Clinical trial NCT03370120
Conditions: Drug-Resistant Epilepsy Focal-Onset Seizures
Keywords: Drug-Resistant Epilepsy Padsevonil
Sponsor: UCB Biopharma SRL
Start date: 2018-08-27; Completion date: 2020-12-11
Enrollment: 406 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the long-term safety and tolerability of Padsevonil administered at individualized doses as adjunctive treatment for subjects with drug-resistant epilepsy.

Detailed description:

Arms: arm 1: Padsevonil will be administered in an open-label manner. The individual starting dose of each subject will be the one at the end of the parent study.

Once subjects enter EP0093 further individual dose adjustments are allowed after 1 week to the extent possible with the combination of tablet strengths available.
Interventions: intervention 1: Padsevonil
Intervention descriptions: intervention 1: * Pharmaceutical Form: film-coated tablet
* Route of Administration: Oral use

Protocol documents:
Prot_000.pdf: 
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PROTOCOL EP0093 AMENDMENT 2.0 
AN OPEN-LABEL, MULTICENTER, EXTENSION STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF PADSEVONIL 
AS ADJUNCTIVE TREATMENT OF FOCAL-ONSET SEIZURES 
IN ADULT SUBJECTS WITH DRUG-RESISTANT EPILEPSY 
PHASE 2/3 
EudraCT Number: 2017-003241-26  
IND Number: 135622  
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Protocol/Amendment number 
Date 
Type of 
amendment 
Final Protocol 
25 Oct 2017 
Not applicable 
Protocol Amendment 0.1 (Bulgaria) 
15 Aug 2018 
Nonsubstantial 
Protocol Amendment 1a 
26 Oct 2018 
Substantial 
Protocol Amendment 1.1 (Switzerland) 
15 Jul 2019 
Nonsubstantial 
Protocol Amendment 2b 
04 Feb 2020 
Substantial 
a Protocol Amendment 1 incorporated changes in Protocol Amendment 0.1 
(Bulgaria).  
b Protocol Amendment 2 incorporates changes in Protocol Amendment 1.1 
(Switzerland).  
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 SRL 
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 BIOSCIENCES, Inc 
810 Arco Corporate Drive 
Raleigh, NC 27617 
United States 
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 .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 13 
2.1 Drug-resistant epilepsy .................................................................................................... 13 
2.2 Padsevonil mechanism of action ...................................................................................... 13 
2.3 Nonclinical studies ........................................................................................................... 13 
2.4 Clinical studies ................................................................................................................. 13 
2.5 Benefit Risk Assessment .................................................................................................. 14 
2.6 Rationale for this study .................................................................................................... 16 
3 
STUDY OBJECTIVES .................................................................................................... 16 
3.1 Primary objective ............................................................................................................. 16 
3.2 Secondary objective ......................................................................................................... 16 
3.3 Exploratory objective ....................................................................................................... 16 
4 
STUDY VARIABLES ..................................................................................................... 17 
4.1 Safety variables ................................................................................................................ 17 
4.1.1 
Primary safety variables ...................................................................................... 17 
4.1.2 
Other safety variables .......................................................................................... 17 
4.2 Efficacy variables ............................................................................................................. 17 
4.2.1 
Primary efficacy variable ..................................................................................... 17 
4.2.2 
Other efficacy variables ....................................................................................... 17 
4.3 Pharmacokinetic and pharmacodynamic variables .......................................................... 18 
5 
STUDY DESIGN ............................................................................................................. 18 
5.1 Study description ............................................................................................................. 18 
5.1.1 
Study duration per subject ................................................................................... 19 
5.1.2 
Planned number of subjects and sites .................................................................. 19 
5.1.3 
Anticipated regions and countries ....................................................................... 19 
5.2 Schedule of study assessments ......................................................................................... 20 
5.3 Rationale for study design and selection of dose ............................................................. 25 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 25 
6.1 Inclusion criteria .............................................................................................................. 25 
6.2 Exclusion criteria ............................................................................................................. 27 
6.3 Withdrawal criteria .......................................................................................................... 28 
6.3.1 
Potential drug-induced liver injury PSL discontinuation criteria ........................ 30 
6.3.2 
Echocardiogram valvular abnormalities assessments .......................................... 31 
7 
STUDY TREATMENTS ................................................................................................. 32 
7.1 Description of investigational medicinal product ............................................................ 32 
7.2 Treatments to be administered ......................................................................................... 32 
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7.3 Packaging ......................................................................................................................... 33 
7.4 Labeling ........................................................................................................................... 33 
7.5 Handling and storage requirements.................................................................................. 33 
7.6 Drug accountability .......................................................................................................... 33 
7.7 Procedures for monitoring subject compliance ................................................................ 34 
7.8 Concomitant medications/treatments ............................................................................... 34 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 34 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 35 
7.8.3 
Rescue medication ............................................................................................... 35 
7.9 Blinding ............................................................................................................................ 35 
7.10 Randomization and numbering of subjects ...................................................................... 35 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 35 
8.1 Evaluation Period ............................................................................................................. 36 
8.1.1 
Visit 1 (Entry Visit; Day 1) ................................................................................. 36 
8.1.2 
Visit 2 (Week 2 ±1 week) .................................................................................... 37 
8.1.3 
Visit 3 (Week 4 ±1 week) .................................................................................... 37 
8.1.4 
Visit 4 (Month 2 ±1 week) ................................................................................... 38 
8.1.5 
Visit 5 (Month 3 ±1 week) ................................................................................... 38 
8.1.6 
Visit 6 (Month 6), Visit 7 (Month 9), Visit 8 (Month 12), Visit 9 (Month 15), 
Visit 10 (Month 18), and Visit 11 (Month 21) ±1 month .................................... 39 
8.1.7 
Early Discontinuation Visit ................................................................................. 40 
8.1.8 
End of Study Visit ............................................................................................... 40 
8.2 Taper Period ..................................................................................................................... 41 
8.2.1 
End of Taper Visit; up to 4 weeks (± 1 week) including 1 week of drug free ..... 41 
8.3 Safety Follow-up .............................................................................................................. 42 
8.3.1 
Safety Follow-up Visit (30 days after the last PSL intake) ± 1 week .................. 42 
8.4 Unscheduled Visit/Telephone Call .................................................................................. 42 
9 
ASSESSMENT OF SAFETY .......................................................................................... 43 
9.1 Adverse events ................................................................................................................. 43 
9.1.1 
Definitions ........................................................................................................... 43 
9.1.1.1 
Adverse event ............................................................................................ 43 
9.1.1.2 
Serious adverse event ................................................................................ 43 
9.1.1.3 
Adverse events of special interest ............................................................. 45 
9.1.2 
Procedures for reporting and recording adverse events ....................................... 45 
9.1.3 
Description of adverse events .............................................................................. 45 
9.1.4 
Rule for repetition of an adverse event ................................................................ 45 
9.1.5 
Additional procedures for reporting serious adverse events ................................ 45 
9.1.6 
Follow up of adverse events ................................................................................ 46 
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9.1.7 
Pregnancy ............................................................................................................ 46 
9.1.8 
Suspected transmission of an infectious agent .................................................... 47 
9.1.9 
Overdose of investigational medicinal product ................................................... 47 
9.1.10 
Safety signal detection ......................................................................................... 48 
9.2 Laboratory measurements ................................................................................................ 48 
9.2.1 
Evaluation of PDILI ............................................................................................ 49 
9.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 53 
9.2.1.2 
Immediate action: determination of PSL discontinuation ......................... 53 
9.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 54 
9.2.1.4 
Follow-up evaluation ................................................................................. 55 
9.3 Other safety measurements .............................................................................................. 55 
9.3.1 
Vital signs measurement ...................................................................................... 56 
9.3.2 
Electrocardiograms .............................................................................................. 56 
9.3.3 
Echocardiograms ................................................................................................. 56 
9.3.4 
Physical examination ........................................................................................... 57 
9.3.5 
Neurological examination .................................................................................... 57 
9.3.6 
Assessment of suicidality .................................................................................... 58 
9.3.7 
Psychiatric and Mental Status .............................................................................. 58 
9.3.8 
Withdrawal monitoring ........................................................................................ 58 
10 ASSESSMENT OF EFFICACY ...................................................................................... 59 
10.1 Seizure frequency ............................................................................................................. 59 
10.2 Quality of Life Inventory in Epilepsy-31-P ..................................................................... 59 
10.3 Seizure Severity Global Item ........................................................................................... 59 
10.4 Hospital Anxiety and Depression Scale ........................................................................... 60 
10.5 Health-related outcomes and healthcare resource utilization .......................................... 60 
10.6 Treatment Satisfaction ..................................................................................................... 60 
10.7 Personal outcomes assessment ......................................................................................... 61 
10.8 Caregiver survey .............................................................................................................. 61 
11 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 61 
11.1 Adherence to protocol ...................................................................................................... 61 
11.2 Monitoring ....................................................................................................................... 61 
11.2.1 
Definition of source data ..................................................................................... 62 
11.2.2 
Source data verification ....................................................................................... 63 
11.3 Data handling ................................................................................................................... 63 
11.3.1 
Case Report form completion .............................................................................. 63 
11.3.2 
Database entry and reconciliation ........................................................................ 63 
11.3.3 
Subject Enrollment log/Subject Identification Code list ..................................... 64 
11.4 Termination of the study .................................................................................................. 64 
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11.5 Archiving and data retention ............................................................................................ 64 
11.6 Audit and inspection ........................................................................................................ 64 
11.7 Good Clinical Practice ..................................................................................................... 65 
12 STATISTICS ................................................................................................................... 65 
12.1 Definition of analysis sets ................................................................................................ 65 
12.1.1 
Enrolled Set ......................................................................................................... 65 
12.1.2 
Safety Set ............................................................................................................. 65 
12.1.3 
Full Analysis Set .................................................................................................. 65 
12.2 General statistical considerations ..................................................................................... 65 
12.3 Planned safety analyses .................................................................................................... 65 
12.4 Planned efficacy analyses ................................................................................................ 66 
12.4.1 
Analysis of the primary efficacy variable ............................................................ 66 
12.4.2 
Analysis of the other efficacy variables ............................................................... 66 
12.4.3 
Analysis of the subject/caregiver personal outcomes .......................................... 67 
12.5 Handling of protocol deviations ....................................................................................... 67 
12.6 Handling of dropouts or missing data .............................................................................. 67 
12.7 Planned interim analysis and data monitoring ................................................................. 67 
12.8 Determination of sample size ........................................................................................... 67 
13 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 68 
13.1 Informed consent ............................................................................................................. 68 
13.2 Subject identification cards .............................................................................................. 68 
13.3 Institutional Review Boards and Independent Ethics Committees .................................. 68 
13.4 Subject privacy ................................................................................................................. 69 
13.5 Protocol amendments ....................................................................................................... 69 
14 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 69 
15 REFERENCES ................................................................................................................ 70 
16 APPENDICES ................................................................................................................. 73 
16.1 Protocol Amendment 1.0 ................................................................................................. 73 
16.2 Protocol Amendment 2.0 ............................................................................................... 104 
17 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 113 
18 SPONSOR DECLARATION ........................................................................................ 114 
 
LIST OF TABLES 
Table 5-1: 
Schedule of assessments .................................................................................. 21 
Table 6-1: 
Valvular abnormality grading criteria .............................................................. 31 
Table 9‒1: 
Anticipated SAEs for the epilepsy population ................................................. 44 
Table 9‒2: 
Laboratory measurements ................................................................................ 49 
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Table 9-3: 
Required investigations and follow up for PDILI............................................ 51 
Table 9‒4: 
PDILI laboratory measurements ...................................................................... 54 
Table 9‒5: 
PDILI information to be collected ................................................................... 55 
Table 9‒6: 
Laboratory measurements ................................................................................ 95 
Table 9‒7: 
Laboratory measurements ................................................................................ 96 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
bid 
twice daily 
BP 
blood pressure 
cBZR 
central benzodiazepine receptor 
CDMS 
clinical data management system 
CIWA-B 
Clinical Institute Withdrawal Assessment-Benzodiazepines 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EDV 
early discontinuation visit 
EOS 
End of Study 
ES 
Enrolled Set 
GABA-A 
gamma-aminobutyric acid-A 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HADS 
Hospital Anxiety and Depression Scale 
HRU 
healthcare resources utilization 
IB 
Investigator’s Brochure 
ICF 
Informed Consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
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IRT 
interactive response technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
OLE 
open-label extension 
PDILI 
potential drug-induced liver injury 
PK 
pharmacokinetics 
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 
RR 
responder rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDV 
source data verification 
SFU 
Safety Follow-up 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SSG 
Seizure Severity Global Item 
SV2 
synaptic vesicle 2 
TEAE 
treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
upper limit of normal 
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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, which constitute a substantial threat to their health and 
well-being. 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. This open-label, 
long-term study will provide subjects, who participated in previous PSL studies, the opportunity 
to have continued access to PSL. 
The primary objective of this study is to evaluate the long-term safety and tolerability of PSL 
administered at individualized doses between 100mg/day and 800mg/day as adjunctive treatment 
for subjects with drug-resistant epilepsy. The secondary objective is to evaluate the long-term 
efficacy of PSL as an adjunctive treatment for focal-onset seizures in adults with drug-resistant 
epilepsy. 
This study will enroll subjects who have completed a PSL parent study. Subjects will continue to 
report their seizures in a diary. After the Entry Visit (Visit 1), subjects will return to the clinic for 
the following visit schedule during the Evaluation Period:  
 Every 2 weeks during Month 1 
 Every month during Month 2 and Month 3 
 Every 3 months after Month 3 to the end of Year 2 
Dose adjustment of PSL, and/or concomitant antiepileptic drugs (AEDs), and/or 
neurostimulation devices is allowed at any time during the study, if seizure control is 
insufficient, or in case of safety or tolerability issues. Subjects who complete the study and do 
not continue PSL treatment or who discontinue early from the study will return for an End of 
Study (EOS) Visit or Early Discontinuation Visit (EDV) and will be progressively tapered off 
PSL over 4 weeks and return to the site after the last PSL intake for a Safety Follow-Up (SFU) 
Visit 30 days after the last PSL intake (including echocardiogram) and a 6-month follow-up 
echocardiogram to complete echocardiographic monitoring.  
Safety will be evaluated based on the incidence of treatment-emergent adverse events (TEAEs) 
reported by the subject and/or caregiver; subject withdrawals due to adverse events (AEs); 
changes in periodic clinical laboratory tests; electrocardiogram (ECG) parameters; 
echocardiography results; withdrawal symptoms, vital signs; Psychiatric and Mental Status; and 
findings from physical and neurological examinations. 
The primary efficacy variable will be the change from Baseline from the respective parent study 
in observable focal-onset seizure frequency over the Evaluation Period. Secondary and other 
efficacy variables will allow further exploration of the effect of PSL on seizure frequency during 
the entire Evaluation Period, seizure severity, quality of life, anxiety and depression, and 
unforeseen medical resource utilization. 
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The total duration of the study per subject will be up to approximately 2 years. Subjects 
benefitting from the drug and willing to continue will either take commercial drug, if available, 
or will be transferred to a Managed Access Program or another PSL study, depending on local 
regulations.  
It is estimated that up to 1000 subjects will be included at approximately 350 sites worldwide. 
2 
INTRODUCTION 
2.1 
Drug-resistant epilepsy 
The International League Against Epilepsy (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). 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. 
2.2 
Padsevonil mechanism of action 
Padsevonil is a novel chemical entity that has selective affinity for SV2 proteins and postsynaptic 
cBZR sites on the GABA-A receptor. It has shown compelling efficacy in several preclinical 
models of epilepsy, including the amygdala kindling model. This model is considered the most 
translatable approach to assess compounds with potential efficacy against drug-resistant focal 
epilepsy. Based on this compelling preclinical profile, UCB designed and conducted a 
proof-of-concept study (EP0069) in patients with highly drug-resistant focal epilepsy. 
2.3 
Nonclinical studies 
A comprehensive nonclinical development program has been conducted with PSL, including oral 
toxicology studies up to 26 weeks in rats and 39 weeks in dogs, a standard battery of 
genotoxicity studies, safety pharmacology and secondary pharmacology studies, and fertility and 
embryofetal development studies in rats and rabbits. Details of these nonclinical studies can be 
found in the Investigator’s Brochure (IB). Padsevonil was well tolerated up to 150mg/kg twice 
daily (bid) (ie, 300mg/kg/day) over 26 weeks in rats and up to 50mg/kg bid (ie, 100mg/kg/day) 
over 39 weeks in dogs. The minimal cardiac findings reported in a limited number of animals in 
the 39-week toxicity study in dogs were judged to be of very low risk (long-term exposure) to 
nonexistent risk (short-term exposure) to humans by a panel of internal and external experts. 
Furthermore, echocardiographic screening of human study participants at Baseline (to exclude 
study participants with valvulopathies) and ongoing echocardiographic monitoring during 
treatment and post treatment has been implemented in the Phase 2 studies. There have been no 
major findings to date. 
2.4 
Clinical studies 
Clinical development (Phase 1 and Phase 2) of PSL is underway, the objective of which is to 
address an unmet medical need by developing a treatment that will provide incremental efficacy 
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when added to existing AED treatment for patients with drug-resistant epilepsy. The proposed 
indication of PSL is as an adjunctive therapy in the treatment of focal-onset seizures in adult 
patients with epilepsy.  
Phase 1 
Studies of single oral doses of PSL up to 490mg and repeated oral dose of up to 400mg bid for 
up to 12 days have been completed. In addition, studies to determine SV2A receptor occupancy 
and pharmacokinetics (PK) in Japanese study participants are ongoing. Tolerability up to 
400mg bid was considered acceptable to progress to Phase 2. At the time of initiation of Phase 2, 
the important identified risks based on the human pharmacology studies included drug-drug 
interactions with potent cytochrome P450(CYP)3A4 enzyme inducers and the risk of developing 
psychiatric symptoms. Further details of the Phase 1 studies are available in the IB. 
Phase 2 
A Phase 2 study, EP0069, conducted in the in the EU to evaluate the potential efficacy, 
safety/tolerability, and PK profile of PSL administered to subjects with highly drug-resistant 
focal epilepsy was recently completed. The analysis is ongoing, but the study showed that 
PSL 400mg bid as an adjunctive treatment to each study participant’s current, stable AED 
regimen was associated with clinically meaningful improvements in seizure control. There were 
no new or unexpected safety signals. Interim data (cutoff date of 07 Mar 2017) from the ongoing 
open-label extension (OLE) study (EP0073) to EP0069 indicate that the safety and tolerability 
profile continues to remain acceptable and support the maintenance of PSL efficacy. Refer to the 
IB for full details regarding the safety and efficacy. 
UCB proposes the initiation of a Phase 2 dose-finding study of PSL (EP0091) and the current 
OLE study (EP0093), in adult patients having focal-onset seizures associated with drug-resistant 
epilepsy. 
2.5 
Benefit Risk Assessment 
The following is the benefit risk assessment based on a cut-off date of 06 Dec 2019 and 
presented in the current version of the Investigator’s Brochure.   
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 focal unaware or focal to bilateral 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 SUDEP (Devinsky, 2011) when compared with the general 
population. An estimated 1% of patients diagnosed with drug-resistant epilepsy die every year of 
SUDEP, and 12% die within 2 years of the diagnosis from all causes (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). 
Padsevonil is an AED with a dual mechanism of action (acting at presynaptic SV2 proteins and 
postsynaptic GABAA receptors), specifically synthesized and designed for an increased 
anticonvulsant activity and hence for the treatment of seizures in patients with epilepsies 
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resistant to current available drug therapies. The efficacy of PSL has been demonstrated in 
10 nonclinical models of epilepsy and a more recently completed Phase 2 study in patients with 
highly drug resistant epilepsy revealed clinically meaningful reductions in seizure frequency. 
Study participants in the PSL/PSL treatment group were 4.14 times more likely to achieve a 
≥75% reduction from the Baseline Period in focal seizure frequency during the 2-week Inpatient 
Period compared with study participants in the Placebo/PSL treatment group (p=0.0679). The 
75% responder rate (RR) approached statistical significance and was clinically meaningful. The 
median percentage of seizure-free days during the 2-week Inpatient Period in the PSL/PSL 
treatment group (57.14%) was greater than in the Placebo/PSL treatment group (21.43%). 
Therefore, based on the evidence demonstrating superior seizure control compared with other 
marketed AEDs across several preclinical models of epilepsy (Leclercq et al, 2017), and the 
results of the proof of concept study, EP0069 (Muglia et al, 2017), treatment with PSL has the 
potential to benefit an underserved epilepsy population with high unmet medical need.  
Overall, the clinical pharmacology and clinical studies in drug-resistant epilepsy demonstrated 
the AE profile of PSL is generally consistent with the pharmacological activity of the product, 
and in the context of early dose-escalation studies in healthy study participants and patients with 
epilepsy. The safety findings to date suggest that the AEs experienced by study participants 
receiving single and repeated doses of PSL are limited principally to CNS effects. The AEs tend 
to be dose-related in frequency and intensity, self-limiting, and tend to decrease in intensity over 
the first few days of dosing. 
Potential risks identified and relevant to clinical studies (cardiovascular events, psychiatric 
events, suicidal ideation and behavior [class risk], interactions with other medicinal products, 
pregnancy and lactation, worsening of seizures, substance abuse and dependence, and overdose) 
are all described in detail in Section 6.3 of the Investigator’s Brochure and suggested lay 
language is provided to sites for study participants in the Informed Consent form (ICF). Reported 
acute psychiatric SAEs are consistent with adverse effects of other AEDs, including SV2A 
ligands. Although events were transient and acute, the occurrence of acute psychiatric effects in 
3 study participants administered PSL in completed clinical studies required admission to 
psychiatric care and medical treatment. Therefore, the possibility of significant psychiatric 
adverse effects highlights the need to maintain vigilance for such effects. In view of the 
nonclinical histopathological cardiac findings of some minor asymptomatic, focal cardiac 
valvular, and epicardial inflammatory lesions in dogs, screening of study participants at Baseline 
and ongoing echocardiogram monitoring during treatment and post-treatment have been 
implemented as a precaution in the studies that have a >3-week treatment duration. To date, no 
clinically significant echocardiogram findings (only minor/trace or Grade 1 findings) have been 
observed. Based on vital signs, ECGs, echocardiograms, and cardiovascular TEAEs evaluated in 
clinical studies to date, there is no evidence that PSL causes cardiovascular harm in study 
participants. Data from in vitro studies and clinical pharmacology studies in healthy study 
participants and epilepsy patients have shown that PSL at high doses moderately increased 
exposure of sensitive substrates of cytochrome P450 (CYP)2C19. Although less clear, strong 
inhibitors and inducers of CYP2C19 may also impact the PK and metabolism of PSL and 
metabolites. Strong inducers of CYP3A4 have also been shown to have a significant interaction 
with PSL. Therefore, concomitant administration of strong inducers and inhibitors of CYP3A4 
with PSL is prohibited. Additionally, when moderate CYP3A4 inhibitors are introduced or 
withdrawn from a study participant’s treatment regimen, the study participant should be closely 
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monitored for changes in clinical response and tolerability. Risks associated with suicidal 
ideation and behavior, pregnancy and lactation, worsening of seizures, and potential overdose are 
common to all AEDs.  
Risk minimization activities for all relevant risks include study protocol inclusion, exclusion, and 
withdrawal criteria, and safety monitoring measures as deemed appropriate. The routine core 
pharmacovigilance activities include: signal detection for any new and existing safety concerns, 
specific follow-up, and aggregate reporting as well as questionnaires for suicidality, withdrawal 
symptoms, psychiatric and mental status, and anxiety and depression. 
Additional routine risk minimization activities include: ICFs that describe the applicable 
potential risks and discomforts and risks associated with procedures; inclusion, exclusion, and 
withdrawal criteria and safety monitoring measures as deemed appropriate in clinical study 
protocols; ECG monitoring for arrhythmias; and clinical laboratory panels for hepatotoxicity. 
Study participants will also have routine echocardiograms performed, which provide a grading 
for valvular findings and/or the presence of any accompanying clinical signs/symptoms. 
Important risks associated with PSL treatment are managed through standard safety surveillance 
and routine pharmacovigilance activities. In addition, all ongoing studies are overseen by an 
independent DMC. Systematic review of aggregate safety data and AE reporting will be 
performed by the DMC (for all clinical studies) in order to identify safety trends and signals.  
2.6 
Rationale for this study 
This open-label, long-term study will provide subjects, who participated in previous PSL studies, 
the opportunity to have continued access to PSL. 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. 
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of PSL 
administered at individualized doses between 100mg/day and 800mg/day as adjunctive treatment 
for subjects with focal-onset seizures and drug-resistant epilepsy.  
3.2 
Secondary objective 
The secondary objective is to evaluate the long-term efficacy of PSL as an adjunctive treatment 
for focal-onset seizures in adults with drug-resistant epilepsy. 
3.3 
Exploratory objective 
The exploratory objective is to assess the impact of PSL as an adjunctive treatment for subjects 
with focal-onset seizures and drug-resistant epilepsy on health-related outcomes and healthcare 
resources utilization (HRU). 
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4 
STUDY VARIABLES 
4.1 
Safety variables 
4.1.1 
Primary safety variables 
The primary safety variables are the following: 
 Incidence of TEAEs reported by the subject and/or caregiver or observed by the Investigator 
 Incidence of TEAEs leading to study withdrawal 
4.1.2 
Other safety variables 
Other safety variables are the following: 
 Changes in laboratory tests (including hematology, blood chemistry, urinalysis) 
 Changes in 12-lead ECG parameters 
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the EOS Visit, to the end of Taper Period and 
to the end of the SFU Period (30 days after last PSL intake) 
 Changes in vital sign parameters (pulse rate, blood pressure [BP], and respiratory rate) 
 Occurrence of a clinically-significant valvular change or pericardial effusion or other 
clinically-significant abnormalities as identified by 2-dimensional Doppler echocardiogram 
at each assessment by central reader 
 Physical examination (including body weight) and neurological examination findings 
 Changes in Psychiatric and Mental Status 
4.2 
Efficacy variables 
Seizure frequency refers to 28-day adjusted frequency.  
Observable focal-onset seizures refers to Type IA1, IB, and IC (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. 
4.2.1 
Primary efficacy variable 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in observable focal-onset seizure frequency over the Evaluation Period.  
4.2.2 
Other efficacy variables 
The other efficacy variables are the following: 
 Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period 
 Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period 
 The 50%, 75%, and 90% responder rate (RR) by 3-month intervals for observable focal-onset 
seizures over the Evaluation Period. A 50%, 75%, and 90% responder is defined as a subject 
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with a ≥50%, ≥75%, or ≥90% reduction in the observable focal-onset seizure frequency 
relative to the Baseline Period defined in the parent study. 
 The 50%, 75%, and 90% RR by 3-month intervals for focal-onset seizures (Type I) over the 
Evaluation Period  
 Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
 Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation Period 
 Time to discontinuation 
 Change from Baseline from parent study in the Seizure Severity Global Item (SSG) scores at 
each assessment 
 Changes from Baseline from parent study in Quality of Life Inventory in Epilepsy-31-P 
(QOLIE-31-P) scores at each assessment 
 Changes from Baseline from parent study in Hospital Anxiety and Depression Scale (HADS) 
scores at each assessment 
 Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8, and to Visit 12 or EOS 
 Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications, and hospitalizations 
4.3 
Pharmacokinetic and pharmacodynamic variables 
No PK nor pharmacodynamic variables will be assessed in this study. 
5 
STUDY DESIGN 
5.1 
Study description 
This is an OLE study that will assess the safety, tolerability, and change in focal-onset seizure 
frequency associated with long-term oral PSL as an adjunctive therapy in adult subjects with 
drug-resistant epilepsy. This study will enroll consenting subjects, or subjects whose legal 
representatives have given consent, and who have completed a PSL parent study (eg, EP0091 or 
subsequent PSL studies). 
At the Entry Visit (same day as the end of Conversion Period Visit in the parent study), 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 by the Investigator. Eligible subjects must be educated to 
record all types of seizures that occur in their seizure diary and to complete their diary entries 
after each seizure or at least once a day. A caregiver is allowed to help the subject with the 
completion of the subject diary.  
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Evaluation Period 
After the Entry Visit (Visit 1), subjects will return to the clinic for visits as follows:  
 Every 2 weeks during Month 1 
 Every month during Month 2 and Month 3 
 Every 3 months after Month 3 to the end of Year 2 
Dose adjustment of PSL and/or concomitant AEDs and/or settings to neurostimulation devices is 
allowed at any time during the study, if seizure control is insufficient, or in case of safety or 
tolerability issue. Concomitant AED(s) may be tapered and discontinued to achieve PSL 
monotherapy, if clinically appropriate in which case the UCB Physician or delegate must be 
contacted to discuss with the Investigator. New concomitant AEDs, as allowed per protocol (see 
Section 7.8.1), may be introduced to optimize seizure control. Subjects who are not able to 
tolerate or who do not benefit from the PSL treatment may be tapered off PSL and withdrawn 
from the study. 
Taper Period 
Subjects who complete the study or who discontinue early will return for an End-of-Study Visit 
or EDV, respectively, and will be progressively tapered off over 4 weeks and return to the site 1 
week after the last PSL intake for an end of Taper Visit. If a subject transfers into either a 
Managed Access Program or another PSL study, or takes commercially available PSL, the Taper 
Period may be skipped and the subject may continue treatment without tapering.  
Safety Follow-up Period 
Safety follow up will consist of 1 required visit (SFU Visit) 30 days after the last PSL intake. A 
follow-up echocardiograms will be required at approximately 1 month and 6 months after the last 
PSL intake. 
5.1.1 
Study duration per subject 
The total study duration per subject will be up to approximately 2 years. Subjects benefitting 
from the drug and willing to continue will either take commercial drug, if available, or will be 
transferred to a Managed Access Program or another PSL study, depending on local regulations. 
The end of the study is defined as the date of the last SFU Visit (30 days after the last PSL 
intake) of the last subject in the study. Serious adverse events (SAEs) will continue to be 
reported until the 6-month follow-up echocardiogram is obtained. 
5.1.2 
Planned number of subjects and sites 
It is estimated that approximately 1000 subjects will be included in approximately 350 sites 
worldwide. Additional sites may be added if the study is extended to other regions or countries.  
5.1.3 
Anticipated regions and countries 
The study will be conducted in North America, Europe, Japan, and China with possible 
extension to other regions or countries. 
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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 
 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk drug 
free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 Wk 
 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of Subject 
Trial card 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of withdrawal 
criteria 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Medical history update 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS since last visit d 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HADS  d 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
SSG 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
QOLIE-31-P  d 
 
 
 
 
 
X 
 
X 
X 
 
 
 
CIWA-B  d 
 
 
 
 
 
 
 
Xe 
X 
X 
X 
 
TSQM-9 d 
 
 
 
 
 
 
 
X 
X 
 
 
 
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Table 5-1: 
Schedule of assessments 
 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk drug 
free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 Wk 
 
 
Vital signs f 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight 
X* 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Physical examination g  
(XF = Full – XB = Brief) 
XF* 
 
XB 
 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
 
Neurological examination h  
(XF = Full – XB = Brief) 
XF* 
 
XB 
 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
 
Psychiatric and Mental 
Status 
X* 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Personal Outcomes 
assessmenti 
 
 
 
 
 
X 
X 
 
 
 
 
 
12-lead ECG j 
X* 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
Echocardiogram k 
 
X 
 
 
X 
X 
X 
X k 
 
 
X 
 
Blood/urine sample for 
clinical laboratory analysis 
X* 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pregnancy test (female 
subjects only) l 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Table 5-1: 
Schedule of assessments 
 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk drug 
free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 Wk 
 
 
Seizure evaluation (count 
and type) m 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
and procedures n 
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 
 
Health-related outcomes and 
HRU 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IRT call 
X 
 
 
 
 
 
 
 
 
 
X 
 
PSL dispensing (IRT) 
X 
X 
X 
X 
X 
X 
X 
X p 
X 
 
 
 
PSL accountability and  
return o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study termination 
 
 
 
 
 
 
 
X q 
 
 
X r 
 
AED=antiepileptic drug; BP=blood pressure; CIWA-B=Clinical Institute Withdrawal Assessment-Benzodiazepines; C-SSRS=Columbia-Suicide Severity 
Rating Scale; ECG=electrocardiogram; EDV=Early discontinuation Visit; EOS=End of Study; HADS=Hospital Anxiety and Depression Scale; 
HRU=healthcare resource utilization; IRT=interactive response technology; M=month; PSL=padsevonil; QOLIE-31-P=Quality of Life Inventory in Epilepsy-
31-P; SFU=Safety Follow-up; SSG=Seizure Severity Global Item; TC=telephone call; TSQM=Treatment Satisfaction Questionnaire for Medication; 
Unsch=unscheduled; V=visit; Wk=week 
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a At any point during the Evaluation Period, an unscheduled visit may be conducted due to safety or efficacy reasons. Appropriate assessments will be conducted 
in relation to the reason for the visit. 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. 
 b Entry Visit (Visit 1) will be done on the same day as the last visit of parent study. Data from parent study will be used (identified by *) and corresponding 
assessments will not be repeated. 
c The Taper Period is only valid for subjects discontinuing the study or completing without continuation of the PSL treatment. This period will last for 3 weeks 
plus a 1-week drug-free period. 
 d Questionnaires to be completed by all subjects prior to any other study procedures at the visit, when possible. 
e Assessment is only valid for subjects discontinuing PSL treatment.  
 f Vital signs measured in supine position after 5 minutes of rest include pulse rate, respiratory rate, systolic BP, and diastolic BP. 
 g Full physical examination will include assessment of 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 examination will include in addition, evaluation of cranial nerves, motor system (general muscle strength and tone), and sensations in upper/lower 
extremities. 
i Personal outcome assessments will be completed at Visit 6 (Month 6) and Visit 11 (Month 21) (for subjects who agree to participate). 
 j An ECG at the SFU will be performed only if abnormal at the EOS or EDV Visit. All ECG recordings will be performed with the subject resting in supine 
position for at least 5 minutes.  
 k Only subjects who do not require tapering of PSL at M24 will have an echocardiogram at M24. All other subjects will have an echocardiogram at the SFU Visit 
and at 6 months after the last dose of PSL. A repeat echocardiogram will be performed for subjects with a new finding, Grade 2 severity (moderate), or Grade 3 
severity (severe) (see Section 6.3). 
 l Results of a serum pregnancy test performed during parent study will be used at Visit 1 together with a urine test performed at Visit 1. Urine pregnancy tests 
will be used at all other visits for female subjects of childbearing potential.  
 mSeizure counts are collected on the subject’s daily record card on a daily basis. 
 n Assessment includes AED history. 
 o Medication should be presented at each visit for check on compliance. 
p PSL will be dispensed at the EOS Visit only to subjects who will be tapered off PSL.  
q The study termination assessment at the EOS visit is for subjects who will transfer into either a Managed Access Program or another PSL study. 
r The study termination assessment at the SFU Visit is for subjects who withdraw early or who complete the study, but will not be transferred to either a Managed 
Access Program or another PSL study. 
 
 
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5.3 
Rationale for study design and selection of dose 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. 
This OLE study will provide subjects, who participated in previous PSL studies, the opportunity 
to have continued access to PSL. 
The individual starting dose of each subject will be the one recommended at the end of the parent 
study.  
This entry dose level was selected considering benefit-risk and is based on clinical pharmacology 
and positron emission tomography 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 the parent study, a full SV2A 
occupancy is desirable to obtain a meaningful anticonvulsive effect while the minimal 
benzodiazepine binding more likely will make a better tolerance to GABA-related central 
nervous system toxicity. On the other hand, participants exposed to a high maintenance dose of 
PSL in the parent study (800mg/day), a 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 are allowed between 100mg/day up 
to a maximum of 800mg/day to the extent possible with combination of tablet strengths available 
(ie, 25mg, 100mg, and 200mg).  
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 legal representative (where 
legally permitted). The ICF or a specific Assent form, where required, will be signed and 
dated by minors, according to country-specific regulations. 
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. 
3. Subject is an adult (18 years of age or more). 
Epilepsy 
4. Subject with epilepsy who has completed 1 of the previous PSL studies which allow access 
to the present study. 
Birth control 
5. Female subjects of child bearing potential must have a serum negative pregnancy test at the 
Entry Visit, which is confirmed to be negative by urine testing prior to further dispensing at 
each study visit thereafter. Subjects will be withdrawn from the study as soon as pregnancy is 
known. 
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Female subjects will use an efficient form of contraception for the duration of the study and for a 
period of 3 months after their final dose of PSL. Hormonal contraception may be susceptible to 
an interaction with PSL, 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 a condom) also be used.  
Birth control methods considered as efficient forms 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 the Entry Visit [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 Entry Visit 
[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 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 of non-childbearing potential, defined 
as being postmenopausal (for at least 2 years before the Entry Visit), verified by serum 
follicle stimulating hormone level >40mIU/mL at the Entry Visit, or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, bilateral salpingectomy), or 
congenitally sterile. 
 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 final intake of PSL. 
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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 any severe medical, neurological, or psychiatric condition, or laboratory value 
which may have an impact on the safety of the subject. 
2. 
 as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the Columbia-Suicide Severity 
Rating Scale (C-SSRS). The subject should be referred immediately to a mental healthcare 
professional and must be withdrawn from the study. 
Laboratory parameters 
3. Subject has >2x 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) at the Entry 
Visit. If the subject has elevations only in total bilirubin that are >ULN and <1.5xULN, 
fractionated bilirubin must be used to identify possible undiagnosed Gilbert’s syndrome 
(ie, direct bilirubin <35%). 
For enrolled subjects with a Baseline result >ULN for ALT, AST, ALP, or total bilirubin, a 
Baseline diagnosis and/or the cause of any clinically-significant elevation must be 
understood and recorded. 
If subject has >ULN for ALT, AST, or ALP that does not meet the exclusion limit at the 
Entry Visit (ie, the value is >ULN but ≤2xULN at the Entry Visit of EP0093), the tests must 
be repeated, if possible, prior to dosing to ensure there is no further ongoing 
clinically-significant increase. In case of a clinically-significant increase, inclusion of the 
subject must be discussed with the Medical Monitor. 
Medical conditions 
4. 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) >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. 
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5. Subject has an abnormality on echocardiogram at last echocardiogram assessment, or 
foreseen in parent study 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, 2017; Zoghbi et al 2017). 
Pregnancy 
6. Female subject who plans to be 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 and/or Investigator do(es) not think that PSL is effective (ie, lack or loss of efficacy). 
5. Subject cannot tolerate the minimum PSL dose of 50mg bid (100mg/day). 
6. Subject takes prohibited concomitant medications, prescribed or over-the-counter as defined 
in this protocol. 
7. 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. 
8. 
Subjects 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 PSL. 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).  
9. Changes in the ECG that are regarded as clinically significant and/or that worsens 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. 
10. 
 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 the benefit/risk ratio of continuing the 
subject in the study on PSL. 
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 
 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. 
11. Subject develops an illness that would interfere with his/her continued participation. 
12. For subject developing psychiatric/mood/behavioral signs or disturbances (see examples in 
list below) that are clinically concerning or that worsen over time, the PSL dose should be 
gradually reduced and, if symptoms persist, withdrawal from the study should be considered. 
The subject should be referred to a mental health professional, and continuation of PSL 
should only be allowed with the approval and under close oversight of the mental health 
specialist, and upon confirmation of the positive benefit/risk by the Investigator.  
 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 
13. 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, 
pancreatitis, myositis, arthritis, or hematologic system involvement combined with 
at least one 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 
14. 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 
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(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 PSL discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if PSL 
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 PSL: 
 Subjects with either of the following: 
 ALT or AST ≥5xULN 
 ALT or AST ≥3xULN and coexisting total bilirubin ≥2xULN 
The PDILI criterion below requires immediate discontinuation of PSL: 
 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 PSL at the discretion of the 
Investigator. 
 Subjects with ALT or AST ≥3xULN (and ≥2x Baseline) and <5xULN, total bilirubin 
<2xULN, and no eosinophilia (ie, ≤5%), with no fever, rash, or symptoms of hepatitis 
(eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness). 
Evaluation of PDILI must be initiated immediately. It consists of the diagnostic testing and 
continued monitoring (specific tests dependent on laboratory results and corresponding 
symptoms) and consultation with a 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. Additional investigation 
and monitoring may be required and adapted based on the diagnosis after the cause of the liver 
injury/abnormality is confirmed.  
Evaluation of PDILI must be initiated as described in Section 9.2.1. If subjects are unable to 
comply with the applicable monitoring schedule, PSL must be discontinued immediately. 
Investigators should attempt to obtain information on subjects in the case of PSL 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 PSL discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for PSL discontinuation. 
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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. 
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 
Symptomsa : 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
Signs: 
Pulmonary arterial pressure 
>40mmHg 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. 
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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 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. 
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 is 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 
PSL. 
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. If the clinical symptoms are mild, the subject is not required to 
discontinue. Investigators may contact the Medical Monitor if they wish to discuss the subject’s 
clinical signs/symptoms. 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 product 
Padsevonil will be supplied by UCB as 25mg, 100mg, and 200mg film-coated tablets of different 
sizes and appearance (ie, shape and color). 
7.2 
Treatments to be administered 
Padsevonil will be administered in an open-label manner. All subjects will be instructed to take 
2 doses approximately 12 hours apart each day 30 minutes after food when practically feasible. 
The individual starting dose of each subject will be the one at the end of the parent study. The 
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first dose of the study will be the dose on the day of Visit 1. Once subjects enter EP0093 further 
individual dose adjustments are allowed after 1 week, between 100mg/day up to a maximum of 
800mg/day to the extent possible with the combination of tablet strengths available (ie, 25mg, 
100mg and 200mg). Integrity of the tablets should not be tampered with (eg, cut) to obtain lower 
dosages. Twice daily dosing with equivalent morning and evening doses approximately 12 hours 
apart is deemed necessary to ensure more regular exposure over the 24-hour interval; however, 
the dosing schedule may be adjusted as needed to improve tolerability and efficacy. The decision 
to advise subjects to divide their morning and evening daily dose unequally should be 
documented in the eCRF and the UCB Study Physician or delegate should be notified. Increases 
or decreases to the dose of PSL should not exceed a maximum 200mg/day per week. A 
faster/slower decrease/increase of the dose than 200mg/day per week is allowed in case of 
emergency in the Investigator's medical judgment. 
7.3 
Packaging 
Padsevonil tablets are manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations. Padsevonil will be supplied in 
bottles for each dosage strength. Appropriate bottle size will be dispensed through the interactive 
response technology (IRT) system as per visit schedule and visit interval. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language. 
7.5 
Handling and storage requirements 
The Investigator (or designee) is responsible for the safe and proper storage of PSL 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 a 
time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
in the investigational medicinal product (IMP) Handling Manual. 
The Investigator (or designee) will instruct the subject to store the PSL following the instructions 
on the label. 
7.6 
Drug accountability 
A Drug Accountability form will be used to record PSL dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any PSL 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. 
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The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of PSL 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 PSL 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 PSL must be reconciled and either 
destroyed at site according to local laws, regulations, and UCB Standard Operating Procedures 
(SOPs) returned to UCB (or designee). Padsevonil 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 PSL is dispensed and at the end of the Taper Period, subjects must return all 
unused PSL and empty PSL 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 <75% or >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) 
Concomitant AEDs and AED dose(s), or settings for vagus nerve stimulation or other 
neurostimulation device for epilepsy may be adjusted throughout the study as per the 
Investigator’s clinical judgment based on tolerability and seizure control for each individual 
subject. 
Tapering of all concomitant AED(s) to achieve PSL monotherapy, if clinically appropriate, 
should only be made in agreement with Study Physician and Sponsor. 
New concomitant AEDs may be introduced to optimize tolerability and seizure reduction with 
the following restrictions: 
 Vigabatrin, retigabine, and felbamate are allowed and count as add-on AEDs  
 if taken for more than 2, 1, and 4 years respectively prior to Visit 1 in parent PSL study 
and, if requirements mentioned in the relevant Exclusion Criteria pertaining to vigabatrin, 
retigabine, and felbamate in parent PSL study were met. 
 
Although omeprazole is classified as a sensitive substrate, high doses of omeprazole have 
been well tolerated, and adjustment of the omeprazole dose is not generally required 
except with severe hepatic impairment and if long-term treatment is indicated. Therefore, 
omeprazole is permitted (see omeprazole prescribing information). 
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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, benzodiazepines or nonbenzodiazepines like zolpidem) taken >3 times within 
7 days. Regular intake of benzodiazepines with an indication for epileptic seizures is not 
allowed. However, PRN intake of GABA-A-ergic drugs up to 3 times within 7 days is 
allowed, ie, for emergencies. 
 Strong CYP3A4 inhibitors/inducers (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). 
 AEDs including carbamazepine, phenytoin, phenobarbital, and primidone 
 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, , 
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 3 doses within 7 days. 
7.9 
Blinding 
This is an open-label study. Therefore, no blinding is required.  
7.10 
Randomization and numbering of subjects 
Randomization is not applicable in the current study. Subjects will be identified with the subject 
number they received in the parent study.  
An IRT will generate individual assignments for subject kits of PSL, as appropriate, according to 
the visit schedule and the dose the subject should receive. 
The subject number will be required in all communication between the Investigator or designee 
and the IRT regarding a particular subject. 
8 
STUDY PROCEDURES BY VISIT 
Details of the study assessments to be performed at specific time points prior to and after PSL 
administration are provided in Table 5-1, and an outline of all assessments performed is provided 
in the sections below. 
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8.1 
Evaluation Period 
8.1.1 
Visit 1 (Entry Visit; Day 1) 
The Entry Visit (Visit 1) will be done the same day as the last visit of the parent study.  
The following procedures will be performed: 
 Obtain written informed consent (for subjects/caregivers willing to perform the personal 
outcomes interview/survey, sign and date consent). 
 Dispense Subject Trial card 
 Completion of HADS and SSG 
 Obtain medical history update 
 Collect demographic data 
 Verify Inclusion and Exclusion criteria (consider results from last scheduled assessment from 
parent study where relevant (eg, laboratory tests, ECG where applicable)  
 Call IRT 
 Dispense PSL using IRT 
The following assessments noted with * will be obtained in the parent study and do not need to 
be recorded on the eCRF for this study: 
 * Obtain C-SSRS data since last visit 
 * Obtain full physical examination data (refer to Section 9.3.4 for details) 
 * Obtain full neurological examination data (refer to Section 9.3.5 for details) 
 * Obtain vital signs data (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 * Obtain body weight measurement data 
 * Seizure evaluation (count and type) from subject’s daily record card  
 * Record concomitant medication and procedures  
 * Record AEs 
 * Record health-related outcomes and HRU (refer to Section 10.5 for details) 
 * Perform Psychiatric and Mental Status assessment 
 * Collect blood and urine samples for clinical laboratory analyses 
 * Collect 12-lead ECG data  
 * Collect results of serum pregnancy test from parent study (End-of-Treatment Visit) and 
perform urine pregnancy test (end of conversion visit) (female subjects only)  
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8.1.2 
Visit 2 (Week 2 ±1 week) 
The following procedures will be performed: 
 Verify withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Perform urine pregnancy test (female subjects only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication and procedures 
 Obtain echocardiogram 
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details), with the 
exception of socio-professional status  
 Call IRT 
 Dispense PSL 
 Check PSL accountability 
8.1.3 
Visit 3 (Week 4 ±1 week) 
The following procedures will be performed: 
 Verify withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 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 and procedures  
 Record AEs 
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 Record health-related outcomes and HRU (refer to Section 10.5 for details), with the 
exception of socio-professional status  
 Dispense PSL 
 Check PSL accountability 
8.1.4 
Visit 4 (Month 2 ±1 week) 
The following procedures will be performed: 
 Verify withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Collect blood and urine samples for clinical laboratory analyses 
 Perform urine pregnancy test (female subjects only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details), with the 
exception of socio-professional status  
 Dispense PSL 
 Check PSL accountability 
8.1.5 
Visit 5 (Month 3 ±1 week) 
The following procedures will be performed: 
 Verify withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Obtain SSG 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 for details) 
 Perform Psychiatric and Mental Status assessment  
 Obtain 12-lead ECG 
 Obtain echocardiogram 
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 Collect blood and urine samples for clinical laboratory analyses 
 Perform urine pregnancy test (female subjects only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details), with the 
exception of socio-professional status 
 Dispense PSL 
 Check PSL accountability 
8.1.6 
Visit 6 (Month 6), Visit 7 (Month 9), Visit 8 (Month 12), Visit 9 
(Month 15), Visit 10 (Month 18), and Visit 11 (Month 21) ±1 month 
The following procedures will be performed: 
 Verify withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data  
 Obtain SSG data 
 Obtain QOLIE-31-P data (Visit 6, Visit 8, and Visit 10 only) 
 Perform Personal Outcomes assessment (Visit 6 and Visit 11 only) 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG (Visit 7, Visit 9, and Visit 11 only) 
 Obtain echocardiogram  
 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 and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details), with the 
exception of socio-professional status 
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 Dispense PSL 
 Check PSL accountability 
8.1.7 
Early Discontinuation Visit  
The following procedures will be performed by all subjects discontinuing the study early: 
 Verify withdrawal criteria 
 Obtain TSQM-9 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain QOLIE-31-P data 
 Obtain SSG 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 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 and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) 
 Dispense PSL for the Taper Period  
 Check PSL accountability 
8.1.8 
End of Study Visit 
The following procedures will be performed by all subjects completing the study: 
 Obtain TSQM-9 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain QOLIE-31-P data 
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 Obtain SSG 
 Obtain CIWA-B data (in case of discontinuation of PSL treatment) 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Obtain echocardiogram if required. Only subjects who do not require tapering of PSL at M24 
will have an echocardiogram at M24. All other subjects will have an echocardiogram at the 
SFU Visit and at 6 months after the last dose of PSL.  
 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 and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) 
 Dispense PSL to those subjects requiring a Taper Period 
 Check PSL accountability 
 Study termination (for subjects completing the study and continuing PSL treatment) 
8.2 
Taper Period 
8.2.1 
End of Taper Visit; up to 4 weeks (± 1 week) including 1 week of drug 
free 
The following procedures will be performed for subjects discontinuing the study or completing it 
without continuation of PSL treatment: 
 Obtain C-SSRS data since the last visit 
 Obtain CIWA-B data 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
 Perform brief physical examination (refer to Section 9.3.4 for details) 
 Perform brief neurological examination  
 Perform Psychiatric and Mental Status assessment  
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 Perform urine pregnancy test (female subjects of childbearing potential only) 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) with the 
exception of socio-professional status 
 Check PSL accountability 
8.3 
Safety Follow-up 
8.3.1 
Safety Follow-up Visit (30 days after the last PSL intake) ± 1 week 
The following procedures will be performed for subjects discontinuing the study or completing it 
without continuation of PSL treatment: 
 Obtain C-SSRS data since the last visit 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Obtain echocardiogram 
 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) with the 
exception of socio-professional status 
 Call IRT 
 End of diary recording 
 Study termination 
An echocardiogram will be performed 6 months after last PSL intake for all subjects. 
8.4 
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 
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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. 
9 
ASSESSMENT OF SAFETY 
9.1 
Adverse events 
9.1.1 
Definitions 
9.1.1.1 
Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding or echocardiogram), 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 PSL 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 PSL 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, including their participation in parent studies. 
9.1.1.2 
Serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria: 
 Death 
 Life-threatening 
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.) 
 Significant or persistent disability/incapacity 
 Congenital anomaly/birth defect (including that occurring in a fetus) 
 Important medical event that, based upon appropriate medical judgment, may jeopardize the 
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 9.1.1.3]), allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse) 
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 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 criterion 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.) 
9.1.1.2.1 
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 9.1.2. 
Table 9‒1: 
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 
Falla, fracturea, injurya 
Nervous system disorders 
Cluster seizures, convulsion, incontinencea, 
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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9.1.1.3 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated to be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
subject. 
9.1.2 
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. 
9.1.3 
Description of adverse events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation. 
Details for completion of the Adverse Event eCRF (including judgment of relationship to PSL) 
are described in the eCRF Completion Guidelines. 
9.1.4 
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 
9.1.5 
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. 
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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 PSL administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the PSL 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. Expedited reporting to regulatory authorities will be in line with local laws. 
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 PSL), up to 
6 months from last PSL 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 PSL 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. 
9.1.6 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequela, 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 PSL. 
Information on SAEs obtained after final clinical database lock will be captured through the 
Patient Safety (PS) database without limitation of time. 
9.1.7 
Pregnancy 
If an Investigator is notified that a subject has become pregnant after the first intake of any PSL, 
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 PSL or be tapered as instructed at the 
EDV.  
 Safety Follow-up Visit should be scheduled 1 week after the subject has discontinued PSL. 
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The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives. 
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the Investigator and filed at the site. 
UCB’s 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. 
9.1.8 
Suspected transmission of an infectious agent 
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
9.1.9 
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). 
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9.1.10 
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 PSL so that Investigators, clinical study subjects, regulatory 
authorities, and IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative. 
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory, ECG and echocardiogram results) for which data will be periodically reviewed 
during the course of the study. 
In addition, an unblinded Data Monitoring Committee (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.  
9.2 
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 9‒2. 
The total blood volume drawn for clinical laboratory assessments per subject will be a maximum 
of 7mL by sampling, which includes 2mL for hematology and 5mL for blood chemistry. 
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Table 9‒2: 
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; FSH=Follicle Stimulating Hormone; HDL=high-density lipoprotein; 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 
In addition, for females of childbearing potential, a urine pregnancy test (beta-human chorionic 
gonadotropin) will be performed at the scheduled time points presented in Table 5-1. If 
pregnancy is suspected at any time during the study, an interim test should be performed. 
9.2.1 
Evaluation of PDILI 
The PDILI PSL 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 9.1.1.3), and, if applicable, also reported as an 
SAE (see Section 9.1.1.2). 
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Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 9-3 (specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 9.2.1.1). 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 9.2.1.4). 
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 PSL 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 PSL is stopped due to PDILI (as described in Section 6.3.1), PSL 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 9.2.1.2.1 are met, rechallenge with PSL 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 9-3. 
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Table 9-3: 
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 PSL 
discontinuation. 
Essential: Must 
have repeat liver 
chemistry values 
and additional 
testing completed 
ASAP (see 
Section 9.2.1.3); 
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, PSL 
discontinuation. 
≥3xULN 
(and ≥2x 
Baseline) 
and 
<5xULN 
<2xULN 
No 
Discussion with 
Medical Monitor 
required if the 
criterion that allows 
for PSL continuation 
is met. 
Further investigation 
– immediate PSL 
discontinuation not 
required (see 
Section 9.2.1.2). 
Not required 
unless otherwise 
medically 
indicated (at 
discretion of 
Investigator). 
≥5xULN 
(and ≥2x 
Baseline) 
<2xULN 
No 
Discussion with 
Medical Monitor 
required. 
Immediate, 
permanent PSL 
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 9.2.1.3). 
Monitoring of liver chemistry 
values at least twice per week 
until values normalize, stabilize, 
or return to within Baseline 
value. d 
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ALP=alkaline phosphatase; ALT=alanine aminotransferase; ASAP=as soon as possible; AST=aspartate aminotransferase; HCP=healthcare practitioner; NA=not 
applicable; PDILI=potential drug-induced liver injury; ULN=upper limit of normal  
 a Hepatitis symptoms include fatigue, nausea, vomiting, and right upper quadrant pain or tenderness; hypersensitivity symptoms include eosinophilia (>5%), 
rash, and fever (without clear alternative cause). 
 b If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed with the Medical Monitor. 
.c Details provided in Section 9.2.1.1. 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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9.2.1.1 
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 9.2.1.3) and SAE report (if applicable). 
9.2.1.2 
Immediate action: determination of PSL 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 PSL (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 9-3 for details). 
When PSL 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. 
9.2.1.2.1 
Padsevonil 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 PSL due to having met certain criteria for 
PDILI (as described in Section 6.3.1 and Table 9-3), but for whom an alternative diagnosis is 
confirmed, can rarely restart PSL. Rechallenge with PSL can occur only if ALL of the following 
requirements are met: 
 The results of additional testing and monitoring described in Section 9.2.1.3 and 
Section 9.2.1.4 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 PSL. 
 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 Study 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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9.2.1.3 
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 PSL are detailed in 
Table 9‒4 (laboratory measurements) and Table 9‒5 (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 9‒4: 
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 9‒5: 
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 
9.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 9-3. 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 Study Physician, as needed. 
9.3 
Other safety measurements 
Other safety measurements will include vital signs measurement, 12-lead ECGs, 
echocardiograms, physical examination, neurological examination, assessment of suicidality, 
assessment of withdrawal symptoms, and Psychiatric and Mental Status assessments. These will 
be conducted at the time points shown in Table 5-1. 
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9.3.1 
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. 
9.3.2 
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. The ECGs 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. The 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. 
9.3.3 
Echocardiograms 
Echocardiograms will be performed at the scheduled time points presented in Table 5-1. The 
echocardiogram will be repeated at 6 months (±1 month) after the last PSL intake to assess any 
abnormalities that may have newly occurred or worsened after the last dose. 
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 
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For subjects whose echocardiograms are not interpretable by transthoracic echocardiography 
during the study, alternative assessments should be done using either transesophageal 
echocardiography or cardiac magnetic resonance imaging 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 Echocardiography Manual.  
A repeat echocardiogram will be performed for subjects with a new finding or Grade 2 severity 
(moderate) or Grade 3 severity (severe).  
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 (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 including an 
echocardiogram within approximately 1 month after last PSL intake and should also return for a 
6-month echocardiogram. The corresponding TEAEs occurring before the SFU echocardiogram 
visit should be followed up until they have resolved, have stable sequelae, or the subject is lost to 
follow up. During the 6-month echocardiogram period, Investigators will report any SAEs 
through the UCB SAE reporting process until the final echocardiogram is obtained.  
9.3.4 
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 
Entry Visit will be recorded as AEs. 
A full physical examination will include, assessment of 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. 
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. 
9.3.5 
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 Entry 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. 
9.3.6 
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 for the parent study as well as to assess suicidal ideation 
and behavior that may occur during the study. The Investigator’s decision about subject 
continuation in the study or subject withdrawal from the study if the subject has a positive 
response to the C-SSRS Question 4, should be based on the benefit/risk balance for continuation 
or discontinuation of study treatment in view of the individual subject 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 C-SSRS) and provided to UCB via the SAE reporting process. 
9.3.7 
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 Entry Visit 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. 
9.3.8 
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 questions 
and observations 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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10 
ASSESSMENT OF EFFICACY 
The efficacy variables are described in detail in Section 4.2. 
10.1 
Seizure frequency 
During the study, subjects will keep diaries to record daily seizure activity from the Entry Visit 
until the end of study participation. Subjects should be reminded to bring their diaries with them 
to each clinic visit. 
The written information will be discussed with the subjects at each visit in order to ensure 
completeness and accuracy. As a result of the discussion, the Investigator will assess the seizures 
according to the ILAE codes and record the seizure types and frequency in the eCRF; he/she will 
also confirm the presence of AEs if applicable. 
Subjects should be educated to complete their diary entries after each seizure or at least once a 
day (eg, when taking evening tablets). A caregiver can assist in completing the diary if 
necessary. Substantial noncompliance with diary completion (seizure recording) may result in 
subject discontinuation from the study at any time by the Investigator or the Sponsor; see 
Section 6.3. 
The following seizure information will be recorded in the diary: 
 Seizure type 
 Seizure frequency 
10.2 
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 
Section 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 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. 
10.3 
Seizure Severity Global Item 
The SSG consist of 1 or 2 items from the Seizure Severity Questionnaire asking the subjects to 
evaluate the severity of their seizures for the last 4-weeks and/or since the Baseline (in parent 
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study). Subjects should describe their most common type of seizure when answering the 
questions.  
The SSG will be completed according to the tabular schedule of study procedures in 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. 
10.4 
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 et al, 2017; Wiglush et al, 2016; 
de Oliviera 2014). The HADS scores for anxiety and for depression range from 0 to 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.  
10.5 
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 in Table 5-1. 
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 
10.6 
Treatment Satisfaction 
The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 is a 9-item questionnaire 
developed to provide a suitable measure of treatment satisfaction with medication 
(Bharmal et al, 2009). It has 5 to 7 Likert response options per item and consists of 3 subscales: 
effectiveness (3 items), convenience (3 items), and a global satisfaction scale (3 items). The 
TSQM-9 was developed from the TSQM-12, which has an additional subscale that measures side 
effects (3 items) (Atkinson et al, 2004). The estimated completion time for this questionnaire is 
less than 5 minutes. Scores range from 0 (worst) to 100 (best). 
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The TSQM-9 will be completed according to the tabular schedule of assessments (Table 5-1). At 
the very beginning of the visit, the TSQM-9 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.  
10.7 
Personal outcomes assessment 
Subjects who have accepted to participate in the entry and exit personal outcome interview 
during the parent study will be invited to further provide qualitative follow-up interviews/surveys 
after 6 months and 21 months in the OLE study. Participation in this additional portion of the 
study is optional and does not preclude participation in the main study. For subjects who choose 
to participate, the interviews will be conducted by a study nurse/study personnel using a 
semistructured interview guide and will be audio-recorded (refer to Section 12.4.3 for details on 
analyses of the corresponding data). 
The aim of the 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 his/her Early Discontinuation Visit. 
10.8 
Caregiver survey 
Caregivers who participated in the entry and exit caregiver survey for the parent study will be 
invited at the 6 Month and 21 Month Visits to complete an additional survey. Participation in the 
caregiver survey is optional and does not preclude a subject's participation in the main study.  
The optional caregiver survey aims to gather the caregiver's perspective on the impact of 
epilepsy on the subject's life and expectations of meaningful change. The caregiver's 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 12.4.3 for details on analyses of the corresponding data. 
11 
STUDY MANAGEMENT AND ADMINISTRATION 
11.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
Sponsor. 
After implementation of such measure, the Investigator must notify the Clinical Project Manager 
of the Sponsor within 24 hours and follow any local regulatory requirements. 
11.2 
Monitoring 
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring SOPs, ICH-GCP 
guidelines, and applicable regulatory requirements, and to ensure that study initiation, conduct, 
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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 participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records. 
11.2.1 
Definition of source data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Source documents should be kept in a secure, limited access area. 
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 
 Physical and neurological examinations 
 Psychiatric and Mental Status 
 Health care 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 
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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). 
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 patient identifier, 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 IMP, the subject’s medical history, the concomitant medication treatments and dates 
(including contraceptive treatment), AEs and SAEs, and the dates of the visits. The source 
documents should provide evidence that Inclusion/Exclusion criteria have been met. 
11.2.2 
Source data verification 
Source data verification (SDV) 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 11.2.1. A risk-based 
approach will be used to monitor the data from the site including tools such as SDV and remote 
data review. These processes will be described in the study manuals. 
11.3 
Data handling 
11.3.1 
Case Report form completion 
This study is performed using remote data capture. The Investigator is responsible for prompt 
reporting of accurate, complete, and legible data in the eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
11.3.2 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. 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. 
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11.3.3 
Subject Enrollment log/Subject Identification Code list 
The subject’s 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, assent forms (where applicable), caregiver consent (where applicable), 
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. 
11.4 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity. 
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/Institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The 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 PSL and other material in accordance with UCB procedures for the study. 
11.5 
Archiving and data retention 
The Investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data. 
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the PSL. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The Investigator will contact 
UCB for authorization prior to the destruction of any study records or in the event of accidental 
loss or destruction of any study records. The Investigator will also notify UCB should he/she 
relocate or move the study-related files to a location other than that specified in the Sponsor’s 
study master file. 
11.6 
Audit and inspection 
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities. 
The main purposes of an audit or inspection are to confirm that the rights and 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 
PSL have been processed and reported in compliance with the planned arrangements, the 
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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). 
11.7 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, Institution, Institution staff, or designees of the Sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
12 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
12.1 
Definition of analysis sets 
12.1.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all subjects who have signed the ICF. 
12.1.2 
Safety Set 
The Safety Set (SS) will consist of all enrolled subjects who were administered at least 1 dose of 
PSL. 
12.1.3 
Full Analysis Set 
The Full Analysis Set will consist of all enrolled subjects who were administered at least 1 dose 
of PSL or a partial dose of PSL and completed at least 1 seizure diary during the Evaluation 
Period. 
12.2 
General statistical considerations 
Descriptive statistics, such as the mean, standard deviation, standard error, median, minimum 
value, and maximum value for quantitative variables, and counts and percentages for categorical 
variables, will be provided. Key supporting data will be provided in data listings. Summary 
statistics will be presented by the overall PSL group, unless otherwise indicated. 
12.3 
Planned safety analyses 
All safety variables will be analyzed by descriptive methods and listed on the SS. 
Treatment-emergent AEs will be summarized by study period (Evaluation, Taper, and SFU) and 
reported for cumulative 3-month time intervals and categories of total duration of exposure, 
using the Medical Dictionary for Regulatory Activities (MedDRA®) primary System Organ 
Class (SOC) and Preferred Term in incidence tables. Separate tables will be provided for AEs 
leading to withdrawal from the study and SAEs overall and by the subcategories listed above. 
Laboratory values, ECG data (heart rate, PR interval, QTcB, QTcF, and QRS interval), vital 
signs, and weight will be summarized by period and visit (actual values and change from Entry 
Visit). Possible clinically significant treatment-emergent abnormalities for laboratory values, 
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vital signs, and weight will be listed and summarized by period and visit. Electrocardiogram 
abnormalities will also be listed by period and visit. 
Summary tables (and graphical outputs if needed) will be performed on the Doppler 
echocardiography data. 
Physical and neurological examinations, psychiatric assessments and the withdrawal symptoms 
using the CIWA-B assessment will be provided as listing by period and visit (actual values and 
change from Entry Visit). The C-SSRS results will be displayed in a listing.  
Any additional listings or tabulations will be described in the SAP. 
12.4 
Planned efficacy analyses 
12.4.1 
Analysis of the primary efficacy variable 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in observable focal-onset seizure frequency over the Evaluation Period. 
Seizure frequency will be standardized to a 28-day duration. Potential sensitivity analyses of the 
primary efficacy variable will be described in the SAP. 
12.4.2 
Analysis of the other efficacy variables 
The following efficacy variables will be summarized with descriptive statistics: 
 Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period; the median will be considered as the key statistic 
 Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period; the median will be considered as the key statistic 
 The 50%, 75%, and 90% RR by 3-month intervals or observable focal-onset seizures over the 
Evaluation Period. A 50%, 75%, and 90% responder is defined as a subject with a ≥50%, 
≥75%, or ≥90% reduction in observable focal-onset seizure frequency relative to the Baseline 
Period in the parent study. 
 The 50%, 75%, and 90% RR by 3-month intervals for focal-onset (Type I) seizures over the 
Evaluation Period  
 Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
 Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation Period 
 Change from Baseline from parent study in the Seizure Severity Global Item (SSG) scores at 
each assessment 
 Changes from Baseline from parent study in QOLIE-31-P scores at each assessment 
 Changes from Baseline from parent study in HADS scores at each assessment 
 Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8 and to Visit12 or EOS 
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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 
12.4.3 
Analysis of the subject/caregiver personal outcomes 
The data from the qualitative personal outcomes interviews/surveys are considered exploratory 
and will be maintained separate from the clinical database. 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. 
12.5 
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 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. 
12.6 
Handling of dropouts or missing data 
The methods for handling dropouts will be described in the SAP. Safety and efficacy variables 
will be analyzed as they are available. Days with missing information will be ignored in the 
calculation of the seizure frequency. Since subjects will drop out at different times from the 
study, results will be presented by categories of duration of exposure. 
12.7 
Planned interim analysis and data monitoring 
No formal interim analysis is planned. However, data may be reported prior to the completion of 
this study to support annual reports, regulatory submissions, and publications. 
A DMC will systematically monitor and report on the progress, safety, and/or critical efficacy 
endpoints of this study by convening to review the ongoing program safety and efficacy data. 
This includes evaluating the safety signals and benefit-risk ratio for the study subjects in 
relationship to new data relevant for PSL efficacy and safety. 
A DMC Charter will define the composition, roles, and responsibilities of the DMC, specify the 
data to be reviewed and the periodicity of data review, and determine the procedures to be 
followed.  
12.8 
Determination of sample size 
For this OLE study, no sample size calculation is needed. The sample size will depend upon 
recruitment into and completion of the previous study. Approximately 1000 subjects may be 
included. 
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13 
ETHICS AND REGULATORY REQUIREMENTS 
13.1 
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. 
13.2 
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. 
13.3 
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. 
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. 
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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. 
13.4 
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 the Entry Visit. 
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). 
13.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective. 
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented. 
14 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements. 
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Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable. 
15 
REFERENCES 
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measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication 
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Azuma H, Akechi T. Effects of psychosocial functioning, depression, seizure frequency, and 
employment on quality of life in patients with epilepsy. Epilepsy Behav. 2014;41:18-20. 
Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a 
European study. Epilepsia. 1997;38(3):353-62. 
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of an 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among patients on 
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Commission on Classification and Terminology of the International League Against Epilepsy. 
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CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
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de Oliveira GN, Lessa JM, Goncalves AP, Portela EJ, Sander JW, Teixeira Al. Screening for 
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(HADS-D), and Beck depression inventory (BDI). Epilepsy Behav. 2014;34:50-4. 
Devinsky O. Sudden, unexpected death in epilepsy. N Engl J Med. 2011;365:1801-11. 
Fazel S, Wolf A, Långström N, Newton CR, Lichtenstein P. Premature mortality in epilepsy and 
the role of psychiatric comorbidity: a total population study. Lancet. 2013;382:1646-54. 
Food and Drug Administration. Development Resources. Drug development and drug 
interactions: Table of substrates, inhibitor and inducers. Accessed Sep 2017. 
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abeling/ucm093664.htm  
Food and Drug Administration. Guidance for Industry. Guidelines for the clinical evaluation of 
antiepileptic drugs (adults and children). US Department of Health and Human Services. Center 
for Drug Evaluation and Research, 81-3110, 01/1981. 
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Giussani G, Canelli V, Bianchi E, Erba G, Franchi C, Nobili A, et al. Long-term prognosis of 
epilepsy, prognostic patterns and drug resistance: a population-based study. Eur J Neurol. 
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Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: Potential role of antiepileptic 
drugs. CNS Drugs. 2013;27(2):113-9.  
Holst AG, Winkel BG, Risgaard B, Nielsen JB, Rasmussen PV, Haunsø S, et al. Epilepsy and 
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Iung B, Vahanian A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol. 
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Jehi L. Neurology's Silent Killer: Drug-Resistant Epilepsy. Epilepsy Curr. 2016;16:232-3. 
Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. 
J Neurol Neurosurg Psychiatry. 2004;75(10):1376-81. 
Leclercq K, Matagne A, Provins L, Klitgaard H, Kaminski R. Protective effects of padsevonil in 
acute seizure models. (Abstract 1.272), 2017. www.aesnet.org.  
Lin CY, Pakpour AH. Using Hospital Anxiety and Depression Scale (HADS) on patients with 
epilepsy: Confirmatory factor analysis and Rasch models. Seizure. 2017;45:42-6. 
Muglia P, Toledo T, Steinhoff, BJ, et al. Efficacy and tolerability of adjunctive padsevonil in 
adults with drug-resistant focal onset seizures: a randomized, double-blind, placebo-controlled, 
proof-of-concept trial. (Abstract 1.283), 2017. American Epilepsy Society Annual Meeting, 
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Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77. 
Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, et al. Is the underlying 
cause of epilepsy a major prognostic factor for recurrence? Neurology. 1998;51(5):1256-62. 
Sperling MR. The consequences of uncontrolled epilepsy. CNS Spectr. 2004;9(2):98-101, 106-9. 
Taylor DC, McMackin D, Staunton H, Delanty N, Phillips J. Patients' aims for epilepsy surgery: 
desires beyond seizure freedom. Epilepsia. 2001;42(5):629-33. 
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Sep 2017. http://www.whocc.no/atc_ddd_index/ 
Wiglusz MS, Landowski J, Michalak L, Cubala WJ. Validation of the Hospital Anxiety and 
Depression Scale in patients with epilepsy. Epilepsy Behav. 2016;58:97-101. 
Zack MM, Kobau R. National and state estimates of the numbers of adults and children with 
active epilepsy-United States, 2015. MMWR Morb Mortal Wkly Rep 2017;66:821-825. 
Zigmond RP, Snaith AS. The Hospital Anxiety and Depression Scale. Act Psychiatr, Scand, 
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Zhoghbi WA, Adams D, Bonow RO, Enriquwz-Sarano M, Foster E, Grayburn PA, et al. 
Recommendations for noninvasive evaluation of native valvular regurgitation: A report from the 
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American Society of Echocardiography developed in collaboration with the society for 
cardiovascular magnetic resonance. JASE. 2017;30:303-71.  
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16 
APPENDICES 
16.1 
Protocol Amendment 1.0 
Rationale for the amendment 
The protocol did allow subjects without access to a Managed Access Plan to continue 
participation in EP0093 after the second year and until a Marketing Authorization is granted by 
any health authority for the adjunctive treatment of focal-onset seizures in adults with 
drug-resistant epilepsy. This amendment limits duration of participation of all subjects to 2 years. 
Subjects without access to a Managed Access Plan will be offered the option to transfer to 
another study if approved by the relevant country agencies. This has been noted in several 
locations in the protocol.   
Other changes include the following: 
 Updates to study contact information. 
 Increase in number of sites from 150 to approximately 350.  
 Modification of the proposed indication statement (removal of drug-resistant).  
 Clarification of study objectives to specify that subjects have focal-onset seizures as well as 
drug-resistant epilepsy. 
 Removal of log-transformation of observable focal-onset seizures for the analysis. 
 Addition of other efficacy variable, time to discontinuation. 
 Minor revisions to wording of some variables.  
 Specification that follow-up echocardiograms at 1 and 6 months after the last PSL intake are 
required.  
 Addition of China to anticipated regions and countries in which the study will be conducted.  
 Revisions to the Schedule of Study Assessments consistent with the main change in the 
amendment. This includes a split of the EDV and EOT (now called End of Study) visits into 
separate visits. This is also reflected in the Study Procedures by Visit Section. In addition, 
some footnotes were added/clarified.  
 Substitution of “where legally permitted” for “where applicable” in Inclusion Criteria 1 and 
2. 
 Revision of valvular abnormality grading criteria and withdrawal criterion pertaining to 
echocardiographic findings to add stenosis wherever regurgitation is noted. This makes the 
criterion consistent with those in the feeder studies. 
 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 
cardiologist. Therefore, the protocol was modified to say that it is only necessary that the 
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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.  
 Revision of prohibited concomitant treatments to make them consistent with the feeder 
studies.  
 Addition of FSH to the laboratory measurements with specification that it is only applicable 
to postmenopausal women. In addition, a footnote was added to urine microscopy to indicate 
this is only performed in case of other abnormalities. This makes the table consistent with the 
feeder studies.  
 The description of the measurements and observations included in the echocardiograms was 
revised for consistency with the feeder studies.  
 The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 has been added to study 
assessments. References pertaining to this questionnaire have been added.  
 Clarifications regarding administration of the QOLIE-31-P, SSG, and HADS. 
Modifications and changes 
Specific changes 
Change #1 
Study contact information (bolded information revised) 
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 information 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 SL1 3WE Slough, 
UK 
Phone: 
 
 
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Change #2 
List of Abbreviations 
Has been added: 
EOS=End of Study (replaces EOT) 
TSQM=Treatment Satisfaction Questionnaire for Medication 
Change #3 
Section 1, Summary (bolded text has been deleted) 
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, which constitute a substantial threat to their health and 
well-being. 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. This open-label, 
long-term study will provide subjects, who participated in previous PSL studies, the opportunity 
to have continued access to PSL. 
The primary objective of this study is to evaluate the long-term safety and tolerability of PSL 
administered at individualized doses between 100mg/day and 800mg/day as adjunctive treatment 
for subjects with drug-resistant epilepsy. The secondary objective is to evaluate the long-term 
efficacy of PSL as an adjunctive treatment for focal-onset seizures in adults with drug-resistant 
epilepsy. 
This study will enroll subjects who have completed a PSL parent study. Subjects will continue to 
report their seizures in a diary. After the Entry Visit (Visit 1), subjects will return to the clinic for 
the following visit schedule during the Evaluation Period:  
 Every 2 weeks during Month 1 
 Every month during Month 2 and Month 3 
 Every 3 months after Month 3 to the end of Year 2 
 Every 6 months from the beginning of Year 3 
Dose adjustment of PSL, and/or concomitant antiepileptic drugs (AEDs), and/or 
neurostimulation devices is allowed at any time during the study, if seizure control is 
insufficient, or in case of safety or tolerability issues. Subjects who complete the study (and do 
not continue PSL treatment) or who discontinue early from the study will return for an End of 
Treatment (EOT) Visit or Early Discontinuation Visit (EDV) and will be progressively tapered 
off PSL over 4 weeks and return to the site after the last PSL intake for a Safety Follow-Up 
(SFU) Visit 30 days after the last PSL intake (including echocardiogram) and a 6-month 
follow-up echocardiogram to complete echocardiographic monitoring. In case PSL becomes 
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available either via a Managed Access Program or after Marketing Authorization, the 
Taper Period may be skipped and the subjects may continue treatment without tapering. 
Safety will be evaluated based on the incidence of treatment-emergent adverse events (TEAEs) 
reported by the subject and/or caregiver; subject withdrawals due to adverse events (AEs); 
changes in periodic clinical laboratory tests; electrocardiogram (ECG) parameters; 
echocardiography results; withdrawal symptoms, vital signs; Psychiatric and Mental Status; and 
findings from physical and neurological examinations. 
The primary efficacy variable will be the change from Baseline from the respective parent study 
in log-transformed observable focal-onset seizure frequency over the Evaluation Period. 
Secondary and other efficacy variables will allow further exploration of the effect of PSL on 
seizure frequency during the entire Evaluation Period, seizure severity, quality of life, anxiety 
and depression, and unforeseen medical resource utilization. 
The total duration of the study per subject will be up to 2 years, in countries where subjects can 
be transferred to a Managed Access Program. Subjects may continue in EP0093 in 
countries where a Managed Access Program is inexistent until a Marketing Authorization 
is granted by any health authority for the adjunctive treatment of focal-onset seizures in 
adults with drug-resistant epilepsy. It is estimated that up to 1000 subjects will be included at 
approximately 150 sites worldwide. 
Has been changed to (new text bolded): 
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, which constitute a substantial threat to their health and 
well-being. 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. This open-label, 
long-term study will provide subjects, who participated in previous PSL studies, the opportunity 
to have continued access to PSL. 
The primary objective of this study is to evaluate the long-term safety and tolerability of PSL 
administered at individualized doses between 100mg/day and 800mg/day as adjunctive treatment 
for subjects with drug-resistant epilepsy. The secondary objective is to evaluate the long-term 
efficacy of PSL as an adjunctive treatment for focal-onset seizures in adults with drug-resistant 
epilepsy. 
This study will enroll subjects who have completed a PSL parent study. Subjects will continue to 
report their seizures in a diary. After the Entry Visit (Visit 1), subjects will return to the clinic for 
the following visit schedule during the Evaluation Period:  
 Every 2 weeks during Month 1 
 Every month during Month 2 and Month 3 
 Every 3 months after Month 3 to the end of Year 2 
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Dose adjustment of PSL, and/or concomitant antiepileptic drugs (AEDs), and/or 
neurostimulation devices is allowed at any time during the study, if seizure control is 
insufficient, or in case of safety or tolerability issues. Subjects who complete the study and do 
not continue PSL treatment or who discontinue early from the study will return for an End of 
Study (EOS) Visit or Early Discontinuation Visit (EDV) and will be progressively tapered off 
PSL over 4 weeks and return to the site after the last PSL intake for a Safety Follow-Up (SFU) 
Visit 30 days after the last PSL intake (including echocardiogram) and a 6-month follow-up 
echocardiogram to complete echocardiographic monitoring.  
Safety will be evaluated based on the incidence of treatment-emergent adverse events (TEAEs) 
reported by the subject and/or caregiver; subject withdrawals due to adverse events (AEs); 
changes in periodic clinical laboratory tests; electrocardiogram (ECG) parameters; 
echocardiography results; withdrawal symptoms, vital signs; Psychiatric and Mental Status; and 
findings from physical and neurological examinations. 
The primary efficacy variable will be the change from Baseline from the respective parent study 
in observable focal-onset seizure frequency over the Evaluation Period. Secondary and other 
efficacy variables will allow further exploration of the effect of PSL on seizure frequency during 
the entire Evaluation Period, seizure severity, quality of life, anxiety and depression, and 
unforeseen medical resource utilization. 
The total duration of the study per subject will be up to 2 years. Subjects benefitting from the 
drug and willing to continue will either take commercial drug, if available, or will be 
transferred to a Managed Access Program or another PSL study, depending on local 
regulations.  
It is estimated that up to 1000 subjects will be included at approximately 350 sites worldwide. 
Change #4 
Section 2.4, Clinical studies, Paragraph 1 (bolded text has been deleted) 
Clinical development (Phase 1 and Phase 2) of PSL is underway, the objective of which is to 
address an unmet medical need by developing a treatment that will provide incremental efficacy 
when added to existing AED treatment for patients with drug-resistant epilepsy. The proposed 
indication of PSL is an adjunctive therapy in the treatment of focal-onset seizures in adult 
patients with drug-resistant epilepsy.  
Has been changed to (new text bolded): 
Clinical development (Phase 1 and Phase 2) of PSL is underway, the objective of which is to 
address an unmet medical need by developing a treatment that will provide incremental efficacy 
when added to existing AED treatment for patients with drug-resistant epilepsy. The proposed 
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indication of PSL is as an adjunctive therapy in the treatment of focal-onset seizures in adult 
patients with epilepsy.  
Change #5 
Section 3.1, Primary objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of PSL 
administered at individualized doses between 100mg/day and 800mg/day as adjunctive treatment 
for subjects with drug-resistant epilepsy. 
Has been changed to (new text bolded): 
The primary objective of this study is to evaluate the long-term safety and tolerability of PSL 
administered at individualized doses between 100mg/day and 800mg/day as adjunctive treatment 
for subjects with focal-onset seizures and drug-resistant epilepsy. 
Change #6 
Section 3.3, Exploratory objective 
The exploratory objective is to assess the impact of PSL as an adjunctive treatment for subjects 
with drug-resistant epilepsy on health-related outcomes and healthcare resources utilization 
(HRU). 
Has been changed to (new text bolded): 
The exploratory objective is to assess the impact of PSL as an adjunctive treatment for subjects 
with focal-onset seizures and drug-resistant epilepsy on health-related outcomes and healthcare 
resources utilization (HRU). 
Change #7 
Section 4.1.2, Other safety variables, bullets 3 and 5 (bolded text has been deleted) 
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the EOT Visit, to the end of Taper Period and 
to the end of the SFU Period (30 days after last PSL intake) 
 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 (new text bolded): 
 Changes in withdrawal symptoms using Clinical Institute Withdrawal 
Assessment-Benzodiazepines (CIWA-B) from the EOS Visit, to the end of Taper Period and 
to the end of the SFU Period (30 days after last PSL intake) 
 Occurrence of a clinically-significant valvular change or pericardial effusion or other 
clinically-significant abnormalities as identified by 2-dimensional Doppler echocardiogram 
at each assessment by central reader 
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Change #8 
Section 4.2.1, Primary efficacy variable (bolded text has been deleted) 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in log-transformed observable focal-onset seizure frequency over the Evaluation Period.  
Has been changed to: 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in observable focal-onset seizure frequency over the Evaluation Period.  
Change #9 
Section 4.2.2, Other efficacy variables (bolded text has been deleted) 
The other efficacy variables are the following: 
 Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period 
 Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period 
 The 50%, 75%, and 90% responder rate (RR) status by 3-month intervals for observable 
focal-onset seizures over the Evaluation Period. A 50%, 75%, and 90% responder is defined 
as a subject with a ≥50%, ≥75%, or ≥90% reduction in the observable focal-onset seizure 
frequency relative to the Baseline Period defined in the parent study. 
 The 50%, 75%, and 90% RR status by 3-month intervals for focal-onset seizures (Type I) 
over the Evaluation Period  
 Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
 Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation Period 
 Change from Baseline from parent study in the Seizure Severity Global Item (SSG) scores at 
each assessment 
 Changes from Baseline from parent study in Quality of Life Inventory in Epilepsy-31-P 
(QOLIE-31-P) scores at each assessment 
 Changes from Baseline from parent study in Hospital Anxiety and Depression Scale (HADS) 
scores at each assessment 
 Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8, and to Visit 12 or EOT 
 Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications, and hospitalizations 
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Has been changed to (new text bolded): 
The other efficacy variables are the following: 
 Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period 
 Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period 
 The 50%, 75%, and 90% responder rate (RR) by 3-month intervals for observable focal-onset 
seizures over the Evaluation Period. A 50%, 75%, and 90% responder is defined as a subject 
with a ≥50%, ≥75%, or ≥90% reduction in the observable focal-onset seizure frequency 
relative to the Baseline Period defined in the parent study. 
 The 50%, 75%, and 90% RR by 3-month intervals for focal-onset seizures (Type I) over the 
Evaluation Period  
 Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
 Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation Period 
 Time to discontinuation 
 Change from Baseline from parent study in the Seizure Severity Global Item (SSG) scores at 
each assessment 
 Changes from Baseline from parent study in Quality of Life Inventory in Epilepsy-31-P 
(QOLIE-31-P) scores at each assessment 
 Changes from Baseline from parent study in Hospital Anxiety and Depression Scale (HADS) 
scores at each assessment 
 Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8, and to Visit 12 or EOS 
 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 5.1, Study description (bolded text has been deleted) 
This is an OLE study that will assess the safety, tolerability, and change in focal-onset seizure 
frequency associated with long-term oral PSL as an adjunctive therapy in adult subjects with 
drug-resistant epilepsy. This study will enroll consenting subjects, or subjects whose legal 
representatives have given consent, and who have completed a PSL parent study (eg, EP0091 or 
subsequent PSL studies). 
At the Entry Visit (same day as the end of Conversion Period Visit in the parent study), 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 
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basis of the inclusion/exclusion criteria by the Investigator. Eligible subjects must be educated to 
record all types of seizures that occur in their seizure diary and to complete their diary entries 
after each seizure or at least once a day. A caregiver is allowed to help the subject with the 
completion of the subject diary.  
Evaluation Period 
After the Entry Visit (Visit 1), subjects will return to the clinic for visits as follows:  
 Every 2 weeks during Month 1 
 Every month during Month 2 and Month 3 
 Every 3 months after Month 3 to the end of Year 2 
 Every 6 months from the beginning of Year 3 (see Section 5.1.1) 
Dose adjustment of PSL and/or concomitant AEDs and/or settings to neurostimulation devices is 
allowed at any time during the study, if seizure control is insufficient, or in case of safety or 
tolerability issue. Concomitant AED(s) may be tapered and discontinued to achieve PSL 
monotherapy, if clinically appropriate in which case the UCB Physician or delegate must be 
contacted to discuss with the Investigator. New concomitant AEDs, as allowed per protocol (see 
Section 7.8.1), may be introduced to optimize seizure control. Subjects who are not able to 
tolerate or who do not benefit from the PSL treatment may be tapered off PSL and withdrawn 
from the study. 
Taper Period 
Subjects who complete the study after the 2-year Evaluation Period or who discontinue early 
will return for an End-of-Study Visit or EDV, respectively, and will be progressively tapered off 
over 4 weeks and return to the site 1 week after the last PSL intake for an end of Taper Visit. In 
case PSL becomes available either via a Managed Access Program or after a Marketing 
Authorization, the Taper Period may be skipped and the subjects may continue treatment 
without tapering.  
Safety Follow-up Period 
Safety follow up will consist of 1 required visit (SFU Visit) 30 days after the last PSL intake. A 
follow-up echocardiogram will be performed at approximately 1 month and 6 months after the 
last PSL intake. 
Has been changed to (new text bolded): 
This is an OLE study that will assess the safety, tolerability, and change in focal-onset seizure 
frequency associated with long-term oral PSL as an adjunctive therapy in adult subjects with 
drug-resistant epilepsy. This study will enroll consenting subjects, or subjects whose legal 
representatives have given consent, and who have completed a PSL parent study (eg, EP0091 or 
subsequent PSL studies). 
At the Entry Visit (same day as the end of Conversion Period Visit in the parent study), 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 by the Investigator. Eligible subjects must be educated to 
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record all types of seizures that occur in their seizure diary and to complete their diary entries 
after each seizure or at least once a day. A caregiver is allowed to help the subject with the 
completion of the subject diary.  
Evaluation Period 
After the Entry Visit (Visit 1), subjects will return to the clinic for visits as follows:  
 Every 2 weeks during Month 1 
 Every month during Month 2 and Month 3 
 Every 3 months after Month 3 to the end of Year 2 
Dose adjustment of PSL and/or concomitant AEDs and/or settings to neurostimulation devices is 
allowed at any time during the study, if seizure control is insufficient, or in case of safety or 
tolerability issue. Concomitant AED(s) may be tapered and discontinued to achieve PSL 
monotherapy, if clinically appropriate in which case the UCB Physician or delegate must be 
contacted to discuss with the Investigator. New concomitant AEDs, as allowed per protocol (see 
Section 7.8.1), may be introduced to optimize seizure control. Subjects who are not able to 
tolerate or who do not benefit from the PSL treatment may be tapered off PSL and withdrawn 
from the study. 
Taper Period 
Subjects who complete the study or who discontinue early will return for an End-of-Study Visit 
or EDV, respectively, and will be progressively tapered off over 4 weeks and return to the site 1 
week after the last PSL intake for an end of Taper Visit. If a subject transfers into either a 
Managed Access Program or another PSL study, or takes commercially available PSL, the 
Taper Period may be skipped and the subject may continue treatment without tapering.  
Safety Follow-up Period 
Safety follow up will consist of 1 required visit (SFU Visit) 30 days after the last PSL intake. A 
follow-up echocardiograms will be required at approximately 1 month and 6 months after the 
last PSL intake. 
Change #11 
Section 5.1.1, Study duration per subject, Paragraph 1 (bolded text has been deleted) 
The total study duration per subject will be up to approximately 2 years in countries where 
subjects can be transferred to a Managed Access Program. In countries where a Managed 
Access Program is inexistent, subjects may continue in EP0093 until a Marketing 
Authorization is granted by the health authority for the adjunctive treatment of focal-onset 
seizures in adults with drug-resistant epilepsy. 
Has been changed to (new text bolded): 
The total study duration per subject will be up to approximately 2 years. Subjects benefitting 
from the drug and willing to continue will either take commercial drug, if available, or will 
be transferred to a Managed Access Program or another PSL study, depending on local 
regulations.  
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Change #12 
Section 5.1.2, Planned number of subjects and sites (bolded text has been deleted) 
It is estimated that approximately 1000 subjects will be included in approximately 150 sites 
worldwide. 
Has been changed to (new text bolded): 
It is estimated that approximately 1000 subjects will be included in approximately 350 sites 
worldwide. Additional sites may be added if the study is extended to other regions or 
countries. 
Change #13 
Section 5.1.3, Anticipated regions and countries (bolded text has been deleted) 
The study will be conducted in North America, Europe, and Japan, with possible extension to 
other regions or countries. 
Has been changed to (new text bolded): 
The study will be conducted in North America, Europe, Japan, and China with possible 
extension to other regions or countries. 
Change #14 
Section 5.2, Table 5-1: Schedule of study assessments 
Has been changed to: 
The following changes have been made:  
 Column with heading, “Visits every 6 M” in the Evaluation Period has been removed.  
 The column for the EOT/EDV Visit was split into 2 columns, one for the EOT visit, which is 
now called the End of Study (EOS) Visit, and a second for the EDV Visit.  
 The TSQM-9 was added to the table, and the abbreviation was defined under the table.  
 An echocardiogram was added to the EOS Visit.  
 The following footnotes have been removed:  
 Footnote b: The total duration per subject will be up to 2 years. In countries where 
allowed, subjects will be transferred to a Managed Access Program. In countries where a 
Managed Access Program is inexistent, subjects may continue in EP0093 until a 
Marketing Authorization is granted by any health authority for the adjunctive treatment 
of focal-seizure epilepsy in adults with drug-resistant epilepsy. If subjects participate in 
the study beyond the end of Year 2, subjects will return for clinic visits every 6 months. 
 Footnote q: For subject completing the study and continuing PSL treatment in case PSL 
becomes available either via a Managed Access Program or after Marketing 
Authorization.  
 Footnote e (now footnote d) was revised as follows:  
From:  
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Questionnaires to be completed by all subjects prior to any other study procedures at the 
visit. 
To (new text bolded):  
Questionnaires to be completed by all subjects prior to any other study procedures at the 
visit, when possible. 
 Footnote j (now footnote i) was revised as follows:  
From:  
Personal outcome assessments will be completed at Visit 6 (Month 6) and Visit 11 
(Month 21). 
To: 
Personal outcome assessments will be completed at Visit 6 (Month 6) and Visit 11 
(Month 21) (for subjects who agree to participate). 
 Footnote k (now footnote j) was revised as follows: 
From (bolded text has been deleted):  
An ECG at the SFU 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 
supine position for at least 5 minutes 
To (new text bolded): 
An ECG at the SFU will be performed only if abnormal at the EOS or EDV Visit. All ECG 
recordings will be performed with the subject resting in supine position for at least 5 minutes 
 Footnote l (now footnote k) was revised as follows: 
From (bolded text has been deleted):  
An echocardiogram will also be performed 6 months after the subject’s last PSL intake. 
A repeat echocardiogram will be performed for subjects with a new finding, Grade 2 severity 
(moderate), or Grade 3 severity (severe) (see Section 6.3).  
To (new text bolded): 
Only subjects who do not require tapering of PSL at M24 will have an echocardiogram 
at M24. All other subjects will have an echocardiogram at the SFU Visit and at 6 
months after the last dose of PSL. A repeat echocardiogram will be performed for subjects 
with a new finding, Grade 2 severity (moderate), or Grade 3 severity (severe) (see 
Section 6.3). 
 Footnote p was added to PSL dispensing (IRT) at the EOS Visit:  
PSL will be dispensed at the EOS Visit only to subjects who will be tapered off PSL. 
 A new footnote q was added to Study termination at the EOS Visit:  
The study termination assessment at the EOS visit is for subjects who will transfer into either 
a Managed Access Program or another PSL study. 
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 Footnote r was added to Study termination at the SFU Visit:  
The study termination assessment at the SFU Visit is for subjects who withdraw early or who 
complete the study, but will not be transferred to either a Managed Access Program or 
another PSL study. 
Change #15 
Section 6.1, Inclusion Criteria, Inclusion Criterion 1 (bolded text has been deleted) 
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 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. 
Has been changed to (new text bolded): 
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 legal representative (where 
legally permitted). The ICF or a specific Assent form, where required, will be signed and 
dated by minors, according to country-specific regulations. 
Change #16 
Section 6.1, Inclusion Criteria, 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 (new text bolded): 
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 #17 
Section 6.3, Withdrawal criteria, Withdrawal criterion 8 
8. Subjects 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 PSL. 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 (new text bolded): 
8. Subjects 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 PSL. Additionally, a jump of 2 grades 
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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 #18 
Section 6.3.2, Table 6-1: Valvular abnormality grading criteria 
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 
Symptomsa : 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
Signs: 
Pulmonary arterial pressure 
>40mmHg 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 (new text 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 
Symptomsa : 
Shortness of breath on 
exertion or at rest; 
palpitation; syncope; 
anginal or pericarditic 
chest pain; fatigue or 
weakness 
 
Signs: 
Pulmonary arterial pressure 
>40mmHg 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 #19 
Section 6.3.2, Echocardiogram valvular abnormalities assessments, text below Table 6-1 
(bolded text has been deleted) 
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 
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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. 
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) 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 is 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) 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 
PSL. 
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. If the clinical symptoms are mild, the subject is not required to 
discontinue. Investigators may contact the Medical Monitor if they wish to discuss the subject’s 
clinical signs/symptoms. 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 discontinuations. 
Has been changed to (new text bolded): 
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. 
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.  
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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 is 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 
PSL. 
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. If the clinical symptoms are mild, the subject is not required to 
discontinue. Investigators may contact the Medical Monitor if they wish to discuss the subject’s 
clinical signs/symptoms. 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. 
Change #20 
Section 7.8.2, Prohibited concomitant treatments (medications and therapies) (bolded text 
has been deleted) 
The following concomitant medications are prohibited during the study: 
 Benzodiazepines (GABA-A-ergic drugs be it agonists [ie, barbiturates] or receptor positive 
allosteric modulators [ie, benzodiazepines or nonbenzodiazepines like zolpidem]) taken 
>3 times per week. Benzodiazepines with an indication for epileptic seizures like 
clonazepam or clobazam are not allowed as concomitant drugs. 
 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). 
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Has been changed to (new text bolded): 
The following concomitant medications are prohibited during the study: 
 GABA-A-ergic drugs: including agonists (ie, barbiturates) or receptor positive allosteric 
modulators (ie, benzodiazepines or nonbenzodiazepines like zolpidem) taken >3 times per 
week. Regular intake of benzodiazepines with an indication for epileptic seizures is not 
allowed. However, PRN intake of GABA-A-ergic drugs <3 times per week is allowed, ie, 
for emergencies. 
 Strong CYP3A4 inhibitors/inducers (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). 
 AEDs including carbamazepine, phenytoin, phenobarbital, and primidone 
 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). 
Change #21 
Section 8.1.7, Visit 12 and every 6 months thereafter (± 1 week) 
Has been changed to: 
This visit was deleted. 
Change #22 
Section 8.1.8, Early Discontinuation Visit or End of Treatment (bolded text has been 
deleted) 
Section 8.1.8 Early Discontinuation Visit or End of Treatment 
The following procedures will be performed by all subjects discontinuing the study or 
completing it: 
 Verify withdrawal criteria 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain QOLIE-31-P data 
 Obtain SSG 
 Obtain CIWA-B data (in case of discontinuation of PSL treatment) 
 Measure vital signs (pulse rate, systolic BP, diastolic BP, and respiratory rate), in supine 
position after 5 minutes of rest 
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 Measure body weight 
 Perform brief physical examination (refer to Section 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 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 and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) 
 Dispense PSL unless PSL becomes available either via a Managed Access Program or 
after Marketing Authorization)  
 Check PSL accountability 
 Study termination (for subjects completing the study and continuing PSL treatment) 
Has been changed to (new text bolded): 
Section 8.1.7 Early Discontinuation Visit  
The following procedures will be performed by all subjects discontinuing the study early: 
 Verify withdrawal criteria 
 Obtain TSQM-9 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain QOLIE-31-P data 
 Obtain SSG 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
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 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 and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) 
 Dispense PSL to those subjects requiring a Taper Period  
 Check PSL accountability 
Change #23 
Section 8.1.8, End of Study Visit 
This is a new section. 
Has been changed to (new text bolded): 
Section 8.1.8 End of Study Visit 
The following procedures will be performed by all subjects completing the study: 
 Obtain TSQM-9 
 Obtain C-SSRS data since the last visit 
 Obtain HADS data 
 Obtain QOLIE-31-P data 
 Obtain SSG 
 Obtain CIWA-B data (in case of discontinuation of PSL treatment) 
 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 9.3.4 for details) 
 Perform brief neurological examination (refer to Section 9.3.5 for details) 
 Perform Psychiatric and Mental Status assessment 
 Obtain 12-lead ECG 
 Obtain echocardiogram if required. Only subjects who do not require tapering of PSL 
at M24 will have an echocardiogram at M24. All other subjects will have an 
echocardiogram at the SFU Visit and at 6 months after the last dose of PSL. 
 Collect blood and urine samples for clinical laboratory analyses 
 Perform urine pregnancy test (female subjects of childbearing potential only) 
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 Seizure evaluation (count and type) from subject’s daily record card 
 Record concomitant medication and procedures  
 Record AEs 
 Record health-related outcomes and HRU (refer to Section 10.5 for details) 
 Dispense PSL to those subjects requiring a Taper Period 
 Check PSL accountability 
 Study termination (for subjects completing the study and continuing PSL treatment) 
Change #24 
Section 9.2, 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 9-2. 
The total blood volume drawn for clinical laboratory assessments per subject will be a maximum 
of 7mL by sampling, which includes 2mL for hematology and 5mL for blood chemistry. 
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Table 9‒6: 
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) 
MCHC 
Chloride 
 
MCV 
Creatinine 
 
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; 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 
In addition, for females of childbearing potential, a urine pregnancy test (beta-human chorionic 
gonadotropin) will be performed at the scheduled time points presented in Table 5-1. 
Has been changed to (new text bolded): 
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 9-2. 
The total blood volume drawn for clinical laboratory assessments per subject will be a maximum 
of 7mL by sampling, which includes 2mL for hematology and 5mL for blood chemistry. 
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Table 9‒7: 
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; Follicle Stimulating Hormone; HDL=high-density lipoprotein; 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 
In addition, for females of childbearing potential, a urine pregnancy test (beta-human chorionic 
gonadotropin) will be performed at the scheduled time points presented in Table 5-1. If 
pregnancy is suspected at any time during the study, an interim test should be performed. 
Change #25 
Section 9.3.2, Electrocardiograms, Paragraph 3 (bolded text has been deleted) 
The Investigator should review all ECG recordings and determine if there are any abnormalities 
that are considered clinically significant for a particular subject. The ECGs will also be sent to a 
specified central reader for review as detailed in the ECG Manual. The ECGs will also be sent 
to a 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. 
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Has been changed to: 
The Investigator should review all ECG recordings and determine if there are any abnormalities 
that are considered clinically significant for a particular subject. The 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. 
Change #26 
Section 9.3.3, Echocardiograms (bolded text has been deleted) 
Echocardiograms will be performed at the scheduled time points presented in Table 5-1. The 
echocardiogram will be repeated at 6 months (±1 month) after the last PSL intake to assess any 
abnormalities that may have newly occurred or worsened after the last dose. 
Two-dimensional Doppler echocardiography will be performed with: 
1. Diastolic measurements (mitral forward flow E and A waves and deceleration time) 
2. Tissue Doppler on medial and lateral mitral valve annulus (S, E, and A waves) 
3. Standardized views for left atrial volume measurements 
In the event echocardiograms are not interpretable by transthoracic echocardiography during the 
study, alternative assessments should be done using either transesophageal echocardiography or 
cardiac magnetic resonance imaging in these particular instances. 
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 Echocardiography Manual.  
A repeat echocardiogram will be performed for subjects with a new finding or Grade 2 severity 
(moderate) or Grade 3 severity (severe).  
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 
moderate severity, accompanied by moderate or severe signs/symptoms; (2) a Grade 3 finding of 
severe severity (with or without accompanying symptoms); or (3) a deterioration 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 including an 
echocardiogram within approximately 1 month after last PSL intake. The corresponding TEAEs 
should be followed up until they have resolved, have a stable sequelae, or the subject is lost to 
follow up. 
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Has been changed to (new text bolded): 
Echocardiograms will be performed at the scheduled time points presented in Table 5-1. The 
echocardiogram will be repeated at 6 months (±1 month) after the last PSL intake to assess any 
abnormalities that may have newly occurred or worsened after the last dose. 
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 
For subjects whose echocardiograms are not interpretable by transthoracic echocardiography 
during the study, alternative assessments should be done using either transesophageal 
echocardiography or cardiac magnetic resonance imaging 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 Echocardiography Manual.  
A repeat echocardiogram will be performed for subjects with a new finding or Grade 2 severity 
(moderate) or Grade 3 severity (severe).  
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 (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 including an 
echocardiogram within approximately 1 month after last PSL intake and should also return for 
a 6-month echocardiogram. The corresponding TEAEs occurring before the SFU 
echocardiogram visit should be followed up until they have resolved, have stable sequelae, or 
the subject is lost to follow up. During the 6-month echocardiogram period, Investigators 
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will report any SAEs through the UCB SAE reporting process until the final 
echocardiogram is obtained.  
Change #27 
Section 10.2, Quality of Life Inventory in Epilepsy-31-P, Paragraph 4 (bolded text has been 
deleted) 
The QOLIE-31-P will be completed according to the tabular schedule of study procedures in 
Section 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. 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 (new text bolded): 
The QOLIE-31-P will be completed according to the tabular schedule of study procedures in 
Section 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 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. 
Change #28 
Section 10.3, Seizure Severity Global Item, Paragraph 2 (bolded text has been deleted) 
The SSG will be completed according to the tabular schedule of study procedures in 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 (new text bolded): 
The SSG will be completed according to the tabular schedule of study procedures in 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 #29 
Section 10.4, 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 et al, 2017; Wiglush et al, 2016; 
de Oliviera 2014). The HADS scores for anxiety and for depression range from 0 to 21 with 
higher scores indicating worse state. A score below 8 is considered to be normal 
(Zigmond and Snaith, 1983). 
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Has been changed to (new text bolded): 
The HADS was chosen for its well-established psychometric properties both in general 
population and more recently in patients with epilepsy (Lin et al, 2017; Wiglush et al, 2016; 
de Oliviera 2014). The HADS scores for anxiety and for depression range from 0 to 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 #30 
Section 10.6, Treatment Satisfaction  
Has been changed to (new section added): 
The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 is a 9-item questionnaire 
developed to provide a suitable measure of treatment satisfaction with medication 
(Bharmal et al, 2009). It has 5 to 7 Likert response options per item and consists of 3 subscales: 
effectiveness (3 items), convenience (3 items), and a global satisfaction scale (3 items). The 
TSQM-9 was developed from the TSQM 1.42, which has an additional subscale that measures 
side effects (3 items) (Atkinson et al, 2004). The estimated completion time for this 
questionnaire is less than 5 minutes. Scores range from 0 (worst) to 100 (best). 
The TSQM-9 will be completed according to the tabular schedule of assessments (Table 5-1). At 
the very beginning of the visit, the TSQM-9 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.  
Change #31 
Section 12.4.1, Analysis of the primary efficacy variable, Paragraph 1 (bolded text has been 
deleted) 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in log-transformed observable focal-onset seizure frequency over the Evaluation Period. 
Has been changed to: 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in observable focal-onset seizure frequency over the Evaluation Period. 
Change #32 
Section 12.4.2, Analysis of the other efficacy variables (bolded text has been deleted) 
The following efficacy variables will be summarized with descriptive statistics: 
 Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period; the median will be considered as the key statistic 
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 Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period; the median will be considered as the key statistic 
 The 50%, 75%, and 90% RR status by 3-month intervals or observable focal-onset seizures 
over the Evaluation Period. A 50%, 75%, and 90% responder is defined as a subject with a 
≥50%, ≥75%, or ≥90% reduction in observable focal-onset seizure frequency relative to the 
Baseline Period in the parent study. 
 The 50%, 75%, and 90% RR status by 3-month intervals for focal-onset (Type I) seizures 
over the Evaluation Period  
 Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
 Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation Period 
 Change from Baseline from parent study in the Seizure Severity Global Item (SSG) scores at 
each assessment 
 Changes from Baseline from parent study in QOLIE-31-P scores at each assessment 
 Changes from Baseline from parent study in HADS scores at each assessment 
 Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8, and to Visit 12 or EOT) 
 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 (new text bolded): 
The following efficacy variables will be summarized with descriptive statistics: 
 Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period; the median will be considered as the key statistic 
 Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period; the median will be considered as the key statistic 
 The 50%, 75%, and 90% RR by 3-month intervals or observable focal-onset seizures over the 
Evaluation Period. A 50%, 75%, and 90% responder is defined as a subject with a ≥50%, 
≥75%, or ≥90% reduction in observable focal-onset seizure frequency relative to the Baseline 
Period in the parent study. 
 The 50%, 75%, and 90% RR by 3-month intervals for focal-onset (Type I) seizures over the 
Evaluation Period  
 Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
 Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation Period 
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 Change from Baseline from parent study in the Seizure Severity Global Item (SSG) scores at 
each assessment 
 Changes from Baseline from parent study in QOLIE-31-P scores at each assessment 
 Changes from Baseline from parent study in HADS scores at each assessment 
 Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8, and to Visit 12 or EOS) 
 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 #33 
Section 12.7, Planned interim analysis and data monitoring 
A DMC will systematically monitor and report on the progress, safety, and/or critical efficacy 
endpoints of this study by convening to review the ongoing program safety and efficacy data. 
This includes evaluating the safety signals and benefit-risk ratio for the study subjects in 
relationship to new data relevant for PSL efficacy and safety. 
A DMC Charter will define the composition, roles, and responsibilities of the DMC, specify the 
data to be reviewed and the periodicity of data review, and determine the procedures to be 
followed.  
Has been changed to (new text bolded): 
No formal interim analysis is planned. However, data may be reported prior to the 
completion of this study to support annual reports, regulatory submissions, and 
publications. 
A DMC will systematically monitor and report on the progress, safety, and/or critical efficacy 
endpoints of this study by convening to review the ongoing program safety and efficacy data. 
This includes evaluating the safety signals and benefit-risk ratio for the study subjects in 
relationship to new data relevant for PSL efficacy and safety. 
A DMC Charter will define the composition, roles, and responsibilities of the DMC, specify the 
data to be reviewed and the periodicity of data review, and determine the procedures to be 
followed.  
Change #34 
Section 15, References 
Has been changed to (new text bolded): 
The following 2 references have been added:  
Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, et al. Validation of a general 
measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication 
(TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:12. 
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Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of an 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among patients on 
antihypertensive medications. Health Qual Life Outcomes. 2009;7:36. 
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16.2 
Protocol Amendment 2.0 
Rationale for the amendment 
The primary rationale for this global amendment is to update the name of the legal form of the 
Sponsor, UCB Biopharma. Belgium has recently adopted a new Code of Companies and 
Associations, resulting in a mandatory change of the name of the legal form of the entity “société 
privée à responsabilité limitée”, abbreviated “SPRL”, to “société à responsabilité limitée”, 
abbreviated “SRL”. This change does not involve any change to the legal form itself, and the 
company name, company number and VAT number of UCB Biopharma remain the same. 
A benefit risk assessment in order to comply with Section 6 of the ICH-GCP. This summary has 
been revised as part of the most recent Investigator’s Brochure update and is now included in this 
global protocol amendment.  
The detailed dosage of 400mg/day as staring dose was deleted to allow more flexibility when 
adding further parent studies. The starting dose is defined as the dose at the end of the parent 
study. 
Modifications and changes 
Specific changes 
Change #1 
Sponsor name on the title page and in the study contact information (bolded text revised) 
Sponsor 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Has been changed to (new text bolded):  
Sponsor 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
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Change #2  
Sponsor Contact Information (bolded text has been 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 SL1 3WE Slough, 
UK 
Phone: 
 
Has been changed to: 
Sponsor Study Physician 
Name: 
 MD PhD 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
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Clinical Project Manager 
Name: 
 
Address: 
UCB Biosciences GmbH 
Alfred Nobel Strasse, 10 
40789 Monheim am Rhein, 
Germany 
Phone: 
 
Clinical Trial Biostatistician 
Name: 
 
Address: 
UCB BIOSCIENCES, Inc 
810 Arco Corporate Drive 
Raleigh, NC 27617 
United States 
Phone: 
 
Change #3  
Summary, second to last paragraph 
The total duration of the study per subject will be up to 2 years. Subjects benefitting from the 
drug and willing to continue will either take commercial drug, if available, or will be transferred 
to a Managed Access Program or another PSL study, depending on local regulations.  
Has been changed to (bolded text has been added): 
The total duration of the study per subject will be up to approximately 2 years. Subjects 
benefitting from the drug and willing to continue will either take commercial drug, if available, 
or will be transferred to a Managed Access Program or another PSL study, depending on local 
regulations.  
Change #4 
Section 2.5, Benefit Risk Assessment 
This section has been added. The section number of the following section, Rationale for this 
study, has been increased from 2.5 to 2.6.  
Change #5 
Section 5.3, Rationale for study design and selection of dose, bolded text deleted or revised 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. 
This OLE study will provide subjects, who participated in previous PSL studies, the opportunity 
to have continued access to PSL. 
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The individual starting dose of each subject will be the one recommended at the end of the parent 
study (400mg/day).  
This entry dose level was selected considering benefit-risk and is based on clinical pharmacology 
and positron emission tomography 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 the parent study, a full SV2A 
occupancy is desirable to obtain a meaningful anticonvulsive effect while the minimal 
benzodiazepine binding more likely will make a better tolerance to GABA-related central 
nervous system toxicity. On the other hand, participants exposed to a high maintenance dose of 
PSL in the parent study (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 are allowed between 
100mg/day up to a maximum of 800mg/day to the extent possible with combination of tablet 
strengths available (ie, 25mg, 100mg, and 200mg).  
Has been changed to (bolded text has been added): 
EP0093 will assess the long-term safety, tolerability, and efficacy of PSL as an adjunctive 
treatment for focal-onset seizures in adult subjects with drug-resistant epilepsy. 
This OLE study will provide subjects, who participated in previous PSL studies, the opportunity 
to have continued access to PSL. 
The individual starting dose of each subject will be the one recommended at the end of the parent 
study.  
This entry dose level was selected considering benefit-risk and is based on clinical pharmacology 
and positron emission tomography 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 the parent study, a full SV2A 
occupancy is desirable to obtain a meaningful anticonvulsive effect while the minimal 
benzodiazepine binding more likely will make a better tolerance to GABA-related central 
nervous system toxicity. On the other hand, participants exposed to a high maintenance dose of 
PSL in the parent study (800mg/day), a 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 are allowed between 100mg/day up 
to a maximum of 800mg/day to the extent possible with combination of tablet strengths available 
(ie, 25mg, 100mg, and 200mg).  
Change #6 
Section 7.2, Treatments to be administered (bolded text has been deleted) 
Padsevonil will be administered in an open-label manner. All subjects will be instructed to take 
2 doses approximately 12 hours apart each day 30 minutes after food when practically feasible. 
The individual starting dose of each subject will be the one at the end of the parent study 
(400mg/day). The first dose of the study will be the dose on the day of Visit 1. Once subjects 
enter EP0093 further individual dose adjustments are allowed after 1 week, between 100mg/day 
up to a maximum of 800mg/day to the extent possible with the combination of tablet strengths 
available (ie, 25mg, 100mg and 200mg). Integrity of the tablets should not be tampered with 
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(eg, cut) to obtain lower dosages. Twice daily dosing with equivalent morning and evening doses 
approximately 12 hours apart is deemed necessary to ensure more regular exposure over the 
24-hour interval; however, the dosing schedule may be adjusted as needed to improve tolerability 
and efficacy. The decision to advise subjects to divide their morning and evening daily dose 
unequally should be documented in the eCRF and the UCB Study Physician or delegate should 
be notified. Increases or decreases to the dose of PSL should not exceed a maximum 200mg/day 
per week. A faster/slower decrease/increase of the dose than 200mg/day per week is allowed in 
case of emergency in the Investigator's medical judgment. 
Has been changed to: 
Padsevonil will be administered in an open-label manner. All subjects will be instructed to take 
2 doses approximately 12 hours apart each day 30 minutes after food when practically feasible. 
The individual starting dose of each subject will be the one at the end of the parent study. The 
first dose of the study will be the dose on the day of Visit 1. Once subjects enter EP0093 further 
individual dose adjustments are allowed after 1 week, between 100mg/day up to a maximum of 
800mg/day to the extent possible with the combination of tablet strengths available (ie, 25mg, 
100mg and 200mg). Integrity of the tablets should not be tampered with (eg, cut) to obtain lower 
dosages. Twice daily dosing with equivalent morning and evening doses approximately 12 hours 
apart is deemed necessary to ensure more regular exposure over the 24-hour interval; however, 
the dosing schedule may be adjusted as needed to improve tolerability and efficacy. The decision 
to advise subjects to divide their morning and evening daily dose unequally should be 
documented in the eCRF and the UCB Study Physician or delegate should be notified. Increases 
or decreases to the dose of PSL should not exceed a maximum 200mg/day per week. A 
faster/slower decrease/increase of the dose than 200mg/day per week is allowed in case of 
emergency in the Investigator's medical judgment. 
Change #7 
Section 7.5, Handling and storage requirements, Paragraph 3 (bolded text has been 
deleted) 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
in the investigational medicinal product (IMP) Handling Manual. 
Has been changed to: 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
in the IMP Handling Manual. 
Change #8  
Section 7.8.1, Permitted concomitant treatments (medications and therapies), 
Concomitant AEDs and AED dose(s), or settings for vagus nerve stimulation or other 
neurostimulation device for epilepsy may be adjusted throughout the study as per the 
Investigator’s clinical judgment based on tolerability and seizure control for each individual 
subject. 
Tapering of all concomitant AED(s) to achieve PSL monotherapy, if clinically appropriate, 
should only be made in agreement with Study Physician and Sponsor. 
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New concomitant AEDs may be introduced to optimize tolerability and seizure reduction with 
the following restrictions: 
 Vigabatrin, retigabine, and felbamate are allowed and count as add-on AEDs  
 if taken for more than 2, 1, and 4 years respectively prior to Visit 1 in parent PSL study 
and, if requirements mentioned in the relevant Exclusion Criteria pertaining to vigabatrin, 
retigabine, and felbamate in parent PSL study were met. 
Has been changed to (bolded text has been added): 
 Vigabatrin, retigabine, and felbamate are allowed and count as add-on AEDs  
 if taken for more than 2, 1, and 4 years respectively prior to Visit 1 in parent PSL study 
and, if requirements mentioned in the relevant Exclusion Criteria pertaining to vigabatrin, 
retigabine, and felbamate in parent PSL study were met. 
 
Although omeprazole is classified as a sensitive substrate, high doses of omeprazole 
have been well tolerated, and adjustment of the omeprazole dose is not generally 
required except with severe hepatic impairment and if long-term treatment is 
indicated. Therefore, omeprazole is permitted (see omeprazole prescribing 
information). 
Change #9 
Section 7.8.2, Prohibited concomitant treatments (medications and therapies) (bolded text 
has been deleted) 
The following concomitant medications are prohibited during the study: 
 GABA-A-ergic drugs: including agonists (ie, barbiturates) or receptor positive allosteric 
modulators (ie, benzodiazepines or nonbenzodiazepines like zolpidem) taken >3 times per 
week. Regular intake of benzodiazepines with an indication for epileptic seizures is not 
allowed. However, PRN intake of GABA-A-ergic drugs <3 times per week is allowed, ie, for 
emergencies. 
 Strong CYP3A4 inhibitors/inducers (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). 
 AEDs including carbamazepine, phenytoin, phenobarbital, and primidone 
 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). 
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Has been changed to (bolded text has been added): 
The following concomitant medications are prohibited during the study: 
 GABA-A-ergic drugs: including agonists (ie, barbiturates) or receptor positive allosteric 
modulators (ie, benzodiazepines or nonbenzodiazepines like zolpidem) taken >3 times 
within 7 days. Regular intake of benzodiazepines with an indication for epileptic seizures is 
not allowed. However, PRN intake of GABA-A-ergic drugs up to 3 times within 7 days is 
allowed, ie, for emergencies. 
 Strong CYP3A4 inhibitors/inducers (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). 
 AEDs including carbamazepine, phenytoin, phenobarbital, and primidone 
 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, , 
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 #10 
Section 8.1.6, Visit 6 (Month 6), Visit 7 (Month 9), Visit 8 (Month 12), Visit 9 (Month 15), 
Visit 10 (Month 18), and Visit 11 (Month 21) ±1 week 
Section title has been changed to (visit window for Visit 11 has been 
revised from 1 week to 1 month): 
Visit 6 (Month 6), Visit 7 (Month 9), Visit 8 (Month 12), Visit 9 (Month 15), Visit 10 
(Month 18), and Visit 11 (Month 21) ±1 month 
Change #11 
Section 9.1.5, Additional procedures for reporting serious adverse events, Paragraph 3 
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 PSL administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the PSL 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner. 
Has been changed to (bolded text from Amendment 1.1 for Switzerland has 
been added): 
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 PSL administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the PSL 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
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expedited manner. Expedited reporting to regulatory authorities will be in line with local 
laws. 
Change #12 
Section 9.3.8, Withdrawal monitoring, Paragraph 1 (bolded text has been deleted) 
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). 
Has been changed to (bold text has been added): 
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 questions 
and observations which are selected to distinguish withdrawal symptoms from other symptoms 
(Busto et al, 1989). 
Change #13  
Section 10.6, Treatment Satisfaction, Paragraph 1 (bolded text has been revised) 
The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 is a 9-item questionnaire 
developed to provide a suitable measure of treatment satisfaction with medication 
(Bharmal et al, 2009). It has 5 to 7 Likert response options per item and consists of 3 subscales: 
effectiveness (3 items), convenience (3 items), and a global satisfaction scale (3 items). The 
TSQM-9 was developed from the TSQM 1.42, which has an additional subscale that measures 
side effects (3 items) (Atkinson et al, 2004). The estimated completion time for this 
questionnaire is less than 5 minutes. Scores range from 0 (worst) to 100 (best). 
Has been changed to (bolded text is the revised text): 
The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 is a 9-item questionnaire 
developed to provide a suitable measure of treatment satisfaction with medication 
(Bharmal et al, 2009). It has 5 to 7 Likert response options per item and consists of 3 subscales: 
effectiveness (3 items), convenience (3 items), and a global satisfaction scale (3 items). The 
TSQM-9 was developed from the TSQM-12, which has an additional subscale that measures 
side effects (3 items) (Atkinson et al, 2004). The estimated completion time for this 
questionnaire is less than 5 minutes. Scores range from 0 (worst) to 100 (best). 
Change #14 
Section 15, References 
The following references have been added: 
Azuma H, Akechi T. Effects of psychosocial functioning, depression, seizure frequency, and 
employment on quality of life in patients with epilepsy. Epilepsy Behav. 2014;41:18-20. 
Baker GA, Jacoby A, Buck D, Stalgis C, Monnet D. Quality of life of people with epilepsy: a 
European study. Epilepsia. 1997;38(3):353-62. 
Devinsky O. Sudden, unexpected death in epilepsy. N Engl J Med. 2011;365:1801-11. 
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Fazel S, Wolf A, Långström N, Newton CR, Lichtenstein P. Premature mortality in epilepsy and 
the role of psychiatric comorbidity: a total population study. Lancet. 2013;382:1646-54. 
Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: Potential role of antiepileptic 
drugs. CNS Drugs. 2013;27(2):113-9.  
Holst AG, Winkel BG, Risgaard B, Nielsen JB, Rasmussen PV, Haunsø S, et al. Epilepsy and 
risk of death and sudden unexpected death in the young: a nationwide study. Epilepsia. 
2013;54(9):1613-20. 
Jehi L. Neurology's Silent Killer: Drug-Resistant Epilepsy. Epilepsy Curr. 2016;16:232-3. 
Leclercq K, Matagne A, Provins L, Klitgaard H, Kaminski R. Protective effects of padsevonil in 
acute seizure models. (Abstract 1.272), 2017. www.aesnet.org.  
Muglia P, Toledo T, Steinhoff, BJ, et al. Efficacy and tolerability of adjunctive padsevonil in 
adults with drug-resistant focal onset seizures: a randomized, double-blind, placebo-controlled, 
proof-of-concept trial. (Abstract 1.283), 2017. American Epilepsy Society Annual Meeting, 
www.aesnet.org. 
Sperling MR. The consequences of uncontrolled epilepsy. CNS Spectr. 2004;9(2):98-101, 106-9. 
Taylor DC, McMackin D, Staunton H, Delanty N, Phillips J. Patients' aims for epilepsy surgery: 
desires beyond seizure freedom. Epilepsia. 2001;42(5):629-33. 
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17 
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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18 
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:
EP0093-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000148104
Title:
EP0093 Protocol Amendment 2
Approved Date:
06 Feb 2020
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Statistical Analysis Plan                                       Padsevonil (UCB0942)                                                           EP0093 
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STATISTICAL ANALYSIS PLAN  
 
Study: EP0093 
Product: Padsevonil (UCB0942) 
AN OPEN LABEL, MULTICENTER, EXTENSION STUDY TO EVALUATE THE SAFETY 
AND EFFICACY OF PADSEVONIL AS ADJUNCTIVE TREATMENT OF FOCAL-ONSET 
SEIZURES IN ADULT SUBJECTS WITH DRUG-RESISTANT EPILEPSY 
 
 
 
PHASE 2/3 
 
SAP 
Date 
Final SAP 
18 Jan 2019 
Amendment 1 25 SEP 2020 
 
 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, 
published, or otherwise used without the express permission of UCB. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 
Study objectives ............................................................................................................. 8 
2.1.1 
Primary objective ................................................................................................... 8 
2.1.2 
Secondary objective ............................................................................................... 8 
2.1.3 
Exploratory Objective ............................................................................................ 8 
2.2 
Study variables ............................................................................................................... 8 
2.2.1 
Safety variables ...................................................................................................... 8 
2.2.1.1 
Primary safety variables .............................................................................. 8 
2.2.1.2 
Other safety variables .................................................................................. 8 
2.2.2 
Efficacy variables .................................................................................................. 9 
2.2.2.1 
Primary efficacy variable ............................................................................ 9 
2.2.2.2 
Other efficacy variables ............................................................................... 9 
2.2.2.3 
Pharmacokinetic and pharmacodynamic variables ................................... 10 
2.3 
Study design and conduct ............................................................................................ 10 
2.4 
Determination of sample size ....................................................................................... 19 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 19 
3.1 
General presentation of summaries and analyses ........................................................ 19 
3.2 
General study level definitions .................................................................................... 19 
3.2.1 
Initial processing of diary data for seizure frequency.......................................... 19 
3.2.2 
Analysis time points ............................................................................................ 20 
3.2.2.1 
First and last dose of PSL .......................................................................... 20 
3.2.2.2 
Relative day ............................................................................................... 20 
3.2.2.3 
Study Entry visit ........................................................................................ 20 
3.2.2.4 
The Entry Visit (EV, Visit 1) will be done on the same day as the last visit 
of the parent study. End date of the Evaluation Period ............................. 20 
3.2.3 
Analysis periods ................................................................................................... 21 
3.2.3.1 
Mapping of assessments performed at early discontinuation .................... 21 
3.2.4 
Last visit during the Exposure Period .................................................................. 22 
3.2.5 
Interval duration ................................................................................................... 22 
3.2.6 
Number of completers by time interval ............................................................... 22 
3.3 
Definition of Baseline values ....................................................................................... 22 
3.3.1 
Baseline for variables based on seizure count ..................................................... 23 
3.3.2 
Baseline for other variables ................................................................................. 23 
3.4 
Protocol deviations....................................................................................................... 23 
3.5 
Analysis sets................................................................................................................. 23 
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3.5.1 
Enrolled Set ......................................................................................................... 23 
3.5.2 
Safety Set ............................................................................................................. 24 
3.5.3 
Full Analysis Set .................................................................................................. 24 
3.6 
Treatment assignment and treatment groups ............................................................... 24 
3.7 
Sites pooling strategy ................................................................................................... 24 
3.8 
Coding dictionaries ...................................................................................................... 24 
3.9 
Changes to protocol-defined analyses ......................................................................... 24 
3.10 
COVID-19 eCRF ......................................................................................................... 26 
4 
STATISTICAL / ANALYTICAL ISSUES ..................................................................... 26 
4.1 
Handling of dropouts or missing data .......................................................................... 26 
4.1.1 
Handling of missing data in seizure frequency .................................................... 26 
4.1.2 
Handling of missing data for adverse events and concomitant medications ....... 26 
4.1.2.1 
Imputation of Partial Start Dates ............................................................... 27 
4.1.2.2 
Imputation of Partial Stop Dates ............................................................... 27 
4.1.3 
Incomplete dates for first epileptic seizure .......................................................... 27 
4.2 
Interim analyses and data monitoring .......................................................................... 28 
4.3 
Multicenter studies ....................................................................................................... 28 
4.4 
Examination of subgroups ........................................................................................... 28 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 28 
5.1 
Subject disposition ....................................................................................................... 28 
5.2 
Protocol deviations....................................................................................................... 29 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 29 
6.1 
Demographics .............................................................................................................. 29 
6.2 
Other baseline characteristics ...................................................................................... 30 
6.3 
Medical history and concomitant diseases ................................................................... 30 
6.3.1 
Medical history .................................................................................................... 30 
6.3.2 
Medical history of epilepsy ................................................................................. 30 
6.3.2.1 
Epileptic seizure profile ............................................................................. 31 
6.3.2.2 
History of epileptic seizures and diagnosis of epilepsy............................. 31 
6.4 
Concomitant medications............................................................................................. 31 
6.4.1 
AED medication .................................................................................................. 31 
6.4.2 
Use of vagus nerve stimulation ............................................................................ 31 
6.4.3 
Non-AED medication .......................................................................................... 31 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 32 
8 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 32 
9 
SAFETY ANALYSES ..................................................................................................... 32 
9.1 
Extent of exposure ....................................................................................................... 32 
9.2 
Adverse events ............................................................................................................. 32 
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9.3 
Clinical laboratory evaluations .................................................................................... 34 
9.4 
Subjects with potential drug-induced liver injury (PDILI) .......................................... 35 
9.5 
Vital signs, physical findings, and other observations related to safety ...................... 36 
9.5.1 
Vital signs ............................................................................................................ 36 
9.5.2 
Electrocardiograms .............................................................................................. 36 
9.5.3 
Echocardiogram ................................................................................................... 37 
9.5.4 
Other safety variables .......................................................................................... 37 
9.5.4.1 
Changes in CIWA-B ................................................................................. 37 
9.5.4.2 
The Columbia-Suicide Severity Rating Scale (C-SSRS) .......................... 38 
9.5.4.3 
Physical Examination ................................................................................ 38 
9.5.4.4 
Neurologic Examination ............................................................................ 38 
9.5.4.5 
Changes in Psychiatric and Mental Status ................................................ 38 
10 EFFICACY ANALYSES ................................................................................................ 39 
10.1 
Statistical analysis of the primary efficacy variables ................................................... 39 
10.1.1 
Derivations of primary efficacy variable ............................................................. 39 
10.1.2 
Primary analysis of the primary efficacy variable ............................................... 39 
10.2 
Analysis of other efficacy variables ............................................................................. 39 
10.2.1 
Derivations of other efficacy variables ................................................................ 40 
10.2.1.1 
Percent reduction in seizure frequency from Baseline of parent study ..... 40 
10.2.1.2 
50%, 75% and 90% Responder ................................................................. 40 
10.2.1.3 
Seizure-free status (Yes or No) ................................................................. 40 
10.2.1.4 
Number and percentage of Seizure-free days ............................................ 40 
10.2.1.5 
Seizure Severity Global Item (SSG) variables .......................................... 40 
10.2.1.6 
QOLIE-31-P .............................................................................................. 40 
10.2.1.7 
Hospital Anxiety and Depression Scale (HADS) score variables ............. 41 
10.2.1.8 
Time to Discontinuation to Treatment ...................................................... 41 
10.2.1.9 
Treatment satisfaction ............................................................................... 41 
10.2.2 
Analysis of other efficacy variables .................................................................... 42 
10.2.2.1 
Seizure frequency by 3-month interval over the Evaluation Period.......... 42 
10.2.2.2 
50%, 75% and 90% responder rates by 3-month interval for observable 
focal onset seizures over the Evaluation Period ........................................ 43 
10.2.2.3 
50%, 75% and 90% responder rates for focal- onset seizures (all Type I) 
over the Evaluation Period ........................................................................ 43 
10.2.2.4 
Seizure-freedom status for all seizure types by 3-month interval over the 
Evaluation Period ...................................................................................... 43 
10.2.2.5 
Percentage of seizure-free days (for all seizure types) by 3-month interval 
over the Evaluation Period ........................................................................ 43 
10.2.2.6 
Percentage of reduction in seizure frequency by 3-month interval over the 
Evaluation Period ...................................................................................... 43 
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10.2.2.7 
Change in the SSG score ........................................................................... 43 
10.2.2.8 
Changes in the QOLIE-31-P score ............................................................ 43 
10.2.2.9 
Change in Hospital Anxiety and Depression Scale (HADS) score ........... 44 
10.2.2.10 
Health-related Outcomes and HRU ........................................................... 44 
10.2.2.11 
Time to Discontinuation to Treatment ...................................................... 44 
10.2.2.12 
Treatment satisfaction ............................................................................... 45 
11 COVID-19 IMPACT ....................................................................................................... 45 
12 REFERENCES ................................................................................................................ 46 
13 APPENDICES ................................................................................................................. 47 
13.1 
LABORATORY ASSESSMENTS – PCST ................................................................ 47 
13.1.1 
Hematology .......................................................................................................... 47 
13.1.2 
Blood chemistry ................................................................................................... 49 
13.1.3 
Urinalysis ............................................................................................................. 53 
13.2 
VITAL SIGN ASSESSMENTS - ABNORMAL ......................................................... 54 
13.3 
ELECTROCARDIOGRAM (ECG) – ABNORMAL .................................................. 56 
13.4 
Echocardiogram Valvular Abnormality Grading Criteria ........................................... 57 
14 AMENDMENT(S) TO THE SAP ................................................................................... 59 
14.1 
Amendment 1 ............................................................................................................... 59 
15 ADDENDUM .................................................................................................................. 91 
16 STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ............................................. 92 
 
LIST OF TABLES 
Table 2-1: 
Schedule of assessments .................................................................................. 12 
Table 3‒1: 
Start and end of EP0093 analysis periods ........................................................ 21 
Table 9‒1: 
Laboratory Measurements ............................................................................... 32 
 
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LIST OF ABBREVIATIONS 
AE  
adverse event 
AED  
antiepileptic drug 
ALP  
alkaline phosphatase 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
bid 
twice daily 
BMI 
body mass index 
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 
ECG  
electrocardiogram 
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 
IPD 
Important protocol deviation 
MedDRA®  
Medical Dictionary for Regulatory Activities® 
OLE  
open-label extension 
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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 
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 
VNS 
vagus nerve stimulation 
WHO 
World Health Organization  
WHO DD 
World Health Organization Drug Dictionary 
 
 
 
 
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 
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clinical study report (CSR). The SAP is based on the following study document: Protocol 
EP0093 Amendment 2, 4 February 2020. 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: 2017-003241-26; 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 objectives 
2.1.1 
Primary objective 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
Padsevonil (PSL) administered at individualized doses between 100mg/day and 800mg/day as 
adjunctive treatment for subjects with focal-onset seizures and drug-resistant epilepsy.  
2.1.2 
Secondary objective 
The secondary objective is to evaluate the long-term efficacy of PSL as an adjunctive treatment 
for focal-onset seizures in adults with drug-resistant epilepsy. 
2.1.3 
Exploratory Objective 
The exploratory objective is to assess the impact of PSL as an adjunctive treatment for subjects 
with focal-onset seizures and drug-resistant epilepsy on health-related outcomes and healthcare 
resources utilization (HRU). 
2.2 
Study variables 
2.2.1 
Safety variables 
2.2.1.1 
Primary safety variables 
The primary safety variables are the following: 
• Incidence of treatment-emergent adverse events (TEAEs) reported by the subject and/or 
caregiver or observed by the Investigator 
• Incidence of TEAEs leading to study withdrawal 
2.2.1.2 
Other safety variables 
Other safety variables are the following: 
• Changes in laboratory tests (including hematology, blood chemistry, urinalysis) 
• Changes in 12-lead electrocardiogram (ECG) parameters 
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• Changes in withdrawal symptoms using Clinical Institute Withdrawal Assessment 
Benzodiazepines (CIWA-B) from the End-of-Study (EOS) Visit, to the end of Taper 
Period and to the end of the Safety Follow-up (SFU) Period (30 days after last PSL 
intake) 
• Changes in vital sign parameters (pulse rate, blood pressure [BP], and respiratory rate) 
• Occurrence of a clinically significant valvular change or pericardial effusion or other 
clinically significant abnormalities as identified by 2-dimensional Doppler 
echocardiogram at each assessment by central reader 
• Physical examination (including body weight) and neurological examination findings 
• Changes in Psychiatric and Mental Status 
2.2.2 
Efficacy variables 
Seizure frequency refers to 28-day adjusted frequency.  
Observable focal-onset seizures refer to Type IA1, IB, and IC (according to the International 
League Against Epilepsy [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. 
2.2.2.1 
Primary efficacy variable 
The primary efficacy variable will be the change from Baseline (from the respective parent 
study) in observable focal-onset seizure frequency over the Evaluation Period. 
2.2.2.2 
Other efficacy variables 
The other efficacy variables are the following: 
• Observable focal-onset seizure frequency per 28 days by 3-month intervals over the 
Evaluation Period 
• Observable focal-onset seizure frequency per 28 days by seizure type and by 3-month 
intervals over the Evaluation Period 
• The 50%, 75%, and 90% responder rate (RR) by 3-month intervals for observable focal-
onset seizures over the Evaluation Period. A 50%, 75%, and 90% responder is defined as 
a subject with a ≥50%, ≥75%, or ≥90% reduction in the observable focal onset seizure 
frequency relative to the Baseline Period defined in the parent study. 
• The 50%, 75%, and 90% RR by 3-month intervals for focal-onset seizures (Type I) over 
the Evaluation Period  
• Percentage of seizure-free days (for all seizure types) by 3-month intervals over the 
Evaluation Period 
• Seizure-freedom status for all seizure types by 3-month intervals over the Evaluation 
Period 
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• Time to Discontinuation 
• Change from Baseline from parent study in the Seizure Severity Global Item (SSG) 
scores at each assessment 
• Changes from Baseline from parent study in Quality of Life Inventory in Epilepsy-31-P 
(QOLIE-31-P) scores at each assessment 
• Changes from Baseline from parent study in Hospital Anxiety and Depression Scale 
(HADS) scores at each assessment 
• Use of health-related outcomes and HRU, including healthcare provider consultations not 
foreseen by protocol, caregiver support, concurrent medical procedures, concomitant 
medications, and hospitalizations. 
2.2.2.3 
Pharmacokinetic and pharmacodynamic variables 
• No pharmacokinetic (PK) nor pharmacodynamic variables will be assessed in this study. 
2.3 
Study design and conduct 
This is an open-label extension (OLE) study that will assess the safety, tolerability, and change 
in focal-onset seizure frequency associated with long term oral PSL as an adjunctive therapy in 
adult subjects with drug-resistant epilepsy. This study will enroll consenting subjects, or subjects 
whose legal representatives have given consent, and who have completed a PSL parent study (eg, 
EP0091 or subsequent PSL studies). The total study duration per subject will be up to 
approximately 2 years. 
Evaluation Period 
The Entry Visit (EV, Visit 1) will be done the same day as the last visit of the parent study. After 
the Entry Visit (EV, Visit 1), subjects will return to the clinic for visits as follows:  
• Every 2 weeks during Month 1 
• Every month during Month 2 and Month 3 
• Every 3 months after Month 3 to the end of Year 2 
Dose adjustment of PSL and/or concomitant AEDs and/or settings to neurostimulation devices is 
allowed at any time during the study, if seizure control is insufficient, or in case of safety or 
tolerability issue. Subjects who are not able to tolerate or who do not benefit from the PSL 
treatment may be tapered off PSL and withdrawn from the study. 
Taper Period 
Subjects who complete the study or who discontinue early will return for an End of Study (EOS) 
Visit or Early Discontinuation Visit (EDV), respectively, and will be progressively tapered off 
over 4 weeks and return to the site 1 week after the last PSL intake for an end of Taper Visit.  
Safety Follow-up Period 
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Safety follow-up will consist of 1 required visit (SFU Visit) 30 days after the last PSL intake. A 
follow up echocardiogram will be required at approximately 1 month and 6 months after the last 
PSL intake. 
Subjects must return to the clinic for scheduled visits as outlined in Table 2-1.
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Table 2-1: 
Schedule of assessments 
 
Setting 
(Required 
Onsite s) 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk 
drug free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper 
Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 
Wk 
 
 
Written informed consent 
NA – V1 as 
per UCB 
requirement 
had to be 
performed 
onsite 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of Subject 
Trial card 
NA – V1 as 
per UCB 
requirement 
had to be 
performed 
onsite 
X 
 
 
 
 
 
 
 
 
 
 
 
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Table 2-1: 
Schedule of assessments 
 
Setting 
(Required 
Onsite s) 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk 
drug free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper 
Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 
Wk 
 
 
Demographic data 
NA – V1 as 
per UCB 
requirement 
had to be 
performed 
onsite 
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
inclusion/exclusion 
criteria 
NA – V1 as 
per UCB 
requirement 
had to be 
performed 
onsite 
X 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
withdrawal criteria 
Partially 
required 
onsite 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
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Table 2-1: 
Schedule of assessments 
 
Setting 
(Required 
Onsite s) 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk 
drug free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper 
Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 
Wk 
 
 
Medical history update 
NA – V1 as 
per UCB 
requirement 
had to be 
performed 
onsite 
X 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS since last visit d 
no 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HADS  d 
no 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
SSG 
no 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
 
QOLIE-31-P  d 
no 
 
 
 
 
 
X 
 
X 
X 
 
 
 
CIWA-B  d 
no 
 
 
 
 
 
 
 
Xe 
X 
X 
X 
 
TSQM-9 d 
no 
 
 
 
 
 
 
 
X 
X 
 
 
 
Vital signs f 
yes 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight 
no 
X* 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
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Table 2-1: 
Schedule of assessments 
 
Setting 
(Required 
Onsite s) 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk 
drug free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper 
Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 
Wk 
 
 
Physical examination g  
(XF = Full – XB = Brief) 
yes 
XF* 
 
XB 
 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
 
Neurological examination 
h  
(XF = Full – XB = Brief) 
yes 
XF* 
 
XB 
 
XB 
XB 
XB 
XB 
XB 
XB 
XB 
 
Psychiatric and Mental 
Status 
no 
X* 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Personal Outcomes 
assessmenti 
yes 
 
 
 
 
 
X 
X 
 
 
 
 
 
12-lead ECG j 
yes 
X* 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
Echocardiogram k 
yes 
 
X 
 
 
X 
X 
X 
X k 
 
 
X 
 
Blood/urine sample for 
clinical laboratory 
analysis 
yes 
X* 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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Table 2-1: 
Schedule of assessments 
 
Setting 
(Required 
Onsite s) 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk 
drug free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper 
Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 
Wk 
 
 
Pregnancy test (female 
subjects only) l 
yes 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Seizure evaluation (count 
and type) m 
no 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
and procedures n 
no 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Recording of adverse 
events 
no 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Health-related outcomes 
and HRU 
no 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IRT call 
no 
X 
 
 
 
 
 
 
 
 
 
X 
 
PSL dispensing (IRT) 
no 
X 
X 
X 
X 
X 
X 
X 
X p 
X 
 
 
 
PSL accountability and  
return o 
no 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
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Table 2-1: 
Schedule of assessments 
 
Setting 
(Required 
Onsite s) 
 
Evaluation Period a 
Taper 
Period 
(including 
1 Wk 
drug free) 
SFU 
(30 days 
after last 
PSL 
intake) 
 
Entry 
Visit 
Bi-weekly 
Visits 
Monthly 
Visits 
Visits every 
3 M 
EOS 
Visit 
EDV 
Visit 
End of 
Taper 
Visit 
SFU Visit 
Unsch 
Visit/TC 
V1 b 
V2 
V3 
V4 
V5 
V6, 
V8, 
V10 
V7, 
V9, 
V11 
EOS c 
EDV c 
Assessments 
 
Wk  
0 
Wk 
2 
Wk 
4 
M2 
M3 
M6, 
M12, 
M18 
M9, 
M15, 
M21 
M24 
 
Up to 4 
Wk 
 
 
Study termination 
NA – this is 
not an 
assessment 
 
 
 
 
 
 
 
X q 
 
 
X r 
 
 
AED=antiepileptic drug; BP=blood pressure; CIWA-B=Clinical Institute Withdrawal Assessment-Benzodiazepines; C-SSRS=Columbia-Suicide Severity 
Rating Scale; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EOS=End of Study; HADS=Hospital Anxiety and Depression Scale; 
HRU=healthcare resource utilization; IRT=interactive response technology; M=month; PSL=padsevonil; QOLIE-31-P=Quality of Life Inventory in Epilepsy-
31-P; SFU=Safety Follow-up; SSG=Seizure Severity Global Item; TC=telephone call; TSQM=Treatment Satisfaction Questionnaire for Medication; 
Unsch=unscheduled; V=visit; Wk=week, NA=Not Applicable 
a At any point during the Evaluation Period, an unscheduled visit may be conducted due to safety or efficacy reasons. Appropriate assessments will be conducted 
in relation to the reason for the visit. 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. 
 b Entry Visit (Visit 1) will be done on the same day as the last visit of parent study. Data from parent study will be used (identified by *) and corresponding 
assessments will not be repeated. 
c The Taper Period is only valid for subjects discontinuing the study or completing without continuation of the PSL treatment. This period will last for 3 weeks 
plus a 1-week drug-free period. 
 d Questionnaires to be completed by all subjects prior to any other study procedures at the visit, when possible. 
e Assessment is only valid for subjects discontinuing PSL treatment.  
 f Vital signs measured in supine position after 5 minutes of rest include pulse rate, respiratory rate, systolic BP, and diastolic BP. 
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 g Full physical examination will include assessment of 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 examination will include in addition, evaluation of cranial nerves, motor system (general muscle strength and tone), and sensations in upper/lower 
extremities. 
i Personal outcome assessments will be completed at Visit 6 (Month 6) and Visit 11 (Month 21) (for subjects who agree to participate). 
 j An ECG at the SFU will be performed only if abnormal at the EOS or EDV Visit. All ECG recordings will be performed with the subject resting in supine 
position for at least 5 minutes.  
 k Only subjects who do not require tapering of PSL at M24 will have an echocardiogram at M24. All other subjects will have an echocardiogram at the SFU Visit 
and at 6 months after the last dose of PSL. A repeat echocardiogram will be performed for subjects with a new finding, Grade 2 severity (moderate), or Grade 3 
severity (severe). 
 l Results of a serum pregnancy test performed during parent study will be used at Visit 1 together with a urine test performed at Visit 1. Urine pregnancy tests 
will be used at all other visits for female subjects of childbearing potential.  
 m Seizure counts are collected on the subject’s daily record card on a daily basis. 
 n Assessment includes AED history. 
 o Medication should be presented at each visit for check on compliance. 
p PSL will be dispensed at the EOS Visit only to subjects who will be tapered off PSL.  
q The study termination assessment at the EOS visit is for subjects who will transfer into either a Managed Access Program or another PSL study. 
r The study termination assessment at the SFU Visit is for subjects who withdraw early or who complete the study, but will not be transferred to either a 
Managed Access Program or another PSL study. 
Error! Reference source not found. Data may be collected through phone or video calls for visits that do not require onsite assessment because of 
COVID-19 pandemic. 
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2.4 
Determination of sample size 
For this OLE study, no sample size calculation is needed. The sample size will depend upon 
recruitment into and completion of a PSL parent studies (eg, EP0091 or subsequent PSL studies). 
Approximately 1000 subjects with focal-onset seizures and drug resistant epilepsy may be 
included. 
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. 
 
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. 
Derived variables in general will display the mean, SD and median to 1 more decimal place than 
the variables used in the derivation. If the number of decimal places reported in the raw data is 
varied then use either the maximum raw number of reported decimal places or 3, whichever is 
the lowest, as a guide for the descriptive statistics. 
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. 
The total daily dose (mg/day) is presented in EP0093. 
Unless otherwise stated, safety and efficacy summaries will be presented for all subjects. 
Selected summaries will also be presented by region.  
In general, all data collected in the EP0093 clinical database and parent study data included in 
the analyses 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 electronic Case Report form (eCRF)/diary. Each seizure code in the clinical 
database will be mapped to exactly 1 of the following ILAE classification codes: I, IA, IA1, IA2, 
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IA3, IA4, IB, IB1, IB2, IC, II, IIA, IIB, IIC, IID, IIE, IIF, or III. 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 
First and last dose of PSL 
Unless otherwise noted, all references to the first dose of PSL in this SAP refer to the first dose 
of PSL during EP0093 (i.e. not the first dose of PSL from the parent studies in which subjects 
participated in prior to EP0093).  
At the time of a clinical cutoff, for subjects who are ongoing and don’t have the End of Taper 
Visit, the last dose of PSL will be set to the date of the clinical cutoff for the interim analyses. 
For subjects who are ongoing but had the End of Taper Visit at the time of a clinical cutoff, the 
last dose of PSL will be set to the last dosing date on the Study Medication Administration eCRF 
for the interim analyses. 
3.2.2.2 
Relative day 
Relative days for an event or measurement occurring before the date of first dose of PSL in 
EP0093 will have a ‘-’ prefix and will be calculated as follows: 
Relative Day=−[(Event date-Date of first dose)] 
Relative days for an event or measurement occurring on or after the date of first dose of PSL but 
not after the date of last dose of PSL in EP0093 will be calculated as follows:  
• Relative Day = (Event date-Date of first dose) + 1 
For events or measurements occurring after the date of last dose of PSL in EP0093, relative day 
in this case will be prefixed with ‘+’ in the data listings and will be calculated as follows:  
• Relative Day = + (Event date-Date of last dose) 
All study level variables should be defined in subsections below. This includes analysis time 
points and definitions of study periods to be analyzed. 
3.2.2.3 
Study Entry visit 
3.2.2.4 
The Entry Visit (EV, Visit 1) will be done on the same day as the last 
visit of the parent study. End date of the Evaluation Period 
The end date of the Evaluation Period will be either EOS at Month 24 or EDV for subjects who 
discontinue early. If a subject does not have an EOS or EDV Visit, then the final contact date 
will define the end date of the Evaluation Period.  At the time of a clinical cutoff prior to the 
study completion, if a subject is ongoing and doesn’t have the EDV, the end of the Evaluation 
Period is set to the clinical cutoff date. 
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3.2.3 
Analysis periods 
The start and end dates of each study period are used for the classification of seizure data and 
TEAEs for applicable summaries. The exact start and end of each of these periods is described 
for calculation purposes in Table 3‒3.21. Measurements from diaries returned on the start date of 
a subsequent period would be included in calculations for the previous period.  
Table 3‒3.21: Start and end of EP0093 analysis periods 
Description 
Start  
End  
Details 
 
 
 
 
Evaluation Period 
Entry Visit (EV, 
Visit 1)   
EOS or EDV or the last contact 
date if neither EOS or EDV visit is 
available.   
At the time of a clinical cutoff prior 
to the study completion, if a subject 
is ongoing and doesn’t have the 
EDV, the end of the period is set to 
the clinical cutoff date.  
The Entry Visit (EV, Visit 
1) will be done on the same 
day as the last visit of the 
parent study. Subjects will 
return to clinic every 2 
weeks during Month 1, 
every month during Month 
2-3, every 3 months after 
Month 3 up to Month 24. 
Taper Period/ Safety 
Follow-Up Period 
1 day after end 
date of evaluation 
period.  
The date of final contact. 
At the time of a clinical cutoff prior 
to the study completion, if a subject 
is ongoing, the end of the period is 
set to the clinical cutoff date. 
Applies only to patients 
who discontinue the study 
or complete it without 
continuation of PSL 
treatment. 
Exposure Period 
Date of first dose 
of PSL  
Date of last dose of PSL 
Extends from the date of 
first dose until the last dose 
of PSL in EP0093. It may 
include the Evaluation and 
Taper Period. (Section 
3.2.2.1). 
At the time of a clinical cutoff prior to the study completion, subjects without the Study 
Termination eCRF will be classified as “ongoing.” Only the data on or prior to the clinical cutoff 
date will be included in the analyses.  
3.2.3.1 
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, in-clinic safety assessments such as vital signs, ECGs, and blood collection for 
clinical laboratory assessments, should correspond to that scheduled visit. In-clinic safety 
assessments at an EDV that occurs on a day between two scheduled visits will be assigned to the 
next scheduled clinic visit. All other efficacy assessments and questionnaire 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. 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. 
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Seizure data collected by diary are associated with periods defined within the study and as such 
there is no need to map them to visits. If a subject withdraws between visits an effort is made to 
recover all diary records for use in calculation of seizure frequencies. 
3.2.4 
Last visit during the Exposure Period 
The Last Visit for an assessment is the last non-missing assessment prior to or on the date of last 
dose of PSL (Section 3.2.2.1). All scheduled and unscheduled will be considered. Last Visit will 
be determined separately for each study assessment. Last Visit during the Exposure Period will 
be included in the by-visit summary unless noted otherwise. Similarly, the minimum and 
maximum values are defined as the minimum and maximum values prior to or on the date of last 
dose of PSL.  
3.2.5 
Interval duration  
A month is defined as 30 days and time intervals based on monthly durations are defined as a 
multiple of 30 days (eg, 12 months is defined as 360 days).  
Interval Duration Definition: 
- 
Months 0-3 Days 1-90 
- 
Months >3-6 Days 91-180 
- 
Months >6-9 Days 181-270 
- 
Months >9-12 Days 271-360 
Subsequent intervals are defined in a similar manner. For the analysis of seizure data during the 
Evaluation Period, 3-month intervals will be derived for the Evaluation Period. For the analysis 
of AEs and safety variables, 3-month intervals will be derived for the Exposure Period.  
3.2.6 
Number of completers by time interval 
Each subject will be classified into one or more of the following intervals based on the duration 
of the Evaluation Period: 
≥3 months   = ≥90 days 
≥6 months   = ≥180 days 
≥12 months = ≥360 days 
≥18 months =  ≥540 days 
≥24 months =  ≥720 days 
The duration of the Evaluation Period is calculated as the date of the end of the Evaluation 
Period – EV +1. Selected efficacy variables will be analyzed for completers by time intervals. 
The number of completers by time interval is also defined as completer cohort. 
3.3 
Definition of Baseline values 
Baseline refers to the baseline of the parent study unless noted otherwise. 
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3.3.1 
Baseline for variables based on seizure count 
The current study does not provide a baseline period. Baseline values for observable focal-onset 
seizures (Types IA1, IB, and IC) and for all Type I seizures will be derived from subject diary 
data collected during the 4-week Prospective Baseline Period of the parent studies.  
[Definition from parent studies: The Baseline value will be the seizure frequency per 28 days 
prior to the day of the first dose of IMP 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.]  
3.3.2 
Baseline for other variables 
Unless otherwise specified, Baseline values from the parent study will be used in the analysis 
which is defined as the last valid measurement before the first study medication administration, 
including the pre-dose assessments on the day of Visit 2. If a Baseline visit measurement is 
missing, and a Screening visit measurement is available, the most recent Screening value will be 
utilized. 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 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. 
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 final database lock and integrated into the clinical 
database.  
3.5 
Analysis sets 
Primary and other safety endpoints will be analyzed using the Safety Set (SS). Primary and other 
efficacy endpoints will be analyzed using the Full Analysis Set (FAS). 
These analysis sets are described below. 
3.5.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all subjects who have signed the ICF. 
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3.5.2 
Safety Set 
The Safety Set (SS) will consist of all enrolled subjects who were administered at least 1 dose of 
PSL, based on the first dose date from the First Administration of Study Medication CRF.  
3.5.3 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all enrolled subjects who were administered at least 1 
dose of PSL or a partial dose of PSL and completed at least 1 seizure diary during the Evaluation 
Period. 
3.6 
Treatment assignment and treatment groups 
The individual starting dose of each subject will be the one recommended at the end of the parent 
study. Further individual dose adjustments are allowed between 100mg/day up to a maximum of 
800mg/day to the extent possible with combination of tablet strengths available (ie, 25mg, 
100mg, and 200mg). 
3.7 
Sites pooling strategy 
Pooling strategy is not planned for this study.  
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/2017 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 22.1 or higher of Medical Dictionary for 
Regulatory Activities (MedDRA®) according to UCB Standard Operating Procedures (SOP). 
3.9 
Changes to protocol-defined analyses 
Due to the COVID-19 impact on site initiation and enrollment as well as  early termination of the 
study, the following items in the protocol were updated in the SAP 
Section in 
this SAP 
Description 
Change from the protocol 
Table 2-1:  Schedule of 
Assessments 
Added: 
Setting (Required Onsite) column to include data that may be 
collected through phone or video calls for visit, during the 
pandemic. 
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3.10 
COVID-19 
eCRF 
Added, see section 3.10 for details 
4.4 
Examination of 
subgroups 
Removed China as a region 
10.2.1.8 
Derivation of 
other efficacy 
variables 
Removed: Drug Loads of AEDs 
Changes in drug load are captured by number of products and 
daily dose per given product recorded in the AED Medication 
CRF. Drug load will be assessed using ratio of actual daily 
dose and World Health Organization defined daily dose 
(DDD). 
“https://www.whocc.no/atc_ddd_index/?code=N03A&showde
scription=no”.  
The daily dose of the administered AED will be calculated at 
Entry Visit, Visit 8, and EOS. All AEDs which has the stop 
date at the visit (EV, Visit 8, EOS) or ongoing and the start 
date prior to the visit will considered administered at that 
specific visit.  
The drug load of all AEDs will be calculated as the sum of 
ratios of dose and DDD for each of the AEDs at the respective 
visit. The drug load of each AED class will be calculated as 
the sum of ratios of dose and DDD for each of the AEDs 
within the AED class. AED classes included in this analysis 
are: 
• SV2A: levetiracetam and brivaracetam 
• BZD: ATC code N05BA 
• sodium channel-blocking AED (SCB (+): 
carbamazepine, oxcarbazepine, eslicarbazepine, 
phenytoin and lamotrigine 
Ratio of dose and DDD, absolute change from EV in the ratio, 
and percent change from EV in the ratio will be summarized 
by all AEDs, AED drug class and by each of the AEDs. For 
two visits, the absolute change of a given AED drug load can 
be calculated if the product is administered at one of the visits; 
and the percent change can only be calculated if the AED is 
administered at EV.  The change in number of all AEDs at 
Visit 8 and EOS relative to EV will also be summarized. 
11 
COVID-19 
The impact of COVID-19 global pandemic on this study is 
detailed in section 3.10. COVID-19 impact will be listed by 
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Impact 
impacted visit, date, impact category, and relationship to 
COVID-19 (confirmed, suspected, general circumstances 
around COVID-19 without infection or other) for each subject 
in the ES. 
15 
Addendum 
Added: 
All tables described in the SAP will be repeated for Japan and 
non-Japan subgroups. 
 
3.10 
COVID-19 eCRF 
A new COVID-19 eCRF, to evaluate the impact of global pandemic was created and 
implemented to collect the information on impacted visit, impact category, and relationship to 
COVID-19. 
Listing and table (see Section 11 for details) to describe the impact on the interpretability of 
efficacy and safety endpoints will be performed to assess the impact of the changes on the 
planned analyses due to COVID-19. 
4 
STATISTICAL / ANALYTICAL ISSUES 
General statistical and analytical issues are provided in the following sections. 
4.1 
Handling of dropouts or missing data 
4.1.1 
Handling of missing data in seizure frequency 
Seizure frequency will be calculated over non missing diary days during an analysis period or 
time interval. Days with missing seizure diary (ie, “Not Done” is ticked on the Seizure Count 
CRF) will not be considered in the calculation of seizure frequency or seizure free days. No 
imputation will be applied to missing seizure diary data. Seizure frequency during a time interval 
will be calculated if seizure data are available for at least 1 day during the interval.    
4.1.2 
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.  
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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). Note that imputed times and dates should not 
be presented in the patient data listing. 
Partial AE and concomitant medication start dates will be imputed as described in the following 
sections. 
4.1.2.1 
Imputation of Partial Start Dates  
• If only the month and year are specified and the month and year of first dose 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 is the same 
as the month and year of the start date, then use the date of first dose 
• If only the year is specified, and the year of first dose 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 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, then use the date of first dose. 
• If the imputed start date is after the known stop date, set the start date to be the same as 
the stop date.  
4.1.2.2 
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 
4.1.3 
Incomplete dates for first epileptic seizure 
To calculate the time since the first seizure relative to the date of EV of EP0093 at onset of first 
seizure, 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. 
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4.2 
Interim analyses and data monitoring 
No formal interim analysis is planned. However, data may be reported prior to the completion of 
this study to support annual reports, regulatory submissions, and publications.  
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. 
4.3 
Multicenter studies 
In generally, efficacy and safety summaries and analyses will be presented across investigative 
sites, countries and regions.  
4.4 
Examination of subgroups 
Selected summaries will be provided for the following subgroups: 
• Region 
Countries will be stratified to geographic regions as follows: 
Geographic region 
country 
North America 
Canada, US, Mexico 
Europe 
Australia, Austria, Belgium, Bosnia and Herzegovina, Bulgaria, 
Croatia, Czech Republic, Denmark, Estonia, Finland, France, 
Germany, Greece, Hungary, Ireland, Italy, Lithuania, Netherlands, 
Norway, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Sweden, 
Switzerland, Turkey, United Kingdom. 
Japan 
Japan  
Further sites in countries not yet included in this table are possible. 
 
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 CRF (dates of screen failure and last contact and reason for screen 
failure). 
Details on the last study visit are obtained from the Study Termination CRF. Variables include 
date of last administration of study medication, date of final contact with the subject, subject 
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status at study termination, date of premature study termination and primary reason for 
premature study termination (as listed on CRF).  
The disposition of subjects will be summarized for the ES, and SS overall and by region, country 
as well as by investigator.  
Summaries of the numbers of screened subjects and reasons for screen failures will be produced 
overall for the ES. 
The disposition will also be presented as the number and percentage of subjects who started, 
completed or discontinued the study. Discontinuation of study includes a breakdown of primary 
reasons for discontinuation. These tables are presented overall and by region for the SS.  
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 summarized for the SS. 
Of note, the corresponding table is required for data transparency reporting.   
Listings will be provided for disposition, reason for discontinuation and visit dates. 
5.2 
Protocol deviations 
IPDs are defined in Section 3.4. All IPDs will be listed by subject and will include, at a 
minimum, deviation type (as collected under the important deviation collection plan), deviation 
number, deviation description, and date of deviation.  
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock. After all data have been verified/entered into a database and prior to database 
lock, a final data evaluation meeting will take place. Protocol deviations will not lead to 
exclusion from any analysis set. 
A summary of number and percentage of subjects with an IPD will be produced for the SS. The 
summary will be overall (any IPD) and by type of deviation.  
  
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
Demographic variables are collected on the Demographics CRF. The following demographic 
variables will be summarized for the SS by region:  
Based on data collected at EV of EP0093: 
- 
Age (in years)  
- 
The following age categories will be summarized in the same table:  (i) ≤18 years, 19 - <65 
years and ≥65 years; (ii) 18- <65 years, 65 - <85 years and ≥ 85 years 
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Based on data collected at study entry of the parent study: 
- 
Sex (male, female) 
- 
Race (all categories on the CRF) 
- 
Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
- 
Ethnic sub-group (Japanese, non-Japanese) 
- 
Height (in cm) 
- 
Weight (in kg) 
- 
Body mass index (BMI) (kg/m2) and BMI category (<18.5, 18.5 to <25, 25 to <30, 30 to 
<40, ≥40) 
- 
Vagus Nerve Stimulation (Yes, No) 
- 
Parent study (EP0091, EP0092) 
6.2 
Other baseline characteristics 
The following data collected at the time of entry into the parent study will be summarized for the 
SS. The parameters derived in the parent will be directly used. 
• Number of lifetime AEDs taken prior to the parent study: <4, 4 or 5, 6 or 7, 8 to 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 eCRF. 
• Number of AEDs taken at the entry of the parent study: 1, 2, 3, and > 3 AEDs 
• Current use of AEDs with binding to SV2A proteins (LEV and/or BRV): Yes or No 
6.3 
Medical history and concomitant diseases 
6.3.1 
Medical history  
Medical history reported at the entry of the parent study and any medical history update will be 
summarized and listed 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. 
A medical history update is done at the Entry Visit. Of note, medical history update CRF should 
only be used after the database of the parent study is already locked. All efforts will be taken to 
make sure medical history are completed in the database of the parent study.  
6.3.2 
Medical history of epilepsy 
Selected medical history of epilepsy collected at the entry of the parent study will be summarized 
for the SS.  
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6.3.2.1 
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. 
6.3.2.2 
History of epileptic seizures and diagnosis of epilepsy 
History of epileptic seizures, including 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 first seizure relative to the Entry Visit of EP0093 (ie, 
Entry Visit of EP0093 minus the date of the first epileptic seizure plus 1 divided by 365.25) and 
the age at onset of first seizure will be summarized for the SS. 
6.4 
Concomitant medications 
Concomitant AED and non-AED medication are collected on separate CRFs. These include the 
AED Medication CRF and the Concomitant medication CRF. All concomitant medication started 
in the parent studies and are ongoing at the time of Entry Visit in EP0093 are collected on 
separate CRFs (Prior and Concomitant Medications_Parent Study CRF, AED Medication_Parent 
Study CRF). 
A medication will be included in a concomitant summary if:  
• (Date of first dose of PSL in EP0093) ≤ (Start date of medication) ≤ (Date of last dose of 
PSL in EP0093); or  
• Start date of medication is prior to the first dose of PSL in EP0093 or unknown, but 
medication is ongoing at study entry. 
6.4.1 
AED medication 
The number and percentage of subjects taking concomitant AED medications will be 
summarized by chemical/therapeutic/pharmacological subgroup (ATC classification level 4), and 
preferred drug name.  
6.4.2 
Use of vagus nerve stimulation 
The number and percentage of subjects with Vagus Nerve Stimulation (VNS) in Previous Study 
(collected at EV) will be summarized. Subjects with VNS setting changed during the Evaluation 
Period will also be summarized. All other VNS data will be provided in subject data listings and 
will not be summarized for the SS. 
6.4.3 
Non-AED medication 
The number and percentage of subjects (SS) 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. 
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7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Information reported on the CRF regarding the number of tablets dispensed and returned and 
doses taken in the morning and evening will be reported in subject data listings. 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.  
PSL treatment compliance will be evaluated through the review of important protocol deviations.  
8 
PHARMACOKINETICS AND PHARMACODYNAMICS   
No pharmacokinetic or pharmacodynamic analyses will be conducted.   
9 
SAFETY ANALYSES 
All safety analysis will be provided for the SS.   
9.1 
Extent of exposure 
The overall duration of exposure of the study will be calculated as the date of last dose of PSL 
minus the date of first dose of PSL (Section 3.2.2.1) in EP0093 plus 1 day.  
Modal daily dose of a subject will be calculated as the daily dose the subject received for the 
longest duration during EP0093. In the event of a tie, the modal dose will be set to the lower of 
the tied doses. Modal daily dose will be categorized as ≤200mg/day, >200mg/day to 
≤400mg/day, >400mg/day to ≤600mg/day, and >600mg/day.  
The duration of exposure will be summarized overall and by modal dose for the SS and by 
region:   
• Cumulative months of exposure: duration of exposure in days will be summarized. 
Duration of exposure will also be categorized into the following cumulative months 
categories of exposure:  >=3 months, >=6 months, >=9 months, >=12 months, >=18 
months, and >=24 months.  
Listings will include the study medication exposure per subject and the administration of study 
medication per dispense interval. Data collected on the Prescribed Padsevonil Dose CRF will be 
listed.  
9.2 
Adverse events 
Adverse events are recorded on the Adverse Event 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). Also, adverse events ongoing at the Entry Visit in EP0093 will be 
recorded in the Adverse Event_Parent Study CRF.  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the first dose of study treatment in this study or any unresolved event already present 
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before initiation of the first dose that worsens in intensity following exposure to the treatment. 
TEAEs are AEs with start dates on or after the date of first dose of PSL in EP0093. The number 
and percentage of subjects who experience TEAEs at any time during the study will be 
summarized (using the SS) by SOC and PT.  
Unless noted otherwise, TEAEs during the study will be summarized. At the time of a clinical 
cutoff, TEAEs with onset date prior to or on the clinical cutoff date will be included. TEAEs are 
assigned into an analysis period or time interval based on the start date. Adverse event 
summaries will be ordered in terms of decreasing frequency for SOC, and PT within SOC. The 
following tabular summaries will be presented for the SS: 
• Ongoing AEs at EP0093 study entry 
• Incidence of TEAEs during the Study – Overview by Region  
• Incidence of TEAEs by Region 
• Incidence of TEAEs by 3-month time interval during the Exposure Period 
• Incidence of Serious TEAEs  
• Incidence of TEAEs by Relationship 
• Incidence of SAEs by Relationship. Of note, this table is needed for data transparency 
reporting.   
• Incidence of Fatal TEAEs by Relationship. Of note, this table is needed for data 
transparency reporting.  
• Incidence of TEAEs by Maximum Intensity 
• Incidence of TEAEs leading to discontinuation (ie, drop out) 
• Incidence of TEAEs leading to dose reduction  
• Incidence of TEAEs occurring in at least 5% of Subjects  
• Incidence of TEAEs by Dose at Onset (≤ 200mg/day, >200mg/day to ≤400mg/day, 
>400mg/day to ≤600mg/day, and >600mg/day) during the Exposure Period.  
• Incidence of Non-Serious TEAEs above the Threshold of 5% of Subjects. This table is 
needed for data transparency reporting.  
Summary tables will contain counts of subjects, percentages of subjects in parentheses and the 
number of events where applicable. A subject who has multiple events in the same SOC and PT 
will be counted only once in the subject counts, but all events will be included. 
In summaries of relationship to study treatment per the investigator, the following relationships 
will be summarized: ‘Not related’, ‘Related’. Events with missing relationship will be considered 
as ‘Related’ for summary purposes but recorded as missing in the listings. 
In summaries of maximum intensity, the following intensity categories will be summarized: 
‘Mild’, ‘Moderate’, ‘Severe’. Subjects who experience the same event multiple times will be 
included in the most severe category. Events with missing intensity will be considered as 
‘Severe’ events for summary purposes but recorded as missing in the listings. 
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Listings will be provided for AEs, SAEs, AEs leading to discontinuation (ie, drop out), and AEs 
leading to death by subject for the SS. 
9.3 
Clinical laboratory evaluations 
Clinical laboratory hematology, chemistry and urinalysis measurements obtained from 
blood/urine samples collected throughout the study are presented in Table 9-1.   
Table 9-1: 
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; FSH=Follicle Stimulating Hormone, HDL=high-density lipoprotein; 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 for postmenopausal women 
 
A blood and urine sample for clinical laboratory analysis will be obtained at Entry Visit, Visit 3 
up to EOS/EDV Visit. Samples are analyzed in a central laboratory. During the study, non-
protocol-specified lab parameter values (unplanned) may be collected. Summaries of lab 
parameter values will only include those of planned visits as specified in the protocol. All lab 
parameter values will be listed and summarized using international units. Per-subject listings 
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include flag for possibly clinically significant treatment-emergent (PCST) result and calculated 
change from Baseline for each laboratory variable. If the subject had both scheduled sampling 
and unscheduled sampling at the same date/time, scheduled sample will be flagged as the 
analysis record.  For the subjects with DILI event, lab tests are done locally for more rapid 
results, a concurrent sample should also be sent to the central laboratory. The central lab results 
will be flagged as the analysis record. 
The observed value and change from Baseline will be summarized (SS) descriptively by 
scheduled study visit, as well as including Last Visit, maximum value, and minimal value. These 
summaries will also be organized by lab function panel and parameter. Data collected at 
unscheduled visits will not be summarized.  
For hematology and blood chemistry parameters that are identified in Table 10-1, the shift from 
Baseline in category (relative to normal range: low, normal, high) to the maximum and minimal 
values during the exposure period will be presented. Categorical urinalysis results will be 
summarized by visit. 
PCST criteria have been developed for the PSL program based on FDA Division of 
Neuropharmacologic Drug Products guidelines with some UCB-defined additions and are 
provided in Appendix 12.1. For lab parameters with treatment emergent PCST criteria, the 
number and percentage of subjects with a PCST will be summarized for the overall and by 3-
month interval during the Exposure Period. Subject numbers for those meeting the PCST will 
also be presented. Results of additional tests like the urine pregnancy test will be listed.   
9.4 
Subjects with potential drug-induced liver injury (PDILI) 
There are specific criteria described in the protocol Section 9.2.1 to evaluate subjects for PDILI. 
The evaluations required by protocol for PDILI subjects are collected on the following CRFs:  
• Most Recent Study Medication Administration, for DILI 
• Laboratory Tests DILI 
• Physical Examination for DILI 
• Vital Signs DILI 
• Hepatic Event Supplemental Medical History for DILI 
• Potential Hepato-Toxic Medications Inquiry for DILI 
• Symptoms of Hepatitis and Hypersensitivity for DILI 
• Lifestyle DILI 
• Family Medical History for DILI 
PDILI is suspected if potential Hy’s Law applies. In order to meet potential Hy’s Law, 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 potential Hy’s law criteria 
(see protocol section 6.3.1 and 9.1.1.3 for further details). 
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 Potential Hy’s Law is defined as:  
• AST ≥3xULN or ALT ≥3xULN and 
• Total Bilirubin ≥2xULN 
A summary of number and percent of subjects meeting PDILI criteria for potential Hy’s Law 
will be provided by visit and for any visit. Additionally, a per-subject listing for subjects with 
PDILI by visit for the potential Hy’s law criteria relevant lab values will be provided. Further 
CRF information regarding DILI and PDILI will be listed. Visits due to PDILI which cannot be 
mapped to any study visits will only be listed. 
9.5 
Vital signs, physical findings, and other observations related to 
safety 
9.5.1 
Vital signs 
Vital measurements (including SBP, DBP, PR and RR) are taken at every scheduled visit. These 
measurements 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 including absolute change from Baseline and abnormality criteria 
flag. 
The observed value and absolute change from Baseline will be summarized (SS) descriptively by 
scheduled study visit, as well as Last Visit, maximum value, and minimal value Data collected at 
unscheduled visits will not be included in the by-visit summary.   
The number and percentage of subjects with abnormal vital signs described in Appendix 13.2 
will be summarized for the overall and by 3-month interval during the Exposure Period. Subject 
numbers for those meeting the abnormal criteria will also be presented. 
9.5.2 
Electrocardiograms 
The following ECG parameters will be recorded: heart rate, PR-interval, QRS-duration, QT-
interval, QTcB [QT corrected for heart rate using Bazett’s formula] or QTcF [QT corrected for 
heart rate using Fridericia’s formula], and Investigator’s conclusion on ECG profile. 
The 12-Lead ECG results are collected at Entry Visit, Visit 3, Visit 5 and at visits every 6 
months thereafter. An ECG at the SFU will be performed only if abnormal at EOS or EDV Visit.  
For each ECG, the overall ECG result, is also collected, categorized by the investigator as one 
of: no abnormality, an abnormal but not clinically significant finding, or a clinically significant 
finding. 
QTcB and QTcF will also be presented by following classification per visit:  
• Observed results: <450ms, 450-<480ms, 480-<500ms and >=500ms  
• Change from Baseline: <30ms, 30-<60ms, >=60ms 
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The observed ECG parameter values and their absolute change from Baseline will be 
summarized (SS) descriptively for each scheduled assessment visit, as well as Last Visit, 
maximum value, and minimal value.   
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 percentage of subjects with an abnormal ECG value described in Appendix 13.3 
will be summarized for the overall and by 3-month interval during the Exposure Period. Subject 
numbers for those meeting the abnormal criteria will also be presented. 
All 12-Lead ECG parameters will be listed per visit, including the change from baseline and a 
abnormality criteria flag. In addition, the data from patients with at least one finding will be 
listed with the finding.  
9.5.3 
Echocardiogram 
Echocardiogram data are collected at Visit 2, Visit 5 and then every 3 months and at the Safety 
Follow-Up Visit. Only subjects who will remain in the study will have an echocardiogram at 
Month 24. Subjects who will taper off PSL will have an echocardiogram at the SFU Visit and at 
6 months after the last dose of PSL. The data of the follow-up echocardiogram after 6 months 
will be obtained after data base lock and therefore analyzed separately.  
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 each scheduled visit and by the number and 
percentage of subjects with an abnormality. 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. 
9.5.4 
Other safety variables 
9.5.4.1 
Changes in CIWA-B 
 Subjects are tapered off study medication if they discontinue the study or complete it without 
continuation of PSL treatment. As part of monitoring of subjects for withdrawal symptoms 
during the Taper Period, the CIWA-B evaluation is performed at the EOS/EDV Visit, at the end 
of the Taper Period, and at the Safety Follow-Up Visit. The CIWA-B questionnaire contains 17 
questions and 3 observations, 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). Sub scores of each of the first 20 questions/observations (scores 
from 0-4) are summed up to a total score: 
Total score 
Interpretation 
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1-20 
Mild withdrawal 
21-40 
Moderate withdrawal 
41-60 
Severe withdrawal 
61-80 
Very severe withdrawal 
In case there is any sub score missing, no total score can be calculated. 
There are additional two items for sleeping duration and time to fall asleep, but both are not 
considered in the score.  
Data listings will be provided. 
9.5.4.2 
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 Entry Visit, and at each 
subsequent study visit. C-SSRS data will be provided in subject listing for subjects with suicidal 
ideation and suicide behavior. 
9.5.4.3 
Physical Examination 
At Entry Visit the full Physical Examination is performed. The brief Physical Examination 
including the body weight measurement is performed at Visit 3, Visit 5 and at each visit 
thereafter. The body weight is not collected at End of Taper Visit. Findings that are considered 
clinically-significant changes will be recorded as AEs. 
Data from the Physical Examination are only provided in subject data listings displaying all data 
collected for all subjects by subject and visit. No summaries will be provided.  
9.5.4.4 
Neurologic Examination 
At Entry Visit the full Neurological Examination is performed. The brief Neurological 
Examination is performed at Visit 3, Visit 5 and at each visit thereafter. Data from the 
Neurological Examination are collected on the Neurological Examination Complete and 
Neurological Examination Brief CRFs Findings that are considered clinically-significant changes 
will be recorded as AEs. 
A brief neurological examination will include general assessment and the evaluation of reflexes, 
muscle strength and coordination, and cerebellar function. 
Data from the Neurological Examination are only provided in subject data listings presented by 
subject and visit, displaying all data collected for all subjects. No summaries will be provided.  
9.5.4.5 
Changes in Psychiatric and Mental Status 
The Psychiatric and Mental Status is performed at Entry Visit, Visit 3, Visit 5 and at each visit 
thereafter. 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 
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trained in the identification of psychiatric symptoms. The parameters to be evaluated are 
orientation, attention, memory, mood, and calculus.  
For each of these assessments, data is provided in subject data listings presented by subject and 
visit, displaying all data collected for all subjects 
There are no derived outcomes for the Psychiatric and Mental Status evaluation and no 
imputation rules for missing response values and no date imputation rules are applicable.  
10 
EFFICACY ANALYSES 
Analyses of efficacy endpoints will be performed on the FAS. 
10.1 
Statistical analysis of the primary efficacy variables 
10.1.1 
Derivations of primary efficacy variable 
Seizure frequency (SF) refers to the 28-day adjusted seizure frequency, which is defined as:  
SF = (Number of Seizures) x (28 / D)  
− where Number of Seizures = total number of seizures during an analysis period or 
time interval. For cluster seizures, the number of cluster episodes will be included. 
− D = number of days for which the diary was available during the analysis period or 
time interval. 
Change from Baseline in seizure frequency will be calculated as seizure frequency during an 
analysis period or time interval minus the Baseline seizure frequency.  
The primary efficacy variable is the change from Baseline in the observable focal-onset seizure 
frequency over the Evaluation Period.  
 
10.1.2 
Primary analysis of the primary efficacy variable 
The observed and the absolute change in 28-day adjusted observable focal-onset seizure 
frequency will be summarized (FAS) for the overall Evaluation Period. The summary will be 
repeated for each region. A per-subject listing (FAS) will be provided with details of seizure 
diary including type of seizure, cluster, number of seizures per diary. No additional statistical 
testing or modelling will be performed. 
10.2 
Analysis of other efficacy variables 
Other efficacy variables are listed in Section 2.2.2.2. 
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10.2.1 
Derivations of other efficacy variables 
This section describes variable derivation and calculation of descriptive statistics to be used for 
analyses. 
10.2.1.1 
Percent reduction in seizure frequency from Baseline of parent study 
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 or time interval and SFB corresponds to the Baseline seizure frequency. A 
negative PRD indicates an increase in seizure frequency from Baseline of parent study.  
10.2.1.2 
50%, 75% and 90% Responder 
Responder status (yes or no) of a subject is determined by the percent reduction in seizure 
frequency (PRD) from Baseline of parent study. A subject is defined as a XX% responder if s/he 
has a reduction in seizure frequency (PRD) of at least XX% from the Baseline. The XX% 
responder rate (RR) will be calculated as the proportion of XX% responders.  
10.2.1.3 
Seizure-free status (Yes or No) 
Subjects will be considered seizure-free for a given period or time interval if the subject, 
completes the period, reports zero seizures during the period, and has no more than 10% of days 
in the period for which seizure data is not available (ie, “Not Done” is reported on the Seizure 
Count CRF). 
10.2.1.4 
Number and percentage of Seizure-free days 
The number of seizure-free days will be the total number of days within an analysis period or 
time 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.  
10.2.1.5 
Seizure Severity Global Item (SSG) variables 
The SSG consists of 2 items from the Seizure Severity Questionnaire and asks the subjects to 
evaluate the severity of their seizures for the last 4 weeks. The subject describes all seizure types 
when answering the questions. Seizure Severity will be asked for Entry Visit, Visit 5, and every 
3 months thereafter until EOS/EDV Visit at the beginning of each visit. The seizure-intensity 
during the last 4 weeks is collected on a 7-point scale with 7 = very severe and the assessment of 
change since starting IMP, is also collected on a 7-point scale with 7 = much worse. 
10.2.1.6 
QOLIE-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. 
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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 at Visit 6 and 6 months thereafter. It 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.  
10.2.1.7 
Hospital Anxiety and Depression Scale (HADS) score variables 
The HADS questionnaire is filled out by subjects at Visits 1, 4, and every 3 months until EOS 
Visit or Early Discontinuation Visit.  
The HADS assessment consists of 14 items that are each scored on a 4-point scale ranging from 
0 to 3, with a higher score corresponding to worse anxiety or depression. The depression and 
anxiety scores will be calculated by summing the scores for the items corresponding to each 
subscale, as described in the Hospital Anxiety and Depression Scale Manual (Snaith and 
Zigmond, 1994): the depression score is calculated as the sum of all even-numbered items; the 
anxiety score is calculated as the sum of all odd-numbered items. Scores for each subscale range 
from 0 to 21, with higher scores corresponding to a greater level of anxiety or depression. 
Missing items will be replaced by the mean of non-missing items from the same subscale when 
calculating the above, provided at least 50% of the items (ie, at least 4 of 7 items) within the 
subscale are present. A subscale score will not be calculated if more than 50% of the items are 
missing within a subscale. This rule applies separately to the subscale scores for anxiety and 
depression; for example, it may be possible to calculate the depression score in cases where the 
anxiety score is not calculated due to non-response. 
10.2.1.8 
Time to Discontinuation to Treatment 
Time to discontinuation of treatment is calculated by the date of the last PSL dose minus the date 
of first dose +1.  
10.2.1.9 
Treatment satisfaction 
The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 is a 9-item questionnaire 
developed to provide a suitable measure of treatment satisfaction with medication (Bharmal et al, 
2009). It has 5 to 7 Likert response options per item and consists of 3 subscales: effectiveness (3 
items), convenience (3 items), and a global satisfaction scale (3 items).  
The TSQM-9 was developed from the TSQM 1.42, which has an additional subscale that 
measures side effects (3 items) (Atkinson et al, 2004). Scores range from 0 (worst) to 100 (best). 
The questionnaire is administered at EOS or EDV Visit, respectively. 
Effectiveness 
Responses 
1.How satisfied or dissatisfied are you with the ability of the 
medication to prevent or treat your condition? 
1=Extremely dissatisfied to 
7=extremely satisfied 
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2.How satisfied or dissatisfied are you with the way the 
medication relieves your symptoms? 
1=extremely dissatisfied to 
7=extremely satisfied 
3.How satisfied or dissatisfied are you with the amount of time 
it takes the medication to start working? 
1=extremely dissatisfied to 
7=extremely satisfied 
Convenience 
 
4.How easy or difficult is it to use the medication in its current 
form? 
1=extremely difficult 
7=extremely easy 
5.How easy or difficult is it to plan when you will use the 
medication each time? 
1=extremely difficult 
7=extremely easy 
6.How convenient or inconvenient is it to take the medication 
as instructed? 
1=extremely inconvenient 
7=extremely convenient 
Global satisfaction 
 
7.Overall, how confident are you taking this medication is a 
good thing for you? 
1=Not at all confident 
5=extremely confident 
8.How certain are you that the good things about your 
medication outweigh the bad things? 
1=not at all certain 
5=extremely certain 
9.Taking all things into account, how satisfied or dissatisfied 
are you with this medication? 
1=extremely dissatisfied 
7=extremely satisfied 
10.2.2 
Analysis of other efficacy variables 
All summaries and listings provided for the efficacy variables are calculated on FAS unless 
noted otherwise. 
10.2.2.1 
Seizure frequency by 3-month interval over the Evaluation Period 
The observed and the absolute change in 28-day adjusted seizure frequency of observable focal-
onset seizures by the 3-month intervals over the Evaluation Period will be summarized by region 
in descriptive tables. The same summary will be repeated for the completer cohorts.  
The observed and change from baseline in seizure frequency of Type IA1, IB, and IC seizures 
will be summarized separately by seizure type. Summary will be provided for the overall and by 
3-month interval during the Evaluation Period. Summary will also be provided by 3-month 
interval for each completer cohort. The same summary will also be provided for the all Type I 
seizures.  
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10.2.2.2 
50%, 75% and 90% responder rates by 3-month interval for 
observable focal onset seizures over the Evaluation Period 
Summaries and listings for the 50%, 75% and 90% responder rates for observable focal-onset 
seizures will be provided for the overall Evaluation Period and by 3-month interval. Summaries 
will also be provided by 3-month interval for each completer cohort. 
10.2.2.3 
50%, 75% and 90% responder rates for focal- onset seizures (all Type 
I) over the Evaluation Period  
Summaries for the 50%, 75% and 90% responder rates for all Type I seizures will be provided 
for the overall Evaluation Period and by 3-month interval. Summaries will also be provided by 3-
month interval for each completer cohort. 
10.2.2.4 
Seizure-freedom status for all seizure types by 3-month interval over 
the Evaluation Period 
The number and percentage of subjects achieving a seizure-free status will be summarized by 3-
month interval for each completer cohort. After the study completion, the same summary will be 
performed for the overall and by 3-month interval for the Evaluation Period.     
10.2.2.5 
Percentage of seizure-free days (for all seizure types) by 3-month 
interval over the Evaluation Period 
The percentage of seizure-free days and change from baseline in percentage of seizure-free days 
will be summarized for the overall Evaluation Period and by 3-month interval. Summaries will 
also be provided by 3-month interval for each completer cohort. 
10.2.2.6 
Percentage of reduction in seizure frequency by 3-month interval 
over the Evaluation Period 
The percentage of reduction in seizure frequency from baseline for observable focal-onset 
seizures and all Type I seizures will be summarized for the overall Evaluation Period and by 3-
month interval. Summaries will also be provided by 3-month interval for each completer cohort.  
10.2.2.7 
Change in the SSG score 
Data will be listed for each scheduled visit and the Last Visit during the Evaluation Period by 
subject. 
10.2.2.8 
Changes in the QOLIE-31-P score 
Observed values 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, and Health Status will be listed for Visit 6, Visit 8, 
Visit 10 and EOS Visit. 
For each time point, the change from baseline of the parent study will be listed by subject for 
total and subscales. 
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10.2.2.9 
Change in Hospital Anxiety and Depression Scale (HADS) score 
Changes in the HADS scores will be calculated from Baseline from parent study to Entry Visit, 
Visit 4, Visit 6 and to Visits every 3 months thereafter until EOS or EDV Visit. The observed 
scores and changes in the scores for depression and anxiety will be presented in a subject listing.  
10.2.2.10 
Health-related Outcomes and HRU 
Health-related outcomes data and HRU data will be listed for the SS. 
• Socio-professional status 
Socio-professional status data are collected at Entry Visit and EOS/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.  
• Healthcare provider consultations not foreseen by the protocol 
Healthcare consultations by type of provider (general practitioner, specialist physician, nurse, 
and other) will be listed for each subject during the study. 
• Hospital and ER visits 
ER visits will be extracted from the Hospitalization/ER Visit CRF page (if the initial entry point 
is ER).  
• Caregiver assistance 
Caregiver assistance data is collected on the CRFs “Caregiver Assistance”.  
• Number of school or working days lost 
Number of school/working days lost data are collected on the CRFs “School and Workdays 
Lost”. The number and percentages of subjects who lose school or work days as a result of 
epilepsy will be listed by visit. The percentage of days lost will be calculated as:  
100 × (end date of absence – start date of absence +1)/ (3 × 30 + 1) for the Entry Visit. If 
the end date of absence is missing or after Entry Visit date, the end date of absence will 
be set to Entry Visit; if the start date of absence is missing or prior to Entry Visit-90, the 
start date of absence will be set to Entry Visit-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. 
10.2.2.11 
Time to Discontinuation to Treatment 
Kaplan-Meier estimates of the percentage of subjects completing 3, 6, 12, 18, and 24 months of 
treatment will be provided for the SS. For subjects who discontinued from the study, the event 
date is set to the date of last dose of PSL and the time to event will be calculated as the date of 
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last dose minus the date of first dose of PSL in EP0093 plus 1. Subjects who completed the study 
will be censored as of the date of last dose of PSL in EP0093. At a clinical cutoff, subjects who 
are ongoing will be censored as of the date of last dose of PSL defined for the interim analyses 
(Section 3.2.2.1). 
10.2.2.12 
Treatment satisfaction 
A per-subject listing will be provided with all subscale scores for FAS overall. 
11 
COVID-19 IMPACT 
The impact of COVID-19 global pandemic on this study is detailed in section 3.10. COVID-19 
impact will be listed by impacted visit, date, impact category, and relationship to COVID-19 
(confirmed, suspected, general circumstances around COVID-19 without infection or other) in 
the ES. Impact of COVID-19 for any reason by country will be tabulated in the ES. 
 
 
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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 
LABORATORY ASSESSMENTS – PCST 
The following criteria will be applied in the determination of possibly clinically significant treatment emergent laboratory assessment 
values. 
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 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional) 
ABNORMALITY 
CRITERIA 
(conventional) 
UNIT 
(standard) 
ABNORMALITY 
CRITERIA 
(standard) 
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 
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 
Blood chemistry 
PARAMETER 
AGE RANGE 
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
UNIT 
(standard)
ABNORMALITY 
CRITERIA 
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) 
>432 (F) 
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 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
UNIT 
(standard)
ABNORMALITY 
CRITERIA 
Total Protein 
2m-<1y 
g/dL 
<3.0 
g/L 
<30 
≥1y 
<4.3 
<43 
Albumin 
<1y 
g/dL 
<1.6 
g/L 
<16 
≥1y 
<2.4 
<24 
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 
mmol/L 
<1.725 
1y - <18y 
<7.4 
<1.85 
≥18y 
<7.9 >11.1 
≤1.975 
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PARAMETER 
AGE RANGE 
UNIT 
(conventional)
ABNORMALITY 
CRITERIA 
UNIT 
(standard)
ABNORMALITY 
CRITERIA 
Phosphorous 
<1y 
mg/dL 
<1.8 
mmol/L 
<0.5814 
≥1y 
<1.8 
<0.5814 
Potassium 
<1y 
mEq/L 
<3.0 
mmol/L 
<3.0 
≥1y 
<3.0 
<3.0 
Sodium 
>1m 
mEq/L 
≤130 
mmol/L 
≤130 
Glucose 
>1m 
mg/dL 
<50 
mmol/L 
<2.775 
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 <12):   Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine Cockroft equation (patients >12): 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 
VITAL SIGN ASSESSMENTS - ABNORMAL 
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 
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 
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PARAMETER 
AGE RANGE 
ABNORMALITY CRITERIA 
≥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 
ELECTROCARDIOGRAM (ECG) – ABNORMAL 
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 
EP0093 (including unscheduled visits) and not meeting the same criteria during Baseline in the 
parent study.  
 
 
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13.4 
Echocardiogram Valvular Abnormality Grading Criteria 
Note: Based on the New York Heart Association Classification of symptoms. Other 
echocardiogram measurements are described in the study Echocardiogram Manual. 
Echocardiogra
m 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/stenosi
s 
Minimal to none 
None; continued 
observation  
Grade 2 
Moderate: 
regurgitation/ 
stenosis with 
intermediate values 
Symptoms: 
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/stenosi
s 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 
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Echocardiogra
m Valvular 
Abnormality 
Severity / 
Description 
Potential 
Cardiovascular 
Signs/Symptoms 
Action  
signs/symptoms results in 
subject discontinuation. 
A jump of 2 grades to 
Grade 3/severe 
(with/without symptoms) 
will result in subject 
discontinuation. 
 
 
 
 
 
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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 clarify details in the planned analyses and the early 
termination of the study.  
Modifications and changes 
Major specific changes 
Change #1 
The following has been added:  
Table 2-1: Schedule of assessments 
 
Change #2 
The following has been deleted: 
2.2.2.1 Other efficacy variables 
Changes in drug load (ie, number of products, daily dose per given product, ratio of dose and 
Defined Daily Dose [WHO Collaborating Centre for Drug Statistics Methodology], 
frequency, drug class) of AEDs from Baseline to Visit 8, and to Visit 12 or EOS 
 
Change #3 
The following has been deleted: 
2.4 Determination of sample size 
The individual starting dose of each subject is 400 mg/day. This entry dose level was selected 
considering benefit-risk and is based on clinical pharmacology and positron emission 
tomography data in healthy human subjects. Once subjects enter EP0093, further individual dose 
adjustments are allowed between 100mg/day up to a maximum of 800mg/day to the extent 
possible with combination of tablet strengths available (ie, 25mg, 100mg, and 200mg). Integrity 
of the tablets should not be tampered with (eg, cut) to obtain lower dosages. More details on 
dosing can be found in the protocol in section 7.2 
 
Change #4 
The following has changed: 
3.2.2.2 Relative day 
Study day for each subject is calculated relative to the date of the first study visit (Entry Visit). 
The date format in the study is dd-MMM-yyyy. Relative day is calculated as the current date in 
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the study minus the date of the first study visit plus 1. For days after the last dose of study drug 
(during safety follow-up), 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). 
 
Generally, relative days for an event or measurement occurring during the study will be 
calculated as follows: 
• Relative Day = (Event Date-Date of first visit) + 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 
Date. Relative day in this case will be prefixed with ‘+’ in the data listings and will be calculated 
as follows: 
• Relative Day = + (Event Date-Reference Date) 
All study level variables should be defined in subsections below. This includes analysis time 
points and definitions of study periods to be analyzed. 
Has been changed to: 
Relative days for an event or measurement occurring before the date of first dose of PSL in 
EP0093 will have a ‘-’ prefix and will be calculated as follows: 
Relative Day=−[(Event date-Date of first dose)] 
Relative days for an event or measurement occurring on or after the date of first dose of PSL but 
not after the date of last dose of PSL in EP0093 will be calculated as follows:  
Relative Day = (Event date-Date of first dose) + 1 
For events or measurements occurring after the date of last dose of PSL in EP0093, relative day 
in this case will be prefixed with ‘+’ in the data listings and will be calculated as follows:  
Relative Day = + (Event date-Date of last dose) 
All study level variables should be defined in subsections below. This includes analysis time 
points and definitions of study periods to be analyzed 
 
Change #5 
3.2.2.3 Study Entry Visit 
The study Entry Visit (EV) corresponds to assessments performed at the time of entry into the 
EP0093. Subjects will not have any interruption in study drug dosing during the transition to 
EP0093. Selected assessments from the EOS Visit of the parent study will be transferred to the 
EV of EP0093 study. The following assessments are to be performed for all subjects at the above 
time points: 
 
C-SSRS since last visit, vital signs, body weight, physical and neurological examination, 
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psychiatric and mental status, 12-lead ECG, blood/urine sample, pregnancy test, seizure 
evaluation, concomitant medications and procedures, adverse events, health related outcomes 
and HRU. 
Has been changed to: 
The Entry Visit (EV, Visit 1) will be done on the same day as the last visit of the parent study.  
 
Change #6 
The following has been changed: 
3.2.2.4 End date of the Treatment Period 
The Treatment Period is called Evaluation Period in EP0093. The end date of the Evaluation 
Period will be either EOS at Month 24 or EDV for subjects who discontinue early. If a subject 
does not have an EOS or EDV Visit, then either the date of the last scheduled or unscheduled 
visit during the Evaluation Period or the date of last known dose of study drug during the 
Evaluation Period, whichever is later, will define the end date of the Evaluation Period. Subjects 
benefitting from the drug and willing to continue on it will either take commercial drug, if 
available, or will be transferred to a Managed Access Program or another PSL study, depending 
on local regulations. 
Has been changed to: 
3.2.2.4 End date of the Evaluation Period 
The end date of the Evaluation Period will be either EOS at Month 24 or EDV for subjects who 
discontinue early. If a subject does not have an EOS or EDV Visit, then the date of last available 
visit before end of taper visit will define the end date of the Evaluation Period.  At the time of a 
clinical cutoff prior to the study completion, if a subject is ongoing and doesn’t have the EDV, 
the end of the Evaluation Period is set to the clinical cutoff date. 
 
Change #7 
3.2.3 Study Periods 
The start and end dates of each study period are used for the classification of seizure data into 
study periods and for the classification of TEAEs by study period for applicable summaries. The 
End Date of the Evaluation Period is also used for the calculation of the duration of exposure to 
study drug for the Evaluation Period. The exact start and end of each of these periods is 
described for calculation purposes in Table 3‒1. 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 
Start and end of EP0093 study periods 
Period 
Start of Period 
End of Period 
Details 
 
 
 
 
Entry Visit (Visit 1) 
Day 1 of Study 
N/A  
The Entry Visit will be 
done on the same day as 
the last visit of the 
parent study. 
Evaluation Period 
The date of Visit 
2 (week 2, Day 2 
-Day 21) 
 
EOS at Month 24 (Day 
730, Day 686 – Day 744) 
or the date of EDV. 
 
Subjects will return to 
clinic every 2 weeks during 
Month 1, every month 
during Month 2-3, every 3 
months after Month 3 up to 
Month 24. 
Taper Period/ Safety 
Follow-Up Period 
1 day after EOS 
or EDV. 
The date of the Safety 
Follow-Up Visit (30 days 
after last PSL dose) 
Applies only to patients 
who discontinue the study 
or complete it without 
continuation of PSL 
treatment. 
 
Has been changed to: 
3.2.3 Analysis Periods 
The start and end dates of each study period are used for the classification of seizure data and 
TEAEs for applicable summaries. The exact start and end of each of these periods is described 
for calculation purposes in Table 3‒3.21.  
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Table 3‒14.11: 
Start and end of EP0093 analysis periods 
Description 
Start  
End  
Details 
 
 
 
 
Evaluation Period 
Entry Visit (EV, 
Visit 1)   
EOS or EDV or the last contact 
date  if neither EOS or EDV Visit is 
available.   
At the time of a clinical cutoff prior 
to the study completion, if a subject 
is ongoing and doesn’t have the 
EDV, the end of the period is set to 
the clinical cutoff date.  
The Entry Visit (EV, Visit 
1) will be done on the same 
day as the last visit of the 
parent study. Subjects will 
return to clinic every 2 
weeks during Month 1, 
every month during Month 
2-3, every 3 months after 
Month 3 up to Month 24. 
Taper Period/ Safety 
Follow-Up Period 
1 day after end of 
evaluation period.  
The date of final contact. 
At the time of a clinical cutoff prior 
to the study completion, if a subject 
is ongoing, the end of the period is 
set to the clinical cutoff date. 
Applies only to patients 
who discontinue the study 
or complete it without 
continuation of PSL 
treatment. 
Exposure Period 
Date of first dose 
of PSL  
Date of last dose of PSL 
Extends from the date of 
first dose until the last dose 
of PSL in EP0093. It may 
include the Evaluation and 
Taper Period. (Section 
3.2.2.1). 
At the time of a clinical cutoff prior to the study completion, subjects without the Study 
Termination Case Report Form (CRF) will be classified as “ongoing.” Only the data on or prior 
to the clinical cutoff date will be included in the analyses.  
 
Change #8 
The following sentence was changed: 
3.2.3.1 Mapping of data from early discontinuation visits 
In-clinic safety assessments at an EDV that occurs on a day between two scheduled visits will be 
assigned to the next clinic visit. 
Was changed to: 
In-clinic safety assessments at an EDV that occurs on a day between two scheduled visits will be 
assigned to the next scheduled clinic visit. 
 
Change #9 
The following was deleted: 
3.2.3.2 Mapping of data to visits 
 
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Change #10 
The following were deleted: 
3.2.4 Study duration and study medication exposure 
3.2.5 Last visit during the treatment period 
 
Change #11 
The following were added: 
3.2.4 Last visit during Exposure Period 
The Last Visit for an assessment is the last non-missing assessment prior to or on the date of last 
dose of PSL (Section 3.2.2.1). All scheduled and unscheduled will be considered. Last Visit will 
be determined separately for each study assessment. Last Visit during the Exposure Period will 
be included in the by-visit summary unless noted otherwise. Similarly, the minimum and 
maximum values are defined as the minimum and maximum values prior to or on the date of last 
dose of PSL.  
3.2.5 Interval duration 
A month is defined as 30 days and time intervals based on monthly durations are defined as a 
multiple of 30 days (eg, 12 months is defined as 360 days).  
Interval Duration Definition: 
- 
Months 0-3 Days 1-90 
- 
Months >3-6 Days 91-180 
- 
Months >6-9 Days 181-270 
- 
Months >9-12 Days 271-360 
Subsequent intervals are defined in a similar manner. For the analysis of seizure data during the 
Evaluation Period, 3-month intervals will be derived for the Evaluation Period. For the analysis 
of AEs and safety variables, 3-month intervals will be derived for the Exposure Period.  
3.2.6 Number of completers by time interval 
Each subject will be classified into one or more of the following intervals based on the duration 
of the Evaluation Period: 
≥3 months   = ≥90 days 
≥6 months   = ≥180 days 
≥12 months = ≥360 days 
≥18 months =  ≥540 days 
≥24 months =  ≥720 days 
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The duration of the Evaluation Period is calculated as the date of the end of the Evaluation 
Period – EV +1. Selected efficacy variables will be analyzed for completers by time intervals. 
The number of completers by time interval is also defined as completer cohort. 
 
Change #12 
The following was deleted: 
3.3 Definition of Baseline values 
Entry visit refers to Visit 1 of EP0093. 
 
Change #13 
The following was removed: 
3.3.1 Baseline for variables based on seizure count 
Baseline values for observable focal-onset seizures need to be obtained from the parent 
studies for each patient who enters the study. 
 
Change #14 
The following was changed: 
3.3.2 Baseline for other variables 
For calculating change in other efficacy variables (SSG, QOLIE-31-P, HADS and in AED drug 
load) also the Baseline period of the parent study is used. For calculating change in safety 
variables the Entry Visit is used. 
 
Has been changed to: 
3.3.2 Baseline for other variables 
Unless otherwise specified, Baseline values from the parent study will be used in the analysis 
which is defined as the last valid measurement before the first study medication administration, 
including the pre-dose assessments on the day of Visit 2. If a Baseline visit measurement is 
missing, and a Screening visit measurement is available, the most recent Screening value will be 
utilized. 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 will be determined separately for each variable. An exception is 
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blood pressure, where a complete set of both systolic and diastolic blood pressure should be 
selected for Baseline. 
 
Change #15 
The following sentence was changed: 
3.6 Treatment assignment and treatment groups 
For all subjects the same PSL transition dose of 400mg/day will be administered at the start of 
the study. 
Has been changed to: 
The individual starting dose of each subject will be the one recommended at the end of the parent 
study. 
 
Change #16 
The following was added: 
3.9 Changes to protocol-defined analyses 
Due to COVID-19 impact on site initiation and enrollment and due to early termination of the 
study, the following items in the protocol were updated in the SAP. 
 
Section in 
this SAP 
Description 
Change from the protocol 
Table 2-1:  Schedule of 
Assessments 
Added: 
Setting (Required Onsite) column to include data that may be 
collected through phone or video calls for visit, during the 
pandemia. 
3.10 
COVID-19 
eCRF 
Added, see section 3.10 for details 
4.4 
Examination of 
subgroups 
Removed China as a region 
10.2.1.8 
Derivation of 
other efficacy 
variables 
Removed: Drug Loads of AEDs 
Changes in drug load are captured by number of products and 
daily dose per given product recorded in the AED Medication 
CRF. Drug load will be assessed using ratio of actual daily 
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dose and World Health Organization defined daily dose 
(DDD). 
“https://www.whocc.no/atc_ddd_index/?code=N03A&showde
scription=no”.  
The daily dose of the administered AED will be calculated at 
Entry Visit, Visit 8, and EOS. All AEDs which has the stop 
date at the visit (EV, Visit 8, EOS) or ongoing and the start 
date prior to the visit will considered administered at that 
specific visit.  
The drug load of all AEDs will be calculated as the sum of 
ratios of dose and DDD for each of the AEDs at the respective 
visit. The drug load of each AED class will be calculated as 
the sum of ratios of dose and DDD for each of the AEDs 
within the AED class. AED classes included in this analysis 
are: 
• SV2A: levetiracetam and brivaracetam 
• BZD: ATC code N05BA 
• sodium channel-blocking AED (SCB (+): 
carbamazepine, oxcarbazepine, eslicarbazepine, 
phenytoin and lamotrigine 
Ratio of dose and DDD, absolute change from EV in the ratio, 
and percent change from EV in the ratio will be summarized 
by all AEDs, AED drug class and by each of the AEDs. For 
two visits, the absolute change of a given AED drug load can 
be calculated if the product is administered at one of the visits; 
and the percent change can only be calculated if the AED is 
administered at EV.  The change in number of all AEDs at 
Visit 8 and EOS relative to EV will also be summarized. 
11 
COVID-19 
Impact 
The impact of COVID-19 global pandemic on this study is 
detailed in section 3.10. COVID-19 impact will be listed by 
impacted visit, date, impact category, and relationship to 
COVID-19 (confirmed, suspected, general circumstances 
around COVID-19 without infection or other) for each subject 
in the ES. 
15 
Addendum 
Added: 
All tables described in the SAP will be repeated for Japan and 
non-Japan subgroups. 
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Change #17 
The following has been added: 
3.10 COVID-19 eCRF 
A new COVID-19 eCRF, to evaluate the impact of global pandemic was created and 
implemented to collect the information on impacted visit, impact category, and relationship to 
COVID-19. 
Listing and table (see Section 11 for details) to describe the impact on the interpretability of 
efficacy and safety endpoints will be performed to assess the impact of the changes on the 
planned analyses due to COVID-19. 
 
Change #18 
The following has been changed: 
4.1.1 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. 
Handling of missing data for efficacy variables based on diary-collected seizure frequency: 
Seizure frequency will be computed over non-missing diary days. 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. 
Changed to: 
4.1.1 Handling of missing data in seizure frequency 
Seizure frequency will be calculated over non missing diary days during an analysis period or 
time interval. Days with missing seizure diary (ie, “Not Done” is ticked on the Seizure Count 
CRF) will not be considered in the calculation of seizure frequency or seizure free days. No 
imputation will be applied to missing seizure diary data. Seizure frequency during a time interval 
will be calculated if seizure data are available for at least 1 day during the interval.    
 
Change #19 
The following has been added: 
4.1.3 Incomplete dates for first epileptic seizure 
To calculate the time since the first seizure relative to the date of EV of EP0093 at onset of first 
seizure, 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 
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. 
 
Change #20 
The following has been removed: 
4.4 Examination of subgroups 
• Parent study 
• China 
 
Change #21 
The following has been removed: 
5.2 Protocol deviations 
A by-subject listing of subjects excluded from each of the analysis datasets (for SS) will be 
prepared. The listing will include the categorized reason for exclusion as well as the specific 
reason. 
 
Change #22 
The following has been changed: 
6.1 Demographics 
Demographic variables are collected on the Demographics CRF. 
All demographic collected in EP0093 (age in years, sex, weight and country), obtained at the 
Entry Visit will be summarized descriptively for ES, FAS and SS. 
• The following age categories will be summarized in the same table: (i) ≤18 years, 19 - 
<65 years and ≥65 years; (ii) 18- <65 years, 65 - <85 years and ≥ 85 years. 
• 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 from the parent 
studies will be included as baseline characteristics. Seizure counts are collected by diary. 
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• The number of previous AEDs used by the subject will be summarized descriptively. The 
count for an individual subject is the number of unique Preferred Names, using the      
current version of WHODD. 
 
Listings including all demographic variables as well as socio-economic status and child-bearing 
potential will be provided. 
 
Has been changed to: 
6.1 Demographics 
Demographic variables are collected on the Demographics CRF. The following demographic 
variables will be summarized for the SS by region:  
Based on data collected at EV of EP0093: 
- 
Age (in years)  
- 
The following age categories will be summarized in the same table:   (i) ≤18 years, 19 - <65 
years and ≥65 years; (ii) 18- <65 years, 65 - <85 years and ≥ 85 years 
Based on data collected at study entry of the parent study: 
- 
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) 
- 
Weight (in kg) 
- 
Body mass index (BMI) (kg/m2) and BMI category (<18.5, 18.5 to <25, 25 to <30, 30 to 
<40, ≥40) 
 
Change #23 
The following has been added: 
6.2 Other Baseline characteristics 
The following data collected at the time of entry into the parent study will be summarized for the 
SS. The parameters derived in the parent will be directly used. 
• Number of lifetime AEDs taken prior to the parent study: <4, 4 or 5, 6 or 7, 8 to 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 eCRF 
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• Number of AEDs taken at the entry of the parent study: 1, 2, 3, and > 3 AEDs 
• Current use of AEDs with binding to SV2A proteins (LEV and/or BRV): Yes or No 
 
Change #24 
The following has been changed: 
6.2 Medical history and concomitant diseases 
A medical history update is done at the Entry Visit. All medical conditions that were not reported 
in the prior study including start and stop dates are captured in the Medical History CRF. 
Medical history update will be summarized and listed 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. 
  
Has been changed to: 
6.3 Medical history and concomitant diseases 
6.3.1 Medical History 
Medical history reported at the entry of the parent study and any medical history update will be 
summarized and listed 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. 
A medical history update is done at the Entry Visit. Of note, medical history update CRF should 
only be used after the database of the parent study is already locked. All efforts will be taken to 
make sure medical history are completed in the database of the parent study.  
6.3.2 Medical history of epilepsy 
Selected medical history of epilepsy collected at the entry of the parent study will be summarized 
for the SS.  
6.3.2.1 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. 
6.3.2.2 History of epileptic seizures and diagnosis of epilepsy 
History of epileptic seizures, including 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 first seizure relative to the Entry Visit of EP0093 (ie, 
Entry Visit of EP0093 minus the date of the first epileptic seizure plus 1 divided by 365.25) and 
the age at onset of first seizure will be summarized for the SS. 
 
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Change #25 
The following has been changed: 
6.3 Concomitant medications/procedures 
Concomitant AED and non-AED medication are collected on separate CRFs. These include the 
AED Medication CRF and the Concomitant medication CRF. All concomitant medication started 
in the parent studies and are ongoing at the time of Entry Visit in EP0093 are collected on 
separate CRFs (Prior and Concomitant Medications_Parent Study CRF, AED Medication_Parent 
Study CRF). 
 
A medication will be included in a concomitant summary if: 
• (Date of Entry Visit) ≤ (Start date of medication) ≤ (Date of last IMP intake); or 
 
• Start date of medication is unknown but medication is ongoing at study entry. 
 
The number and percentage of subjects (SS) taking 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. Summaries will be 
provided for concomitant non-AED medication started in parent study, AED medication started 
in parent study, concomitant AED medication, and concomitant non-AED medication. Subjects 
with more than one medication within a level of categorization are counted only once within that 
level. For each CRF a listing is provided including dose per intake, frequency, indication and 
start and stop dates. 
 
Previous AEDs are AEDs taken previously and which has stopped prior to the Entry Visit. The 
data will be taken from the parent studies. 
 
Vagus nerve stimulation status is collected in the Vagus Nerve Stimulation Status CRF and all 
visits with Vagus nerve stimulation will be prepared as listing. 
 
Concomitant medical procedures will be listed only, including date of procedure, reported term 
and relation. 
Has been changed to: 
6.4 Concomitant medications 
Concomitant AED and non-AED medication are collected on separate CRFs. These include the 
AED Medication CRF and the Concomitant medication CRF. All concomitant medication started 
in the parent studies and are ongoing at the time of Entry Visit in EP0093 are collected on 
separate CRFs (Prior and Concomitant Medications_Parent Study CRF, AED Medication_Parent 
Study CRF). 
A medication will be included in a concomitant summary if:  
• (Date of first dose of PSL in EP0093) ≤ (Start date of medication) ≤ (Date of last dose of 
PSL in EP0093); or  
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• Start date of medication is prior to the first dose of PSL in EP0093 or unknown but 
medication is ongoing at study entry. 
6.4.1 AED medication 
The number and percentage of subjects taking concomitant AED medications will be 
summarized by chemical/therapeutic/pharmacological subgroup (ATC classification level 4), and 
preferred drug name.  
6.4.2 Use of vagus nerve stimulation 
The number and percentage of subjects with Vagus Nerve Stimulation (VNS) in Previous Study 
(collected at EV) will be summarized. Subjects with VNS setting changed during the Evaluation 
Period will also be summarized. All other VNS data will be provided in subject data listings and 
will not be summarized for the SS. 
6.4.3 Non-AED medication 
The number and percentage of subjects (SS) 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. 
 
Change #26 
7. Treatment Compliance 
The following was added: 
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.  
 
Change #27 
The following has been changed: 
9.1 Extent of exposure 
Extent of exposure will be presented in the following way: 
• Cumulative months of exposure: Study medication exposure defined in section 3.2.4 will 
becategorized into the following cumulative months categories of exposure: >0 weeks, 
>=3 months, >=6 months, >=9 months, >=12 months, >=15 months and >=21 months. 
 
• Study medication exposure as defined in section 3.2.4. 
 
• Total time at risk (subject-years) as defined in section 3.2.4. 
 
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Exposure will be summarized overall and for Evaluation Period. 
A summary of the PSL doses per visit will be provided. The exact PSL doses at each visit will be 
classified according to the following 8 categories: 
 
<100mg/day 
≥100mg/day - <200mg/day 
≥200mg/day - <300mg/day 
≥300mg/day - <400mg/day 
≥400mg/day - <500mg/day 
≥500mg/day - <600mg/day 
≥600mg/day - <700mg/day 
≥700mg/day - ≤800mg/day. 
Listings will include the study medication exposure per subject and the administration of study 
medication per dispense interval. 
 
Of special interest will be the tolerability of the study drug; a worse tolerability will lead to dose 
reductions. A listing of subjects with dose reductions in the prescribed dose since the prior visit 
will be provided. The Prescribed Padsevonil Dose CRF will contain all information on this. 
 
Has been changed to: 
9.1 Extent of exposure 
The overall duration of exposure of the study will be calculated as the date of last dose of PSL 
minus the date of first dose of PSL (Section 3.2.2.1) in EP0093 plus 1 day.  
Modal daily dose of a subject will be calculated as the daily dose the subject received for the 
longest duration during EP0093. In the event of a tie, the modal dose will be set to the lower of 
the tied doses. Modal daily dose will be categorized as ≤200mg/day, >200mg/day to 
≤400mg/day, >400mg/day to ≤600mg/day, and >600mg/day.  
The duration of exposure will be summarized overall and by modal dose for the SS and by 
region:   
• Cumulative months of exposure: duration of exposure in days will be summarized. 
Duration of exposure will also be categorized into the following cumulative months 
categories of exposure:  >=3 months, >=6 months, >=9 months, >=12 months, >=18 
months, and >=24 months.  
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Total time at risk (subject-years of exposure) will be calculated by summing the exposure 
duration in days for all subjects and dividing the resulting value by 365.25.  
Listings will include the study medication exposure per subject and the administration of study 
medication per dispense interval. Data collected on the Prescribed Padsevonil Dose CRF will be 
listed.  
 
Change #28 
The following has been changed: 
9.2 Adverse events 
Adverse events are recorded on the Adverse Event 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). Also, adverse events during the respective parent study will be 
recorded in the Adverse Event_Parent Study CRF. 
 
Overview summaries and listings will be also done for adverse events during the respective 
parent study. 
 
SAEs will be included in the Safety Database up to the completion of the 6-month 
echocardiogram. 
 
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the first dose of study treatment in this study 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) by SOC and PT. All AEs will be coded using the latest available 
MedDRA version (MedDRA 21.1). 
 
The following tables will be provided for the entire study and stratified by the respective parent 
study using the SS: 
 
• Overview of Incidence of AEs reported over the entire study 
• Overview of Incidence of AEs reported over the parent study 
• Incidence of TEAEs reported by the subject and/or caregiver or observed by the 
Investigator during the entire study Incidence of TEAEs reported by the subject and/or 
caregiver or observed by the Investigator during parent study 
• Incidence of serious TEAEs 
• Incidence of TEAEs (subjects and events) leading to Dose Reduction 
• Incidence of TEAEs (subjects and events) leading permanent Discontinuation of Study 
Drug 
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• Incidence of TEAEs by Maximum Relationship 
• Incidence of TEAEs by Relationship 
• Incidence of TEAEs by Maximum Intensity 
In addition a summary of the occurrence of any TEAE and any drug-related TEAE during the 
entire study per PSL dose at the time of the TEAE onset will pre presented. 
 
The following per-subject listings will be prepared using the SS showing all AEs per patient 
including the mapped visit and date: 
• All AEs 
• SAEs 
• AEs leading to discontinuation of study 
• AEs leading to dose reduction 
• AEs leading to death (just to be prepared if an AE leading to death occurred) 
These summaries will be presented based on standard Sponsor AE table formats or other 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 to suggest that the AE started prior to the first dose of 
study treatment or the investigator determines the AE is unrelated to 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. 
 
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT 
within SOC. 
 
Has been changed to: 
9.2 Adverse events 
Adverse events are recorded on the Adverse Event 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). Also, adverse events ongoing at the Entry Visit in EP0093 will be 
recorded in the Adverse Event_Parent Study CRF.  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
initiation of the first dose of study treatment in this study or any unresolved event already present 
before initiation of the first dose that worsens in intensity following exposure to the treatment. 
TEAEs are AEs with start dates on or after the date of first dose of PSL in EP0093. The number 
and percentage of subjects who experience TEAEs at any time during the study will be 
summarized (using the SS) by SOC and PT.  
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Unless noted otherwise, TEAEs during the study will be summarized. At the time of a clinical 
cutoff, TEAEs with onset date prior to or on the clinical cutoff date will be included. TEAEs are 
assigned into an analysis period or time interval based on the start date. Adverse event 
summaries will be ordered in terms of decreasing frequency for SOC, and PT within SOC. The 
following tabular summaries will be presented for the SS: 
• Ongoing AEs at EP0093 study entry 
• Incidence of TEAEs during the Study – Overview by Region  
• Incidence of TEAEs by Region 
• Incidence of TEAEs by 3-month time interval during the Exposure Period 
• Incidence of Serious TEAEs  
• Incidence of TEAEs by Relationship 
• Incidence of SAEs by Relationship. Of note, this table is needed for data transparency 
reporting.   
• Incidence of Fatal TEAEs by Relationship. Of note, this table is needed for data 
transparency reporting.  
• Incidence of TEAEs by Maximum Intensity 
• Incidence of TEAEs leading to discontinuation (ie, drop out) 
• Incidence of TEAEs leading to dose reduction  
• Incidence of TEAEs occurring in at least 5% of Subjects  
• Incidence of TEAEs by Dose at Onset (≤ 200mg/day, >200mg/day to ≤400mg/day, 
>400mg/day to ≤600mg/day, and >600mg/day) during the Exposure Period.  
• Incidence of Non-Serious TEAEs above the Threshold of 5% of Subjects. This table is 
needed for data transparency reporting.  
Summary tables will contain counts of subjects, percentages of subjects in parentheses and the 
number of events where applicable. A subject who has multiple events in the same SOC and PT 
will be counted only once in the subject counts, but all events will be included. 
In summaries of relationship to study treatment per the investigator, the following relationships 
will be summarized: ‘Not related’, ‘Related’. Events with missing relationship will be considered 
as ‘Related’ for summary purposes but recorded as missing in the listings. 
In summaries of maximum intensity, the following intensity categories will be summarized: 
‘Mild’, ‘Moderate’, ‘Severe’. Subjects who experience the same event multiple times will be 
included in the most severe category. Events with missing intensity will be considered as 
‘Severe’ events for summary purposes but recorded as missing in the listings. 
Listings will be provided for AEs, SAEs, AEs leading to discontinuation (ie, drop out), and AEs 
leading to death by subject for the SS. 
 
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Change #29 
The following has been modified: 
9.3.1 Subjects with potential drug-induced liver injury (PDILI) 
Hy’s Law is defined as:  
• AST ≥3xULN or ALT ≥3xULN and 
• Total Bilirubin ≥2xULN 
 Has been changed to: 
9.4 Subjects with potential drug-induced liver injury (PDILI) 
Potential Hy’s Law is defined as:  
• AST ≥3xULN or ALT ≥3xULN and 
• Total Bilirubin ≥2xULN 
 
Change #30 
9.4.1 Vital signs 
Vital measurements (including SBP, DBP, PR and RR) are taken at every scheduled visit. These 
measurements 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 (SS) 
will be prepared for vitals variables including absolute change from Entry Visit and PCST 
abnormality. 
 
The observed value and absolute change from Entry Visit will be summarized (SS) descriptively 
by scheduled study visit for all vital signs. These summaries will be organized by vital signs. 
Data collected at unscheduled visits will not be summarized. 
 
Possibly clinically significant (PCS) have been developed for the PSL program based on FDA 
Division of Neuropharmacologic Drug Products guidelines with some UCB-defined additions 
and are provided in Appendix 12.1. For vital sign parameters with PCS criteria, the number and 
percentage of subjects with a treatment emergent potentially clinically significant low or high 
value by visit will be summarized. In the same table, the number and percentage of subjects with 
a treatment emergent PCS will be summarized for all scheduled visits. 
 
 Has been changed to: 
9.5.1 Vital signs 
Vital measurements (including SBP, DBP, PR and RR) are taken at every scheduled visit. These 
measurements 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 
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be prepared for vitals variables including absolute change from Baseline and abnormality criteria 
flag. 
The observed value and absolute change from Baseline will be summarized (SS) descriptively by 
scheduled study visit, as well as Last Visit, maximum value, and minimal value Data collected at 
unscheduled visits will not be included in the by-visit summary.   
The number and percentage of subjects with abnormal vital signs (Appendix 12.2) will be 
summarized for the overall and by 3-month interval during the Exposure Period. Subject 
numbers for those meeting the abnormal criteria will also be presented. 
 
Change #31 
The following has been removed: 
9.5.2 Electrocardiograms 
The QTcB [QT corrected for heart rate using Bazett’s formula], and QTcF [QT corrected for 
heart rate using Fridericia’s formula] will be derived for each subject as shown below:   
𝑄𝑇𝑐𝐵=
𝑄𝑇
√60/𝐻𝑅 
 𝑎𝑛𝑑 𝑄𝑇𝑐𝐹= 
𝑄𝑇
√60/𝐻𝑅
3
 
where QT is the QT interval as reported in the ECG transfer and HR is the heart rate as reported 
in the ECG transfer. 
 
Change #32 
The following has been removed: 
9.5.4.1 Changes in CIWA-B 
A descriptive summary table will be prepared of observed and absolute change in CIWA-B 
scores from Entry Visit by scheduled visit. 
Change #33 
The following has been removed: 
9.5.4.5 Changes in Psychiatric and Mental Status 
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.  
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Change #34 
The following has been changed: 
10. Efficacy analyses 
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). 
10.1.1 Derivations of primary efficacy variable 
The primary efficacy variable is the change from Baseline in the observable focal-onset seizure 
frequency over the Evaluation 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 Evaluation Period. The diary days for this period, which are collected onto 
the Seizure Count eCRF, are obtained from the diaries returned at Evaluation Period Visit 2 up to 
EOS in cases where the patient completed the Evaluation Period. Otherwise diary days for this 
period will be obtained from the diaries returned between Visit 2 and Early Discontinuation 
Visit. 
 
The patient’s 28-day adjusted seizure frequency of observable focal-onset seizures (Types IA1, 
IB, and IC) during the Evaluation Period will be calculated by dividing the number of seizures in 
the Evaluation 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. 
 
• Calculation of absolute Change from Baseline of the parent study in seizure frequency: 
 
The (absolute) change from Baseline is calculated for each subject by subtracting the 28-day 
adjusted seizure frequency during the 4-week Baseline period of the parent study from the 28- 
day adjusted seizure frequency during the Evaluation Period as follows: 
 
focal-onset seizure frequency during Evaluation – focal-onset seizure frequency during Baseline 
of the parent study, where seizure frequency refers to the 28-day adjusted frequency for the 
period. 
 
Has been changed to: 
10. Efficacy analyses 
Unless noted otherwise, analyses of efficacy endpoints will be performed on the FAS. 
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10.1.1 Derivations of primary efficacy variable 
10.1.1.1 Seizure frequency 
Seizure frequency (SF) refers to the 28-day adjusted seizure frequency, which is defined as:  
SF = (Number of Seizures) x (28 / D)  
− where Number of Seizures = total number of seizures during an analysis period or 
time interval. For cluster seizures, the number of cluster episodes will be included. 
− D = number of days for which the diary was available during the analysis period or 
time interval. 
 
Change from Baseline in seizure frequency will be calculated as seizure frequency during an 
analysis period or time interval minus the Baseline seizure frequency.  
The primary efficacy variable is the change from Baseline in the observable focal-onset seizure 
frequency over the Evaluation Period.  
 
Change #35 
The following was deleted: 
10.2.1.1 Other efficacy variables based on seizure frequencies 
Seizure frequency calculations 
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. The diary days 
for the 3-month intervals which are collected onto the Seizure Count eCRF, are obtained from 
the diaries returned at Visit 2 – Visit 12 or EDV Visit. In case of an Early Discontinuation Visit, 
the last available 3-month period is used. 
 
The subject’s 28-day adjusted seizure frequency of observable focal-onset seizures (types IA1, 
IB, IC) will be calculated as in section 8.1.1 for the following 3-months intervals: 
 
Visit 1-Visit 5 (seizure count refers to time between week 0 and month 3) 
Visit 6 (refers to time between month 4 and 6) 
Visit 7 (refers to time between month 7 and 9) 
Visit 8 (refers to time between month 10 and 12) 
Visit 9 (refers to time between month 13 and 15) 
Visit 10 (refers to time between month 16 and 18) 
Visit 11 (refers to time between month 19 and 21) 
Visit 12 (refers to time between month 22 and 24). 
 
Seizure-free status 
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Seizure-free status (yes/no) for all seizure types is calculated over the same time intervals as the 
seizure frequency. The corresponding visits are the 3-month time periods between Visit 5 and 
Visit 12. Additionally, seizure free status will be determined for the overall Evaluation Period up 
to EOS or EDV Visit, respectively. 
 
A subject is defined as seizure free during a specific evaluation period if all of the following 
criteria are met: 
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. 
 
Seizure-free rate 
The seizure-free rate (%) for a specific time period considers all seizure types and will be 
calculated as: 
Count of seizure free subjects during the period 
x 100 
Seizure-free count of subjects + Non-seizure free count of subjects 
during the period 
 
Seizure-free days 
The percentage of seizure-free days for a specific time period considers all seizure types and will 
be calculated as: 
 
Count of seizure free days during the period 
x 100 
Seizure-free day count + Non-seizure free day count during the period 
 
Change #36 
The following were added: 
10.2.1.1 Percent reduction in seizure frequency from Baseline of parent study 
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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 or time interval and SFB corresponds to the Baseline seizure frequency. A 
negative PRD indicates an increase in seizure frequency from Baseline of parent study.  
10.2.1.2 50%, 75% and 90% Responder 
Responder status (yes or no) of a subject is determined by the percent reduction in seizure 
frequency (PRD) from Baseline of parent study. A subject is defined as a XX% responder if s/he 
has a reduction in seizure frequency (PRD) of at least XX% from the Baseline. The XX% 
responder rate (RR) will be calculated as the proportion of XX% responders.  
10.2.1.3 Seizure-free status (Yes or No) 
Subjects will be considered seizure-free for a given period or time interval if the subject, 
completes the period, reports zero seizures during the period, and has no more than 10% of days 
in the period for which seizure data is not available (ie, “Not Done” is reported on the Seizure 
Count CRF). 
10.2.1.4 Number and percentage of Seizure-free days 
The number of seizure-free days will be the total number of days within an analysis period or 
time 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.  
 
Change #37 
The following were renumbered: 
10.2.1.2 Seizure Severity Global Item (SSG) variables 
10.2.1.3 QOLIE-31-P 
10.2.1.4 Hospital Anxiety and Depression Scale (HADS) score variables 
10.2.1.7 Treatment satisfaction 
Renumbered to: 
10.2.1.5 Seizure Severity Global Item (SSG) variables 
10.2.1.6 QOLIE-31_P 
10.2.1.7 Hospital Anxiety and Depression Scale (HADS) score variables 
10.2.1.9 Treatment satisfaction 
 
 
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Change #38 
The following has been removed: 
10.2.1.5 Drug Load of AEDs 
Changes in drug load are captured by number of products and daily dose per given product 
recorded in the AED Medication CRF. The ratio of daily dose and Defined Daily Dose (DDD) 
gives details on the daily dose compared to the average maintenance dose used for its main 
indication for adults [WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD 
Index 2017]. DDDs for AEDs can be found in Appendix 12.4. 
 
The daily dose of every administered AED will be collected at each study visit. The change from 
Visit 8 to Entry Visit and to EOS Visit will be calculated for daily dose and number of products. 
All AEDs which has the same start or stop date as at the visit (Entry Visit, Visit 8, EOS) or 
which is ongoing and the start date is prior to the visit will be used for calculation. The change in 
the number of products is defined as the absolute difference in the number of simultaneously 
given products. The absolute change in the daily dose is calculated per product. For two visits a 
change can only be calculated if the same product is administered at both visits. Otherwise no 
change will be calculated. 
 
Change #39 
The following has been changed: 
10.2.1.6 Time to Discontinuation 
Time to discontinuation is defined as the time to discontinuation of treatment. Time to 
discontinuation of treatment is calculated by the date of the last PSL dose minus the date of 
Entry Visit +1. All subjects who will not have a last PSL dose as they are transferred in a 
Managed Access Program or another PSL study are considered as censored. Time to 
discontinuation is analyzed by Kaplan-Meier method. 
 
Has been changed to: 
10.2.1.8 Time to Discontinuation to Treatment 
Time to discontinuation of treatment is calculated by the date of the last PSL dose minus the date 
of first dose +1.  
 
Change #40 
The following has been changed: 
10.2.2.1 Seizure frequency by 3-month interval 
The observed and the absolute change in 28-day adjusted seizure frequency of observable focal 
onset seizures by the 3-month intervals over the Evaluation Period will be summarized in 
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descriptive tables for all seizures and for type I seizures only. 
 
The seizure free rate is summarized by 3-month interval over the Evaluation Period and overall 
as number of subjects who are seizure-free, percentages and 95%-confidence intervals using the 
Binomial exact method. The number of seizure free days is summarized over the Evaluation 
Period and by 3-month intervals over the Evaluation Period. A per-subject listing will include the 
number of seizure-free days during the Evaluation Period. 
10.2.2.2 50%, 70%, and 90% responder rate for all types of observable focal onset seizures 
Summaries and listings for the 50%, 75% and 90% responder rate will be provided for the 
specified 3-month intervals over the Evaluation Period and for the complete Evaluation Period. 
 
10.2.2.3 50%, 70%, and 90% responder rate for Type I observable focal onset seizures  
Summaries for the 50%, 75% and 90% responder rate will be provided for the specified 3-month 
intervals over the Evaluation Period and for complete Evaluation Period. 
10.2.2.4 Seizure-freedom status for all seizure types by 3-month intervals over the 
Evaluation Period 
By Visit summaries about the seizure freedom status including the seizure-free rate and the 
corresponding 95% confidence intervals will be provided by 3 months intervals over the 
Evaluation Period as well as a descriptive summary table of seizure free days, including n, mean, 
95%CI for the mean, SD, Min, Max, Median, Q1 and Q3. In addition, the seizure freedom status 
as well as seizure free days will be captured in a listing. 
 
Has been changed to: 
10.2.2.1 Seizure frequency by 3-month interval 
The observed and the absolute change in 28-day adjusted seizure frequency of observable focal-
onset seizures by the 3-month intervals over the Evaluation Period will be summarized by region 
in descriptive tables. The same summary will be repeated for the number of completers by time 
interval.  
The observed and change from baseline in seizure frequency of Type IA1, IB, and IC seizures 
will be summarized separately by seizure type. Summary will be provided for the overall and by 
3-month interval during the Evaluation Period. Summary will also be provided by 3-month 
interval for each completer cohort. The same summary will also be provided for the all Type I 
seizures.  
10.2.2.2 50%, 70%, and 90% responder rates by 3-month interval for observable focal 
onset seizures over the Evaluation Period 
Summaries and listings for the 50%, 75% and 90% responder rates for observable focal-onset 
seizures will be provided for the overall Evaluation Period and by 3-month interval. Summaries 
will also be provided by 3-month interval for number of completers by time interval. 
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10.2.2.3 50%, 70%, and 90% responder rates for focal-onset seizures (all Type I) over the 
Evaluation Period 
Summaries for the 50%, 75% and 90% responder rates for all Type I seizures will be provided 
for the overall Evaluation Period and by 3-month interval. Summaries will also be provided by 3-
month interval number of completers by time interval.  
10.2.2.4 Seizure-freedom status for all seizure types by 3-month interval over the 
Evaluation Period 
The number and percentage of subjects achieving a seizure-free status will be summarized by 3-
month interval for each completer cohort. After the study completion, the same summary will be 
performed for the overall and by 3-month interval for the Evaluation Period.     
 
Change #41 
The following have been added: 
10.2.2.5 Percentage of seizure-free days (for all seizure types) by 3-month interval over the 
Evaluation Period 
The percentage of seizure-free days and change from baseline in percentage of seizure-free days 
will be summarized for the overall Evaluation Period and by 3-month interval. Summaries will 
also be provided by 3-month interval for number of completers by time interval. 
10.2.2.6 Percentage of reduction in seizure frequency by 3-month interval over the 
Evaluation Period 
The percentage of reduction in seizure frequency from baseline for observable focal-onset 
seizures and all Type I seizures will be summarized for the overall Evaluation Period and by 3-
month interval. Summaries will also be provided by 3-month interval for each completer cohort.  
 
Change #42 
The following have been renumbered: 
10.2.2.5 Change in the SSG Score 
10.2.2.6 Change in the QOLIE-31-P score 
10.2.2.7 Change in Hospital Anxiety and Depression Scale (HADS) score 
10.2.2.9 Health-related Outcomes and HRU 
10.2.2.10 Time to discontinuation 
10.2.2.11 Treatment satisfaction 
 
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 Have been renumbered to: 
10.2.2.7 Change in the SSG Score 
10.2.2.8 Change in the QOLIE-31-P score 
10.2.2.9 Change in Hospital Anxiety and Depression Scale (HADS) score 
10.2.2.10 Health-related Outcomes and HRU 
10.2.2.11 Time to Discontinuation to Treatment 
10.2.2.12 Treatment satisfaction 
 
Change #43 
The following has been changed: 
10.2.2.7 Change in the SSG score 
The numbers and percentages of subjects in each severity category will be summarized 
descriptively for Entry Visit 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 each scheduled visit and the Last Visit during the Evaluation 
Period. All data will be listed by subject 
Changed to: 
Data will be listed for each scheduled visit and the Last Visit during the Evaluation Period by 
subject. 
 
Change #44 
The following has been changed: 
10.2.2.8 Changes in the QOLIE-31-P score 
For each time point, summary statistics will be presented for the change from baseline of the 
parent study in addition to summaries of the observed values. Only subjects with a non-missing 
change from baseline will be summarized at each time point. 
In addition, all data will be listed by subject for total and subscales. 
 
Changed to: 
For each time point, the change from baseline of the parent study will be listed by subject for 
total and subscales. 
Change #45 
The following has been changed: 
10.2.2.9 Changes in the Hospital Anxiety and Depression Scale (HADS) score 
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The observed scores and changes in the scores will be summarized using descriptive statistics 
and in addition presented in a subject listing. 
 
Changed to: 
The observed scores and changes in the scores for depression and anxiety will be presented in a 
subject listing. 
 
Change #46 
The following has been changed: 
10.2.2.9 Health-related Outcomes and HRU 
Health-related outcomes data and HRU data will be listed for the ES and summarized 
descriptively for the SS. 
 
• Socio-professional status 
 
Socio-professional status data are collected at Entry Visit and EOS/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 Entry Visit, EOS or the Last Visit during the 
Evaluation Period. 
 
• Healthcare provider consultations not foreseen by the protocol 
 
The number of health care provider consultations per subject with onset during the Evaluation 
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 Evaluation 
Period. 
 
• Hospital and ER visits 
The number of hospitalization per subject will be summarized as a continuous variable and 
categorical variable for the Evaluation 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”. 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 Evaluation Period will be 
summarized using the categories 0, 1, 2, and 3 or more. 
 
Has been changed to: 
Health-related outcomes data and HRU data will be listed for the SS. 
• Socio-professional status 
Socio-professional status data are collected at Entry Visit and EOS/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.  
• Healthcare provider consultations not foreseen by the protocol 
Healthcare consultations by type of provider 
(general practitioner, specialist physician, nurse, and other) will be listed for each subject during 
the study. 
• Hospital and ER visits 
ER visits will be extracted from the 
Hospitalization/ER Visit CRF page (if the initial entry point is ER).  
• Caregiver assistance 
Caregiver assistance data is collected on the CRFs “Caregiver Assistance”.  
 
• Number of school or working days lost 
Number of school/working days lost data are collected on the CRFs “School and Workdays 
Lost”. The number and percentages of subjects who lose school or work days as a result of 
epilepsy will be listed by visit. The percentage of days lost will be calculated as:  
100 × (end date of absence – start date of absence +1)/ (3 × 30 + 1) for the Entry Visit. If 
the end date of absence is missing or after Entry Visit date, the end date of absence will 
be set to Entry Visit; if the start date of absence is missing or prior to Entry Visit-90, the 
start date of absence will be set to Entry Visit-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. 
Change #47 
The following has been changed: 
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10.2.2.10 Time to discontinuation  
Time to discontinuation is summarized descriptively for FAS overall and by region and parent 
study. 
A Kaplan-Meier figure will be provided for all subjects and by region and parent study. 
 Has been changed to: 
10.2.2.11 Time to discontinuation  
Kaplan-Meier estimates of the percentage of subjects completing 3, 6, 12, 18, and 24 months of 
treatment will be provided for the SS. For subjects who discontinued from the study, the event 
date is set to the date of last dose of PSL and the time to event will be calculated as the date of 
last dose minus the date of first dose of PSL in EP0093 plus 1. Subjects who completed the study 
will be censored as of the date of last dose of PSL in EP0093. At a clinical cutoff, subjects who 
are ongoing will be censored as of the date of last dose of PSL defined for the interim analyses 
(Section 3.2.2.1). 
 
Change #48 
The following has been removed: 
10.2.2.12 Treatment satisfaction 
Subscale items will be summarized descriptively for FAS overall and by region. 
 
Change #49 
 
The following has been added: 
 
11. COVID-19 impact 
 
The impact of COVID-19 global pandemic on this study is detailed in section 3.10. COVID-19 
impact will be listed by impacted visit, date, impact category, and relationship to COVID-19 
(confirmed, suspected, general circumstances around COVID-19 without infection or other) in 
the ES. Impact of COVID-19 for any reason by country will be tabulated in the ES 
 
Change #50 
 
The following has been added: 
 
15. Addendum 
All tables described in the SAP will be repeated for Japan and non-Japan subgroups. 
 
 
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15 
ADDENDUM 
All tables described in the SAP will be repeated for Japan and non-Japan subgroups. 
 
 
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16 
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:
EP0093-SAP-Amend1
Version:
1. 0
Document Number:
CLIN-000159894
Title:
EP0093 Statistical Analysis Plan Amendment 1
Approved Date:
25 Sep 2020
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-Sep-2020 13:38:38 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-Sep-2020 13:50:41 GMT+0000
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