Section 7.1 Description of investigational medicinal products, Table 7-1 
(bolded text in Note has been revised)
Table 7-1:
Description of investigational medicinal product
UCB0942
Placebo for UCB0942
Dosage form
Tablets (white, film-coated), in 
2 strengths:
-
100mg
-
200mg
100mg and 200mg tablets have 
the same size and appearance 
Tablets (white, film-coated):
Provided in a size and 
appearance matching UCB0942.
Manufacturer
Batch/lot number
Will be assigned according to GMP
Expiry date
Will be assigned according to GMP
GMP=Good Manufacturing Practice
Note: For the Inpatient Period, 1 kit per treatment period and per dose will be packaged. Each kit will contain 
blister packs, each covering 1 week of treatment. For the Outpatient Period, UCB0942 tablets will be 
provided in bottles, containing 37 tablets per bottle, either 200mg tablets for subjects on 
UCB0942 400mg bid, or 100mg tablets for subjects who reduce dose to UCB0942 200mg bid. The bottles 
containing 37 UCB0942 100mg tablets will be dispensed for the Taper Period.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 107 of 125
Has been changed to (bolded text in table and in Note has been added): 
Table 7-1:
Description of investigational medicinal product
UCB0942
Placebo for UCB0942
Dosage form
Tablets (white, film-coated), in 
2 strengths:
-
100mg
-
200mg
100mg and 200mg tablets have 
the same size and appearance 
Tablets (white, film-coated):
Provided in a size and 
appearance matching UCB0942.
Manufacturer
Batch/lot number
Will be assigned according to GMP
Expiry date
Will be assigned according to GMP
GMP=Good Manufacturing Practice
Note: For the Inpatient Period, 1 kit per treatment period and per dose will be packaged. Each kit will contain 
blister packs, each covering 1 week of treatment. For the Outpatient Period, UCB0942 tablets will be 
provided in bottles, containing 37 tablets per bottle, either 200mg tablets for subjects on UCB0942 400mg bid
or UCB0942 200mg bid, or 100mg tablets for subjects who reduce dose to UCB0942 100mg bid. The bottles 
containing 37 UCB0942 100mg tablets will be dispensed for the Taper Period.
Change #27
Section 7.9.1.3 Breaking the treatment blind for taper of dose during the 
study
If the IMP is not tolerated during the Inpatient Period by an individual subject, the dose can 
be tapered to UCB0942 200mg bid. This is only permitted if the subject has great difficulty 
tolerating the IMP and the Investigator does not think that tolerability will improve. When it 
is decided to reduce the dose, the blind will have to be broken, following the procedure 
described in Section 7.9.1.2.
Has been changed to: 
When the Investigator and Sponsor Study Physician agree that a subject cannot titrate to the 
maximum dose or that a dose reduction is necessary during the Inpatient Period (See 
Section 5.1, the blind will have to be broken, following the procedure described in 
Section 7.9.1.2.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 108 of 125
Change #28
Section 8.2.1 Titration Week (Visit 3, Day T1 to Day T7)
Added the following assessment: 
!
Diary Addendum (T1)
Change #29
Section 8.3.1 Outpatient Maintenance Period (Visit 6 to Visit 15, Day OP1 
to Day OP57)
Added the following assessment:
!
Diary Addendum (OP57)
Change #30
Section 8.3.3 Safety Follow-Up (Visit 18 to 20, Day SFU7, SFU14, and 
SFU28), bullet #8
!
Echocardiogram after last dose and 6 months later (±1 month)
Has been changed to: 
!
Echocardiogram after last dose and 6 months later (±1 month). For subjects who 
withdraw during the Inpatient Period and for subjects who withdraw during the 
Outpatient Period, see Section 8.4 for echocardiogram requirements following 
withdrawal. 
Change #31
Section 8.3.4 Echocardiograph follow up
For subjects who do not continue in the OLE study, it is mandatory that they have an 
echocardiogram at 6 months (±1 month) after the last dose of IMP (in addition to the 
echocardiogram at Screening, during dosing, and after the last dose).
Has been changed to (bolded text added): 
For subjects who complete this study but do not continue in the OLE study, it is mandatory 
that they have an echocardiogram at 6 months (±1 month) after the last dose of IMP (in 
addition to the echocardiogram at Screening, during dosing, and after the last dose). 
Change #32
Section 8.4 Withdrawal Visit, bullet #6
!
Echocardiogram after last dose and 6 months later (±1 month)
Has been changed to: 
!
Echocardiogram
∀
Withdrawal during the Inpatient Period: The SFU7 echocardiogram should be 
performed. If there is no abnormality, the echocardiogram does not need to be 
repeated. If there is an abnormality, the echocardiogram should be repeated at 
6 months (±1 month) after the last dose of IMP. 
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
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Page 109 of 125
∀
Withdrawal during the Outpatient Period: The SFU7 echocardiogram should be 
performed, and the echocardiogram should be repeated at 6 months (±1 month) after 
the last dose of IMP. 
Change #33
Section 8.4 Withdrawal Visit
Added the following assessment:
!
Diary Addendum
Change #34
Section 9.4 Diary Addendum
This Section has been added: 
A Diary Addendum will be completed according to the tabular schedule of study procedures 
in Table 5-4 as well as at the Withdrawal Visit, if applicable. The Diary Addendum will 
consist of a series of open-ended questions including the following: 
!
Why did you agree to take part in this study? 
!
What are your hopes for this new treatment? 
!
What are the biggest impacts of seizures on your life currently? 
!
What was your experience like during the study?
!
Did participating in the study fulfill any of the hopes you had going into the study? 
!
How do you describe the impact of seizures on your life now? Has that changed since the 
beginning of the study? 
Subjects will be instructed to leave any question blank that he/she does not feel comfortable 
answering. 
Change #35
Section 11.3 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.
There are no adverse events of special interest to be reported for UCB0942.
Has been changed to: 
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.
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 subject.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 110 of 125
Change #36
Section 11.7.3 Echocardiograms
Echocardiograms will be performed during Screening, during dosing (Day OP22 ±1 week), 
after the last dose of IMP, and at 6 months after the last dose of IMP, as described in
Table 5-4.
2D Doppler echocardiography will be performed with:
1. Diastolic measurements (mitral forward flow E and A waves and deceleration time)
2. Tissue Doppler on medial and lateral mitral valve annulus (S, E, and A waves)
3. Standardized views for left atrial volume measurements
Images will be recorded and stored digitally and retained if further analysis is needed. A 
complete echocardiography manual will be provided.
Has been changed to: 
Echocardiograms will be performed during Screening, during dosing (Day OP22 ±1 week), 
and after the last dose of IMP (SFU7), as described in Table 5-4. The echocardiogram will be 
repeated at 6 months (±1 month) after the last dose in the following subjects: 
!
Subjects who complete this study but do not enter the OLE study
!
Subjects who withdraw from the Outpatient Period 
!
Subjects who withdraw from the Inpatient Period and have an abnormal SFU7 
echocardiogram
2D Doppler echocardiography will be performed with:
1. Diastolic measurements (mitral forward flow E and A waves and deceleration time)
2. Tissue Doppler on medial and lateral mitral valve annulus (S, E, and A waves)
3. Standardized views for left atrial volume measurements
Images will be recorded and stored digitally and retained if further analysis is needed. A
complete echocardiography manual will be provided.
Change #37
Section 11.6 Laboratory assessments
Added Section 11.6.1 Evaluation of PDILI:
The PDILI IMP discontinuation criteria for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI 
events must be reported as an AE and reported to the study site and sponsor within 24 hours 
of learning of their occurrence. Any PDILI event that meets the criterion for potential Hy’s 
Law must be reported as an AE of special interest (see Section 11.3), and, if applicable, also 
reported as an SAE (see Section 11.1.1).
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11-3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.6.1.1). 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 
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UCB
10 Oct 2016
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gastroenterologist. Additional investigation and monitoring may be required and adapted 
based on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.6.1.4). 
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 CRF 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 6.3.1), IMP must be permanently 
discontinued unless a subsequent alternative diagnosis fully explains the hepatic findings. If a 
subsequent alternative diagnosis fully explains the hepatic findings, and the requirements 
provided in Section 11.6.1.2.1 are met, rechallenge with IMP may be appropriate. 
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may 
be fatal, and must not occur.
The table below summarizes the approach to investigate PDILI.
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10 Oct 2016
Clinical Study Protocol
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Table11-3:
Required investigations and follow up for PDILI
Laboratory value
Immediate
Follow up
ALT or 
AST
Total 
bilirubin
Symptomsa of 
hepatitis or 
hypersensitivity
Consultation 
requirements
Actions
Testing
Evaluation
≥3xULN
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b
NA
Hepatology consult.c
Medical Monitor 
must be notified 
within 24 hours 
(eg, by laboratory 
alert) and subject 
discussed with 
Medical Monitor 
ASAP.
Immediate, 
permanent IMP 
discontinuation.
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 11.6.1.3);
recommended to 
occur at the site 
with HCP.
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values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d
≥8xULN
NA
NA
≥3xULN
NA
Yes
Immediate, 
temporary or 
permanent, IMP 
discontinuation.
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(and ≥2x 
baseline) 
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<5xULN
<2xULN
No
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for IMP continuation 
is met.
Further investigation 
– immediate IMP 
discontinuation not 
required (see 
Section 11.6.1.2).
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
investigator).
≥5xULN 
(and ≥2x 
baseline) 
<2xULN
No
Discussion with 
Medical Monitor 
required.
Immediate, 
permanent IMP 
discontinuation.
Essential: Every 
attempt must be 
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repeat liver 
chemistry values 
and additional 
testing completed 
within 48 hours 
at the site with 
HCP (see 
Section 11.6.1.3).
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within baseline 
values.d
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UCB
10 Oct 2016
Clinical Study Protocol
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EP0069
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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 If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor.
c Details provided in Section 11.6.1.1. 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 Unless an alternative monitoring schedule is agreed by the investigator and UCB responsible physician. Determination of stabilization is at the discretion of the 
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11.6.1.1
Consultation with the 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 subject must be discussed with the Medical 
Monitor as soon as possible. If required, the subject 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 11.6.1.3) and SAE report (if 
applicable).
11.6.1.2
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 ranges from continuation of IMP (followed by immediate investigation) 
to immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒3 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.
11.6.1.2.1
IMP restart/rechallenge (if applicable)
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may 
be fatal, and must not occur.
Subjects who are immediately discontinued from IMP due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 11‒3), but for whom an alternative diagnosis 
is confirmed, can rarely restart IMP. Rechallenge with IMP can occur only if ALL of the 
following requirements are met:
!
The results of additional testing and monitoring described in Section 11.6.1.3 and 
Section 11.6.1.4 confirm a nondrug-related cause for the abnormal hepatic laboratory 
parameters and any associated symptoms (ie, a subsequent alternative diagnosis fully 
explains the hepatic findings). 
!
No alternative treatment options are available to the subject.
!
The subject has shown clear therapeutic benefit from the IMP.
!
Subject’s ALT or AST elevations do not exceed ≥3xULN.
!
Subject’s total bilirubin is <1.5xULN.
!
Subject has no signs or symptoms of hypersensitivity. 
!
The rechallenge is approved by the UCB responsible physician and a hepatologist. The 
hepatologist must be external to UCB. It is recommended that the hepatologist be a local 
hepatology expert or the hepatologist treating the subject.
!
Subject agrees to the investigator-recommended monitoring plan.
11.6.1.3
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 
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UCB
10 Oct 2016
Clinical Study Protocol
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Page 115 of 125
in Table 11-4 (laboratory measurements) and Table 11-5 (additional information). Results of 
the laboratory measurements and information collected are to be submitted to the sponsor on 
the corresponding CRF. If the medical history of the subject 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.
The following measurements are to be assessed:
Table 11-4: 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 subjects with ALT >8xULN, elevations in total bilirubin, and symptoms of hepatitis or 
hypersensitivity. Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or 
tenderness; hypersensitivity symptoms include eosinophilia (>5%), rash, and fever (without clear alternative 
cause).
The following additional information is to be collected:
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Table 11-5: 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:
!
History of liver disease (eg, autoimmune hepatitis, nonalcoholic steatohepatitis or other “fatty 
liver disease”)
!
Adverse reactions to drugs
!
Allergies
!
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency)
!
Recent travel 
!
Progression of malignancy involving the liver (Note: Metastatic disease to the liver, by itself, 
should not be used as an explanation for significant AST and/or ALT elevations.)
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, decreased appetite, abdominal pain, jaundice, fever, or 
rash)
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function
Alcohol and illicit drug use
Results of liver imaging or liver biopsy, if done
Results of any specialist or hepatology consult, if done
Any postmortem/pathology reports
ALT=alanine aminotransferase; AST=aspartate aminotransferase; PDILI=potential drug-induced liver injury
11.6.1.4
Follow-up evaluation
Potential drug-induced liver injury events require follow-up and monitoring as described in 
Table 11‒3. 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.
Change #38
Section 11.7.5 Assessment of suicidality
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 C-SSRS will be completed according to the tabular schedule 
of study procedures (Section 5.2)
Has been changed to (bolded text added): 
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 C-SSRS will be completed according to the tabular schedule 
of study procedures (Section 5.2). The Investigator’s decision about patient continuation 
in the study or patient withdrawal from the study if the patient has a positive response 
to the CSSRS Question 4, should be based on the Benefit /Risk balance for continuation 
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UCB
10 Oct 2016
Clinical Study Protocol
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Page 117 of 125
or discontinuation of study treatment in view of the individual patient circumstances, 
condition, attained efficacy, causality, alternative risk management options, etc. Details 
of the case must be documented by the investigator (PI or investigator physician, not 
site staff conducting the CSSRS) and provided to UCB via the SAE reporting process.
Change #39
Section 13.7 Planned interim analyses and data monitoring
This Section has been added: 
An interim analysis will be performed if needed for purposes of planning and designing of 
future studies. If performed, this analysis will be conducted when at least 75% of patients 
have been randomized and completed through the Inpatient Period (completed through 
Visit 5).
All subjects who have completed through Visit 5 at the time of the data snapshot will be 
included in the interim analysis.
All statistical analyses will be described in detail in the interim SAP.
For the interim analysis, the primary efficacy variable (75%RR) will be analyzed using the 
methods described for the primary efficacy analysis. In addition, seizure-free rate, 50%RR, 
and percent reduction in focal seizure frequency will be analyzed as described for the 
secondary/exploratory analyses.
The 75%RR, Seizure-free rate, and 50%RR variables may also be analyzed using Bayesian 
logistic regression. If Bayesian analysis is peformed, the percent reduction in focal seizure 
frequency from the Baseline will be estimated using Bayesian analysis of variance (ANOVA) 
and/or ANCOVA. For these analyses, posterior medians, 95% credible intervals for the 
treatment effect, and additional posterior probabilities will be presented. Non informative and 
informative priors will be considered, and sensitivity to different prior settings will be 
assessed. Other efficacy variables may also be analyzed in the Bayesian framework.
The following safety data will also be presented: 
!
Treatment emergent AEs
!
AEs leading to drop-out or withdrawal
!
SAEs
!
Laboratory assessments out of normal range
!
BPRS
The study will not be terminated early for either efficacy or futility based on the results of 
this interim analysis and therefore, an alpha penalty of 0.001 to be assessed on the primary 
efficacy analysis is considered appropriate.  
The study is not expected to be stopped due to safety reasons during this interim analysis, 
since there are ongoing quarterly Safety Review Group meetings already planned for this 
purpose. Therefore, no criteria for evaluation of early stopping due to safety are included.  
An unblinded team will be established at both the Sponsor and CRO and will include the 
following roles (all unblinded): Data Manager, Statistician, Statistical Programmer, and 
Project Lead. All staff involved in the conduct of the study, including staff at UCB, the CRO, 
participating vendors, and the participating sites will remain blinded to individual treatment 
identity and will not be informed of the results of the interim analysis until final unblinding. 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 118 of 125
17.4
Protocol Amendment 4.0
Rationale for the Amendment
The primary reason for Amendment 4.0 is to describe a tiered approach to database lock and 
unblinding. 
Other changes include: 
!
Correction of an inconsistency between the Summary section and the Study Design 
section pertaining to allowable dose changes 
!
Clarification of the reporting period for adverse events
!
Specification that the Baseline version of the SSQ is to be used in all instances where it is 
administered 
!
Correction of the number of questions in the SSQ was from 11 to 10. 
!
Correction of several cross references 
!
Other minor administrative changes 
Modifications and changes
Specific changes
Change #1
Summary (revised for consistency with Section 5, Study Design)
Titration to UCB0942 400mg bid will occur over the course of 1 week in the clinical unit. 
For subjects in the active arm, doses will be titrated to UCB0942 400mg bid during the first 
inpatient week. For subjects who initially received placebo, doses will be titrated to 
UCB0942 400mg bid during the last week of the Inpatient Period. For subjects in the active 
arm who do not tolerate UCB0942 400mg bid, during the third week of the Inpatient Period, 
the dose can be tapered to UCB0942 200mg bid before starting the Outpatient Maintenance 
Period. Similarly, for subjects in the placebo group the dose can be tapered to UCB0942 
200mg bid during the Outpatient Maintenance Period. Dose tapering to UCB0942 100mg bid 
may be permitted after discussion with the Sponsor’s Study Physician. All subjects will stay 
in the clinical unit for a total of 3 weeks and will then be discharged for an 8-week 
Outpatient Maintenance Period.
Has been changed to: 
Titration to UCB0942 400mg bid will occur over the course of 1 week in the clinical unit. 
For subjects in the active arm, doses will be titrated to UCB0942 400mg bid during the first 
inpatient week. For subjects who initially received placebo, doses will be titrated to 
UCB0942 400mg bid during the last week of the Inpatient Period. Dose reductions will be 
allowed during titration and maintenance in the Inpatient Period, but this should be discussed 
with the Sponsor Study Physician unless this is not possible due to the circumstances. 
Multiple adjustments (tapering or increase) of the dose are allowed during the Outpatient 
Maintenance Period (minimum 100mg bid and maximum 400mg bid); however, any change 
of dose in the Outpatient Maintenance Period should first be discussed with the Sponsor 
Study Physician.
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 119 of 125
Change #2
Section 5.1.3 Anticipated regions and countries
The study is planned to be performed in The 
. 
Other countries in the 
 can be added if deemed necessary by the Sponsor.
Has been changed to: 
The study is planned to be performed in The 
 
 
 
 
 
 and 
 
Change #3
Table 5-4, row header, Table 5-5 row header and footnote m, Section 8 – Study Procedures 
by Visit: SSQ has been revised to SSQ (Baseline version) to make it clear that whenever the 
SSQ is administered, the Baseline version is to be used. 
Change #4
Table 5-4, row header had been revised to correct the duration of the Taper and Safety 
Follow-up Periods. The Taper Period is up to 2 weeks, and the Safety Follow-up Period is 
4 weeks.  
Change #5
Section 9.2 Seizure severity questionnaire
The SSQ (Cramer et al, 2002) is a review of various aspects of seizures. The person who has 
seizures may ask people who have observed the seizures (family, friends) to help answer 
some of the questions asking about events, but not about feelings. There are 11 questions in 3 
sections asking about events before, during, and after typical seizures.
The subject should describe their most common type of seizure when answering the 
questions. If subjects are unsure about how to answer a question, they should give the best 
answer they can and write a comment or explanation on the side of the page. 
The SSQ will be completed according to the tabular schedule of study procedures, Table 5-4. 
For this study the recall period will be set to 1 week rather than the original 4 weeks. At the 
very beginning of the visit, the SSQ will be provided to all subjects. The subject will be asked 
to complete the questionnaire on his/her own. Once completed, the subject will return the 
completed questionnaire to the Investigator or designee, who will verify that all questions 
have been answered. Further details about the SSQ will be covered in the Study Manual.
Has been changed to (changes bolded):
The SSQ (Cramer et al, 2002) is a review of various aspects of seizures. The person who has 
seizures may ask people who have observed the seizures (family, friends) to help answer 
some of the questions asking about events, but not about feelings. There are 10 questions in 3 
sections asking about events before, during, and after typical seizures.
The subject should describe their most common type of seizure when answering the 
questions. If subjects are unsure about how to answer a question, they should give the best 
answer they can and write a comment or explanation on the side of the page. 
The Baseline SSQ will be completed according to the tabular schedule of study procedures,
Table 5-4. The Baseline version of the SSQ will be used for all visits during which the SSQ 
is to be completed. For this study the recall period will be set to 1 week rather than the 
original 4 weeks. At the very beginning of the visit, the SSQ will be provided to all subjects. 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 120 of 125
The subject will be asked to complete the questionnaire on his/her own. Once completed, the 
subject will return the completed questionnaire to the Investigator or designee, who will 
verify that all questions have been answered. Further details about the SSQ will be covered in 
the Study Manual.
Change #6
Section 11.1.1, Definition of adverse event, paragraph 2
In order to ensure complete safety data collection, all AEs occurring during the study 
(ie, after the signing of the Informed Consent form), including any pretreatment and 
posttreatment periods required by the protocol, must be reported in the eCRF even if no IMP 
was taken but specific study procedures were conducted. This includes all AEs not present 
prior to the initial visit and all AEs that recurred or worsened after the initial visit.
Has been changed to (change bolded): 
In order to ensure complete safety data collection, all AEs occurring during the study 
(ie, after the signing of the Informed Consent form), including any pretreatment and 
posttreatment periods required by the protocol, ie, through the end of the Taper/Safety 
Follow-up Period, 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.
Change #7
Section 11.1.4, Follow up of of adverse events, paragraph 2
If an AE is ongoing at the end of the study for a subject, 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 subject 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 subject has discontinued his/her IMP.
Has been changed to (changes bolded): 
If an AE is ongoing at the end of the Taper/Safety Follow-up Period, 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 subject 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 subject has discontinued his/her IMP.
Adverse events should not be recorded in the eCRF after the end of the Taper/Safety 
Follow-up Period.
Change #8
Section 11.1.9, Safety Review Group, paragraph 3
The SRG will remain blinded during the study unless emergent safety information requires 
unblinding of individual drug allocation for optimal assessment and response to AEs of 
concern.
Has been changed to: 
The SRG will remain blinded through the first database lock (see Section 12.3.3) unless 
emergent safety information requires unblinding of individual drug allocation for optimal 
assessment and response to AEs of concern. At the time of the first database lock, the Study 
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 121 of 125
Physician(s), clinical pharmacologist, DS representative, biostatistician, and other UCB 
personnel will be unblinded as to all subjects’ treatment allocation at the beginning of the 
Inpatient Period. 
Change #9
Section 11.6.1, Evaluation of PDILI
Several incorrect table and section references have been corrected. 
Change #10
Section 12.3.3, Database lock – section has been added: 
The database lock and unblinding may occur in a tiered approach. 
Details regarding the tiered database lock will be described in the Data Management Plan. 
Plans for analysis of data and production of tables, figures and listings will be described in 
the Statistical Analysis Plan (SAP).
Change #11
Section 13.5, Handling of protocol deviations, paragraph 1
After all data have been verified/entered into a database and prior to database lock, a data 
evaluation meeting will take place. The purpose of the data evaluation will be to examine all 
protocol deviations, define the PPS, and to verify the quality of the data. The data evaluation 
will also help in guiding decisions on how to manage data issues on a case-by-case basis (eg, 
withdrawals, dropouts, and protocol deviations).
Has been changed to (changes bolded): 
After all lockable data have been verified/entered into a database and prior to the first 
database lock, a data evaluation meeting will take place. The purpose of the data evaluation 
will be to examine all protocol deviations, define the PPS, and to verify the quality of the 
data. The data evaluation will also help in guiding decisions on how to manage data issues on 
a case-by-case basis (eg, withdrawals, dropouts, and protocol deviations).
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UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 122 of 125
18
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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This document cannot be used to support any marketing authorization applicatio
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or variations thereof. 

UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 123 of 125
19
DECLARATION AND SIGNATURE OF COORDINATING 
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.
Coordinating Investigator (
_____________________________
Date/Signature
REDACTED COPY 
This document cannot be used to support any marketing authorization application 
____
___
ature
ature
and any extensions 
ments 
ents 
or 
be
be
variations thereof. 

UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 124 of 125
20
DECLARATION AND SIGNATURE OF COORDINATING 
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.
Coordinating Investigator:
_____________________________
Date/Signature
REDACTED COPY 
This document cannot be used to support any marketing authorization application 
__
__
urere
and 
_
any extensions 
ents w
ents w
or variations 
e
thereof. 

UCB
10 Oct 2016
Clinical Study Protocol
UCB0942
EP0069
Confidential
Page 125 of 125
21
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. 

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