Conditions: Drug-resistant Epilepsy Focal-Onset Seizures
Keywords: Epilepsy Padsevonil
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 411
Healthy volunteers: no

Brief summary:
The purpose of the study is to characterize the dose-response relationship with respect to efficacy of Padsevonil administered concomitantly with up to 3 anti-epileptic drugs (AEDs) for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy.

Detailed description:

Arms:
arm 1: Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding. arm 2: Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding. arm 3: Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding. arm 4: Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding. arm 5: Subjects randomized to the placebo group will receive a combination of several Placebo tablets to maintain the blinding.

Interventions: intervention 1: Padsevonil intervention 2: Placebo
Intervention descriptions: intervention 1: Padsevonil in different dosages. intervention 2: Placebo will be provided matching Padsevonil.

Protocol document:
Prot_000.pdf: 
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PROTOCOL EP0091 AMENDMENT 2 
ARISE: pAdsevonil in drug-ResIStant Epilepsy 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
DOSE FINDING STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF PADSEVONIL AS ADJUNCTIVE TREATMENT OF 
FOCAL-ONSET SEIZURES IN ADULT SUBJECTS WITH 
DRUG-RESISTANT EPILEPSY 
PHASE 2 
EudraCT Number: 2017-003200-48 
IND number: 135622 
Sponsor: 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
24 Oct 2017 
Not applicable 
Protocol Amendment 1 
09 Mar 2018 
Substantial 
Protocol Amendment 2 
12 Oct 2018 
Substantial 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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STUDY CONTACT INFORMATION 
Sponsor 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Sponsor Study Physician 
Name: 
, MD PhD 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB Pharma Ltd 
280 Bath Road 
Berkshire SL 13WE Slough, 
UK 
Phone: 
 
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Clinical Monitoring Contract Research Organization 
Name: 
PAREXEL International (IRL) Limited 
Address: 
70 Sir John Rogerson’s Quay 
Dublin 2 
Ireland 
Phone: 
+353 1 473 9500 
Fax: 
+353 1 477 3390 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
USA: +1 800 880 6949 
 
or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com or DSICT.-@ucb.com 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 11 
1 
SUMMARY ..................................................................................................................... 14 
2 
INTRODUCTION ........................................................................................................... 15 
2.1 
Drug-resistant epilepsy ................................................................................................ 15 
2.2 
Padsevonil mechanism of action .................................................................................. 16 
2.3 
Clinical studies ............................................................................................................. 16 
2.3.1 
Adverse event profile ........................................................................................... 18 
2.4 
Rationale for this study ................................................................................................ 19 
3 
STUDY OBJECTIVES .................................................................................................... 19 
3.1 
Primary objective ......................................................................................................... 19 
3.2 
Secondary objective ..................................................................................................... 19 
3.3 
Other objectives ........................................................................................................... 20 
3.3.1 
Efficacy objectives ............................................................................................... 20 
3.3.2 
Pharmacokinetic objectives ................................................................................. 20 
3.3.3 
Exploratory nonhereditary pharmacogenomics and pharmacogenetics .............. 20 
4 
STUDY VARIABLES ..................................................................................................... 20 
4.1 
Efficacy variables......................................................................................................... 20 
4.1.1 
Primary efficacy variable ..................................................................................... 20 
4.1.1.1 
Primary efficacy variable for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 ............................................... 20 
4.1.1.2 
Primary efficacy variable for EMA and regulatory authorities who 
reference EMA .......................................................................................... 20 
4.1.2 
Secondary efficacy variables ............................................................................... 20 
4.1.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 .............................. 20 
4.1.2.2 
Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA .......................................................................................... 21 
4.1.3 
Other efficacy variables (This list applies for all regulatory authorities) ............ 21 
4.2 
Safety variables ............................................................................................................ 22 
4.2.1 
Primary safety variables ...................................................................................... 22 
4.2.2 
Other safety variables .......................................................................................... 23 
4.3 
Other variables ............................................................................................................. 23 
4.3.1 
Pharmacokinetic variables ................................................................................... 23 
4.3.2 
Exploratory nonhereditary pharmacogenomics variables.................................... 24 
4.3.3 
Exploratory pharmacogenetic variables............................................................... 24 
4.3.4 
Exploratory pharmacokinetic evaluation ............................................................. 24 
5 
STUDY DESIGN ............................................................................................................. 24 
5.1 
Study description ......................................................................................................... 24 
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5.1.1 
Genetic substudy .................................................................................................. 26 
5.1.2 
Study duration per subject ................................................................................... 27 
5.1.3 
Planned number of subjects and sites .................................................................. 27 
5.1.4 
Anticipated regions and countries ....................................................................... 27 
5.2 
Schedule of study assessments..................................................................................... 27 
5.3 
Schematic diagram ....................................................................................................... 33 
5.4 
Rationale for study design and selection of dose ......................................................... 35 
5.4.1 
Choice of study design and endpoints ................................................................. 35 
5.4.2 
Rationale for dose selection ................................................................................. 36 
5.4.3 
Justification for genomic and biomarker strategy ............................................... 37 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 37 
6.1 
Inclusion criteria .......................................................................................................... 37 
6.2 
Exclusion criteria ......................................................................................................... 40 
6.3 
Withdrawal criteria ...................................................................................................... 43 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 45 
6.3.2 
Echocardiogram valvular abnormalities assessments .......................................... 46 
7 
STUDY TREATMENTS ................................................................................................. 48 
7.1 
Description of investigational medicinal products ...................................................... 48 
7.2 
Treatments to be administered ..................................................................................... 48 
7.2.1 
Titration Period .................................................................................................... 49 
7.2.2 
Taper Period ......................................................................................................... 50 
7.2.3 
Conversion Period ............................................................................................... 50 
7.3 
Packaging ..................................................................................................................... 51 
7.4 
Labeling ....................................................................................................................... 51 
7.5 
Handling and storage requirements ............................................................................. 51 
7.6 
Drug accountability ...................................................................................................... 52 
7.7 
Procedures for monitoring subject compliance ............................................................ 52 
7.8 
Concomitant medications/treatments ........................................................................... 52 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 52 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 53 
7.8.3 
Rescue medication ............................................................................................... 53 
7.9 
Blinding........................................................................................................................ 53 
7.9.1 
Procedures for maintaining and breaking the treatment blind ............................. 53 
7.9.1.1 
Maintenance of study treatment blind ....................................................... 53 
7.9.1.2 
Breaking the treatment blind in an emergency situation ........................... 54 
7.10 
Randomization and numbering of subjects .................................................................. 54 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 54 
8.1 
Baseline Period (4 weeks) ............................................................................................ 54 
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8.1.1 
Visit 1 (Week -4) ................................................................................................. 54 
8.2 
Treatment Period (16 weeks ±1 week from Visit 2) .................................................... 56 
8.2.1 
Titration Period (3 weeks ±1 week from Visit 2) ................................................ 56 
8.2.1.1 
Visit 2, Baseline (Day 1, 4 to 5 weeks after Visit 1) ................................. 56 
8.2.1.2 
Telephone call (Week 1 ±3 days) .............................................................. 57 
8.2.1.3 
Visit 3 (Week 2 ±1 week) .......................................................................... 57 
8.2.2 
Stabilization Period (1 week ±3 days) ................................................................. 57 
8.2.2.1 
Telephone call (Week 3) ........................................................................... 57 
8.2.3 
Maintenance Period (12 weeks ± 1 week) ........................................................... 57 
8.2.3.1 
Visit 4 (Week 4 ±1 week) .......................................................................... 57 
8.2.3.2 
Visit 5 (Week 8 ±1 week) and Visit 6 (Week 12 ±1 week) ...................... 58 
8.2.3.3 
Visit 7 (Week 16±1 week for End-of-Treatment or earlier for 
Early Discontinuation Visit) ...................................................................... 59 
8.3 
Taper/Conversion Period (3 to 4 weeks ±1 week) ....................................................... 60 
8.3.1 
Telephone call (after 1 or 2 weeks in tapering/converting, as needed) ............... 60 
8.3.2 
Visit 8 (Week 19/20 ±1 week, end of Taper/Conversion) ................................... 60 
8.4 
Safety Follow-Up (Visit 9 [Week 23 or earlier for EDV, approximately 30 days after 
last IMP intake]) .......................................................................................................... 61 
8.5 
Unscheduled Visit/Telephone call ............................................................................... 62 
8.6 
Open-label extension study (EP0093) ......................................................................... 62 
9 
ASSESSMENT OF EFFICACY ...................................................................................... 62 
9.1 
Seizure frequency......................................................................................................... 62 
9.2 
Seizure Severity Global Item ....................................................................................... 63 
9.3 
Quality of Life Inventory in Epilepsy-31-P ................................................................. 63 
9.4 
Hospital Anxiety and Depression Scale ....................................................................... 63 
9.5 
Health-related outcomes and healthcare resource utilization ...................................... 63 
9.6 
Entry and exit personal outcomes interview ................................................................ 64 
9.7 
Caregiver survey .......................................................................................................... 64 
10 ASSESSMENT OF PHARMACOKINETIC AND EXPLORATORY VARIABLES ... 65 
10.1 
Pharmacokinetic variables ........................................................................................... 65 
10.1.1 
PK sampling procedures ...................................................................................... 65 
10.1.1.1 
PSL assay .................................................................................................. 65 
10.1.1.2 
Concomitant AED and exploratory pharmacokinetic evaluation .............. 65 
10.2 
Exploratory variables ................................................................................................... 66 
11 ASSESSMENT OF SAFETY .......................................................................................... 66 
11.1 
Adverse events ............................................................................................................. 66 
11.1.1 
Definitions ........................................................................................................... 66 
11.1.1.1 
Adverse events .......................................................................................... 66 
11.1.1.2 
Serious adverse events ............................................................................... 66 
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11.1.2 
Procedures for reporting and recording adverse events ....................................... 68 
11.1.2.1 
Description of adverse events .................................................................... 68 
11.1.2.2 
Rule for repetition of an adverse event...................................................... 68 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 68 
11.1.3 
Follow up of adverse events ................................................................................ 69 
11.1.4 
Pregnancy ............................................................................................................ 69 
11.1.5 
Suspected transmission of an infectious agent .................................................... 70 
11.1.6 
Overdose of investigational medicinal product ................................................... 70 
11.1.7 
Safety signal detection ......................................................................................... 70 
11.2 
Laboratory measurements ............................................................................................ 71 
11.2.1 
Evaluation of PDILI ............................................................................................ 73 
11.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 76 
11.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 76 
11.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 77 
11.2.1.4 
Follow-up evaluation ................................................................................. 78 
11.3 
Other safety measurements .......................................................................................... 78 
11.3.1 
Vital signs measurement ...................................................................................... 79 
11.3.2 
Electrocardiograms .............................................................................................. 79 
11.3.3 
Echocardiograms ................................................................................................. 79 
11.3.4 
Physical examination ........................................................................................... 80 
11.3.5 
Neurological examination .................................................................................... 80 
11.3.6 
Assessment of suicidality .................................................................................... 81 
11.3.7 
Psychiatric and Mental Status .............................................................................. 81 
11.3.8 
Withdrawal monitoring ........................................................................................ 81 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 82 
12.1 
Adherence to protocol .................................................................................................. 82 
12.2 
Monitoring ................................................................................................................... 82 
12.2.1 
Definition of source data ..................................................................................... 82 
12.2.2 
Source data verification ....................................................................................... 83 
12.3 
Data handling ............................................................................................................... 83 
12.3.1 
Case Report form completion .............................................................................. 83 
12.3.2 
Database entry and reconciliation ........................................................................ 84 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 84 
12.4 
Termination of the study .............................................................................................. 84 
12.5 
Archiving and data retention ........................................................................................ 84 
12.6 
Audit and inspection .................................................................................................... 85 
12.7 
Good Clinical Practice ................................................................................................. 85 
13 STATISTICS ................................................................................................................... 85 
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13.1 
Definition of analysis sets ............................................................................................ 85 
13.1.1 
Enrolled Set ......................................................................................................... 85 
13.1.2 
Randomized Set ................................................................................................... 85 
13.1.3 
Safety Set ............................................................................................................. 85 
13.1.4 
Full Analysis Set .................................................................................................. 85 
13.1.5 
Per-Protocol Set ................................................................................................... 86 
13.1.6 
Pharmacokinetic/Pharmacodynamic Set ............................................................. 86 
13.2 
General statistical considerations ................................................................................. 86 
13.3 
Planned efficacy analyses ............................................................................................ 86 
13.3.1 
Analysis of the primary efficacy variable ............................................................ 86 
13.3.1.1 
Analysis of the primary efficacy variable for the US FDA, PMDA, and 
other regulatory authorities not specified in Section 4.1.1.2 ..................... 86 
13.3.1.2 
Analysis of the primary efficacy variable for EMA and regulatory 
authorities who reference EMA................................................................. 87 
13.3.2 
Secondary efficacy analysis ................................................................................. 87 
13.3.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 .............................. 87 
13.3.2.2 
Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA .......................................................................................... 87 
13.3.3 
Other efficacy analyses ........................................................................................ 87 
13.4 
Planned safety and other analyses................................................................................ 88 
13.4.1 
Safety analyses ..................................................................................................... 88 
13.4.2 
Pharmacokinetic analyses .................................................................................... 88 
13.4.3 
Entry and exit personal outcomes interview and caregiver survey ..................... 89 
13.5 
Handling of protocol deviations................................................................................... 89 
13.6 
Handling of dropouts or missing data .......................................................................... 89 
13.7 
Planned interim analysis and data monitoring ............................................................. 89 
13.8 
Determination of sample size ....................................................................................... 90 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 91 
14.1 
Informed consent ......................................................................................................... 91 
14.2 
Subject identification cards .......................................................................................... 91 
14.3 
Institutional Review Boards and Independent Ethics Committees .............................. 91 
14.4 
Subject privacy............................................................................................................. 92 
14.5 
Protocol amendments ................................................................................................... 92 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 93 
16 REFERENCES ................................................................................................................ 94 
17 APPENDICES ................................................................................................................. 97 
17.1 
Protocol Amendment 1 ................................................................................................ 97 
17.2 
Protocol Amendment 2 .............................................................................................. 127 
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18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 151 
19 SPONSOR DECLARATION ........................................................................................ 152 
 
LIST OF TABLES 
Table 5-1: 
Schedule of assessments .................................................................................. 28 
Table 6-1: 
Valvular abnormality grading criteria .............................................................. 47 
Table 7-1: 
Titration Period dosing .................................................................................... 49 
Table 7-2: 
Dosing during fallback option ......................................................................... 49 
Table 7-3: 
Taper Period dosing ......................................................................................... 50 
Table 7-4: 
Conversion Period dosing ................................................................................ 51 
Table 11‒1: 
Anticipated SAEs for the epilepsy population ................................................. 67 
Table 11‒2: 
Laboratory measurements ................................................................................ 72 
Table 11-3: 
Required investigations and follow up for PDILI............................................ 74 
Table 11‒4: 
PDILI laboratory measurements ...................................................................... 77 
Table 11‒5: 
PDILI information to be collected ................................................................... 78 
 
LIST OF FIGURES 
Figure 5‒1: 
Study design ..................................................................................................... 34 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
bid 
twice daily 
BP 
blood pressure 
BZD 
benzodiazepine 
cBZR 
central benzodiazepine receptor 
CDMS 
clinical data management system 
CI 
confidence interval 
CIWA-B 
Clinical Institute Withdrawal Assessment-Benzodiazepines 
CNS 
central nervous system 
CPM 
Clinical Project Manager 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ED50 
median effective dose 
EEG 
electroencephalogram 
eCRF 
electronic Case Report form 
EDV 
Early Discontinuation Visit 
EMA 
European Medicines Agency 
Emax 
maximum dose effect 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GABA-A 
gamma-aminobutyric acid-A 
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HADS 
Hospital Anxiety and Depression Scale 
HDRE 
highly drug-resistant epilepsy 
HRU 
healthcare resource utilization 
IB 
Investigator’s Brochure 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LEV 
levetiracetam 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
OLE 
open-label extension 
PD 
pharmacodynamics 
PDILI 
potential drug-induced liver injury 
PET 
positron-emission tomography 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
Per-Protocol Set 
PRN 
(pro re nata) as needed 
PS 
Patient Safety 
PSL 
padsevonil 
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 
RNA 
ribonucleic acid 
RS 
Randomized Set 
SAE 
serious adverse event 
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SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SFU 
Safety Follow Up 
SOP 
Standard Operating Procedure 
SSG 
Seizure Severity Global Item 
SS 
Safety Set 
SUDEP 
sudden unexpected death in epilepsy 
SV2 
synaptic vesicle 2 
TTE 
transthoracic echocardiogram 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VAMS 
volumetric absorptive microsampling  
VNS 
vagus nerve stimulation 
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1 
SUMMARY 
Padsevonil (PSL) is a novel chemical entity that has selective affinity for both presynaptic 
synaptic vesicle 2 (SV2) proteins and postsynaptic central benzodiazepine receptor (cBZR) sites 
on the gamma-aminobutyric acid-A (GABA-A) receptor. Specifically synthesized and designed 
for an increased anticonvulsant activity, PSL has the potential to benefit an underserved 
population with high unmet medical need, namely those with drug-resistant epilepsy and 
uncontrolled focal-onset seizures that constitute substantial threats to their health and well-being. 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
uncontrolled focal-onset seizures despite treatment with at least 4 tolerated, appropriately chosen 
and used prior antiepileptic drugs (AEDs), including current AEDs (Kwan et al, 2010). 
The primary objectives of this study are to characterize the dose-response relationship with 
respect to efficacy of PSL administered concomitantly with up to 3 AEDs for treatment of 
observable focal-onset seizures in subjects with drug-resistant epilepsy and to evaluate the 
efficacy of the 4 selected dose regimens of PSL compared with placebo. The secondary objective 
is to assess the safety and tolerability of all doses of PSL in relation to placebo. 
The study is comprised of the following periods: a 4-week Baseline Period; a 16-week Treatment 
Period consisting of a 3-week Titration Period followed by a 1-week Stabilization Period and a 
12-week Maintenance Period; a 3-week Conversion Period for all subjects who choose to enroll 
in the open-label extension (OLE) study, EP0093, at the end of the Maintenance Period; or a 
4-week Taper Period, in case the subjects discontinue or do not enroll in EP0093. During the 
Titration Period, the investigational medicinal product (IMP) will be increased approximately 
every 3 to 7 days depending on the treatment arm. For subjects with tolerability issues at their 
target dose, 1 fallback option to a predefined lower dose will be allowed during the Stabilization 
Period. During the entire 12-week Maintenance Period, the dose of IMP and concomitant AEDs 
must remain stable. Subjects who withdraw from the study or decide not to participate in the 
OLE study will be progressively tapered off the IMP. Safety follow up for these subjects will 
consist of 1 Safety Follow-up (SFU) Visit 30 days after the last IMP intake (including an 
echocardiogram) and a 6-month follow-up echocardiogram, depending on the duration of 
exposure to IMP. 
The assessment of efficacy is based on seizure frequency. For the US Food and Drug 
Administration (FDA), Pharmaceuticals and Medical Devices Agency (PMDA), and other 
regulatory authorities not specified in Section 4.1.1.2, the primary efficacy variable is the change 
from Baseline in log-transformed observable focal-onset seizure frequency (for the purpose of 
this protocol defined as Types IA1, IB, and IC, according to the International League Against 
Epilepsy [ILAE] classification [ILAE Classification of Epileptic Seizures, 1981]) over the 
12-week Maintenance Period. For the European Medicines Agency (EMA) and regulatory 
authorities who reference EMA, the primary efficacy variable is the 75% responder rate, where a 
responder is a subject experiencing a ≥75% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
Secondary and other efficacy variables will allow further exploration of the effect of PSL on 
seizure frequency during the entire Treatment Period, seizure severity, quality of life, Hospital 
Anxiety and Depression Scale (HADS) score, health-related outcomes, and healthcare resource 
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utilization (HRU). Safety will be evaluated based on the occurrence of adverse events (AEs) 
reported by the subject and/or caregiver; subject withdrawals or premature tapering due to AEs; 
the results of periodic clinical laboratory, electrocardiogram (ECG), echocardiogram, withdrawal 
symptom monitoring, vital sign monitoring; and physical and neurological examinations. 
The total duration of study per subject will be up to 27 weeks with a maximum of 19 weeks 
exposure to PSL. It is estimated that approximately 500 subjects will be included at 
approximately 200 sites worldwide; 400 subjects are expected to be randomized. 
During this study, subjects will also have the option of providing additional informed consent for 
exploratory deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and 
lipidomics/proteomics/additional blood biomarker analyses to understand the cause, progression, 
and appropriate treatment of drug-resistant epilepsy. Participation in this additional portion of the 
study is optional and does not preclude participation in the main study. The additional genomic 
samples must not be collected if the subject has not consented to participate in this exploratory 
genomic substudy. 
A Data Monitoring Committee (DMC) will be established for the study. 
2 
INTRODUCTION 
2.1 
Drug-resistant epilepsy 
The ILAE defines drug resistance as failure of adequate trials of 2 tolerated and appropriately 
chosen AEDs either as monotherapy or in combination to achieve sustained seizure freedom 
(Kwan et al, 2010). In the US, there are 3 million adults with active epilepsy 
(Zack and Kobau, 2017). Assuming epilepsy with focal-onset seizures in 60% of patients and 
resistance to AEDs in 20% to 40% of patients, approximately 360,000 to 720,000 patients suffer 
from drug-resistant epilepsy (Semah, et al, 1998; Kwan and Sander, 2004; Giussani et al, 2016). 
It is this drug-resistant epilepsy population that represents the greatest burden of disease for 
individuals, physicians, and the healthcare system. A treatment that provides a significant 
reduction in seizure frequency will reduce mortality and significantly improve quality of life. 
In patients with drug-resistant epilepsy, seizures have a negative impact on mortality, 
psychosocial functioning, and quality of life across multiple domains. Patients with resistant, 
focal epilepsy, and complex partial or tonic-clonic seizures have a 5 to 10 times higher mortality 
rate (Fazel et al, 2013; Hesdorffer and Tomson, 2013; Holst et al, 2013; Sperling, 2004), 
including a risk of sudden unexpected death in epilepsy (SUDEP) (Devinsky, 2011) when 
compared with the general population. An estimated 1% of patients diagnosed with 
drug-resistant epilepsy die every year of SUDEP (Jehi, 2016). Moreover, resistant, focal epilepsy 
is regarded by many experts as a progressive disease in which ongoing seizures result in an 
increased risk of further seizures. These patients are prone to falls and injuries; cannot drive; can 
rarely live independently; feel isolated and stigmatized; have difficulty finding and keeping a 
job; and often depend on disability benefits (Azuma and Akechi, 2014; Taylor et al, 2001; 
Baker et al, 1997). It is well known that even with the development of several AEDs in the recent 
past, the proportion of patients with epilepsy who are able to achieve complete control of their 
seizures has only increased minimally, from 64% to 68% (Brodie et al, 2012). 
Moreover, it is important to highlight that there is a continuum of drug resistance within the 
population classified as drug-resistant according to ILAE criteria. The likelihood of achieving 
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complete seizure control diminishes as the number of failed AED regimens increases. When a 
patient with drug-resistant epilepsy has failed to achieve seizure freedom with the second AED 
regimen, he or she has a 10% chance of achieving complete seizure control with subsequent 
AED regimens (Steinhoff et al, 2014; Beyenburg et al, 2012; Chung et al, 2010a; 
Schiller and Najjar, 2008; Mohanraj and Brodie, 2006).  
Although effective pharmacologic treatment options are limited for this patient population, some 
patients may benefit from surgical options. Resective surgery may provide long-term (up to 
5 years) seizure freedom in up to 52% of patients (de Tisi et al, 2011). Surgery is associated with 
several risks, both those inherent to surgery (infection, bleeding) and those specific to resective 
epilepsy surgery (loss of function after removal of brain tissue). The ILAE recommends that 
patients with focal epilepsy be evaluated for surgery after failing to achieve seizure freedom with 
the second AED regimen; however, in most European and North American countries patients are 
referred for surgery only after failing multiple AED regimens (Engel, 2013). Due to various 
factors (limited number of epilepsy surgery centers, inability to localize the seizure focus, 
surgical contraindications, etc) only a small percentage of patients meeting ILAE 
recommendations are evaluated for surgery (Engel, 2013). Therefore, the vast majority of 
patients with drug-resistant, focal epilepsy have no treatment options – pharmacological or 
surgical – that can provide complete seizure control or a clinically meaningful reduction in the 
number of seizures. 
A treatment that provides a significant reduction in seizure frequency will reduce mortality 
(Laxer et al, 2014) and significantly improve quality of life (Choi et al, 2014; Baker et al, 1997) 
by increasing patients’ ability to attain basic safety, freedom from the risk of falls and injuries, 
and reach the milestones that most people take for granted: a feeling of belonging and social 
integration; the ability to form intimate relationships and a family; and having a productive and 
rewarding profession; or other means of self-realization. 
2.2 
Padsevonil mechanism of action 
Padsevonil is a novel chemical entity that has selective affinity both for presynaptic SV2 proteins 
and for postsynaptic cBZR sites on the GABA-A receptor. At presynaptic sites, PSL binds with 
high affinity to all 3 subtypes of the human synaptic vesicle 2 protein (ie, SV2A, SV2B, and 
SV2C), and at postsynaptic sites acts as a partial agonist, binding with moderate affinity to the 
cBZR sites. Whereas SV2A ligands are characterized by broad-spectrum anticonvulsant activity, 
GABA-A receptors mediate inhibitory neurotransmission, and their allosteric modulation by 
cBZR site offers robust protection against seizures. The synergistic anticonvulsive effect 
observed when combining levetiracetam (LEV) with benzodiazepines (BZDs) in preclinical 
models (Kaminski et al, 2009) was the motivation that led to the design of PSL. 
In nonclinical studies, PSL has shown higher potency than LEV combined with a BZD 
(diazepam) at matching in vivo occupancies of SV2A and cBZR, respectively. This suggests that 
PSL’s preclinical potency is not only due to the combination of these 2 precedented mechanisms 
of action, but that a unique interaction of PSL with SV2 proteins may also play a role.  
Preclinical experience with PSL is described extensively in the Investigator’s Brochure (IB). 
2.3 
Clinical studies 
To date, PSL has been administered in the following 9 completed human pharmacology studies: 
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 N01360—a single, ascending dose safety, pharmacokinetic (PK), and pharmacodynamic 
(PD) study  
 N01386—a multiple, ascending dose safety, PK, and PD study  
 UP0010—a single-dose absorption, distribution, metabolism, and elimination study  
 UP0001—a single- and multiple-dose comparative PK and food effect study  
 UP0013—a multiple-dose, 2-part drug-drug interaction (DDI) study  
 N01383—a positron-emission tomography (PET) study evaluating the brain GABA-A 
receptor occupancy following multiple dosing of PSL  
 UP0002—a multiple-dose study in subjects with epilepsy investigating the effect of PSL on 
the PK of carbamazepine epoxide and the PK, safety, and tolerability of PSL in the presence 
of concomitant AEDs  
 UP0036—an adaptive, open-label, single-dose PET study evaluating SV2A occupancy 
 UP0039— a single- and multiple-dose safety and PK study in healthy Japanese and 
Caucasian subjects 
In addition, the following Phase 2 studies have been performed: EP0069 and EP0073 (ongoing). 
EP0069 was a multi-center, randomized, double-blind placebo-controlled parallel group study; 
and EP0073 is a multicenter, OLE to evaluate the long-term safety, tolerability, and efficacy of 
PSL when used as adjunctive therapy for partial-onset seizures in adult subjects with highly 
drug-resistant focal epilepsy. The study subjects who enrolled in the Phase 2 study, EP0069, and 
OLE study, EP0073, had highly drug-resistant epilepsy (HDRE) which was defined in these 
studies as subjects who had ≥4 focal seizures with or without secondary generalization per week 
and who had failed to achieve seizure control with ≥4 AED regimens of adequate dose and 
duration. Patients with HDRE are considered to be a subset of the drug-resistant epilepsy 
population, the proposed patient population for the registration program including, EP0091 and 
EP0093. 
In the Phase 2 proof of concept study, EP0069, a total of 55 subjects were randomized to receive 
placebo or PSL titrated up to 400mg twice daily (bid) for a 2-week Inpatient Period administered 
concomitantly with each subject’s current and stable AED regimen. In the placebo arm, the 
2-week inpatient placebo treatment was followed by up-titration to 400mg bid PSL in Week 3. 
All subjects continued on PSL in an 8-week open-label Outpatient Period. The primary objective 
of the study was to evaluate the efficacy of PSL compared with placebo, administered 
concomitantly with each subject’s current, stable AED regimen. Adjunctive therapy with PSL 
was associated with clinically meaningful improvements in seizure frequency in adult patients 
with highly drug-resistant focal epilepsy and frequent seizures compared with placebo. 
Three subjects (n=3/27) (11.1%) in the placebo/PSL treatment group and 8 subjects (n=8/26) 
(30.8%) in the PSL/PSL treatment group had a ≥75% reduction from the Baseline Period in 
focal seizure frequency during the 2-week Inpatient Period. The 75% responder rate approached 
statistical significance (p=0.0679) and was clinically meaningful. The median percent reduction 
in weekly focal seizure frequency from Baseline to the 2-week Inpatient Period in the PSL/PSL 
treatment group (53.68%) was greater than in the placebo/PSL treatment group (12.50%). The 
median difference vs placebo for the PSL treatment group was 34.0% (95% confidence interval 
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[CI]: 3.0, 67.5). Secondary analyses demonstrated the maintenance of effect during the 
Outpatient Period, last 4 weeks of the Outpatient Period, and on-PSL treatment overall. 
Additional details regarding the efficacy can be found in the IB. 
A total of 42 study subjects have been enrolled in EP0073, the open-label extension study to 
EP0069. 
2.3.1 
Adverse event profile 
In general, in EP0069, there were no new or unexpected safety signals. The most frequently 
reported treatment-emergent adverse events (TEAEs) for subjects overall were somnolence, 
dizziness, headache, fatigue, and irritability. Overall, the most frequently reported TEAEs 
considered drug-related by the Investigator were somnolence, dizziness, and fatigue. 
Four serious TEAEs were reported for 2 subjects (1 subject had a serious TEAE of status 
epilepticus and 1 subject had serious TEAEs of impaired judgment, delirium, and dysphoria) 
during the On-PSL Overall Period. There were no deaths reported during the study. During the 
On-PSL Overall Period, in the 18 subjects who reported TEAEs leading to a dose reduction of 
PSL, the most common TEAEs were dizziness, somnolence, and fatigue. One subject withdrew 
from the study due to TEAEs of dysphoria and mood swings. There was no evidence for any 
consistent effect on laboratory parameters, vital signs, weight, ECG evaluations, physical 
examinations, or neurological examinations in the overall population. Based on the study results, 
treatment with PSL was generally well tolerated, with an acceptable tolerability and safety 
profile pointing to an overall positive benefit/risk balance. 
No study subjects have completed the OLE study (EP0073). At the time of the interim analysis 
(Dec 2016), maintenance of the effect of PSL on seizure control appears to be supported through 
Month 3. As of the 07 Mar 2017 data cut for safety for the April 2017 DMC, 5 subjects (11.9%) 
had discontinued; 1 subject (2.4%) due to an AE, 2 subjects (4.8%) due to lack of efficacy, 
1 subject (2.4%) due to consent withdrawn, and 1 subject (2.4%) for other (negative benefit/risk). 
In summary, in the Phase 1 program 129 healthy subjects and 20 patients with epilepsy (male 
and female) have been exposed to PSL at single doses up to 490mg (26 healthy volunteers) and 
repeated doses up to 400mg bid for up to 12 days (103 healthy subjects and 20 patients) in 
completed studies. In the Phase 2 proof of concept study (EP0069), 55 subjects were exposed at 
doses up to 400mg bid during the maintenance phase of the trial. A total of 42 of the 55 subjects 
enrolled in the OLE study, during which they were allowed to adjust their PSL dose. 
The psychiatric findings currently reported are consistent with the AE profile of other AEDs, 
including other SV2A ligands. Acute psychiatric effects occurred in 3 subjects administered PSL 
(2 in Phase 1 and 1 in Phase 2a). The events were transient, acute, and required admission to 
psychiatric care and antipsychotics. No definite dose relationship could be determined, and the 
events occurred after variable periods of time after the first administration of the IMP. The 
occurrence of these behavioral AEs highlights the need to consider the possibility of significant 
AEs and to maintain vigilance for them.  
With regard to cardiovascular effects, minor, transient, reductions in blood pressure (BP) were 
observed in the Phase 1 and Phase 2 studies; however, these were not clinically meaningful and 
resolved without intervention. The degrees of reduction seen in both systolic and diastolic BP are 
consistent with the GABA-A-targeted mechanism of action of PSL and do not appear likely to 
have a clinically significant effect in therapeutic use (Jones et al, 1979). In regard to ECG results, 
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all nonclinical and clinical Phase 1 and Phase 2 cardiac data in totality were reviewed by an 
expert cardiologist consultant whose opinion was that “overall, there is no clear evidence that 
PSL is associated with any increase in incidence of ectopy, change in QTc interval, or 
clinically-significant arrhythmia in clinical trials to date. Echocardiographic screening of study 
subjects at Baseline (to exclude study subjects with valvulopathies) and ongoing 
echocardiographic monitoring during treatment and posttreatment has been implemented in the 
Phase 2 studies. No major findings were observed in EP0069 and in the ongoing OLE, EP0073. 
Cardiac monitoring (eg, ECGs, vital signs, echocardiograms) is planned throughout the duration 
of the development program in order to better understand and mitigate any risks. 
In general, the safety profile has been consistent with the pharmacological properties of the drug 
and consistent with studies of AEDs in regards to the type and severity of nervous system and 
psychiatric AEs reported, with most AEs reported as mild or moderate. The overall safety profile 
during the clinical program to date can be found in the IB. 
2.4 
Rationale for this study 
With over approximately 25 AEDs approved (15 in the last 15 years), the majority of patients 
with epilepsy and focal-onset or focal to bilateral tonic-clonic (previously called “secondary 
generalized”) seizures have options for effective monotherapy and/or combination therapies 
early in the treatment paradigm; however, none of the options differentiate by superior efficacy. 
Seizure control only has changed marginally even with the latest new AED treatments 
(Brodie et al, 2012) and for the majority of severely affected and drug-resistant patients, there are 
few, if any, treatment options remaining.  
Padsevonil is an AED with a dual mechanism of action, specifically synthesized and designed 
for an increased anticonvulsant activity and hence for the treatment of seizures in patients with 
epilepsies resistant to current available drug therapies. Based on the evidence of unprecedented 
superiority of seizure control compared with other marketed AEDs across several preclinical 
models of epilepsy and the results of the proof of concept study, EP0069, treatment with PSL has 
the potential to benefit an underserved epilepsy population with high unmet medical need, 
namely those who have drug-resistant epilepsy whose uncontrolled focal-onset seizures 
constitute a substantial threat to their health and well-being. The current study, EP0091, will 
characterize the dose-response relationship with respect to efficacy and safety of PSL 
administered concomitantly with up to 3 AEDs for treatment of observable focal-onset seizures.  
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
The primary objectives of this study are to characterize the dose-response relationship with 
respect to efficacy of PSL administered concomitantly with up to 3 AEDs for treatment of 
observable focal-onset seizures in subjects with drug-resistant epilepsy and to evaluate the 
efficacy of the 4 selected dose regimens of PSL compared with placebo. 
3.2 
Secondary objective 
The secondary objective is to assess the safety and tolerability of all doses of PSL in relation to 
placebo.  
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3.3 
Other objectives 
3.3.1 
Efficacy objectives 
The other efficacy objective is to: 
 Assess the HRU and quality of life 
3.3.2 
Pharmacokinetic objectives 
The PK objectives are to: 
 Evaluate the steady-state PK profiles of PSL and the exposure-response relationship 
 Evaluate the impact of enzyme-inducing concomitant AEDs on PSL exposure  
 Evaluate concomitant AED (and/or relevant metabolites) plasma levels 
3.3.3 
Exploratory nonhereditary pharmacogenomics and 
pharmacogenetics 
The other nonhereditary pharmacogenomics and pharmacogenetics objectives are to: 
 Identify genetic polymorphisms, gene expression patterns, plasma proteins, plasma 
metabolites, plasma lipids, or other plasma and serum substances that predict or are 
associated with disease etiology, drug response, or tolerability 
4 
STUDY VARIABLES 
4.1 
Efficacy variables 
Seizure frequency refers to 28-day adjusted frequency. Observable focal-onset seizures refer to 
Type IA1, IB, and IC (ILAE Classification of Epileptic Seizures, 1981). Focal-onset seizures 
include all Type I seizures. Seizure-free status and seizure-free days include all (Types I, II, and 
III) seizure types.  
4.1.1 
Primary efficacy variable 
4.1.1.1 
Primary efficacy variable for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 
The primary efficacy variable is the change in log-transformed observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
4.1.1.2 
Primary efficacy variable for EMA and regulatory authorities who 
reference EMA 
The primary efficacy variable is the 75% responder rate, where a responder is a subject 
experiencing a ≥75% reduction in observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period. 
4.1.2 
Secondary efficacy variables 
4.1.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 
The secondary efficacy variables are as follows:  
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 The 75% responder rate, where a responder is a subject experiencing a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
4.1.2.2 
Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA 
The secondary efficacy variables are as follows:  
 The change in log-transformed observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
4.1.3 
Other efficacy variables (This list applies for all regulatory 
authorities) 
The other efficacy variables are as follows:  
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
first 4 weeks, second 4 weeks, and third 4 weeks of the 12-week Maintenance Period 
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
16-week Treatment Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 16-week Treatment Period 
 The 75% responder rate, where a responder is a subject experiencing a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 16-week Treatment Period  
 The 90% responder rate, where a responder is a subject experiencing a ≥90% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
16-week Treatment Period 
 Change from Baseline in log-transformed focal-onset (Type I) seizure frequency over the 
12-week Maintenance Period 
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 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 The 75% responder rate, where a responder is a subject experiencing as a ≥75% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 The 90% responder rate, where a responder is a subject experiencing a ≥90% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in focal-onset (Type I) seizure frequency from Baseline, over the 12-week 
Maintenance Period and the 16-week Treatment Period 
 Seizure-freedom status (yes/no) during the 12-week Maintenance and the 16-week Treatment 
Period 
 Percentage of seizure-free days during the 12-week Maintenance Period and the 16-week 
Treatment Period 
 Cumulative responder rate during the 16-week Treatment Period 
 Change in the Seizure Severity Global Item (SSG) scores from Baseline to Week 4 during 
the Maintenance Period (Visit 4) and the end of the 16-week Treatment Period (Visit 7) 
 Change in Quality of Life Inventory in Epilepsy-31-P (QOLIE-31-P) scores from Baseline to 
Week 4 during the Maintenance Period (Visit 4) and the end of the 16-week Treatment 
Period (Visit 7) 
 Change in HADS scores from Baseline to Week 4 during the Maintenance Period (Visit 4) 
and to the end of the 16-week Treatment Period (Visit 7) 
 Time to return to baseline 28-day observable focal-onset seizure count during the 12-week 
Maintenance Period 
 Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications and hospitalizations 
4.2 
Safety variables 
4.2.1 
Primary safety variables 
The safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the entire study 
 Incidence of TEAEs leading to study withdrawal 
 Incidence of treatment-emergent serious adverse events (SAEs) during the entire study 
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4.2.2 
Other safety variables 
Other safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the following periods: 16-week Treatment Period, 12-week Maintenance Period, 
4-week Titration/Stabilization Period, and 3-week Taper Period 
 Number of and reason for subjects requiring premature tapering due to TEAEs 
 Number of and reason for subjects requiring a dose reduction during the Stabilization Period 
due to TEAEs 
 Incidence of treatment-emergent SAEs during the following periods: 16-week Treatment 
Period, 12-week Maintenance Period, 4-week Titration/Stabilization Period 
 Changes in clinical laboratory test parameters (including hematology, blood chemistry, and 
urinalysis) 
 Changes in vital sign parameters (including pulse rate, systolic BP, diastolic BP, and 
respiratory rate) 
 Changes in 12-lead ECG parameters 
 Physical examination (including body weight) and neurological examination findings 
 Changes in Psychiatric and Mental Status 
 Occurrence of valvular abnormalities or pericardial effusion changes or other significant 
abnormalities as identified by 2-dimensional Doppler echocardiogram at each assessment by 
central reader  
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the End of Treatment Visit (Visit 7) to end of 
the Taper Period (Visit 8) and end of the SFU Period (Visit 9 [30 days after the last IMP 
intake]). 
4.3 
Other variables 
4.3.1 
Pharmacokinetic variables 
Blood concentrations of PSL and metabolites will be determined from samples obtained in the 
study during the Titration and Maintenance Periods in order to investigate the following 
variables: 
 The exposure-response relationship for PSL and active metabolite 
 The population PK profiles of PSL and active metabolite 
Blood concentrations of PSL and active (
 metabolite will be used to derive 
PK-population parameters (using population-PK analysis). Subjects will be asked to provide 
these samples whenever possible. 
Blood concentrations of concomitantly administered AEDs will also be evaluated for evidence of 
DDI with PSL at steady state. 
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4.3.2 
Exploratory nonhereditary pharmacogenomics variables 
Where local regulations permit, blood samples will be collected at time points specified in 
Table 5-1 and stored for up to 20 years to allow for potential exploratory analyses of RNA, 
proteins, lipids, and metabolites biomarkers. Candidate serum biomarkers may also be explored. 
These samples will be used to support biomarker strategies related to epilepsy and drug response 
(including safety, efficacy, and tolerability of PSL and concomitant therapies). 
4.3.3 
Exploratory pharmacogenetic variables  
Additional blood samples will be collected at specific time points (Table 5-1) from subjects who 
consent to participate in the pharmacogenetic substudy to measure DNA biomarkers in order to 
assess: 
 Pharmacogenetic variants associated with drug-resistant epilepsy or AED resistance and drug 
response 
The samples may be used for further genetic analyses to understand drug-resistant epilepsy, 
AED resistance, and PK. The samples will be stored up to 20 years for the research purposes 
stated in this protocol.  
4.3.4 
Exploratory pharmacokinetic evaluation 
Comparison will be made of blood concentration data of PSL and 
 metabolite derived 
from either conventional venous sampling or from the volumetric absorptive microsampling 
(VAMS) MITRA® technology. 
Additionally, evaluation of PSL and major metabolites in plasma will be undertaken from trough 
samples. The collection of plasma samples for this comparison may cease during the course of 
the study based on periodic review of the data.  
5 
STUDY DESIGN 
5.1 
Study description 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
uncontrolled focal-onset seizures despite treatment with at least 4 tolerated, appropriately chosen 
and used prior AEDs, including current AEDs (Kwan et al, 2010). All eligible subjects will have 
an epilepsy diagnosis and at least 4 observable focal-onset seizures per 28 days despite treatment 
with at least 1 to 3 AEDs with or without neurostimulation devices.  
Subjects should be educated to complete their diary entries accurately as per instruction.  
The study is composed of 4 periods (see Figure 5‒1 for a schematic diagram): 
Baseline Period (4 weeks) 
During the Screening Visit (Visit 1, Week -4), subjects will sign a written Informed Consent 
form (ICF) prior to the conduct of any study-related procedure or pre-treatment assessments, and 
the subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria. 
Subject eligibility related to seizure frequency will be evaluated based on Investigator 
assessment of the subject report on historical seizure count during the 8 weeks prior to the 
Screening Visit (Visit 1) for the retrospective seizure baseline. Eligible subjects will be given a 
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diary and receive instructions to further document seizures during the 4-week Baseline Period for 
a prospective seizure baseline. All subjects must have been on a stable dose of their present 
AEDs during the 8-week period prior to the Screening Visit (Visit 1). For the neurostimulation 
device (if applicable), the settings should be stable for 12 weeks prior to Screening Visit 
(Visit 1). Both should be stable throughout the study until the end of Treatment Period. The 
Investigator will be asked to send documentation of video-electroencephalogram (EEG) report as 
per instruction to the UCB Study Physician or representative for confirmation of eligibility 
before randomization of the subject. 
Treatment Period (16 weeks) 
The 16-week Treatment Period includes a 3-week Titration Period followed by a 1-week 
Stabilization Period and a 12-week Maintenance Period. Four weeks after the Screening Visit 
(Visit 1), subjects will return to the clinic for the Baseline Visit (Visit 2, Day 1). Subjects who 
continue to fulfill the inclusion and exclusion criteria will be randomized to 1 of the 5 treatment 
arms in a 1:1:1:1:1 ratio (random permuted blocks) to ensure the balance to 1 of the 5 treatment 
arms. Randomization will be stratified by current use of AEDs with binding to SV2A proteins 
(LEV or brivaracetam) and by region (North America, Europe, and Asia) at the time of 
randomization.  
After the Baseline Visit (Visit 2), subjects will return to the clinic for regular visits for the 
remainder of the Titration Phase. Investigational medicinal product will be increased 
approximately every 3 to 7 days depending on treatment arms (refer to Table 7-1 for details). 
Subjects will be instructed to take the IMP in 2 equally divided doses, approximately 12 hours 
apart in the morning and evening. 
During the entire 16-week Treatment Period, the dose of concomitant AEDs and the settings for 
neurostimulation devices must remain stable. The dose of IMP should remain stable during the 
Maintenance Period. 
Subjects who cannot tolerate IMP prior to Week 3 will be withdrawn from the study. For 
subjects with tolerability issues experienced at their target dose, one fallback option to a 
predefined dose based on the randomized dose (see Table 7-2) will be allowed during the 
Stabilization Period and at least 2 days prior to start of maintenance (Visit 4). The Study 
Physician or delegate should be consulted prior to use of the fallback option and the date as well 
as the reason for fallback will be recorded in the source documents and in the electronic Case 
Report form (eCRF). 
Fallback may be managed via an unscheduled visit. Fallback IMP packs will be allocated via the 
Interactive Response Technology (IRT). After fallback, the dose will be kept stable for the rest 
of the Maintenance Period. Further dose changes (ie, titration) are not allowed. Subjects, who are 
not able to tolerate the IMP during titration and after the fallback, will be tapered off IMP in a 
blinded fashion and will be withdrawn from the study. 
At Visit 4 (at the end of the Stabilization Period), subjects will enter a 12-week Maintenance 
Period during which they will receive their target dose (or their fallback dose, if applicable). 
During the entire 12-week Maintenance Period, the dose of IMP (target dose or fallback dose) 
and concomitant AEDs must remain stable. Subjects must return to the clinic for scheduled visits 
as outlined in Table 5-1. 
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Subjects who complete the Maintenance Period will return for an End of Treatment Visit. 
Subjects who discontinue early from the study will return for an Early Discontinuation Visit 
(EDV). Subjects completing the Maintenance Period will have the opportunity to enroll into the 
OLE study, EP0093. They will be converted to the entry dose of the EP0093 study, 400mg/day. 
Subjects withdrawing from the study or deciding not to participate in the OLE study (EP0093) 
will be progressively tapered off the IMP. 
For subjects discontinuing the study: 
Taper Period (4 weeks) 
The 4-week Taper Period will be required for subjects who choose not to enroll in the OLE study 
or who discontinue prior to the end of the Maintenance Period. Subjects participating in the 
4-week Taper Period should be gradually tapered off the IMP over a 3-week period (Table 7-3) 
followed by 1-week drug-free period. A faster or slower taper schedule than the suggested 
3 weeks may be implemented, if medically necessary, as per the Investigator's medical 
judgement. Subjects will start their taper at the EDV/End-of-Treatment (Visit 7) and will return 
1 week after last intake of IMP for the End-of-Taper Visit at Visit 8. Changes to concomitant 
AED(s) are not allowed during the taper of PSL unless they are medically necessary as per the 
Investigator’s medical judgement to treat rebound seizures. 
Safety Follow-Up Period 
Safety follow up for subjects not entering the OLE will consist of 1 required visit, 30 days after 
the last IMP intake (Week 23 or sooner in case of early discontinuation) including an 
echocardiogram. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks. 
For subjects continuing to the OLE study: 
Conversion Period (3 weeks) 
The 3-week Conversion Period will be required for subjects who choose to enroll in the OLE 
study at the end of the Maintenance Period. Doses for subjects participating in the 3-week 
Conversion Period will be gradually adapted (increased or decreased) in a blinded way to reach 
the entry dose for the OLE. Subjects who took placebo during the maintenance phase will 
progressively receive PSL. 
5.1.1 
Genetic substudy 
During this study, subjects will have the option of providing additional informed consent for 
exploratory DNA, RNA, and lipidomics/proteomics/additional blood biomarker analyses. 
Participation in this additional portion of the study is optional and does not preclude participation 
in the main study. The additional pharmacogenetic sample must not be collected if the subject 
has not consented to participate in this exploratory genetic substudy. A volume of 6mL of whole 
blood samples will be collected at Baseline (Visit 2). 
Any exploratory pharmacogenetic analysis will only be related to the exploration of the 
underlying causes of drug-resistant epilepsy, AED resistance, and drug response. 
Justification for additional genomic analyses is detailed in Section 5.4.3. 
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Details on the collection, storage, preparation, and shipping of samples will be presented in the 
Laboratory Manual, provided separately. 
5.1.2 
Study duration per subject 
The total duration of study per subject will be up to 27 weeks with a maximum of 19 weeks 
exposure to PSL. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks and 
either discontinuing the study or not entering the OLE.  
The end of the study is defined as the date of the last SFU Visit (30-days after the last IMP 
intake) of the last subject in the study. Additionally, the reporting of SAEs will continue until the 
6-month follow-up echocardiogram. 
5.1.3 
Planned number of subjects and sites 
It is estimated that approximately 500 subjects will be included at approximately 200 sites 
worldwide; 400 subjects are expected to be randomized. 
5.1.4 
Anticipated regions and countries 
The study will be conducted in North America, Europe, and Japan with possible extension to 
other regions or countries.  
5.2 
Schedule of study assessments 
The schedule of assessments in presented in Table 5-1.  
 
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Table 5-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) 
a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit 
b
 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week ) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT
) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Call IRT to obtain subject 
number and dispensation of 
Subject Trial Card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of withdrawal 
criteria 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
General 
medical/procedures history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history including 
etiology, diagnosis, 
surgery, and seizure history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of MRI 
(within 10 years) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of 
video-EEG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Habits and lifestyle 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Baseline 
c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 5-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) 
a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit 
b
 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week ) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT
) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
C-SSRS since last visit  c d 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
HADS  c 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
SSG  c 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
QOLIE-31-P  c 
  
X 
 
 
 
X 
 
 
X 
 
 
X 
 
CIWA-B c 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Vital signs 
e 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Body weight and height 
f 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
Physical examination 
g  
(XF = Full – XB = Brief) 
XF 
XB 
 
 
 
XB 
 
 
XF 
 
XF 
XB 
 
Neurological examination 
h 
(XF = Full – XB = Brief) 
XF 
XB 
 
 
 
XB 
 
 
XF 
 
XF 
XB 
 
Psychiatric and Mental 
Status 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
12-lead ECG 
i 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
Echocardiogram 
j 
X 
 
 
 
 
 
 
X 
 
 
 
X 
k 
 
Blood/urine sample for 
clinical laboratory analyses 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
Blood sample for 
concomitant AED assay 
l m 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
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Table 5-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) 
a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit 
b
 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week ) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT
) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
Blood sample for PSL PK 
analysis 
n m 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Blood sample for DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for RNA 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Blood sample for 
proteins/lipids/metabolites 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Pregnancy test 
o 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Seizure evaluation  
(count & type) 
p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
(AEDs and non-AEDs) and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Recording of adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Health-related outcomes 
and HRU 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
IMP dispensing (IRT) 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
IMP accountability and 
return 
q 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
Entry and exit personal 
outcome interview 
r 
X 
 
 
 
 
 
X 
 
 
 
 
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Table 5-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) 
a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit 
b
 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week ) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT
) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
Study termination 
 
 
 
 
 
 
 
 
 
 
X 
X 
s 
 
AED=antiepileptic drug; BL=Baseline; BP=blood pressure; CIWA-B=Clinical Institute Withdrawal Assessment-Benzodiazepines; C-SSRS=Columbia-
Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; ECG=electrocardiogram; EDV=Early discontinuation Visit; EEG=electroencephalogram; 
EOT=End of Treatment; HADS=Hospital Anxiety and Depression Scale; HRU=healthcare resource utilization; IMP=investigative medicinal product; 
IRT=interactive response technology; MRI=magnetic resonance imaging; OLE=open-label extension; PK=pharmacokinetic; PSL=padsevonil; QOLIE-31-
P=Quality of Life Inventory in Epilepsy-31-P; RNA= ribonucleic acid; SFU=Safety Follow-Up; SSG=Seizure Severity Global Item; Stab=Stabilization 
Period; TC=telephone call; Unsch=unscheduled; V=visit; Wk=Week 
 a Taper Period, for subjects who choose to not enter OLE study EP0093, will last for 3 weeks plus 1 week of drug-free period. Conversion Period, for subjects 
who choose to enter OLE study EP0093, will last for 3 weeks. 
b At any time, the subject may have an additional study visit if the Investigator or the subject and/or legal representative deem it necessary. Appropriate 
assessments will be conducted in relation to the reason for the visit. 
 c Questionnaires to be completed by all subjects prior to any other study procedures at the visit, when possible. 
 d If an unscheduled visit is conducted due to safety or efficacy reasons, a C-SSRS assessment will be performed with the subject during the visit. If an 
unscheduled visit is conducted for reasons other than safety or efficacy concerns (eg, replacement of lost medication, repeated collection of a laboratory 
specimen due to collection, or analysis issues), a C-SSRS will not be required at these visits. 
 e Vital signs measured in supine position after 5 minutes of rest include pulse rate, respiratory rate, systolic BP, and diastolic BP.  
f Height will only be measured at Visit 1. 
 g Full physical examinations will assess cardiac and respiratory function via auscultation and review of the following body systems: general appearance; ear, 
nose, and throat; eyes; hair and skin; respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological; and mental status. Brief physical 
examinations will include a review of the following body systems: general appearance (including mental status); skin; respiratory; cardiovascular; 
gastrointestinal; and hepatic. 
 h Brief neurological examination will include a general assessment and evaluation of reflexes, muscle strength and coordination, and cerebellar function. 
Full neurological examinations will include in addition, evaluation of cranial nerves, motor system (general muscle strength and tone), sensations in 
upper/lower extremities. 
 i Baseline ECG has to be scheduled and results received before Visit 2. An ECG at the SFU Visit will be performed only if abnormal at end of treatment or 
premature discontinuation visit. All ECG recordings will be performed with the subject resting in the supine position for at least 5 minutes. 
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 j The echocardiogram will be conducted at Visit 1. Echocardiograms will be repeated at Visit 6 for subjects continuing the OLE study. Subjects discontinuing 
will have an echocardiogram 30 days after last IMP intake at the SFU Visit (except if performed at Visit 6). A repeat echocardiogram will be performed for 
subjects with a new finding, Grade 2 (moderate severity), or Grade 3 (severe severity).  
k An echocardiogram will also be performed 6 months after last IMP intake for subjects exposed to >3 weeks to IMP and discontinuing the study (but not for 
subjects with <3 weeks exposure). 
l AED samples will ideally be taken immediately prior to dose of concomitant medication on each occasion. If this is not possible, then the sample may be taken 
at any time after dose and the timing of sample in relation to dose should be kept the same (±1 hour) on each occasion for each subject. Therefore, the timing of 
visits for each subject when AED samples are collected should be scheduled approximately at the same time whenever possible. Assay of parent PSL and 
metabolites may be included in the AED panel of tests at Visits 6 and 7.  
m On Visits 6 and 7, unless the concomitant AED sample is within ±5 minutes of a scheduled MITRA sample for PSL assay, a separate, additional MITRA 
sample will be taken at same time as the concomitant AED blood sample. 
 n  Subjects are requested to provide blood samples for measurement of PSL and metabolites whenever possible. On Visits 3, 5, and 6, site personnel should 
obtain blood samples for measurement of random PSL levels at any time between IMP intake and record accurately the time of last IMP intake and the time of 
sample collection. On Visits 4 and 7, blood samples for measurement of sparse PK profiles will be collected as follows: immediately before IMP intake 
(maximum 15 minutes before intake) and then 3 times after (between 30 minutes and 3 hours after IMP intake), taken at least 30 minutes apart. All samples 
may be taken either at home or in the site or partly at home and partly at the site.  
 o For all female subjects, serum pregnancy test at Visits 1 and 7 (in case the subject enters into the OLE study) and where applicable. Urine pregnancy test will 
be used at other visits for female subjects of childbearing potential. 
 p Seizure counts are collected on the subject’s daily record card on a daily basis. 
 q At each visit following an IMP dispensation, IMP should be presented to check for compliance. 
r Subject entry interview will be performed on a voluntary basis either at Visit 1 or Visit 2. Subject/caregiver exit interview/survey will be performed on a 
voluntary basis either at Visit 6 or Visit 7. 
s The SFU Visit will be performed only for subjects who do not enter EP0093. 
 
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5.3 
Schematic diagram 
A schematic diagram is provided in Figure 5‒1. 
 
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Figure 5‒1: Study design 
 
OLE=open-label extension, TC=telephone call; V=visit, WK=week 
 
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5.4 
Rationale for study design and selection of dose 
5.4.1 
Choice of study design and endpoints 
The target indication for PSL is as adjunctive therapy in the treatment of focal-onset seizures in 
adult patients with drug-resistant epilepsy. The key inclusion criteria are aimed at selecting a 
sample of study subjects from this target population. The criterion for drug resistance or failure 
to achieve control of seizures, with ≥4 tolerated and appropriately chosen past or current AEDs, 
is based on observations that when patients with drug-resistant epilepsy have not been able to 
control their seizures despite treatment with 4 or more AED regimens, the likelihood of 
achieving complete seizure control with another AED regimen is further reduced to 1% to 4% 
(Schiller and Najjar, 2008; Mohanraj and Brodie, 2006). Study subjects also will be required to 
have on average at least 4 spontaneous and observable focal-onset seizures (IA1, IB, or IC) per 
28 days during each 4-week interval of the 8-week retrospective Baseline Period prior to entry 
and during the 4-week Baseline Period. This minimum seizure frequency was selected to provide 
assurance that a meaningful change in percent reduction in seizure frequency over 28 days and 
50%, 75%, and 90% responder rates could be demonstrated during the 12-week Maintenance 
Period.  
The key exclusion criteria are intended to further ensure correct diagnosis of epilepsy, that the 
disease is relatively stable, that there are no drugs/treatments which could confound analyses or 
present a safety issue as a result of DDI or efficacy against seizures, that there is no evidence of 
previous safety issues with other drugs that share PSL’s mechanisms of action, and to mitigate 
risks or potential risks study subjects from this target population. 
The decision to use the continuous variable, log change in seizure frequency, as opposed to a 
binary variable, responder rate, as the primary outcome was based on the reduction in power 
consequent to the loss of information when a dichotomous variable is used compared to when a 
continuous variable is used (Altman and Royston, 2006). 
UCB regards the 12-week duration for the Maintenance Period as adequate to distinguish 
long-term from short-term efficacy. Moreover, 12 weeks is consistent with registration studies 
for recently approved AEDs as adjunctive therapy for focal-onset seizures (Moseley et al, 2016; 
Chung et al, 2010b; Elger et al, 2009) and conforms to the guidance documents by the 
FDA, Guidance for Industry, 1981 and European Medicines Agency 
(CHMP/EWP/566/98 Rev.2/Corr, 2010). Given the increased risk of SUDEP in patients with 
uncontrolled seizures (Jehi, 2016) and in those randomized to placebo in clinical trials 
(Ryvlin et al, 2011), UCB considers that requiring patients to remain on placebo longer or for all 
enrolled patients to exclude dose adjustments is not acceptable. Because of the increased 
incidence of SUDEP, subjects should be monitored closely and, depending on the Investigator’s 
judgment, withdrawn from the study in the event of seizure worsening, particularly subjects 
experiencing an increase in secondarily generalized seizures. Additionally, a 3-week Titration 
Period, a 1-week Stabilization Period, and a 12-week Maintenance Period has been assessed as 
adequate to evaluate the potential for the development of tolerance to BZDs associated with a 
reduction in long-term efficacy for both clobazam and brivaracetam. 
Similarly, UCB proposes to perform an examination of the reduction in seizure frequency from 
Baseline to assess whether there is any evidence of a notable change in treatment effect during 
the course of the 16-week Treatment Period for EP0091, and subsequent registration studies. 
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5.4.2 
Rationale for dose selection 
Dose selection for EP0091 was informed by data derived from the following: 
1. UP0036: PET-derived human SV2A receptor occupancy vs exposure relationship 
2. N01383: PET-derived human GABA-A receptor occupancy  
3. The maximum tolerated dose (MTD) of 400mg bid in Phase 1 
4. EP0069: efficacy-exposure analysis 
5. Preclinical pharmacological exposure-response data 
Four dose levels of PSL (equally spaced on the logarithmic scale), 100mg/day, 200mg/day, 
400mg/day, and 800mg/day, administered bid have been selected to fully explore the 
dose-response curve for PSL in patients with drug-resistant epilepsy. 
Two PET studies, UP0036: PET-derived human SV2A receptor occupancy and 
N01383: PET-derived human GABA-A receptor occupancy, were performed to inform dose 
selection for the clinical studies. Using population-PK modeling of the PK and PET data with a 
SV2A ligand in UP0036, simulations projected SV2A receptor occupancy in human brain 
regions to be greater than 90% over the whole dosing interval for 90% of a population treated 
with the 400 and 300mg bid dosing, and greater than 90% for 75% of a population at 100mg bid 
dosing. In N01383, modeling of the receptor occupancy of PSL at brain GABA-A receptors 
measured using the PET ligand, flumazenil, demonstrated that subjects treated with PSL 200mg 
bid had maximal GABA-A receptor occupancy ranging from lower limit quantification (5%) to 
9.7%. Subjects treated with PSL 400mg bid had maximal GABA-A receptor occupancy ranging 
from 7.6% to 16.8%. 
The rationale for the selection of the maximum dose, 400mg bid (800mg/day), is based on the 
MTD seen in Phase 1 single dose and multiple dose clinical studies, and is in line with receptor 
occupancy at the SV2A receptor and the nonclinical data described above. Furthermore, 
800mg/day has demonstrated clinically meaningful efficacy (EP0069 primary outcome analysis) 
with acceptable tolerability. The maximum dose is supported further by nonclinical data that 
demonstrate that high levels of SV2A receptor occupancy are required for efficacy in the primary 
model of resistant epilepsy (amygdala kindling, mean effective dose [ED50]=95%). Conversely, 
receptor occupancy at the GABA site associated with efficacy was relatively low (ED50=9%). 
Therefore, it is reasonable to conclude that the high dose level should be associated with 
occupancy consistent with these levels observed at SV2A and GABA-A receptors and 
maintained for SV2A. 
However, for brivaracetam, an AED with SV2A mode of action, a dose with demonstrated 
therapeutic efficacy (200mg), had an observed SV2A receptor occupancy below 90% 
(UCB internal data, EP0074). In this context, the lowest dose for PSL in EP0091 has been set at 
100mg/day (50mg bid) based on preliminary simulations that indicate that a dose around 
50mg bid will have an SV2A occupancy roughly equivalent to that associated with a therapeutic 
dose of brivaracetam. Of note, data from N01383 indicates that, at this lower dose level, 
GABA-A receptor occupancy may be below quantifiable levels, but even very low levels of 
occupancy may provide some synergy with SV2 mechanisms. 
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Finally, the 2 intermediate doses were selected based on equal spacing between the high and low 
doses on log-scale and SV2A and GABA-A receptor occupancy: 
 100mg bid (200mg/day) which represent an SV2A receptor occupancy >90% with no 
quantifiable GABA-A occupancy 
 200mg bid (400mg/day) which represent an SV2A receptor occupancy >90% with 
quantifiable GABA-A occupancy 
Subjects completing the Maintenance Period in EP0091 will be offered the option to enter the 
OLE study EP0093 with open-label treatment with PSL. This will be achieved through a 
Conversion Period to ensure blinding of the parent study. All subjects who choose to transition to 
EP0093 will enter the study after the 3-week Conversion Period at an intermediate dose of 
400mg/day PSL before further individual dose adjustment can be made. This dose level was 
selected considering the benefit/risk balance and is based on clinical pharmacology and PET data 
in healthy human subjects suggesting that it will provide full occupancy at the SV2A binding site 
while maintaining some minimal binding to the GABA-A binding site. For subjects previously 
on placebo in EP0091, a full SV2A occupancy is desirable to obtain a meaningful anticonvulsive 
effect while minimal BZD binding will result in fewer GABA-related CNS AEs. On the other 
hand, for subjects exposed to high doses of PSL in EP0091 maintenance (800mg/day), the target 
transition dose of 400mg/day will likely maintain the full SV2A-related effect while not entirely 
eliminating GABA-binding related effects. Once subjects enter EP0093, further individual dose 
adjustments can be made, as needed as per the OLE protocol. 
5.4.3 
Justification for genomic and biomarker strategy 
The biomarker samples will be collected to understand the molecular characteristics of epilepsy 
and drug response (including safety, efficacy, and tolerability of PSL and concomitant therapies), 
which may enable potential molecular stratification in future clinical studies. A broad range of 
molecular data may be generated from each individual sample. The exact format of these 
analyses will be specified at a later time. The samples will be stored at -80°C at the Central 
Laboratory facilities for up to 20 years or according to local laws.  
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: 
General 
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
ICF is signed and dated by the subject or by the parent(s) or by the legal representative, 
where applicable. The ICF or a specific Assent form, where required, will be signed and 
dated by minors, according to country-specific regulations. A separate ICF should be signed 
and dated by the subject to allow for the optional DNA, RNA, and 
lipidomics/proteomics/additional blood biomarker samples.  
2. Subject/legal representative/caregiver (where legally permitted) is considered reliable and 
capable of adhering to the protocol (eg, able to understand and complete diaries), visit 
schedule, or medication intake according to the judgment of the Investigator. 
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3. Subject is an adult (18 years of age or more). 
4. Subject is of normal weight of at least 40kg (for males and females).  
Epilepsy 
5. Subject fulfills diagnostic criteria for epilepsy and has observable focal-onset (IA1, IB, and 
IC) seizures for at least 3 years at the time of enrolment (according to the 
ILAE Classification of Epileptic Seizures, 1981): 
 Epileptic seizures will have been documented using video-EEG recordings or ictal-EEG 
(+/- simultaneous video) in the past (description or report is available). The Investigator 
must consult with the UCB Study Physician or representative for confirmation of 
eligibility as per instructions in the Study Manual. 
If no video-EEG report is available and, in the opinion of the Investigator, epileptic 
seizures are definite (ie, eye-witnessed seizure report, home video documentation of 
habitual events, or other proof), the Investigator must consult with the UCB Study 
Physician or representative for a case review 
 A brain magnetic resonance imaging (MRI) to be performed before randomization, if no 
such scan was performed in the last 10 years, and a report is not available. If a scan was 
performed within the last 10 years but the clinical condition of the subject was 
progressive since the last scan, a new scan should be obtained. If MRI is contraindicated 
a head CT within the last 3 years before randomization will suffice. 
6. Subjects having on average ≥4 spontaneous and observable focal-onset seizures per 28 days 
(based on Investigator assessment of subject report) with at least 1 seizure during each 
4-week interval of the 8-week retrospective Baseline Period prior to entry. Additionally, 
subjects must experience ≥4 spontaneous and observable focal-onset seizures per 28 days 
(based on Investigator assessment of subject report) during the 4-week Baseline Period.  
7. Subject has failed to achieve seizure control with ≥4 tolerated and appropriately chosen prior 
AEDs, including past and ongoing treatment, that were individually optimized for adequate 
dose and duration. Prior discontinued AED treatment would need to be assessed by the 
Investigator considering the patient medical records and patient and/or caregiver interview. 
"Prior AED" is defined as all past and ongoing AED treatments with a start date before the 
Screening Visit (Visit 1). 
Concomitant epilepsy treatment 
8. Subject is currently treated with an individually optimized and stable dose of at least 1 and up 
to 3 AEDs for the 8 weeks prior to the Screening Visit (Visit 1) with or without additional 
concurrent vagus nerve stimulation (VNS) or other neurostimulation treatments. The latter 
will not be counted as AEDs for the purpose of eligibility. 
Laboratory parameter 
9. 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. 
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Birth control  
10. Female subjects of child bearing potential must have a negative serum pregnancy test at the 
Screening Visit (Visit 1), which is confirmed to be negative by urine testing prior to the first 
dose of IMP at Day 1 (Visit 2) and prior to further dispensing at each study visit thereafter. 
Subjects will be withdrawn from the study as soon as pregnancy is known.  
Female subjects will use an efficient form of contraception for the duration of the study 
for a period of 3 months after their last intake of IMP. Hormonal contraception may be 
susceptible to an interaction with the IMP, which may reduce the efficacy of the 
contraception method. The potential for reduced efficacy of any hormonal contraception 
method requires that a barrier method (preferably male condom) also be used. 
Birth control methods considered as an efficient form of contraception: 
 Combined (estrogen- and progesterone-containing) hormonal contraception (oral, 
implant, injectable) associated with inhibition of ovulation, (which must be stable for at 
least 1 full month prior to Screening [Visit 1], and should remain stable during the study) 
in combination with a barrier method (preferably a condom). 
 Progesterone-only hormonal contraceptives (oral, implant, injectable) associated with 
inhibition of ovulation (which must be stable for at least 1 full month prior to Screening 
[Visit 1], and should remain stable during the study) in combination with a barrier 
method (preferably a condom). 
 Progesterone-releasing intrauterine systems or the TCu 380A intrauterine device in 
combination with a barrier method (preferably a condom). 
 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action, in combination with a barrier method (preferably a male 
condom) 
 Male or female condom with spermicide (ie, double-barrier) 
 Cap, diaphragm or sponge with spermicide (ie, double-barrier) 
 Bilateral tubal ligation 
 Vasectomized partner (provided sole partner, and partner has medical proof of surgical 
success) 
 True heterosexual sexual abstinence is an acceptable form of contraception when this is 
in line with the preferred and usual lifestyle of the person. Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of the study, and withdrawal are not acceptable methods of 
contraception. 
 Women not agreeing to use birth control must be abstinent (as described in the preceding 
bullet) or be of nonchildbearing potential, defined as being postmenopausal (for at least 2 
years before the Screening Visit [Visit 1]), verified by serum follicle stimulating hormone 
level >40mIU/mL at the Screening Visit (Visit 1), or permanently sterilized (eg, bilateral 
tubal occlusion, hysterectomy, bilateral salpingectomy), or congenitally sterile. 
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 Both male and female subjects must use the above mentioned contraception during the 
study. 
 To ensure a proper birth control, females who use hormonal contraception should use an 
efficient barrier contraceptive in the 3 months after their last intake of IMP. 
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
General 
1. Subject has previously been randomized in this study or a study of the medication under 
investigation in this study. Re-screening of a subject may be permitted but requires prior 
medical monitor approval, and is not permitted in case of screen failure due to seizure count. 
2. Subject has participated in another study of an investigational medication (or a medical 
device) within the last 30 days or 5 half-lives (whichever is longer) or is currently 
participating in another study of an investigational medication (or a medical device). 
Laboratory parameter 
3. Subject has either:  
 >2.0x 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%). 
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.  
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.  
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be 
repeated once for confirmation before Baseline (Visit 2).  
Medical condition 
4. Subject has a history or current medical condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the subject’s ability to participate in this study. 
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5. Subject has a current psychiatric condition that occurred within the last 12 months which, in 
the opinion of the Investigator, could compromise his/her safety or ability to participate in 
this study including but not limited to schizophrenia, schizoaffective disorder, bipolar 
disorder, severe unipolar depression, dementia, or irreversible severe or progressive 
encephalopathy. 
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 “Screening/Baseline” 
version of the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening. 
7. Subject has a history of chronic alcohol or drug abuse within the last 2 years.  
8. Subject has a history of cerebrovascular accident, including transient ischemic attack, in the 
last 6 months. 
9. Subject has presence of any sign (clinical or imaging techniques) suggesting rapidly 
progressing (ie, not expected to stay stable during study participation) brain disorder or brain 
tumor. Stable lesions such as arteriovenous malformations, meningiomas, or other benign 
tumors are acceptable if no surgical removal is planned or likely for the duration of the study. 
10. Subject has any clinical condition (eg, bone marrow depression, chronic hepatic disease, 
and/or severe renal impairment) that could impair reliable participation in the study or 
necessitate the use of medication not allowed by protocol. 
11. Subject has presence of a terminal illness. 
12. Subject has presence of a serious infection.  
13. 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 interval corrected for heart rate using Bazett’s formula (QTcB) or QT interval 
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, or T-wave configurations are not of sufficient quality 
for assessing QT interval duration 
 Subject has a history of unexplained syncope or a family history of sudden death due to 
long QT syndrome. 
14. Subject has an abnormality on echocardiogram at Screening Visit (Visit 1) as assessed by 
central reader that is accompanied by clinical symptoms (eg, shortness of breath, palpitations, 
and murmur) or a ≥Grade 2*/moderate severity abnormality or a history of rheumatic heart 
disease or other known valvular abnormalities (*according to the ASE Guidelines, 
Zoghbi et al, 2017). 
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Subjects whose echocardiograms are not interpretable at Screening Visit (Visit 1) by 
transthoracic echocardiogram (TTE), eg, due to technical difficulties or position of the heart 
will be excluded from the study. 
Epilepsy 
15. Subject has a history of or signs of generalized (formerly referred to as ‘idiopathic 
generalized’) or combined generalized and focal (formerly referred to as ‘symptomatic 
generalized’) epilepsy (Scheffer IE et al, 2017). 
16. Subject has a history of status epilepticus within the 6-month period prior to Screening Visit 
(Visit 1). 
17. Subject has seizures on a regular basis that are uncountable eg due to clustering (ie, an 
episode lasting less than 30 minutes in which several seizures occur with such frequency that 
the initiation and completion of each individual seizure cannot be distinguished) during the 
8-week retrospective Baseline and during the 4-week Baseline Period.  
18. Subject has isolated auras only (ie, focal-onset seizures which involve subjective sensory or 
psychic phenomena only, without impairment of consciousness or awareness, [formerly 
referred to as simple partial seizures without observable component]). 
19. Subject has a current diagnosis of pseudo- or nonepileptic seizures, or other nonepileptic 
events that could be confused with epileptic seizures. 
20. Subject had resective surgery for epilepsy in the last 6 months prior to study entry or plans 
for such a surgery within the timeframe of the study.  
Epilepsy treatment 
21. Subject had an epilepsy dietary therapy initiated <3 months prior to Screening Visit (Visit 1). 
22. Subject has VNS, deep brain stimulation, Responsive Neurostimulator System, or other 
neurostimulation for epilepsy device  
 implanted and activated <1 year prior to enrollment, or  
 with stimulation parameters that have been stable for <3 months, or 
 with battery life of unit not anticipated to extend for duration of trial. 
23. Subject is currently treated with carbamazepine, phenytoin, primidone, or phenobarbital or 
any other drug known as a strong inducer of cytochrome P450 (CYP) 3A4 liver enzymes. 
24. Subjects previously had serious side-effects with drugs having SV2A and GABA-ergic 
mechanisms of action. 
Medical treatment 
25. Subject has a known hypersensitivity to any components of PSL formulation or a history of 
drug or other allergy that, in the opinion of the Investigator or UCB Study Physician or 
delegate, contraindicates her/his participation.  
26. Subject has taken or is taking any prescription, nonprescription, dietary (eg, grapefruit or 
passion fruit), or herbal products (eg, St. John's wort) that are strong inducers or strong 
inhibitors of the CYP3A4 or 2C19 pathway for 2 weeks (or 5 half-lives, whichever is longer) 
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prior to the Baseline Visit (Visit 2). Subjects taking sensitive substrates of CYP2C19 are 
similarly excluded.  Please also note the prohibited concomitant medications listed in 
Section 7.8.2. 
27. Subject has been taking vigabatrin for less than 2 years at study entry.  
28. Subject has been taking vigabatrin for at least 2 years without documented normal visual 
fields following at least 2 years of intake. 
29. Subject with a history of vigabatrin treatment who did not have a visual perimetry test at least 
6 months following conclusion of treatment or the results of the visual perimetry test showed 
either a damage or a visual field defect associated with 1 of the following 2 conditions:  
 there was a change from a visual field test done at some point while the subject was 
taking vigabatrin, or  
 there was a change from a visual field test done within weeks after stopping vigabatrin 
administration. 
30. Subject has been taking felbamate for less than 12 months and/or has no appropriate 
laboratory tests showing no indication of aplastic anemia or hepatic failure. 
31. Subject taking retigabine for less than 4 years. In addition, subject currently taking retigabine 
or having been exposed to retigabine with no documentation (at least every 6 months or 
6 months after last exposure) of normal/stable visual acuity, slit-lamp examination, dilated 
fundus photography and macular Optical Coherence Tomography imaging.  
32. Subject is taking GABA-A-ergic drugs regularly (agonists [ie, barbiturates] or receptor 
positive allosteric modulators [ie, BZDs or non-BZDs]), excluding as needed (PRN) intake of 
GABA-A-ergic AEDs <3 times per week for emergencies. 
Pregnancy 
33. Female subject who plans to become pregnant or is breastfeeding. 
6.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. 
Subjects should be withdrawn from the study if any of the following events occur: 
1. Subject withdraws his/her consent. 
2. The Sponsor or a regulatory agency requests withdrawal of the subject. 
3. Subject is noncompliant with the study procedures or medications in the opinion of the 
Investigator. 
4. Subject takes prohibited concomitant medications, prescribed or over-the-counter as defined 
in this protocol. 
5. Subject develops an illness that would interfere with his/her continued participation. 
6. A prolongation or worsening of overall seizure duration, frequency, type, or pattern 
considered by the Investigator as serious enough to warrant discontinuation from the study. 
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7. Subject with an echocardiogram showing a Grade 2 finding (moderate regurgitation/stenosis) 
if accompanied with moderate to severe signs/symptoms or a Grade 3 finding (severe 
regurgitation/stenosis) will be discontinued from the study regardless of accompanying 
clinical symptoms, and should begin discontinuation of the IMP. Additionally, a jump of 
2 grades, from Grade 0 to Grade 2 (moderate regurgitation/stenosis) accompanied with 
moderate to severe symptoms or from Grade 1 to Grade 3 (severe regurgitation/stenosis) will 
result in subject discontinuation (see Section 6.3.2). 
8. Changes in the ECG that are regarded as clinically significant and/or that worsen over time.  
 An ECG shows an absolute value for QTcB or QTcF ≥500ms or ≥60ms above Baseline. 
 Subject develops second- or third-degree atrioventricular block or another clinically 
relevant change in ECG as determined by the Investigator. 
9. 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 IMP. 
Subject has active suicidal ideation with a specific plan as indicated by a positive 
response (“Yes”) to question 5 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a mental healthcare professional and must be 
withdrawn from the study. 
10. For subjects developing psychiatric/mood/behavioral signs or disturbances (see examples in 
list below) that are clinically concerning or that worsen over time, the subject should be 
referred immediately to a mental healthcare professional and must be withdrawn from the 
study. 
 Auditory or visual hallucinations 
 Delusions/paranoia/grandeur 
 Disorganized thought process 
 Agitation/aggression/apathy 
 Dysphoria/depression/mood lability/euphoria 
 Disinhibition 
 Cognitive changes/memory impairment/delirium 
 Aberrant motor behavior  
11. Subject is suspected of having a serious multiorgan hypersensitivity reaction. Serious 
suspected multiorgan hypersensitivity cases may be identified and reported to the Sponsor by 
the Investigator using the following algorithm: 
 An AE or laboratory value (as defined below) suggestive of internal organ involvement 
including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, 
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pancreatitis, myositis, arthritis, or hematologic system involvement) combined with 
at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia 
 Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
 Eosinophils percentage ≥10% 
 Eosinophils absolute ≥0.5G/L 
 Neutrophils absolute <1.5G/L 
 Platelets absolute ≤100G/L 
12. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. 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 eCRF must document the primary reason for withdrawal or discontinuation. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
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 ≥5x ULN 
 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%). 
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). 
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Evaluation of PDILI must be initiated as described in Section 11.2.1. 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 eCRF must document the primary 
reason for IMP discontinuation. 
6.3.2 
Echocardiogram valvular abnormalities assessments 
Table 6-1 shows the grading of valvular abnormalities defined by a 0 to 3 Grade scale (according 
to the ASE Guidelines, 2017; Zoghbi et al, 2017) as well as the respective severity descriptions 
of absent, mild, moderate, and severe. Potential cardiovascular signs/symptoms that may 
accompany valvular abnormalities are included in the table as potential indicators of new or 
increasing severity of valvular changes and will be identified through routine physical 
examinations and AE/symptom reporting. However, symptom reporting often occurs only at an 
advanced stage of the disease (Iung and Vahanian, 2011), suggesting that valvular disease may 
or may not have accompanying clinical symptoms. 
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Table 6-1: 
Valvular abnormality grading criteria 
Echocardiogram 
Valvular 
Abnormality 
Severity / Description Potential 
Cardiovascular 
Signs/Symptoms 
Action  
Grade 0 
Absent: no regurgitation, 
no stenosis 
None reported 
None 
Grade 1 
Mild: trace or barely 
detected 
regurgitation/stenosis 
Minimal to none 
None; continued observation  
Grade 2 
Moderate: 
regurgitation/stenosis 
with intermediate values 
Symptoms
a: 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
Signs:  
Pulmonary arterial 
pressure >40mm Hg and 
rise of >10mmHg; 
pulmonary edema; 
peripheral edema or 
ascites; atrial fibrillation 
or malignant arrhythmia; 
hypotension  
For a Grade 2/moderate severity, a 
decision to discontinue is based on 
severity of clinical signs/symptoms; 
if accompanied with moderate to 
severe signs/symptoms this results 
in subject discontinuation. 
Grade 3 
Severe: 
regurgitation/stenosis in 
the extreme range, often 
accompanied by other 
symptoms 
(eg, pulmonary 
congestion) 
Discontinuation of subject. 
For a Grade 3 of severe, subject 
should be discontinued regardless of 
accompanying clinical symptoms. 
Grade increase by 
2 levels 
Increasing from:  
Grade 0 to 2 or  
Grade 1 to 3 
Rapid onset of above 
signs/symptoms 
A jump of 2 grades to 
Grade 2/moderate accompanied with 
moderate to severe signs/symptoms 
results in subject discontinuation. 
A jump of 2 grades to 
Grade 3/severe (with/without 
symptoms) will result in subject 
discontinuation. 
a New York Heart Association Classification of symptoms; for other echocardiogram measurements, see the 
Echocardiogram Manual. 
Echocardiograms will be obtained every 3 months and will be repeated sooner if new or 
worsening abnormalities are present (detailed below). Echocardiograms will be examined at the 
site by the local physician and then provided to the central reader where all study 
echocardiograms will be centrally read and interpreted by a cardiologist. When local reads 
warrant, central reads will be expedited. An expedited review of an echocardiogram should be 
performed if the following conditions are met: (1) a Grade 2 finding of moderate severity, 
accompanied by moderate or severe signs/symptoms; (2) a Grade 3 finding of severe severity 
(with or without accompanying symptoms; or (3) an increase (or jump) in 2 grades (0 to 2 or 1 to 
3) between echocardiograms. When any of these findings are observed, the Investigator/site 
should initiate an expedited review from the central reader. 
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Subjects with Grade 0 or 1 (absent or mild symptoms) will not undergo any additional 
procedures, other than continued monitoring for any symptomatic clinical events (as listed in 
Table 6-1). 
Subjects with an echocardiogram showing a Grade 2 finding (moderate regurgitation/stenosis) 
will undergo a repeat echocardiogram within 1 month (unscheduled visit) to confirm the finding. 
For a Grade 2 echocardiogram of moderate severity, a decision to discontinue will be based on 
the severity of clinical signs/symptoms; if accompanied with moderate to severe signs/symptoms 
this would result in subject discontinuation. Investigators may contact the Medical Monitor if 
they wish to discuss the subject’s clinical signs/symptoms. 
Subjects with an echocardiogram showing a Grade 3 finding (severe regurgitation/stenosis) will 
undergo a repeat echocardiogram within 2 weeks (unscheduled visit) to confirm the finding. For 
a Grade 3 echocardiogram with a severe severity, the subject should be discontinued from the 
study regardless of accompanying clinical signs/symptoms and should begin discontinuation of 
the IMP. 
Any subject that shows an increase in 2 grades levels (Grade 0 to 2 or Grade 1 to 3) will undergo 
a repeat echocardiogram within 2 weeks (unscheduled visit) to confirm the finding. A jump of 
2 grades to Grade 2 (moderate) accompanied with moderate to severe symptoms will result in 
subject discontinuation. Investigators may contact the Medical Monitor if they wish to discuss 
the subject’s clinical signs/symptoms. If the clinical symptoms are mild, the subject is not 
required to discontinue. However, a jump of 2 grades, to Grade 3 (severe), will result in subject 
discontinuation with/without and signs/symptoms. 
Regulatory authorities will be notified of any subject who is discontinued due to an abnormal 
echocardiogram. 
7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal products 
Padsevonil will be supplied by UCB as 25mg, 100mg, and 200mg film-coated tablets of different 
sizes and appearance (ie, shape and color). Placebo will be provided as tablets of matching size 
and aspect to PSL tablets allowing a double-blind packaging. 
7.2 
Treatments to be administered 
All IMP will be administered in a double-blind manner. 
All subjects will be instructed to take 5 or 6 tablets containing either PSL or placebo bid, 
approximately 12h apart. The IMP should be dosed within 30 minutes after food when 
practically feasible. 
Subjects will be allocated to 1 of the following 5 treatment arms using the IRT system at the 
Randomization Visit (Visit 2): 
 Padsevonil 100mg/day (or 50mg bid) 
 Padsevonil 200mg/day (or 100mg bid) 
 Padsevonil 400mg/day (or 200mg bid) 
 Padsevonil 800mg/day (or 400mg bid) 
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 Placebo 
7.2.1 
Titration Period 
Titration to PSL maintenance doses will occur over the course of 3 weeks as presented in 
Table 7-1. 
Table 7-1: 
Titration Period dosing 
Dose Arm 
Dose in mg per intake (morning-evening) during titration 
Day 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 
Week 
Week 1 
Week 2 
Week 3 
PSL 800mg/day 
50-50 
100-100 
150-150 
200-200 
300-300a 
PSL 400mg/day 
200-200 
PSL 200mg/day 
100-100 
PSL 100mg/day 
50-50 
Placebo 
1-1 
PSL=padsevonil 
a On Day 22, the target dose will be administered. 
A variation of ±1 day is allowed for each period of 3 or 4 days and a variation of ±3 days by 
week is acceptable, but the overall Titration Period variance in length should not exceed 
±1 week. 
For subjects with tolerability issues experienced at their target dose, 1 fallback option to a 
predefined dose based on the randomized dose will be allowed during the Stabilization Period 
and at least 2 days prior to start of maintenance (Visit 4). The UCB Study Physician or delegate 
should be consulted prior to use of the fallback option and the date as well as the reason for 
fallback will be recorded in the source documents and in the eCRF. The dosing during the 
fallback option is presented in Table 7-2. 
Fallback may be managed via an unscheduled visit. Fallback IMP packs will be allocated via the 
IRT system. 
Table 7-2: 
Dosing during fallback option 
Dose arm 
Fallback (mg/day) 
PSL 800mg/day 
PSL 600mg/day 
PSL 400mg/day 
PSL 300mg/day 
PSL 200mg/day 
PSL 150mg/day 
PSL 100mg/day 
PSL 50mg/day 
Placebo 
Placebo 
PSL=padsevonil 
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After fallback, the dose will be kept stable for the duration of the Maintenance Period. Further 
titration is not allowed. 
7.2.2 
Taper Period 
The Taper Period, in case of withdrawal or completion of the study, will comprise 3 weeks as 
presented in Table 7-3. A faster or slower taper schedule than the suggested 3 weeks may be 
implemented if medically necessary, as per the Investigator’s medical judgment. During the 
Taper Period, the dose of PSL must always be administered as bid morning and evening doses, 
approximately 12 hours apart. Concomitant AED dosages should be kept stable throughout the 
entire study including the Taper Period. 
Subjects should be monitored during the Taper Period for withdrawal symptoms, including 
behavioral changes, withdrawal-related AEs or rebound seizures as well as the severity of the 
CIWA-B withdrawal scores. Withdrawal symptoms may require medical treatment for 
management of severe withdrawal symptoms. Additional AEDs (excluding prohibited 
medications) may be added and/or changes to dose regimens of concomitant AEDs are permitted 
if medically necessary as per Investigator's medical judgement to manage rebound seizures. 
Table 7-3: 
Taper Period dosing 
Dose Arm 
Dose in mg per intake (morning-evening) during tapera 
Week 
Week 16 
Week 17 
Week 18 
PSL 800mg/day 
300-300 
200-200 
150-150 
100-100 
50-50 
PSL 600mg/day 
PSL 400mg/day 
200-200 
PSL 300mg/day 
150-150 
100-100 
50-50 
PSL 200mg/day 
100-100 
PSL 150mg/day 
75-75 
PSL 100mg/day 
50-50 
PSL 50mg/day 
25-25 
Placebo 
1-1 
PSL=padsevonil 
a Taper Period for subjects who choose an early discontinuation may occur before Week 16.  
Note: Taper steps may vary in length by ±3 days per week. 
7.2.3 
Conversion Period 
In case the subjects wish to proceed to the OLE study, the treatments and doses will be adjusted 
gradually in a blinded way to reach the single-entry dose into the OLE study (PSL 400mg/day) 
as presented in Table 7-4. During the Conversion Period, the dose of IMP must always be 
administered as bid morning and evening doses, approximately 12 hours apart. 
Subjects taking placebo will be converted to active PSL. 
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Table 7-4: 
Conversion Period dosing 
Dose Arm 
Dose per day (morning-evening) during conversion 
Week: 
Week 16 
Week 17 
Week 18 
PSL 800mg/day 
300-300 
200-200 
PSL 600mg/day 
PSL 400mg/day 
200-200 
PSL 300mg/day 
PSL 200mg/day 
100-100 
150-150 
200-200 
PSL 150mg/day 
PSL 100mg/day 
50-50 
100-100 
150-150 
PSL 50mg/day 
Placebo 
OLE=-open-label extension; PSL=padsevonil 
After completion of Week 18, the dose will be 200-200, the entry dose in the OLE study, EP0093. 
Note: Dose adjustments steps may vary in length by ±3 days per week while overall Conversion Period length 
should not change by more than 1 week. 
7.3 
Packaging 
Padsevonil tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations.  
The IMP will be provided in blister-packed treatment cards, each providing 3, 4, or 7 days’ 
treatment of active or placebo (plus some reserve tablets in case of unexpected event). 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice 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 according to the storage conditions mentioned on the label. 
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a weekly basis, including the capture of minimum and maximum temperatures reached over 
the time interval.  
In case an out-of-range temperature is noted, it must be immediately reported as per instruction 
contained in the IMP Handling Manual. 
The Investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label. 
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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, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the Sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers) or partially used, unused, damaged, and expired IMP must be reconciled and either 
destroyed at site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol. 
7.7 
Procedures for monitoring subject compliance 
At each visit after IMP is dispensed and at the end of the Taper/Conversion Period, subjects must 
return all unused IMP and empty IMP containers. 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 reviewed at each visit. 
7.8 
Concomitant medications/treatments 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
All subjects should continue to take their Baseline AED regimen (1 to 3 AEDs) unchanged over 
the whole study period. During the Taper Period, the Investigator is allowed to adjust AED 
dosing and/or add additional AED(s), only if medically necessary, based on his/her medical 
judgement. 
 Drugs with possible CNS effects are allowed if at a stable dose from at least 1 month before 
Visit 1 and during the whole study period. 
 Drugs with no CNS effects, and which are not strong CYP enzyme inducers/inhibitors or 
sensitive CYP2C19 substrates, are allowed. In cases of uncertainty the Study Physician (or 
designee) should be contacted before initiating or stopping any medication during study 
unless it was a medical emergency. 
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 Vigabatrin, retigabine, and felbamate are allowed and count as add-on AEDs 
 if taken for more than 2, 4, and 1 years, respectively, and 
 if requirements mentioned in the Exclusion Criteria (Section 6.2) were met. 
7.8.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications are prohibited during the study: 
 GABA-A-ergic drugs including agonists (ie, barbiturates) or receptor-positive allosteric 
modulators (ie, BZDs or non-BZDs like zolpidem) taken >2 times per week. Regular intake 
of benzodiazepines with an indication for epileptic seizures as concomitant drugs is not 
allowed. However, PRN intake of GABA-A drugs <3 times per week is allowed, ie, for 
emergencies.  
 Strong CYP3A4 inhibitors/inducers  
 AEDs including carbamazepine, phenytoin, phenobarbital, primidone  
 Non-AED strong CYP3A4 enzyme inducers/inhibitors (ie, prescription drugs, 
nonprescription drugs, medical cannabis, cannabidiol, dietary [eg, grapefruit or passion 
fruit]. For more details refer to Table 3-2 and Table 3-3 in FDA Drug Development 
Resources, Drug development and drug interactions: Table of substrates, inhibitor and 
inducers. 
 Strong CYP2C19 sensitive substrates/inhibitors/inducers including S-mephenytoin, 
omeprazole, fluconazole, fluoxetine, fluvoxamine, ticlopidine, rifampin, ritonavir (for more 
details refer to Table 3-1, Table 3-2, and Table 3-3 in FDA Drug Development Resources, 
Drug development and drug interactions: Table of substrates, inhibitor and inducers). 
7.8.3 
Rescue medication 
Benzodiazepines (as a rescue medication) are allowed for up to two doses within 7 days. 
Each BZD intake for “as needed” must be listed individually in the eCRF, either on the 
concomitant AED medication page or on the concomitant non-AED medication page, according 
to the indication. 
7.9 
Blinding 
This is a study with a double-blind study during all study periods (ie, Titration Period, Treatment 
Period, and Taper/Conversion Period). At the start of the Titration Period, subjects will be 
randomized to 1 of the 5-treatment arms in a 1:1:1:1:1 ratio (random permuted blocks). 
Randomization will be stratified by current use of AEDs with binding to SV2A proteins (LEV or 
brivaracetam) and region (North America, Europe, and Asia) at the time of randomization. 
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 IRT system. Details of the 
IRT system will be addressed in a separate randomization schedule specification document. 
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7.9.1.2 
Breaking the treatment blind in an emergency situation 
In the event of an emergency, it will be possible to determine to which treatment arm and dose 
the subject has been allocated 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 Clinical Project Manager (CPM) 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. 
7.10 
Randomization and numbering of subjects 
An IRT will be used for assigning eligible subjects to a treatment regimen (as applicable) based 
on a predetermined production randomization and/or packaging schedule provided by the IRT 
vendor. The IRT will generate individual assignments for subject kits of IMP, 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 Visit (Visit 1) that serves as the subject identifier throughout the study. The subject 
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 2), the Investigator or designee will contact the IRT and provide 
brief details about the subject to be randomized. The IRT will allocate kit numbers to the subject 
based on the subject number during the course of the study. The randomization number must be 
incorporated into the eCRF. 
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 5-1, and an outline of all assessments performed is provided 
in the sections below. 
Visit windows are provided below by visit. The site should adjust the time of the visits to 
maintain the overall timeframe of the study or study periods. 
8.1 
Baseline Period (4 weeks) 
8.1.1 
Visit 1 (Week -4) 
The following procedures will be performed: 
 Obtain written informed consent. For subjects willing to participate in the genotyping 
substudy, signature and date of the Genetics Informed Consent form. For subjects/caregivers 
willing to perform the entry and exit personal outcomes interview/survey, signature and date 
of consent. 
 Call IRT to obtain subject number  
 Dispense Subject Trial Card 
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 Collect demographic data, including habits and lifestyle 
 Verify Inclusion and Exclusion criteria (laboratory parameters/ECG/echocardiogram/MRI 
results may not be available at the visit but assessments need to be performed and evaluated 
before Visit 2) 
 Collect general medical and procedure history 
 Collect epilepsy history including etiology, diagnosis, surgery, and seizure history 
 Brain MRI to be performed before Visit 2 if no brain MRI was performed in the past 10 years 
and/or no report is available. If a scan was performed within the last 10 years but the clinical 
condition of the subject was progressive since the last scan, a new scan should be obtained. 
 Obtain the report of past video-EEG by the subject and send to UCB or delegate for review 
before Visit 2 
 Collect AED history 
 Obtain Baseline C-SSRS data 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Measure body weight and height 
 Perform full physical examination (refer to Section 11.3.4 for details) 
 Perform full neurological examination (refer to Section 11.3.5 for details) 
 Perform 12-lead ECG and have it assessed by central reader before Visit 2 
 Perform echocardiogram and have it assessed by central reader before Visit 2 
 Collect blood and urine samples for clinical laboratory analyses 
 Collect blood sample for concomitant AED assay 
 Perform serum pregnancy test (for all female subjects) 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs since the signature of the informed consent 
 Record health-related outcomes and HRU (refer to Section 9.5 for details)  
 Dispense diary and provide instructions on proper completion 
 Perform entry personal outcomes interview/survey (can be done at Visit 2 instead) if the 
subject consented to take part in this activity 
 Provide appointment to next visit in 4 weeks 
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8.2 
Treatment Period (16 weeks ±1 week from Visit 2) 
8.2.1 
Titration Period (3 weeks ±1 week from Visit 2) 
8.2.1.1 
Visit 2, Baseline (Day 1, 4 to 5 weeks after Visit 1) 
The following procedures will be performed: 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain SSG data 
 Obtain QOLIE-31-P data 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Measure body weight 
 Perform brief physical examination (refer to Section 11.3.4 for details) 
 Perform brief neurological examination (refer to Section 11.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Collect blood and urine samples for clinical laboratory analyses 
 Collect blood sample for concomitant AED assay 
 Obtain blood samples for DNA (to be performed only in adults – mentally impaired subjects 
will be excluded – having given specific consent for it, where ethically accepted and 
authorized by regulatory agencies), RNA, protein, lipids, and metabolites 
 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card  
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs  
 Verify Inclusion and Exclusion criteria (including results of laboratory samples, ECG, MRI, 
echocardiogram results performed since Visit 1). In the event one of these results is not 
available, the visit may be delayed by 1 week. 
 Verify withdrawal criteria 
 Randomize subjects using IRT 
 Record health-related outcomes and HRU (refer to Section 9.5 for details), with the 
exception of socio-professional status 
 Perform entry personal outcomes interview (if not done at Visit 1) if the subject consented to 
take part in this activity 
 Dispense IMP using IRT 
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8.2.1.2 
Telephone call (Week 1 ±3 days) 
Subject will be interviewed to check his/her health condition including, seizure experience, 
concomitant medications and procedures, and AEs. 
8.2.1.3 
Visit 3 (Week 2 ±1 week) 
The following procedures will be performed: 
 Verification of withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Vital signs measurement (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Obtain blood sample for random PSL levels at any time between IMP intakes and record 
accurately the time of last IMP intake and time of the sample 
 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 9.5 for details), with the 
exception of socio-professional status  
 Dispense IMP using IRT 
 Check IMP accountability 
8.2.2 
Stabilization Period (1 week ±3 days) 
8.2.2.1 
Telephone call (Week 3) 
Subject will be interviewed to check his/her health condition including seizure experience, 
concomitant medications and procedures, and AEs. Subject should be informed to call the 
Investigator within 3 days in case of AEs (in order to eventually consider fallback). 
8.2.3 
Maintenance Period (12 weeks ± 1 week) 
8.2.3.1 
Visit 4 (Week 4 ±1 week) 
The following procedures will be performed: 
 Verification of withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data  
 Obtain SSG data 
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 Obtain QOLIE-31-P data 
 Measure vital signs (pulse rate, systolic BP blood, diastolic BP, and respiratory rate), in 
supine position after 5 minutes of rest 
 Measure body weight  
 Perform brief physical examination (refer to Section 11.3.4 for details) 
 Perform brief neurological examination (refer to Section 11.3.5 for details) 
 Perform Psychiatric and Mental Status assessment  
 Obtain 12-lead ECG 
 Collect blood and urine samples for clinical laboratory analyses 
 Obtain MITRA blood samples immediately before IMP intake (maximum 15 minutes before 
IMP intake) and then 3 times after (between 30 minutes and 3 hours after IMP intake) taken 
at least 30 minutes apart 
 Obtain blood samples for RNA, protein, lipids, and metabolites  
 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 9.5 for details), with the 
exception of socio-professional status  
 Dispense IMP using IRT 
 Check IMP accountability 
8.2.3.2 
Visit 5 (Week 8 ±1 week) and Visit 6 (Week 12 ±1 week) 
The following procedures will be performed: 
 Verification of withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Measure vital signs (pulse rate, systolic BP blood, diastolic BP, and respiratory rate), in 
supine position after 5 minutes of rest 
 Measure body weight  
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG (only at Visit 5/Week 8)  
 Obtain echocardiogram (only at Visit 6/Week 12) for subjects continuing into the OLE 
 Collect blood and urine samples for clinical laboratory analyses (only at Visit 6/Week 12) 
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 Collect blood samples for concomitant AED assay (only at Visit 6/Week 12) including an 
additional MITRA sample if the AED sample is not within ±5 minutes of 1 of the scheduled 
PSL PK samples 
 Obtain MITRA blood sample for random PSL levels at any time between IMP intakes and 
record accurately the time of last IMP intake and time of the sample. 
 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 9.5 for details), with the 
exception of socio-professional status  
 Dispense IMP using IRT 
 Check IMP accountability 
 Perform exit personal outcomes interview/survey (at Visit 6, or can be done at Visit 7) if the 
subject/caregiver consented to take part in this activity 
8.2.3.3 
Visit 7 (Week 16±1 week for End-of-Treatment or earlier for 
Early Discontinuation Visit) 
The following procedures will be performed: 
 Verification of withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain SSG data  
 Obtain QOLIE-31-P data  
 Obtain CIWA-B data (only for subjects tapering) 
 Measure vital signs (pulse rate, systolic BP blood, diastolic BP, and respiratory rate), in 
supine position after 5 minutes of rest 
 Measure body weight  
 Perform full physical examination (refer to Section 11.3.4 for details) 
 Perform full neurological examination (refer to Section 11.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG  
 Collect blood and urine samples for clinical laboratory analyses 
 Collect blood sample for concomitant AED assay including an additional MITRA sample if 
the AED sample is not within ±5 minutes of 1 of the scheduled PSL PK samples 
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 Obtain MITRA blood samples immediately before IMP intake (maximum 15 minutes before 
IMP intake) and then 3 times after (between 30 minutes and 3 hours after IMP intake) taken 
at least 30 minutes apart. 
 Obtain blood samples for RNA, protein, lipids, and metabolites  
 Perform urine pregnancy test (for female subjects of childbearing potential discontinuing the 
study only) and serum pregnancy test (for female subjects continuing in the OLE study) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 9.5 for details) 
 Dispense IMP using IRT 
 Check IMP accountability 
 Perform exit personal outcomes interview/survey (if not done at Visit 6) if the 
subject/caregiver consented to take part in this activity 
8.3 
Taper/Conversion Period (3 to 4 weeks ±1 week) 
8.3.1 
Telephone call (after 1 or 2 weeks in tapering/converting, as needed) 
Subject will be interviewed to check his/her health condition including seizure experience, 
concomitant medications and procedures, and AEs. 
8.3.2 
Visit 8 (Week 19/20 ±1 week, end of Taper/Conversion) 
The following procedures will be performed: 
 Obtain C-SSRS data since the last visit 
 Obtain CIWA-B data only for subjects tapering 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Measure body weight 
 Perform full physical examination (refer to Section 11.3.4 for details) 
 Perform full neurological examination (refer to Section 11.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Collect blood and urine samples for clinical laboratory analyses 
 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
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 Record AEs 
 Record health-related outcomes and HRU (refer to Section 9.5 for details), with the 
exception of socio-professional status  
 Check IMP accountability 
 Study termination (only for subjects enrolling in OLE study, EP0093) 
8.4 
Safety Follow-Up (Visit 9 [Week 23 or earlier for EDV, 
approximately 30 days after last IMP intake]) 
The following procedures will be performed:  
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain SSG data  
 Obtain QOLIE-31-P data  
 Obtain CIWA-B data  
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Measure body weight 
 Perform brief physical examination (refer to Section 11.3.4 for details) 
 Perform brief neurological examination (refer to Section 11.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Obtain echocardiogram for subjects discontinuing the study (except if performed at Visit 6) 
 Collect blood and urine samples for clinical laboratory analyses 
 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication (AEDs and non-AEDs) and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 9.5 for details), with the 
exception of socio-professional status  
 End of diary recording 
 Study termination, only for subjects who do not enter EP0093  
An additional follow-up echocardiogram will be performed at 6 months (±1 month) after the last 
IMP intake only for discontinued subjects exposed to IMP for more than 3 weeks and subjects 
not entering the OLE. 
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8.5 
Unscheduled Visit/Telephone call 
At any time, the subject may have an unscheduled study visit/telephone call if the Investigator 
and/or the subject deem it necessary. An unscheduled visit may be conducted due to safety or 
efficacy reasons and appropriate assessments will be conducted in relation to the reason for the 
visit. All information, including reason for visit/telephone call, any information on AEs, etc, 
should be collected in the source documents and recorded in the appropriate section of the eCRF. 
8.6 
Open-label extension study (EP0093) 
Subjects from this study, have the option of taking PSL during an OLE study, EP0093. 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 potential risks of 
long-term exposure to PSL and the potential benefit and risks of other treatment options 
available. 
9 
ASSESSMENT OF EFFICACY 
The efficacy variables are described in detail in Section 4.1. 
9.1 
Seizure frequency 
At the Screening Visit (Visit 1), seizure count will be based on Investigator assessment of 
subjects’ reports during the 8 weeks prior to the Screening Visit (Visit 1). The subject should 
report on average a minimum of 4 spontaneous and observable focal-onset seizures per 28 days 
with at least 1 seizure during each 4-week interval of the 8-week retrospective baseline. During 
the 4-week Baseline Period, the subject should experience a minimum of 4 spontaneous and 
observable focal-onset (based on Investigator assessment of subject report). During the study, 
subjects will keep diaries to record daily seizure activity from the Screening Visit (Visit 1) 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 and confirm 
the seizures according to the ILAE codes and record the seizure types and frequency in the 
eCRF/diary; he/she will also confirm the presence of AEs if applicable. 
Subjects should record all types of seizures that occur in their diary and 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. If the subject does not complete diary 
entry as per instruction, this may result in subject discontinuation from the study at any time by 
the Investigator or the Sponsor (Section 6.3). 
The following seizure information will be recorded in the diary: 
 Seizure type 
 Seizure frequency 
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9.2 
Seizure Severity Global Item 
The SSG consists of 1 or 2 items from the Seizure Severity Questionnaire and asks the subjects 
to evaluate the severity of their seizures for the last 4 weeks and/or since the Baseline (in 
EP0091). The subjects should describe all types of seizures when answering the questions.  
The SSG will be completed according to the tabular schedule of study procedures, Table 5-1. At 
the very beginning of the visit, the SSG will be provided to all subjects. It is preferred that the 
subject complete the questionnaire on his/her own; however, assistance may be provided by 
either the study staff or caregiver if needed. 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 SSG 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 31 items grouped into 7 multi item subscales (Seizure 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 5-1. At the very beginning of the visit, the QOLIE-31-P will be provided to all subjects. It 
is preferred that the subject will be asked to complete the questionnaire on his/her own; however, 
assistance may be provided by the study staff or caregiver if needed. 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 
Hospital Anxiety and Depression Scale 
The HADS was chosen for its well-established psychometric properties both in general 
population and more recently in patients with epilepsy (Lin and Pakpour, 2017; 
Wiglusz et al, 2016; de Oliviera et al, 2014). The HADS scores for anxiety and for depression 
range from 0-21 with higher scores indicating worse state. A score below 8 is considered to be 
normal (Zigmond and Snaith, 1983). It is preferred that the subject complete the questionnaire on 
his/her own; however, assistance may be provided by either the study staff or caregiver if 
needed. 
9.5 
Health-related outcomes and healthcare resource utilization 
Health-related outcomes and HRU will be collected in the eCRF and/or diary during the study 
according to the tabular schedule of study procedures, Table 5-1. 
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These assessments will include:  
 Socio-professional status  
 Healthcare provider consultations not foreseen by protocol including the type of provider 
(general practitioner, specialist physician, nurse), the site of care (office-private, 
office-hospital, home, emergency room) and the reason leading to the consultation 
 Concurrent medical procedures 
 Concomitant medications 
 Hospitalizations including the reason leading to the hospitalization, the admission ward 
transfers and length of stay 
 Caregiver support needs 
 Number of school or working days lost due to the medical condition of the subjects 
9.6 
Entry and exit personal outcomes interview 
Participation in this additional portion of the study is optional and does not preclude participation 
in the main study. Please refer to Section 13.4.3 for details on analysis of the corresponding data. 
Subjects will be invited to participate in a qualitative interview that may last approximately 30 to 
45 minutes (before treatment starts [Visit 1 or Visit 2]), and in another 30-minute qualitative 
interview at the end of the study (Visit 6 or Visit 7). For subjects who choose to participate, the 
interviews will be conducted by a study nurse/study personnel using a semi-structured interview 
guide and will be audio-recorded.  
The aim of the entry interview is to gather insight into how epilepsy impacts the subject’s life 
(beyond seizure count) across various domains (social, relationship, independence, work, 
psychological, etc), what is most restrictive for the subject, and to understand what would 
constitute a meaningful change when trying a new therapy and the trade-off across various 
domains. 
The aim of the exit interview is to evaluate if and which aspects (domains) of the subject’s life is 
impacted by the treatment and the extent to which the treatment achieves what is considered a 
meaningful change by the subject. If a subject leaves the study prematurely, he/she will also be 
invited to participate in an exit interview at this/her final visit (Visit 7). 
9.7 
Caregiver survey 
Participation in the caregiver survey is optional and does not preclude a subject's participation in 
the main study. The caregiver optional survey aims to gather their perspective on the impact of 
epilepsy on the subject’s life and expectations of meaningful change. The caregiver survey will 
also assess the impact of caring for a subject with epilepsy on his/her own life across various 
domains (social, relationship, independence, work, etc). This survey will allow UCB to gather 
differences in perspective and expectations from the subject and his/her caregiver’s point of 
view. 
Refer to Section 13.4.3 for details on analysis of the corresponding data. 
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10 
ASSESSMENT OF PHARMACOKINETIC AND 
EXPLORATORY VARIABLES 
Blood samples for PK and exploratory variables will be obtained at the scheduled time points 
presented in Table 5-1 and details of the collection, storage, preparation, and shipping of samples 
will be presented in a Laboratory Manual. 
10.1 
Pharmacokinetic variables 
The PK variables for parent PSL and metabolites are described in detail in Section 4.3.1. 
Calculations of PK parameters will be made using population PK modeling. Additionally, 
plasma concentration data for concomitantly administered AEDs will be evaluated by comparing 
ratios of steady state levels vs Baseline levels. For details of PK analyses, refer to Section 13.4.2. 
Detailed information on the collection, storage, preparation, and shipping of samples will be 
presented in a Laboratory Manual. 
10.1.1 
PK sampling procedures 
10.1.1.1 
PSL assay 
Subjects are requested to provide blood samples for measurement of PSL and metabolite levels 
whenever possible using the VAMS technology on the MITRA microsampling device. Site 
personnel are requested to discuss the importance of PK samples to measure blood levels of PSL 
and inform the selection of the safety and efficacy of the doses examined in this study. Site 
personnel should educate subjects regarding the importance of accurately recording the time of 
the last IMP intake and their concomitant AEDs. 
On Visits 3, 5, and 6, site personnel should obtain blood samples for random PSL levels at any 
time between IMP intakes and record accurately the time of last IMP intake and time of the 
sample. 
On Visits 4 and 7, blood samples for measurement of sparse PK profiles should be collected as 
follows: immediately before IMP intake (maximum 15 minutes before intake) and then 3 times 
after (between 30 minutes and 3 hours after IMP intake) taken at least 30 minutes apart. 
All samples may be taken either at home or at the site when possible or partly at home and partly 
at the site. 
10.1.1.2 
Concomitant AED and exploratory pharmacokinetic evaluation 
Subjects are requested to provide blood samples for concomitant AED assay (to evaluate any 
DDI with PSL) at Visits 1, 2, 6, and 7. 
On Visits 6 and 7, if the time point of sampling is not within 5 minutes of 1 of the scheduled 
PSL PK collections, then an additional MITRA sample will be taken alongside (±5 minutes) the 
concomitant AED sample. This process will only be done at some pre-selected sites for a limited 
number of subjects. 
Assay of PSL metabolites may be included in the concomitant AED assay screen. 
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10.2 
Exploratory variables 
Detailed information on the collection, storage, preparation, and shipping of samples for DNA, 
RNA, lipidomics, and proteomics analysis will be presented in a Laboratory Manual. 
Results for the exploratory parameters obtained from DNA, RNA, lipidomics, and proteomics 
analysis, and serum biomarkers will be described in a separate report.  
11 
ASSESSMENT OF SAFETY 
11.1 
Adverse events 
11.1.1 
Definitions 
11.1.1.1 
Adverse events 
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 or echocardiogram finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the ICF until the SFU Visit), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied (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 with the clinical profile known 
to the Investigator from the subject’s history or the Baseline Period. 
11.1.1.2 
Serious adverse events 
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 
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, but are not limited to, potential Hy’s Law [see 
Section 11.1.1.2.2 ], allergic bronchospasm requiring intensive treatment in an emergency 
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room or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse) 
 Initial inpatient hospitalization or prolongation of hospitalization 
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event]. 
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
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.) 
11.1.1.2.1 
Anticipated serious adverse events 
The following anticipated SAEs are anticipated to occur in the epilepsy population at some 
frequency that is independent of drug exposure.  
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 11.1.2.3. 
Table 11‒1: Anticipated SAEs for the epilepsy population 
MedDRA System Organ Class 
MedDRA Preferred Term 
Congenital and hereditary disorders 
Teratogenicity 
General disorders and administration site conditions 
Sudden unexplained death in epilepsy 
Injury, poisoning, and procedural complication 
Fall 
a, fracture  a, injury  a 
Nervous system disorders 
Cluster seizures, convulsion, incontinence  a 
memory impairment, status epilepticus 
Pregnancy, puerperium, and perinatal disorders 
Abortion spontaneous 
Psychiatric disorders 
Abnormal behavior, acute psychosis, anxiety, 
cognitive disorder, confusional state, psychotic 
behavior, sleep disorder and disturbances 
Reproductive system and breast disorders 
Impotence, menstrual disorder 
MedDRA=Medical Dictionary for Regulatory Activities, Version 19.1; SAE=serious adverse event; SOC=System 
Organ Class  
 a Event are anticipated when occurring in the context of seizure, but not classified in MedDRA primary SOC. 
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11.1.1.2.2 
Adverse events of special interest 
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. 
11.1.2 
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. 
11.1.2.1 
Description of adverse events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the 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. 
11.1.2.2 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with: 
 The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening” 
 The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one 
11.1.2.3 
Additional procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the SAE 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 
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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 
6 months from last IMP intake for each subject (ie, until the 6-month follow-up 
echocardiogram), 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. 
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the IB. 
11.1.3 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
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. 
Information on SAEs obtained after final clinical database lock will be captured through the 
Patient Safety (PS) database without limitation of time. 
11.1.4 
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 PS 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 urine pregnancy test), and the following should be completed: 
 The subject should return for an EDV. 
 The subject should immediately stop the intake of the IMP or be tapered as instructed at the 
EDV.  
 An SFU 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. 
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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 PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up. 
In cases where the partner of a male 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 IRB/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 PS department (for contact details see SAE reporting information at the beginning of this 
protocol) only after the partner has agreed that additional information can be captured and has 
provided the signed Partner Pregnancy Consent form. UCB’s PS department is also the primary 
contact for any questions related to the data collection for the partner pregnancy, eventual birth, 
and follow up. 
A pregnancy becomes 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. 
11.1.5 
Suspected transmission of an infectious agent 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the CRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
11.1.6 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt). 
11.1.7 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
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The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, 
vital signs, laboratory, ECG, and echocardiogram results) for which data will be periodically 
reviewed during the course of the study. 
In addition, an unblinded independent DMC will oversee safety data approximately every 6 
months (subject to DMC recommendation) during the course of the study during which the 
safety of PSL will be assessed. The safety variables and the decision rules to be used will be 
specified in the DMC charter. This analysis will inform any decisions regarding changes in study 
conduct and/or study termination. The precise membership, scope, and responsibilities of the 
DMC are described in the DMC charter.  
11.2 
Laboratory measurements 
Laboratory assessments will be conducted using standard methods at a central laboratory. The 
central laboratory will provide the Investigator with dedicated, standardized sampling equipment 
(labels, needles, tubes), and a study-specific Laboratory Manual, which will explain how to use 
the equipment and how to ship the samples to the central laboratory. The laboratory parameters 
measured are presented in Table 11‒2. 
The total blood volume drawn for clinical laboratory assessments per subject will be a maximum 
of 31.6mL by sampling, which includes 2mL for hematology, 5mL for blood chemistry, 5mL 
and 20µL for AED and PSL plasma level (including back-up samples for AED assay), 6mL for 
genetic substudy, 13.5mL for genomic assessments, and 80µL for PK measurements.  
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Table 11‒2: Laboratory measurements 
Hematology 
Chemistry 
Urinalysis 
Basophils 
ALP 
Glucose 
Eosinophils 
ALT 
pH 
Hematocrit 
AST 
RBC 
Hemoglobin 
Bilirubin 
Total protein 
Lymphocytes 
BUN or urea 
WBC 
MCH 
Calcium 
Microscopy (WBC, RBC, casts, 
crystals, bacteria) 
a 
MCHC 
Chloride 
Other 
MCV 
Creatinine 
FSHb 
Monocytes 
Glucose 
 
Neutrophils 
HDL 
 
Platelet count 
LDH 
 
RBC count 
LDL 
 
WBC count 
Magnesium 
 
 
Potassium 
 
 
Sodium 
 
 
Total bilirubin 
 
 
Total cholesterol 
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; HDL=high density lipoprotein; FSH=follicle stimulating hormone; LDH=lactate dehydrogenase; 
LDL=low density lipoprotein; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin 
concentration; MCV=mean corpuscular volume; RBC=red blood cell; WBC=white blood cell 
a Microscopy will be performed only in case of abnormalities. 
b Only applicable to postmenopausal women 
Where applicable (ie, for women of childbearing potential), a serum pregnancy test (β-human 
chorionic gonadotropin levels) will be conducted at Visits 1 and 7 only. Urine pregnancy test 
will be used at other visits. If pregnancy is suspected at any time during the study, an interim test 
should be performed. 
Women not agreeing to use birth control must be abstinent or be of nonchildbearing potential, 
defined as being postmenopausal (for at least 2 years before the Screening Visit [Visit 1]), 
verified by serum follicle stimulating hormone level >40mIU/mL at the Screening Visit (Visit 1), 
or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), 
or congenitally sterile. 
Sampling time and last AED intake should be recorded in the eCRF.  
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11.2.1 
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 11.1.1.2.2 ), and, if applicable, also reported as 
an SAE (see Section 11.1.1.2). 
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 11.2.1.1). The local 
hepatologist is the expert usually consulted by the treating physician for assessment and 
management of potential hepatic disease. This would usually be a hepatologist, but may be a 
gastroenterologist. Additional investigation and monitoring may be required and adapted based 
on the diagnosis after the cause of the liver injury/abnormality is confirmed (details in 
Section 11.2.1.4). 
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed waiting for the repeat result. 
If tests are done locally for more rapid results, a concurrent sample should also be sent to the 
central laboratory whenever possible. Medical care decisions are to be made initially using the 
most rapidly available results and a conservative approach must be taken if the results from the 
2 laboratory tests are significantly different. Data from the local and central laboratory are to be 
recorded on the applicable eCRF pages. 
When IMP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should also be discontinued. In these cases, the Investigator should also 
consider dose reduction for medically necessary concomitant medication and consider changing 
any medically required concomitant medication known to be hepatotoxic to a suitable 
alternative. 
When IMP is stopped due to PDILI (as described in Section 6.3.1), 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 11.2.1.2.1 are met, rechallenge with IMP may be appropriate after discussion 
with the Sponsor.  
Rechallenge with a substance potentially causing drug-induced liver injury is dangerous, may be 
fatal, and must not occur. 
The approach to investigate PDILI is summarized in Table 11-3. 
 
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Table 11-3: Required investigations and follow up for PDILI 
Laboratory value 
 
Immediate 
Follow up 
ALT or 
AST 
Total 
bilirubin 
Symptoms 
a of 
hepatitis or 
hypersensitivity 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
≥2xULN 
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 11.2.1.3); 
recommended to 
occur at the site 
with HCP. 
Monitoring of liver chemistry 
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. 
≥3xULN 
(and ≥2x 
Baseline) 
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 11.2.1.2). 
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 
Section 11.2.1.3). 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, 
stabilize, or return to within 
Baseline values. d 
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  
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 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 11.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
 d Unless an alternative monitoring schedule is agreed by the Investigator and UCB Study Physician. Determination of stabilization is at the discretion of the 
Investigator in consultation with the hepatologist (as applicable) and UCB Study Physician, as needed. 
 
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11.2.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours (eg, by laboratory alert), and the 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 11.2.1.3) and SAE report (if applicable). 
11.2.1.2 
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. 
11.2.1.2.1 
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 11.2.1.3 and 
Section 11.2.1.4 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, DMC, and a hepatologist. 
The hepatologist must be external to UCB but may be a member of the DMC. 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. 
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11.2.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information required for the assessment of PDILI events when 
there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 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 eCRF. 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=hepatitis B core antibody; 
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). 
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The following additional information is to be collected: 
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 
11.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up 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. 
11.3 
Other safety measurements 
Other safety measurements will include vital signs measurement, 12-lead ECGs, 
echocardiograms, physical examination, neurological examination, assessment of suicidality, and 
Psychiatric and Mental Status. These will be conducted at the time points shown in Table 5-1. 
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11.3.1 
Vital signs measurement 
Vital signs will be measured at the scheduled time points presented in Table 5-1. 
Vital signs including pulse rate, systolic BP, diastolic BP, and respiratory rate 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. 
11.3.2 
Electrocardiograms 
The 12-lead ECG recordings will be measured by a qualified technician at the scheduled time 
points presented in Table 5-1.  
All ECG recordings will be performed with the subject resting in the supine position for at least 
5 minutes. ECG will be recorded at a speed of 25mm/s and with a calibration of 1cm/mV. 
The Investigator should review all ECG recordings and, determine if there are any abnormalities 
that are considered clinically significant for a particular subject. ECGs will also be sent to a 
specified central reader for review as detailed in the ECG Manual. The following ECG 
parameters will be recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTcB or QTcF, 
and Investigator’s conclusion on ECG profile. 
11.3.3 
Echocardiograms 
Echocardiograms will be performed at the scheduled time points presented in Table 5-1. An 
echocardiogram will be performed at Visit 6 if the subject is continuing in the OLE study. All 
subjects discontinuing the study will have an echocardiogram performed 30 days (±1 week) after 
the last IMP intake except for subjects who have had an echocardiogram performed at Visit 6. 
For subjects discontinuing with more than 3 weeks exposure to IMP or for subject not entering 
the OLE, an echocardiogram will be performed at 6 months (±1 month) after the last IMP intake.  
Two-dimensional Doppler echocardiography will include the following 
measurements/observations: 
 Epicardial Abnormalities 
 Functional measurements 
 Diastology (ie, Mitral Valve E/A waves, etc.) 
 Systolic (ie, Left Ventricular Ejection Fraction, LVEF, etc.) 
 Epicardial Effusion 
 Amount of effusion 
 Pericardial thickness 
 Valvular Abnormalities 
 Measurement of valve regurgitation/stenosis 
 Measurement of left atrial volume 
Subjects whose echocardiograms are not interpretable by TTE at study entry, eg, due to technical 
difficulties or position of the heart, will not be randomized. In the event echocardiograms are not 
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interpretable by TTE during the study, alternative assessments should be done using either 
transesophageal echocardiography or cardiac MRI in these particular instances. 
Echocardiograms should be acquired by a qualified technician. The echocardiograms will be 
examined by the local physician. Echocardiograms will also be sent to a central cardiologist for 
review as detailed in the Echocardiogram Manual. 
A repeat echocardiogram will be performed for subjects with a new finding or Grade 2 
(moderate severity) or Grade 3 (severe severity) (see Section 6.3). 
Subjects with an echocardiogram showing an abnormality meeting the withdrawal criteria (see 
Section 6.3) are to be discontinued from the study. An expedited review of an echocardiogram 
(at the central reader) should be requested if the following conditions are met: (1) a Grade 2 
finding of moderate severity, accompanied by moderate or severe signs/symptoms; (2) a Grade 3 
finding of severe severity (with or without accompanying symptoms); or (3) an increase (or 
jump) in 2 grades (0 to 2 or 1 to 3) between echocardiograms. When any of these conditions are 
met, the Investigator/site should initiate an expedited review from the central reader (see 
Echocardiography Manual). Regulatory authorities will be notified of any discontinuations. 
In case of discontinuation, the subject should return for an EDV and SFU Visit (Visit 9) 
including an echocardiogram within approximately 1 month after last IMP intake and if taking 
IMP greater than 3 weeks, should also return for a 6-month echocardiogram. The corresponding 
TEAEs should be followed up until they have resolved, have a stable sequelae, or the subject is 
lost to follow-up. 
11.3.4 
Physical examination 
Physical examinations will be performed at the scheduled time points presented in Table 5-1. 
Findings that are considered clinically significant changes since the physical examination at the 
Baseline Visit will be recorded as AEs. 
A full physical examination will include, cardiac and respiratory function via auscultation and 
review of the following body systems: general appearance; ear, nose, and throat; eyes; hair and 
skin; respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological; and 
mental status. 
A brief physical examination will include, review of the following body systems: general 
appearance including mental status; skin; respiratory; cardiovascular; gastrointestinal; and 
hepatic. 
In addition, height will be measured at the Screening Visit (Visit 1) 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 5-1. 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. 
11.3.5 
Neurological examination 
Neurological examinations will be performed at the scheduled time points presented in 
Table 5-1. Findings that are considered clinically significant changes since the neurological 
examination at the Baseline Visit will be recorded as AEs. 
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A full neurological examination will include, general assessment; evaluation of reflexes, muscle 
strength and coordination and cerebellar function; evaluation of cranial nerves, motor system 
(general – muscle strength and tone); and sensations in upper/lower extremities. 
A brief neurological examination will include, general assessment and the evaluation of reflexes, 
muscle strength and coordination and cerebellar function. 
11.3.6 
Assessment of suicidality 
The C-SSRS will be completed at the scheduled time points presented in Table 5-1.  
Suicidality will be assessed by trained study personnel using the C-SSRS (Posner et al, 2011). 
This scale will be used for screening as well as to assess suicidal ideation and behavior that may 
occur during the study. The Investigator’s decision about 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. 
If an additional visit (or unscheduled visit) is conducted due to safety or efficacy reasons, a 
C-SSRS assessment will be performed with the subject during the visit. If an additional visit 
(or unscheduled visit) is conducted for reasons other than safety or efficacy concerns 
(eg, replacement of lost medication, repeated collection of a laboratory specimen due to 
collection or analysis issues), a C-SSRS will not be required at these visits.  
Details of the case must be documented by the Investigator (PI or Investigator physician, not site 
staff conducting the CSSRS) and provided to UCB via the SAE reporting process. 
11.3.7 
Psychiatric and Mental Status 
The psychiatric and mental status 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. The Psychiatric and Mental Status 
assessment will be performed at Baseline and all scheduled visits (Table 5-1). The parameters 
that will be evaluated are orientation, attention, memory, mood, calculus, behavior, and thinking 
or feeling. These parameters will be assessed as normal or abnormal and then determined 
whether clinically significant. If present and abnormal, psychiatric symptoms, mental 
impairment, and behavioral problems will be assessed as to whether they are clinically 
significant. 
11.3.8 
Withdrawal monitoring 
Any symptoms of withdrawal reactions will be monitored using the CIWA-B questionnaire at 
the scheduled time points presented in Table 5-1. The CIWA-B questionnaire contains 
22 questions which are selected to distinguish withdrawal symptoms from other symptoms 
(Busto et al, 1989). 
Subjects should be monitored during the Taper Period for withdrawal symptoms, including 
withdrawal-related AEs or seizures as well as the severity of the CIWA-B withdrawal scores. 
Withdrawal symptoms may require medical treatment for management of severe withdrawal 
symptoms. 
Further details about this questionnaire will be covered in the Study Manual. 
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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 subject from immediate hazard 
before notifying UCB (or its representative) and the IRB/IEC in writing regarding the type of 
emergency and the course of action taken.  
After implementation of such measure, the Investigator must notify the CPM of the Sponsor 
within 24 hours and follow any local regulatory requirements. 
12.2 
Monitoring 
UCB (or designee) will monitor the study to meet the Sponsor’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 UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s). 
The Investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study subject). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
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). 
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. 
If they are not included in the clinical dossier/hospital file of the subjects, the following data may 
be written directly in the eCRF and will therefore be considered as source data 
 Demographic data 
 Childbearing potential and birth control 
 Vital signs  
 Body weight and height 
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 Physical and neurological examinations 
 Healthcare provider consultation not foreseen by the protocol 
 Caregiver use 
 Socio-professional data 
 Number of school/working days lost 
Diaries will be transcribed into the eCRF and will be considered as source documentation. 
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 records, must be saved and stored as instructed 
by UCB (or designee). 
For subjects randomized to investigational product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study-related identifiers (such as randomization/treatment number, or similar), they should 
mention the subject’s participation in the study and identification of that study (study title or 
number), they should record the obtaining of consent (date of consent), the exposure to 
investigational product, the subject’s medical history, the concomitant medication treatments and 
dates (including contraceptive treatment), AEs and SAEs, and the date of the visits. The source 
documents should provide evidence that inclusion/exclusion criteria have been met. 
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 and reports, 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. A risk based approach will be 
used to monitor the data from the site including tools such as source data verification and remote 
data review. These processes will be described in the study manuals.  
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 electronic 
eCRF. 
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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 eCRFs 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 
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 IRB/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 subjects 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 
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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 arrangements, the 
protocol, investigational site, and IRB/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 the planned statistical methods is provided in the sections that follow. Full 
details will be provided in the Statistical Analysis Plan (SAP). 
13.1 
Definition of analysis sets 
13.1.1 
Enrolled Set 
The Enrolled Set consists of all subjects who have given informed consent. 
13.1.2 
Randomized Set 
The Randomized Set (RS) consists of all subjects randomized into the study. 
13.1.3 
Safety Set 
The Safety Set (SS) consists of all subjects who were administered at least 1 dose or a partial 
dose of IMP. The SS will be used to summarize and analyze all safety variables. In case of 
dosing administration error, summaries and analyses using the SS will be conducted according to 
actual treatment received. 
13.1.4 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects in the RS who were administered at least 
1 dose or a partial dose of IMP and have Baseline and at least 1 post-Baseline seizure frequency 
data during the Treatment Period. In case of dosing administration error, or change in treatment 
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dose, summaries and analyses using the FAS will be conducted according to randomized 
treatment. The FAS will be the primary analysis set for all efficacy summaries and analyses. 
13.1.5 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS, consisting of those subjects who had at least 
1 post-Baseline efficacy measurement and who had no major protocol deviation affecting the 
primary efficacy variable, as confirmed during a pre-analysis data review meeting, conducted 
prior to study unblinding. 
13.1.6 
Pharmacokinetic/Pharmacodynamic Set 
The Pharmacokinetic/Pharmacodynamic Set is defined as a subset of the FAS, consisting of 
those subjects who provide at least 1 PSL concentration measure and at least 1 post-Baseline PD 
variable. 
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], standard error, minimum, maximum, 25th and 75th percentiles) will be 
tabulated. Unless otherwise mentioned, statistical hypothesis tests will be 2-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 28 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 28-day period. It is 
computed as the number of seizures recorded over a period, divided by the total number of days 
in that period, multiplied by 28. Observable focal-onset seizures refers to Type IA1, IB, and IC 
seizures (according to the ILAE Classification of Epileptic Seizures, 1981). Focal-onset seizures 
include all Type I seizures. Seizure free status and seizure-free days include all (Type I, II, and 
III) seizure types. 
13.3.1 
Analysis of the primary efficacy variable 
13.3.1.1 
Analysis of the primary efficacy variable for the US FDA, PMDA, and 
other regulatory authorities not specified in Section 4.1.1.2 
Pairwise comparisons of 400mg, 200mg and 100mg dose groups versus placebo will be carried 
out using the analysis model below. Type 1 error will be controlled by the Hochberg step-up 
procedure within SAS® Proc Multtest. If all the results of the pairwise comparisons are 
statistically significant then the 50mg dose group will be compared to placebo. 
For the US FDA, PMDA, and other regulatory authorities not specified in Section 4.1.1.2, the 
primary efficacy variable is the change in log-transformed observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. The 28-day Baseline and 
post-Baseline (maintenance) seizure frequency will be transformed with the natural logarithm, 
specifically ln(x+1), where x represents the 28-day seizure frequency. The transformed seizure 
frequency data will be analyzed using analysis of covariance (ANCOVA) with treatment group 
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as the main factor, Baseline log-adjusted seizure frequency as a continuous covariate, and 
Baseline SV2A use and Region as categorical factors. Pairwise contrasts will be constructed to 
compute estimated effects of each dose from placebo. 
All pairwise analyses of the primary efficacy variable will be repeated on the PPS. 
13.3.1.2 
Analysis of the primary efficacy variable for EMA and regulatory 
authorities who reference EMA 
For EMA and regulatory authorities who reference EMA, the primary efficacy variable will be 
the 75% responder rate in observable focal-onset seizures during the Maintenance Period and 
will be analyzed using logistic regression with factors for treatment group, Baseline seizure 
frequency, Region, and Baseline SV2A use. If there are issues with convergence, Baseline SV2A 
use will be dropped.  
The same methodology carried out in Section 13.3.1.1 will be applied to the pairwise analyses. 
13.3.2 
Secondary efficacy analysis 
13.3.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 
The 75% responder rate in observable focal-onset seizures during the Maintenance Period is a 
secondary efficacy variable for the FDA. It is the primary efficacy variable for EMA. The 
analyses are described in Section 13.3.1.2.  
In addition, the 50% responder rate in observable focal-onset seizures during the Maintenance 
Period will be analyzed using logistic regression as described in Section 13.3.1.2. Analyses of 
the percent change in seizure reduction endpoints will be performed using the Wilcoxon-Mann-
Whitney test. The Hodges-Lehmann nonparametric estimator will be used to estimate the median 
percent reduction in seizures between groups and its corresponding 95% confidence interval (CI) 
will be provided. 
13.3.2.2 
Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA 
The change in log-transformed observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period is a secondary efficacy variable for EMA. It is the primary efficacy 
variable for the FDA. The analyses are described in Section 13.3.1.1.  
In addition, the 50% responder rate in observable focal-onset seizures during the Maintenance 
Period will be analyzed using logistic regression as described in Section 13.3.1.2.   
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used to 
estimate the median percent reduction in seizures between groups and its corresponding 95% CI 
will be provided. 
13.3.3 
Other efficacy analyses 
All other analyses of the 75% and 50% responder rate endpoints will be analyzed using the same 
logistic regression model as specified in Section 13.3.1.2. Analyses of 90% responder rate and 
seizure freedom will use the same methodology. In addition to observable focal-onset seizures 
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and focal-onset seizures, analyses will also be carried out on all seizures (seizure-free status and 
seizure-free days) during the 12-week Maintenance Period and the 16-week Treatment Period. 
All other analyses of the change from Baseline in seizure frequency will be analyzed using the 
ANCOVA model on the log-transformed data, as specified in Section 13.3.1.1. 
The time to return to baseline 28-day observable focal-onset seizure count during the 12-week 
Maintenance Period will be analyzed using Kaplan-Meier methodology. Additional details of the 
analysis will be captured in the SAP. 
The QOLIE-31-P and SSG assessments will be summarized using descriptive statistics by each 
available visit.  
13.4 
Planned safety and other 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, QTcB, QTcF, and QRS) and arrhythmias, 
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 echocardiogram results 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 Mental Status assessment and CIWA-B data will also be 
included using listings. 
13.4.2 
Pharmacokinetic analyses  
Blood concentrations of PSL and metabolites will be determined from blood samples obtained in 
the study, during the Titration and Maintenance Periods in order to investigate the PK of PSL 
and metabolites. 
The PK parameters calculated include, AUC(0-τ), AUC, Cmax, tmax, t½, Ctrough, and Cmax ss. 
The PK variables will be derived from population PK modeling. 
The PK parameters of PSL and 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, arithmetic mean, SD, median, and minimum and maximum 
values. Graphical outputs over time will be produced on the trough plasma PSL concentrations. 
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Plasma concentration data for concomitantly administered AEDs will be assessed by evaluating 
ratios of steady state levels while on maintenance PSL vs Baseline (pre-PSL) levels. 
An exploratory comparison of PSL blood levels derived from the MITRA samples with 
conventional venous sampling may be made. An exploratory evaluation of PSL metabolites may 
be undertaken. 
13.4.3 
Entry and exit personal outcomes interview and caregiver survey 
The data from the qualitative personal outcomes interviews/surveys are considered exploratory, 
will be maintained separate from the clinical database, and results made available only after 
database lock of the primary study. The subject/caregiver’s interviews/surveys will be analyzed 
by a third party not involved in the clinical conduct of the study and will be reported outside the 
clinical study report. 
13.5 
Handling of protocol deviations 
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). 
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 
Seizure frequency will be computed over non-missing diary days. Unless noted otherwise, for 
subjects who prematurely discontinued the study, last observation carried forward (LOCF) 
method will be applied to obtain a seizure frequency estimate for the Maintenance Period: 
 Subjects discontinued during the Titration and Stabilization Period: seizure frequency will be 
calculated using all available data in the Titration and Stabilization Period and carry forward 
for the Maintenance Period. 
 Subjects discontinued during the Maintenance Period: seizure frequency will be calculated 
using all available data in the Maintenance Period. 
Additional details and sensitivity analyses for missing data will be described in the SAP.  
13.7 
Planned interim analysis and data monitoring 
An independent DMC will be formed to monitor the ongoing safety of the study. The DMC will 
consist of at least 3 individuals. Voting members of the DMC will include external physicians 
with experience in treating drug-resistant epilepsy and a cardiologist. Additionally, at least 1 
member may be a statistician. All members will have experience and expertise in clinical trials. 
The DMC members may not participate in the study as principal or co-Investigators, or as study 
subject care physicians. The DMC will regularly review study data and evaluate the treatments 
for excess adverse effects and other potential safety issues. Actions that the DMC can take 
following a review may include providing recommendations to the Sponsor concerning 
continuation, termination or other modifications of the study based on the observed adverse 
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effects of the treatment under investigation. Such recommendations may include stopping 
enrollment into a padsevonil dose arm for safety and tolerability reasons and allocating 
remaining patients to remaining padsevonil dose or placebo arms. The DMC will consist of 
members independent from UCB. Study enrollment will not be halted during DMC review of the 
safety data. The DMC may also be asked to provide a review of final study results, as deemed 
appropriate. The detailed role, scope, composition, responsibilities, and operation of the DMC, as 
well as the identity of the DMC members will be defined in a separate DMC Charter. 
Safety and tolerability data will be made available to the DMC at each meeting as described in 
the DMC Charter. The data will be provided in a semi-unblinded fashion (data will be visualized 
by real treatment groups, but the treatment/dose assigned to each group will remain blinded) and 
the full unblinding can be requested by the DMC members, if appropriate. Pharmacokinetic data 
may be provided to the DMC at their request. These safety, tolerability, and PK data will be 
presented by individuals not otherwise involved in the conduct of the study. The deliberations 
and decisions of the DMC will be formally documented. 
Ad hoc DMC meetings can be held for other reasons if deemed appropriate by the Sponsor or the 
DMC members. 
In addition to ongoing review of safety data and safety signal detection within UCB, the 
occurrence of AEs of interest including cardiac and behavioral adverse events, in particular, will 
be monitored by the DMC to provide an assessment of the risk of occurrence of these events in 
the study. Statistical modeling may be used to provide estimates for quantification of the level of 
risk in the study based on the risk in the epilepsy population and in the intended patient 
population in the study (see Inclusion and Exclusion Criteria in Section 6). This analysis may 
inform any decisions regarding changes in study conduct and/or study termination. 
The DMC procedures will ensure that the data remain blinded to the study team and 
Investigators at all times throughout the conduct of the study until the data have been unblinded. 
Only DMC members and an independent statistical group will have access to unblinded safety 
data emerging from the study. DMC members will also have access to unblinded efficacy data 
when required. It is understood that maintaining validity and integrity of the study is of 
paramount importance to ensure its acceptability to the Sponsor, the scientific community and 
health authorities. 
13.8 
Determination of sample size 
The sample size was calculated based on achieving 90% power to observe a statistically 
significant result for either the 400mg bid and 200mg bid or 200mg bid and 100mg bid doses 
when compared to placebo, for a change from Baseline of the log-transformed (ln x +1) 28-day 
adjusted seizure frequency. Multiplicity is controlled for using the Hochberg step up procedure. 
The log-reduction from Baseline in seizure frequency was assumed to be 0.195 for placebo and 
0.492, 0.670, 0.754, and 0.780 for the 50mg bid, 100mg bid, 200mg bid, and 400mg bid doses of 
PSL, respectively. A common SD of 0.985 was assumed. These estimates are based on prior 
experience in epilepsy together with the EP0069 study results. 
With power of 90%, a 2-sided Type-1 error of 5%, and all dose groups of the same size, 
80 subjects are required per arm, giving a total of 400 subjects. 
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Assuming a screening failure rate of approximately 20%, it is anticipated to enroll around 
500 subjects and randomize 400 subjects in this study. 
The study is also powered to give over 80% power to observe a statistically significant result for 
the 75% response rate. For the 75% responder rate, assumptions were a 0.121 responder rate for 
placebo and corresponding responder rates of 0.233, 0.301, 0.332, and 0.342 for the 50mg bid, 
100mg bid, 200mg bid, and 400mg bid doses of PSL, respectively.  
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 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, IRB/IEC review, and 
regulatory inspection. 
If the ICF is amended during the study, the Investigator (or the Sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization 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 ICF. 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. 
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 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
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The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, ICF, IB, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
subject-related documents to be used for the study to the IRB/IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to 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 IRB/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 IRB/IEC, 
as allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
14.4 
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 
IRB/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). 
14.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
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Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, 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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16 
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Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of 
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17 
APPENDICES 
17.1 
Protocol Amendment 1 
Rationale for the amendment 
The protocol has been amended primarily to increase the potential for the study to be 1 of 2 
adequate and well-controlled studies that supports registration. This requires an increase in the 
sample size to allow for pairwise comparisons and the use of the 75% responder rate status as the 
primary endpoint for EMA (CHMP/EWP/566/98 Rev.2/Corr, 2010).  
Per EMA guidance, the primary endpoint in add-on epilepsy trials should dichotomize the data 
into responders/non-responders, where responders are patients who obtained at least a certain 
pre-defined percentage reduction of seizure frequency. An improvement of >75% is regarded as 
clinically more meaningful than >50% and seems feasible given the premise of greater efficacy 
of PSL based upon nonclinical animal data and EP0069 results. Therefore, the 75% responder 
rate has been selected as the primary endpoint, rather than the more commonly used 50% 
responder rate. 
Another important addition to the protocol is that the DMC may stop enrollment into a 
padsevonil dose arm for safety and tolerability reasons and allocate remaining patients to 
remaining padsevonil dose or placebo arms. This addition does not reflect a change in intent. 
Rather, the plan had been to describe this possibility in the DMC Charter, but it is now also being 
included in the protocol to avoid disruption to the trial via a subsequent amendment in the 
unlikely event that a dose arm is dropped from the trial for safety/tolerability reasons. 
Modifications and changes 
Specific changes 
Change #1  
LIST OF ABBREVIATIONS (deletion bolded) 
ANCOVA = analysis of variance 
ICH = International Council on Harmonization 
Has been changed to (revisions bolded): 
ANCOVA = analysis of covariance 
ICH = International Council for Harmonization  
The following abbreviations have been added:  
EMA = European Medicines Agency 
PMDA = Pharmaceuticals and Medical Devices Agency 
PRN = (pro re nata) as needed 
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Change #2 
Section 1 Summary, Paragraph 2 (deletion bolded) 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
focal-onset seizures despite treatment with at least 4 prior antiepileptic drug (AED) regimens 
including past and current treatment. 
Has been changed to (revisions bolded): 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
uncontrolled focal-onset seizures despite treatment with at least 4 tolerated, appropriately 
chosen and used prior antiepileptic drugs (AEDs), including current AEDs (Kwan et al, 
2010). 
Change #3 
Section 1 Summary, Paragraph 3 (key deletions bolded) 
The primary objective of this study is to characterize the dose-response relationship with respect 
to efficacy of PSL administered concomitantly with up to 3 AEDs for treatment of observable 
focal-onset seizures in patients with drug-resistant epilepsy. The secondary objectives are to 
assess safety and tolerability of PSL and efficacy of the 4 selected dose regimens (100mg/day, 
200mg/day, 400mg/day, and 800mg/day) compared with placebo.  
Has been changed to (revisions bolded): 
The primary objectives of this study are to characterize the dose-response relationship with 
respect to efficacy of PSL administered concomitantly with up to 3 AEDs for treatment of 
observable focal-onset seizures in subjects with drug-resistant epilepsy and to evaluate the 
efficacy of the 4 selected dose regimens of PSL compared with placebo. The secondary 
objective is to assess the safety and tolerability of all doses of PSL in relation to placebo. 
Change #4 
Section 1 Summary, Paragraph 4, final sentence 
Subjects who withdraw from the study or decide not to participate in the OLE study will be 
progressively tapered off the IMP. Safety follow up will consist of 1 Safety Follow-up (SFU) 
Visit after the last IMP intake (including echocardiogram) and a 6-month follow-up 
echocardiogram, depending on the duration of exposure to IMP. 
Has been changed to (revisions bolded): 
Subjects who withdraw from the study or decide not to participate in the OLE study will be 
progressively tapered off the IMP. Safety follow up for these subjects will consist of 1 Safety 
Follow-up (SFU) Visit 30 days after the last IMP intake (including an echocardiogram) and a 
6-month follow-up echocardiogram, depending on the duration of exposure to IMP. 
Change #5 
Section 1 Summary, Paragraph 5 
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The assessment of efficacy is based on seizure frequency. The primary efficacy variable is the 
change from Baseline in log-transformed observable focal-onset seizure frequency (for the 
purpose of this protocol defined as Types IA1, IB, and IC, according to the International League 
Against Epilepsy [ILAE] classification [ILAE Classification of Epileptic Seizures, 1981]) over 
the 12-week Maintenance Period. 
Has been changed to (revisions bolded): 
The assessment of efficacy is based on seizure frequency. For the US Food and Drug 
Administration (FDA), Pharmaceuticals and Medical Devices Agency (PMDA), and other 
regulatory authorities not specified in Section 4.1.1.2, the primary efficacy variable is the 
change from Baseline in log-transformed observable focal-onset seizure frequency (for the 
purpose of this protocol defined as Types IA1, IB, and IC, according to the International League 
Against Epilepsy [ILAE] classification [ILAE Classification of Epileptic Seizures, 1981]) over 
the 12-week Maintenance Period. For the European Medicines Agency (EMA) and 
regulatory authorities who reference EMA, the primary efficacy variable is the 75% 
responder rate status, defined as a ≥75% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
Change #6 
Section 1 Summary, Paragraph 7 (deletions bolded) 
The total duration of study per subject will be up to 24 weeks with a maximum of 20 weeks 
exposure to PSL. It is estimated that approximately 300 subjects will be included at 
approximately 140 sites worldwide; 250 subjects are expected to be randomized. 
Has been changed to (revisions are bolded): 
The total duration of study per subject will be up to 27 weeks with a maximum of 20 weeks 
exposure to PSL. It is estimated that approximately 500 subjects will be included at 
approximately 200 sites worldwide; 400 subjects are expected to be randomized. 
Change #7 
Section 1 Summary, Paragraph 8 
During this study, subjects will also have the option of providing additional informed consent for 
exploratory deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) analyses to understand the 
cause, progression, and appropriate treatment of drug-resistant epilepsy. Participation in this 
additional portion of the study is optional and does not preclude participation in the main study. 
The additional genomic samples must not be collected if the subject has not consented to 
participate in this exploratory genomic substudy. 
Has been changed to (revision bolded): 
During this study, subjects will also have the option of providing additional informed consent for 
exploratory deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and 
lipidomics/proteomics/additional blood biomarker analyses to understand the cause, 
progression, and appropriate treatment of drug-resistant epilepsy. Participation in this additional 
portion of the study is optional and does not preclude participation in the main study. The 
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additional genomic samples must not be collected if the subject has not consented to participate 
in this exploratory genomic substudy. 
Change #8 
Section 2.1 
Drug-resistant epilepsy, Paragraph 1, first sentence (deletion bolded) 
The ILAE defines drug resistance as failure of adequate trials of 2 tolerated and appropriately 
chosen AEDs either as monotherapy or in combination to achieve sustained seizure freedom 
(ILAE Classification of Epileptic Seizures, 1981). 
Has been changed to (revision bolded): 
The ILAE defines drug resistance as failure of adequate trials of 2 tolerated and appropriately 
chosen AEDs either as monotherapy or in combination to achieve sustained seizure freedom 
(Kwan et al, 2010). 
Change #9 
Section 2.1 
Drug-resistant epilepsy, Paragraph 2, (deletion bolded) 
An estimated 12% of patients diagnosed with drug-resistant epilepsy die every year of SUDEP 
(Jehi, 2016). 
Has been changed to (revision bolded): 
An estimated 1% of patients diagnosed with drug-resistant epilepsy die every year of SUDEP 
(Jehi, 2016).  
Change #10 
Section 2.3 
Clinical studies, Paragraph 1 (deletions bolded) 
To date, PSL has been administered in the following 7 completed human pharmacology 
studies: N01360—a single, ascending dose safety, pharmacokinetic (PK), and pharmacodynamic 
(PD) study; N01386—a multiple, ascending dose safety, PK, and PD study; UP0010—a single-
dose absorption, distribution, metabolism, and elimination study; UP0001—a single- and 
multiple-dose comparative PK and food effect study; UP0013—a multiple-dose, 2-part 
drug-drug interaction (DDI) study; N01383—a positron-emission tomography (PET) study 
evaluating the brain GABA-A receptor occupancy following multiple dosing of PSL; and 
UP0002—a multiple-dose study in subjects with epilepsy investigating the effect of PSL on the 
PK of carbamazepine epoxide and the PK, safety, and tolerability of PSL in the presence of 
concomitant AEDs. The 2 ongoing clinical pharmacology studies with PSL include UP0036 
and UP0039. 
Has been changed to (revisions bolded): 
To date, PSL has been administered in the following 9 completed human pharmacology 
studies: 
 N01360—a single, ascending dose safety, pharmacokinetic (PK), and pharmacodynamic 
(PD) study  
 N01386—a multiple, ascending dose safety, PK, and PD study  
 UP0010—a single-dose absorption, distribution, metabolism, and elimination study  
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 UP0001—a single- and multiple-dose comparative PK and food effect study  
 UP0013—a multiple-dose, 2-part drug-drug interaction (DDI) study  
 N01383—a positron-emission tomography (PET) study evaluating the brain GABA-A 
receptor occupancy following multiple dosing of PSL  
 UP0002—a multiple-dose study in subjects with epilepsy investigating the effect of PSL on 
the PK of carbamazepine epoxide and the PK, safety, and tolerability of PSL in the presence 
of concomitant AEDs  
 UP0036—an adaptive, open-label, single-dose PET study evaluating SV2A occupancy 
 UP0039— a single- and multiple-dose safety and PK study in healthy Japanese and 
Caucasian subjects 
Change #11 
Section 3.1 
Primary objective (deletions bolded) 
The primary objective of this study is to characterize the dose-response relationship with respect 
to efficacy of PSL administered concomitantly with up to 3 AEDs for treatment of observable 
focal-onset seizures in subjects with drug-resistant epilepsy. 
Has been changed to (revisions bolded): 
The primary objectives of this study are to characterize the dose-response relationship with 
respect to efficacy of PSL administered concomitantly with up to 3 AEDs for treatment of 
observable focal-onset seizures in subjects with drug-resistant epilepsy and to evaluate the 
efficacy of the 4 selected dose regimens of PSL compared with placebo. 
Change #12 
Section 3.2 
Secondary objectives (deletions bolded) 
The secondary objectives are to:  
 Assess the safety and tolerability of PSL 
 Evaluate the efficacy of the 4 selected dose regimens of PSL compared with placebo 
 Assess the safety and tolerability of all doses of PSL in relation to placebo   
Has been changed to: 
Section 3.2 
Secondary objective 
The secondary objective is to assess the safety and tolerability of all doses of PSL in relation to 
placebo.  
Change #13 
Section 3.3.2 Pharamcokinetic objectives 
The PK objectives are to: 
 Evaluate the steady-state PK profiles of PSL and the exposure-response relationship 
 Evaluate the impact of enzyme-inducing concomitant AEDs on PSL exposure  
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Has been changed to (revision bolded): 
The PK objectives are to: 
 Evaluate the steady-state PK profiles of PSL and the exposure-response relationship 
 Evaluate the impact of enzyme-inducing concomitant AEDs on PSL exposure  
 Evaluate concomitant AED (and/or relevant metabolites) plasma levels 
Change #14 
Section 4.1.1 Primary efficacy variable 
The key change is that the original primary efficacy variable now will apply only to the US FDA, 
PMDA, and other regulatory authorities not specified in Section 4.1.1.2, and the primary efficacy 
variable for EMA and regulatory authorities who reference EMA will be the 75% responder rate, 
consistent with European guidance. The primary efficacy variable for FDA/PMDA/other 
regulatory authorities not specified in Section 4.1.1.2 will be a secondary efficacy variable for 
EMA and regulatory authorities who reference EMA. The 75% responder rate remains a 
secondary efficacy variable for FDA/PMDA/other regulatory authorities not specified in Section 
4.1.1.2.  
Old text: 
The primary efficacy variable is the change in log-transformed observable focal onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
Has been changed to (revisions bolded): 
4.1.1.1  
Primary efficacy variable for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 
The primary efficacy variable is the change in log-transformed observable focal onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
4.1.1.2  
Primary efficacy variable for EMA and regulatory authorities who reference 
EMA 
The primary efficacy variable is the 75% responder rate status, defined as a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance Period. 
Change #15 
Section 4.1.2 Secondary efficacy variables 
Old text: 
 The 75% responder rate status, defined as a ≥75% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 The 50% responder rate status, defined as a ≥50% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period 
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Has been changed to (revisions bolded): 
4.1.2.1  
Secondary efficacy variables for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 
The secondary efficacy variables are as follows:  
 The 75% responder rate status, defined as a ≥75% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 The 50% responder rate status, defined as a ≥50% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
4.1.2.2  
Secondary efficacy variables for EMA and regulatory authorities who reference 
EMA 
The secondary efficacy variables are as follows:  
 The change in log-transformed observable focal onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
 The 50% responder rate status, defined as a ≥50% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period 
Change #16 
Section 4.1.3 Other efficacy variables 
Old heading: Other efficacy variables 
Has been changed to (revision bolded): 
Heading has been changed to: Other efficacy variables (This list applies for all regulatory 
authorities) 
Change #17 
Section 4.1.3 Other efficacy variables, Bullet 18 (deletions bolded) 
 Time to loss of efficacy (defined as return to Baseline observable focal-onset seizure 
frequency) during the 12-week Maintenance Period 
Has been changed to (revisions bolded): 
 Time to return to baseline observable focal-onset seizure frequency during the 12-week 
Maintenance Period 
Change #18 
Section 4.2.1 Other safety variables, Bullet 10 (deletions bolded) 
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Occurrence of a clinically-significant valvular or pericardial effusion change or other clinically-
significant abnormalities as identified by 2-dimensional Doppler echocardiogram at each 
assessment by central reader 
Has been changed to (revisions bolded): 
Occurrence of valvular abnormalities or pericardial effusion changes or other significant 
abnormalities as identified by 2-dimensional Doppler echocardiogram at each assessment by 
central reader 
Change #19 
Section 4.3.3 Exploratory pharmacogenetic variables 
Additional blood samples will be collected at specific time points (Table 5-1) from subjects who 
consent to participate in the pharmacogenetic substudy to measure DNA biomarkers in order to 
assess: 
 Pharmacogenetic variants associated with drug-resistant epilepsy or AED resistance and drug 
response 
The samples may be used for further genetic analyses to understand drug-resistant epilepsy, 
AED resistance, and PK. 
Has been changed to (revision bolded): 
Additional blood samples will be collected at specific time points (Table 5-1) from subjects who 
consent to participate in the pharmacogenetic substudy to measure DNA biomarkers in order to 
assess: 
 Pharmacogenetic variants associated with drug-resistant epilepsy or AED resistance and drug 
response 
The samples may be used for further genetic analyses to understand drug-resistant epilepsy, 
AED resistance, and PK. The samples will be stored up to 20 years for the research purposes 
stated in this protocol. 
Change #20 
Section 4.3.4 Exploratory pharmacokinetic evaluation, Paragraph 2 (deletion bolded) 
Additionally, evaluation of PSL and major metabolites in plasma will be undertaken from trough 
samples collected by a subset of qualified sites. 
Has been changed to (revision bolded): 
Additionally, evaluation of PSL and major metabolites in plasma will be undertaken from trough 
samples. The collection of plasma samples for this comparison may cease during the course 
of the study based on periodic review of the data. 
Change #21 
Section 5.1 
Study description, Paragraph 1 (deletion bolded) 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
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uncontrolled focal-onset seizures despite treatment with at least 4 prior AED regimens including 
current AED regimens. All eligible subjects will have an epilepsy diagnosis and at least 
4 observable focal-onset seizures per 28 days despite treatment with at least 1 to 3 AEDs with or 
without neurostimulation devices. 
Has been changed to (revisions bolded): 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
uncontrolled focal-onset seizures despite treatment with at least 4 tolerated, appropriately 
chosen and used prior AEDs, including current AEDs (Kwan et al, 2010). All eligible subjects 
will have an epilepsy diagnosis and at least 4 observable focal-onset seizures per 28 days despite 
treatment with at least 1 to 3 AEDs with or without neurostimulation devices. 
Change #22 
Section 5.1 
Study description, Treatment Period, Paragraph 7 (minor rearrangement of 
first sentence for improved clarity) 
Subjects who complete the Maintenance Period or who discontinue early from the study 
will return for an End-of-Treatment Visit or Early Discontinuation Visit (EDV), 
respectively. Subjects completing the Maintenance Period will have the opportunity to enroll 
into the OLE study, EP0093. They will be converted to the entry dose of the EP0093 study, 
400mg/day. Subjects withdrawing from the study or deciding not to participate in the OLE study 
(EP0093) will be progressively tapered off the IMP. 
Has been changed to (revision bolded): 
Subjects who complete the Maintenance Period will return for an End of Treatment Visit. 
Subjects who discontinue early from the study will return for an Early Discontinuation 
Visit (EDV). Subjects completing the Maintenance Period will have the opportunity to enroll 
into the OLE study, EP0093. They will be converted to the entry dose of the EP0093 study, 
400mg/day. Subjects withdrawing from the study or deciding not to participate in the OLE study 
(EP0093) will be progressively tapered off the IMP. 
Change #23 
Section 5.1 
Study description, Safety Follow-Up Period 
Safety follow up for subjects not entering the OLE will consist of 1 required visit, 30 days after 
the last IMP intake (Week 23) including an echocardiogram. An additional follow-up 
echocardiogram will be performed at 6 months (±1 month) after the last IMP intake only for 
subjects exposed to IMP for more than 3 weeks. 
Has been changed to (revision bolded): 
Safety follow up for subjects not entering the OLE will consist of 1 required visit, 30 days after 
the last IMP intake (Week 23 or sooner in case of early discontinuation) including an 
echocardiogram. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks. 
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Change #24 
Section 5.1.1 Genetic substudy, Paragraph 1 
During this study, subjects will have the option of providing additional informed consent for 
exploratory genetic (DNA) analyses. Participation in this additional portion of the study is 
optional and does not preclude participation in the main study. The additional pharmacogenetic 
sample must not be collected if the subject has not consented to participate in this exploratory 
genetic substudy. A volume of 6mL of whole blood samples will be collected at Baseline 
(Visit 2). 
Has been changed to (revision bolded): 
During this study, subjects will have the option of providing additional informed consent for 
exploratory DNA, RNA, and lipidomics/proteomics/additional blood biomarker analyses. 
Participation in this additional portion of the study is optional and does not preclude participation 
in the main study. The additional pharmacogenetic sample must not be collected if the subject 
has not consented to participate in this exploratory genetic substudy. A volume of 6mL of whole 
blood samples will be collected at Baseline (Visit 2). 
Change #25 
Section 5.1.2 Study duration per subject, Paragraph 1 (deletion bolded) 
The total duration of study per subject will be up to 24 weeks with a maximum of 20 weeks 
exposure to PSL. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks and 
either discontinuing the study or not entering the OLE.  
Has been changed to (revision bolded): 
The total duration of study per subject will be up to 27 weeks with a maximum of 20 weeks 
exposure to PSL. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks and 
either discontinuing the study or not entering the OLE.  
Change #26 
Section 5.1.3 Planned number of subjects and sites (deletions bolded) 
It is estimated that approximately 300 subjects will be included at approximately 140 sites 
worldwide; 250 subjects are expected to be randomized. 
Has been changed to (revisions bolded): 
It is estimated that approximately 500 subjects will be included at approximately 200 sites 
worldwide; 400 subjects are expected to be randomized. 
Change #27 
Section 5.2 
Schedule of study assessments, footnote l 
AED samples will ideally be taken immediately prior to dose of concomitant medication on each 
occasion. If this is not possible, then the sample may be taken at any time after dose and the 
timing of sample in relation to dose should be kept the same (±1 hour) on each occasion for each 
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subject. Therefore, the timing of visits for each subject when AED samples are collected should 
be scheduled approximately at the same time whenever possible. Assay of parent PSL and 
metabolites may be included in the AED panel of tests. 
Has been changed to (revision bolded): 
AED samples will ideally be taken immediately prior to dose of concomitant medication on each 
occasion. If this is not possible, then the sample may be taken at any time after dose and the 
timing of sample in relation to dose should be kept the same (±1 hour) on each occasion for each 
subject. Therefore, the timing of visits for each subject when AED samples are collected should 
be scheduled approximately at the same time whenever possible. Assay of parent PSL and 
metabolites may be included in the AED panel of tests at Visits 6 and 7. 
Change #28 
Section 5.4.1 Choice of study design and endpoints, Paragraph 1 (deletion bolded) 
The target indication for PSL is as adjunctive therapy in the treatment of focal-onset seizures in 
adult patients with drug-resistant epilepsy. The key inclusion criteria are aimed at selecting a 
sample of study subjects from this target population. The criterion for drug resistance or failure 
to achieve control of seizures, with ≥4 tolerated and appropriately chosen past or current AED 
regimens, is based on observations that when patients with drug-resistant epilepsy have not been 
able to control their seizures despite treatment with 4 or more AED regimens, the likelihood of 
achieving complete seizure control with another AED regimen is further reduced to 1% to 4% 
(Schiller and Najjar, 2008; Mohanraj and Brodie, 2006). Study subjects also will be required to 
have on average at least 4 spontaneous and observable focal-onset seizures (IA1, IB, or IC) per 
28 days during each 4-week interval of the 8-week retrospective Baseline Period prior to entry 
and during the 4-week Baseline Period. This minimum seizure frequency was selected to provide 
assurance that a meaningful change in percent reduction in seizure frequency over 28 days and 
50%, 75%, and 90% responder rates could be demonstrated during the 12-week Maintenance 
Period.  
Has been changed to (revision bolded): 
The target indication for PSL is as adjunctive therapy in the treatment of focal-onset seizures in 
adult patients with drug-resistant epilepsy. The key inclusion criteria are aimed at selecting a 
sample of study subjects from this target population. The criterion for drug resistance or failure 
to achieve control of seizures, with ≥4 tolerated and appropriately chosen past or current AEDs, 
is based on observations that when patients with drug-resistant epilepsy have not been able to 
control their seizures despite treatment with 4 or more AED regimens, the likelihood of 
achieving complete seizure control with another AED regimen is further reduced to 1% to 4% 
(Schiller and Najjar, 2008; Mohanraj and Brodie, 2006). Study subjects also will be required to 
have on average at least 4 spontaneous and observable focal-onset seizures (IA1, IB, or IC) per 
28 days during each 4-week interval of the 8-week retrospective Baseline Period prior to entry 
and during the 4-week Baseline Period. This minimum seizure frequency was selected to provide 
assurance that a meaningful change in percent reduction in seizure frequency over 28 days and 
50%, 75%, and 90% responder rates could be demonstrated during the 12-week Maintenance 
Period.  
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Change #29 
Section 5.4.3 Justification for genomic and biomarker strategy 
The biomarker samples will be collected to understand the molecular characteristics of epilepsy 
and drug response (including safety, efficacy, and tolerability of PSL and concomitant therapies), 
which may enable potential molecular stratification in future clinical studies. A broad range of 
molecular data may be generated from each individual sample. The exact format of these 
analyses will be specified at a later time. 
Has been changed to (revision bolded): 
The biomarker samples will be collected to understand the molecular characteristics of epilepsy 
and drug response (including safety, efficacy, and tolerability of PSL and concomitant therapies), 
which may enable potential molecular stratification in future clinical studies. A broad range of 
molecular data may be generated from each individual sample. The exact format of these 
analyses will be specified at a later time. The samples will be stored at -80°C at the Central 
Laboratory facilities for up to 20 years or according to local laws.  
Change #30 
Section 6.1 
Inclusion criteria, Inclusion Criterion 1 (deletion bolded) 
An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written ICF 
is signed and dated by the subject or by the parent(s) or by the legal representative, where 
applicable. The ICF or a specific Assent form, where required, will be signed and dated by 
minors, according to country-specific regulations. 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. 
Has been changed to (revision bolded): 
An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written ICF 
is signed and dated by the subject or by the parent(s) or by the legal representative, where 
applicable. The ICF or a specific Assent form, where required, will be signed and dated by 
minors, according to country-specific regulations. A separate ICF should be signed and dated by 
the subject to allow for the optional DNA, RNA, and lipidomics/proteomics/additional blood 
biomarker samples. 
Change #31 
Section 6.1 
Inclusion criteria, Inclusion Criterion 7 (deletion bolded) 
Subject has failed to achieve seizure control with ≥4 tolerated and appropriately chosen prior 
AED regimens of adequate dose and duration, including past and ongoing treatment. Prior 
discontinued AED treatment would need to be assessed by the Investigator considering the 
patient medical records and patient and/or caregiver interview. "Prior AED" is defined as all past 
and ongoing AED treatments with a start date before the Screening Visit (Visit 1). 
Has been changed to (revsions bolded): 
Subject has failed to achieve seizure control with ≥4 tolerated and appropriately chosen prior 
AEDs, including past and ongoing treatment, that were individually optimized for adequate 
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dose and duration. Prior discontinued AED treatment would need to be assessed by the 
Investigator considering the patient medical records and patient and/or caregiver interview. 
"Prior AED" is defined as all past and ongoing AED treatments with a start date before the 
Screening Visit (Visit 1 
Change #32 
Section 6.1 
Inclusion criteria, Inclusion Criterion 8 
Subject is currently treated with a stable dose of at least 1 and up to 3 AEDs for the 8 weeks 
prior to the Screening Visit (Visit 1) with or without additional concurrent vagus nerve 
stimulation (VNS) or other neurostimulation treatments. The latter will not be counted as AEDs 
for the purpose of eligibility. 
Has been changed to (revision bolded): 
Subject is currently treated with an individually optimized and stable dose of at least 1 and up 
to 3 AEDs for the 8 weeks prior to the Screening Visit (Visit 1) with or without additional 
concurrent vagus nerve stimulation (VNS) or other neurostimulation treatments. The latter will 
not be counted as AEDs for the purpose of eligibility.  
Change #33 
Section 6.1 
Inclusion criteria, Inclusion Criterion 10, Paragraph 1 (deletion bolded) 
Female subjects of child bearing potential must have a negative serum pregnancy test at the 
Screening Visit (Visit 1), which is confirmed to be negative by urine testing prior to the first dose 
of IMP at Week 1 (Visit 2) and prior to further dispensing at each study visit thereafter. Subjects 
will be withdrawn from the study as soon as pregnancy is known. 
Has been changed to (revision bolded): 
Female subjects of child bearing potential must have a negative serum pregnancy test at the 
Screening Visit (Visit 1), which is confirmed to be negative by urine testing prior to the first dose 
of IMP at Day 1 (Visit 2) and prior to further dispensing at each study visit thereafter. Subjects 
will be withdrawn from the study as soon as pregnancy is known. 
Change #34 
Section 6.1 
Inclusion criteria, Inclusion Criterion 10, birth control method 10 
Women not agreeing to use birth control must be of nonchildbearing potential, defined as being 
postmenopausal (for at least 2 years before the Screening Visit [Visit 1]), verified by serum 
follicle stimulating hormone level >40mIU/mL at the Screening Visit (Visit 1), or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), or congenitally 
sterile. 
Has been changed to (revision bolded): 
Women not agreeing to use birth control must be abstinent (as described in the preceding 
bullet) or be of nonchildbearing potential, defined as being postmenopausal (for at least 2 years 
before the Screening Visit [Visit 1]), verified by serum follicle stimulating hormone level 
>40mIU/mL at the Screening Visit (Visit 1), or permanently sterilized (eg, bilateral tubal 
occlusion, hysterectomy, bilateral salpingectomy), or congenitally sterile. 
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Change #35 
Section 6.2 
Exclusion criterion 13, Line 2 
>2.0 upper limit of normal (ULN) of any of the following: 
Has been changed to (revision bolded): 
>2.0x upper limit of normal (ULN) of any of the following: 
Change #36 
Section 6.2 
Exclusion criterion 14 (deletion bolded) 
Subject has an abnormality on echocardiogram at Screening Visit (Visit 1) as assessed by central 
reader that is accompanied by clinical symptoms (eg, shortness of breath, palpitations, and 
murmur) or a Grade 2* (or higher)/moderate severity abnormality or a history of rheumatic 
heart disease or other known valvular abnormalities (* according to the ASE Guidelines, 
Zoghbi et al, 2017). 
Subjects whose echocardiograms are not interpretable at Screening Visit (Visit 1) by 
transthoracic echocardiogram (TTE), eg, due to technical difficulties or position of the 
heart will be excluded from the study. 
Has been changed to (revisions are bolded): 
Subject has an abnormality on echocardiogram at Screening Visit (Visit 1) as assessed by central 
reader that is accompanied by clinical symptoms (eg, shortness of breath, palpitations, and 
murmur) or a ≥Grade 2*/moderate severity abnormality or a history of rheumatic heart disease 
or other known valvular abnormalities (*according to the ASE Guidelines, Zoghbi et al, 2017). 
Subjects whose echocardiograms are not interpretable at Screening Visit (Visit 1) by 
transthoracic echocardiogram (TTE), eg, due to technical difficulties or position of the heart 
will be excluded from the study. 
Change #37 
Section 6.2 
Exclusion criterion 15 (deletions bolded) 
Subject has a history of or signs for idiopathic generalized (genetic) epilepsy. 
Has been changed to (revisions bolded): 
Subject has a history of or signs of generalized (formerly referred to as ‘idiopathic 
generalized’) or combined generalized and focal (formerly referred to as ‘symptomatic 
generalized’) epilepsy (Scheffer IE et al, 2017). 
Change #38 
Section 6.2 
Exclusion criterion 22 (deletion bolded) 
Subject has VNS, deep brain stimulation, Responsive Neurostimulator System, or other 
neurostimulation for epilepsy device  
 implanted or activated <1 year prior to enrollment, or  
 with stimulation parameters that have been stable for <3 months, or 
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 with battery life of unit not anticipated to extend for duration of trial. 
Has been changed to (revisions bolded): 
Subject has VNS, deep brain stimulation, Responsive Neurostimulator System, or other 
neurostimulation for epilepsy device  
 implanted and activated <1 year prior to enrollment, or  
 with stimulation parameters that have been stable for <3 months, or 
 with battery life of unit not anticipated to extend for duration of trial. 
Change #39 
Section 6.2 
Exclusion criterion 32 
Subject is taking GABA-A-ergic drugs (agonists [ie, barbiturates] or receptor positive allosteric 
modulators [ie, BZDs or non-BZDs]) excluding GABA-A-ergic AEDs >2 times per week for any 
indication. 
Has been changed to (revisions bolded): 
Subject is taking GABA-A-ergic drugs regularly (agonists [ie, barbiturates] or receptor positive 
allosteric modulators [ie, BZDs or non-BZDs]), excluding as needed (PRN) intake of 
GABA-A-ergic AEDs <3 times per week for emergencies. 
Change #40 
Section 6.3 
Withdrawal Criterion 7 
Subject with an echocardiogram showing a Grade 2 finding (moderate regurgitation) if 
accompanied with moderate to severe signs/symptoms or a Grade 3 finding (severe 
regurgitation) will be discontinued from the study regardless of accompanying clinical 
symptoms, and should begin discontinuation of the IMP. Additionally, a jump of 2 grades, from 
Grade 0 to Grade 2 (moderate regurgitation) accompanied with moderate to severe symptoms or 
from Grade 1 to Grade 3 (severe regurgitation) will result in subject discontinuation (see Section 
6.3.2).  
Has been changed to (revisions bolded): 
Subject with an echocardiogram showing a Grade 2 finding (moderate regurgitation/stenosis) if 
accompanied with moderate to severe signs/symptoms or a Grade 3 finding (severe 
regurgitation/stenosis) will be discontinued from the study regardless of accompanying clinical 
symptoms, and should begin discontinuation of the IMP. Additionally, a jump of 2 grades, from 
Grade 0 to Grade 2 (moderate regurgitation/stenosis) accompanied with moderate to severe 
symptoms or from Grade 1 to Grade 3 (severe regurgitation/stenosis) will result in subject 
discontinuation (see Section 6.3.2). 
Change #41 
Section 6.3.2 Echocardiogram valvular abnormalities assessments, Table 6-1 
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Table 6-1:   
Valvular abnormality grading criteria 
Echocardiogram 
Valvular 
Abnormality 
Severity / Description Potential 
Cardiovascular 
Signs/Symptoms 
Action  
Grade 0 
Absent: no regurgitation, 
no stenosis 
None reported 
None 
Grade 1 
Mild: trace or barely 
detected regurgitation 
Minimal to none 
None; continued observation  
Grade 2 
Moderate: regurgitation 
with intermediate values 
Symptoms
a: 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
Signs:  
Pulmonary arterial 
pressure >40mm Hg and 
rise of >10mmHg; 
pulmonary edema; 
peripheral edema or 
ascites; atrial fibrillation 
or malignant arrhythmia; 
hypotension  
For a Grade 2/moderate severity, a 
decision to discontinue is based on 
severity of clinical signs/symptoms; 
if accompanied with moderate to 
severe signs/symptoms this results 
in subject discontinuation. 
Grade 3 
Severe: regurgitation in 
the extreme range, often 
accompanied by other 
symptoms 
(eg, pulmonary 
congestion) 
Discontinuation of subject. 
For a Grade 3 of severe, subject 
should be discontinued regardless of 
accompanying clinical symptoms. 
Grade increase by 
2 levels 
Increasing from:  
Grade 0 to 2 or  
Grade 1 to 3 
Rapid onset of above 
signs/symptoms 
A jump of 2 grades to 
Grade 2/moderate accompanied with 
moderate to severe signs/symptoms 
results in subject discontinuation. 
A jump of 2 grades to 
Grade 3/severe (with/without 
symptoms) will result in subject 
discontinuation. 
a New York Heart Association Classification of symptoms; for other echocardiogram measurements, see the 
Echocardiogram Manual. 
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Has been changed to (revision bolded): 
Table 6-1:   
Valvular abnormality grading criteria 
Echocardiogram 
Valvular 
Abnormality 
Severity / Description Potential 
Cardiovascular 
Signs/Symptoms 
Action  
Grade 0 
Absent: no regurgitation, 
no stenosis 
None reported 
None 
Grade 1 
Mild: trace or barely 
detected 
regurgitation/stenosis 
Minimal to none 
None; continued observation  
Grade 2 
Moderate: 
regurgitation/stenosis 
with intermediate values 
Symptoms
a: 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
Signs:  
Pulmonary arterial 
pressure >40mm Hg and 
rise of >10mmHg; 
pulmonary edema; 
peripheral edema or 
ascites; atrial fibrillation 
or malignant arrhythmia; 
hypotension  
For a Grade 2/moderate severity, a 
decision to discontinue is based on 
severity of clinical signs/symptoms; 
if accompanied with moderate to 
severe signs/symptoms this results 
in subject discontinuation. 
Grade 3 
Severe: 
regurgitation/stenosis in 
the extreme range, often 
accompanied by other 
symptoms 
(eg, pulmonary 
congestion) 
Discontinuation of subject. 
For a Grade 3 of severe, subject 
should be discontinued regardless of 
accompanying clinical symptoms. 
Grade increase by 
2 levels 
Increasing from:  
Grade 0 to 2 or  
Grade 1 to 3 
Rapid onset of above 
signs/symptoms 
A jump of 2 grades to 
Grade 2/moderate accompanied with 
moderate to severe signs/symptoms 
results in subject discontinuation. 
A jump of 2 grades to 
Grade 3/severe (with/without 
symptoms) will result in subject 
discontinuation. 
a New York Heart Association Classification of symptoms; for other echocardiogram measurements, see the 
Echocardiogram Manual. 
Change #42 
Section 6.3.2 Echocardiogram valvular abnormalities assessments, Paragraphs 4 and 5 
Subjects with an echocardiogram showing a Grade 2 finding (moderate regurgitation) will 
undergo a repeat echocardiogram within 1 month (unscheduled visit) to confirm the finding. For 
a Grade 2 echocardiogram of moderate severity, a decision to discontinue will be based on the 
severity of clinical signs/symptoms; if accompanied with moderate to severe signs/symptoms 
this would result in subject discontinuation. Investigators may contact the Medical Monitor if 
they wish to discuss the subject’s clinical signs/symptoms. 
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Subjects with an echocardiogram showing a Grade 3 finding (severe regurgitation) will undergo 
a repeat echocardiogram within 2 weeks (unscheduled visit) to confirm the finding. For a 
Grade 3 echocardiogram with a severe severity, the subject should be discontinued from the 
study regardless of accompanying clinical signs/symptoms and should begin discontinuation of 
the IMP. 
Has been changed to (revisions bolded): 
Subjects with an echocardiogram showing a Grade 2 finding (moderate regurgitation/stenosis) 
will undergo a repeat echocardiogram within 1 month (unscheduled visit) to confirm the finding. 
For a Grade 2 echocardiogram of moderate severity, a decision to discontinue will be based on 
the severity of clinical signs/symptoms; if accompanied with moderate to severe signs/symptoms 
this would result in subject discontinuation. Investigators may contact the Medical Monitor if 
they wish to discuss the subject’s clinical signs/symptoms. 
Subjects with an echocardiogram showing a Grade 3 finding (severe regurgitation/stenosis) will 
undergo a repeat echocardiogram within 2 weeks (unscheduled visit) to confirm the finding. For 
a Grade 3 echocardiogram with a severe severity, the subject should be discontinued from the 
study regardless of accompanying clinical signs/symptoms and should begin discontinuation of 
the IMP. 
Change #43 
Section 6.3.2 Echocardiogram valvular abnormalities assessments, final paragraph 
(deletion bolded) 
Regulatory authorities will be notified of any discontinuations. 
Has been changed to (revision bolded): 
Regulatory authorities will be notified of any subject who is discontinued due to an abnormal 
echocardiogram. 
Change #44 
Section 7.2.2 Taper Period, Table 7-3  
Has been changed to: 
The following footnote has been added:  
Taper Period for subjects who choose an early discontinuation may occur before Week 16. 
Change #45 
Section 7.8.2 Prohibited concomitant treatments (medications and therapies) (deletions 
bolded) 
The following concomitant medications are prohibited during the study: 
 Benzodiazepines (GABA-A-ergic drugs: including agonists [ie, barbiturates] or 
receptor-positive allosteric modulators [ie, BZDs or non-BZDs like zolpidem] taken >2 times 
per week). Benzodiazepines with an indication for epileptic seizures like clonazepam or 
clobazam are not allowed as concomitant drugs. 
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Strong CYP3A4 inhibitors/inducers: AEDs including carbamazepine, phenytoin, 
phenobarbital, primidone (for more details refer to Table 3-2 and Table 3-3 in FDA Drug 
Development Resources, Drug development and drug interactions: Table of substrates, 
inhibitor and inducers). 
Non-AED strong CYP3A4 enzyme inducers/inhibitors (ie, prescription drugs, 
nonprescription drugs, medical cannabis, cannabidiol, dietary [eg, grapefruit or passion fruit]. 
 Strong CYP2C19 strong sensitive substrates/inhibitors/inducers including S-mephenytoin, 
omeprazole, fluconazole, fluoxetine, fluvoxamine, ticlopidine, rifampin, ritonavir (for more 
details refer to Table 3-1, Table 3-2, and Table 3-3 in FDA Drug Development Resources, 
Drug development and drug interactions: Table of substrates, inhibitor and inducers). 
Has been changed to (revisions bolded): 
The following concomitant medications are prohibited during the study: 
 GABA-A-ergic drugs including agonists (ie, barbiturates) or receptor-positive allosteric 
modulators (ie, BZDs or non-BZDs like zolpidem) taken >2 times per week. Regular intake 
of benzodiazepines with an indication for epileptic seizures as concomitant drugs is not 
allowed. However, PRN intake of GABA-A drugs <3 times per week is allowed, ie, for 
emergencies.  
 Strong CYP3A4 inhibitors/inducers  
 AEDs including carbamazepine, phenytoin, phenobarbital, primidone  
 Non-AED strong CYP3A4 enzyme inducers/inhibitors (ie, prescription drugs, 
nonprescription drugs, medical cannabis, cannabidiol, dietary [eg, grapefruit or passion 
fruit]. For more details refer to Table 3-2 and Table 3-3 in FDA Drug Development 
Resources, Drug development and drug interactions: Table of substrates, inhibitor and 
inducers. 
 Strong CYP2C19 sensitive substrates/inhibitors/inducers including S-mephenytoin, 
omeprazole, fluconazole, fluoxetine, fluvoxamine, ticlopidine, rifampin, ritonavir (for more 
details refer to Table 3-1, Table 3-2, and Table 3-3 in FDA Drug Development Resources, 
Drug development and drug interactions: Table of substrates, inhibitor and inducers). 
Change #46 
Section 7.10 Randomization and numbering of subjects, Paragraph 1 (deletion bolded) 
An IRT will be used for assigning eligible subjects to a treatment regimen (as applicable) 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 IMP, as appropriate, according to the visit 
schedule. 
Has been changed to: 
An IRT will be used for assigning eligible subjects to a treatment regimen (as applicable) based 
on a predetermined production randomization and/or packaging schedule provided by the IRT 
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vendor. The IRT will generate individual assignments for subject kits of IMP, as appropriate, 
according to the visit schedule. 
Change #47 
Section 8.2.3.3 
Visit 7 (Week 16±1 week, End-of-Treatment or Early Discontinuation 
Visit) 
Has been changed to: 
The heading has been changed to (revisions bolded):  
Visit 7 (Week 16±1 week for End-of-Treatment or earlier for Early Discontinuation Visit) 
Change #48 
Section 8.4 
Safety Follow-Up (Visit 9 [Week 23, approximately 30 days after last IMP 
intake]) 
Has been changed to: 
The heading has been changed to (revision bolded):  
Safety Follow-Up (Visit 9 [Week 23 or earlier for EDV, approximately 30 days after last IMP 
intake]) 
Change #49 
Section 9.2 
Seizure Severity Global Item, Paragraph 1 (deletion bolded) 
The SSG consists of 1 or 2 items from the Seizure Severity Questionnaire and asks the subjects 
to evaluate the severity of their seizures for the last 4 weeks and/or since the Baseline (in 
EP0091). The subjects should describe their most common type of seizure when answering the 
questions.  
Has been changed to (revision bolded): 
The SSG consists of 1 or 2 items from the Seizure Severity Questionnaire and asks the subjects 
to evaluate the severity of their seizures for the last 4 weeks and/or since the Baseline (in 
EP0091). The subjects should describe all types of seizures when answering the questions.  
Change #50 
Section 10.1.1.2 Concomitant AED assay 
Has been changed to (revision bolded): 
The heading has been change to: Concomitant AED and exploratory pharmacokinetic 
evaluation 
Change #51 
Section 10.1.1.2 Concomitant AED and exploratory pharmacokinetic evaluation, final 
paragraph (deletion bolded) 
Assay of PSL metabolites will be included in the concomitant AED assay screen. 
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Has been changed to (revision bolded): 
Assay of PSL metabolites may be included in the concomitant AED assay screen. 
Change #52 
Section 10.2 Exploratory variables, Paragraph 2 (deletion bolded) 
Results for the exploratory parameters obtained from DNA, mRNA, lipidomics, and proteomics 
analysis, and serum biomarkers will be described in a separate report. 
Has been changed to (revision bolded): 
Results for the exploratory parameters obtained from DNA, RNA, lipidomics, and proteomics 
analysis, and serum biomarkers will be described in a separate report.  
Change #53 
Section 11.1.1.2.2  
Adverse events of special interest 
This is a new section. The text was moved from another location, but was not revised.  
Has been changed to: 
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. 
Change #54 
Section 11.1.7  
Safety signal detection, Paragraph 4 
In addition, an unblinded DMC will oversee safety data approximately every 6 months (subject 
to DMC recommendation) during the course of the study during which the safety of PSL will be 
assessed. The safety variables and the decision rules to be used will be specified in the DMC 
charter. This analysis will inform any decisions regarding changes in study conduct and/or study 
termination. The precise membership, scope, and responsibilities of the DMC are described in 
the DMC charter.  
Has been changed to (revison bolded): 
In addition, an unblinded independent DMC will oversee safety data approximately every 6 
months (subject to DMC recommendation) during the course of the study during which the 
safety of PSL will be assessed. The safety variables and the decision rules to be used will be 
specified in the DMC charter. This analysis will inform any decisions regarding changes in study 
conduct and/or study termination. The precise membership, scope, and responsibilities of the 
DMC are described in the DMC charter. 
Change #55 
Section 11.2 Laboratory measurements, Paragraph 2 (deletion bolded) 
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The total blood volume drawn for clinical laboratory assessments per subject will be a maximum 
of 31.5mL by sampling, which includes 2mL for hematology, 5mL for blood chemistry, 5mL 
and 20µL for AED and PSL plasma level (including back-up samples for AED assay), 6mL for 
genetic substudy, 13.5mL for genomic assessments, and 80µL for PK measurements.  
Has been changed to (revision bolded): 
The total blood volume drawn for clinical laboratory assessments per subject will be a maximum 
of 31.6mL by sampling, which includes 2mL for hematology, 5mL for blood chemistry, 5mL 
and 20µL for AED and PSL plasma level (including back-up samples for AED assay), 6mL for 
genetic substudy, 13.5mL for genomic assessments, and 80µL for PK measurements.  
Change #56 
Section 11.2 Laboratory measurements, Table 11-2 
Has been changed to: 
FSH test has been added to the table and to the list of abbreviations for the table.  
Change #57 
Section 11.2 Laboratory measurements, a second paragraph below Table 11-2 has been 
added. 
Has been added: 
Women not agreeing to use birth control must be abstinent or be of nonchildbearing potential, 
defined as being postmenopausal (for at least 2 years before the Screening Visit [Visit 1]), 
verified by serum follicle stimulating hormone level >40mIU/mL at the Screening Visit (Visit 1), 
or permanently sterilized (eg, bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), 
or congenitally sterile. 
Change #58 
Section 11.3.3  
Echocardiograms, Paragraph 2 
Two-dimensional Doppler echocardiography will be performed with: 
 Diastolic measurements (mitral forward flow E and A waves and deceleration time) 
 Tissue Doppler on medial and lateral mitral valve annulus (S, E, and A waves) 
 Standardized views for left atrial volume measurements 
Has been changed to: 
Two-dimensional Doppler echocardiography will include the following 
measurements/observations: 
 Epicardial Abnormalities 
 Functional measurements 
 Diastology (ie, Mitral Valve E/A waves, etc.) 
 Systolic (ie, Left Ventricular Ejection Fraction, LVEF, etc.) 
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 Epicardial Effusion 
 Amount of effusion 
 Pericardial thickness 
 Valvular Abnormalities 
 Measurement of valve regurgitation/stenosis 
 Measurement of left atrial volume 
Change #59 
Section 11.3.3  
Echocardiograms, final paragraph  
In case of discontinuation, the subject should return for an EDV and SFU Visit (Visit 9) 
including an echocardiogram within approximately 1 month after last IMP intake. The 
corresponding TEAEs should be followed up until they have resolved, have a stable sequelae, or 
the subject is lost to follow-up. 
Has been changed to (revision bolded): 
In case of discontinuation, the subject should return for an EDV and SFU Visit (Visit 9) 
including an echocardiogram within approximately 1 month after last IMP intake and if taking 
IMP greater than 3 weeks, should also return for a 6-month echocardiogram. The 
corresponding TEAEs should be followed up until they have resolved, have a stable sequelae, or 
the subject is lost to follow-up 
Change #60 
Section 12.2.1  
Definition of source data, final paragraph  
For subjects randomized to investigational product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study-related identifiers (such as randomization/treatment number, or similar), they should 
mention the subject’s participation in the study and identification of that study (study title or 
number), they should record the obtaining of consent (date of consent), the exposure to 
investigational product, the subject’s medical history, the concomitant medication treatments and 
dates (including contraceptive treatment), AEs and SAEs, and the of the visits. The source 
documents should provide evidence that inclusion/exclusion criteria have been met. 
Has been changed to (revision bolded): 
For subjects randomized to investigational product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study-related identifiers (such as randomization/treatment number, or similar), they should 
mention the subject’s participation in the study and identification of that study (study title or 
number), they should record the obtaining of consent (date of consent), the exposure to 
investigational product, the subject’s medical history, the concomitant medication treatments and 
dates (including contraceptive treatment), AEs and SAEs, and the date of the visits. The source 
documents should provide evidence that inclusion/exclusion criteria have been met 
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Change #61 
Section 13.3.1  
Analysis of the primary efficacy variable 
Subsections 13.3.1.1 and 13.3.1.2 have been added to account for the analysis of different 
primary efficacy variables for FDA/PMDA/other regulatory authorities not specified in Section 
4.1.1.2 and for EMA and regulatory authorities who reference EMA.  
Old text (deletions bolded): 
The primary efficacy variable is the change from Baseline in observable focal-onset seizure 
frequency per 28 days, over the 12-week Maintenance Period. The 28-day Baseline and 
post-Baseline (maintenance) seizure frequency will be transformed with the natural logarithm, 
specifically ln(x+1), where x represents the 28-day seizure frequency. The transformed seizure 
frequency data will be analyzed using analysis of covariance (ANCOVA) with treatment group 
as the main factor, Baseline log-adjusted seizure frequency as a continuous covariate, and 
Baseline SV2A use as a categorical factor. Linear contrasts will be constructed to compare 
the dose-response trend and pairwise contrasts will be constructed to compute estimated effects 
of each dose from placebo. 
The ANCOVA model on the log-transformed, change from Baseline in observable focal-onset 
seizure frequency will be used to assess the doses, corresponding responses, and final dose. 
The dose-response relationship for change from Baseline in observable focal-onset seizure 
frequency across 4 doses of PSL and placebo will be evaluated using the MCP-Mod 
methodology. Monotonic dose-response trends will be tested using the appropriate contrasts as 
determined by the MCP-Mod methodology such that the overall Type 1 error rate is controlled at 
0.05 (2-sided testing). Four different dose-response models (“candidate models”) were identified: 
sigmoidal Emax, Emax, log-linear, and logistic, and the MCP-Mod methodology controls for 
multiplicity. 
The SAP will describe additional features and detail around the MCP-Mod methodology as well 
as handling of missing data. 
All aforementioned analyses of the primary efficacy variable will be repeated on the PPS. 
Assuming at least 1 statistically significant result is obtained from the primary MCP-Mod 
analysis each of the 4 dose groups will be compared with placebo using the above analysis 
model. Type 1 error will be controlled by the Hochberg step-up procedure within SAS® Proc 
Multtest. Full details will be provided in the SAP. 
Has been changed to (revisions bolded): 
13.3.1.1 
Analysis of the primary efficacy variable for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 
Prior to the primary analysis, the dose-response relationship for change from Baseline in 
observable focal-onset seizure frequency across 4 doses of PSL and placebo will be evaluated 
using the MCP-Mod methodology. Monotonic dose-response trends will be tested using the 
appropriate contrasts as determined by the MCP-Mod methodology such that the overall Type 1 
error rate is controlled at 0.05 (2sided testing). Four different dose-response models (“candidate 
models”) were identified: sigmoidal Emax, Emax, log-linear, and logistic, and the MCP-Mod 
methodology controls for multiplicity. 
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The SAP will describe additional features and detail around the MCP-Mod methodology as well 
as handling of missing data. 
Assuming at least 1 statistically significant result is obtained from the primary MCP-Mod 
analysis, then pairwise comparisons of 400mg, 200mg and 100mg dose groups versus 
placebo will be carried out using the analysis model below. Type 1 error will be controlled by 
the Hochberg step-up procedure within SAS® Proc Multtest. If all the results of the pairwise 
comparisons are statistically significant then the 50mg dose group will be compared to 
placebo. 
For the US FDA, PMDA, and other regulatory authorities not specified in Section 4.1.1.2 
the primary efficacy variable is the change in log-transformed observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. The 28-day Baseline and 
post-Baseline (maintenance) seizure frequency will be transformed with the natural logarithm, 
specifically ln(x+1), where x represents the 28-day seizure frequency. The transformed seizure 
frequency data will be analyzed using analysis of covariance (ANCOVA) with treatment group 
as the main factor, Baseline log-adjusted seizure frequency as a continuous covariate, and 
Baseline SV2A use and Region as categorical factors. Pairwise contrasts will be constructed to 
compute estimated effects of each dose from placebo. 
All pairwise analyses of the primary efficacy variable will be repeated on the PPS. 
A sensitivity analysis of the primary efficacy continuous variable will be carried out using a 
Mixed Model Repeated Measures analysis. Full details will be provided in the SAP. 
13.3.1.2 
Analysis of the primary efficacy variable for EMA and regulatory authorities 
who reference EMA 
For EMA and regulatory authorities who reference EMA, the primary efficacy variable 
will be the 75% responder rate status and will be analyzed using logistic regression with 
factors for treatment group, Baseline seizure frequency, Region, and Baseline SV2A use. If 
there are issues with convergence, Baseline SV2A use will be dropped. The responder rates 
are defined as a ≥75% reduction in the observable focal-onset seizure frequency from 
Baseline over the 12-week Maintenance Period. 
The same methodology carried out in Section 13.3.1.1 will be applied to MCP-Mod and the 
pairwise analyses. 
Change #62 
Section 13.3.1.1 Sensitivity analysis of the primary efficacy variable 
This section has been deleted.  
Change #63 
Section 13.3.2  
Secondary efficacy analysis 
Subsections 13.3.2.1 and 13.3.2.2 have been added to account for differences in secondary 
efficacy variables for FDA/PMDA/other regulatory authorities not specified in Section 4.1.1.2 
and for EMA and regulatory authorities who reference EMA.  
Old text (deletions bolded):  
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The primary efficacy variable will be used to conduct secondary efficacy analyses of 
pairwise comparisons of each PSL dose versus placebo, and will be further adjusted to 
account for multiplicity. The same underlying model used for the primary efficacy analysis, 
will be used for the pairwise analyses. To control for Type I error inflation, these analyses 
will only be conducted if the primary efficacy analysis, using the MCP-Mod methodology, 
shows statistical significance for at least 1 of the dose-response models. Pairwise testing will 
then be conducted using the appropriate multiplicity adjusted methods (eg, sequential 
testing, Hochberg, etc) to control for Type I error inflation, due to multiple pairwise dose 
comparison hypothesis. Details of the multiplicity adjustments will be pre-specified and 
captured in the study SAP. 
The 75% responder rate status and 50% responder rate will be analyzed using logistic regression 
with factors for treatment group, Baseline seizure frequency, and Baseline SV2A use. If there are 
issues with convergence, Baseline SV2A use will be dropped. The responder rates are defined as 
follows: 
 75% responder rate status: a ≥75% reduction in the observable focal-onset seizure frequency 
from Baseline over the 12-week Maintenance Period  
 50% Responder rate: a ≥50% reduction in observable focal-onset seizure frequency from 
Baseline over the 12-week Maintenance Period 
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used to 
estimate the median percent reduction in seizures between groups and its corresponding 95% 
confidence interval (CI) will be provided. 
Has been changed to (revisions bolded): 
13.3.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 
The 75% responder rate status and 50% responder rate will be analyzed using logistic regression 
with factors for treatment group, Baseline seizure frequency, Region, and Baseline SV2A use. If 
there are issues with convergence, Baseline SV2A use will be dropped. The responder rates are 
defined as follows: 
 75% responder rate status: a ≥75% reduction in the observable focal-onset seizure frequency 
from Baseline over the 12-week Maintenance Period  
 50% Responder rate status: a ≥50% reduction in observable focal-onset seizure frequency 
from Baseline over the 12-week Maintenance Period 
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used to 
estimate the median percent reduction in seizures between groups and its corresponding 95% 
confidence interval (CI) will be provided. 
13.3.2.2 
Secondary efficacy variables for EMA and regulatory authorities who reference 
EMA 
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The change in log-transformed observable focal-onset seizure frequency from Baseline, 
over the 12-week Maintenance Period will be analyzed in the same way as for the primary 
analysis used for the FDA ie, pairwise comparisons of 400mg, 200mg and 100 mg dose 
groups versus placebo will be carried out using the analysis model described inSection 
13.3.1.1. Type 1 error will be controlled by the Hochberg step-up procedure within SAS® 
Proc Multtest. If the results of all pairwise comparisons are statistically significant, then 
the 50mg dose group will be compared to placebo. 
In addition, the 50% responder rate will be analyzed using logistic regression with factors 
for treatment group, Baseline seizure frequency, Region, and Baseline SV2A use. If there 
are issues with convergence, Baseline SV2A use will be dropped. The responder rates are 
defined as follows: 
 50% Responder rate status: a ≥50% reduction in observable focal-onset seizure 
frequency from Baseline over the 12-week Maintenance Period 
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used 
to estimate the median percent reduction in seizures between groups and its corresponding 
95% (CI will be provided. 
Change #64 
Section 13.3.3  
Other efficacy analyses, Paragraph 3 (deletion bolded) 
The time-to-loss of efficacy will be analyzed using Kaplan-Meier methodology. Additional 
details of the analysis will be captured in the SAP. 
Has been changed to (revision bolded): 
The time-to-return to baseline observable focal-onset seizure frequency will be analyzed 
using Kaplan-Meier methodology. Additional details of the analysis will be captured in the SAP. 
Change #65 
Section 13.7 Planned interim analysis and data monitoring (deletions bolded) 
A DMC will be formed to monitor the ongoing safety of the study. The DMC will consist of at 
least 3 individuals. Voting members of the DMC will include external physicians with 
experience in treating refractory epilepsy and a cardiologist. Additionally, at least 1 member may 
be a statistician. All members will have experience and expertise in clinical trials. The DMC 
members may not participate in the study as principal or co-Investigators, or as study subject 
care physicians. The duration of membership for the DMC will be inclusive of planned 
analyses for EP0091. The DMC will periodically review study data and evaluate the treatments 
for excess adverse effects and other potential safety issues. The DMC may also be asked to 
provide a review of final study results, as deemed appropriate. The detailed role, scope, 
composition, responsibilities, and operation of the DMC, as well as the identity of the DMC 
members, will be defined in a separate DMC Charter. 
Safety and tolerability data will be made available to the DMC at each meeting as described in 
the DMC Charter. The data will be provided in a semi-unblinded fashion (data will be visualized 
by real treatment groups, but the treatment/dose assigned to each group will remain blinded) and 
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the full unblinding can be requested by the DMC members, if appropriate. Pharmacokinetic data 
may be provided to the DMC at their request. These safety, tolerability, and PK data will be 
presented by individuals not otherwise involved in the conduct of the study. The deliberations 
and decisions of the DMC will be formally documented. 
Ad hoc DMC meetings can be held for other reasons if deemed appropriate by the Sponsor or the 
DMC members. 
In addition to ongoing review of safety data and safety signal detection within UCB, the 
occurrence of AEs of interest including cardiac and behavioral adverse events, in particular, will 
be monitored by the DMC to provide an assessment of the risk of occurrence of these events in 
the study. Statistical modeling will be used to provide estimates for quantification of the level of 
risk in the study based on the risk in the epilepsy population and in the intended patient 
population in the study (see Inclusion and Exclusion Criteria in Section 6). This analysis will 
inform any decisions regarding changes in study conduct and/or study termination. 
The DMC procedures will ensure that the data remain blinded to the study team and 
Investigators at all times throughout the conduct of the study until the data have been unblinded. 
Has been changed to (revisions bolded): 
An independent DMC will be formed to monitor the ongoing safety of the study. The DMC will 
consist of at least 3 individuals. Voting members of the DMC will include external physicians 
with experience in treating drug-resistant epilepsy and a cardiologist. Additionally, at least 1 
member may be a statistician. All members will have experience and expertise in clinical trials. 
The DMC members may not participate in the study as principal or co-Investigators, or as study 
subject care physicians. The DMC will regularly review study data and evaluate the treatments 
for excess adverse effects and other potential safety issues. Actions that the DMC can take 
following a review may include providing recommendations to the Sponsor concerning 
continuation, termination or other modifications of the study based on the observed 
adverse effects of the treatment under investigation. Such recommendations may include 
stopping enrollment into a padsevonil dose arm for safety and tolerability reasons and 
allocating remaining patients to remaining padsevonil dose or placebo arms. The DMC will 
consist of members independent from UCB. Study enrollment will not be halted during 
DMC review of the safety data. The DMC may also be asked to provide a review of final study 
results, as deemed appropriate. The detailed role, scope, composition, responsibilities, and 
operation of the DMC, as well as the identity of the DMC members will be defined in a separate 
DMC Charter. 
Safety and tolerability data will be made available to the DMC at each meeting as described in 
the DMC Charter. The data will be provided in a semi-unblinded fashion (data will be visualized 
by real treatment groups, but the treatment/dose assigned to each group will remain blinded) and 
the full unblinding can be requested by the DMC members, if appropriate. Pharmacokinetic data 
may be provided to the DMC at their request. These safety, tolerability, and PK data will be 
presented by individuals not otherwise involved in the conduct of the study. The deliberations 
and decisions of the DMC will be formally documented. 
Ad hoc DMC meetings can be held for other reasons if deemed appropriate by the Sponsor or the 
DMC members. 
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In addition to ongoing review of safety data and safety signal detection within UCB, the 
occurrence of AEs of interest including cardiac and behavioral adverse events, in particular, will 
be monitored by the DMC to provide an assessment of the risk of occurrence of these events in 
the study. Statistical modeling may be used to provide estimates for quantification of the level of 
risk in the study based on the risk in the epilepsy population and in the intended patient 
population in the study (see Inclusion and Exclusion Criteria in Section 6). This analysis may 
inform any decisions regarding changes in study conduct and/or study termination. 
The DMC procedures will ensure that the data remain blinded to the study team and 
Investigators at all times throughout the conduct of the study until the data have been unblinded. 
Only DMC members and an independent statistical group will have access to unblinded 
safety data emerging from the study. DMC members will also have access to unblinded 
efficacy data when required. It is understood that maintaining validity and integrity of the 
study is of paramount importance to ensure its acceptability to the Sponsor, the scientific 
community and health authorities. 
Change #66 
Section 13.8 Determination of sample size (deletions bolded) 
The size of this study is governed by determining whether there is a dose-response 
relationship across the 4 doses of PSL and placebo using the MCP-Mod methodology, as 
described in Section 13.3.1. The primary endpoint of the study is change from Baseline of the 
log-transformed (ln x +1) 28-day adjusted seizure frequency. Four different dose-response 
models (“candidate models”) were identified: sigmoidal Emax, Emax, log-linear, and logistic, 
and the MCP-Mod methodology controls for multiplicity. 
The sample size assessment was estimated using the “Dose Finding” library in the R 
statistical package (Bretz et al, 2005). This software library implements design and analysis 
aspects of the MCP-Mod method. The sample size requirement was obtained for each 
candidate model in turn and the maximum value was taken, thus maintaining the power 
requirement. 
The log-reduction from Baseline in seizure frequency was assumed to be 0.195 for placebo and 
0.780 for PSL. A common SD of 0.985 was assumed. These estimates are based on prior 
experience in epilepsy together with the EP0069 study results. 
With power of 90%, a 2-sided Type-1 error of 5%, and all dose groups of the same size, 
50 subjects are required per arm, for a total of 250 subjects. 
Assuming a screening failure rate of approximately 20%, it is anticipated to enroll around 
300 subjects and randomize 250 subjects in this study. 
Has been changed to (revisions bolded): 
The sample size is based on achieving 90% power to observe a statistically significant result 
for either the 400mg and 200mg or 200mg and 100mg doses when compared to placebo, a 
primary endpoint of change from Baseline of the log-transformed (ln x +1) 28-day adjusted 
seizure frequency. Multiplicity is controlled for using the Hochberg step up procedure in 
Proc Multtest. 
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The log-reduction from Baseline in seizure frequency was assumed to be 0.195 for placebo and 
0.780 for PSL. A common SD of 0.985 was assumed. These estimates are based on prior 
experience in epilepsy together with the EP0069 study results. 
With power of 90%, a 2-sided Type-1 error of 5%, and all dose groups of the same size, 
80 subjects are required per arm, giving a total of 400 subjects. 
Assuming a screening failure rate of approximately 20%, it is anticipated to enroll around 
500 subjects and randomize 400 subjects in this study. 
The study is also powered to give over 80% power to observe a statistically significant 
result for either the 400mg and 200mg or 200mg and 100mg doses when compared to 
placebo for the 75% response rate endpoint, the primary endpoint specified for EMA.  
Change #67 
Section 16  
References 
Has been added: 
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, 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.  
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L. ILAE Classification 
of the epilepsies: Position paper of the ILAE Commission for Classification Terminology. 
Epilepsia. 2017;58(4):512-21.  
Has been deleted:  
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in 
dose-response studies. Biometrics. 2005;61(3):738-48. 
 
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17.2 
Protocol Amendment 2 
Rationale for the amendment 
The main reason the protocol has been amended is to clarify that the primary efficacy analysis is 
comparing each padsevonil dose to placebo with Type I error controlled for all comparisons. 
MCP-Mod analysis has been removed since it will no longer contribute to the overall study 
conclusion and dose selection for future studies.  
Other changes include the following:  
 Updates to study contact information. 
 Minor refinements to the wording describing responder rate variables.  
 Correction of the maximum duration of exposure to PSL from 20 to 19 weeks.  
 Clarification of the rationale for the study to state that dose-response relationship will be 
evaluated with respect to safety as well as efficacy. 
 Revised other efficacy variable, number of seizure-free days to percentage of seizure-free 
days.  
 Revised other efficacy variable, time to return to baseline observable focal-onset seizure 
frequency to time to return to baseline 28-day observable seizure count.  
 Revision of designation of TEAEs, TEAEs leading to withdrawal, and SAEs from “safety 
variables” to “primary safety variables.” A heading was added for these primary variables. 
 Clarification of a Schedule of Assessments footnote that questionnaires should be completed 
prior to other study procedures, when possible. Previously it was mandated that these be 
completed prior to other procedures.  
 Removal of efficiencies of the MCP-Mod model based design and analysis as one of the 
drivers for EP0091 dose selection. In addition, the rationale for selection of intermediate 
doses was revised due to the elimination of MCP-Mod analysis.  
 Revision of Inclusion Criterion 2 to account for the fact that use of legal 
representative/caregiver may not be legally permitted in some countries.  
 Modification of Inclusion Criterion 5 to facilitate the acceptance of ambulatory EEGs which 
are used more frequently in some regions, to require (must versus should) consultation with 
the UCB Study Physician or representative when determining subject eligibility based on 
eye-witness seizure report, home video documentation, or other proof, and to allow 
substitution of head CT for MRI if MRI is contraindicated.  
 Modification of Exclusion Criterion 1 to allow re-screening of subjects under certain 
circumstances. 
 Clarification of the description of the interpretation of echocardiograms  
 The original description stated that the echocardiograms would be interpreted at the sites 
by local cardiologists and then provided to a central reader where they would be 
interpreted. Given that all echocardiograms are to be centrally read and a report provided 
within 7 business days of receipt, in the absence of queries, there is no need for local 
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cardiologist. Therefore, the protocol was modified to say that it is only necessary that the 
local physician examines the echocardiograms for suitability for central reading and for 
determination if an expedited review by the central reader is required. It has also been 
made explicit that the central reader is a cardiologist.  
 Clarification of the Titration Period Dosing Table 7-1 to indicate that this period consists of 
Week 1, Week 2, and Week 3 (versus previous unclear designations of Day 1, Week 1 and 
Week 2).  
 Clarifications regarding administration of the Seizure Severity Global Item, Quality of Life 
Inventory inEpilepsy-31-P, and Hospital Anxiety and Depression Scale.  
 Other modifications to the Statistics section (in addition to those related to the removal of 
MCP-Mod analysis), such as inclusion of information on handling of dropouts and missing 
data and further details about the determination of sample size.  
Modifications and changes 
Specific changes 
Change #1 
Study Contact Information 
Sponsor Study Physician 
Name: 
 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
Belgium 
Phone: 
+
 
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Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Has been changed to (bolded text added or revised): 
Sponsor Study Physician 
Name: 
 MD Phd 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Clinical Project Manager 
Name: 
 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Clinical Trial Biostatistician  
Name: 
 
Address: 
UCB Pharma Ltd 
280 Bath Road 
Berkshire SL 13WE Slough, 
UK 
Phone: 
 
Change #2 
List of Abbreviations 
Has been added: 
LOCF=last observation carried forward 
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Change #3 
Section 1: Summary, Paragraph 5 (bolded text deleted) 
The assessment of efficacy is based on seizure frequency. For the US Food and Drug 
Administration (FDA), Pharmaceuticals and Medical Devices Agency (PMDA), and other 
regulatory authorities not specified in Section 4.1.1.2, the primary efficacy variable is the change 
from Baseline in log-transformed observable focal-onset seizure frequency (for the purpose of 
this protocol defined as Types IA1, IB, and IC, according to the International League Against 
Epilepsy [ILAE] classification [ILAE Classification of Epileptic Seizures, 1981]) over the 
12-week Maintenance Period. For the European Medicines Agency (EMA) and regulatory 
authorities who reference EMA, the primary efficacy variable is the 75% responder rate status, 
defined as a ≥75% reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period. 
Has been changed to (bolded text added): 
The assessment of efficacy is based on seizure frequency. For the US Food and Drug 
Administration (FDA), Pharmaceuticals and Medical Devices Agency (PMDA), and other 
regulatory authorities not specified in Section 4.1.1.2, the primary efficacy variable is the change 
from Baseline in log-transformed observable focal-onset seizure frequency (for the purpose of 
this protocol defined as Types IA1, IB, and IC, according to the International League Against 
Epilepsy [ILAE] classification [ILAE Classification of Epileptic Seizures, 1981]) over the 
12-week Maintenance Period. For the European Medicines Agency (EMA) and regulatory 
authorities who reference EMA, the primary efficacy variable is the 75% responder rate, where 
a responder is a subject experiencing a ≥75% reduction in observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
Change #4 
Section 1: Summary, Paragraph 7 (bolded text deleted) 
The total duration of study per subject will be up to 27 weeks with a maximum of 20 weeks 
exposure to PSL. It is estimated that approximately 500 subjects will be included at 
approximately 200 sites worldwide; 400 subjects are expected to be randomized. 
Has been changed to (bolded text added): 
The total duration of study per subject will be up to 27 weeks with a maximum of 19 weeks 
exposure to PSL. It is estimated that approximately 500 subjects will be included at 
approximately 200 sites worldwide; 400 subjects are expected to be randomized. 
Change #5 
Section 2.4: Rationale for this study, Paragraph 2 
Padsevonil is an AED with a dual mechanism of action, specifically synthesized and designed 
for an increased anticonvulsant activity and hence for the treatment of seizures in patients with 
epilepsies resistant to current available drug therapies. Based on the evidence of unprecedented 
superiority of seizure control compared with other marketed AEDs across several preclinical 
models of epilepsy and the results of the proof of concept study, EP0069, treatment with PSL has 
the potential to benefit an underserved epilepsy population with high unmet medical need, 
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namely those who have drug-resistant epilepsy whose uncontrolled focal-onset seizures 
constitute a substantial threat to their health and well-being. The current study, EP0091, will 
characterize the dose-response relationship with respect to efficacy of PSL administered 
concomitantly with up to 3 AEDs for treatment of observable focal-onset seizures.  
Has been changed to (bolded text added): 
Padsevonil is an AED with a dual mechanism of action, specifically synthesized and designed 
for an increased anticonvulsant activity and hence for the treatment of seizures in patients with 
epilepsies resistant to current available drug therapies. Based on the evidence of unprecedented 
superiority of seizure control compared with other marketed AEDs across several preclinical 
models of epilepsy and the results of the proof of concept study, EP0069, treatment with PSL has 
the potential to benefit an underserved epilepsy population with high unmet medical need, 
namely those who have drug-resistant epilepsy whose uncontrolled focal-onset seizures 
constitute a substantial threat to their health and well-being. The current study, EP0091, will 
characterize the dose-response relationship with respect to efficacy and safety of PSL 
administered concomitantly with up to 3 AEDs for treatment of observable focal-onset seizures.  
Change #6  
Section 4.1.1.2: Primary efficacy variable for EMA and regulatory authorities who 
reference EMA (bolded text deleted) 
The primary efficacy variable is the 75% responder rate status, defined as a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance Period. 
Has been changed to (bolded text added): 
The primary efficacy variable is the 75% responder rate, where a responder is a subject 
experiencing a ≥75% reduction in observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period. 
Change #7  
Section 4.1.2.1: Secondary efficacy variables for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 (bolded text deleted) 
The secondary efficacy variables are as follows:  
 The 75% responder rate status, defined as a ≥75% reduction in observable focal-onset 
seizure frequency from Baseline, over the 12-week Maintenance Period 
 The 50% responder rate status, defined as a ≥50% reduction in observable focal-onset 
seizure frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
Has been changed to (bolded text added): 
The secondary efficacy variables are as follows:  
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 The 75% responder rate, where a responder is a subject experiencing a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
Change #8  
Section 4.1.2.2: Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA (bolded text deleted) 
The secondary efficacy variables are as follows:  
 The change in log-transformed observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
 The 50% responder rate status, defined as a ≥50% reduction in observable focal-onset 
seizure frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
Has been changed to (bolded text added): 
The secondary efficacy variables are as follows:  
 The change in log-transformed observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
Change #9  
Section 4.1.3: Other efficacy variables (This list applies for all regulatory authorities) 
(bolded text deleted) 
The other efficacy variables are as follows:  
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
first 4 weeks, second 4 weeks, and third 4 weeks of the 12-week Maintenance Period 
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
16-week Treatment Period 
 The 50% responder rate status, defined as a ≥50% reduction in observable focal-onset 
seizure frequency from Baseline, over the 16-week Treatment Period 
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 The 75% responder rate status, defined as a ≥75% reduction in observable focal-onset 
seizure frequency from Baseline, over the 16-week Treatment Period  
 The 90% responder rate status, defined as a ≥90% reduction in observable focal-onset 
seizure frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
16-week Treatment Period 
 Change from Baseline in log-transformed focal-onset (Type I) seizure frequency over the 
12-week Maintenance Period 
 The 50% responder rate status, defined as a ≥50% reduction in focal-onset (Type I) seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 The 75% responder rate status, defined as a ≥75% reduction in focal-onset (Type I) seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 The 90% responder rate status, defined as a ≥90% reduction in focal-onset (Type I) seizure 
frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in focal-onset (Type I) seizure frequency from Baseline, over the 12-week 
Maintenance Period and the 16-week Treatment Period 
 Seizure-freedom status (yes/no) during the 12-week Maintenance and the 16-week Treatment 
Period 
 Number of seizure-free days during the 12-week Maintenance Period and the 16-week 
Treatment Period 
 Cumulative responder rate during the 16-week Treatment Period 
 Change in the Seizure Severity Global Item (SSG) scores from Baseline to Week 4 during 
the Maintenance Period (Visit 4) and the end of the 16-week Treatment Period (Visit 7) 
 Change in Quality of Life Inventory in Epilepsy-31-P (QOLIE-31-P) scores from Baseline to 
Week 4 during the Maintenance Period (Visit 4) and the end of the 16-week Treatment 
Period (Visit 7) 
 Change in HADS scores from Baseline to Week 4 during the Maintenance Period (Visit 4) 
and to the end of the 16-week Treatment Period (Visit 7) 
 Time to return to baseline observable focal-onset seizure frequency during the 12-week 
Maintenance Period 
 Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications and hospitalizations 
Has been changed to (bolded text added): 
The other efficacy variables are as follows:  
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
first 4 weeks, second 4 weeks, and third 4 weeks of the 12-week Maintenance Period 
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 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
16-week Treatment Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 16-week Treatment Period 
 The 75% responder rate, where a responder is a subject experiencing a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 16-week Treatment Period  
 The 90% responder rate, where a responder is a subject experiencing a ≥90% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
16-week Treatment Period 
 Change from Baseline in log-transformed focal-onset (Type I) seizure frequency over the 
12-week Maintenance Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 The 75% responder rate, where a responder is a subject experiencing as a ≥75% reduction 
in focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 The 90% responder rate, where a responder is a subject experiencing a ≥90% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in focal-onset (Type I) seizure frequency from Baseline, over the 12-week 
Maintenance Period and the 16-week Treatment Period 
 Seizure-freedom status (yes/no) during the 12-week Maintenance and the 16-week Treatment 
Period 
 Percentage of seizure-free days during the 12-week Maintenance Period and the 16-week 
Treatment Period 
 Cumulative responder rate during the 16-week Treatment Period 
 Change in the Seizure Severity Global Item (SSG) scores from Baseline to Week 4 during 
the Maintenance Period (Visit 4) and the end of the 16-week Treatment Period (Visit 7) 
 Change in Quality of Life Inventory in Epilepsy-31-P (QOLIE-31-P) scores from Baseline to 
Week 4 during the Maintenance Period (Visit 4) and the end of the 16-week Treatment 
Period (Visit 7) 
 Change in HADS scores from Baseline to Week 4 during the Maintenance Period (Visit 4) 
and to the end of the 16-week Treatment Period (Visit 7) 
 Time to return to baseline 28-day observable focal-onset seizure count during the 12-week 
Maintenance Period 
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 Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications and hospitalizations 
Change #10  
Section 4.2: Safety variables 
The safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the entire study 
 Incidence of TEAEs leading to study withdrawal 
 Incidence of treatment-emergent serious adverse events (SAEs) during the entire study 
4.2.1 Other safety variables 
Other safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the following periods: 16-week Treatment Period, 12-week Maintenance Period, 
4-week Titration/Stabilization Period, and 3-week Taper Period 
 Number of and reason for subjects requiring premature tapering due to TEAEs 
 Number of and reason for subjects requiring a dose reduction during the Stabilization Period 
due to TEAEs 
 Incidence of treatment-emergent SAEs during the following periods: 16-week Treatment 
Period, 12-week Maintenance Period, 4-week Titration/Stabilization Period 
 Changes in clinical laboratory test parameters (including hematology, blood chemistry, and 
urinalysis) 
 Changes in vital sign parameters (including pulse rate, systolic BP, diastolic BP, and 
respiratory rate) 
 Changes in 12-lead ECG parameters 
 Physical examination (including body weight) and neurological examination findings 
 Changes in Psychiatric and Mental Status 
 Occurrence of valvular abnormalities or pericardial effusion changes or other significant 
abnormalities as identified by 2-dimensional Doppler echocardiogram at each assessment by 
central reader  
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the End of Treatment Visit (Visit 7) to end of 
the Taper Period (Visit 8) and end of the SFU Period (Visit 9 [30 days after the last IMP 
intake]). 
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Has been changed to (added a level 3 heading for the safety variables and 
designated them as primary safety variables): 
4.2.1 Primary safety variables 
The safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the entire study 
 Incidence of TEAEs leading to study withdrawal 
 Incidence of treatment-emergent serious adverse events (SAEs) during the entire study 
4.2.2 Other safety variables 
Other safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the following periods: 16-week Treatment Period, 12-week Maintenance Period, 
4-week Titration/Stabilization Period, and 3-week Taper Period 
 Number of and reason for subjects requiring premature tapering due to TEAEs 
 Number of and reason for subjects requiring a dose reduction during the Stabilization Period 
due to TEAEs 
 Incidence of treatment-emergent SAEs during the following periods: 16-week Treatment 
Period, 12-week Maintenance Period, 4-week Titration/Stabilization Period 
 Changes in clinical laboratory test parameters (including hematology, blood chemistry, and 
urinalysis) 
 Changes in vital sign parameters (including pulse rate, systolic BP, diastolic BP, and 
respiratory rate) 
 Changes in 12-lead ECG parameters 
 Physical examination (including body weight) and neurological examination findings 
 Changes in Psychiatric and Mental Status 
 Occurrence of valvular abnormalities or pericardial effusion changes or other significant 
abnormalities as identified by 2-dimensional Doppler echocardiogram at each assessment by 
central reader  
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the End of Treatment Visit (Visit 7) to end of 
the Taper Period (Visit 8) and end of the SFU Period (Visit 9 [30 days after the last IMP 
intake]). 
Change #11  
Section 5.1.2: Study duration per subject, Paragraph 1 (bolded text deleted) 
The total duration of study per subject will be up to 27 weeks with a maximum of 20 weeks 
exposure to PSL. An additional follow-up echocardiogram will be performed at 6 months 
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(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks and 
either discontinuing the study or not entering the OLE.  
Has been changed to (bolded text added): 
The total duration of study per subject will be up to 27 weeks with a maximum of 19 weeks 
exposure to PSL. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks and 
either discontinuing the study or not entering the OLE.  
Change #12  
Section 5.2: Schedule of study assessments, Table 5-1, footnote c 
Questionnaires to be completed by all subjects prior to any other study procedures at the visit. 
Has been changed to (bolded text added): 
Questionnaires to be completed by all subjects prior to any other study procedures at the visit, 
when possible. 
Change #13  
Section 5.4.2: Rationale for dose selection (bolded text deleted)  
Dose selection for EP0091 was informed by data derived from the following: 
1. Efficiencies of the MCP-Mod model-based design and analysis  
2. UP0036: PET-derived human SV2A receptor occupancy vs exposure relationship 
3. N01383: PET-derived human GABA-A receptor occupancy  
4. The maximum tolerated dose (MTD) of 400mg bid in Phase 1 
5. EP0069: efficacy-exposure analysis 
6. Preclinical pharmacological exposure-response data 
Four dose levels of PSL (equally spaced on the logarithmic scale), 100mg/day, 200mg/day, 
400mg/day, and 800mg/day, administered bid have been selected to fully explore the 
dose-response curve for PSL in patients with drug-resistant epilepsy. 
Two PET studies, UP0036: PET-derived human SV2A receptor occupancy and 
N01383: PET-derived human GABA-A receptor occupancy, were performed to inform dose 
selection for the clinical studies. Using population-PK modeling of the PK and PET data with a 
SV2A ligand in UP0036, simulations projected SV2A receptor occupancy in human brain 
regions to be greater than 90% over the whole dosing interval for 90% of a population treated 
with the 400 and 300mg bid dosing, and greater than 90% for 75% of a population at 100mg bid 
dosing. In N01383, modeling of the receptor occupancy of PSL at brain GABA-A receptors 
measured using the PET ligand, flumazenil, demonstrated that subjects treated with PSL 200mg 
bid had maximal GABA-A receptor occupancy ranging from lower limit quantification (5%) to 
9.7%. Subjects treated with PSL 400mg bid had maximal GABA-A receptor occupancy ranging 
from 7.6% to 16.8%. 
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The rationale for the selection of the maximum dose, 400mg bid (800mg/day), is based on the 
MTD seen in Phase 1 single dose and multiple dose clinical studies, and is in line with receptor 
occupancy at the SV2A receptor and the nonclinical data described above. Furthermore, 
800mg/day has demonstrated clinically meaningful efficacy (EP0069 primary outcome analysis) 
with acceptable tolerability. The maximum dose is supported further by nonclinical data that 
demonstrate that high levels of SV2A receptor occupancy are required for efficacy in the primary 
model of resistant epilepsy (amygdala kindling, mean effective dose [ED50]=95%). Conversely, 
receptor occupancy at the GABA site associated with efficacy was relatively low (ED50=9%). 
Therefore, it is reasonable to conclude that the high dose level should be associated with 
occupancy consistent with these levels observed at SV2A and GABA-A receptors and 
maintained for SV2A. 
However, for brivaracetam, an AED with SV2A mode of action, a dose with demonstrated 
therapeutic efficacy (200mg), had an observed SV2A receptor occupancy below 90% 
(UCB internal data, EP0074). In this context, the lowest dose for PSL in EP0091 has been set at 
100mg/day (50mg bid) based on preliminary simulations that indicate that a dose around 
50mg bid will have an SV2A occupancy roughly equivalent to that associated with a therapeutic 
dose of brivaracetam. Of note, data from N01383 indicates that, at this lower dose level, 
GABA-A receptor occupancy may be below quantifiable levels, but even very low levels of 
occupancy may provide some synergy with SV2 mechanisms. 
Finally, the 2 intermediate doses, in the ascending part of the dose-response curve, were 
selected to increase the efficiencies of the MCP-Mod model-based design and analysis of 
EP0091 for dose finding: 
 100mg bid (200mg/day) which represent an SV2A receptor occupancy >90% with no 
quantifiable GABA-A occupancy 
 200mg bid (400mg/day) which represent an SV2A receptor occupancy >90% with 
quantifiable GABA-A occupancy 
Subjects completing the Maintenance Period in EP0091 will be offered the option to enter the 
OLE study EP0093 with open-label treatment with PSL. This will be achieved through a 
Conversion Period to ensure blinding of the parent study. All subjects who choose to transition to 
EP0093 will enter the study after the 3-week Conversion Period at an intermediate dose of 
400mg/day PSL before further individual dose adjustment can be made. This dose level was 
selected considering the benefit/risk balance and is based on clinical pharmacology and PET data 
in healthy human subjects suggesting that it will provide full occupancy at the SV2A binding site 
while maintaining some minimal binding to the GABA-A binding site. For subjects previously 
on placebo in EP0091, a full SV2A occupancy is desirable to obtain a meaningful anticonvulsive 
effect while minimal BZD binding will result in fewer GABA-related CNS AEs. On the other 
hand, for subjects exposed to high doses of PSL in EP0091 maintenance (800mg/day), the target 
transition dose of 400mg/day will likely maintain the full SV2A-related effect while not entirely 
eliminating GABA-binding related effects. Once subjects enter EP0093, further individual dose 
adjustments can be made, as needed as per the OLE protocol. 
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Has been changed to: 
Dose selection for EP0091 was informed by data derived from the following: 
1. UP0036: PET-derived human SV2A receptor occupancy vs exposure relationship 
2. N01383: PET-derived human GABA-A receptor occupancy  
3. The maximum tolerated dose (MTD) of 400mg bid in Phase 1 
4. EP0069: efficacy-exposure analysis 
5. Preclinical pharmacological exposure-response data 
Four dose levels of PSL (equally spaced on the logarithmic scale), 100mg/day, 200mg/day, 
400mg/day, and 800mg/day, administered bid have been selected to fully explore the 
dose-response curve for PSL in patients with drug-resistant epilepsy. 
Two PET studies, UP0036: PET-derived human SV2A receptor occupancy and 
N01383: PET-derived human GABA-A receptor occupancy, were performed to inform dose 
selection for the clinical studies. Using population-PK modeling of the PK and PET data with a 
SV2A ligand in UP0036, simulations projected SV2A receptor occupancy in human brain 
regions to be greater than 90% over the whole dosing interval for 90% of a population treated 
with the 400 and 300mg bid dosing, and greater than 90% for 75% of a population at 100mg bid 
dosing. In N01383, modeling of the receptor occupancy of PSL at brain GABA-A receptors 
measured using the PET ligand, flumazenil, demonstrated that subjects treated with PSL 200mg 
bid had maximal GABA-A receptor occupancy ranging from lower limit quantification (5%) to 
9.7%. Subjects treated with PSL 400mg bid had maximal GABA-A receptor occupancy ranging 
from 7.6% to 16.8%. 
The rationale for the selection of the maximum dose, 400mg bid (800mg/day), is based on the 
MTD seen in Phase 1 single dose and multiple dose clinical studies, and is in line with receptor 
occupancy at the SV2A receptor and the nonclinical data described above. Furthermore, 
800mg/day has demonstrated clinically meaningful efficacy (EP0069 primary outcome analysis) 
with acceptable tolerability. The maximum dose is supported further by nonclinical data that 
demonstrate that high levels of SV2A receptor occupancy are required for efficacy in the primary 
model of resistant epilepsy (amygdala kindling, mean effective dose [ED50]=95%). Conversely, 
receptor occupancy at the GABA site associated with efficacy was relatively low (ED50=9%). 
Therefore, it is reasonable to conclude that the high dose level should be associated with 
occupancy consistent with these levels observed at SV2A and GABA-A receptors and 
maintained for SV2A. 
However, for brivaracetam, an AED with SV2A mode of action, a dose with demonstrated 
therapeutic efficacy (200mg), had an observed SV2A receptor occupancy below 90% 
(UCB internal data, EP0074). In this context, the lowest dose for PSL in EP0091 has been set at 
100mg/day (50mg bid) based on preliminary simulations that indicate that a dose around 
50mg bid will have an SV2A occupancy roughly equivalent to that associated with a therapeutic 
dose of brivaracetam. Of note, data from N01383 indicates that, at this lower dose level, 
GABA-A receptor occupancy may be below quantifiable levels, but even very low levels of 
occupancy may provide some synergy with SV2 mechanisms. 
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Finally, the 2 intermediate doses were selected based on equal spacing between the high 
and low doses on log-scale and SV2A and GABA-A receptor occupancy: 
 100mg bid (200mg/day) which represent an SV2A receptor occupancy >90% with no 
quantifiable GABA-A occupancy 
 200mg bid (400mg/day) which represent an SV2A receptor occupancy >90% with 
quantifiable GABA-A occupancy 
Subjects completing the Maintenance Period in EP0091 will be offered the option to enter the 
OLE study EP0093 with open-label treatment with PSL. This will be achieved through a 
Conversion Period to ensure blinding of the parent study. All subjects who choose to transition to 
EP0093 will enter the study after the 3-week Conversion Period at an intermediate dose of 
400mg/day PSL before further individual dose adjustment can be made. This dose level was 
selected considering the benefit/risk balance and is based on clinical pharmacology and PET data 
in healthy human subjects suggesting that it will provide full occupancy at the SV2A binding site 
while maintaining some minimal binding to the GABA-A binding site. For subjects previously 
on placebo in EP0091, a full SV2A occupancy is desirable to obtain a meaningful anticonvulsive 
effect while minimal BZD binding will result in fewer GABA-related CNS AEs. On the other 
hand, for subjects exposed to high doses of PSL in EP0091 maintenance (800mg/day), the target 
transition dose of 400mg/day will likely maintain the full SV2A-related effect while not entirely 
eliminating GABA-binding related effects. Once subjects enter EP0093, further individual dose 
adjustments can be made, as needed as per the OLE protocol. 
Change #14  
Section 6.1: Inclusion criterion 2 
2 Subject/legal representative/caregiver is considered reliable and capable of adhering to the 
protocol (eg, able to understand and complete diaries), visit schedule, or medication intake 
according to the judgment of the Investigator. 
Has been changed to (bolded text added): 
2 Subject/legal representative/caregiver (where legally permitted) is considered reliable and 
capable of adhering to the protocol (eg, able to understand and complete diaries), visit 
schedule, or medication intake according to the judgment of the Investigator. 
Change #15  
Section 6.1: Inclusion criterion 5 (bolded text deleted) 
5 Subject fulfills diagnostic criteria for epilepsy and has observable focal-onset (1A1, 1B, and 
1C) seizures for at least 3 years at the time of enrolment (according to the 
ILAE Classification of Epileptic Seizures, 1981): 
 Epileptic seizures will have been documented using video-EEG recordings in the past 
(description or report is available). The Investigator must consult with the UCB Study 
Physician or representative for confirmation of eligibility as per instructions in the 
Study Manual. 
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If no video-EEG report is available and, in the opinion of the Investigator, epileptic 
seizures are definite (ie, eye-witnessed seizure report, ictal EEG evidence during 
clinical event, home video documentation of habitual events), the Investigator should 
consult with the UCB Study Physician or representative for a case review 
 A brain magnetic resonance imaging (MRI) to be performed before randomization, if no 
such scan was performed in the last 10 years, and a report is not available. If a scan was 
performed within the last 10 years but the clinical condition of the subject was 
progressive since the last scan, a new scan should be obtained. 
Has been changed to (bolded text added): 
5 Subject fulfills diagnostic criteria for epilepsy and has observable focal-onset (IA1, IB, and 
IC) seizures for at least 3 years at the time of enrolment (according to the 
ILAE Classification of Epileptic Seizures, 1981): 
 Epileptic seizures will have been documented using video-EEG recordings or ictal-EEG 
(+/- simultaneous video) in the past (description or report is available). The Investigator 
must consult with the UCB Study Physician or representative for confirmation of 
eligibility as per instructions in the Study Manual. 
 If no video-EEG report is available and, in the opinion of the Investigator, epileptic 
seizures are definite (ie, eye-witnessed seizure report, home video documentation of 
habitual events, or other proof), the Investigator must consult with the UCB Study 
Physician or representative for a case review 
 A brain magnetic resonance imaging (MRI) to be performed before randomization, if no 
such scan was performed in the last 10 years, and a report is not available. If a scan was 
performed within the last 10 years but the clinical condition of the subject was 
progressive since the last scan, a new scan should be obtained. If MRI is 
contraindicated a head CT within the last 3 years before randomization will suffice. 
Change #16  
Section 6.2: Exclusion criterion 1 (bolded text deleted) 
1. Subject has previously participated in this study or subject has previously been assigned 
to treatment in a study of the medication under investigation in this study 
Has been changed to (bolded text added): 
1. Subject has previously been randomized in this study or a study of the medication under 
investigation in this study. Re-screening of a subject may be permitted but requires prior 
medical monitor approval, and is not permitted in case of screen failure due to seizure 
count. 
Change #17  
Section 6.3.2: Echocardiogram valvular abnormalities assessments, Paragraph immediately 
below Table 6-1. (bolded text deleted) 
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Echocardiograms will be obtained every 3 months and will be repeated sooner if new or 
worsening abnormalities are present (detailed below). Echocardiograms will be interpreted at 
the site by the local cardiologist and then provided to the central reader where all study 
echocardiograms will be centrally read and interpreted. When local reads warrant, central reads 
will be expedited. An expedited review of an echocardiogram should be performed if the 
following conditions are met: (1) a Grade 2 of moderate severity, accompanied by moderate or 
severe signs/symptoms; (2) a Grade 3 finding of severe severity (with or without accompanying 
symptoms; or (3) an increase (or jump) in 2 grades (0 to 2 or 1 to 3) between echocardiograms. 
When any of these findings are observed, the Investigator/site should initiate an expedited review 
from the central reader. 
Has been changed to (bolded text added): 
Echocardiograms will be obtained every 3 months and will be repeated sooner if new or 
worsening abnormalities are present (detailed below). Echocardiograms will be examined at the 
site by the local physician and then provided to the central reader where all study 
echocardiograms will be centrally read and interpreted by a cardiologist. When local reads 
warrant, central reads will be expedited. An expedited review of an echocardiogram should be 
performed if the following conditions are met: (1) a Grade 2 finding of moderate severity, 
accompanied by moderate or severe signs/symptoms; (2) a Grade 3 finding of severe severity 
(with or without accompanying symptoms; or (3) an increase (or jump) in 2 grades (0 to 2 or 1 to 
3) between echocardiograms. When any of these findings are observed, the Investigator/site 
should initiate an expedited review from the central reader. 
Change #18  
Section 7.2.1: Titration Period, Table 7-1 (bolded text deleted) 
Table 7-1:  
Titration Period dosing 
Dose Arm 
Dose in mg per intake (morning-evening) during titration 
Day 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 
Day/Week 
Day 1 
Week 1 
Week 2 
PSL 800mg/day 
50-50 
100-100 
150-150 
200-200 
300-300 
PSL 400mg/day 
200-200 
PSL 200mg/day 
100-100 
PSL 100mg/day 
50-50 
Placebo 
1-1 
PSL=padsevonil 
On Day 22, the target dose will be administered. 
Has been changed to (bolded text added, footnote added): 
Table 7-1:  
Titration Period dosing 
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Dose Arm 
Dose in mg per intake (morning-evening) during titration 
Day 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 
Week 
Week 1 
Week 2 
Week 3 
PSL 800mg/day 
50-50 
100-100 
150-150 
200-200 
300-300a 
PSL 400mg/day 
200-200 
PSL 200mg/day 
100-100 
PSL 100mg/day 
50-50 
Placebo 
1-1 
PSL=padsevonil 
a On Day 22, the target dose will be administered. 
Change #19  
Section 9.2: Seizure Severity Global Item, Paragraph 2 (bolded text deleted) 
The SSG will be completed according to the tabular schedule of study procedures, Table 5-1. At 
the very beginning of the visit, the SSG 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 SSG will be covered in the Study Manual. 
Has been changed to (bolded text added): 
The SSG will be completed according to the tabular schedule of study procedures, Table 5-1. At 
the very beginning of the visit, the SSG will be provided to all subjects. It is preferred that the 
subject complete the questionnaire on his/her own; however, assistance may be provided by 
either the study staff or caregiver if needed. 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 SSG will be covered in the Study Manual. 
Change #20  
Section 9.3: Quality of Life Inventory in Epilepsy-31-P, Paragraph 4 (bolded text deleted) 
The QOLIE-31-P will be completed according to the tabular schedule of study procedures in 
Table 5-1. 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 in a quiet place. 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. 
Has been changed to (bolded text added): 
The QOLIE-31-P will be completed according to the tabular schedule of study procedures in 
Table 5-1. At the very beginning of the visit, the QOLIE-31-P will be provided to all subjects. It 
is preferred that the subject will be asked to complete the questionnaire on his/her own; 
however, assistance may be provided by the study staff or caregiver if needed. Once 
completed, the subject will return the completed questionnaire to the Investigator or designee, 
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who will verify that all questions have been answered. Further details about the QOLIE-31-P 
will be covered in the Study Manual. 
Change #21  
Section 9.4: Hospital Anxiety and Depression Scale 
The HADS was chosen for its well-established psychometric properties both in general 
population and more recently in patients with epilepsy (Lin and Pakpour, 2017; 
Wiglusz et al, 2016; de Oliviera et al, 2014). The HADS scores for anxiety and for depression 
range from 0-21 with higher scores indicating worse state. A score below 8 is considered to be 
normal (Zigmond and Snaith, 1983). 
Has been changed to (bolded text added): 
The HADS was chosen for its well-established psychometric properties both in general 
population and more recently in patients with epilepsy (Lin and Pakpour, 2017; 
Wiglusz et al, 2016; de Oliviera et al, 2014). The HADS scores for anxiety and for depression 
range from 0-21 with higher scores indicating worse state. A score below 8 is considered to be 
normal (Zigmond and Snaith, 1983). It is preferred that the subject complete the 
questionnaire on his/her own; however, assistance may be provided by either the study 
staff or caregiver if needed. 
Change #22  
Section 11.2: Laboratory measurements, Table 11-2 
Has been changed to (a footnote b applicable to measurement of FSH has 
been added): 
b 
Only applicable to postmenopausal women 
Change #23  
Section 11.3.3: Echocardiograms, second paragraph below numbered list (bolded text 
deleted) 
Echocardiograms should be acquired by a qualified technician. The echocardiograms will be 
interpreted locally by a qualified cardiologist who should also determine the clinical 
significance of any abnormality. Echocardiograms will also be sent to a central reader for 
review as detailed in the Echocardiogram Manual. 
Has been changed to (bolded text added): 
Echocardiograms should be acquired by a qualified technician. The echocardiograms will be 
examined by the local physician. Echocardiograms will also be sent to a central cardiologist 
for review as detailed in the Echocardiogram Manual. 
Change #24  
Section 11.3.3: Echocardiograms, fourth paragraph below numbered list  
Subjects with an echocardiogram showing an abnormality meeting the withdrawal criteria (see 
Section 6.3) are to be discontinued from the study. An expedited review of an echocardiogram 
(at the central reader) should be requested if the following conditions are met: (1) a Grade 2 of 
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moderate severity, accompanied by moderate or severe signs/symptoms; (2) a Grade 3 finding of 
severe severity (with or without accompanying symptoms); or (3) an increase (or jump) in 
2 grades (0 to 2 or 1 to 3) between echocardiograms. When any of these conditions are met, the 
Investigator/site should initiate an expedited review from the central reader (see 
Echocardiography Manual). Regulatory authorities will be notified of any discontinuations. 
Has been changed to (bolded text added): 
Subjects with an echocardiogram showing an abnormality meeting the withdrawal criteria (see 
Section 6.3) are to be discontinued from the study. An expedited review of an echocardiogram 
(at the central reader) should be requested if the following conditions are met: (1) a Grade 2 
finding of moderate severity, accompanied by moderate or severe signs/symptoms; (2) a Grade 3 
finding of severe severity (with or without accompanying symptoms); or (3) an increase (or 
jump) in 2 grades (0 to 2 or 1 to 3) between echocardiograms. When any of these conditions are 
met, the Investigator/site should initiate an expedited review from the central reader (see 
Echocardiography Manual). Regulatory authorities will be notified of any discontinuations. 
Change #25  
Section 13.1.4: Full Analysis Set (bolded text deleted)  
The Full Analysis Set (FAS) consists of all subjects in the RS who were administered at least 
1 dose or a partial dose of IMP and have at least 1 post-Baseline visit during the Treatment 
Period. In case of dosing administration error, or change in treatment dose, summaries and 
analyses using the FAS will be conducted according to randomized treatment. The FAS will be 
the primary analysis set for all efficacy summaries and analyses. 
Has been changed to (bolded text added): 
The Full Analysis Set (FAS) consists of all subjects in the RS who were administered at least 
1 dose or a partial dose of IMP and have Baseline and at least 1 post-Baseline seizure 
frequency data during the Treatment Period. In case of dosing administration error, or change in 
treatment dose, summaries and analyses using the FAS will be conducted according to 
randomized treatment. The FAS will be the primary analysis set for all efficacy summaries and 
analyses. 
Change #26  
Section 13.3.1.1: Analysis of the primary efficacy variable for the US FDA, PMDA, and 
other regulatory authorities not specified in Section 4.1.12 (bolded text deleted) 
Prior to the primary analysis, the dose-response relationship for change from Baseline in 
observable focal-onset seizure frequency across 4 doses of PSL and placebo will be 
evaluated using the MCP-Mod methodology. Monotonic dose-response trends will be tested 
using the appropriate contrasts as determined by the MCP-Mod methodology such that the 
overall Type 1 error rate is controlled at 0.05 (2sided testing). Four different dose-response 
models (“candidate models”) were identified: sigmoidal Emax, Emax, log-linear, and logistic, 
and the MCP-Mod methodology controls for multiplicity. 
The SAP will describe additional features and detail around the MCP-Mod methodology as 
well as handling of missing data. 
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Assuming at least 1 statistically significant result is obtained from the primary MCP-Mod 
analysis, then pairwise comparisons of 400mg, 200mg and 100mg dose groups versus placebo 
will be carried out using the analysis model below. Type 1 error will be controlled by the 
Hochberg step-up procedure within SAS® Proc Multtest. If all the results of the pairwise 
comparisons are statistically significant then the 50mg dose group will be compared to placebo. 
For the US FDA, PMDA, and other regulatory authorities not specified in Section 4.1.1.2, the 
primary efficacy variable is the change in log-transformed observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. The 28-day Baseline and 
post-Baseline (maintenance) seizure frequency will be transformed with the natural logarithm, 
specifically ln(x+1), where x represents the 28-day seizure frequency. The transformed seizure 
frequency data will be analyzed using analysis of covariance (ANCOVA) with treatment group 
as the main factor, Baseline log-adjusted seizure frequency as a continuous covariate, and 
Baseline SV2A use and Region as categorical factors. Pairwise contrasts will be constructed to 
compute estimated effects of each dose from placebo. 
All pairwise analyses of the primary efficacy variable will be repeated on the PPS. 
A sensitivity analysis of the primary efficacy continuous variable will be carried out using a 
Mixed Model Repeated Measures analysis. Full details will be provided in the SAP. 
Has been changed to: 
Pairwise comparisons of 400mg, 200mg and 100mg dose groups versus placebo will be carried 
out using the analysis model below. Type 1 error will be controlled by the Hochberg step-up 
procedure within SAS® Proc Multtest. If all the results of the pairwise comparisons are 
statistically significant then the 50mg dose group will be compared to placebo. 
For the US FDA, PMDA, and other regulatory authorities not specified in Section 4.1.1.2, the 
primary efficacy variable is the change in log-transformed observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. The 28-day Baseline and 
post-Baseline (maintenance) seizure frequency will be transformed with the natural logarithm, 
specifically ln(x+1), where x represents the 28-day seizure frequency. The transformed seizure 
frequency data will be analyzed using analysis of covariance (ANCOVA) with treatment group 
as the main factor, Baseline log-adjusted seizure frequency as a continuous covariate, and 
Baseline SV2A use and Region as categorical factors. Pairwise contrasts will be constructed to 
compute estimated effects of each dose from placebo. 
All pairwise analyses of the primary efficacy variable will be repeated on the PPS. 
Change #27  
Section 13.3.1.2: Analysis of the primary efficacy variable for EMA and regulatory 
authorities who reference EMA (bolded text deleted) 
For EMA and regulatory authorities who reference EMA, the primary efficacy variable will be 
the 75% responder rate status and will be analyzed using logistic regression with factors for 
treatment group, Baseline seizure frequency, Region, and Baseline SV2A use. If there are issues 
with convergence, Baseline SV2A use will be dropped. The responder rates are defined as a 
≥75% reduction in the observable focal-onset seizure frequency from Baseline over the 
12-week Maintenance Period. 
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The same methodology carried out in Section 13.3.1.1 will be applied to MCP-Mod and the 
pairwise analyses. 
Has been changed to (bolded text added): 
For EMA and regulatory authorities who reference EMA, the primary efficacy variable will be 
the 75% responder rate in observable focal-onset seizures during the Maintenance Period and 
will be analyzed using logistic regression with factors for treatment group, Baseline seizure 
frequency, Region, and Baseline SV2A use. If there are issues with convergence, Baseline SV2A 
use will be dropped.  
The same methodology carried out in Section 13.3.1.1 will be applied to the pairwise analyses. 
Change #28  
Section 13.3.2.1: Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 (bolded text deleted) 
The 75% responder rate status and 50% responder rate will be analyzed using logistic 
regression with factors for treatment group, Baseline seizure frequency, Region, and 
Baseline SV2A use. If there are issues with convergence, Baseline SV2A use will be 
dropped. The responder rates are defined as follows: 
 75% responder rate status: a ≥75% reduction in the observable focal-onset seizure 
frequency from Baseline over the 12-week Maintenance Period  
 50% Responder rate status: a ≥50% reduction in observable focal-onset seizure 
frequency from Baseline over the 12-week Maintenance Period 
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used to 
estimate the median percent reduction in seizures between groups and its corresponding 
95% confidence interval (CI) will be provided. 
Has been changed to (bolded text added): 
The 75% responder rate in observable focal-onset seizures during the Maintenance Period 
is a secondary efficacy variable for the FDA. It is the primary efficacy variable for EMA. 
The analyses are described in Section 13.3.1.2.  
In addition, the 50% responder rate in observable focal-onset seizures during the 
Maintenance Period will be analyzed using logistic regression as described in 
Section 13.3.1.2. Analyses of the percent change in seizure reduction endpoints will be 
performed using the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric 
estimator will be used to estimate the median percent reduction in seizures between groups and 
its corresponding 95% confidence interval (CI) will be provided. 
Change #29  
Section 13.3.2.2: Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA (bolded text deleted) 
The change in log-transformed observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period will be analyzed in the same way as for the primary analysis 
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used for the FDA ie, pairwise comparisons of 400mg, 200mg and 100 mg dose groups 
versus placebo will be carried out using the analysis model described in Section 13.3.1.1. 
Type 1 error will be controlled by the Hochberg step-up procedure within SAS® Proc 
Multtest. If the results of all pairwise comparisons are statistically significant, then the 
50mg dose group will be compared to placebo. 
In addition, the 50% responder rate will be analyzed using logistic regression with factors for 
treatment group, Baseline seizure frequency, Region, and Baseline SV2A use. If there are 
issues with convergence, Baseline SV2A use will be dropped. The responder rates are 
defined as follows: 
 50% Responder rate status: a ≥50% reduction in observable focal-onset seizure 
frequency from Baseline over the 12-week Maintenance Period 
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used to 
estimate the median percent reduction in seizures between groups and its corresponding 95%  CI 
will be provided. 
Has been changed to (bolded text added): 
The change in log-transformed observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period is a secondary efficacy variable for EMA. It is the primary 
efficacy variable for the FDA. The analyses are described in Section 13.3.1.1.  
In addition, the 50% responder rate in observable focal-onset seizures during the 
Maintenance Period will be analyzed using logistic regression as described in 
Section 13.3.1.2.  
Analyses of the percent change in seizure reduction endpoints will be performed using the 
Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator will be used to 
estimate the median percent reduction in seizures between groups and its corresponding 95% CI 
will be provided. 
Change #30  
Section 13.3.3: Other efficacy analyses (bolded text deleted) 
All other analyses of the 75% and 50% responder rate and seizure freedom endpoints will be 
analyzed using the same logistic regression model as specified for the secondary efficacy 
analysis for the 75% responder rate. Analyses of 90% responder rate and seizure freedom will 
use the same methodology. In addition to observable focal-onset seizures and focal-onset 
seizures, analyses will also be carried out on all seizures (seizure-free status and seizure-free 
days) during the 12-week Maintenance Period and the 16-week Treatment Period. 
All other analyses of the change from Baseline in seizure reduction will be analyzed using the 
ANCOVA model on the log-transformed data, as specified for the primary efficacy analysis 
for the change from Baseline in focal-onset seizure frequency. 
The time-to-return to baseline observable focal-onset seizure frequency will be analyzed using 
Kaplan-Meier methodology. Additional details of the analysis will be captured in the SAP. 
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The QOLIE-31-P and SSG assessments will be summarized using descriptive statistics by each 
available visit.  
Has been changed to (bolded text added): 
All other analyses of the 75% and 50% responder rate endpoints will be analyzed using the same 
logistic regression model as specified in Section 13.3.1.2. Analyses of 90% responder rate and 
seizure freedom will use the same methodology. In addition to observable focal-onset seizures 
and focal-onset seizures, analyses will also be carried out on all seizures (seizure-free status and 
seizure-free days) during the 12-week Maintenance Period and the 16-week Treatment Period. 
All other analyses of the change from Baseline in seizure frequency will be analyzed using the 
ANCOVA model on the log-transformed data, as specified in Section 13.3.1.1. 
The time to return to baseline 28-day observable focal-onset seizure count during the 12-week 
Maintenance Period will be analyzed using Kaplan-Meier methodology. Additional details of 
the analysis will be captured in the SAP. 
The QOLIE-31-P and SSG assessments will be summarized using descriptive statistics by each 
available visit.  
Change #31  
Section 13.4.2: Pharmacokinetic analyses, Paragraphs 6 and 7 (bolded text deleted) 
An exploratory comparison of PSL blood levels derived from the MITRA sampler with 
conventional venous sampling will be made. 
An exploratory evaluation of PSL metabolites will be undertaken. 
Has been changed to (bolded text added): 
An exploratory comparison of PSL blood levels derived from the MITRA samples with 
conventional venous sampling may be made. An exploratory evaluation of PSL metabolites may 
be undertaken. 
Change #32  
Section 13.6: Handing of dropouts or missing data (bolded text deleted) 
The methods for handling dropouts will be described in the SAP. 
Has been changed to: 
Seizure frequency will be computed over non-missing diary days. Unless noted otherwise, for 
subjects who prematurely discontinued the study, last observation carried forward (LOCF) 
method will be applied to obtain a seizure frequency estimate for the Maintenance Period: 
 Subjects discontinued during the Titration and Stabilization Period: seizure frequency will be 
calculated using all available data in the Titration and Stabilization Period and carry forward 
for the Maintenance Period. 
 Subjects discontinued during the Maintenance Period: seizure frequency will be calculated 
using all available data in the Maintenance Period. 
Additional details and sensitivity analyses for missing data will be described in the SAP.  
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Change #33  
Section 13.8: Determination of sample size (bolded text deleted) 
The sample size is based on achieving 90% power to observe a statistically significant result for 
either the 400mg and 200mg or 200mg and 100mg doses when compared to placebo, a primary 
endpoint of change from Baseline of the log-transformed (ln x +1) 28-day adjusted seizure 
frequency. Multiplicity is controlled for using the Hochberg step up procedure in Proc Multtest. 
The log-reduction from Baseline in seizure frequency was assumed to be 0.195 for placebo and 
0.780 for PSL. A common SD of 0.985 was assumed. These estimates are based on prior 
experience in epilepsy together with the EP0069 study results. 
With power of 90%, a 2-sided Type-1 error of 5%, and all dose groups of the same size, 
80 subjects are required per arm, giving a total of 400 subjects. 
Assuming a screening failure rate of approximately 20%, it is anticipated to enroll around 
500 subjects and randomize 400 subjects in this study. 
The study is also powered to give over 80% power to observe a statistically significant result for 
either the 400mg and 200mg or 200mg and 100mg doses when compared to placebo for the 
75% response rate endpoint, the primary endpoint specified for EMA.  
Has been changed to (bolded text added): 
The sample size was calculated based on achieving 90% power to observe a statistically 
significant result for either the 400mg bid and 200mg bid or 200mg bid and 100mg bid doses 
when compared to placebo, for a change from Baseline of the log-transformed (ln x +1) 28-day 
adjusted seizure frequency. Multiplicity is controlled for using the Hochberg step up procedure. 
The log-reduction from Baseline in seizure frequency was assumed to be 0.195 for placebo and 
0.492, 0.670, 0.754, and 0.780 for the 50mg bid, 100mg bid, 200mg bid, and 400mg bid 
doses of PSL, respectively. A common SD of 0.985 was assumed. These estimates are based on 
prior experience in epilepsy together with the EP0069 study results. 
With power of 90%, a 2-sided Type-1 error of 5%, and all dose groups of the same size, 
80 subjects are required per arm, giving a total of 400 subjects. 
Assuming a screening failure rate of approximately 20%, it is anticipated to enroll around 
500 subjects and randomize 400 subjects in this study. 
The study is also powered to give over 80% power to observe a statistically significant result for 
the 75% response rate. For the 75% responder rate, assumptions were a 0.121 responder 
rate for placebo and corresponding responder rates of 0.233, 0.301, 0.332, and 0.342 for the 
50mg bid, 100mg bid, 200mg bid, and 400mg bid doses of PSL, respectively.  
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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 
 
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19 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
 
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Approval Signatures
Name:
ep0091-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000125670
Title:
EP0091 Protocol Amendment 2
Approved Date:
15 Oct 2018
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Oct-2018 18:48:23 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 14-Oct-2018 20:04:02 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 15-Oct-2018 07:14:41 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan                            Padsevonil (UCB0942)                                                                     EP0091 
      
 
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Page 1 of 121 
 
STATISTICAL ANALYSIS PLAN  
 
Study: EP0091 
Product: Padsevonil (UCB0942) 
ARISE: pAdsevonil in drug-ResIStant Epilepsy 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE FINDING STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF PADSEVONIL AS ADJUNCTIVE 
TREATMENT OF FOCAL-ONSET SEIZURES IN ADULT SUBJECTS WITH DRUG-
RESISTANT EPILEPSY 
 
SAP/Amendment 
Number 
Date 
Final SAP 
29 Mar 2018 
Amendment 1 
10 Dec 2018 
Amendment 2 
13 Dec 2019 
Amendment 3 
12 Feb 2020 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Statistical Analysis Plan                            Padsevonil (UCB0942)                                                                     EP0091 
      
 
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Page 2 of 121 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 9 
1 
INTRODUCTION ........................................................................................................... 12 
2 
PROTOCOL SUMMARY ............................................................................................... 12 
2.1 
Study objective(s) ........................................................................................................ 12 
2.1.1 
Primary objective(s) ............................................................................................. 12 
2.1.2 
Secondary objective(s) ......................................................................................... 12 
2.1.3 
Other Objectives .................................................................................................. 12 
2.1.3.1 
Other Efficacy Objectives ......................................................................... 12 
2.1.3.2 
Pharmacokinetic Objectives ...................................................................... 12 
2.1.3.3 
Exploratory nonhereditary pharmacogenomics and pharmacogenetic 
objectives ................................................................................................... 12 
2.2 
Study variables ............................................................................................................. 13 
2.3 
Efficacy variables......................................................................................................... 13 
2.3.1 
Primary efficacy variable ..................................................................................... 13 
2.3.1.1 
Primary efficacy variable for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 ............................................... 13 
2.3.1.2 
Primary efficacy variable for EMA and regulatory authorities who 
reference EMA .......................................................................................... 13 
2.3.2 
Secondary efficacy variables ............................................................................... 13 
2.3.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 .............................. 13 
2.3.2.2 
Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA .......................................................................................... 13 
2.3.3 
Other efficacy variables (This list applies for all regulatory authorities) ............ 14 
2.4 
Safety variables ............................................................................................................ 15 
2.4.1 
Primary safety variables ...................................................................................... 15 
2.4.2 
Other safety variables .......................................................................................... 15 
2.5 
Other variables ............................................................................................................. 16 
2.5.1 
Pharmacokinetic variables ................................................................................... 16 
2.5.2 
Exploratory nonhereditary pharmacogenomics variables.................................... 16 
2.5.3 
Exploratory pharmacogenetic variables............................................................... 16 
2.5.4 
Exploratory pharmacokinetic evaluation ............................................................. 17 
2.6 
Study Design and Conduct........................................................................................... 17 
2.6.1 
Study description ................................................................................................. 17 
2.6.2 
Study duration per subject ................................................................................... 19 
2.6.3 
Treatments to be administered ............................................................................. 19 
2.7 
Determination of sample size ....................................................................................... 26 
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Statistical Analysis Plan                            Padsevonil (UCB0942)                                                                     EP0091 
      
 
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3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 26 
3.1 
General presentation of summaries and analyses ........................................................ 26 
3.2 
General study level definitions .................................................................................... 27 
3.2.1 
Initial processing of diary data for seizure frequency.......................................... 27 
3.2.2 
Analysis time points ............................................................................................ 27 
3.2.2.1 
Relative day ............................................................................................... 27 
3.2.2.2 
End of the 16-week treatment period ........................................................ 28 
3.2.3 
Analysis periods ................................................................................................... 28 
3.2.4 
Mapping of assessments performed at early discontinuation .............................. 30 
3.2.5 
Last Visit during the Treatment Period ............................................................... 30 
3.3 
Definition of Baseline values ....................................................................................... 30 
3.3.1 
Baseline for variables based on seizure count ..................................................... 30 
3.3.2 
Baseline for other variables ................................................................................. 30 
3.4 
Protocol deviations....................................................................................................... 31 
3.5 
Analysis sets................................................................................................................. 31 
3.5.1 
Enrolled Set ......................................................................................................... 31 
3.5.2 
Randomized Set ................................................................................................... 31 
3.5.3 
Safety Set ............................................................................................................. 31 
3.5.4 
Full Analysis Set .................................................................................................. 31 
3.5.5 
Per Protocol Set ................................................................................................... 31 
3.5.6 
Completer Set ...................................................................................................... 32 
3.5.7 
Other analysis sets ............................................................................................... 32 
3.5.7.1 
Pharmacokinetic Set .................................................................................. 32 
3.5.7.2 
Pharmacokinetic Per-Protocol Set (PK-PPS) ............................................ 32 
3.5.7.3 
AED Pharmacokinetic Per-Protocol Set (AED-PK-PPS) ......................... 32 
3.6 
Treatment assignment and treatment groups ............................................................... 32 
3.7 
Sites pooling strategy ................................................................................................... 33 
3.8 
Coding dictionaries ...................................................................................................... 33 
3.9 
Changes to protocol-defined analyses ......................................................................... 33 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 33 
4.1 
Adjustments for covariates .......................................................................................... 33 
4.2 
Handling of dropouts or missing data .......................................................................... 34 
4.2.1 
Handling of missing data in seizure frequency .................................................... 34 
4.2.1.1 
Missing data caused by missing seizure diary ........................................... 34 
4.2.1.2 
Missing seizure data caused by discontinuation ........................................ 34 
4.2.2 
Handling of missing data for adverse events and concomitant medications ....... 35 
4.2.2.1 
Imputation of Partial Start Dates ............................................................... 35 
4.2.2.2 
Imputation of Partial Stop Dates ............................................................... 35 
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4.2.3 
Handling of missing data for history of epileptic seizures and diagnosis of 
epilepsy ................................................................................................................ 35 
4.2.3.1 
Incomplete dates for first epileptic seizure ................................................ 35 
4.2.3.2 
Incomplete dates for last epileptic seizure................................................. 36 
4.2.3.3 
Incomplete dates for first epilepsy diagnosis ............................................ 36 
4.3 
Interim analyses and data monitoring .......................................................................... 36 
4.4 
Multicenter studies ....................................................................................................... 36 
4.5 
Multiple comparisons/multiplicity ............................................................................... 36 
4.6 
Use of an efficacy subset of subjects ........................................................................... 37 
4.7 
Active-control studies intended to show equivalence .................................................. 37 
4.8 
Examination of subgroups ........................................................................................... 37 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 37 
5.1 
Subject disposition ....................................................................................................... 37 
5.2 
Protocol deviations....................................................................................................... 38 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 39 
6.1 
Demographics .............................................................................................................. 39 
6.2 
Other Baseline characteristics ...................................................................................... 39 
6.3 
Medical history and concomitant diseases ................................................................... 39 
6.3.1 
Medical history and ongoing medical conditions ................................................ 39 
6.3.2 
Procedure history ................................................................................................. 40 
6.3.3 
Medical history of epilepsy ................................................................................. 40 
6.3.3.1 
Etiology of epilepsy ................................................................................... 40 
6.3.3.2 
Epilepsy surgery status .............................................................................. 40 
6.3.3.3 
Epileptic seizure profile ............................................................................. 40 
6.3.3.4 
Focus localization ...................................................................................... 40 
6.3.3.5 
History of epileptic seizures and diagnosis of epilepsy............................. 40 
6.3.3.6 
Historical seizure count and cluster count ................................................. 40 
6.3.3.7 
Seizure types experienced during the Baseline Period .............................. 40 
6.3.3.8 
Baseline focal seizure frequency ............................................................... 41 
6.3.3.9 
Brain magnetic resonance imaging (MRI) ................................................ 41 
6.4 
Prior and concomitant medications .............................................................................. 41 
6.4.1 
AED medications ................................................................................................. 41 
6.4.2 
Use of vagus nerve stimulation ............................................................................ 42 
6.4.3 
Prior and Concomitant non-AED medications .................................................... 42 
7 
MEASUREMENTS OF COMPLIANCE ........................................................................ 42 
7.1 
Treatment compliance .................................................................................................. 42 
7.2 
Diary compliance ......................................................................................................... 43 
8 
EFFICACY ANALYSES ................................................................................................ 44 
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8.1 
Statistical analysis of the primary efficacy variables ................................................... 45 
8.1.1 
Derivations of primary efficacy variables ........................................................... 45 
8.1.1.1 
Seizure frequency ...................................................................................... 45 
8.1.1.2 
Change in log-transformed seizure frequency from Baseline ................... 45 
8.1.1.3 
Percent reduction in seizure frequency from Baseline .............................. 45 
8.1.1.4 
75% Responder .......................................................................................... 45 
8.1.2 
Analysis of the primary efficacy variables .......................................................... 46 
8.1.2.1 
Primary variable for submission to the US FDA, PMDA, and other 
regulatory authorities not referencing EMA.............................................. 46 
8.1.2.2 
Supportive and sensitivity analyses for the primary variable for 
submission to the US FDA, PMDA, and other regulatory authorities not 
referencing EMA ....................................................................................... 46 
8.1.2.3 
Primary variable for submission to the EMA and regulatory authorities 
who reference EMA .................................................................................. 48 
8.1.2.4 
Supportive and sensitivity analyses for the primary variable for 
submission to the EMA and regulatory authorities who reference EMA . 48 
8.1.2.5 
The log of the odds ratio estimates from the logistic regression model are 
used when combining into a single inference using SAS PROC 
MIANALYZE. Subgroup analyses for the primary variables................... 49 
8.2 
Statistical analysis of the secondary efficacy variables ............................................... 49 
8.2.1 
Analysis of the secondary efficacy variables for submission to the US FDA, 
PMDA, and other regulatory authorities not referencing EMA .......................... 49 
8.2.1.1 
75% Responder Rate over the 12-week Maintenance Period ................... 49 
8.2.1.2 
50% Responder Rate over the 12-week Maintenance Period ................... 49 
8.2.1.3 
Percent reduction from Baseline in observable focal-onset seizure 
frequency over the 12-week Maintenance Period ..................................... 49 
8.2.2 
Analysis of the secondary efficacy variables for submission to EMA and 
regulatory authorities who reference EMA ......................................................... 50 
8.2.2.1 
The change in log-transformed observable focal onset seizure frequency 
from Baseline, over the 12-week Maintenance Period .............................. 50 
8.2.2.2 
50% Responder Rate status over the 12-week Maintenance Period ......... 50 
8.2.2.3 
Percent reduction in observable focal-onset seizure frequency from 
Baseline, over the 12-week Maintenance Period ...................................... 50 
8.3 
Analysis of other efficacy variables ............................................................................. 50 
8.3.1 
Derivations of other efficacy variables ................................................................ 50 
8.3.1.1 
Seizure-freedom status (Yes/No) .............................................................. 50 
8.3.1.2 
Seizure-free days ....................................................................................... 50 
8.3.1.3 
Seizure Severity Global Item (SSG) variables .......................................... 51 
8.3.1.4 
QOLIE-31-P variables ............................................................................... 51 
8.3.1.5 
Hospital Anxiety and Depression Scale (HADS) score variables ............. 51 
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8.3.2 
Analysis of other efficacy variables .................................................................... 51 
8.3.2.1 
Change from Baseline in log-transformed observable focal-onset seizure 
frequency over the first 4 weeks, second 4 weeks, and third 4 weeks of the 
12-week Maintenance Period .................................................................... 52 
8.3.2.2 
Change from Baseline in log-transformed observable focal-onset seizure 
frequency over the16-week Treatment Period .......................................... 52 
8.3.2.3 
The 50% responder rate over the 16-week Treatment Period ................... 52 
8.3.2.4 
The 75% responder rate over the 16-week Treatment Period ................... 52 
8.3.2.5 
The 90% and 100% responder rates over the 12-week Maintenance Period52 
8.3.2.6 
Percent reduction in observable focal-onset seizure frequency from 
Baseline, over the 16-week Treatment Period ........................................... 52 
8.3.2.7 
Change from Baseline in log-transformed focal-onset (Type I) seizure 
frequency over the 12-week Maintenance Period ..................................... 52 
8.3.2.8 
The 50% responder rate status for focal-onset (Type I) seizures over the 
12-week Maintenance Period .................................................................... 53 
8.3.2.9 
The 75% responder rate for focal onset (Type I) seizures over the 12-week 
Maintenance Period ................................................................................... 53 
8.3.2.10 
The 90% and 100% responder rates for focal-onset (Type I) seizures over 
the 12-week Maintenance Period .............................................................. 53 
8.3.2.11 
Percent reduction in focal-onset (Type I) seizure frequency from Baseline, 
over the 12-week Maintenance Period and the 16-week Treatment Period53 
8.3.2.12 
Change from Baseline in log-transformed Type IA1, IB, or IC seizure 
frequency over the12-week Maintenance Period ...................................... 53 
8.3.2.13 
The 50% responder rate for Type IA1, IB, or IC seizure over the 12-week 
Maintenance Period ................................................................................... 53 
8.3.2.14 
The 75% responder rate for Type IA1, IB, or IC seizure over the 12-week 
Maintenance Period ................................................................................... 53 
8.3.2.15 
Percent reduction in Type IA1, IB, or IC seizure frequency from Baseline, 
over the 12-week Maintenance Period and the 16-week Treatment Period54 
8.3.2.16 
Seizure-freedom status (yes/no) during the 12-week Maintenance and the 
16-week Treatment Period ........................................................................ 54 
8.3.2.17 
Percentage of seizure-free days during the 12-week Maintenance Period 
and the 16-week Treatment Period ............................................................ 54 
8.3.2.18 
Cumulative responder rate during the 16-week Treatment Period ............ 54 
8.3.2.19 
Change in the SSG score ........................................................................... 54 
8.3.2.20 
Change in the QOLIE-31-P score ............................................................. 54 
8.3.2.21 
Change in Hospital Anxiety and Depression Scale (HADS) score ........... 55 
8.3.2.22 
Time to return to the Baseline 28-day adjusted observable focal-onset 
seizure count .............................................................................................. 55 
8.3.2.23 
Change from baseline in seizure frequency............................................... 55 
8.3.2.24 
Additional figures for efficacy variables ................................................... 55 
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8.3.2.25 
Use of health-related outcomes and HRU ................................................. 55 
9 
PHARMACOKINETICS ................................................................................................. 57 
9.1 
Plasma concentrations of PSL and its major metabolites ............................................ 57 
9.2 
Plasma concentrations of concomitant AEDs .............................................................. 58 
9.3 
Other PK analyses/variables ........................................................................................ 58 
10 SAFETY ANALYSES ..................................................................................................... 58 
10.1 
Extent of exposure ....................................................................................................... 59 
10.2 
Adverse events ............................................................................................................. 59 
10.3 
Clinical laboratory evaluations .................................................................................... 60 
10.3.1 
Subjects with potential drug-induced liver injury (PDILI) .................................. 62 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 63 
10.4.1 
Vital Signs ........................................................................................................... 63 
10.4.2 
Electrocardiograms .............................................................................................. 64 
10.4.3 
Echocardiograms ................................................................................................. 64 
10.4.4 
Other safety variable(s) ........................................................................................ 64 
10.4.4.1 
Physical Examination ................................................................................ 64 
10.4.4.2 
Neurologic Examination Data ................................................................... 65 
10.4.4.3 
Psychiatric and Mental Status Data ........................................................... 65 
10.4.4.4 
The Columbia-Suicide Severity Rating Scale (C-SSRS) .......................... 65 
10.4.4.5 
Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) .. 65 
11 OTHER ANALYSIS ....................................................................................................... 66 
12 REFERENCES ................................................................................................................ 67 
13 APPENDICES ................................................................................................................. 68 
13.1 
PCST Criteria for Hematology, Serum Chemistry and Urinalysis Parameters ........... 68 
13.1.1 
Hematology .......................................................................................................... 68 
13.1.2 
Serum Chemistry ................................................................................................. 70 
13.1.3 
Urinalysis ............................................................................................................. 74 
13.2 
Abnormal Criteria for Vital Sign and Body Weight Parameters ................................. 75 
13.3 
Abnormal Criteria for ECG ......................................................................................... 77 
13.4 
Echocardiogram Valvular Abnormality Grading Criteria ........................................... 78 
14 AMENDMENT(S) TO THE SAP ................................................................................... 79 
14.1 
Amendment 1 ............................................................................................................... 79 
14.2 
Amendment 2 ............................................................................................................. 105 
14.3 
Amendment 3 ............................................................................................................. 112 
15 ADDENDUM ................................................................................................................ 120 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ................................................... 121 
 
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LIST OF TABLES 
Table 2-1: 
Schedule of assessments .................................................................................. 20 
Table 3‒1: 
Start and end of EP0091 analysis periods ........................................................ 29 
Table 8‒1: 
Summary of seizure frequency variables ......................................................... 44 
Table 10‒1: 
Laboratory measurements ................................................................................ 62 
 
LIST OF FIGURES 
Figure 2‒1: 
Study design ..................................................................................................... 25 
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 LIST OF ABBREVIATIONS 
AE  
adverse event 
AED  
antiepileptic drug 
ALP  
alkaline phosphatase 
ALT  
alanine aminotransferase 
ANCOVA  
analysis of variance 
AST  
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
bid  
twice daily 
BRV 
brivaracetam 
CI  
confidence interval 
CIWA-B 
Clinical Institute Withdrawal Assessment-Benzodiazepines 
CSR 
Clinical Study Report 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
DBP 
diastolic blood pressure 
DMC  
Data Monitoring Committee 
DNA  
deoxyribonucleic acid 
ECG  
electrocardiogram 
EEG  
electroencephalogram 
eCRF  
electronic Case Report form 
EDV  
Early Discontinuation Visit 
EMA 
European Medicines Agency 
ES 
Enrolled Set 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
HADS 
Hospital Anxiety and Depression Scale 
HRU  
healthcare resource utilization 
ICF  
Informed Consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ILAE  
International League Against Epilepsy 
IMP  
investigational medicinal product 
IRT  
interactive response technology 
LEV  
levetiracetam 
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LOCF 
Last observation carried forward 
IPD 
Important protocol deviation 
LS 
least squares 
MedDRA®  
Medical Dictionary for Regulatory Activities® 
MMRM 
Mixed Model Repeated Measures 
MRI  
magnetic resonance imaging 
NRI 
non-responder imputation 
OLE  
open-label extension 
PDILI  
potential drug-induced liver injury 
PK  
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS  
Per-Protocol Set 
PSL  
Padsevonil 
PT 
Preferred Term 
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 
RNA  
ribonucleic acid 
RS  
Randomized Set 
SAE  
serious adverse event 
SAP  
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SD  
standard deviation 
SFU  
Safety Follow Up 
SOC 
System Organ Class 
SOP  
Standard Operating Procedure 
SSG  
Seizure Severity Global Item 
SS  
Safety Set 
SV2A  
synaptic vesicle 2A 
TEAE  
treatment-emergent adverse event 
ULN  
upper limit of normal 
VAMS  
volumetric absorptive microsampling 
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VNS 
vagus nerve stimulation 
WHO 
World Health Organization  
WHO DD 
World Health Organization Drug Dictionary 
 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report (CSR). The SAP is based on the following study document: Protocol 
EP0091 Amendment 2, 12 October 2018. All references to study protocol hereafter refer to this 
version of the protocol. Unless otherwise specified, the study will be analyzed as described in the 
most recent version of the protocol (EudraCT-Number: 2017-003200-48; IND number 135622). 
If a future protocol amendment necessitates a substantial change to the statistical analysis of the 
study data, or if analysis definitions must be modified or updated, this SAP will be amended 
accordingly. The content of this SAP is compatible with the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)/Food and 
Drug Administration (FDA) E9 Guidance documents (ICH E9, 1998). 
2 
PROTOCOL SUMMARY 
2.1 
Study objective(s) 
2.1.1 
Primary objective(s) 
The primary objectives of this study are to characterize the dose-response relationship with 
respect to efficacy of padsevonil (PSL) administered concomitantly with up to 3 antiepileptic 
drugs (AEDs) for treatment of observable focal-onset seizures in subjects with drug-resistant 
epilepsy and to evaluate the efficacy of the 4 selected dose regimens of PSL compared with 
placebo. 
2.1.2 
Secondary objective(s) 
The secondary objective of the study is to assess the safety and tolerability of all doses of PSL in 
relation to placebo. 
2.1.3 
Other Objectives 
2.1.3.1 
Other Efficacy Objectives 
The other efficacy objective is to: 
 Assess the healthcare resource utilization (HRU) and quality of life. 
2.1.3.2 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives are to: 
 Evaluate the steady-state PK profiles of PSL and the exposure-response relationship 
 Evaluate the impact of enzyme-inducing concomitant AEDs on PSL exposure  
 Evaluate concomitant AED (and/or relevant metabolites) plasma concentrations 
2.1.3.3 
Exploratory nonhereditary pharmacogenomics and pharmacogenetic 
objectives 
The other nonhereditary pharmacogenomics and pharmacogenetics objectives are to: 
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 Identify genetic polymorphisms, gene expression patterns, plasma proteins, plasma 
metabolites, plasma lipids, or other plasma and serum substances that predict or are 
associated with disease etiology, drug response, or tolerability. 
2.2 
Study variables 
2.3 
Efficacy variables 
Seizure frequency refers to 28-day adjusted frequency. Observable focal-onset seizures refer to 
Type IA1, IB, and IC (ILAE Classification of Epileptic Seizures, 1981). Focal-onset seizures 
include all Type I seizures.  
Seizure-free status and seizure-free days include all (Types I, II, and III) seizure types.  
2.3.1 
Primary efficacy variable 
2.3.1.1 
Primary efficacy variable for the US FDA, PMDA, and other regulatory 
authorities not specified in Section 4.1.1.2 
The primary efficacy variable is the change in log-transformed observable focal-onset seizure 
frequency from Baseline, over the 12-week Maintenance Period. 
2.3.1.2 
Primary efficacy variable for EMA and regulatory authorities who 
reference EMA 
The primary efficacy variable is the 75% responder rate, where a responder is a subject 
experiencing a ≥75% reduction in observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period. 
2.3.2 
Secondary efficacy variables 
2.3.2.1 
Secondary efficacy variables for the US FDA, PMDA, and other 
regulatory authorities not specified in Section 4.1.1.2 
The secondary efficacy variables are as follows:  
 The 75% responder rate, where a responder is a subject experiencing a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
2.3.2.2 
Secondary efficacy variables for EMA and regulatory authorities who 
reference EMA 
The secondary efficacy variables are as follows:  
 The change in log-transformed observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
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 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
12-week Maintenance Period  
2.3.3 
Other efficacy variables (This list applies for all regulatory 
authorities) 
The other efficacy variables are as follows:  
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
first 4 weeks, second 4 weeks, and third 4 weeks of the 12-week Maintenance Period 
 Change from Baseline in log-transformed observable focal-onset seizure frequency over the 
16-week Treatment Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 16-week Treatment Period 
 The 75% responder rate, where a responder is a subject experiencing a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 16-week Treatment Period  
 The 90% responder rate, where a responder is a subject experiencing a ≥90% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period 
 Percent reduction in observable focal-onset seizure frequency from Baseline, over the 
16-week Treatment Period 
 Change from Baseline in log-transformed focal-onset (Type I) seizure frequency over the 
12-week Maintenance Period 
 The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 The 75% responder rate, where a responder is a subject experiencing as a ≥75% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 The 90% responder rate, where a responder is a subject experiencing a ≥90% reduction in 
focal-onset (Type I) seizure frequency from Baseline, over the 12-week Maintenance Period 
 Percent reduction in focal-onset (Type I) seizure frequency from Baseline, over the 12-week 
Maintenance Period and the 16-week Treatment Period 
 Seizure-freedom status (yes/no) during the 12-week Maintenance and the 16-week Treatment 
Period 
 Percentage of seizure-free days during the 12-week Maintenance Period and the 16-week 
Treatment Period 
 Cumulative responder rate during the 16-week Treatment Period 
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 Change in the Seizure Severity Global Item (SSG) scores from Baseline to Week 4 during 
the Maintenance Period (Visit 4) and the end of the 16-week Treatment Period (Visit 7) 
 Change in Quality of Life Inventory in Epilepsy-31-P (QOLIE-31-P) scores from Baseline to 
Week 4 during the Maintenance Period (Visit 4) and the end of the 16-week Treatment 
Period (Visit 7) 
 Change in HADS scores from Baseline to Week 4 during the Maintenance Period (Visit 4) 
and to the end of the 16-week Treatment Period (Visit 7) 
 Time to return to baseline 28-day observable focal-onset seizure count during the 12-week 
Maintenance Period 
 Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications and hospitalizations 
2.4 
Safety variables 
2.4.1 
Primary safety variables 
The safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the entire study 
 Incidence of TEAEs leading to study withdrawal 
 Incidence of treatment-emergent serious adverse events (SAEs) during the entire study 
2.4.2 
Other safety variables 
Other safety variables are as follows: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
during the following periods: 16-week Treatment Period, 12-week Maintenance Period, 
4-week Titration/Stabilization Period, and 3-week Taper Period 
 Number of and reason for subjects requiring premature tapering due to TEAEs 
 Number of and reason for subjects requiring a dose reduction during the Stabilization Period 
due to TEAEs 
 Incidence of treatment-emergent SAEs during the following periods: 16-week Treatment 
Period, 12-week Maintenance Period, 4-week Titration/Stabilization Period 
 Changes in clinical laboratory test parameters (including hematology, blood chemistry, and 
urinalysis) 
 Changes in vital sign parameters (including pulse rate, systolic BP, diastolic BP, and 
respiratory rate) 
 Changes in 12-lead ECG parameters 
 Physical examination (including body weight) and neurological examination findings 
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 Changes in Psychiatric and Mental Status 
 Occurrence of valvular abnormalities or pericardial effusion changes or other significant 
abnormalities as identified by 2-dimensional Doppler echocardiogram at each assessment by 
central reader  
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the End of Treatment Visit (Visit 7) to end of 
the Taper Period (Visit 8) and end of the SFU Period (Visit 9 [30 days after the last IMP 
intake]). 
2.5 
Other variables 
2.5.1 
Pharmacokinetic variables 
Blood concentrations of PSL and metabolites will be determined from samples obtained in the 
study during the Titration and Maintenance Periods in order to investigate the following 
variables: 
 The population PK profiles of PSL and active metabolite 
 The exposure-response relationship for PSL and active metabolite 
Blood concentrations of PSL and active 
 will be used to derive 
PK-population parameters (using population-PK analysis). Subjects will be asked to provide 
these samples whenever possible. 
Blood concentrations of concomitantly administered AEDs will also be evaluated for evidence of 
drug-drug interaction with PSL at steady state. 
2.5.2 
Exploratory nonhereditary pharmacogenomics variables 
Where local regulations permit, blood samples will be collected at time points specified in 
Table 2-1 and stored for up to 20 years to allow for potential exploratory analyses of RNA, 
proteins, lipids, and metabolites biomarkers. Candidate serum biomarkers may also be explored. 
These samples will be used to support biomarker strategies related to epilepsy and drug response 
(including safety, efficacy, and tolerability of PSL and concomitant therapies). 
2.5.3 
Exploratory pharmacogenetic variables  
Additional blood samples will be collected at specific time points (Table 2-1) from subjects who 
consent to participate in the pharmacogenetic substudy to measure DNA biomarkers in order to 
assess: 
 Pharmacogenetic variants associated with drug-resistant epilepsy or AED resistance and drug 
response 
The samples may be used for further genetic analyses to understand drug-resistant epilepsy, 
AED resistance, and PK. The samples will be stored up to 20 years for the research purposes 
stated in this protocol.  
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2.5.4 
Exploratory pharmacokinetic evaluation 
Comparison will be made of blood concentration data of PSL and 
 derived 
from either conventional venous sampling or from the volumetric absorptive microsampling 
(VAMS) MITRA® technology. 
 Additionally, evaluation of PSL and major metabolites in plasma will be undertaken from 
trough samples. The collection of plasma samples for this comparison may cease during the 
course of the study based on periodic review of the data. 
2.6 
Study Design and Conduct 
2.6.1 
Study description 
EP0091 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
dose-finding study in adults (≥18 years of age) with drug-resistant epilepsy who continue to have 
uncontrolled focal-onset seizures despite treatment with at least 4 tolerated, appropriately chosen 
and used prior AEDs, including current AEDs (Kwan et al, 2010). All eligible subjects will have 
an epilepsy diagnosis and at least 4 observable focal-onset seizures per 28 days despite treatment 
with at least 1 to 3 AEDs with or without neurostimulation devices.  
Subjects should be educated to complete their diary entries accurately as per instruction.  
The study is composed of 4 periods (see Figure 2‒1) for a schematic diagram): 
Baseline Period (4 weeks) 
During the Screening Visit (Visit 1, Week -4), subjects will sign a written Informed Consent 
form (ICF) prior to the conduct of any study-related procedure or pre-treatment assessments, and 
the subject’s eligibility will be determined on the basis of the inclusion/exclusion criteria. 
Subject eligibility related to seizure frequency will be evaluated based on Investigator 
assessment of the subject report on historical seizure count during the 8 weeks prior to the 
Screening Visit (Visit 1) for the retrospective seizure baseline. Eligible subjects will be given a 
diary and receive instructions to further document seizures during the 4-week Baseline Period for 
a prospective seizure baseline. All subjects must have been on a stable dose of their present 
AEDs during the 8-week period prior to the Screening Visit (Visit 1). For the neurostimulation 
device (if applicable), the settings should be stable for 12 weeks prior to Screening Visit 
(Visit 1). Both should be stable throughout the study until the end of Treatment Period. The 
Investigator will be asked to send documentation of video-electroencephalogram (EEG) report as 
per instruction to the UCB Study Physician or representative for confirmation of eligibility 
before randomization of the subject. 
Treatment Period (16 weeks) 
The 16-week Treatment Period includes a 3-week Titration Period followed by a 1-week 
Stabilization Period and a 12-week Maintenance Period. Four weeks after the Screening Visit 
(Visit 1), subjects will return to the clinic for the Baseline Visit (Visit 2, Day 1). Subjects who 
continue to fulfill the inclusion and exclusion criteria will be randomized to 1 of the 5 treatment 
arms in a 1:1:1:1:1 ratio (random permuted blocks) to ensure the balance to 1 of the 5 treatment 
arms. Randomization will be stratified by current use of AEDs with binding to SV2A proteins 
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(LEV or brivaracetam) (Yes or No) and by region (North America, Europe, and Asia) at the time 
of randomization.  
After the Baseline Visit (Visit 2), subjects will return to the clinic for regular visits for the 
remainder of the Titration Phase. Investigational medicinal product will be increased 
approximately every 3 to 7 days depending on treatment arms. Subjects will be instructed to take 
the IMP in 2 equally divided doses, approximately 12 hours apart in the morning and evening. 
During the entire 16-week Treatment Period, the dose of concomitant AEDs and the settings for 
neurostimulation devices must remain stable. The dose of IMP should remain stable during the 
Maintenance Period. 
Subjects who cannot tolerate IMP prior to Week 3 will be withdrawn from the study. For 
subjects with tolerability issues experienced at their target dose, one fallback option to a 
predefined dose based on the randomized dose will be allowed during the Stabilization Period 
and at least 2 days prior to start of maintenance (Visit 4). The Study Physician or delegate should 
be consulted prior to use of the fallback option and the date as well as the reason for fallback will 
be recorded in the source documents and in the electronic Case Report form (eCRF). 
Fallback may be managed via an unscheduled visit. Fallback IMP packs will be allocated via the 
Interactive Response Technology (IRT). After fallback, the dose will be kept stable for the rest 
of the Maintenance Period. Further dose changes (ie, titration) are not allowed. Subjects, who are 
not able to tolerate the IMP during titration and after the fallback, will be tapered off IMP in a 
blinded fashion and will be withdrawn from the study. 
At Visit 4 (at the end of the Stabilization Period), subjects will enter a 12-week Maintenance 
Period during which they will receive their target dose (or their fallback dose, if applicable). 
During the entire 12-week Maintenance Period, the dose of IMP (target dose or fallback dose) 
and concomitant AEDs must remain stable. Subjects must return to the clinic for scheduled visits 
as outlined in Table 2-1. 
Subjects who complete the Maintenance Period will return for an End of Treatment Visit. 
Subjects who discontinue early from the study will return for an Early Discontinuation Visit 
(EDV). Subjects completing the Maintenance Period will have the opportunity to enroll into the 
OLE study, EP0093. They will be converted to the entry dose of the EP0093 study, 400mg/day. 
Subjects withdrawing from the study or deciding not to participate in the OLE study (EP0093) 
will be progressively tapered off the IMP. 
For subjects discontinuing the study: 
Taper Period (4 weeks) 
The 4-week Taper Period will be required for subjects who choose not to enroll in the OLE study 
or who discontinue prior to the end of the Maintenance Period. Subjects participating in the 
4-week Taper Period should be gradually tapered off the IMP over a 3-week period followed by 
1-week drug-free period. A faster or slower taper schedule than the suggested 3 weeks may be 
implemented, if medically necessary, as per the Investigator's medical judgement. Subjects will 
start their taper at the EDV/End-of-Treatment (Visit 7) and will return 1 week after last intake of 
IMP for the End-of-Taper Visit at Visit 8. Changes to concomitant AED(s) are not allowed 
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during the taper of PSL unless they are medically necessary as per the Investigator’s medical 
judgement to treat rebound seizures. 
Safety Follow-Up Period 
Safety follow up for subjects not entering the OLE will consist of 1 required visit, 30 days after 
the last IMP intake (Week 23 or sooner in case of early discontinuation) including an 
echocardiogram. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks. 
For subjects continuing to the OLE study: 
Conversion Period (3 weeks) 
The 3-week Conversion Period will be required for subjects who choose to enroll in the OLE 
study at the end of the Maintenance Period. Doses for subjects participating in the 3-week 
Conversion Period will be gradually adapted (increased or decreased) in a blinded way to reach 
the entry dose for the OLE. Subjects who took placebo during the maintenance phase will 
progressively receive PSL. 
2.6.2 
Study duration per subject 
The total duration of study per subject will be up to 27 weeks with a maximum of 19 weeks 
exposure to PSL. An additional follow-up echocardiogram will be performed at 6 months 
(±1 month) after the last IMP intake only for subjects exposed to IMP for more than 3 weeks and 
either discontinuing the study or not entering the OLE.  
The end of the study is defined as the date of the last SFU Visit (30-days after the last IMP 
intake) of the last subject in the study. Additionally, the reporting of SAEs will continue until the 
6-month follow-up echocardiogram. 
2.6.3 
Treatments to be administered 
All IMP will be administered in a double-blind manner. 
All subjects will be instructed to take 5 or 6 tablets containing either PSL or placebo bid, 
approximately 12h apart. The IMP should be dosed within 30 minutes after food when 
practically feasible. 
Subjects will be allocated to 1 of the following 5 treatment arms using the IRT system at the 
Randomization Visit (Visit 2): 
 Padsevonil 100mg/day (or 50mg bid) 
 Padsevonil 200mg/day (or 100mg bid) 
 Padsevonil 400mg/day (or 200mg bid) 
 Padsevonil 800mg/day (or 400mg bid) 
 Placebo 
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Table 2-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit b 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Call IRT to obtain subject 
number and dispensation of 
Subject Trial Card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of withdrawal 
criteria 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
General 
medical/procedures history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy history including 
etiology, diagnosis, 
surgery, and seizure history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of MRI 
(within 10 years) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of 
video-EEG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AED history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Habits and lifestyle 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Baseline c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Padsevonil (UCB0942) 
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Table 2-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit b 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
C-SSRS since last visit  c d 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
HADS  c 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
SSG  c 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
QOLIE-31-P  c 
  
X 
 
 
 
X 
 
 
X 
 
 
X 
 
CIWA-B c 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Vital signs e 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Body weight and height f 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
Physical examination g 
(XF = Full – XB = Brief) 
XF 
XB 
 
 
 
XB 
 
 
XF 
 
XF 
XB 
 
Neurological examination h
(XF = Full – XB = Brief) 
XF 
XB 
 
 
 
XB 
 
 
XF 
 
XF 
XB 
 
Psychiatric and Mental 
Status 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
12-lead ECG i 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
Echocardiogram j 
X 
 
 
 
 
 
 
X 
 
 
 
X k 
 
Blood/urine sample for 
clinical laboratory analyses 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
 
Blood sample for 
concomitant AED assay lm 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Blood sample for PSL PK 
analysis nm 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
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Table 2-1: 
Schedule of assessments 
 
BL 
Period 
(4 Wk) 
Treatment Period (16 Wk ±1 week from Visit 2) 
Taper/Conversion 
Period  
(3 to 4 Wk 
±1 week) a 
SFU  
(30 days 
after 
IMP 
intake) 
Unsch 
Visit b 
Titration Period 
(3 Wk ±1 week) 
(±3 days per week) 
Stab 
(1 Wk 
±3 days) 
Maintenance Period 
(12 Wk ±1 week) 
(±3 days per week) 
 
Visits 
V1 
V2 
BL 
TC 
V3 
TC 
V4 
V5 
V6 
V7  
(EDV/EOT) 
TC 
V8 
V9 
 
Assessments 
Start of  
Week x 
Wk -4 
D 1 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
 
Wk 19/20 
Wk 23 
 
Blood sample for DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for RNA 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Blood sample for 
proteins/lipids/metabolites 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Pregnancy test o 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Seizure evaluation  
(count & type) p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
(AEDs and non-AEDs) and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Recording of adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Health-related outcomes 
and HRU 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
IMP dispensing (IRT) 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
IMP accountability and 
return q 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
Entry and exit personal 
outcome interview r 
X 
 
 
 
 
 
X 
 
 
 
 
Study termination 
 
 
 
 
 
 
 
 
 
 
X 
X s 
 
 
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AED=antiepileptic drug; BL=Baseline; BP=blood pressure; CIWA-B=Clinical Institute Withdrawal Assessment-Benzodiazepines; C-SSRS=Columbia-Suicide 
Severity Rating Scale; DNA=deoxyribonucleic acid; ECG=electrocardiogram; EDV=Early discontinuation Visit; EEG=electroencephalogram; ; HADS=Hospital 
Anxiety and Depression Scale; HRU=healthcare resource utilization; IMP=investigative medicinal product; IRT=interactive response technology; 
MRI=magnetic resonance imaging; OLE=open-label extension; PK=pharmacokinetic; PSL=padsevonil; QOLIE-31-P=Quality of Life Inventory in Epilepsy-31-
P; RNA= ribonucleic acid; SFU=Safety Follow-Up; SSG=Seizure Severity Global Item; Stab=Stabilization Period; TC=telephone call; Unsch=unscheduled; 
V=visit; Wk=Week 
 
 a Taper Period, for subjects who choose to not enter OLE study EP0093, will last for 3 weeks plus 1 week of drug-free period. Conversion Period, for subjects 
who choose to enter OLE study EP0093, will last for 3 weeks. 
b At any time, the subject may have an additional study visit if the Investigator or the subject and/or legal representative deem it necessary. Appropriate 
assessments will be conducted in relation to the reason for the visit. 
 c Questionnaires to be completed by all subjects prior to any other study procedures at the visit, when possible. 
 d If an unscheduled visit is conducted due to safety or efficacy reasons, a C-SSRS assessment will be performed with the subject during the visit. If an 
unscheduled visit is conducted for reasons other than safety or efficacy concerns (eg, replacement of lost medication, repeated collection of a laboratory 
specimen due to collection, or analysis issues), a C-SSRS will not be required at these visits. 
 e Vital signs measured in supine position after 5 minutes of rest include pulse rate, respiratory rate, systolic BP, and diastolic BP.  
f Height will only be measured at Visit 1. 
 g Full physical examinations will assess cardiac and respiratory function via auscultation and review of the following body systems: general appearance; ear, 
nose, and throat; eyes; hair and skin; respiratory; cardiovascular; gastrointestinal; musculoskeletal; hepatic; neurological; and mental status. Brief physical 
examinations will include a review of the following body systems: general appearance (including mental status); skin; respiratory; cardiovascular; 
gastrointestinal; and hepatic. 
 h Brief neurological examination will include a general assessment and evaluation of reflexes, muscle strength and coordination, and cerebellar function. 
Full neurological examinations will include in addition, evaluation of cranial nerves, motor system (general muscle strength and tone), sensations in upper/lower 
extremities. 
 i Baseline ECG has to be scheduled and results received before Visit 2. An ECG at the SFU Visit will be performed only if abnormal at end of treatment or 
premature discontinuation visit. All ECG recordings will be performed with the subject resting in the supine position for at least 5 minutes. 
 j The echocardiogram will be conducted at Visit 1. Echocardiograms will be repeated at Visit 6 for subjects continuing the OLE study. Subjects discontinuing 
will have an echocardiogram 30 days after last IMP intake at the SFU Visit (except if performed at Visit 6). A repeat echocardiogram will be performed for 
subjects with a new finding, Grade 2 (moderate severity), or Grade 3 (severe severity).  
k An echocardiogram will also be performed 6 months after last IMP intake for subjects exposed to >3 weeks to IMP and discontinuing the study (but not for 
subjects with <3 weeks exposure). 
l AED samples will ideally be taken immediately prior to dose of concomitant medication on each occasion. If this is not possible, then the sample may be taken 
at any time after dose and the timing of sample in relation to dose should be kept the same (±1 hour) on each occasion for each subject. Therefore, the timing of 
visits for each subject when AED samples are collected should be scheduled approximately at the same time whenever possible. Assay of parent PSL and 
metabolites may be included in the AED panel of tests at Visits 6 and 7. 
m On Visits 6 and 7, unless the concomitant AED sample is within ±5 minutes of a scheduled MITRA sample for PSL assay, a separate, additional MITRA 
sample will be taken at same time as the concomitant AED blood sample. 
 n  Subjects are requested to provide blood samples for measurement of PSL and metabolites whenever possible. On Visits 3, 5, and 6, site personnel should 
obtain blood samples for measurement of random PSL concentrations at any time between IMP intake and record accurately the time of last IMP intake and the 
time of sample collection. On Visits 4 and 7, blood samples for measurement of sparse PK profiles will be collected as follows: immediately before IMP intake 
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(maximum 15 minutes before intake) and then 3 times after (between 30 minutes and 3 hours after IMP intake), taken at least 30 minutes apart. All samples may 
be taken either at home or in the site or partly at home and partly at the site.  
 o For all female subjects, serum pregnancy test at Visits 1 and 7 (in case the subject enters into the OLE study) and where applicable. Urine pregnancy test will 
be used at other visits for female subjects of childbearing potential. 
 p Seizure counts are collected on the subject’s daily record card on a daily basis. 
 q At each visit following an IMP dispensation, IMP should be presented to check for compliance. 
r Subject entry interview will be performed on a voluntary basis either at Visit 1 or Visit 2. Subject/caregiver exit interview/survey will be performed on a 
voluntary basis either at Visit 6 or Visit 7. 
s The SFU Visit will be performed only for subjects who do not enter EP0093. 
 
 
 
 
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Figure 2‒1: Study design 
 
 
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2.7 
Determination of sample size 
The sample size was calculated based on achieving 90% power to observe a statistically 
significant result for either the 400mg bid and 200mg bid or 200mg bid and 100mg bid doses 
when compared to placebo, for a change from Baseline of the log-transformed (ln x +1) 28-day 
adjusted seizure frequency. Multiplicity is controlled for using the Hochberg step up procedure. 
The log-reduction from Baseline in seizure frequency was assumed to be 0.195 for placebo and 
0.492, 0.670, 0.754, and 0.780 for the 50mg bid, 100mg bid, 200mg bid, and 400mg bid doses of 
PSL, respectively. A common SD of 0.985 was assumed. These estimates are based on prior 
experience in epilepsy together with the EP0069 study results. 
With power of 90%, a 2-sided Type-1 error of 5%, and all dose groups of the same size, 
80 subjects are required per arm, giving a total of 400 subjects. 
Assuming a screening failure rate of approximately 20%, it is anticipated to enroll around 
500 subjects and randomize 400 subjects in this study. 
The study is also powered to give over 80% power to observe a statistically significant result for 
the 75% response rate. For the 75% responder rate, assumptions were a 0.121 responder rate for 
placebo and corresponding responder rates of 0.233, 0.301, 0.332, and 0.342 for the 50mg bid, 
100mg bid, 200mg bid, and 400mg bid doses of PSL, respectively. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS Version 9.3 or higher. All tables and listings will use Courier New 
font size 9. 
Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical variables, the number and percentage of subjects in each category will be presented. 
Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will 
be displayed for zero counts, and no decimal will be presented when the percentage is 100%. For 
continuous variables, descriptive statistics will include number of subjects with available 
measurements (n), mean, SD, median, minimum, and maximum.  
Decimal places for descriptive statistics will always apply the following rules: 
• 
“n” will be an integer 
• 
Mean, SD, and median will use one additional decimal place compared to the original data 
• 
Minimum and maximum will have the same number of decimal places as the original value. 
Unless otherwise specified, statistical tests of efficacy variables will be presented as two-sided p 
values rounded to three decimal places. P-values less than 0.001 will be presented as “<0.001” 
and p-values greater than 0.999 will be presented as “>0.999.” Statistical comparisons will be 
two-sided and will be performed at the 0.05 level of significance. 
A complete set of data listings containing all documented data as well as calculated data (e.g., 
change from Baseline), as applicable, will be generated. 
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Treatment groups will be displayed as: Placebo, PSL 50 mg bid, PSL 100mg bid, PSL 200mg 
bid, and PSL 400mg bid.  
Log-transformation is based on natural logarithm. For analyses on log-transformed values, model 
estimates will be back-transformed to anti-log space for table presentation. See Section 8.1.1 for 
details. 
Data collected at scheduled visits will be included the by-visit summary. Data collected at 
unscheduled visits will not be included in the by-visit summary, but will be considered when 
determining the Last Visit, minimum, and maximum post-Baseline values during the Treatment 
Period. Data collected on Visit 8 will be summarized separately for subjects in the Conversion 
Period versus the Taper and Safety FU Period. 
In general, all CRF data will be presented in the subject listings.  
3.2 
General study level definitions 
3.2.1 
Initial processing of diary data for seizure frequency 
Subjects are instructed to record in their diary all types of seizures that occur, after each seizure 
or at least once a day. The investigator will assess and confirm the seizures according to the 
ILAE codes (ILAE Classification of Epileptic Seizures, 1981) and record the seizure types and 
frequency in the eCRF/diary. With regard to cluster seizures, investigators are to report the 
number of cluster episodes rather than reporting the estimated number of individual seizures. 
3.2.2 
Analysis time points 
3.2.2.1 
Relative day 
Study day for each subject is calculated relative to the date of the first administration of study 
drug. The date format in the study is dd-MMM-yyyy. Relative day is calculated as the current 
date in the study minus the date of first dose of study drug for days prior to the first dose of study 
drug, and the current date minus the date of first dose of study drug plus 1 for days on or after the 
day of first dose of study drug and prior to or on the day of last study drug dose (e.g., the day of 
first dose will be Day 1 and the day prior to first dose will be Day -1). For days after the last dose 
of study drug, relative day will be calculated as the current date minus the date of last dose of 
study drug and including a “+” to denote posttreatment days (e.g., the day after the last dose will 
be Day +1).  
Similarly, relative days for an event or measurement occurring before a reference date (generally 
the date of the first dose of study drug) are calculated as follows:  
 Relative Day = (Event Date-Reference Date) 
Relative days for an event or measurement occurring on or after the reference date to the last day 
of dose administration are calculated as follows:  
 Relative Day = (Event Date-Reference Date) + 1  
For events or measurements occurring after the date of last dose of study drug (as defined 
above), the relative day will be calculated with the date of last dose administration as reference. 
Relative day in this case will be prefixed with ‘+’ in the data listings and will be calculated as 
follows:  
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 Relative Day = + (Event Date-Reference Date) 
3.2.2.2 
End of the 16-week treatment period 
The end of the 16-week overall treatment period will be either the date of Visit 7 for subjects 
completing the Treatment Period, or the date of the early discontinuation visit (EDV), for 
subjects who discontinued during the Treatment Period. If a subject does not have a 
Visit 7/EDV, then the date of the final contact will define the end date of the Treatment Period.  
3.2.3 
Analysis periods 
The start and end dates of each analysis period (following the study design) are used for the 
classification of efficacy and safety data. The exact start and end of each of these periods is 
described for calculation purposes in Table 3‒1. Note that measurements obtained from diaries 
returned on the start date of the Titration and Stabilization Period would be included in the 
Baseline Period calculations. Refer to Section 3.3.1.  Similarly, measurements from diaries 
returned on the start date of a subsequent period would be included in calculations for the 
previous period. 
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Table 3‒1: 
Start and end of EP0091 analysis periods 
Analysis Period 
 
Details 
Description 
Start 
End 
Baseline 
(Week -4) 
Date of informed 
consent at Visit 1  
Date of the day before the 
date of Visit 2. 
 
This is an approximate 28-day 
period for calculation of Baseline 
seizure frequencies. Study drug is 
dispensed, and first dose is 
generally taken the day of the 
Baseline Visit (Visit 2, Day 1). 
Note the pre-dose assessments will 
also be included in the Baseline 
Period.  
Titration and 
Stabilization* 
The date of the 
Baseline Visit, 
(Visit 2, Day 1).  
The date of the day before 
Visit 4 or the end of the 
treatment period if the 
subject has discontinued 
prior to Visit 4. 
For evaluation purposes, if results 
are presented by analysis period, the 
Titration and the Stabilization 
interval will be considered together 
(approximately 4 weeks in total). 
Titration is a period of dose 
increases to reach the protocol 
specified dose. Stabilization is an 
approximate week-long interval to 
stabilize at the target dose level. 
During stabilization the dose may 
be adjusted once (i.e. to a fallback 
dose).  
Maintenance* 
The date of Visit 
4. 
The date of Visit 7 or the end 
of the treatment period if the 
subject has discontinued 
prior to Visit 7. 
This is a 12-week period where the 
subject remains on the randomized 
target dose (or fallback dose, if 
applicable).  
16-week Treatment 
Period* 
The date of the 
Baseline visit 
(Visit 2)  
The date of Visit 7 or the end 
of the treatment period if the 
subject has discontinued 
prior to Visit 7. 
Titration and Stabilization Period 
and Maintenance Period combined.  
Conversion 
The date of the 
day after Visit 7 
The date of Visit 8.  
This is a 3-week period of dose 
conversion to enable the subjects to 
enroll into the OLE study EP0093. 
Taper and Safety 
Follow-up 
The date of the 
day after Visit 
7/EDV or the 
date of day after 
Visit 8 if the 
subject tapered 
after conversion 
The date of final contact.  
Subjects who withdraw from the 
study or decide not to participate in 
the OLE study will be tapered off 
the IMP during a 3-week period 
followed by a 1-week drug-free 
period.  A SFU visit will be 
performed 30 days after the last 
IMP intake. 
OLE=open-label extension; SFU=Safety Follow Up 
* Only seizure data prior to and on the date of last dose of study medication will be included in the analysis. 
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3.2.4 
Mapping of assessments performed at early discontinuation 
Unlike other scheduled visits, an early discontinuation visit (EDV) doesn’t have a predetermined 
visit window and can occur at any days during the study. If an EDV occurs at the day of a 
scheduled visit, assessments (in-clinic safety assessments such as vital signs, ECGs, and blood 
collection for clinical laboratory assessments) should correspond to that scheduled visit. 
Assessments at an EDV that occurs on a day between two scheduled visits will be assigned to the 
next scheduled visit. All other assessments (such as questionnaire and PK samples) collected on 
an EDV will not be mapped.  
In the by-visit summary tables, only nominal (scheduled) visits where the assessment is 
scheduled will be included. For example, if a subject had an EDV after Visit 4 and before Visit 
5, the applicable assessments will be mapped to Visit 5 (ie, the next scheduled visit). Vital signs 
and ECGs collected at the EDV will be summarized under Visit 5 in the by-visit summary tables. 
However, Visit 5 will not be included in the by-visit summary tables for the clinical laboratory 
assessments as lab assessments are not scheduled on Visit 5. Unscheduled visits will not be 
mapped to scheduled visits. In the subject listing, data will be presented under the actual visits, 
including EDV and unscheduled visits. 
Seizure data collected by diary are associated with periods defined within the study and as such 
need no mapping to visits. If a subject withdraws between visits an effort is made to recover all 
diary records for use in calculation of seizure frequencies. 
3.2.5 
Last Visit during the Treatment Period 
The Last Visit for an assessment is the last non-missing assessment during the Treatment Period. 
All scheduled and unscheduled assessments within the Treatment Period will be considered. Last 
Visit will be determined separately each study assessment. Last Visit during the Treatment 
Period will be included in the by-visit summary unless noted otherwise. 
3.3 
Definition of Baseline values 
3.3.1 
Baseline for variables based on seizure count 
Baseline values for seizure frequency variables will be derived from diary data recorded by the 
subject during the 4-week Baseline Period. This diary is collected at the Baseline Visit (Visit 2, 
Day 1). The Baseline value will be the seizure frequency per 28 days during the Baseline Period 
and is defined as the number of seizures standardized to a 28-day baseline period. It is computed 
for each subject as the number of seizures recorded over the subject’s baseline diary period, 
divided by the subject’s total number of non-missing days in that period, multiplied by 28. See 
details for calculation of seizure frequency in Section 8.1.1.1. 
3.3.2 
Baseline for other variables 
Unless otherwise specified, the last valid measurement before the first study medication 
administration will be used as the Baseline value, including the pre-dose assessments on the day 
of Visit 2. Unless otherwise stated, if a Baseline visit measurement is missing, and a Screening 
visit measurement is available, the most recent Screening value will be utilized as Baseline. Both 
scheduled and unscheduled Screening visits will be considered. If a scheduled Baseline 
assessment is taken on the same day as first administration of study medication and no time is 
collected, it will be assumed to have been taken prior to study medication. The time point used 
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for Baseline will be determined separately for each variable. An exception is blood pressure, 
where a complete set of both systolic and diastolic blood pressure should be selected for 
baseline. Baseline values for PK evaluations included in this SAP is defined in Section 9. 
3.4 
Protocol deviations 
Important protocol deviations (IPD) are those deviations from the protocol identified by the 
study team as important which will be summarized in the clinical report, in accordance with ICH 
E3.  The criteria for identifying important protocol deviations will be defined within the 
appropriate protocol-specific document at study start. All protocol deviations will be reviewed 
periodically through the study as part of the ongoing data cleaning process and those identified 
as important will be documented prior to unblinding and integrated into the clinical database.  
3.5 
Analysis sets 
Primary and secondary efficacy endpoints will be analyzed using the Full Analysis Set (FAS). 
Sensitivity analysis on the primary endpoints will be performed using the Per Protocol Set (PPS). 
Safety variables will be analyzed using the Safety Set (SS). Pharmacokinetic data summaries will 
use the PK Per Protocol Set (PK-PPS) or AED PK Per Protocol Set (AED-PK-PPS). 
These analysis sets are described below. 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) consists of all subjects who have given informed consent.  
3.5.2 
Randomized Set 
The Randomized Set (RS) consists of all subjects randomized into the study; this includes all 
subjects who have a randomization number issued by the IRT, even if misrandomized. 
3.5.3 
Safety Set 
The SS consists of all subjects who were administered at least 1 dose or a partial dose of IMP, 
based on the first dose date from the First Administration of Study Medication CRF. The SS will 
be used to summarize and analyze all safety variables. In case of dosing administration error, 
summaries and analyses using the SS will be conducted according to actual treatment 
administered.  
3.5.4 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects in the RS who were administered at least 1 
dose or a partial dose of IMP and have Baseline and at least 1 post-Baseline seizure frequency 
data during the Treatment Period.  In case of dosing administration error, or change in treatment 
dose, summaries and analyses will be conducted according to randomized treatment and not the 
actual treatment received. The FAS will be the primary analysis set for all efficacy summaries 
and analyses. 
3.5.5 
Per Protocol Set 
The Per Protocol Set (PPS) is a subset of the FAS, consisting of those subjects who had at least 1 
post-Baseline efficacy measurement and who had no major protocol deviation affecting the 
primary efficacy variable, as confirmed during a pre-analysis data review meeting, conducted 
prior to study unblinding. Criteria will be developed and documented (in a separate document) 
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prior to study unblinding to identify subjects with major protocol deviations so that they may be 
excluded from the PPS. The PPS will be used for sensitivity analyses of selected efficacy 
endpoints as described later in the SAP. 
3.5.6 
Completer Set 
The Completer Set is a subset of the FAS, consisting of those subjects who completed the 16-
week treatment period.  
3.5.7 
Other analysis sets 
3.5.7.1 
Pharmacokinetic Set 
The Pharmacokinetic Set (PKS) consists of those subjects who provide at least 1 PSL plasma 
concentration measurement. Note that it is possible for a subject in the PK-Set to have missing 
data for some evaluations (such as of the primary 
). 
3.5.7.2 
Pharmacokinetic Per-Protocol Set (PK-PPS)  
A PK Per Protocol Set (PK-PPS) will be a subset of the PKS and identified for active treatment 
groups, which would exclude subjects or PK sample data points with major deviations that could 
impact PK evaluations e.g. when there is evidence that the sample collected is not at steady-state 
due to missing doses, dose alterations or interacting concomitant medications, etc. Subjects or 
PK sample data points to be excluded from this PK-PPS, will be identified during a pre-analysis 
data review.  
3.5.7.3 
AED Pharmacokinetic Per-Protocol Set (AED-PK-PPS)  
An AED PK Per Protocol Set (AED-PK-PPS) will be identified, which would exclude subjects 
or AED PK sample data points with major deviations that could impact AED PK evaluations. 
Subjects or AED PK sample data points to be excluded from this AED-PK-PPS, will be 
identified during a pre-analysis data review.  
3.6 
Treatment assignment and treatment groups 
At Baseline, eligible subjects will be randomly assigned to treatment regimens as described in 
Section 2.3. Prior to unblinding, the study team should identify and review all cases in which 
subjects received an incorrect study drug (dosing errors resulting in treatment crossover). Note 
that while dispensing errors can be identified prior to unblinding, actual treatment crossovers can 
only be identified via IRT report (only identifying the subject number), or after unblinding.  
The FAS will be the primary analysis set for all efficacy summaries and analyses. Treatment 
crossover Subjects (including any subjects with dosing errors) will be analyzed for efficacy 
according to their randomized treatment assignment and not the actual treatment received.  
Safety analyses will be based on the SS. It is expected that subjects will receive the randomized 
treatment and be analyzed according to that assigned treatment. However, if a subject were to 
experience a dosing error resulting in treatment crossover, incorrectly treated subjects will be 
evaluated during the blinded data evaluation meetings to assess the potential impact of such 
cases and any special considerations for statistical analyses. 
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3.7 
Sites pooling strategy 
Since “site” per se is not considered as a factor in the planned analyses there is no strategy in 
place for pooling data from sites with low number of patients to another particular site. Data will 
be combined across all sites within region, according to the specified analysis. To ensure at least 
5 subjects in each region in the FAS at each treatment group, Japan will be pooled with North 
America to form a non-Europe region for the efficacy analyses.   
3.8 
Coding dictionaries 
All prior and concomitant medications other than study drug will be classified by World Health 
Organization WHO Anatomical Therapeutic Chemical (ATC) Classification, presenting 
Anatomical Main Group (ATC Level 1), Pharmacological Subgroup (ATC level 3), and 
preferred term, using Version SEP/2015 or higher of the World Health Organization Drug 
Dictionary (WHO-DD). Coding will be performed in accordance with UCB standard operating 
procedures (SOP). 
Medical history and AEs will be coded by primary system organ class (SOC), high level term 
(HLT) and preferred term (PT) using version 19.0 or higher of Medical Dictionary for 
Regulatory Activities (MedDRA®) according to UCB Standard Operating Procedures (SOP). 
3.9 
Changes to protocol-defined analyses 
Not applicable; there have not been any changed to protocol defined analyses. 
4 
STATISTICAL/ANALYTICAL ISSUES 
General statistical and analytical issues are provided in the following sections. 
4.1 
Adjustments for covariates 
The primary and selected efficacy analyses will be adjusted for baseline log-transformed seizure 
frequency and for the stratification factors: 
 Current use of AEDs with binding to SV2A proteins (LEV and/or brivaracetam): Yes or No 
 Geographical Region: Investigative sites have been identified in the following regions and 
countries at the time of this SAP amendment. More regions and/or countries may be 
identified and will be included in the analyses in accordance to the randomization strata:  
- 
Europe (Australia, Belgium, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, 
Lithuania, Poland, Portugal, Slovakia, Spain, Turkey, and United Kingdom) 
- 
North America (Canada, Mexico, and United States) 
- 
Asia (Japan) 
To ensure at least 5 subjects in each region in the FAS at each treatment group, Japan will be 
pooled with North America to form a non-Europe region for the efficacy analyses.   
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4.2 
Handling of dropouts or missing data 
4.2.1 
Handling of missing data in seizure frequency 
Unless noted otherwise, the imputation described below will be applied to seizure frequency. 
The responder status will be determined based on the imputed seizure frequency data. Sensitivity 
analyses for missing data are described in Section 8.1.2 for the primary efficacy variable.  
4.2.1.1 
Missing data caused by missing seizure diary 
Seizure frequency will be computed over non-missing diary days. Diary compliance evaluation 
is described in Section 7.2. Subjects with diary data deemed unacceptably incomplete (during 
blinded data review) for the primary efficacy variable will be excluded from the PPS. 
If seizure type is known but the number of seizures is unknown, the number of seizures will be 
imputed using the median for the same seizure type (daily seizure number > 0) during the same 
analysis period (baseline or treatment period). Otherwise, the missing seizure number will be 
imputed using the count of next higher level of seizure type. 
 
4.2.1.2 
Missing seizure data caused by discontinuation 
 Seizure frequency by analysis period: 
For subjects who prematurely discontinued during the Treatment Period, the calculation of 28-
day adjusted seizure frequency over the Treatment Period will be based on available seizure 
diary up to the end of the Treatment Period.  
If a subject had less than 14 days of seizure data during the Titration and Stabilization Period, 
seizure frequency during the Treatment Period will be calculated based on the last 28 days with 
seizure data, including the data in the Baseline Period.  For subjects who prematurely 
discontinued the study, the following methods will be applied to obtain a seizure frequency 
estimate for the Maintenance Period: 
- 
Subjects who discontinued during the Titration and Stabilization Period: If a subject had at 
least 14 days of seizure data, seizure frequency will be calculated using all available data in 
the Titration and Stabilization Period and carry forward for the Maintenance Period. If a 
subject had less than 14 days of seizure data, seizure frequency will be calculated based on 
the last 28 days with seizure data, including the data in the Baseline Period and carry forward 
for the Maintenance Period.  
- 
Subjects discontinued during the Maintenance Period: If a subject had at least 28 days of 
seizure data during the Maintenance Period, seizure frequency will be calculated using all 
available data in the Maintenance Period. If a subject had less than 28 days of seizure data 
during the Maintenance Period, seizure frequency will be calculated based on the last 28 days 
with seizure data, including the data in the Titration and Stabilization Period. 
 Seizure frequency by 4-week interval 
Seizure frequency by 4-week interval will be calculated for the sensitivity analyses (Section 
8.1.2.2 ) and secondary efficacy analyses (Section 8.3.2.1). Seizure frequency during a 4-week 
interval will be calculated as long as seizure data are available for at least 1 day in the given 
interval. No imputation will be applied for discontinuations.  
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4.2.2 
Handling of missing data for adverse events and concomitant 
medications 
For analyses of AEs and concomitant medication usage, a complete date must be established to 
correctly identify the AE or medication as occurring during treatment or not. In the event of 
completely missing dates, or if ambiguity or incomplete data makes it impossible to determine 
whether a medication was concomitant, or an adverse event was treatment emergent, the 
medication will be considered as concomitant or the adverse event will be considered treatment 
emergent.  
For purposes of imputing missing components of partially-reported start and stop dates for AEs 
and for medication use, the algorithms listed below will be followed. Start and stop dates of AEs 
or concomitant medication will be displayed as reported in the subject data listings (i.e., no 
imputed values will be displayed in data listings).  
Partial AE and concomitant medication start dates will be imputed as described in the following 
sections. 
4.2.2.1 
Imputation of Partial Start Dates  
 If only the month and year are specified and the month and year of first dose of IMP is not 
the same as the month and year of the start date, then use the 1st of the month 
 If only the month and year are specified and the month and year of first dose of IMP is the 
same as the month and year of the start date, then use the date of first dose of IMP 
 If only the year is specified, and the year of first dose of IMP is not the same as the year of 
the start date, then use the 1st of January of the year of the start date 
 If only the year is specified, and the year of first dose of IMP is the same as the year of the 
start date, then use the date of first dose 
 If the start date is completely unknown and the stop date is unknown or not prior to the date 
of first dose of IMP, then use the date of first dose of IMP. 
 If the imputed start date is after the known stop date, set the start date to be the same as the 
stop date.  
4.2.2.2 
Imputation of Partial Stop Dates 
 If only the month and year are specified, then use the last day of the month 
 If only the year is specified, then use December 31st of that year 
 If the stop date is completely unknown, do not impute the stop date 
4.2.3 
Handling of missing data for history of epileptic seizures and 
diagnosis of epilepsy 
4.2.3.1 
Incomplete dates for first epileptic seizure 
To calculate the time since the first seizure relative to the date of Visit 1 or age at onset of first 
seizure, January 1st of the year will be imputed for the date of birth, as only year of birth is 
collected on CRF. And a complete date will be imputed for partially missing first seizure date as 
following: 
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 Missing the day, but month and year present, then assign the 1st day of the month. 
 Missing the day and month, but year present, then assign January 1st of the year. 
 Completely missing, no imputation will be done. 
4.2.3.2 
Incomplete dates for last epileptic seizure 
To calculate the time since last seizure relative to the date of Visit 1, a complete date will be 
imputed for partially missing last seizure date as following: 
 Missing the day, but month and year present, then assign the 1st day of the month. 
 Missing the day and month, but year present, then assign January 1st of the year or Visit 1, 
whichever is later in the year. 
 Completely missing, no imputation will be done. 
4.2.3.3 
Incomplete dates for first epilepsy diagnosis 
Month and year of the first epilepsy diagnosis are collected on the CRF. To calculate the 
duration of epilepsy derived from the date of first diagnosis relative to the date of Visit 1, or age 
at epilepsy diagnosis, January 1st of the year will be imputed for the date of birth, as only year of 
birth is collected on CRF. And a complete date will be imputed for partially missing date of the 
first epilepsy diagnosis as following: 
 Month and year present, then assign the 1st day of the month or the date of the first seizure, 
whichever is later in the month. 
 Missing the month, but year present, then assign January 1st of the year or the date of the first 
seizure, whichever is later in the year. 
 Both month and year are missing, no imputation will be done. 
4.3 
Interim analyses and data monitoring 
There is no formal interim analysis planned for the study. 
A Data Monitoring Committee (DMC) will be formed to monitor the ongoing safety of the study 
through periodic review of data summaries. The general scope of DMC activities is presented in 
the protocol and will be described in detail in a separate DMC Charter. Preparation of data 
summaries for review by the DMC will be described in a separate DMC SAP. 
4.4 
Multicenter studies 
In general, efficacy and safety summaries and analyses will be presented across investigative 
sites, countries and regions. When applicable, analyses will include adjustment for region, which 
is one of the stratification factors. 
4.5 
Multiple comparisons/multiplicity 
For the primary efficacy variables, statistical testing will be based on the comparison of 400mg 
bid, 200mg bid and 100mg bid PSL groups versus placebo. Type 1 error will be controlled by the 
Hochberg step-up procedure within SAS® Proc Multtest. Hochberg procedure orders the p-
values from the largest to the smallest. The significance level for the k-th step is given by 0.05/k. 
More specifically, the largest p-value will be compared to 0.05. If it is smaller than 0.05, we will 
stop the testing and conclude significance for all 3 comparisons; otherwise we will move to the 
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second highest p-value. The second largest p value will be compared to 0.025 (=0.05/2). If it is 
smaller than 0.025, we will stop and conclude significance for this comparison and the 
subsequent one that produced p-values smaller than the current one; otherwise we will move to 
the smallest p-value. The smallest p-value will be compared to 0.0167 (0.05/3). If it is smaller 
than 0.0167, we will conclude a significant difference between the dose and the placebo; 
otherwise, stop and no comparison is significant.  
If the 3 higher doses are all statistically different from the placebo, the 50mg bid PSL group will 
be compared to placebo. Because this follows a gatekeeping procedure, testing will be conducted 
at the 0.05 level (2-sides). If the p-value is smaller than 0.05, we will conclude 50mg bid is also 
significantly different from the placebo.  
4.6 
Use of an efficacy subset of subjects 
The FAS will be used as the primary analysis set for all efficacy analyses. Analyses using the 
PPS will also be performed for the FDA and European agency primary efficacy variables. The 
PPS analyses will provide additional information on efficacy evaluations and will describe 
findings in a subset of subjects who adhered more closely to the study protocol. No other 
efficacy subsets are defined for statistical analyses.  
4.7 
Active-control studies intended to show equivalence 
This study is not an active controlled study intended to show equivalence. 
4.8 
Examination of subgroups 
The primary efficacy variable will be evaluated for subgroups of interest including:  
 Age (18 to <65 years, ≥65 years): less than 5 subjects in ≥65 years subgroup in the FAS at 
each treatment group, therefore the subgroup analysis will be omitted. 
 Gender 
 Region (Europe, North America, and Asia): To ensure at least 5 subjects in each region in the 
FAS at each treatment group, Asia (Japan) will be pooled with North America. The subgroup 
analyses will be performed for Europe vs non-Europe.  
 Use of AEDs with binding to synaptic vesicle 2A (SV2A) proteins (levetiracetam [LEV] or 
brivaracetam [BRV], Y/N).  
These evaluations will be descriptive; no statistical testing of treatment-by-subgroup interactions 
nor statistical testing of treatment effects within subgroups will be carried out.  No subgroup 
evaluations are planned for safety variables. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
Screen failure data of screened subjects who did not meet study eligibility criteria are collected 
on the Study Termination Screen Failure CRF (dates of screen failure and last contact and reason 
for screen failure).  
Disposition data of randomized subjects are obtained from the Study Termination CRF. 
Variables include date of last administration of study medication, date of premature study 
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termination, date of final contact with subject, subject status at study termination, primary reason 
for premature study termination (as listed on the CRF), and if the study blind was broken (Y/N 
and date, if applicable).  
Disposition of subjects (ES) will be listed by region, country and investigative site. A listing will 
also be provided for study discontinuation (RS), and for study visit dates (RS). 
Summaries of the numbers of screened subjects and reasons for screen failures will be produced 
overall for the ES.   
The disposition of the ES will be summarized overall and by region, country and site presenting 
the dates of first subject in (first enrolled) and last subject out, number of subjects screened, and 
number of subjects included in the each of the RS, FAS, SS, PPS, and PK-PPS.   
The disposition of the SS will be presented as the number and percentage of subjects who 
completed the study and of subjects who discontinued the study, including a breakdown of the 
primary reason for discontinuation. Of note, the corresponding table is required for data 
transparency reporting.  Subjects who enrolled into EP0093 will also be summarized. The 
number of subjects completing and discontinuing with associated reasons for discontinuation at 
each visit of the Titration and Maintenance Periods will be displayed for the SS. 
In addition, the numbers and percentages of subjects (SS) entering and completing each of the 
following analysis periods: (Titration and Stabilization Period, Maintenance Period, Conversion 
Period, and Taper and SFU Period) will be summarized by treatment group and overall. The 
same summary will be repeated by region.  
The number and percentage of subjects in the SS who discontinued due to AE categorized by 
serious fatal, non-fatal, and non-serious fatal AE incidence will also be presented by treatment 
group and overall. Of note, the corresponding table is required for data transparency reporting.   
5.2 
Protocol deviations 
All IPDs (defined in Section 3.4) will be listed by treatment group and subject, and will include 
at a minimum, deviation type (as collected under the important deviation collection plan), 
deviation number, and deviation description.  
A summary of number and percentage of subjects with an IPD will be produced by treatment 
group and overall for the RS. The summary will be overall (any IPD) and by type of deviation.  
As described in Section 3.5, subjects may be excluded from the PPS based on major protocol 
deviations determined to have a potential effect on primary efficacy variables. Similarly, subjects 
with certain major protocol deviations may be excluded from the PK-PPS. Criteria for exclusion 
of subjects from the PPS or PK-PPS will be defined in a separate document developed in 
conjunction with a formal data review plan. To the extent feasible, rules for identifying major 
protocol deviations will be defined without review of the data and without consideration of the 
frequency of occurrence of such deviations. Important protocol deviations will be reviewed as 
part of the ongoing data cleaning process prior to database lock to identify those that are major 
and confirm exclusion from analysis sets. After all data have been verified/entered into a 
database and prior to database lock, a final data evaluation meeting will take place. The PPS will 
be confirmed at this time.  
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A by-subject listing of subjects excluded from each of the analysis datasets (for SS, FAS, PPS, 
and PK-PPS) will be prepared for the RS. The listing will include the categorized reason for 
exclusion as well as the specific reason. 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS  
By-subject listing will be produced for the ES for the demographics and for the RS for other 
baseline characteristics. All demographic and Baseline characteristics will be summarized 
descriptively for the FAS by treatment group and overall unless noted otherwise. The summary 
tables in Section 6 will be repeated by region.  
6.1 
Demographics 
Data collected on the Demographic CRF at the Screening Visit or at Baseline, include the date of 
birth, age (in years), sex (male, female), race (all categories on the CRF), ethnicity (Hispanic or 
Latino, not Hispanic or Latino), ethnic sub-group (Japanese, not Japanese), height (in cm), and 
weight (in kg). Demographics will be summarized for the RS, SS, and FAS. 
Descriptive statistics presentation will adhere to the guidelines in Section 3.1.  In addition, the 
following age categories will be summarized:  
 ≤18, 19 - <65, and ≥65 years 
 18 - <65, 65 - <85, and ≥ 85 years 
Body mass index (BMI) and BMI categories (<18.5, 18.5 to <25, 25 to <30, 30 to <40, 
≥40kg/m2) will also be summarized.  
Of note, the demographic table is required for data transparency reporting. The age categories are 
also required for the data transparency reporting.  
6.2 
Other Baseline characteristics 
 Randomization is stratified by region (Europe, North America, and Asia), and by current use 
of AEDs with binding to SV2A proteins, such as LEV and/or BRV (yes or no). The 
percentages of subjects in each stratum for each stratification factor will be summarized for 
the RS. 
 Lifestyle information (alcohol and illicit drug use) obtained at the Screening Visit (Lifestyle 
CRF) will be listed for the RS. These variables will be summarized descriptively (number 
and percent of subjects in each category) for the SS. 
6.3 
Medical history and concomitant diseases 
6.3.1 
Medical history and ongoing medical conditions 
Medical history and ongoing medical conditions will be listed and summarized for the SS by 
MedDRA system organ class (SOC) and preferred term (PT). The start date (month and year 
only) and end date (or ongoing if applicable) will be included in the listing. Epilepsy history will 
not be included in these tables. Procedure history will be listed separately by the procedure 
reported term.  
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6.3.2 
Procedure history 
Procedures or surgeries prior to study entry will not be summarized and will only be provided in 
subject data listing. 
6.3.3 
Medical history of epilepsy 
The history of epilepsy data will be listed for all subjects in the RS. The following summaries 
will be produced by treatment group and overall using the FAS unless otherwise specified: 
6.3.3.1 
Etiology of epilepsy 
The number and percentage of subjects with each type of etiology as specified in the Etiology of 
Epilepsy CRF will be presented. 
6.3.3.2 
Epilepsy surgery status 
Epilepsy surgery status parameters are collected on the Epilepsy Surgery Status CRF. The 
number and percentage of subjects who are evaluated for epilepsy surgery and in each of the 
outcome category will be presented.  
6.3.3.3 
Epileptic seizure profile 
Epileptic seizure profile is based on the historical seizure types reported by the subject on the 
ILAE Seizure Classification History form. The number and percentage of subjects experiencing 
each seizure type at any time in the past will be summarized. 
6.3.3.4 
Focus localization 
The number and percentage of subjects with each category of focus localization (unknown, 
frontal, temporal, parietal, occipital) will be summarized. Subjects may be counted in more than 
one category of focal localization. 
6.3.3.5 
History of epileptic seizures and diagnosis of epilepsy 
History of epileptic seizures are collected on the History of Epileptic Seizures CRF. The 
summary will present the number and percentage of subjects with a history of status epilepticus, 
the number and percentage of subjects with a history of withdrawal seizures, and quantitative 
summaries of time since the first seizure relative to the date of Visit 1, time since last seizure 
relative to the date of Visit 1, and age at onset of first seizure. 
The date of diagnosis of epilepsy is collected on Diagnosis of Epilepsy CRF. The duration of 
epilepsy will be derived from the date of first diagnosis relative to the date of Visit 1. The 
duration of epilepsy and age at epilepsy diagnosis will be summarized descriptively.  
6.3.3.6 
Historical seizure count and cluster count 
The Historical Seizure Count and Historical Cluster Count CRF records the number of seizures 
and clusters experienced by the subject during the past 2 months prior to the Screening Visit. The 
number of seizures and clusters will be summarized by seizure type and month. 
6.3.3.7 
Seizure types experienced during the Baseline Period  
The number and percentage of subjects experiencing each seizure type during the Baseline 
Period will be summarized based on data from Seizure Count CRF.  
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6.3.3.8 
Baseline focal seizure frequency 
The 28-day adjusted frequency of observable focal-onset seizures (Types IA1, IB, and IC) and of 
all Type I focal-onset seizures during the Baseline Period will be summarized. Seizure counts are 
collected by diary; calculation of the Baseline 28-day adjusted frequency is provided in Section 
3.3.1.  
6.3.3.9 
Brain magnetic resonance imaging (MRI) 
MRI data will be provided in the subject listing.  
6.4 
Prior and concomitant medications 
In this study, AED medications are collected separately from prior and concomitant non-AED 
medications. Handling of AED and non-AED medication is described in the following sections. 
AED medications will be summarized for the FAS, non-AED medications will be summarized 
for the SS.  
6.4.1 
AED medications 
Each concomitant medication will be classified as either an AED or a non-AED medication. 
AED medication taken and stopped prior to the Visit 1 will be reported on the History of 
Previous Antiepileptic Drug Treatment CRF. AED mediation that started prior to Visit 1 and 
which is ongoing/or AED medication prescribed during the study will be recorded on the AED 
Medication CRF.  
 Previous AEDs are AEDs taken and stopped prior to the Visit 1. Previous AEDs are reported 
on History of Previous Antiepileptic Drug Treatment CRF. 
 AEDs taken at study entry are reported on AED CRF and if: 
- 
(start date of medication) < (the date of Visit 1) and (stop date of medication) ≥ (the date 
of Visit 1) or ongoing  
 Prior AEDs include both previous AEDs and AEDs taken at study entry 
 Concomitant AEDs are reported on AED CRF and if:  
- 
(start date of medication) ≤ (stop date of IMP) and (stop date of medication) ≥ (start date 
of IMP) or ongoing  
- 
start date of medication is unknown but (stop date of medication) ≥ (start date of study 
drug) or ongoing.  
 
The number and percentage of subjects taking AED medications will be summarized by 
chemical/therapeutic/pharmacological subgroup (ATC classification level 4), and preferred drug 
name. The following summaries of AED medications will be produced for the FAS by treatment 
group and overall:  
 Previous AEDs from the History of Previous Antiepileptic Drug Treatment CRF 
 Number of previous AEDs taken: <4, 4-5, 6-7, 8-10,>10 AEDs. 
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 Previous AEDs by reason for AED discontinuation: The number and percentage of subjects 
by reason for discontinuation of previous AEDs will be summarized. Percentages for each 
reason for discontinuation will be relative to the number of subjects taking each AED. 
 AEDs taken at study entry  
 Number of AEDs taken at study entry: 1, 2, 3, and >3AEDs  
 Prior AEDs 
 Number of prior AEDs: <4, 4-5, 6-7, 8-10,>10 AEDs.  
 Concomitant AEDs 
6.4.2 
Use of vagus nerve stimulation  
Vagus Nerve Stimulation (VNS) status at Screening (VNS Status at Screening CRF) will be 
summarized as the number and percent of subjects with VNS at screening and as number and 
percent of subjects with VNS turned on. Subjects with VNS at screening and setting changed 
during treatment period will also be summarized. All other VNS data will be provided in subject 
data listings and will not be summarized for the FAS. 
6.4.3 
Prior and Concomitant non-AED medications 
Medications recorded on the Prior and Concomitant Medication CRF should not include AEDs. 
Non-AED medications will be analyzed separately from AED medications. 
 A prior non-AED medication if: 
- 
(start date of medication) < (start date of IMP) 
- 
start date of medication is unknown but (stop date of medication) < (start date of IMP) 
 A concomitant non-AED medication if:  
- 
(start date of medication) ≤ (stop date of IMP) and (stop date of medication) ≥ (start date 
of IMP) or ongoing  
- 
start date of medication is unknown but (stop date of medication) ≥ (start date of study 
drug) or ongoing.  
 
The number and percentage of subjects taking non-AED medications will be summarized by 
anatomical main group (Anatomical Therapeutic Chemical [ATC] classification level 1), 
therapeutic subgroup (ATC classification level 2), and preferred drug name. The following 
summaries of non-AED medications will be produced for the SS by treatment group and overall:  
 Prior non-AED  
 Concomitant non-AED 
7 
MEASUREMENTS OF COMPLIANCE 
7.1 
Treatment compliance 
The IMP will be provided in blister-packed treatment cards, each providing 3, 4, or 7 days’ 
treatment of active or placebo (plus some reserve tablets in case of unexpected event). At each 
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visit after IMP is dispensed and at the end of the Taper/Conversion Period, subjects must return 
all unused IMP and empty IMP containers. IMP is dispensed at Visits 2, 3, 4, 5, 6, and 7. IMP 
return and IMP accountability evaluation occurs at Visits 3, 4, 5, 6, 7 and 8. Drug accountability 
is recorded on the Drug Accountability form.  
Measurement of treatment compliance with the dosage schedule will be based on dispensed and 
returned pill counts. Drug accountability data will be listed (SS) by treatment group and study 
visit. The listing will include dispense date and number of pills dispensed; return date and 
number of pills returned.  
Subjects are instructed to take medication bid, approximately 12 hours apart. Based on the PSL 
tablet mg amounts provided, subjects will take 10 tablets per day (some containing PSL, some 
placebo) during the Titration and Taper (subjects not entering the EP0093 OLE) periods.  They 
will take 12 tablets per day (some containing PSL, some placebo) during the Stabilization, 
Maintenance, and Conversion (subjects entering the EP0093 OLE) periods. Compliance during 
the entire 16-week Treatment Period, Titration and Stabilization Period, and the Maintenance 
Period will be calculated as 100 times the actual number of tablets taken over the evaluation 
period (based on the Study Medication Administration CRF), and dividing this quantity by the 
number of tablets that should have been taken during this period of time. 
The number of tablets expected (that should be taken) during the periods of interest are: 
 16-week Treatment Period: 10 × duration of Titration Period (days) + 12 × duration of 
Stabilization Period and Maintenance Period (days) 
 Maintenance Period: 12 × duration of the Maintenance Period (days) 
 Titration and Stabilization Period: 10 × duration of Titration Period (days) + 12 × duration of 
Stabilization Period (days) 
Duration of an analysis period in days will be calculated as date of the last dose of IMP in a 
period - date of the first dose at the specific period +1. Compliance is only computed for actual 
time of participation in the study up to the last dose of IMP during the Treatment Period. If a 
subject didn’t enter an analysis period, the compliance for the analysis period will not be 
calculated. 
Percent compliance will be summarized for the FAS using descriptive statistics for each 
treatment group and overall. In addition, the number and percentage of subjects with compliance 
<75%, 75% to 125%, and >125% will be summarized. 
7.2 
Diary compliance 
Primary and secondary, and other efficacy variables are based on diary-collected seizure 
frequencies, and as such, diary compliance will be evaluated along with treatment compliance. 
Subjects are instructed to complete their diary entries at least once a day during the study. A 
dairy day will be considered missing for compliance if the seizure count field is checked as ‘not 
done’. Diary compliance will be evaluated during the Baseline Period, during the entire 16-week 
Treatment Period, and during the Maintenance Period.  
Diary compliance will be calculated as 100 times the number diary days (days with dairy 
completed) during the period and dividing this quantity by the expected number of diary days 
that should have been completed during this period of time. Compliance is only computed for 
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actual time of participation in the study up to the end of the Treatment Period. Only data prior to 
and on the date of last dose of study medication will be included in the compliance calculation. If 
a subject didn’t enter an analysis period, the diary compliance for the analysis period will not be 
calculated.  
Diary compliance data will be listed by subject. Percent diary compliance will be summarized 
for the FAS, by period using descriptive statistics for each treatment group and overall. In 
addition, the number and percentage of subjects with compliance ≤80% and > 80% will be 
summarized. 
8 
EFFICACY ANALYSES 
Unless noted otherwise, analyses of efficacy endpoints will be performed on the FAS. Additional 
analyses of selected efficacy endpoints will be performed using the PPS as described in the 
sections below. For the efficacy variables described below,  seizure frequency refers to a 28-day 
adjusted frequency; observable focal-onset seizures refer to Type IA1, IB, and IC (ILAE 
Classification of Epileptic Seizures, 1981); focal-onset seizures include all Type I seizures; and 
seizure-free status and seizure-free days include all seizure types (Types I, II, and III). Only 
seizure data prior to and on the date of last dose of study medication will be included in the 
analysis. Unless noted otherwise, all efficacy tables will be presented by treatment group. 
As listed in Section 2.3.1, separate primary and secondary seizure frequency efficacy variables 
have been designated for submission to FDA and submission to European regulatory agencies 
along with other seizure frequency efficacy variables used for both submissions. A summary of 
seizure frequency variables and status as primary or secondary is presented in Table 8-1.  
Table 8‒1: 
Summary of seizure frequency variables 
Variable 
12-Week Maintenance Period 
     16-Week Treatment Period 
Observable  
Focal Onset 
(IA1, IB and 
IC) 
 
Focal Onset 
(All Type I) 
All 
Seizures 
(Type I, II 
and III) 
Observable 
Focal Onset 
(IA1, IB and 
IC) 
 
Focal 
Onset 
(All Type 
I) 
All 
Seizures 
(Type I, 
II and 
III) 
Change in log-
SF 
X (a)(c) 
X 
 
X 
 
 
75% RR  
X (b)(c) 
X 
 
X 
 
 
50% RR 
X (c) 
X 
 
X 
 
 
Percent 
Reduction in SF 
X (c) 
X 
 
X 
X 
 
90% RR 
X 
X 
 
 
 
 
100% RR 
X 
X 
 
 
 
 
Change in log-
SF (4-week 
intervals) 
X 
 
 
 
 
 
Seizure Freedom 
 
 
X 
 
 
X 
Number of 
seizure-free days 
 
 
X 
 
 
X 
Cumulative RR 
 
 
 
X 
X 
 
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Table 8‒1: 
Summary of seizure frequency variables 
Variable 
12-Week Maintenance Period 
     16-Week Treatment Period 
Observable  
Focal Onset 
(IA1, IB and 
IC) 
 
Focal Onset 
(All Type I) 
All 
Seizures 
(Type I, II 
and III) 
Observable 
Focal Onset 
(IA1, IB and 
IC) 
 
Focal 
Onset 
(All Type 
I) 
All 
Seizures 
(Type I, 
II and 
III) 
Change from 
baseline in 
seizure 
frequency 
X 
X 
 
X 
X 
 
RR=Responder Rate.  SF=Seizure Frequency. 
(a) Primary endpoint for FDA, PMDA and other Regulatory agencies not referencing EMA 
(b) Primary endpoint EMA 
(c) Secondary Endpoint 
8.1 
Statistical analysis of the primary efficacy variables 
8.1.1 
Derivations of primary efficacy variables 
8.1.1.1 
Seizure frequency 
Seizure frequency (SF) refers to the 28-day adjusted seizure frequency. The 28-day adjusted 
seizure frequency is defined as: SF = (Number of Seizures) x (28 / D). The number of seizures is 
the total number of seizures during an analysis period or time interval. For cluster seizures, the 
number of cluster episodes will be included. D corresponds to the number of days for which the 
diary was available during the analysis period or time interval.  
8.1.1.2 
Change in log-transformed seizure frequency from Baseline 
The 28-day adjusted seizure frequency value will be log-transformed using the function ln(x+1), 
where ln represents the natural logarithm function. The change in the log-transformed seizure 
frequency from Baseline is calculated as: Ln (SFT+1) – Ln (SFB+1), where SFT corresponds to 
the seizure frequency during an analysis period and SFB corresponds to the Baseline period 
seizure frequency.  
For the primary efficacy variable for the FDA, SFT and SFB are the observable focal-onset 
seizure frequency during the 12-week Maintenance Period and Baseline Period, respectively.  
8.1.1.3 
Percent reduction in seizure frequency from Baseline 
The percent reduction in seizure frequency (PRD) from the Baseline is defined as: PRD = [(SFB 
– SFT) / SFB] x 100, where SFT corresponds to the 28-day adjusted seizure frequency during an 
analysis period and SFB corresponds to the Baseline seizure frequency. A negative PRD 
indicates an increase in seizure frequency from Baseline.  
8.1.1.4 
75% Responder 
Responder status (yes or no) for a subject is determined by the percent reduction in seizure 
frequency (PRD) from Baseline. A subject is defined as a 75% responder if s/he has a reduction 
in seizure frequency (PRD) of at least 75% from the Baseline. The 75% responder rate (RR) will 
be calculated as the proportion of 75% responders. For the primary efficacy variable for the 
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EMA, 75% responder status is calculated based on the percent reduction (PRD) from the 
Baseline in observable focal-onset seizure frequency during the 12-week Maintenance Period. 
8.1.2 
Analysis of the primary efficacy variables 
8.1.2.1 
Primary variable for submission to the US FDA, PMDA, and other 
regulatory authorities not referencing EMA 
The primary efficacy variable for the US FDA/PMDA is the change in log-transformed 
observable focal onset seizure frequency from Baseline, over the 12-week Maintenance Period. 
Analyses of the primary variable for the FDA will be performed on the FAS as described below.  
Change from Baseline in observable focal-onset seizure frequency (using the log-transformed 
data) will be analyzed for the FAS using analysis of covariance (ANCOVA) with treatment 
group (PSL 400mg bid, 200mg bid, 100mg bid, 50mg bid, and placebo) as the main factor, 
Baseline log-transformed seizure frequency as a continuous covariate, Baseline SV2A use (Yes 
or No), and Region (Europe or Non-Europe) as factors. Pairwise contrasts will be constructed to 
compute estimated effects of each dose from placebo. 
Treatment effects will be characterized using treatment differen ces based on back-transformation 
of least squares (LS) means obtained from the above ANCOVA model. Percent reduction over 
placebo will be calculated as 100*(1-exp(diff)), where diff is the model estimate of the log ratio 
between each PSL group and placebo group. Similarly, estimates for the upper and lower bounds 
of the 95% confidence interval (CI) will be back-transformed for table presentation as 
exp(lower) and exp(upper), respectively, where upper and lower correspond to the 95% CI of the 
log ratio. If there are issues with convergence, covariates will be dropped sequentially in the 
order of Region, and then Baseline SV2A use (Yes or No) if further needed. 
Pairwise comparisons of the 400mg bid, 200mg bid, and 100mg bid PSL dose groups versus 
placebo will be carried out using the analysis model described above. Type 1 error will be 
controlled using the Hochberg step-up procedure (Section 4.5) within SAS® Proc Multtest. If all 
the results of the 3 pairwise comparisons are statistically significant, then the 50mg bid dose 
group will be compared to placebo, too. Both multiplicity-adjusted and unadjusted p-values will 
be presented.   
8.1.2.2 
Supportive and sensitivity analyses for the primary variable for 
submission to the US FDA, PMDA, and other regulatory authorities 
not referencing EMA 
8.1.2.2.1 
Sensitivity analysis 1: PPS 
The primary analysis of change from Baseline in observable focal-onset seizure frequency for 
submission the FDA described in Section 8.1.2.1 will be repeated for the PPS. 
 
8.1.2.2.2 
Sensitivity analysis 2: multiple imputation 
Multiple imputations will be used to assess the robustness of the primary efficacy analysis 
results. Multiple imputation will be performed based on log (28-day adjusted seizure frequency 
+1) by 4-week visit interval over the 16-week Treatment Period. Seizure frequency during a 4-
week interval will be calculated as long as seizure data are available for at least 1 day in the 
given interval.   
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Imputation for intermediate missing 
Chances of intermittent missing due to completely missing seizure diary during a 4-week interval 
are low.  The intermittent missing seizure frequency before the last 4-week visit interval will be 
assumed as missing at random (MAR). The intermittent missing data will be filled in using 
MCMC method with 30 iterations. The imputation model will include treatment groups, log-
transformed baseline seizure frequency, baseline SV2A use (Yes or No), region (Europe or Non-
Europe), and outcome from each visit interval (in chronological order). Seed=57832. 
8.1.2.2.2.1 
 Sensitivity Analysis 2.1: Missing at random MI 
After the intermittent missing data are imputed, the pattern of the missing data will be monotone. 
To complete the imputation assuming MAR for each treatment group separately, a regression 
method using PROC MI statement MONOTONE REG will be used. The imputation model will 
include explanatory variables for log-transformed baseline seizure frequency, baseline SV2A use 
(Yes or No), region (Europe or Non-Europe), and outcome from each visit interval (in 
chronological order).  Seed=57832. 
Log-transformed seizure frequency during the Maintenance Period will then be computed by 
taking the average of the data in the three 4-week visit intervals during the Maintenance Period. 
Multiple imputed datasets will be analyzed using the same ANCOVA model as in the primary 
analysis. If there are issues with model convergence, covariates will be dropped sequentially in 
the order of Region, and then Baseline SV2A use (Yes or No) if further needed. The result of the 
30 imputed datasets will be combined for overall inference using SAS PROC MIANALYZE. 
8.1.2.2.2.2 
Sensitivity Analysis 2.2: Control-based MI 
The control-based imputation method used the data from the subjects randomized in the placebo 
group to impute the missing value for the subjects in the PSL treatment groups. This assumes the 
subjects on PSL treatment groups will have their efficacy trend toward that of the subjects in the 
placebo group after the treatment discontinuation. Missing data for the first visit interval are 
imputed, then missing data for the second visit interval are imputed using observed data and 
missing data just imputed for the first interval; and so on to the final interval. The imputation will 
be performed via the sequential regression method using PROC MI statement MONOTONE 
REG. Multiple imputed datasets will be analyzed using the same ANCOVA model as in the 
primary analysis. If there are issues with model convergence, covariates will be dropped 
sequentially in the order of Region, and then Baseline SV2A use (Yes or No) if further needed. 
Seed=14823.  
8.1.2.2.2.3 
Sensitivity Analysis 2.3 Tipping point MI  
Following the National Research Council (NRC) report on missing data (NRC, 2010), a 
sensitivity analysis using tipping point method to stress-test the result of MAR by imposing a 
succession of δ adjustments, each one more severe, in the PSL Groups until they are no longer 
statistically significant. This Delta (δ) will be applied just once, at the first visit that has missing 
frequency seizure data for each subject in the PSL groups who discontinued before the end of 
treatment period and hence have missing records for “seizure frequencies”. Use nimpute = 30, 
seed = 56432. 
The tipping point report (table) for each pairwise comparison will include values for the 
LSmeans, the 95% CI, and the p-value for each of the delta value (including 0, until p-values are 
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no longer statistically significant. Only 8 delta values will be tabulated in the report including 
δ=0 until δ=xx.x% shift the p-value to larger than multiplicity adjusted alpha level. 
   
 
8.1.2.3 
Primary variable for submission to the EMA and regulatory 
authorities who reference EMA 
The primary efficacy available for the EMA is the 75% responder rate over the 12-week 
Maintenance Period. Analyses of the primary variable for the EMA submission will be done on 
the FAS as described below. 
The analysis of 75% responder rate will be based on a logistic regression model with factors for 
treatment group (PSL 400mg bid, 200mg bid, 100mg bid, 50mg bid and placebo), Region 
(Europe or Non-Europe), Baseline SV2A use (Yes or No) and log-transformed Baseline seizure 
frequency as a continuous covariate. If there are issues with convergence, covariates will be 
dropped sequentially in the order of Region, and then Baseline SV2A use (Yes or No) if further 
needed. Odds Ratios of PSL dose to placebo will be obtained and tested for difference from unity 
(2-sided) for the dose groups 400mg bid, 200mg bid, and 100mg bid. The evaluation of statistical 
significance will be based on the Hochberg procedure as described in Section 4.5. If all 3 Odd’s 
Ratios of PSL dose relative to placebo are statistically significant, then the 50mg bid dose group 
will be compared to placebo by testing the Odds Ratio for difference from unity, too. Both 
multiplicity adjusted p-values and unadjusted p-value will be presented. 
If there is <2 responders in a treatment group, results will also be provided for an exact 
conditional logistic regression model where treatment group is included in the model and Region 
(Europe or Non-Europe) and Baseline SV2A use (Yes or No) are included as strata.   
 
8.1.2.4 
Supportive and sensitivity analyses for the primary variable for 
submission to the EMA and regulatory authorities who reference 
EMA 
8.1.2.4.1 
Sensitivity analysis 1:  PPS 
The primary analysis (75% responder rate) for submission to the European regulatory agency as 
described in Section 8.1.2.3 will be repeated using the PPS.  
8.1.2.4.2 
Sensitivity analysis 2: non-responder imputation  
A sensitivity analysis of the 75% responder rate will be performed in which subjects who 
discontinued prior to the end of the Maintenance Period will be treated as non-responders. The 
primary analysis in Section 8.1.2.3 will be repeated. 
8.1.2.4.3 Sensitivity analysis 3: multiple imputation 
After the multiple imputation process described in Section 8.1.2.2.2, seizure frequency during 
the Maintenance Period will be calculated as [exp (log-transformed seizure frequency) -1] and 
the 75% responder status will be derived. Multiple imputed datasets will be analyzed using the 
same logistic regression model as in the primary analysis for the MAR imputation and control-
based imputation respectively. If there are issues with model convergence, covariates will be 
dropped sequentially in the order of Region, and then Baseline SV2A use (Yes or No) if further 
needed. The tipping point analysis based on MAR multiple imputation will be repeated until 
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none of the PSL treatment group is significantly different from placebo based on the logistic 
regression model.  
8.1.2.5 
The log of the odds ratio estimates from the logistic regression 
model are used when combining into a single inference using SAS 
PROC MIANALYZE. Subgroup analyses for the primary variables 
The analyses described in Section 8.1.2.1 and 8.1.2.3 will be repeated for the subgroups 
described in Section 4.8. In the subgroup analyses by region and Baseline SV2A use, the 
corresponding stratification factor will be removed from the model. These evaluations will be 
descriptive, and the model estimates and 95% CIs will be presented.  
8.2 
Statistical analysis of the secondary efficacy variables 
Separate secondary efficacy variables have been designated for submission to US FDA/PMDA 
and submission to EMA. 
8.2.1 
Analysis of the secondary efficacy variables for submission to the 
US FDA, PMDA, and other regulatory authorities not referencing EMA 
8.2.1.1 
75% Responder Rate over the 12-week Maintenance Period 
75% responder rate is the secondary efficacy variable for the US FDA and primary efficacy 
variable for the EMA. The analyses are described in Section 8.1.2.3. 
8.2.1.2 
50% Responder Rate over the 12-week Maintenance Period 
Subjects with at least a 50% reduction in seizure frequency will be categorized as a 50% 
responder. The same methodology described in Section 8.1.2.3 will be used for 50% responder 
rate during the 12-week Maintenance Period. No multiplicity adjustment will be applied and tests 
will be carried out at a nominal two-sided 0.05 significance level. 
8.2.1.3 
Percent reduction from Baseline in observable focal-onset seizure 
frequency over the 12-week Maintenance Period 
The third secondary efficacy variable is percent reduction from Baseline in observable focal-
onset seizure frequency, over the 12-week Maintenance Period. The calculation of percent 
reduction from Baseline in seizure frequency is described in Section 8.1.1.2. The percent 
reduction in seizure frequency will be summarized descriptively.  
Statistical comparisons between each PSL dose group and placebo will be performed on the FAS 
using the Wilcoxon-Mann-Whitney test. No multiplicity adjustment will be applied and tests will 
be carried out at a nominal two-sided 0.05 significance level. The Hodges-Lehmann 
nonparametric estimator will be used to estimate the median difference between each PSL dose 
group versus placebo, along with the corresponding 95% CI of the estimate.  
In addition, the number and percentage of subjects within each of the following categories of 
percent reduction from Baseline will be summarized: <-25%, -25% to <25%, 25% to <50%, 50% 
to <75%, 75% to <100%, and 100%. 
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8.2.2 
Analysis of the secondary efficacy variables for submission to EMA 
and regulatory authorities who reference EMA 
8.2.2.1 
The change in log-transformed observable focal onset seizure 
frequency from Baseline, over the 12-week Maintenance Period  
The analysis described in Section 8.1.2.2 (for US FDA, PMDA, and other regulatory authorities 
not referencing EMA) of the change in log-transformed observable focal-onset seizure frequency 
from Baseline, over the 12-week Maintenance Period, serves as the key secondary variable for 
submission to EMA.   
8.2.2.2 
50% Responder Rate status over the 12-week Maintenance Period 
This variable is also a secondary variable for FDA submission and is described in Section 
8.2.1.2. 
8.2.2.3 
Percent reduction in observable focal-onset seizure frequency from 
Baseline, over the 12-week Maintenance Period 
This variable is also a secondary variable for FDA submission and is described in Section 
8.2.1.3. 
8.3 
Analysis of other efficacy variables 
Other efficacy variables are listed in Section 2.2.1.3. These variables are the same for all 
regulatory agencies. 
8.3.1 
Derivations of other efficacy variables 
For other efficacy variables based on seizure frequencies (observable focal-onset (Types IA1, IB, 
IC) and all Type I focal-onset seizures the frequencies), log-transformations, changes from 
Baseline, percent reduction from Baseline and Responder Rates during the evaluation period of 
interest are calculated similarly as described in Section 8.1.1, using the appropriate analysis 
period and responder criterion. 
8.3.1.1 
Seizure-freedom status (Yes/No) 
A subject is defined as seizure free (ie, seizure-freedom status=Yes) during a specific evaluation 
period if they meet all of the following criteria: 
1. The subject completed the specific time period. 
2. The subject did not have any missing diary days over the time period. Missing diary day 
refers to no diary available at all for that day. If the diary for the day is present and ‘no seizures’ 
is checked then the diary day is not missing. 
3. The subject did not report any seizure of any type over the time period.  
8.3.1.2 
Seizure-free days 
The number of seizure-free days will be the total number of days within an interval for which 
daily diary data was available and indicated that no seizures occurred. The percentage of seizure-
free days will be computed as 100 times the number of seizure-free days divided by the number 
of days for which daily diary data was available. Days without the corresponding daily diary data 
will not be used in these computations.  
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8.3.1.3 
Seizure Severity Global Item (SSG) variables 
The SSG consists of 1 item at baseline or 2 items during follow up from the Seizure Severity 
Questionnaire and asks the subjects to evaluate the severity of their seizures for the last 4 weeks 
and/or since the Baseline. The subject describes all seizure types when answering the questions.  
The SSG is completed according to the schedule of study procedures in Table 2-2 (Visits 2, 4, 7 
and 9) and is provided to each subject at the beginning of the visit. The SSG data are collected on 
2 separate CRFs. On the “Seizure Severity Global Item – Baseline”, seizure-intensity during the 
last 4 weeks is collected on a 7-point scale with 7 = very severe; On the “Seizure Severity Global 
Item – Follow-up” CRF, seizure-intensity during last 4 weeks is collected on a 7-point scale with 
7 as very severe. Assessment of change since starting IMP, is also collected on a 7-point scale 
with 7 = much worse.   
8.3.1.4 
QOLIE-31-P variables 
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 31 items grouped into 7 multi item subscales (Seizure 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 schedule of study procedures in Table 2-2 
(Visits 2, 4, 7 and 9) and is provided to each subject at the beginning of the visit. The subject 
completes the questionnaire on his/her own. The Investigator or designee will verify that all 
questions have been answered. Further details about the QOLIE-31-P are provided in the scoring 
manual.  
8.3.1.5 
Hospital Anxiety and Depression Scale (HADS) score variables 
The HADS is administered at Visits 2, 4, 7 and 9. The HADS scores for anxiety and for 
depression range from 0-21 with higher scores indicating a worse state. A score below 8 is 
considered to be normal (Zigmond and Snaith, 1983). HADS subscale scores will be determined 
by summing the scores of the 7 items belonging to each of the two subscales, i.e. anxiety (odd 
numbered questions) and depression (even numbered questions). The following rules will be 
applied for the computation of the subscale scores: 1) Missing items values will be set to the 
mean score of the subscale to which the item belongs, provided 50% or more of the items within 
the subscale are present. 2) The subscale scores will be calculated if 50% or more of the items 
within a subscale are present. 
8.3.2 
Analysis of other efficacy variables 
Other efficacy variables and tests will be carried out at a nominal two-sided 0.05 significance 
level and no multiplicity adjustments will be applied. 
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8.3.2.1 
Change from Baseline in log-transformed observable focal-onset 
seizure frequency over the first 4 weeks, second 4 weeks, and third 4 
weeks of the 12-week Maintenance Period 
The 28-day adjusted seizure frequencies during the Treatment Period will be computed using 
observed diary records for the following 4-week intervals: Visit 2 to Visit 4, Visit 4 to Visit 5, 
Visit 5 to Visit 6, and Visit 6 to Visit 7. The 28-day adjusted seizure frequency during the 
Treatment Period and change from baseline based on the observed data will be summarized 
descriptively by the 4-week interval.  
The change from Baseline in log-transformed observable focal-onset seizure frequency by 4-
week interval will be analyzed using a Mixed Model Repeated Measures (MMRM) model, 
including Baseline log-transformed seizure frequency as a continuous fixed effect covariate, and 
treatment, Region (Europeor Non-Europe), Baseline SV2A use (Yes or No), and visit as fixed 
effect factors, and Baseline × visit and treatment × visit interactions. MMRM assumes that 
missing data are missing at random and estimates the mean outcome at each time interval by 
treatment group. An unstructured covariance structure will be used. If the model does not 
converge, an appropriate covariance structure will be used instead. Estimates of effects and 
comparison contrasts and CI will be back-transformed for display in tables as described in 
Section 8.1.2.1. 
8.3.2.2 
Change from Baseline in log-transformed observable focal-onset 
seizure frequency over the16-week Treatment Period 
The analyses of the change from Baseline in observable focal-onset seizure frequency during the 
entire 16-week Treatment Period will be analyzed for the FAS using the ANCOVA model on the 
log-transformed data, as specified for the primary efficacy analysis (Section 8.1.2). 
8.3.2.3 
The 50% responder rate over the 16-week Treatment Period 
Analysis of the 50% responder rate during the entire 16-week Treatment Period will be analyzed, 
for the FAS, using the same logistic regression model as specified in Section 8.1.2.3. 
8.3.2.4 
The 75% responder rate over the 16-week Treatment Period 
Analysis of the 75% responder rate during the entire 16-week Treatment Period will be analyzed, 
for the FAS, using the same logistic regression model as specified in Section 8.1.2.3. 
8.3.2.5 
The 90% and 100% responder rates over the 12-week Maintenance 
Period 
Analysis of the 90% and 100% responder rates during the 12-week Maintenance Period will be 
analyzed for the FAS, using an exact conditional logistic regression model where treatment 
group is included in the model and region and Baseline SV2A use are included as strata. 
8.3.2.6 
Percent reduction in observable focal-onset seizure frequency from 
Baseline, over the 16-week Treatment Period 
The same methodology described in Section 8.2.1.3 will be applied.  
8.3.2.7 
Change from Baseline in log-transformed focal-onset (Type I) seizure 
frequency over the 12-week Maintenance Period 
The same ANCOVA model described in Section 8.1.2.1 will be applied. 
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8.3.2.8 
The 50% responder rate status for focal-onset (Type I) seizures over 
the 12-week Maintenance Period 
Analysis of the 50% responder rate for Type I focal-onset seizures during the 12-week 
Maintenance Period will be analyzed for the FAS, using the same logistic regression model as 
specified in Section 8.1.2.3).  
8.3.2.9 
The 75% responder rate for focal onset (Type I) seizures over the 12-
week Maintenance Period 
Analysis of the 75% responder rate for Type I focal-onset seizures during the 12-week 
Maintenance Period will be analyzed for the FAS, using the same logistic regression model as 
specified in Section 8.1.2.3. 
8.3.2.10 
The 90% and 100% responder rates for focal-onset (Type I) seizures 
over the 12-week Maintenance Period 
Analysis of the 90% and 100% responder rates for Type I focal-onset seizures during the 12-
week Maintenance Period will be analyzed for the FAS, using an exact conditional logistic 
regression model where treatment group is included in the model and region and Baseline SV2A 
use are included as strata. 
8.3.2.11 
Percent reduction in focal-onset (Type I) seizure frequency from 
Baseline, over the 12-week Maintenance Period and the 16-week 
Treatment Period 
The same methodology described in Section 8.2.2.3 will be applied.  
8.3.2.12 
Change from Baseline in log-transformed Type IA1, IB, or IC seizure 
frequency over the12-week Maintenance Period 
The change from Baseline in Type IA1, IB, or IC seizure frequency during the12-week 
Maintenance Period by each seizure type separately will be analyzed for the FAS using the 
ANCOVA model on the log-transformed data, as specified for the primary efficacy analysis 
(Section 8.1.2). 
8.3.2.13 
The 50% responder rate for Type IA1, IB, or IC seizure over the 12-
week Maintenance Period 
50% responder rate in Type IA1, IB, or IC seizure over the 12-week Maintenance Period by each 
seizure type separately will be analyzed for the FAS, using the same logistic regression model as 
specified in Section 8.1.2.3. 
8.3.2.14 
The 75% responder rate for Type IA1, IB, or IC seizure over the 12-
week Maintenance Period 
50% responder rate in Type IA1, IB, or IC seizure over the 12-week Maintenance Period by each 
seizure type separately will be analyzed for the FAS, using the same logistic regression model as 
specified in Section 8.1.2.3. 
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8.3.2.15 
Percent reduction in Type IA1, IB, or IC seizure frequency from 
Baseline, over the 12-week Maintenance Period and the 16-week 
Treatment Period 
The same methodology described in Section 8.2.2.3 will be applied. Analysis will be done by 
each seizure type separately. 
8.3.2.16 
Seizure-freedom status (yes/no) during the 12-week Maintenance and 
the 16-week Treatment Period 
Seizure freedom status will be evaluated for each treatment by summarizing the percentage of 
seizure-free subjects as a response rate during the 12-week Maintenance Period and during the 
entire 16-week Treatment Period. The seizure freedom rate will be calculated based on the 
Completer Set. The seizure freedom rate for each of these periods will be analyzed using an 
exact conditional logistic regression model where treatment group is included in the model and 
region and Baseline SV2A use are included as strata. 
8.3.2.17 
Percentage of seizure-free days during the 12-week Maintenance 
Period and the 16-week Treatment Period 
The percentage of seizure-free days during the Maintenance Period and Treatment Period will be 
summarized using descriptive statistics. The change in the percentage of seizure-free days from 
the Baseline Period to the Maintenance Period and Treatment Period will also be summarized.  
The percentage of seizure-free days during the 12-week Maintenance Period and during the 16-
week Treatment Period will each be analyzed using ANCOVA with treatment group as the main 
factor, Baseline percentage of seizure-free days as a continuous covariate, and the categorical 
factors Region (Europe or Non-Europe) and Baseline SV2A use (Yes or No). The 95% CI will 
be presented for estimates. 
8.3.2.18 
Cumulative responder rate during the 16-week Treatment Period 
Cumulative responder rate curve will be generated by treatment group for the observable focal-
onset seizures. The percent reduction in seizure frequency ranging from -25% to 100% will be 
shown on the X-axis and the percentage of responders experiencing at least the particular percent 
reduction will be shown on the Y-axis.  
8.3.2.19 
Change in the SSG score 
The numbers and percentages of subjects in each severity category will be summarized 
descriptively for Baseline and at each scheduled assessment visit along with the numbers and 
percentages of subjects in each of the 7 categories of change (much better through much worse). 
Summary will be provided for Visit 2, Visit 4, Visit 7, and the Last Visit during the Treatment 
Period. All data will be listed by subject. 
8.3.2.20 
Change in the QOLIE-31-P score 
The scoring algorithm for QOLIE-31-P is described in Section 8.3.1.3. Observed values and 
change from Baseline for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life, Health Status will be summarized descriptively for 
Visit 2, Visit 4, Visit 7, and the Last Visit during the Treatment Period. All data will be listed by 
subject. 
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8.3.2.21 
Change in Hospital Anxiety and Depression Scale (HADS) score 
The HADS observed scores and changes from Baseline for depression and anxiety will be 
summarized descriptively for Visit 2, Visit 4, Visit 7, and the Last Visit during the Treatment 
Period. All data will be listed by subject.  
8.3.2.22 
Time to return to the Baseline 28-day adjusted observable focal-
onset seizure count 
Time to return to the Baseline 28-day adjusted observable focal-onset seizure count during the 
12-week Maintenance Period will be evaluated using Kaplan-Meier methods (French et al, 
2015). The event date is the earliest date when the total number of seizures since the start of the 
Maintenance Period is equal or greater than the Baseline 28-day adjusted seizure count (ie, 
Baseline seizure frequency per 28-days described in Section 3.3.1). The time to event in days 
will be calculated as (the event date – start date of the Maintenance Period + 1). If the time to 
event is more than 28 days for a subject, it would indicate that during the Maintenance Period, it 
takes longer time for the subject to experience as many seizures as during the Baseline Period in 
28 days, which is the result of reduced seizure frequency during the Maintenance Period. If the 
total number of seizures during the Maintenance Period is less than the Baseline 28-day adjusted 
seizure count, the subject will be censored as of the last day with non-missing seizure data during 
the Maintenance Period. Subjects who discontinued during the Titration and Stabilization Period 
will be censored as of Day 1. The median time to event and the associated 95% CI will be 
estimated using Kaplan-Meier methods. The log-rank test will be used to compare differences 
between each PSL dose group and placebo. The KM curves will be presented by treatment 
group.   
8.3.2.23 
Change from baseline in seizure frequency  
The 28-day adjusted seizure frequency and change from baseline will be summarized 
descriptively by the treatment group in Titration and Stabilization, Maintenance, and Treatment 
Periods for observable focal-onset seizures and Type I seizures. The imputation rule described in 
Section 4.2.1 will be applied. 
8.3.2.24 
Additional figures for efficacy variables  
The following figures will be generated using the FAS: median percent reduction in seizure 
frequency, 75% RR, and 50% RR in observable focal-onset seizures will be displayed for the 16-
week Treatment Period and the 12-week Maintenance Period by treatment group.  
8.3.2.25 
Use of health-related outcomes and HRU 
Health-related outcomes data and HRU data will be listed for the RS and summarized 
descriptively for the SS. Hospital and ER Visits will be listed for SS. 
 Socio-professional status  
Socio-professional status data are collected at Visit 1 and Visit 7/EDV. Variables include highest 
level of education, housing status, current professional status, current unemployed status, need 
for regular assistance due to epilepsy, and ability to drive. The number and percentages of 
subjects in each category will be summarized for Visit 1, Visit 7, and the Last Visit during the 
Treatment Period.  
 Healthcare provider consultations not foreseen by the protocol 
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The number of health care provider consultations per subject with onset during the Treatment 
Period will be summarized as a continuous variable as well as in the following categories: 0, 1, 2, 
3, 4, and 5 or more. Additionally, the number and percentage of consultations by type of provider 
(general practitioner, specialist physician, nurse, and other) will be presented for the Treatment 
Period. 
 Hospital and ER visits 
The number of hospitalizations per subject will be summarized as a continuous variable and 
categorical variable for the Treatment Period. ER visits will be extracted from the 
Hospitalization/ER Visit CRF page (if the initial entry point is ER). The number of ER visits will 
be summarized in the same manner as hospitalizations. Additionally, the number and percentage 
of subjects with each of the following categories of duration of hospital stay will be summarized: 
0 days, 1-5 days, 6-10 days, 11-15 days, and >15 days. 
 Caregiver assistance 
Caregiver assistance data is collected on the CRFs “Caregiver Assistance Screening” and 
“Caregiver Assistance Follow-up”. The number and percentages of subjects having a caregiver 
will be summarized by visit. 
 Concomitant medical procedures 
The number of concomitant medical procedures per subject during the Treatment Period will be 
summarized using the categories 0, 1, 2, and 3 or more. 
 Number of school or working days lost 
Number of school/working days lost data are collected on the CRFs “School and Workdays Lost 
Screening” and “School and Workdays Lost Follow-up”. The number and percentages of 
subjects who lose school or work days as a result of epilepsy will be summarized by visit.  
The percentage of days lost will be summarized by visit for subjects who have more than zero 
total number of school or work days. The percentage of days lost will be calculated as:  
100 × (end date of absence – start date of absence +1)/ (3 × 30 + 1) for the screening visit. If the 
end date of absence is missing or after Visit 1 date, the end date of absence will be set to Visit 1; 
if the start date of absence is missing or prior to Visit 1-90, the start date of absence will be set to 
Visit 1-90.  
100 × (end date of absence – start date of absence +1)/ (visit date of current visit – visit date of 
previous visit) for the later visits. If the end date of absence is missing or after the current visit 
date, the end date of absence will be set to the current visit date; if the start date of absence is 
missing or prior to the previous visit+1, the start date of absence will be set to the previous visit 
date+1. 
If multiple absences are reported at a given visit, the sum of the duration of all absences will be 
used in the numerator.  
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9 
PHARMACOKINETICS 
9.1 
Plasma concentrations of PSL and its major metabolites 
Concentrations of PSL and its major metabolites will be determined from blood samples 
obtained during the Titration and Stabilization and Maintenance Periods (Visits 3, 4, 5, 6 and 7). 
Individual concentrations of PSL,  
 (from venous conventional sampling 
and dried blood (MITRA) sampling) and 
 (from venous conventional 
sampling) will be listed for subjects in PSL treatment groups for the PK-Set and will include 
visit, actual daily dose (mg), date and time of the most recent administration, scheduled sampling 
time per the CRF, actual date and time of sampling, time interval between plasma sample and the 
most recent administration (in hours with 2 decimal places). Samples excluded from the PK-PPS 
will be marked in the listing. 
Values below the limit of quantification (LOQ) will be reported as BLQ (below the limit of 
quantification). 
Concentrations of PSL and its 
 metabolite will be summarized by sampling method 
(venous, dried blood MITRA), PSL dose group, visit, and sampling times for the PK-PPS using 
the following descriptive statistics: number of observations, geometric mean, 95% CI of the 
geometric mean, geometric coefficient of variation, arithmetic mean, SD, median, and minimum 
and maximum values. Measured values below the LOQ will be excluded for the calculation of 
descriptive statistics but listed. Concentrations for 
 (only in venous 
blood) will also be summarized similarly.  Only PSL samples taken up to the (date of the last 
dose of study medication +1) will be included in the summary. 
Of note, geometric mean is calculated as: exp (arithmetic mean of log-transformed 
concentrations); upper and lower bounds of the 95% confidence interval (CI) of the geometric 
mean are calculated as exp (upper) and exp(lower) of the 95% CI of the arithmetic mean of log-
transformed concentrations; geometric coefficient of variation is calculated as: 100 × sqrt [exp 
(variance of log-transformed concentrations)-1]. 
The PK samples will be summarized based on the actual time since the most recent dose using 
the following time categories:  
• 
>0 to <45 min after dosage: 0.5h (30min) 
• 
45 to <75 min after dosage: 1h (60min) 
• 
75 to <105 min after dosage: 1.5h (90min) 
• 
105 to <150 min after dosage: 2h (120min)  
• 
150 to <210 min after dosage: 3h (180min)  
• 
4h: 3.5h to <4.5h 
• 
5h: 4.5 to <5.5h 
• 
6h: 5.5 to <6.5h 
• 
8h:  6.5 to <9h 
• 
10h: 9h to <11h or >-3h to <-1h 
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• 
12h: 11h to <14h or >=-1h to <=0 (time points for the trough concentration,) 
The geometric mean and associated 95% CI for the trough concentrations of PSL and 
 
 from MITRA will be presented by PSL treatment group and visit using semi-log 
plots.  
9.2 
Plasma concentrations of concomitant AEDs 
Blood samples for measurement of concomitant AED concentrations are collected at Visits 1, 2, 
6, and 7. The concomitant AED concentrations will be summarized by visit and treatment group 
using the same descriptive statistics above (<LOQ values will be excluded) for the AED-PK-
PPS. Only AED PK samples taken up to the (date of the last dose of study medication +1) will 
be included in the summary. 
The AEDs investigated with mixed models will be those with data available for at least 10 
evaluable subjects in one of the treatment groups (subset of AED-PK-PPS). An evaluable subject 
is defined as a subject: 
- 
with at least one AED measure (>LOQ) at baseline and at least one AED assessment 
(>LOQ) during the maintenance period  
- 
who received constant dose of AED for at least 14 days prior to the AED samples 
Plasma concentration data for concomitantly administered AEDs (values <LOQ will be 
excluded) will be assessed by evaluating ratios of steady state levels during the Maintenance 
Period vs baseline levels. The baseline concentration is defined as the arithmetic mean 
concentration (if multiple concentrations are available at Visits 1 and 2) or the single 
concentration (if only 1 concentration is available at Visit 1 or Visit 2). Difference between log-
transformed AED concentration at Visits 6 and 7 and baseline will be assessed using Mixed 
Model Repeated Measures (MMRM). The model will include log-transformed baseline 
concentration, visit, treatment, and treatment-by-visit interaction as fixed effects. An 
unstructured covariance structure will be used. If the model does not converge, an appropriate 
covariance structure will be used instead. Geometric least-squares (LS) means ratios and 
associated 90% CIs for each visit, by treatment group and PSL total will be calculated by 
exponentiation of the log-transformed data. Changes in AED concentration during the 
Maintenance Period and baseline will be considered clinically relevant if the respective 90% CIs 
fall entirely outside the conventional 0.80-1.25 limits. Forest plots will be provided on these (LS) 
means ratios and associated 90% CIs.  
9.3 
Other PK analyses/variables  
Other PK analyses, including population PK analyses and exploratory PK analyses will be 
described in a separate PK Data Analysis Plan and will be reported separately.   
10 
SAFETY ANALYSES 
The SS will be used to summarize and analyze all safety variables. In case of dosing 
administration error, summaries and analyses using the SS will be conducted according to actual 
treatment administered according to the rule described in Section 3.6. Safety data will be 
summarized for each treatment group and the PSL total group.   
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10.1 
Extent of exposure 
Extent of exposure will be based on the SS. The date of first dose is reported on First 
Administration of Study Medication CRF. The date of last dose is reported on the Study 
Termination CRF. If the date of last dose is missing due to lost to follow-up, the date of the last 
scheduled or unscheduled visit will be used.  
The duration of study drug exposure for the Treatment Period will be calculated as the date of 
the last dose of study drug during the 16-week Treatment Period minus the date of first dose of 
study drug plus 1 day. Date of the last dose of study drug during the 16-week Treatment Period 
is defined as the overall study last dose date or the end date of the 16-week Treatment Period, 
whichever is earlier.  
Exposure (in days) will be summarized as a continuous variable for the 16-week treatment 
period. The number and percentage of subjects with the following categories of durations of 
exposure for the Treatment Period will also be summarized:  >0 weeks, >=4 weeks, >=8 weeks, 
>=12 weeks, >=16 weeks. The same summaries will be repeated for the subjects who received 
dose reduction during the Stabilization Period.  
10.2 
Adverse events 
Adverse events are recorded on the AE CRF as they occur, from the time informed consent is 
granted until study completion or study termination (end of the SFU period 30 days after the last 
IMP intake). All AEs will be coded using the latest available version of MedDRA.  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the first dose of study treatment or any unresolved event already present before 
initiation of the first dose that worsens in intensity following exposure to the treatment. The 
number and percentage of subjects who experience TEAEs at any time during the study will be 
summarized by SOC and PT. The following tabular summaries will be presented for the SS: 
 Incidence of pre-treatment AEs. Pre-treatment AEs are AEs with start dates prior to the date 
of first dose of IMP.  
 Incidence of TEAEs during the Treatment Period – Overview. Of note, the corresponding 
table is required for data transparency reporting.   
 Incidence of TEAEs by period (Treatment Period, Titration and Stabilization Period, 
Maintenance Period, Conversion Period, and Taper and SFU Period) 
 Incidence of Serious TEAEs by period (Treatment Period, Titration and Stabilization Period, 
and Maintenance Period) 
 Incidence of TEAEs leading to discontinuation by period (Treatment Period, Titration and 
Stabilization Period, and Maintenance Period) 
 Incidence of TEAEs leading to dose reduction during the Stabilization Period 
The following will be presented for TEAEs during the overall Treatment Period:  
 Subject numbers for TEAEs 
 Incidence of TEAEs occurring in at least 5% of subjects in any treatment group 
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 Incidence of TEAEs occurring in at least 2% of subjects in any PSL group and greater than 
placebo group 
 Incidence of TEAEs by Relationship 
 Incidence of TEAEs by Maximum Intensity 
 Incidence of TEAEs of special interest 
 Incidence of SAEs by Relationship. Of note, the corresponding table is required for data 
transparency reporting.   
 Incidence of Fatal TEAEs by Relationship. Of note, the corresponding table is required for 
data transparency reporting.   
 Incidence of Non-Serious TEAEs above the threshold of 5% of subjects in any treatment 
group. Of note, the corresponding table is required for data transparency reporting.   
 Summary of the duration in days per event for the following TEAEs: somnolence, dizziness, 
fatigue, irritability and headache. In this analysis, if an AE is ongoing, the duration will be 
calculated till the date of final contact. 
Summaries will be presented based on standard Sponsor AE table formats and considering 
formats used for the PSL program.   
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent, 
unless there is unmistakable evidence (through comparison of partial dates, see Section 4.2) to 
suggest that the AE started prior to the first dose of study treatment. Summary tables will contain 
counts of subjects, percentages of subjects in parentheses and the number of events where 
applicable. A subject who has multiple events in the same MedDRA category (SOC or PT) will 
be counted only once in the subject count for that category, however all events will be included 
in the event count for the category. In summaries including relationship to study treatment, the 
following relationships will be summarized: ‘Not related’, ‘Related’. A subject may be counted 
more than once according to the relationship to study treatment. Events with missing relationship 
will be considered as ‘Related’ to the last given study product for summary purposes but 
recorded as missing in the listings. In summaries of the maximum intensity, the following 
intensity categories will be summarized: ‘Mild’, ‘Moderate’, ‘Severe’. Subjects who experience 
the same event multiple times, with differing severities, will be included in the most severe 
category. Events with missing intensity will be considered as ‘Severe’ events for summary 
purposes but recorded as missing in the listings. The main reasons for treatment discontinuation 
will be listed by subject. The daily dose of study medication corresponding to the AE onset date 
will be included in the listing. Daily dose will be derived from ‘Study Medication 
Administration’ CRF. 
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT 
within SOC, within the PSL total group column. 
10.3 
Clinical laboratory evaluations 
Clinical laboratory hematology, chemistry and urinalysis measurements obtained from 
blood/urine samples collected throughout the study are presented in Table 10-1.  
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During the study, non-protocol-specified lab parameters (unplanned) may be collected. 
Summaries of lab parameters will only include planned parameters as specified in the protocol. 
All lab parameter values will be listed and summarized using international units. 
The observed value and change from Baseline will be summarized descriptively by treatment 
group and PSL total group and scheduled study visit. The Last Visit, minimum, and maximum 
post-baseline values during the Treatment Period will also be included. These summaries will be 
organized by lab function panel and parameter.  
Shift from Baseline to the maximum and minimal values during the Treatment Period based on 
normal range (Low, Normal, High) will be provided for hematology and blood chemistry 
parameters in Table 10-1.  
Possibly clinically significant treatment-emergent (PCST) criteria have been developed based on 
FDA Division of Neuropharmacologic Drug Products guidelines with some UCB-defined 
additions and are provided in Appendix 13.1. For lab parameters with PCST criteria, the number 
and percentage of subjects with a PCST value at any time (scheduled and unscheduled visits) 
during the Treatment Period will be summarized by treatment group and PSL total group. . 
Treatment-emergent values are those occurring any time on or after the first dose of study 
medication in EP0091. Subject numbers for those meeting the PCST criteria will also be 
presented. 
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Table 10‒1: Laboratory measurements 
Hematology 
Chemistry 
Urinalysis 
Basophils 
ALP 
Glucose 
Eosinophils 
ALT 
pH 
Hematocrit 
AST 
RBC 
Hemoglobin 
Bilirubin 
Total protein 
Lymphocytes 
BUN or urea 
WBC 
MCH 
Calcium 
Microscopy (WBC, RBC, casts, 
crystals, bacteria) a 
MCHC 
Chloride 
Other 
MCV 
Creatinine 
FSHb 
Monocytes 
Glucose 
 
Neutrophils 
HDL 
 
Platelet count 
LDH 
 
RBC count 
LDL 
 
WBC count 
Magnesium 
 
 
Potassium 
 
 
Sodium 
 
 
Total bilirubin 
 
 
Total cholesterol 
 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; HDL=high density lipoprotein; FSH=follicle stimulating hormone; LDH=lactate dehydrogenase; 
LDL=low density lipoprotein; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin 
concentration; MCV=mean corpuscular volume; RBC=red blood cell; WBC=white blood cell 
a Microscopy will be performed only in case of abnormalities. 
b Only applicable to postmenopausal women 
10.3.1 
Subjects with potential drug-induced liver injury (PDILI) 
There are specific criteria described in the protocol Section 11 to evaluate subjects for potential 
drug-induced liver injury (PDILI). The evaluations required by protocol for PDILI subjects are 
collected on the following CRFs:  
 Most Recent Study Medication Administration, for PDILI 
 Laboratory Tests DILI 
 Vital Signs DILI 
 Hepatic Event Supplemental Medical History for PDILI 
 Potential Hepato-Toxic Medications Inquiry for PDILI 
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 Symptoms of Hepatitis and Hypersensitivity for PDILI 
 Lifestyle PDILI 
 Family Medical History for PDILI 
Listings will be prepared presenting subjects with PDILI data. A summary of number and 
percent of subjects meeting PDILI criteria (ALT, AST, total bilirubin, ALP, and presence of 
symptoms) during the Treatment Period (scheduled and unscheduled visits) will be provided 
following the UCB standard table shell for PDILI Data. Subjects who met these criteria will be 
listed. 
ALT Criteria 
AST Criteria 
Total 
Bilirubin 
Criteria 
ALP 
Criteria 
Presence of 
Symptoms 
≥3xULN 
≥3xULN 
≥2xULN 
≥2xULN 
NA 
≥8xULN  
≥8xULN  
NA 
 
NA 
≥3xULN 
≥3xULN 
NA 
 
Y 
≥3xULN -<5xULN and 
≥2x Baseline 
≥3xULN -<5xULN and 
≥2xBaseline 
<2xULN 
 
N 
≥5xULN -<8xULN and 
≥2x Baseline 
≥5xULN -<8xULN and 
≥2xBaseline 
<2xULN 
 
N 
≥5xULN and ≥2xBaseline 
≥5xULN and 
≥2xBaseline 
<2xULN 
 
N 
N=No; NA=Not Applicable; ULN= upper limit of normal; Y=Yes.  
A summary table highlighting the potential cases of Hy’s Law, within each treatment group will 
be presented. Hy’s Law is defined as:  
 AST ≥3xULN or ALT ≥3xULN and 
 Total Bilirubin ≥2xULN 
In order to meet the above criteria, a subject must experience the elevation in bilirubin and ALT 
or AST at the same visit. For example, a subject who experiences a >=2 x ULN elevation of 
bilirubin at one visit and a 3 x ULN elevation in ALT (or AST) at a subsequent visit has not 
fulfilled the Hy’s law criteria. 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital Signs 
Vital measurements (including SBP, DBP, PR, RR and weight) are generally collected in 
standard units. If any measurements are collected in international units, they will be converted to 
standard units for summaries. Subject Listings will be prepared for vitals variables. 
The observed value and change from Baseline will be summarized descriptively by treatment 
group and scheduled study visit. In the same table, the observed value and change from Baseline 
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will be summarized by treatment for all scheduled visits. The Last Visit, minimum, and 
maximum post-baseline values during the Treatment Period will also be included.  
The number and percentages of subjects with abnormal vital signs and body weight during the 
Treatment Period will be presented by treatment group and PSL total group. The abnormal vital 
sign and body weight criteria are provided in Appendix 13.2. Subject numbers for those meeting 
abnormal criteria will also be presented. 
10.4.2 
Electrocardiograms 
ECG parameters include heart rate, PR interval, QRS duration, QT interval, QTcB [QT corrected 
for heart rate using Bazett’s formula], and QTcF [QT corrected for heart rate using Fridericia’s 
formula]. 
The observed ECG parameter values and their change from Baseline will be summarized (SS) 
descriptively by treatment group and PSL total group for each scheduled assessment visit. The 
Last Visit, minimum, and maximum post-baseline values during the Treatment Period will also 
be included. In addition, the number and percentage of subjects with QTc (Bazett and Fridericia 
corrected) classifications of <450ms, 450 to <480ms, 480 to <500ms, and ≥500ms and change 
from baseline of <30ms, 30 to <60ms, and ≥60ms will be presented for each visit.  
For each ECG, the overall ECG result, is also collected, categorized as one of: no abnormality, 
an abnormal but not clinically significant finding, or a clinically significant finding. The number 
and percentage of subjects with no abnormality, an abnormal but not clinically significant 
finding, and a clinically significant finding will be summarized for each of the scheduled 
assessment visits. Percentages for the visit will be relative to the number of subjects with an 
ECG result for the visit.  
The number and percentages of subjects with abnormal ECG during the Treatment Period will be 
presented by treatment group and PSL total group. The abnormal ECG criteria are provided in 
Appendix 13.3. Subject numbers for those meeting abnormal criteria will also be presented. 
10.4.3 
Echocardiograms 
Echocardiogram data are collected at Visit 1, Visit 6, and Visit 9. Depending on the availability 
of data, echocardiogram abnormalities (Left Ventricle, Left Atrium, Right Ventricle, Right 
Atrium, Pericardium, Pulmonary Artery Systolic Pressure and overall assessment) will be 
summarized by treatment group and PSL total group and scheduled visit as the number and 
percentage of subjects with an abnormality. In addition, Echocardiogram Valvular abnormality 
grade (Aortic Valve, Mitral Valve, Tricuspid Valve, Pulmonary Valve) described in Appendix 
13.4 will be summarized descriptively. Valvular abnormality grade equal or larger than grade 2 
is corresponding to valvular abnormal. Subject numbers with abnormality for any assessment 
will be provided. 
10.4.4 
Other safety variable(s) 
10.4.4.1 
Physical Examination 
Data from the Physical Examination are only provided in subject data listings presented by 
treatment group, subject and visit, displaying all data collected for all subjects. No summaries 
will be provided. Findings that are considered clinically significant will be reported AEs. 
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10.4.4.2 
Neurologic Examination Data 
Data from the Neurological Examination are collected on the Neurological Examination 
Complete and Neurological Examination Brief CRFs and are not summarized. Data from the 
Neurological Examination are only provided in subject data listings presented by treatment 
group, subject and visit, displaying all data collected for all subjects. No summaries will be 
provided. Findings that are considered clinically significant will be reported as AEs. 
10.4.4.3 
Psychiatric and Mental Status Data 
The Psychiatric and Mental Status assessment is performed at Baseline and all scheduled visits.  
These data are collected on the Psychiatric and Mental Status CRF. Assessment of specific 
domains of psychiatric and cognitive symptoms will be performed by a staff member trained in 
the identification of psychiatric symptoms. The parameters that evaluated are orientation, 
attention, memory, mood, and calculus. These parameters will be assessed as normal or 
abnormal and then determined whether clinically significant. The presence of psychiatric 
symptoms, mental impairment, or behavioral problems are also assessed and evaluated as normal 
or abnormal, and whether they are clinically significant.  
For each of these assessments, the number and percentage of subjects with an abnormal result, 
and the number and percentage with an abnormal result considered clinically significant, will be 
summarized at each scheduled visit. 
10.4.4.4 
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS questionnaire is self-administered by the subject and assessed by trained study 
personnel. This scale is used to assess suicidal ideation and behavior at Baseline (Visit 1), and at 
each subsequent study visit. C-SSRS data will be provided in subject listing for subjects with 
suicidal ideation and suicide behavior.  
10.4.4.5 
Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) 
Subjects not entering the open label extension study (OLE) are tapered off study medication after 
completing the Maintenance Period (or if discontinued from the study). As part of monitoring of 
subjects for withdrawal symptoms during the Taper Period, the CIWA-B evaluation is performed 
at the end of the Maintenance Period (Visit7), at the end of the Taper Period (Visit 8), and at the 
Safety follow-up visit (Visit 9). The CIWA-B questionnaire contains 22 questions, which are 
utilized to determine the type and the severity of withdrawal symptoms, ranging from mild, 
moderate, severe and very severe withdrawal symptoms (Busto et al, 1989). Subscores of each of 
the first 20 questions (scores from 0-4) are summed up to a total score: 
Total score 
Interpretation 
1-20 
Mild withdrawal 
21-40 
Moderate withdrawal 
41-60 
Severe withdrawal 
61-80 
Very severe withdrawal 
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In case of a missing subscore the total score is set to missing. The remaining two items of the 22 
ask for sleeping duration and time to fall asleep. A by-subject listing will be provided, presenting 
the response values to all assessment parameters as well as the CIWA-B scores. In addition, a 
descriptive summary table will be prepared for total CIWA-B scores at scheduled visits. 
11 
OTHER ANALYSIS 
Analyses for the exploratory nonhereditary pharmacogenomics and pharmacogenetics variables 
will be described in separate documents. 
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12 
REFERENCES 
Busto, UE, Sykora, K, Sellers, EM. A Clinical scale to assess benzodiazepinewithdrawal. Journal 
of Clinical Psychopharmacology. 1989;9(6);412-416. 
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. 
Cramer JA, Van Hammee G, N132 Study Group. Maintenance of improvement in health-related 
quality of life during long-term treatment with levitiracetam. Epilepsy Behav. 2003;4:118-23. 
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. 
French JA, Gil-Nagel A, Malerba S, et al.  Time to prerandomization monthly seizure count in 
perampanel trials: A novel epilepsy endpoint. Neurology 2015;84;2014-2020.  
Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, 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.  
National Research Council (US) Panel on Handling Missing Data in Clinical Trials. The 
Prevention and Treatment of Missing Data in Clinical Trials. Washington (DC): National 
Academies Press (US); 2010. 
Scoring manual for the QOLIE-31-P: Patient-Weighted QUALITY OF LIFE IN EPILEPSY 
(v.2). Provided by the QOLIE Development Group. 
Zigmond RP, Snaith AS. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 
1983;67(6):361-70. 
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13 
APPENDICES 
13.1 
PCST Criteria for Hematology, Serum Chemistry and Urinalysis Parameters 
13.1.1 
Hematology 
PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
Hematocrit 
<2y 
% 
≤27 
>45 
% 
≤27 
>45 
2y - <18y 
≤29 
>47 
≤29 
>47 
≥18y 
≤85% of LLN 
≥115% of ULN) 
≤85% of LLN 
≥115% of ULN 
Hemoglobin 
<2y 
g/dL 
≤9.0 
>15.0 
g/L 
≤90 
>150 
2y - <18y 
≤9.5 
>16.0 
≤95 
>160 
≥18y 
≤85% of LLN 
≥115% of ULN 
≤85% of LLN 
≥115% of ULN 
WBC/Leukocytes 
<12y 
109/L 
<3.5 
>15.0 
G/L 
<3.5 
>15.0 
≥12y 
<3.0 
>12.0 
<3.0 
>12.0 
Neutrophils Absolute 
>1m 
109/L 
<1.5 
G/L 
<1.5 
Lymphocytes 
<6m 
% 
≤30.0 
% 
≤30.0 
6m - <6y 
≤22.0 
≤22.0 
6y - <18y 
≤12.0 
≥80.0 
≤12.0 
≥80.0 
≥18y 
≤10.0 
≥80.0 
≤10.0 
≥80.0 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
Basophils 
>1m 
% 
≥3.0 
% 
≥3.0 
Eosinophils 
>1m 
% 
≥10.0 
% 
≥10.0 
Monocytes 
>1m 
% 
≥20.0 
% 
≥20.0 
Platelets 
>1m 
109/L 
≤100 
>600 
G/L 
≤100 
>600 
RBC/ Erythrocytes 
<2y 
1012/L 
<3.0 
T/L 
<3.0 
≥2y 
<3.5 
<3.5 
Abbreviations: F=female; M=male; m=month; y= year. A month is defined as 30 days; a year is defined as 365.25 days. 
 
 
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13.1.2 
Serum Chemistry 
 
PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
AST (SGOT) 
<14y 
U/L 
>180 
U/L 
>180 
≥14y 
>144 
>144 
ALT (SGPT) 
1y - <18y 
U/L 
>90 
U/L 
>90 
≥18y 
>123 
>123 
Alkaline 
Phosphatase 
<4y 
U/L 
>690 
U/L 
>690 
4y - <10y 
>834 
>834 
10y - <18y 
>1174 
>1174 
≥18y 
>432 (F) 
>933 (M) 
>432 (F) 
>933 (M) 
GGT 
<6m 
U/L 
>522 
U/L 
>522 
6m - <1y 
>279 
>279 
1y - <13y 
>66 
>66 
13y - <18y 
>126 
>126 
≥18y 
>255 
>255 
Total Bilirubin 
>1m 
mg/dL 
≥1.5 
umol/L 
≥25.656 
Total Protein 
2m-<1y 
g/dL 
<3.0 
>10.0 
g/L 
<30 
>100 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
≥1y 
<4.3 
>10.0 
<43 
>100 
Albumin 
<1y 
g/dL 
<1.6 
>6.0 
g/L 
<16 
>60 
≥1y 
<2.4 
>7.0 
<24 
>70 
BUN 
<1y 
mg/dL 
>21 
mmol/L 
>7.497 
≥1y 
>30 
>10.71 
Urea 
<1y 
mg/dL 
>42 
mmol/L 
>7.014 
≥1y 
>60 
>10.02 
Creatinine 
1y - <10y 
mg/dL 
>0.9 
umol/L 
>79.56 
10y - <16y 
>1.4 
>123.76 
≥16y 
>1.6 
>141.44 
Creatinine 
Clearance* 
All 
mL/min 
<70 
mL/s 
<1.169 
Calcium 
<1y 
mg/dL 
<6.9 
>12.2 
mmol/L 
<1.725 
>3.05 
1y - <18y 
<7.4 
>11.7 
<1.85 
>2.925 
≥18y 
<7.9 >11.1 
≤1.975 
≥2.775 
Phosphorous 
<1y 
mg/dL 
<1.8 
>8.2 
mmol/L 
<0.5814 
>2.6486 
≥1y 
<1.8 
>7.4 
<0.5814 
>2.3902 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
Potassium 
<1y 
mEq/L 
<3.0 
>6.5 
mmol/L 
<3.0 
>6.5 
≥1y 
<3.0 
>5.8 
<3.0 
>5.8 
Sodium 
>1m 
mEq/L 
≤130 
≥150 
mmol/L 
≤130 
≥150 
Glucose 
>1m 
mg/dL 
<50 
>180 
mmol/L 
<2.775 
>9.99 
Total Cholesterol 
1y - <18y 
mg/dL 
>250 
mmol/L 
>6.475 
≥18y 
>300 
>7.77 
LDL (calculated) 
1y - <18y 
mg/dL 
>140 
mmol/L 
>3.626 
≥18y 
>200 
>5.18 
HDL 
≤2y 
mg/dL 
<10 
mmol/L 
<0.259 
>2y 
<20 
<0.518 
Triglycerides 
<1y 
mg/dL 
>750 
mmol/L 
>8.475 
≥1y 
>250 
>2.825 
 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
Uric Acid 
<1y 
mg/dL 
>7.7 
umol/L 
>457.996 
1y - <13y 
>6.5 
>386.62 
13y - <18y 
>8.6 
>511.528 
≥18y 
>6.8 (F) 
>404.464 (F) 
>9.6 (M) 
>571.008 (M) 
Thyroxine (T4) 
<1y 
ug/dL 
≤4.3 
nmol/L 
≤55.3453 
≥18.4 
≥236.8264 
≥1y 
≤3.8 
≤48.9098 
≥13.5 
≥173.7585 
Globulin 
<1y 
g/dL 
<1.0 
g/L 
<10 
>3.8 
>38 
≥1y 
<1.2 
<12 
>4.4 
>44 
Abbreviations: ALT= alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; dL = 
deciliter; F=female; GGT: gamma-glutamyltransferase; HDL = high density lipoprotein; LDL = low density lipoprotein; L 
= liter; M=male; m = month (a month is defined as 30 days) mg = milligram; mmol = millimoles; μg = microgram; U = 
unit; ULN = upper limit of normal; y = years (a year is defined as 365.25 days) 
*Schwartz equation (patients <12y):   Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine Cockroft equation (patients 
>12y): Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine); Female: Cr Cl ml/min = [(140-
age) x body weight (kg)] / (72 x serum creatinine)] x 0.85 
 
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13.1.3 
Urinalysis 
Qualitative urine parameters are generally reported by a descriptive score, which differs among 
laboratories. For data analysis purpose, a four-point scale is used. Five-point, six- point, or 
seven-point scales will be collapsed into a four-point scale first. A value is considered possibly 
clinically significant treatment emergent abnormal if an upward shift of at least 2 degrees from 
the baseline occurs under investigational treatment. To collapse the results in a five-point scale 
into a four-point scale, the lowest two positive results will be combined (see example below). 
For results reported with a scale of more than five-point, please consult your study physician for 
how to collapse into four-point scale. 
Original Five-point Scale 
Four-point Scale 
Negative/None 
Negative/None 
Trace/Rare/Mild/A Few 
Trace/1+/Rare/Mild/A Few 
1+ 
 
2+/Mod 
2+/Mod 
3+/Sev 
3+/Sev 
 
 
 
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13.2 
Abnormal Criteria for Vital Sign and Body Weight Parameters 
Abnormality criteria to be applied in the assessment of vital signs parameter values are given 
below. 
PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
Pulse Rate 
(beats/minute) 
<6m 
<100 
>180 
6m - <3y 
<90 
>150 
3y - <12y 
<60 
>130 
12y - <17y 
<50 
>120 
≥17y 
<50 and a decrease from Baseline of ≥15 
>120 and an increase from Baseline of ≥15 
Systolic Blood 
Pressure (mmHg) 
<6m 
<60 
>100 
6m - <3y 
<70 
>120 
3y - <12y 
<80 
>140 
12y - <17y 
<90 
>160 
≥17y 
≤ 90 and a decrease from Baseline of ≥20 
≥ 180 and an increase from Baseline of ≥20 
Diastolic Blood 
Pressure (mmHg) 
<6m 
<40 
>65 
6m - <3y 
<45 
>75 
3y - <12y 
<50 
>80 
12y - <17y 
<50 
>105 
≥17y 
<50 and a decrease from Baseline of ≥15 
>105 and an increase from Baseline of ≥ 15 
Respiratory Rate 
(breaths/minute) 
<6m 
<25 
>55 
6m - <3y 
<20 
>45 
3y - <12y 
<15 
>35 
≥12y 
<10 
>25 
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PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
Temperature 
>1m 
>101 0F (38.3 0C) 
Body Weight 
1m - <17y 
<3% or 97% of the normal body weight growth 
curve ranges based on gender and the age of subject 
on date of weight assessmenta 
≥17y 
≥ 10% change from Baseline (an increase or a 
decrease)a 
Abbreviations: m = month, y = year. A month is defined as 30 days; a year is defined as 365.25 
days. asource: http://www.cdc.gov/growthcharts/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13.3 
Abnormal Criteria for ECG 
Abnormality criteria to be applied in the assessment of ECG parameter values are given 
below: 
Parameter 
Age 
Abnormality Criteria 
QT interval (ms) 
1m-<12y 
>500 
>12y 
>500 or ≥60ms increase from Baseline 
QTc(F) (ms) 
<6m 
>490, or >15% increase from Baseline 
6m-<3y 
>440, or >15% increase from Baseline 
3y-<12y 
>440, or >15% increase from Baseline 
>12y- <17y 
>440, or >15% increase from Baseline 
≥17y 
>500 or ≥60ms increase from Baseline 
QTc(B) (ms) 
<6m 
>490, or >15% increase from Baseline 
6m-<3y 
>450, or >15% increase from Baseline 
3m-<12y 
>450, or >15% increase from Baseline 
>12y- <17y 
>450, or >15% increase from Baseline 
≥17y 
>500 or ≥60ms increase from Baseline 
PR interval (ms) 
<6m 
>150, or >25% increase from Baseline 
6m-<3y 
>170, or >25% increase from Baseline 
3y-<12y 
>180, or >25% increase from Baseline 
>12y - <17y 
>200, or >25% increase from Baseline 
≥17y 
Treatment-emergent value >200, >220, >250 
QRS interval (ms) 
<6m 
>90, or >25% increase from Baseline 
6m-<3y 
>90, or >25% increase from Baseline 
3y-<12y 
>100, or >25% increase from Baseline 
>12y - <17y 
>110, or >25% increase from Baseline 
≥17y 
Treatment-emergent value >100, >120, >140 
Heart rate (bpm) 
<6m 
<100, >180 
6m-<3y 
<90, >150 
3y-<12y 
<60, >130 
>12y 
<50, >120 
Abbreviations: bpm = beats per minute; m = months; ms = milliseconds; QTc = corrected 
QT interval; y = years. A month is defined as 30 days; a year is defined as 365.25 days. 
Note: Treatment-emergent is defined as meeting the criteria at any post-Baseline visit 
during the Treatment Period (including unscheduled visits) and not meeting the same 
criteria during Baseline 
 
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13.4 
Echocardiogram Valvular Abnormality Grading Criteria 
Echocardiogram 
Valvular 
Abnormality 
Severity / Description 
Potential 
Cardiovascular 
Signs/Symptoms 
Action  
Grade 0 
Absent: no regurgitation, 
no stenosis 
None reported 
None 
Grade 1 
Mild: trace or barely 
detected 
regurgitation/stenosis 
Minimal to none 
None; continued observation  
Grade 2 
Moderate: 
regurgitation/stenosis 
with intermediate values 
Symptomsa: 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
 
Signs:  
Pulmonary arterial 
pressure >40mm Hg and 
rise of >10mmHg; 
pulmonary edema; 
peripheral edema or 
ascites; atrial fibrillation 
or malignant arrhythmia; 
hypotension  
For a Grade 2/moderate severity, 
a decision to discontinue is 
based on severity of clinical 
signs/symptoms; if accompanied 
with moderate to severe 
signs/symptoms this results in 
subject discontinuation. 
Grade 3 
Severe: 
regurgitation/stenosis in 
the extreme range, often 
accompanied by other 
symptoms 
(eg, pulmonary 
congestion) 
Discontinuation of subject. 
For a Grade 3 of severe, subject 
should be discontinued 
regardless of accompanying 
clinical symptoms. 
Grade increase by 
2 levels 
Increasing from:  
Grade 0 to 2 or  
Grade 1 to 3 
Rapid onset of above 
signs/symptoms 
A jump of 2 grades to 
Grade 2/moderate accompanied 
with moderate to severe 
signs/symptoms results in 
subject discontinuation. 
A jump of 2 grades to 
Grade 3/severe (with/without 
symptoms) will result in subject 
discontinuation. 
aNote: Based on the New York Heart Association Classification of symptoms. Other echocardiogram measurements 
are described in the study Echocardiogram Manual. 
 
 
 
 
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14 
AMENDMENT(S) TO THE SAP 
14.1 
Amendment 1 
Rationale for the amendment  
The primary purpose of this amendment is to remove Multiple Comparison Procedures – 
Modeling (MCP-Mod) analyses in accordance with Protocol Amendment 2 and to add sensitivity 
analyses to evaluate the impact of missing data on the primary efficacy variable.  
Modifications and changes 
Global Changes 
Section 2 Protocol Summary has been updated to use the same order and text as in the Protocol 
Amendment 2. Selected texts in other sections have been modified to minimize repetitions and 
provide clarifications and additional details to the planned analyses.    
Major specific changes 
Change #1 
Table 3-1 Start and end of EP0091 study periods 
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Period 
Start of Period 
End of Period 
Details 
Baseline 
(Week -4) 
Date of informed 
consent at Visit 1  
Date of the day before the 
date of Visit 2. 
 
This is an approximate 28-day period 
for calculation of Baseline seizure 
frequencies. Study drug is dispensed, 
and first dose is generally taken the 
day of the Baseline Visit (Visit 2, 
Day 1). 
Dose Titration plus 
Stabilization 
The date of the 
Baseline Visit, 
(Visit 2, Day 1).  
The date of the day before 
Visit 4. 
For evaluation purposes, if results are 
presented by study period, the Dose 
Titration and the Stabilization 
interval will be considered together 
(approximately 4 weeks in total). 
Dose Titration is a period of dose 
increases to reach the protocol 
specified dose. Stabilization is an 
approximate week-long interval to 
stabilize at the target dose level. 
During stabilization the dose may be 
adjusted once (i.e. to a fallback 
dose). Note that seizure counts 
collected from the diary returned on 
Day 1 are included in the baseline 
period seizure counts.  
Maintenance 
The date of Visit 
4. 
The date of Visit 7 
This is a 12-week period where the 
subject remains on the protocol-
specified dose. Note that seizure 
counts collected from the diary 
returned at Visit 4 are included in the 
previous period seizure counts. 
16-week Treatment 
Period 
The date of the 
Baseline visit 
(Visit 2)  
The date of Visit 7 
 
Taper/Conversion 
The date of the 
day after Visit 7 
The date of Visit 8 
This is a 3- to 4-week period of dose 
tapering or dose conversion to enable 
the subjects to end the study, or 
enroll into the OLE study EP0093, 
respectively. 
Safety Follow-up  
The date of the 
day after Visit 8 
Date of Visit 9 for subjects 
not entering OLE EP0093  
Only subjects not entering the OLE 
Study EP0093 return for the SFU 
visit. Subjects not entering OLE will 
have an additional ECHO at 6 
months after the SFU visit.  SAEs 
will be collected until the 6-month 
echo.  
OLE=open-label extension; SFU=Safety Follow Up 
Has been changed to: 
 
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Period 
Start of Period 
End of Period 
Details 
Baseline 
(Week -4) 
Date of informed 
consent at Visit 1  
Date of the day before the 
date of Visit 2. 
 
This is an approximate 28-day 
period for calculation of Baseline 
seizure frequencies. Study drug is 
dispensed, and first dose is 
generally taken the day of the 
Baseline Visit (Visit 2, Day 1). 
Note the pre-dose assessments on 
the date of Visit 2 will also be 
included in the Baseline Period.  
Titration and 
Stabilization 
The date of the 
Baseline Visit, 
(Visit 2, Day 1).  
The date of the day before 
Visit 4 or the end of the 
treatment period if the 
subject has discontinued 
prior to Visit 4. 
For evaluation purposes, if results 
are presented by analysis period, the 
Titration and the Stabilization 
interval will be considered together 
(approximately 4 weeks in total). 
Titration is a period of dose 
increases to reach the protocol 
specified dose. Stabilization is an 
approximate week-long interval to 
stabilize at the target dose level. 
During stabilization the dose may 
be adjusted once (i.e. to a fallback 
dose).  
Maintenance 
The date of Visit 
4. 
The date of Visit 7 or the end 
of the treatment period if the 
subject has discontinued 
prior to Visit 7. 
This is a 12-week period where the 
subject remains on the randomized 
target dose (or fallback dose, if 
applicable).  
16-week Treatment 
Period 
The date of the 
Baseline visit 
(Visit 2)  
The date of Visit 7 or the end 
of the treatment period if the 
subject has discontinued 
prior to Visit 7. 
Titration and Stabilization Period 
and Maintenance Period combined.  
Conversion 
The date of the 
day after Visit 7 
The date of Visit 8.  
This is a 3- -week period of dose 
conversion to enable the subjects to 
enroll into the OLE study EP0093. 
Taper and Safety 
Follow-up 
The date of the 
day after Visit 
7/EDV 
The date of final contact.  
Subjects who withdraw from the 
study or decide not to participate in 
the OLE study will be tapered off 
the IMP during a 3-week period 
followed by a 1-week drug-free 
period.  A SFU visit will be 
performed 30 days after the last 
IMP intake. 
OLE=open-label extension; SFU=Safety Follow Up 
Change #2 
The following has been added:  
3.2.5 Last Visit during the Treatment Period  
The Last Visit for an assessment is the last non-missing assessment during the Treatment Period. 
All scheduled and unscheduled assessments within the Treatment Period will be considered. Last 
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Visit will be determined separately each study assessment. Last visit during the Treatment Period 
will be included in the by-visit summary unless noted otherwise. 
Change #3 
Section 3.5.4 Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects in the RS who were administered at least 1 
dose or a partial dose of IMP and have at least 1 post-Baseline visit during the Treatment Period. 
In case of dosing administration error, or change in treatment dose, summaries and analyses 
using the FAS will be conducted according to randomized treatment. The FAS will be the 
primary analysis set for all efficacy summaries and analyses. 
Has been changed to: 
The Full Analysis Set (FAS) consists of all subjects in the RS who were administered at least 1 
dose or a partial dose of IMP and have Baseline and at least 1 post-Baseline seizure frequency 
data during the Treatment Period. In case of dosing administration error, or change in treatment 
dose, summaries and analyses using the FAS will be conducted according to randomized 
treatment. The FAS will be the primary analysis set for all efficacy summaries and analyses. 
Change #4 
Section 3.5.6.2  
Pharmacokinetic Per-Protocol Set  
A PK Per Protocol Set (PK-PPS) may be identified for active treatment groups, which would 
exclude subjects with major deviations that could impact PK evaluations. Subjects to be 
excluded from this PK-PPS, for example, those with values that are BLQ, will be identified 
during a pre-analysis data review meeting of PK variables. 
Has been changed to: 
A PK Per Protocol Set (PK-PPS) will be identified for active treatment groups, which would 
exclude subjects or PK sample data points with major deviations that could impact PK 
evaluations. Subjects or PK sample data points to be excluded from this PK-PPS, will be 
identified during a pre-analysis data review.  
Change #5 
Section 3.6 
Treatment crossover Subjects (including any subjects with dosing errors) will be analyzed for 
efficacy according to their randomized treatment assignment and not the actual treatment 
received.  
Safety analyses will be based on the SS. It is expected that subjects will receive the randomized 
treatment and be analyzed according to that assigned treatment. However, if a subject were to 
experience a dosing error resulting in treatment crossover, the subject will be analyzed as 
follows. If, after unblinding, it is determined that a subject randomized to placebo received PSL 
at any time, then for safety analyses the subject will be reallocated to the appropriate PSL dose 
group. If the dosing error exposes the subject to more than one dose level, the subject will be 
reallocated to the treatment arm for the lowest dose level. If a subject is randomized to PSL but 
experiences a dosing error resulting treatment with placebo, that subject will only be reallocated 
to the placebo treatment group if the subject never received a dose of PSL. 
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Has been changed to: 
The FAS will be the primary analysis set for all efficacy summaries and analyses. Treatment 
crossover Subjects (including any subjects with dosing errors) will be analyzed for efficacy 
according to their randomized treatment assignment and not the actual treatment received.  
Safety analyses will be based on the SS. It is expected that subjects will receive the randomized 
treatment and be analyzed according to that assigned treatment. However, if a subject were to 
experience a dosing error resulting in treatment crossover, incorrectly treated subjects will be 
evaluated during the blinded data evaluation meetings to assess the potential impact of such 
cases and any special considerations for statistical analyses. 
Change #6 
The following has been added in Section 4.1: 
Investigative sites have been identified in the following regions and countries at the time of this 
SAP amendment. More regions and/or countries may be identified and will be included in the 
analyses in accordance to the randomization strata:  
- 
Europe (Australia, Belgium, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, 
Lithuania, Poland, Portugal, Slovakia, Spain, Turkey, and United Kingdom) 
- 
North America (Canada, Mexico, and United States) 
- 
Asia (Japan) 
Change #7 
Section 4.2.1 Handling of missing data for efficacy variables based on diary-collected 
seizure frequency 
Seizure frequency will be computed over non-missing diary days. Calculation of seizure 
frequency is described in Section 8.1.1. Missing seizure diary days will not be considered in the 
calculation of seizure frequency. For subjects who prematurely discontinue, or otherwise have 
missing diary days, the calculation of the seizure frequency over a specified period will be based 
on available seizure diary up to the last diary entry of the period. This effectively imputes the 
unobserved seizures after discontinuation with the seizure frequency observed prior to 
discontinuation. Generally, compliance with the daily seizure diary is expected to be high in a 
refractory population and, therefore, the impact of missing diary data is expected to be minimal. 
However, the impact of missing diary data cannot be ruled out, and missing data will be assessed 
as part of the database pre-lock meeting to ensure an acceptable level of compliance with the 
seizure diary across the study population. Diary compliance evaluation is described in Section 
7.2. Subjects with diary data deemed unacceptably incomplete (during blinded data review) for 
the primary endpoint may be excluded from the PPS supportive analyses.  
 Efficacy analyses of changes from Baseline, Percent reduction from Baseline, and seizure-
free days 
 Continuous variables of change from Baseline, percent reduction from Baseline in seizure 
frequency over the 12-week Maintenance Period, changes from Baseline to successive 4 
week intervals within the Maintenance Period, and number of seizure-free days within 
the 12-week Maintenance Period: 
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The specified primary period of evaluation for changes in 28-day adjusted seizure frequency is 
during the 12-week Maintenance Period. For certain other efficacy variables, the period of 
evaluation is the entire 16-week Treatment Period, or during 3 successive 4-week intervals 
within then Maintenance Period. If a subject completes all or part of the 12 week Maintenance 
Period but has no seizure diary records at all during the period, such that seizure frequency 
cannot be calculated, then the 28-day adjusted seizure frequency will be imputed using the diary 
data from the most recent study period available (starting with the Stabilization Period if 
available, and using the Dose Titration Period data if no data from the Stabilization Period are 
available).  There will be no use of Baseline diary data to compute any post-Baseline seizure 
frequencies.  
 Continuous variables of change from Baseline and percent reduction from Baseline in 
seizure count over the entire 16-week Treatment Period 
Since the calculation of the seizure frequency over a specified period will be based on available 
seizure diary from the start of the Treatment Period up to the last diary entry, for FAS (subjects 
must have at least one post-baseline visit), if at least one diary day entry is returned, missing data 
(unobserved seizures) during the Treatment period are effectively imputed. If there are any 
subjects in the FAS who do not return any seizure diary data at all, those dropouts will not be 
included in the analysis. 
 Seizure clusters 
Investigator sites are to report the number of cluster episodes rather than reporting the estimated 
number of individual seizures. No imputation will be applied for any seizure counts 
corresponding to reports of cluster seizures. 
 Responder Analyses  
For the main analyses of responder rates (RR), including seizure-free status rates, observed data 
will be used, with no imputation of missing status. However, a sensitivity analysis of the 75% 
and 50% RR may be performed in which missing data will be handled using non-responder 
imputation (NRI). That is, subjects who have missing data at the time point or interval of 
evaluation will be treated as though they did not respond to the treatment. 
Has been changed to: 
4.2.1 Handling of missing data in seizure frequency 
Unless noted otherwise, the imputation described below will be applied to seizure frequency. 
The responder status will be determined based on the imputed seizure frequency. Sensitivity 
analyses for missing data are described in Section 8.1.2 for the primary efficacy variable.  
4.2.1.1 Missing data caused by missing seizure diary 
Seizure frequency will be computed over non-missing diary days. Diary compliance evaluation 
is described in Section 7.2. Subjects with diary data deemed unacceptably incomplete (during 
blinded data review) for the primary efficacy variable will be excluded from the PPS. 
4.2.1.2 Missing seizure data caused by discontinuation 
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For subjects who prematurely discontinued during the Treatment Period, the calculation of 28-
day adjusted POS frequency over the Treatment Period will be based on available seizure diary 
up to the end of the Treatment Period.  
For subjects who prematurely discontinued the study, the last observation carried forward 
(LOCF) method will be applied to obtain a seizure frequency estimate for the Maintenance 
Period: 
• 
Subjects who discontinued during the Titration and Stabilization Period: seizure frequency 
will be calculated using all available data in the Titration and Stabilization Period and carry 
forward for the Maintenance Period. 
• 
Subjects discontinued during the Maintenance Period: seizure frequency will be calculated 
using all available data in the Maintenance Period. 
Change #8 
Section 4.5 Multiple comparisons/multiplicity 
Change during the Maintenance Period in log-transformed observable focal-onset seizure 
frequency from Baseline is the primary efficacy variable for FDA submission and the key 
secondary endpoint for submission to European regulatory agencies. For these analyses, the 
dose-response relationship for change from Baseline in observable focal-onset seizure frequency 
across 4 doses of PSL and placebo will be evaluated using Multiple Comparison Procedure-
Modeling (MCP-Mod) methodology (Bretz et al, 2005) to test monotonic dose-response trends 
and controlling the overall Type 1 error rate at 0.05 (2-sided testing), as described in Section 
8.1.2.1. Assuming at least 1 statistically significant result is obtained from the primary MCP-
Mod analysis, then pairwise comparisons of each of the 400mg (800mg/day), 200mg (400 
mg/day) and 100mg (200 mg/day) dose groups versus placebo will be carried out using the 
ANCOVA analysis model described in Section 8.1.2.1. Type 1 error will be controlled by the 
Hochberg step-up procedure within SAS® Proc Multtest. If all the results of the pairwise 
comparisons are statistically significant, then the 50mg (100mg/day) dose group will be 
compared to placebo. 
A similar strategy for Type I error control will be used for the primary variable for the EMA 
submission. Analysis details are provided in Section 8. 
Has been changed to: 
For the primary efficacy variables, statistical testing will be based on the comparison of 400mg 
bid, 200mg bid and 100mg bid PSL groups versus placebo. Type 1 error will be controlled by the 
Hochberg step-up procedure within SAS® Proc Multtest. Hochberg procedure orders the p-
values from the largest to the smallest. The significance level for the k-th step is given by 0.05/k. 
More specifically, the largest p-value will be compared to 0.05. If it is smaller than 0.05, we will 
stop the testing and conclude significance for all 3 comparisons; otherwise we will move to the 
second highest p-value. The second largest p value will be compared to 0.025 (=0.05/2). If it is 
smaller than 0.025, we will stop and conclude significance for this comparison and the 
subsequent one that produced p-values smaller than the current one; otherwise we will move to 
the smallest p-value. The smallest p-value will be compared to 0.0167 (0.05/3). If it is smaller 
than 0.0167, we will conclude a significant difference between the dose and the placebo; 
otherwise, stop and no comparison is significant.  
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If the 3 higher doses are all statistically different from the placebo, the 50mg bid PSL group will 
be compared to placebo. Because this follows a gatekeeping procedure, testing will be conducted 
at the 0.05 level (2-sides). If the p-value is smaller than 0.05, we will conclude 50mg bid is also 
significantly different from the placebo. 
Change #9 
Section 5.1 
 Subject disposition 
Screen failure data of screened subjects who did not meet study eligibility criteria are collected 
on the Study Termination Screen Failure CRF (dates of screen failure and last contact and reason 
for screen failure).  
Disposition data of randomized subjects are obtained from the Study Termination CRF. 
Variables include date of last administration of study medication, date of premature study 
termination, date of final contact with subject, subject status at study termination, primary reason 
for premature study termination (as listed on the CRF), and if the study blind was broken (Y/N 
and date, if applicable).  
Disposition of subjects (ES) will be listed by region, country and investigative site. A listing will 
also be provided for study discontinuation (RS), and for study visit dates (RS). 
The date of first subject first visit (earliest Visit 1), date of last subject last visit (latest scheduled 
or unscheduled visit), and the number of screened subjects will be summarized for all study sites 
and by study site using the ES. 
Summaries of the numbers of screened subjects and reasons for screen failures will be produced 
overall and by region, country and site for the ES.   
The disposition of the ES will be summarized overall and by region, country and site presenting 
the dates of first subject in (first enrolled) and last subject out, number of subjects screened, the 
number randomized to each treatment group, and number of subjects included in the each of the 
RS, FAS, SS, and PK Sets.   
The disposition of subjects into treatments groups and analysis sets (RS, FAS, SS, and PK Set) 
will also be summarized for the RS, overall and by region.   
The disposition of the RS will be presented as the number and percentage of subjects who 
discontinued treatment and of subjects who discontinued the study, including a breakdown of the 
primary reason for discontinuation. Only 1 primary reason for discontinuation should have been 
reported. If more than 1 reason is specified in the clinical database, both reasons will be 
summarized, and a footnote will be added to the summary table to indicate that at least 1 subject 
is counted for multiple reasons for discontinuation. This will also be provided for the FAS and 
SS.  
In addition, the numbers and percentages of subjects (FAS) entering and completing each of the 
following study periods: (Dose Titration plus Stabilization Period, Maintenance Period, and the 
Taper/Conversion Period) will be summarized overall and by treatment group within region. 
The number and percentage of randomized subjects completing each scheduled study visit will 
be summarized overall and by treatment group. Early discontinuation visits (EDV) that 
correspond to scheduled visits will be included in the counts for the scheduled visits to which 
they correspond. 
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Has been changed to: 
Screen failure data of screened subjects who did not meet study eligibility criteria are collected 
on the Study Termination Screen Failure CRF (dates of screen failure and last contact and reason 
for screen failure).  
Disposition data of randomized subjects are obtained from the Study Termination CRF. 
Variables include date of last administration of study medication, date of premature study 
termination, date of final contact with subject, subject status at study termination, primary reason 
for premature study termination (as listed on the CRF), and if the study blind was broken (Y/N 
and date, if applicable).  
Disposition of subjects (ES) will be listed by region, country and investigative site. A listing will 
also be provided for study discontinuation (RS), and for study visit dates (RS). 
Summaries of the numbers of screened subjects and reasons for screen failures will be produced 
overall for the ES.   
The disposition of the ES will be summarized overall and by region, country and site presenting 
the dates of first subject in (first enrolled) and last subject out, number of subjects screened, and 
number of subjects included in the each of the RS, FAS, SS, PPS, and PK-PPS.   
The disposition of the SS will be presented as the number and percentage of subjects who 
completed the study and of subjects who discontinued the study, including a breakdown of the 
primary reason for discontinuation. Of note, the corresponding table is required for data 
transparency reporting.  
In addition, the numbers and percentages of subjects (SS) entering and completing each of the 
following analysis periods: (Titration and Stabilization Period, Maintenance Period, Conversion 
Period, and Taper and SFU Period) will be summarized by treatment group and overall. The 
same summary will be repeated by region.  
The number and percentage of subjects in the SS who discontinued due to AE categorized by 
serious fatal, non-fatal, and non-serious fatal AE incidence will also be presented by treatment 
group and overall. Of note, the corresponding table is required for data transparency reporting.  
Change #10 
Section 8.1.1 Derivations of primary efficacy variables 
8.1.1.1 Primary efficacy variable for submission to the FDA, PMDA, and other regulatory 
authorities not referencing EMA 
The primary efficacy variable is the change from Baseline in the log-transformed observable 
focal-onset seizure frequency from Baseline over the 12-week Maintenance Period.  
 Calculation of seizure frequency: 
The total number of observable focal-onset seizures (Types IA1, IB, and IC) will be calculated 
for each subject across all diary records during the study period being evaluated. For the primary 
variable, this is the 12-week Maintenance Period. The diary days for this period, which are 
collected onto the Seizure Count eCRF, are obtained from the diaries returned at Maintenance 
Period Visits 5, 6, and 7, which document daily seizure counts since Visit 4 (start of 
Maintenance).  
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The patient’s 28-day adjusted seizure frequency of observable focal-onset seizures (Types IA1, 
IB, and IC) during the 12-week Maintenance Period will be calculated by dividing the number of 
seizures in the Maintenance Period by the number of days for which the diary was completed in 
the period and multiplying the resulting value by 28. The corresponding Baseline 28-day 
adjusted seizure frequency for the endpoint is calculated similarly, as described in Section 3.3.  
The 28-day adjusted seizure frequency value for Baseline and the Maintenance Period will be 
log-transformed using the function ln(x+1), where ln represents the natural logarithm function. 
 Calculation of Change in seizure frequency from Baseline: 
In the calculation below the 28-day adjusted seizure frequency refers to the log-transformed 
value. 
The change from Baseline is calculated for each subject by subtracting the 28-day adjusted 
seizure frequency during the 12-week Maintenance Period from the 28-day adjusted seizure 
frequency during the 4-week Baseline period as follows: 
(log-transformed focal-onset seizure frequency during Maintenance) - (log-transformed focal-
onset seizure frequency during Baseline), where seizure frequency refers to the 28-day adjusted 
frequency for the period. 
Seizure frequency estimates obtained using log-transformed values, i.e. ln(x+1), will be back-
transformed for table presentation: table_estimate=exp(ln_estimate)-1. Differences relative to 
placebo will be back-transformed as 100*(1-exp(diff)), where diff is the model estimate of the 
log ratio. Similarly, estimates for the upper and lower bounds of the 95% CI will be back-
transformed for table presentation as exp(upper) and exp(lower), respectively, where upper and 
lower are the estimates from the model performed on log-transformed values.  As applicable for 
a presentation, the difference may be expressed as percent difference relative to placebo. 
8.1.1.2 Primary efficacy variable for submission the EMA and regulatory authorities who 
reference EMA 
The primary efficacy variable will be the 75% responder rate status, defined as a ≥75% reduction 
in observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance 
Period. 
 Responder Rate for reduction in seizure frequency  
A subject is defined as a 75% responder in the evaluation period if s/he has a reduction in seizure 
frequency of at least 75% (≥ 75%) from the Baseline seizure frequency. 
The Responder rate will be calculated as follows: 
Count of responders during the 12-week Maintenance Period 
x 100 
Responder count + Non-responder count during the Maintenance Period 
Has been changed to: 
8.1.1.1 Seizure frequency 
Seizure frequency (SF) refers to the 28-day adjusted seizure frequency. The 28-day adjusted 
seizure frequency is defined as: SF = (Number of Seizures) x (28 / D). The number of seizures is 
the total number of seizures during an analysis period or time interval. For cluster seizures, the 
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Statistical Analysis Plan                 Padsevonil (UCB0942)                                                                              EP0091 
 
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number of cluster episodes will be included. D corresponds to the number of days for which the 
diary was available during the analysis period or time interval.  
8.1.1.2 Change in log-transformed seizure frequency from Baseline 
The 28-day adjusted seizure frequency value will be log-transformed using the function ln(x+1), 
where ln represents the natural logarithm function. The change in the log-transformed seizure 
frequency from Baseline is calculated as: Ln (SFT+1) – Ln (SFB+1), where SFT corresponds to 
the seizure frequency during an analysis period and SFB corresponds to the Baseline period 
seizure frequency.  
For the primary efficacy variable for the FDA, SFT and SFB are the observable focal-onset 
seizure frequency during the 12-week Maintenance Period and Baseline Period, respectively.  
8.1.1.3 Percent reduction in seizure frequency from Baseline 
The percent reduction in seizure frequency (PRD) from the Baseline is defined as: PRD = [(SFB 
– SFT) / SFB] x 100, where SFT corresponds to the 28-day adjusted seizure frequency during an 
analysis period and SFB corresponds to the Baseline seizure frequency. A negative PRD 
indicates an increase in seizure frequency from Baseline.  
8.1.1.4 75% Responder 
Responder status (yes or no) of a subject is determined by the percent reduction in seizure 
frequency (PRD) from Baseline. A subject is defined as a 75% responder if s/he has a reduction 
in seizure frequency (PRD) of at least 75% from the Baseline. The 75% responder rate (RR) will 
be calculated as the proportion of 75% responders. For the primary efficacy variable for the 
EMA, 75% responder status is calculated based on the percent reduction (PRD) from the 
Baseline in observable focal-onset seizure frequency during the 12-week Maintenance Period. 
Change #11 
Section 8.1.2 Analysis of the primary efficacy variables 
8.1.2.1 Primary variable for submission to the FDA, PMDA, and other regulatory 
authorities not referencing EMA 
Analyses of the primary variable for FDA/PMDA submission will be done on the FAS as 
described below. 
1. Dose Response Relationship 
The first step for analyzing the primary variable is to assess the monotonic dose-response 
relationship for change from Baseline in observable focal-onset seizure frequency across 4 doses 
of PSL and placebo using the Multiple Comparison Procedure-Modeling (MCP-Mod) 
methodology (Bretz et al, 2005). MCP-Mod is a testing and model selection approach for clinical 
dose finding studies. During testing, contrasts of dose group means are derived from candidate 
dose response models and a multiple-comparison procedure is applied that controls the alpha 
level for the family of null hypotheses associated with the contrasts. Provided at least one 
contrast is significant, a corresponding set of candidate models is identified. 
The study design evaluates five doses: 0 (placebo), 50, 100, 200 and 400 mg, all administered 
BID. The primary efficacy variable is log change from Baseline in Seizure frequency. The 
candidate models will include adjustments for Baseline log-transformed seizure frequency 
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(continuous covariate), and Baseline SV2A use (Yes or No) and Region (Asia, Europe or North 
America) as categorical factors. Monotonic dose-response trends will be tested using the 
appropriate contrasts as determined by the MCP-Mod methodology such that the overall Type 1 
error rate is controlled at 0.05 (2-sided testing). 
Candidate Models and Corresponding Contrasts 
Four different dose-response models (“candidate models”) were identified: 
1. Sigmoidal Emax 
2. Emax 
3. Log-linear 
4. Logistic 
Four families of models were considered in the candidate set for representing the expected 
response µ𝑑 at dose 𝑑: 
Sigmoidal Emax :  µ𝑑= 𝐸0  + 𝐸𝑚𝑎𝑥 ∗
𝑑ℎ
𝐸𝐷50
ℎ + 𝑑ℎ,  
parameters to estimate: 𝐸0(placebo effect), 𝐸𝑚𝑎𝑥 (asymptotic maximum effect) , 
𝐸𝐷50 (Dose giving half of the asymptotic maximum effect) and h 
(Hill parameter, detremining the steepness of the model at the 𝐸𝐷50). 
Emax :  µ𝑑 = 𝐸0  + 𝐸𝑚𝑎𝑥 ∗
𝑑
𝐸𝐷50 + 𝑑,  
parameters to estimate: 𝐸0, 𝐸𝑚𝑎𝑥   and  𝐸𝐷50. 
 
Linear in log: µ𝑑 = 𝐸0 +  𝛿∗log (𝑑+ 𝑜𝑓𝑓),  
parameters to estimate: 𝐸0 and 𝛿(slope parameter=1 for standardized model)  
 
Logistic:  µ𝑑 = 𝐸0 + 𝐸𝑚𝑎𝑥/{1 + exp [(𝐸𝐷50 −𝑑)/ 𝛿]},  
parameters to estimate: 
𝐸0, 𝐸𝑚𝑎𝑥(asymptotic maximum effect), 𝐸𝐷50(dose giving half of the asymptotic maximum effect) 
and 𝛿(parameter controlling the steepness of the curve) 
 
The specified candidate models for MCD-mod were: 
Sigmoidal Emax :  µ𝑑=  0.195 +  0.780 ∗
𝑑2
502 + 𝑑2, 
Emax :  µ𝑑 =  0.195 +  0.780 ∗
𝑑
75 + 𝑑 
Linear in log: µ𝑑 =  0.195 +  480 ∗log (𝑑+ 1),  
Logistic:  µ𝑑 =  0.195 +  0.780/{1 + exp [(150 −𝑑)/ 75]},  
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Optimal contrasts: 
Dose 
linlog 
emax 
sigEmax 
logistic 
0 
-0.845 
-0.772 
-0.792 
-0.485 
50 
-0.008 
-0.164 
-0.178 
-0.357 
100 
0.138 
0.096 
0.190 
-0.171 
200 
0.284 
0.333 
0.363 
0.289 
400 
0.431 
0.507 
0.417 
0.724 
The contrasts are used to calculate the test statistics and multiplicity adjusted p-values. The 
covariance matrix chosen will be the identity matrix unless the data indicate otherwise, in which 
case a compound symmetry or unstructured covariance matrix may be used instead. If at least 
one model is significant, there is an indication for evidence of a dose-response effect. 
2. Initial Pairwise Comparisons 
Assuming at least 1 statistically significant result is obtained from the MCP-mod analysis, 
described in (1) above, then pairwise comparisons of the 400mg (800mg/day), 200mg 
(400mg/day) and 100mg (200mg/day) dose groups versus placebo will be carried out using the 
analysis model described below. Type 1 error will be controlled using the Hochberg step-up 
procedure within SAS® Proc Multtest. 
Change from Baseline in observable focal-onset seizure frequency (using the log-transformed 
data) will be analyzed for the FAS using analysis of covariance (ANCOVA) with treatment 
group as the main factor, Baseline log-transformed seizure frequency as a continuous covariate, 
and Baseline SV2A use (Yes or No) and Region (Asia, Europe or North America) as categorical 
factors. Pairwise contrasts will be constructed to compute estimated effects of each dose from 
placebo. 
Treatment effects will be characterized using treatment differences based on back-transformation 
of least squares (LS) means obtained for each treatment group from the above ANCOVA model. 
Two-sided 95% confidence intervals for comparisons will also be obtained using the above 
ANCOVA model. Estimates of effects and comparison contrasts and CI will be back-
transformed for display in tables as described in Section 8.1.1.1. 
3.  Additional Comparison 
If all the results of the 3 pairwise comparisons described in (2) above are statistically significant, 
then the 50mg dose group (100mg/day) will be compared to placebo. 
8.1.2.2 Supportive and sensitivity analyses for the primary variable for submission to the 
FDA, PMDA, and other regulatory authorities not referencing EMA 
The primary analysis of change from Baseline in observable focal-onset seizure frequency for 
submission the FDA described in Section 8.1.2.1 will be repeated using the PPS. 
In addition, a sensitivity analysis of the continuous primary efficacy variable will be carried out 
using a Mixed Model Repeated Measures (MMRM) analysis on the FAS. The observable focal-
onset seizure frequency (using the log-transformed data) will be analyzed with treatment group 
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Statistical Analysis Plan                 Padsevonil (UCB0942)                                                                              EP0091 
 
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as the main factor, Baseline log-transformed seizure frequency as a continuous covariate, and 
with Region (Asia, Europe or North America), and Baseline SV2A use (Yes or No) as fixed 
effects. For the MMRM analysis the 28-day adjusted seizure frequencies will be computed using 
diary records for the following visit intervals: Maintenance Period intervals from Visit 4 to Visit 
5, from Visit 5 to Visit 6 and from Visit 6 to Visit 7. These will be utilized as the repeated 
measures (random effect) for the analysis. MMRM estimates the mean outcome at each 
measurement time by treatment arm.  An unstructured covariance structure will be used. If the 
model does not converge, an appropriate covariance structure will be used instead. The variance 
of the outcome measure at each observed time and the covariance between each of the repeated 
measures are all estimated based on the data, without assumption. 
Estimates of effects and comparison contrasts and CI will be back-transformed for display in 
tables as described in Section 8.1.1.1. 
8.1.2.3 Primary variable for submission to the EMA and regulatory authorities who 
reference EMA 
Analyses of the primary variable for EMA submission will be done on the FAS as described 
below. 
1. Dose response relationship 
As done for the FDA/PMDA primary variable analysis, the first step for analyzing the primary 
variable for EMA is to assess the dose-response relationship across 4 doses of PSL and placebo 
using the MCP-Mod methodology. This will be done for the primary EMA submission variable, 
which is the 75% RR binary endpoint. The  As described in Section 8.1.2.1, monotonic dose-
response trends will be tested using the appropriate contrasts as determined by the MCP Mod 
methodology such that the overall Type 1 error rate is controlled at 0.05 (2-sided testing). The 
candidate models will include adjustments for Baseline log-transformed seizure frequency 
(continuous covariate), and Baseline SV2A use (Yes or No) and Region (Asia, Europe or North 
America) as categorical factors. Because the same assumptions for the candidate models’ 
parameters are used, the optimal contrasts are the same as those presented in Section 8.1.2.1. 
2. Initial Pairwise Comparisons 
The primary efficacy variable is the 75% responder rate (RR) status during the Maintenance 
Period. Assuming at least 1 statistically significant result is obtained from the MCP-Mod 
analysis, then pairwise comparisons of the 75% RR, for each of the 400mg (800mg/day), 200mg 
(400mg/day) and 100mg (200mg/day) dose groups versus placebo, will be carried out using a 
logistic regression model on the 75% RR, with factors for treatment group (each PSL dose group 
referenced to the placebo group), Region (Asia, Europe or North America), Baseline SV2A use 
(0, 1) and log-transformed Baseline seizure frequency as a continuous covariate. If there are 
issues with convergence, Baseline SV2A use will be dropped. Odd’s Ratios of PSL dose to 
Placebo will be obtained and tested for difference from unity (2-sided) for the dose groups 
400mg (800mg/day), 200mg (400mg/day) and 100mg (200mg/day).  
3. Additional Comparison 
If all 3 Odd’s Ratios of PSL dose relative to Placebo are statistically significant, then the 50mg 
(100mg/day) dose group will be compared to placebo by testing the Odd’s Ratio for difference 
from unity. 
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8.1.2.4 Supportive and sensitivity analyses for the primary variable for submission to the 
EMA and regulatory authorities who reference EMA 
The primary analysis (75% responder rate) for submission to the European regulatory agency as 
described in Section 8.1.2.3 will be repeated using the PPS.  
In addition, a sensitivity analysis of the 75% and 50% RR may be performed in which missing 
data will be handled using non-responder imputation (NRI). That is, subjects who have missing 
data at the time point or interval of evaluation are to will be treated as though they did not 
respond to the treatment. 
Has been changed to: 
8.1.2.1 Primary variable for submission to the US FDA, PMDA, and other regulatory 
authorities not referencing EMA 
The primary efficacy variable for the US FDA/PMDA is the change in log-transformed 
observable focal onset seizure frequency from Baseline, over the 12-week Maintenance Period. 
Analyses of the primary variable for the FDA will be performed on the FAS as described below.  
Change from Baseline in observable focal-onset seizure frequency (using the log-transformed 
data) will be analyzed for the FAS using analysis of covariance (ANCOVA) with treatment 
group (PSL 400mg bid, 200mg bid, 100mg bid, 50mg bid, and placebo) as the main factor, 
Baseline log-transformed seizure frequency as a continuous covariate, Baseline SV2A use (Yes 
or No), and Region (Europe, North America, or Asia) as categorical factors. Pairwise contrasts 
will be constructed to compute estimated effects of each dose from placebo. 
Treatment effects will be characterized using treatment differences based on back-transformation 
of least squares (LS) means obtained from the above ANCOVA model. Percent reduction over 
placebo will be calculated as 100*(1-exp(diff)), where diff is the model estimate of the log ratio 
between each PSL group and placebo group. Similarly, estimates for the upper and lower bounds 
of the 95% confidence interval (CI) will be back-transformed for table presentation as 
exp(lower) and exp(upper), respectively, where upper and lower correspond to the 95% CI of the 
log ratio. 
Pairwise comparisons of the 400mg bid, 200mg bid, and 100mg bid PSL dose groups versus 
placebo will be carried out using the analysis model described above. Type 1 error will be 
controlled using the Hochberg step-up procedure (Section 4.5) within SAS® Proc Multtest. If all 
the results of the 3 pairwise comparisons are statistically significant, then the 50mg bid dose 
group will be compared to placebo, too. Both multiplicity-adjusted and unadjusted p-values will 
be presented.   
8.1.2.2 Supportive and sensitivity analyses for the primary variable for submission to the 
US FDA, PMDA, and other regulatory authorities not referencing EMA 
8.1.2.2.1 Sensitivity analysis 1: PPS 
The primary analysis of change from Baseline in observable focal-onset seizure frequency for 
submission the FDA described in Section 8.1.2.1 will be repeated for the PPS. 
8.1.2.2.2 Sensitivity analysis 2: “worst case” imputation 
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A “worst case” imputation will be performed to assess the impact of missing data. For subjects 
who discontinued during the Titration and Stabilization, if the seizure frequency during the 
Titration and Stabilization Period is less than the Baseline, the seizure frequency during the 
Maintenance Period will be imputed using the Baseline seizure frequency. For other subjects 
who discontinued early, seizure frequency during the Maintenance Period will be imputed using 
the LOCF methods described in Section 4.2.1.2.  
The primary analysis in Section 8.1.2.1 will be repeated following the “worst case” imputation.  
8.1.2.3 Primary variable for submission to the EMA and regulatory authorities who 
reference EMA 
The primary efficacy available for the EMA is the 75% responder rate over the 12-week 
Maintenance Period. Analyses of the primary variable for the EMA submission will be done on 
the FAS as described below. 
The analysis of 75% responder rate will be based on a logistic regression model with factors for 
treatment group (PSL 400mg bid, 200mg bid, 100mg bid, 50mg bid and placebo), Region 
(Europe, North America, or Asia), Baseline SV2A use (Yes or No) and log-transformed Baseline 
seizure frequency as a continuous covariate. If there are issues with convergence, Baseline SV2A 
use will be dropped. Odd’s Ratios of PSL dose to placebo will be obtained and tested for 
difference from unity (2-sided) for the dose groups 400mg bid, 200mg bid, and 100mg bid. The 
evaluation of statistical significance will be based on the Hochberg procedure as described in 
Section 4.5. If all 3 Odd’s Ratios of PSL dose relative to placebo are statistically significant, then 
the 50mg bid dose group will be compared to placebo by testing the Odd’s Ratio for difference 
from unity, too. Both multiplicity adjusted p-values and unadjusted p-value will be presented. 
8.1.2.4 Supportive and sensitivity analyses for the primary variable for submission to the 
EMA and regulatory authorities who reference EMA 
8.1.2.4.1 Sensitivity analysis 1:  PPS 
The primary analysis (75% responder rate) for submission to the European regulatory agency as 
described in Section 8.1.2.3 will be repeated using the PPS.  
8.1.2.4.2 Sensitivity analysis 2: non-responder imputation  
A sensitivity analysis of the 75% responder rate will be performed in which subjects who 
discontinued prior to the end of the Maintenance Period will be treated as non-responders. The 
primary analysis in Section 8.1.2.3 will be repeated. 
8.1.2.5 Subgroup analyses for the primary variables 
The analyses described in Section 8.1.2.1 and 8.1.2.3 will be repeated for the subgroups 
described in Section 4.8. In the subgroup analyses by region and Baseline SV2A use, the 
corresponding stratification factor will be removed from the model. These evaluations will be 
descriptive and the model estimates and 95% CIs will be presented. 
Change #12 
Section 8.2 Statistical analysis of the secondary efficacy variables 
Separate secondary efficacy variables have been designated for submission to FDA and 
submission to European regulatory agencies. 
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8.2.1 Derivations of secondary efficacy variables  
This section describes variable derivations and calculation of population statistics to be used for 
analyses. 
8.2.1.1 Secondary variables for submission to the FDA, PMDA, and other regulatory 
authorities not referencing EMA 
The secondary endpoint variables described in Section 8.2.2 are based on evaluation of the 12 
week Maintenance Period. Calculations for these endpoint variables are as follows:  
 Responder Rates for reduction in seizure frequency  
The 75% and 50% Responder Rates will be calculated for evaluation as secondary efficacy 
variables for FDA/PMDA submissions. The 90% Responder Rate is considered as one of the 
other efficacy variable (Section 8.3) and will also be calculated. A subject is defined as a XX% 
responder in the evaluation period (where XX refers to 75 or 50) if s/he has a reduction in seizure 
frequency of at least XX% (≥ XX%) from the Baseline seizure frequency. 
Responder rates will be calculated as follows: 
Count of responders during the 12-week Maintenance Period 
x 100 
Responder count + Non-responder count during the Maintenance Period 
 
 The percent reduction from Baseline in the frequency of observable focal onset seizures over 
the 12-week Maintenance Period will be calculated for each subject as: 
Change from Baseline in the 28-day adjusted seizure frequency during Maintenance 
x 100 
28-day adjusted seizure frequency during the Baseline Period 
8.2.1.2 Secondary variables for submission to EMA and regulatory authorities who 
reference EMA 
The derivations for log-transformed observable focal onset seizure frequency from Baseline, 
over the 12-week Maintenance Period, which is also the primary variable for FDA submission, is 
described in Section 8.1.1.1. 
The calculation of 50% responder rate status, defined as a ≥50% reduction in observable focal-
onset seizure frequency from Baseline, over the 12-week Maintenance Period is described in 
Section 8.2.1.1.  
The derivations for the percent reduction from Baseline in the frequency of observable focal 
onset seizures over the 12-week Maintenance Period are described in Section 8.2.1.1. 
8.2.2 Analysis of the secondary efficacy variables for submission to the FDA, PMDA, and 
other regulatory authorities not referencing EMA 
8.2.2.1 75% Responder Rate status over the 12-week Maintenance Period 
The secondary efficacy variable, 75% responder rate status, is defined as a ≥75% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance Period. 
The 75% responder rate status will be analyzed for the FAS using a logistic regression model, 
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with factors for treatment group (each PSL dose group referenced to the placebo group), Region 
(Asia, Europe or North America), Baseline SV2A use (0, 1) and log-transformed Baseline 
seizure frequency as a continuous covariate. If there are issues with convergence, Baseline SV2A 
use will be dropped. Odd’s Ratios of each PSL dose to Placebo will be obtained and tested for 
difference from unity (2-sided). The 95% confidence intervals will be presented for each 
estimate. This analysis will be repeated using the PPS.  
8.2.2.2 50% Responder Rate status over the 12-week Maintenance Period 
The secondary efficacy variable, 50% responder rate status, is defined as a ≥50% reduction in 
observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance Period. 
The 50% responder rate status will also be analyzed for the FAS using a logistic regression 
model, with factors for treatment group (each PSL dose group referenced to the placebo group), 
Region (Asia, Europe or North America), Baseline SV2A use (0, 1) and log-transformed 
Baseline seizure frequency as a continuous covariate. If there are issues with convergence, 
Baseline SV2A use will be dropped. Odd’s Ratios of each PSL dose to Placebo will be obtained 
and tested for difference from unity (2-sided). The 95% confidence intervals will be presented 
for each estimate. The analysis will be repeated using the PPS. 
8.2.2.3 Percent reduction from Baseline in observable focal-onset seizure frequency over 
the 12-week Maintenance Period 
The third secondary efficacy variable is percent reduction from Baseline in observable focal-
onset seizure frequency, over the 12-week Maintenance Period. Analyses of the percent change 
in seizure reduction endpoints will be performed on the FAS using the Wilcoxon-Mann-Whitney 
test. The Hodges-Lehmann nonparametric estimator will be used to estimate the median 
difference between groups in percent reduction in seizures, along with the corresponding 95% 
confidence interval (CI) of the estimate. The Hodges-Lehmann estimator is the median of all 
possible differences (ordered) among subjects in the 2 groups being compared.  
Essentially, for each comparison of a given dose to placebo, a dataset must be created merging 
all responses for the dose and all responses for placebo (using proc SQL) to obtain all possible 
differences in response. These are ordered, and the median is obtained. A detailed method for 
calculating the estimator and distribution-free CI are described in Decker, C., Calculating a 
nonparametric estimate and confidence interval using SAS software. If available, Proc 
StatXact™ 4 for SAS users may be used to calculate the Hodges-Lehmann estimate and 
distribution-free CI. This analysis will be repeated using the PPS.  
8.2.3 Analysis of the secondary efficacy variables for submission to EMA and regulatory 
authorities who reference EMA 
8.2.3.1 Change from Baseline in observable focal-onset seizure frequency  
The analysis described in Section 8.1.2.2 (for FDA, PMDA, and other regulatory authorities not 
referencing EMA) of the change in log-transformed observable focal-onset seizure frequency 
from Baseline, over the 12 week Maintenance Period, serves as the key secondary variable for 
submission to EMA.  To reiterate, Type 1 error will be controlled by the Hochberg step-up 
procedure within SAS® Proc Multtest. If the results of all pairwise comparisons are statistically 
significant, then the 50mg dose group will also be compared to placebo. 
8.2.3.2 50% Responder Rate status over the 12-week Maintenance Period 
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This variable is also a secondary variable for FDA submission and is described in Section 
8.2.2.2. 
8.2.3.3 Percent reduction in observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
This variable is also a secondary variable for FDA submission and is described in Section 
8.2.2.3. 
Has been changed to: 
Separate secondary efficacy variables have been designated for submission to US FDA/PMDA 
and submission to EMA. 
8.2.1 Analysis of the secondary efficacy variables for submission to the US FDA, PMDA, 
and other regulatory authorities not referencing EMA 
8.2.1.1 75% Responder Rate over the 12-week Maintenance Period 
75% responder rate is the secondary efficacy variable for the US FDA and primary efficacy 
variable for the EMA. The analyses are described in Section 8.1.2.3. 
8.2.1.2 50% Responder Rate over the 12-week Maintenance Period 
Subjects with at least a 50% reduction in seizure frequency will be categorized as a 50% 
responder. The same methodology described in Section 8.1.2.3 will be used for 50% responder 
rate during the 12-week Maintenance Period. No multiplicity adjustment will be applied and tests 
will be carried out at a nominal two-sided 0.05 significance level. 
8.2.1.3 Percent reduction from Baseline in observable focal-onset seizure frequency over 
the 12-week Maintenance Period 
The third secondary efficacy variable is percent reduction from Baseline in observable focal-
onset seizure frequency, over the 12-week Maintenance Period. The calculation of percent 
reduction from Baseline in seizure frequency is described in Section 8.1.1.2. The percent 
reduction in seizure frequency will be summarized descriptively.  
Statistical comparisons between each PSL dose group and placebo will be performed on the FAS 
using the Wilcoxon-Mann-Whitney test. No multiplicity adjustment will be applied and tests will 
be carried out at a nominal two-sided 0.05 significance level. The Hodges-Lehmann 
nonparametric estimator will be used to estimate the median difference between each PSL dose 
group versus placebo, along with the corresponding 95% CI of the estimate.  
In addition, the number and percentage of subjects within each of the following categories of 
percent reduction from Baseline will be summarized: <-25%, -25% to <25%, 25% to <50%, 50% 
to <75%, 75% to <100%, and 100%. 
8.2.2 Analysis of the secondary efficacy variables for submission to EMA and regulatory 
authorities who reference EMA 
8.2.2.1 The change in log-transformed observable focal onset seizure frequency from 
Baseline, over the 12-week Maintenance Period  
The analysis described in Section 8.1.2.2 (for US FDA, PMDA, and other regulatory authorities 
not referencing EMA) of the change in log-transformed observable focal-onset seizure frequency 
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from Baseline, over the 12-week Maintenance Period, serves as the key secondary variable for 
submission to EMA.   
8.2.2.2 50% Responder Rate status over the 12-week Maintenance Period 
This variable is also a secondary variable for FDA submission and is described in Section 
8.2.1.2. 
8.2.2.3 Percent reduction in observable focal-onset seizure frequency from Baseline, over 
the 12-week Maintenance Period 
This variable is also a secondary variable for FDA submission and is described in Section 
8.2.1.3. 
Change #13 
The following text has been added in Section 8.3.2:  
8.3.2.21 Use of health-related outcomes and HRU 
Health-related outcomes data and HRU data will be listed for the RS and summarized 
descriptively for the SS.  
• 
Socio-professional status  
Socio-professional status data are collected at Visit 1 and Visit 7/EDV. Variables include highest 
level of education, housing status, current professional status, current unemployed status, need 
for regular assistance due to epilepsy, and ability to drive. The number and percentages of 
subjects in each category will be summarized for Visit 1, Visit 7, and the Last Visit during the 
Treatment Period.  
• 
Healthcare provider consultations not foreseen by the protocol 
The number of health care provider consultations per subject with onset during the Treatment 
Period will be summarized as a continuous variable as well as in the following categories: 0, 1, 2, 
3, 4, and 5 or more. Additionally, the number and percentage of consultations by type of provider 
(general practitioner, specialist physician, nurse, and other) will be presented for the Treatment 
Period. 
• 
Hospital and ER visits 
The number of hospitalization per subject will be summarized as a continuous variable and 
categorical variable for the Treatment Period. ER visits will be extracted from the 
Hospitalization/ER Visit CRF page (if the initial entry point is ER). The number of ER visits will 
be summarized in the same manner as hospitalizations. Additionally, the number and percentage 
of subjects with each of the following categories of duration of hospital stay will be summarized: 
0 days, 1-5 days, 6-10 days, 11-15 days, and >15 days. 
• 
Caregiver assistance 
Caregiver assistance data is collected on the CRFs “Caregiver Assistance Screening” and 
“Caregiver Assistance Follow-up”. The number and percentages of subjects having a caregiver 
will be summarized by visit. 
• 
Concomitant medical procedures 
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The number of concomitant medical procedures per subject during the Treatment Period will be 
summarized using the categories 0, 1, 2, and 3 or more. 
• 
Number of school or working days lost 
Number of school/working days lost data are collected on the CRFs “School and Workdays Lost 
Screening” and “School and Workdays Lost Follow-up”. The number and percentages of 
subjects who lose school or work days as a result of epilepsy will be summarized by visit.  
The percentage of days lost will be summarized by visit for subjects who have more than zero 
total number of school or work days. The percentage of days lost will be calculated as:  
100 × (end date of absence – start date of absence +1)/total number of school or work days 
If a subject didn’t have days lost, the percentage of days lost will be zero. 
Change #14 
Section 9.1 
Pharmacokinetics 
Plasma concentrations of PSL and its major metabolite will be determined from blood samples 
obtained during the Dose Titration and Maintenance Periods (Visits 3, 4, 5, 6 and 7) in order to 
investigate the population PK of PSL and its 
). 
Individual concentrations of PSL will be listed by treatment group for the PK-Set and will 
include the actual and nominal sampling times and the deviation between them. All deviations 
will be calculated relative to the IMP administration. Concentrations will be summarized by 
treatment group and sampling times for the PK-PPS. Geometric means and associated 95% CI of 
plasma concentrations will be tabulated and may be presented graphically for each treatment 
(dose) group by visit. 
Blood samples for measurement of concomitant AED concentrations are collected at Visits 1 
(Screening) and 2 (Baseline). Steady state plasma concentrations of concomitantly administered 
AEDs will be listed by treatment group and will be assessed by evaluating ratios of steady state 
concentrations while on maintenance PSL vs. Baseline (pre-PSL) concentrations. If the Visit 2 
Baseline sample is not available, then the Visit 1 sample may be used. On Visits 6 and 7, unless 
the concomitant AED sample is within ±5 minutes of a scheduled MITRA sample for PSL assay, 
a separate, additional MITRA sample will be taken at same time as the concomitant AED blood 
sample. Subjects are requested to provide blood samples for measurement of PSL and the 
) whenever possible. On Visits 3, 5, and 6, site 
personnel should obtain blood samples for measurement of random PSL concentrations at any 
time between IMP intake and record accurately the time of last IMP intake and the time of 
sample collection. On Visits 4 and 7, blood samples for measurement of sparse PK profiles will 
be collected as follows: immediately before IMP intake (maximum 15 minute before intake) and 
then 3 times after (between 30 minutes and 3 hours after IMP intake), taken at least 30 minutes 
apart. All samples may be taken either at home or in the site or partly at home and partly at the 
site. 
Other PK analyses, including population PK analyses and exploratory PK analyses (such as 
exploratory comparisons of PSL blood concentrations derived from the MITRA sampler with 
conventional venous sampling) will be described in a separate PK Data Analyses Plan (PK 
DAP).  An exploratory evaluation of the PSL 
 will also be undertaken. The 
evaluations described in the PK DAP will be reported separately. 
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Has been changed to: 
9.1 Plasma concentrations of PSL and its major metabolite 
Plasma concentrations of PSL and its major metabolite will be determined from blood samples 
obtained during the Titration and Stabilization and Maintenance Periods (Visits 3, 4, 5, 6 and 7). 
Individual concentrations of PSL and its 
 (from venous conventional 
sampling and dried blood (MITRA) sampling) will be listed for subjects in PSL treatment groups 
for the PK-Set and will include the actual and nominal sampling times and the deviation between 
them. All deviations will be calculated relative to the IMP administration. Values below the 
LLOQ will be reported with a clear sign indicating that they were below the LLOQ. 
Concentrations of PSL and its 
 will be summarized by sampling method 
(venous, dried blood MITRA), PSL dose group, visit, and sampling times for the PK-PPS using 
the following descriptive statistics: number of observations, geometric mean, geometric 
coefficient of variation, arithmetic mean, SD, median, and minimum and maximum values. 
Measured values below the limit of quantification (LOQ) will be set LOQ/2 for the calculation.  
Descriptive statistics of concentrations will be calculated if at least 2/3rd of the individual data 
points are quantifiable (≥LLOQ). 
Of note, geometric mean is calculated as: exp (arithmetic mean of log-transformed 
concentrations); geometric coefficient of variation is calculated as: 100 × sqrt [exp (variance of 
log-transformed concentrations)-1]. 
The PK samples will be summarized using the following nominal time points based on the time 
since last dose:  
• 
15 to <45 min after dosage: 0.5h (30min) 
• 
45 to <75 min after dosage: 1h (60min) 
• 
75 to <105 min after dosage: 1.5h (90min) 
• 
105 to <150 min after dosage: 2h (120min)  
• 
150 to <210 min after dosage: 3h (180min)  
• 
4h: 3.5h to <4.5h 
• 
5h: 4.5 to <5.5h 
• 
6h: 5.5 to <6.5h 
• 
8h:  6.5 to <9h 
• 
10h: 9h to <11h 
• 
12h: 11h to <12h (this window will contain the blood sample pre-dose) 
9.2 Plasma concentrations of concomitant AEDs 
Blood samples for measurement of concomitant AED concentrations are collected at Visits 1, 2, 
6, and 7. The concomitant AED concentrations will be summarized by visit and treatment group 
using the same descriptive statistics above for the PK-Set for AED.  
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The AEDs investigated with mixed models will be those with data available for at least 10 
subjects in one of the treatment groups (subset of PK-Set).  
Plasma concentration data for concomitantly administered AEDs will be assessed by evaluating 
ratios of steady state levels during the Maintenance Period vs baseline levels. The baseline 
concentration is defined as the arithmetic mean concentration (if multiple concentrations are 
available at Visits 1 and 2) or the single concentration (if only 1 concentration is available at 
Visit 1 or Visit 2). Difference between log-transformed AED concentration at Visits 6 and 7 and 
baseline will be assessed using Mixed Model Repeated Measures (MMRM). The model will 
include log-transformed baseline concentration, visit, treatment, and treatment-by-visit 
interaction as fixed effects. An unstructured covariance structure will be used. If the model does 
not converge, an appropriate covariance structure will be used instead. Geometric least-squares 
(LS) means ratios and associated 90% CIs for each visit, by treatment group and PSL total will 
be calculated by exponentiation of the log-transformed data. Changes in AED concentration 
during the Maintenance Period and baseline will be considered clinically relevant if the 
respective 90% CIs fall entirely outside the conventional 0.80-1.25 limits. Forest plots will be 
provided on these (LS) means ratios and associated 90% CIs.  
9.3 Other PK variables  
Other PK analyses, including population PK analyses and exploratory PK analyses will be 
described in a separate PK Data Analyses Plan.  
Change #15: 
Section 10.2 Adverse events 
Adverse events are recorded on the AE CRF as they occur, from the time informed consent is 
granted until study completion or study termination (end of the SFU period 30 days after the last 
IMP intake). All AEs will be coded using the latest available version of MedDRA and will be 
categorized by intensity (mild/moderate/severe). The following subject data listings may be 
provided to the DMC in masked unblinded fashion for the closed session: SAEs, AEs leading to 
dose reduction, AEs leading to withdrawal, and AEs leading to death. Listings will be organized 
by treatment group using the SS. No other AE data listings will be prepared for the DMC. 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the first dose of study treatment or any unresolved event already present before 
initiation of the first dose that worsens in intensity following exposure to the treatment. The 
number and percentage of subjects who experience TEAEs at any time during the study will be 
summarized (using the SS) for each treatment group, for combined PSL groups, and overall 
(combined treatments) by SOC and PT. In the same table, the number and percentage of subjects 
will be summarized by the following treatment periods as defined in Section 2.3.1: Overall, Dose 
Titration plus Stabilization, Maintenance, and Conversion/Taper. The following tabular 
summaries will be presented for the SS: 
• 
Incidence of AEs – Overview 
- 
During the entire study 
• 
Incidence of TEAEs 
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- 
During the following periods: the entire study, the 16-week Treatment Period, the 12-
week Maintenance Period, the 4-week Titration/Stabilization Period, and the 3-week 
Conversion/Taper Period 
• 
Incidence of Serious TEAEs 
During the following periods: the entire study, the 16-week Treatment Period, the 12-week 
Maintenance Period, the 4-week Titration/Stabilization Period, and the 3-week Conversion/Taper 
Period 
• 
Incidence of TEAEs by Relationship 
- 
During the entire study 
• 
Incidence of SAEs by Relationship 
- 
During the entire study 
• 
Incidence of Fatal TEAEs by Relationship 
- 
During the entire study 
• 
Incidence of TEAEs by Maximum Relationship 
- 
During the entire study 
• 
Incidence of TEAEs by Maximum Intensity 
- 
During the entire study 
• 
Incidence of TEAEs (subjects and events) leading to Dose Reduction 
- 
During the Stabilization Period (fall-back option due to a TEAE) 
• 
Incidence of TEAEs leading to Withdrawal 
- 
During the entire study 
The following 2 summary tables will be produced to support results disclosure activities. 
• 
Incidence of Non-Serious TEAEs above the Threshold of 5% of Subjects  
• 
Incidence of Non-Serious TEAEs above the Threshold of 5% of Subjects by Relationship 
Summaries will be presented based on standard Sponsor AE table formats and considering 
formats used for the PSL program.   
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent, 
unless there is unmistakable evidence (through comparison of partial dates, see Section 4.2) to 
suggest that the AE started prior to the first dose of study treatment. Summary tables will contain 
counts of subjects, percentages of subjects in parentheses and the number of events where 
applicable. A subject who has multiple events in the same MedDRA category (SOC or PT) will 
be counted only once in the subject count for that category, however all events will be included 
in the event count for the category. In summaries including relationship to study treatment, the 
following relationships will be summarized: ‘Not related’, ‘Related’. Subjects who experience 
the same event multiple times will be included in the most related category (i.e. a subject 
experiencing both a ‘not related’ and a ‘related’ event in the same MedDRA category will be 
counted as related). Events with missing relationship will be considered as ‘Related’ to the last 
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given study product for summary purposes but recorded as missing in the listings. In summaries 
including intensity, the following intensity categories will be summarized: ‘Mild’, ‘Moderate’, 
‘Severe’. Subjects who experience the same event multiple times, with differing severities, will 
be included in the most severe category. Events with missing intensity will be considered as 
‘Severe’ events for summary purposes but recorded as missing in the listings.   
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT 
within SOC, within the combined treatment group column. 
Illustrative graphs may be prepared of the most frequent AE preferred terms (>=2%) and for 
SAE.  Graphs will present percentage of subjects with the AE (for each severity level) by 
treatment group to visually assess the dose-response relationship. This may also be done for 
percentage of subjects with an SAE. Graphic formats may be adjusted for better illustration 
based on observed frequencies. 
The relationship between somnolence and dose and between fatigue and dose will be explored 
graphically with an event chart presenting subjects on the y-axis (ascending dose group) with 
events charted horizontally over time. Events will be plotted to indicate start and end and will be 
flagged if related to study drug and if severe. 
Has been changed to: 
Adverse events are recorded on the AE CRF as they occur, from the time informed consent is 
granted until study completion or study termination (end of the SFU period 30 days after the last 
IMP intake). All AEs will be coded using the latest available version of MedDRA.  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the first dose of study treatment or any unresolved event already present before 
initiation of the first dose that worsens in intensity following exposure to the treatment. The 
number and percentage of subjects who experience TEAEs at any time during the study will be 
summarized by SOC and PT. The following tabular summaries will be presented for the SS: 
 Incidence of pre-treatment AEs. Pre-treatment AEs are AEs with start dates prior to the date 
of first dose of IMP. 
 Incidence of TEAEs during the Treatment Period – Overview. Of note, the corresponding 
table is required for data transparency reporting.   
 Incidence of TEAEs by period (Treatment Period, Titration and Stabilization Period, 
Maintenance Period, Conversion Period, and Taper and SFU Period) 
 Incidence of Serious TEAEs by period (Treatment Period, Titration and Stabilization Period, 
and Maintenance Period) 
 Incidence of TEAEs leading to discontinuation by period (Treatment Period, Titration and 
Stabilization Period, and Maintenance Period) 
 Incidence of TEAEs leading to dose reduction during the Stabilization Period 
The following will be presented for TEAEs during the overall Treatment Period:  
 Subject numbers for TEAEs 
 Incidence of TEAEs occurring in at least 5% of subjects in any treatment group 
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 Incidence of TEAEs by Relationship 
 Incidence of TEAEs by Maximum Intensity 
 Incidence of SAEs by Relationship. Of note, the corresponding table is required for data 
transparency reporting.   
 Incidence of Fatal TEAEs by Relationship. Of note, the corresponding table is required for 
data transparency reporting.   
 Incidence of Non-Serious TEAEs above the threshold of 5% of subjects in any treatment 
group. Of note, the corresponding table is required for data transparency reporting.   
 Summary of the duration in days per event for the following TEAEs: somnolence, dizziness, 
fatigue, irritability and headache. 
Summaries will be presented based on standard Sponsor AE table formats and considering 
formats used for the PSL program.   
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent, 
unless there is unmistakable evidence (through comparison of partial dates, see Section 4.2) to 
suggest that the AE started prior to the first dose of study treatment. Summary tables will contain 
counts of subjects, percentages of subjects in parentheses and the number of events where 
applicable. A subject who has multiple events in the same MedDRA category (SOC or PT) will 
be counted only once in the subject count for that category, however all events will be included 
in the event count for the category. In summaries including relationship to study treatment, the 
following relationships will be summarized: ‘Not related’, ‘Related’. A subject may be counted 
more than once according to the relationship to study treatment. Events with missing relationship 
will be considered as ‘Related’ to the last given study product for summary purposes but 
recorded as missing in the listings. In summaries of the maximum intensity, the following 
intensity categories will be summarized: ‘Mild’, ‘Moderate’, ‘Severe’. Subjects who experience 
the same event multiple times, with differing severities, will be included in the most severe 
category. Events with missing intensity will be considered as ‘Severe’ events for summary 
purposes but recorded as missing in the listings. The main reasons for treatment discontinuation 
will be listed by subject. 
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT 
within SOC, within the PSL total group column. 
 
 
 
 
 
 
 
 
 
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14.2 
Amendment 2 
Rationale for the amendment  
The primary purpose of this amendment is adding additional sensitivity analyses to evaluate the 
impact of missing data on the primary efficacy variable and update appendices 13.1, 13.2, and 
13.3 with the latest UCB standards.  
Modifications and changes 
Major specific changes 
Change #1 
The following has been added:  
3.5.6.3 AED Pharmacokinetic Per-Protocol Set (AED-PK-PPS)  
An AED PK Per Protocol Set (AED-PK-PPS) will be identified, which would exclude subjects 
or AED PK sample data points with major deviations that could impact AED PK evaluations. 
Subjects or AED PK sample data points to be excluded from this AED-PK-PPS, will be 
identified during a pre-analysis data review.    
Change #2 
The following has been added:  
4.1 Adjustments for covariates 
To ensure at least 5 subjects in each region in the FAS at each treatment group, Japan will be 
pooled with North America to form a non-Europe region for the efficacy analyses.   
Change #3 
4.2.1.2 Missing seizure data caused by discontinuation 
For subjects who prematurely discontinued during the Treatment Period, the calculation of 28-
day adjusted POS frequency over the Treatment Period will be based on available seizure diary 
up to the end of the Treatment Period.  
For subjects who prematurely discontinued the study, the last observation carried forward 
(LOCF) method will be applied to obtain a seizure frequency estimate for the Maintenance 
Period: 
• 
Subjects who discontinued during the Titration and Stabilization Period: seizure frequency 
will be calculated using all available data in the Titration and Stabilization Period and carry 
forward for the Maintenance Period. 
• 
Subjects discontinued during the Maintenance Period: seizure frequency will be calculated 
using all available data in the Maintenance Period. 
Has been changed to:  
4.2.1.2 Missing seizure data caused by discontinuation 
Seizure frequency by analysis period: 
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For subjects who prematurely discontinued during the Treatment Period, the calculation of 28-
day adjusted seizure frequency over the Treatment Period will be based on available seizure 
diary up to the end of the Treatment Period. If a subject had less than 14 days of seizure data 
during the Titration and Stabilization Period, seizure frequency during the Treatment Period will 
be calculated based on the last 28 days with seizure data, including the data in the Baseline 
Period. 
For subjects who prematurely discontinued the study, the following methods will be applied to 
obtain a seizure frequency estimate for the Maintenance Period: 
- 
Subjects who discontinued during the Titration and Stabilization Period: If a subject had at 
least 14 days of seizure data, seizure frequency will be calculated using all available data in 
the Titration and Stabilization Period and carry forward for the Maintenance Period. If a 
subject had less than 14 days of seizure data, seizure frequency will be calculated based on 
the last 28 days with seizure data, including the data in the Baseline Period and carry forward 
for the Maintenance Period.  
- 
Subjects discontinued during the Maintenance Period: If a subject had at least 28 days of 
seizure data during the Maintenance Period, seizure frequency will be calculated using all 
available data in the Maintenance Period. If a subject had less than 28 days of seizure data 
during the Maintenance Period, seizure frequency will be calculated based on the last 28 days 
with seizure data, including the data in the Titration and Stabilization Period. 
Seizure frequency by 4-week interval 
Seizure frequency by 4-week interval will be calculated for the sensitivity analyses (Section 
8.1.2.2) and secondary efficacy analyses (Section 8.3.2.1). Seizure frequency during a 4-week 
interval will be calculated as long as seizure data are available for at least 1 day in the given 
interval. No imputation will be applied for discontinuations.  
Change #4 
The following has been added:  
4.2.3 Handling of missing data for history of epileptic seizures and diagnosis of epilepsy 
4.2.3.1 Incomplete dates for first epileptic seizure 
To calculate the time since the first seizure relative to the date of Visit 1 or age at onset of first 
seizure, January 1st of the year will be imputed for the date of birth, as only year of birth is 
collected on CRF. And a complete date will be imputed for partially missing first seizure date as 
following: 
• 
Missing the day, but month and year present 
Assign the 1st day of the month. 
• 
Missing the day and month, but year present 
Assign January 1st of the year. 
• 
Completely missing 
No imputation will be done. 
4.2.3.2 Incomplete dates for last epileptic seizure 
To calculate the time since last seizure relative to the date of Visit 1, a complete date will be 
imputed for partially missing last seizure date as following: 
• 
Missing the day, but month and year present 
Assign the 1st day of the month. 
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• 
Missing the day and month, but year present 
Assign January 1st of the year or Visit 1, whichever is later in the year. 
• 
Completely missing 
No imputation will be done. 
4.2.3.3 Incomplete dates for first epilepsy diagnosis 
Month and year of the first epilepsy diagnosis are collected on the CRF. To calculate the 
duration of epilepsy derived from the date of first diagnosis relative to the date of Visit 1, or age 
at epilepsy diagnosis, January 1st of the year will be imputed for the date of birth, as only year of 
birth is collected on CRF. And a complete date will be imputed for partially missing date of the 
first epilepsy diagnosis as following: 
• 
Month and year present 
Assign the 1st day of the month or the date of the first seizure, whichever is later in the month. 
• 
Missing the month, but year present 
Assign January 1st of the year or the date of the first seizure, whichever is later in the year. 
• 
Both month and year are missing 
No imputation will be done. 
Change #5 
4.8 Examination of subgroups 
The primary efficacy variable will be evaluated for subgroups of interest including:  
• 
Age (18 to <65 years, ≥65 years) 
• 
Gender 
• 
Region (Europe, North America, and Asia) 
• 
Use of AEDs with binding to synaptic vesicle 2A (SV2A) proteins (levetiracetam [LEV] or 
brivaracetam [BRV], Y/N).  
These evaluations will be descriptive; no statistical testing of treatment-by-subgroup interactions 
nor statistical testing of treatment effects within subgroups will be carried out.  No subgroup 
evaluations are planned for safety variables. 
Has been changed to: 
The primary efficacy variable will be evaluated for subgroups of interest including:  
• 
Age (18 to <65 years, ≥65 years): less than 5 subjects in ≥65 years subgroup in the FAS at 
each treatment group, therefore the subgroup analysis will be omitted. 
• 
Gender 
• 
Region (Europe, North America, and Asia): To ensure at least 5 subjects in each region in the 
FAS at each treatment group, Asia (Japan) will be pooled with North America. The subgroup 
analyses will be performed for Europe vs non-Europe.  
• 
Use of AEDs with binding to synaptic vesicle 2A (SV2A) proteins (levetiracetam [LEV] or 
brivaracetam [BRV], Y/N).  
These evaluations will be descriptive; no statistical testing of treatment-by-subgroup interactions 
nor statistical testing of treatment effects within subgroups will be carried out.  No subgroup 
evaluations are planned for safety variables. 
Change #6 
6.4.3 Use of vagal nerve stimulation at study entry 
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Vagal Nerve Stimulation (VNS) status at Screening (VNS Status at Screening CRF) will be 
summarized as the number and percent of subjects with VNS at screening and as number and 
percent of subjects with VNS turned on. All other VNS data will be provided in subject data 
listings and will not be summarized for the SS. 
Has been changed to: 
6.4.3 Use of vagus nerve stimulation 
Vagus Nerve Stimulation (VNS) status at Screening (VNS Status at Screening CRF) will be 
summarized as the number and percent of subjects with VNS at screening and as number and 
percent of subjects with VNS turned on. Subjects with VNS at screening and setting changed 
during treatment period will also be summarized.  All other VNS data will be provided in subject 
data listings and will not be summarized for the FAS.  
Change #7 
7.1 Treatment compliance 
Percent compliance will be summarized for the SS using descriptive statistics for each treatment 
group and overall. In addition, the number and percentage of subjects with compliance <80%, 
80% to 120%, and >120% will be summarized.   
Has been changed to: 
Percent compliance will be summarized for the FAS using descriptive statistics for each 
treatment group and overall. In addition, the number and percentage of subjects with compliance 
<75%, 75% to125%, and >125% will be summarized.   
Change #8 
The following has been removed: 
8.1.2.2.2 Sensitivity analysis 2: “worst case” imputation 
A “worst case” imputation will be performed to assess the impact of missing data. For subjects 
who discontinued during the Titration and Stabilization, if the seizure frequency during the 
Titration and Stabilization Period is less than the Baseline, the seizure frequency during the 
Maintenance Period will be imputed using the Baseline seizure frequency. For other subjects 
who discontinued early, seizure frequency during the Maintenance Period will be imputed using 
the LOCF methods described in Section 4.2.1.2.  
The primary analysis in Section 8.1.2.1 will be repeated following the “worst case” imputation.  
The following has been added:  
8.1.2.2.2 Sensitivity analysis 2: multiple imputation 
Multiple imputations will be used to assess the robustness of the primary efficacy analysis 
results. Multiple imputation will be performed based on log (28-day adjusted seizure frequency 
+1) by 4-week visit interval over the 16-week Treatment Period. Seizure frequency during a 4-
week interval will be calculated as long as seizure data are available for at least 1 day in the 
given interval.   
Imputation for intermediate missing 
Chances of intermittent missing due to completely missing seizure diary during a 4-week interval 
are low. For subjects with intermittent missing, the last observation carried forward (LOCF) 
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method will be applied to impute the missing seizure frequency during a 4-week interval from a 
previous 4-week interval. 
 Sensitivity analysis 2.1: Missing at random MI 
After the intermittent missing data are imputed, the rest of the missing data will be monotone. 
The first MI analysis assumes MAR for each treatment group separately. Regression method 
using PROC MI statement MONOTONE REG will be used. The imputation model will include 
explanatory variables for log-transformed baseline seizure frequency, baseline SV2A use (Yes or 
No), region (Europe or Non-Europe), and outcome from each visit interval (in chronological 
order). Seed=57832. 
Log-transformed seizure frequency during the Maintenance Period will then be computed by 
taking the average of the data in the three 4-week visit intervals during the Maintenance Period. 
Multiple imputed datasets will be analyzed using the same ANCOVA model as in the primary 
analysis. If there are issues with model convergence, covariates will be dropped sequentially in 
the order of Region, and then Baseline SV2A use (Yes or No) if further needed. The result of the 
100 imputed datasets will be combined for overall inference using SAS PROC MIANALYZE. 
8.1.2.2.2.1 Sensitivity Analysis 2.2: Control-based MI 
The control-based imputation method used the data from the subjects randomized in the placebo 
group to impute the missing value for the subjects in the PSL treatment groups. This assumes the 
subjects on PSL treatment groups will have their efficacy trend toward that of the subjects in the 
placebo group after the treatment discontinuation. Missing data for the first visit interval are 
imputed, then missing data for the second visit interval are imputed using observed data and 
missing data just imputed for the first interval; and so on to the final interval. The imputation will 
be performed via the sequential regression method using PROC MI statement MONOTONE 
REG. Multiple imputed datasets will be analyzed using the same ANCOVA model as in the 
primary analysis. If there are issues with model convergence, covariates will be dropped 
sequentially in the order of Region, and then Baseline SV2A use (Yes or No) if further needed. 
Seed=14823 
8.1.2.2.3.2 Sensitivity Analysis 2.3 Tipping point MI  
In the tipping point analysis, the missing seizure frequencies imputed in the PSL groups using 
MAR will be adjusted repeatedly by a small increment until none of the PSL treatment groups is 
significantly different from placebo. The seed used will be 56432. 
8.1.2.4.3 Sensitivity analysis 3: multiple imputation 
After the multiple imputation process described in Section 8.1.2.2.2, seizure frequency during 
the Maintenance Period will be calculated as [exp (log-transformed seizure frequency) -1] and 
the 75% responder status will be derived. Multiple imputed datasets will be analyzed using the 
same logistic regression model as in the primary analysis for the MAR imputation and control 
based imputation respectively. If there are issues with model convergence, covariates will be 
dropped sequentially in the order of Region, and then Baseline SV2A use (Yes or No) if further 
needed. The tipping point analysis based on MAR multiple imputation will be repeated until 
none of the PSL treatment group is significantly different from placebo based on the logistic 
regression model.  
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The log of the odds ratio estimates from the logistic regression model are used when combining 
into a single inference using SAS PROC MIANALYZE.  
Change #9 
9.1 Plasma concentrations of PSL and its major metabolite 
Plasma concentrations of PSL and its major metabolite will be determined from blood samples 
obtained during the Titration and Stabilization and Maintenance Periods (Visits 3, 4, 5, 6 and 7). 
Individual concentrations of PSL and its 
 metabolite (from venous conventional 
sampling and dried blood (MITRA) sampling) will be listed for subjects in PSL treatment groups 
for the PK-Set and will include visit, actual daily dose (mg), date and time of the most recent 
administration, scheduled sampling time per the CRF, actual date and time of sampling, time 
interval between plasma sample and the most recent administration (in hours). Samples excluded 
from the PK-PPS will be marked in the listing.will include the actual and nominal sampling 
times and the deviation between them. All deviations will be calculated relative to the IMP 
administration. Values below the LLOQ will be reported with a clear sign indicating that they 
were below the LLOQ. 
Concentrations of PSL and its 
 will be summarized by sampling method 
(venous, dried blood MITRA), PSL dose group, visit, and sampling times for the PK-PPS using 
the following descriptive statistics: number of observations, geometric mean, geometric 
coefficient of variation, arithmetic mean, SD, median, and minimum and maximum values. 
Measured values below the limit of quantification (LOQ) will be set LOQ/2 for the calculation.  
Descriptive statistics of concentrations will be calculated if at least 2/3rd of the individual data 
points are quantifiable (≥LLOQ). 
Of note, geometric mean is calculated as: exp (arithmetic mean of log-transformed 
concentrations); geometric coefficient of variation is calculated as: 100 × sqrt [exp (variance of 
log-transformed concentrations)-1]. 
The PK samples will be summarized using the following nominal time points based on the time 
since last dose:  
• 
15 to <45 min after dosage: 0.5h (30min) 
• 
45 to <75 min after dosage: 1h (60min) 
• 
75 to <105 min after dosage: 1.5h (90min) 
• 
105 to <150 min after dosage: 2h (120min)  
• 
150 to <210 min after dosage: 3h (180min)  
• 
4h: 3.5h to <4.5h 
• 
5h: 4.5 to <5.5h 
• 
6h: 5.5 to <6.5h 
• 
8h:  6.5 to <9h 
• 
10h: 9h to <11h 
• 
12h: 11h to <14h (time points for the trough concentration,) 
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Has been changed to: 
9.1 Plasma concentrations of PSL and its major metabolites 
Plasma concentrations of PSL and its major metabolites will be determined from blood samples 
obtained during the Titration and Stabilization and Maintenance Periods (Visits 3, 4, 5, 6 and 7). 
Individual concentrations of PSL and its 
 (from venous conventional 
sampling and dried blood (MITRA) sampling) and concentrations for the 
 will be 
listed for subjects in PSL treatment groups for the PK-Set and will include visit, actual daily dose 
(mg), date and time of the most recent administration, scheduled sampling time per the CRF, 
actual date and time of sampling, time interval between plasma sample and the most recent 
administration (in hours with 2 decimal places). Samples excluded from the PK-PPS will be 
marked in the listing. 
. Values below the limit of quantification (LOQ) will be reported as BLQ (below the limit of 
quantification). 
Concentrations of PSL and its 
 will be summarized by sampling method 
(venous, dried blood MITRA), PSL dose group, visit, and sampling times for the PK-PPS using 
the following descriptive statistics: number of observations, geometric mean, 95% CI of the 
geometric mean, geometric coefficient of variation, arithmetic mean, SD, median, and minimum 
and maximum values. Measured values below the LOQ will be set LOQ/2 for the calculation. 
Concentrations for 
 (only in venous blood) will also be summarized 
similarly.  
Descriptive statistics of concentrations will be calculated if at least 2/3rd of the individual data 
points are quantifiable (≥LOQ). 
Of note, geometric mean is calculated as: exp (arithmetic mean of log-transformed 
concentrations); upper and lower bounds of the 95% confidence interval (CI) of the geometric 
mean are calculated as exp (upper) and exp(lower) of the 95% CI of the arithmetic mean of log-
transformed concentrations; geometric coefficient of variation is calculated as: 100 × sqrt [exp 
(variance of log-transformed concentrations)-1]. 
The PK samples will be summarized based on the actual time since the most recent dose using 
the following time categories:  
• 
>0 to <45 min after dosage: 0.5h (30min) 
• 
45 to <75 min after dosage: 1h (60min) 
• 
75 to <105 min after dosage: 1.5h (90min) 
• 
105 to <150 min after dosage: 2h (120min)  
• 
150 to <210 min after dosage: 3h (180min)  
• 
4h: 3.5h to <4.5h 
• 
5h: 4.5 to <5.5h 
• 
6h: 5.5 to <6.5h 
• 
8h:  6.5 to <9h 
• 
10h: 9h to <11h or >-3h to <-1h 
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• 
12h: 11h to <14h or >=-1h to <=0 (time points for the trough concentration,) 
The geometric mean and associated 95% CI for the trough concentrations of PSL and 
 
 MITRA will be presented by PSL treatment group and visit using semi-log 
plots.  
14.3 
Amendment 3 
Rationale for the amendment  
The primary purpose of this amendment is to clarify details in the planned analyses.  
Modifications and changes 
Major specific changes 
Change #1 
The following has been added:  
3.2.3 Analysis periods 
Table 3‒1: 
Start and end of EP0091 analysis periods 
Only seizure data prior to and on the date of last dose of study medication will be included in the 
analysis. 
Change #2 
The following has been added:  
3.5.6 Completer Set 
The Completer Set is a subset of the FAS, consisting of those subjects who completed the 16-
week treatment period. 
3.5.7.2 Pharmacokinetic Per-Protocol Set (PK-PPS) 
e.g. when there is evidence that the sample collected is not at steady-state due to missing doses, 
dose alterations or interacting concomitant medications, etc. 
Change #3 
The following has been added:  
4.2.1.1 Missing data caused by missing seizure diary 
If seizure type is known but the number of seizures is unknown, the number of seizures will be 
imputed using the median for the same seizure type (daily seizure number > 0) during the same 
analysis period (baseline or treatment period) by subject. Otherwise, the missing seizure number 
will be imputed using the count of next higher level of seizure type. 
Change #4 
The following has been added:  
5.1 Subject disposition 
Subjects who enrolled into EP0093 will also be summarized. 
Change #5 
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6.4.1 Definitions 
Previous AEDs are AEDs taken previously and which has stopped prior to the Visit 1. Previous 
AEDs are reported on History of Previous Antiepileptic Drug Treatment CRF. 
Prior and concomitant medications will be defined for medications reported on AED Medication 
CRF and Prior and Concomitant Medication CRF. Prior medications include any medications 
that started prior to the date of first dose of IMP. Concomitant medications are medications taken 
at least one day in common with the IMP. Medications may be both prior and concomitant.  
• 
A prior medication if: 
- 
(start date of medication) < (start date of IMP) 
- 
start date of medication is unknown but (stop date of medication) < (start date of IMP) 
• 
A concomitant medication if:  
- 
(start date of medication) ≤ (stop date of IMP) and (stop date of medication) ≥ (start date of 
IMP) or ongoing  
- 
start date of medication is unknown but (stop date of medication) ≥ (start date of study drug) 
or ongoing.  
• 
A medication at study entry if: 
- 
(start date of medication) ≤ (the date of Visit 1) and (stop date of medication) > (the date of 
Visit 1) or ongoing  
6.4.2 AED medications 
Each concomitant medication will be classified as either an AED or a non-AED medication. 
AED medication taken previously and which has stopped prior to the Visit 1 will be reported on 
the History of Previous Antiepileptic Drug Treatment CRF. AED mediation that started prior to 
Visit 1 and which is ongoing/or AED medication prescribed during the study will be recorded on 
the AED Medication CRF.  
The number and percentage of subjects taking AED medications will be summarized by 
chemical/therapeutic/pharmacological subgroup (ATC classification level 4), and preferred drug 
name. The following summaries of AED medications will be produced for the SS by treatment 
group and overall:  
• 
Previous AEDs from the History of Previous Antiepileptic Drug Treatment CRF 
• 
Number of previous AEDs taken: <4, 4-5, 6-7, 8-10,>10 AEDs. 
• 
Previous AEDs by reason for AED discontinuation: The number and percentage of subjects 
by reason for discontinuation of previous AEDs will be summarized. Percentages for each reason 
for discontinuation will be relative to the number of subjects taking each AED. 
• 
Prior AEDs 
• 
AEDs taken at study entry  
• 
Number of AEDs taken at study entry: 1, 2, 3, and >3, 4, 5, >5 AEDs  
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• 
Number of lifetime AEDs: <4, 4-5, 6-7, 8-10,>10 AEDs. Lifetime AEDs is defined as AEDs 
with the start date prior to study entry including prior AEDs on AED medication CRF and 
previous AEDs on History of Previous Antiepileptic Drug Treatment CRF.  
• 
Concomitant AEDs 
6.4.4 Prior and Concomitant non-AED medications 
Medications recorded on the Prior and Concomitant Medication CRF should not include AEDs. 
Non-AED medications will be analyzed separately from AED medications. 
The number and percentage of subjects taking non-AED medications will be summarized by 
anatomical main group (Anatomical Therapeutic Chemical [ATC] classification level 1), 
therapeutic subgroup (ATC classification level 2), and preferred drug name. The following 
summaries of non-AED medications will be produced for the SS by treatment group and overall:  
• 
Prior non-AED  
• 
Concomitant non-AED 
Has been changed to:  
6.4.1 AED medications 
Each concomitant medication will be classified as either an AED or a non-AED medication. 
AED medication taken previously and which has stopped prior to the Visit 1 will be reported on 
the History of Previous Antiepileptic Drug Treatment CRF. AED mediation that started prior to 
Visit 1 and which is ongoing/or AED medication prescribed during the study will be recorded on 
the AED Medication CRF.  
• 
Previous AEDs are AEDs taken and stopped prior to the Visit 1. Previous AEDs are reported 
on History of Previous Antiepileptic Drug Treatment CRF. 
• 
AEDs taken at study entry are reported on AED CRF and if: 
- 
(start date of medication) < (the date of Visit 1) and (stop date of medication) ≥ (the  date of 
Visit 1) or ongoing  
• 
Prior AEDs include both previous AEDs and AEDs taken at study entry  
• 
Concomitant AEDs are reported on AED CRF and if:  
- 
(start date of medication) ≤ (stop date of IMP) and (stop date of medication) ≥ (start date of 
IMP) or ongoing  
- 
start date of medication is unknown but (stop date of medication) ≥ (start date of study drug) 
or ongoing.  
The number and percentage of subjects taking AED medications will be summarized by 
chemical/therapeutic/pharmacological subgroup (ATC classification level 4), and preferred drug 
name. The following summaries of AED medications will be produced for the SS FAS by 
treatment group and overall:  
• 
Previous AEDs from the History of Previous Antiepileptic Drug Treatment CRF 
• 
Number of previous AEDs taken: <4, 4-5, 6-7, 8-10,>10 AEDs. 
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• 
Previous AEDs by reason for AED discontinuation: The number and percentage of subjects 
by reason for discontinuation of previous AEDs will be summarized. Percentages for each reason 
for discontinuation will be relative to the number of subjects taking each AED. 
• 
AEDs taken at study entry  
• 
Number of AEDs taken at study entry: 1, 2, 3, and >3AEDs  
• 
Prior AEDs  
• 
Number of prior AEDs: <4, 4-5, 6-7, 8-10,>10 AEDs.  
• 
AEDs taken at study entry  
• 
Number of AEDs taken at study entry: 1, 2, 3, and >3AEDs  
• 
Number of lifetime AEDs: <4, 4-5, 6-7, 8-10,>10 AEDs. Lifetime AEDs is defined as AEDs 
with the start date prior to study entry including prior AEDs on AED medication CRF and 
previous AEDs on History of Previous Antiepileptic Drug Treatment CRF.  
• 
Concomitant AEDs 
6.4.3 Prior and Concomitant non-AED medications 
Medications recorded on the Prior and Concomitant Medication CRF should not include AEDs. 
Non-AED medications will be analyzed separately from AED medications. 
• 
A prior non-AED medication if: 
- 
(start date of medication) < (start date of IMP) 
- 
start date of medication is unknown but (stop date of medication) < (start date of IMP) 
• 
A concomitant non-AED medication if:  
- 
(start date of medication) ≤ (stop date of IMP) and (stop date of medication) ≥ (start date of 
IMP) or ongoing  
- 
start date of medication is unknown but (stop date of medication) ≥ (start date of study drug) 
or ongoing.  
 
A medication at study entry if: 
 
(start date of medication) ≤ (the date of Visit 1) and (stop date of medication) > (the date of 
Visit 1) or ongoing  
The number and percentage of subjects taking non-AED medications will be summarized by 
anatomical main group (Anatomical Therapeutic Chemical [ATC] classification level 1), 
therapeutic subgroup (ATC classification level 2), and preferred drug name. The following 
summaries of non-AED medications will be produced for the SS by treatment group and overall:  
• 
Prior non-AED  
• 
Concomitant non-AED 
Change #6 
The following has been added:  
 
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7.2 Diary compliance 
Only data prior to and on the date of last dose of study medication will be included in the 
compliance calculation. 
Change #7 
Table 8‒1: 
Summary of seizure frequency variables 
Variable 
12-Week Maintenance Period 
     16-Week Treatment Period 
Observable  
Focal Onset 
(IA1, IB and 
IC) 
 
Focal Onset 
(All Type I) 
Observable 
Focal Onset 
(IA1, IB and IC) 
 
Focal Onset 
(All Type I) 
Change in log-SF 
X (a)(c) 
X 
X 
 
75% RR  
X (b)(c) 
X 
X 
 
50% RR 
X (c) 
X 
X 
 
Percent Reduction in 
SF 
X (c) 
X 
X 
X 
90% RR 
X 
X 
 
 
Change in log-SF (4-
week intervals) 
X 
 
 
 
Seizure Freedom 
X 
X 
X 
X 
Number of seizure-
free days 
X 
X 
X 
X 
Cumulative RR 
 
 
X 
X 
Change from baseline 
in seizure frequency 
X 
X 
X 
X 
 
Has been changed to:  
Table 8‒1: 
Summary of seizure frequency variables 
Variable 
12-Week Maintenance Period 
     16-Week Treatment Period 
Observable  
Focal Onset 
(IA1, IB and 
IC) 
 
Focal Onset 
(All Type I) 
All 
Seizures 
(Type I, II 
and III) 
Observable 
Focal Onset 
(IA1, IB and 
IC) 
 
Focal 
Onset 
(All Type 
I) 
All 
Seizures 
(Type I, 
II and 
III) 
Change in log-
SF 
X (a)(c) 
X 
 
X 
 
 
75% RR  
X (b)(c) 
X 
 
X 
 
 
50% RR 
X (c) 
X 
 
X 
 
 
Percent 
Reduction in SF 
X (c) 
X 
 
X 
X 
 
90% RR 
X 
X 
 
 
 
 
100% RR 
X 
X 
 
 
 
 
Change in log-
SF (4-week 
intervals) 
X 
 
 
 
 
 
Seizure Freedom 
 
 
X 
 
 
X 
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Table 8‒1: 
Summary of seizure frequency variables 
Variable 
12-Week Maintenance Period 
     16-Week Treatment Period 
Observable  
Focal Onset 
(IA1, IB and 
IC) 
 
Focal Onset 
(All Type I) 
All 
Seizures 
(Type I, II 
and III) 
Observable 
Focal Onset 
(IA1, IB and 
IC) 
 
Focal 
Onset 
(All Type 
I) 
All 
Seizures 
(Type I, 
II and 
III) 
Number of 
seizure-free days 
 
 
X 
 
 
X 
Cumulative RR 
 
 
 
X 
X 
 
Change from 
baseline in 
seizure 
frequency 
X 
X 
 
X 
X 
 
 
Change #8 
8.1.2.2.2 Sensitivity analysis 2: multiple imputation 
Imputation for intermediate missing 
Chances of intermittent missing due to completely missing seizure diary during a 4-week interval 
are low. For subjects with intermittent missing, the last observation carried forward (LOCF) 
method will be applied to impute the missing seizure frequency during a 4-week interval from a 
previous 4-week interval. 
8.1.2.2.2.3 Sensitivity Analysis 32.3 Tipping point MI  
In the tipping point analysis, the missing seizure frequencies imputed in the PSL groups using 
MAR will be adjusted repeatedly by a small increment (eg, a small percentage of the mean of the 
log-transformed baseline seizure frequency in the Placebo group) until none of the PSL treatment 
groups is significantly different from placebo. The seed used will be 56432.    
Has been changed to:  
Imputation for intermediate missing  
Chances of intermittent missing due to completely missing seizure diary during a 4-week interval 
are low. For subjects with intermittent missing, the last observation carried forward (LOCF) 
method will be applied to impute the missing seizure frequency during a 4-week interval from a 
previous 4-week interval. The intermittent missing seizure frequency before the last 4-week visit 
interval will be assumed as missing at random (MAR). The intermittent missing data will be 
filled in using MCMC method with 30 iterations. The imputation model will include treatment 
groups, log-transformed baseline seizure frequency, baseline SV2A use (Yes or No), region 
(Europe or Non-Europe), and outcome from each visit interval (in chronological order). After the 
intermittent missing data are imputed, the rest of the missing data will be monotone. 
Seed=57832. 
8.1.2.2.2.3 Sensitivity Analysis 2.3 Tipping point MI  
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Following the National Research Council (NRC) report on missing data (NRC, 2010), a 
sensitivity analysis using tipping point method to stress-test the result of MAR by imposing a 
succession of δ adjustments, each one more severe, in the PSL Groups until they are no longer 
statistically significant.  This Delta (δ) will be applied just once, at the first visit that has missing 
frequency seizure data for each subject in the PSL groups who discontinued before the end of 
treatment period and hence have missing records for “seizure frequencies”. Use nimpute = 30, 
seed = 56432. 
The tipping point report (table) for each pairwise comparison will include values for the 
LSmeans, the 95% CI, and the p-value for each of the delta value (including 0, until p-values are 
no longer statistically significant.  Only 8 delta values will be tabulated in the report including 
δ=0 until δ=xx.x% shift the p-value to larger than multiplicity adjusted alpha level. 
Change #9 
The following has been added:  
8.1.2.3 Primary variable for submission to the EMA and regulatory authorities who 
reference EMA 
If there is <2 responders in a treatment group, results will also be provided for an exact 
conditional logistic regression model where treatment group is included in the model and Region 
(Europe or Non-Europe) and Baseline SV2A use (Yes or No) are included as strata.   
Change #10 
8.3.2.5 The 90% responder rate over the 12-week Maintenance Period 
Analysis of the 90% responder rate during the 12-week Maintenance Period will be analyzed for 
the FAS, using the same logistic regression model as specified in Section 8.12.3. 
8.3.2.10 
The 90% responder rate for focal-onset (Type I) seizures over the 12-week 
Maintenance Period 
Analysis of the 90% responder rate for Type I focal-onset seizures during the 12-week 
Maintenance Period will be analyzed for the FAS, using the same logistic regression model as in 
Section 8.1.2.3. 
8.3.2.16 
Seizure-freedom status (yes/no) during the 12-week Maintenance and the 16-
week Treatment Period 
Seizure freedom status will be evaluated for each treatment by summarizing the percentage of 
seizure-free subjects as a response rate during the 12-week Maintenance Period and during the 
entire 16-week Treatment Period. The seizure freedom rate for each of these periods will be 
analyzed using Fisher's Exact Test to compare differences between each PSL dose group and 
placebo. 
Has been changed to:  
8.3.2.5 The 90% and 100% responder rates over the 12-week Maintenance Period 
Analysis of the 90% and 100% responder rates during the 12-week Maintenance Period will be 
analyzed for the FAS, using an exact conditional logistic regression model where treatment 
group is included in the model and region and Baseline SV2A use are included as strata. 
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Statistical Analysis Plan                 Padsevonil (UCB0942)                                                                              EP0091 
 
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Page 119 of 121 
8.3.2.10 
The 90% and 100% responder rates for focal-onset (Type I) seizures over the 
12-week Maintenance Period 
Analysis of the 90% and 100% responder rates for Type I focal-onset seizures during the 12-
week Maintenance Period will be analyzed for the FAS, using an exact conditional logistic 
regression model where treatment group is included in the model and region and Baseline SV2A 
use are included as strata. 
8.3.2.16 
Seizure-freedom status (yes/no) during the 12-week Maintenance and the 16-
week Treatment Period 
Seizure freedom status will be evaluated for each treatment by summarizing the percentage of 
seizure-free subjects as a response rate during the 12-week Maintenance Period and during the 
entire 16-week Treatment Period. The seizure freedom rate will be calculated based on the 
Completer Set. The seizure freedom rate for each of these periods will be analyzed using an 
exact conditional logistic regression model where treatment group is included in the model and 
region and Baseline SV2A use are included as strata. 
Change #11 
9.2 Plasma concentrations of concomitant AEDs 
The AEDs investigated with mixed models will be those with data available for at least 10 
subjects in one of the treatment groups (subset of AED-PK-PPS).  
Has been changed to:  
9.2 Plasma concentrations of concomitant AEDs 
The AEDs investigated with mixed models will be those with data available for at least 10 
evaluable subjects in one of the treatment groups (subset of AED-PK-PPS). An evaluable subject 
is defined as a subject: 
- 
with at least one AED measure (>LOQ) at baseline and at least one AED assessment 
(>LOQ) during the maintenance period  
- 
who received constant dose of AED for at least 14 days prior to the AED samples 
 
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Statistical Analysis Plan                 Padsevonil (UCB0942)                                                                              EP0091 
 
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Page 120 of 121 
15 
ADDENDUM 
All tables described in the SAP will be repeated for Japan and non-Japan subgroups for the 
purpose of Japan specific CSR. 
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UCB                                                                                                                                                           12 Feb 2020 
Statistical Analysis Plan                 Padsevonil (UCB0942)                                                                              EP0091 
 
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Page 121 of 121 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
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Approval Signatures
Name:
ep0091-sap-amend-3
Version:
1. 0
Document Number:
CLIN-000148858
Title:
ep0091-sap-amend-3
Approved Date:
12 Feb 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Feb-2020 18:36:20 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 12-Feb-2020 18:42:21 GMT+0000
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