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: PHASE2
Conditions: Drug-Resistant Epilepsy, Focal-Onset Seizures
Sponsor: UCB Biopharma SRL

UCB 
 
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EP0093 
 
 
 
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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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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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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 
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abeling/ucm093664.htm  
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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 
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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. 
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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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Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266-77. 
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. 
WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2017. Accessed 
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
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 05-Feb-2020 22:25:30 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 06-Feb-2020 08:55:44 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 06-Feb-2020 15:15:42 GMT+0000
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