An Open-label, Multicenter, Follow-up Study to Evaluate the Long-term Safety and Efficacy of Brivaracetam Used as Adjunctive Treatment in Subjects Aged 16 Years or Older With Epilepsy
Phase: PHASE3
Conditions: Epilepsy
Sponsor: UCB BIOSCIENCES, Inc.

UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 1 of 129
PROTOCOL N01379 AMENDMENT 3
AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO
EVALUATE THE LONG-TERM SAFETY AND EFFICACY OF 
BRIVARACETAM USED AS ADJUNCTIVE TREATMENT IN 
SUBJECTS AGED 16 YEARS OR OLDER WITH EPILEPSY
PHASE 3
EudraCT-Number: 2010-020345-27
IND Number: 70,205
Sponsor:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Protocol/Amendment Number
Date
Type of amendment
Final Protocol
15 Sep 2010
Not applicable
Protocol Amendment 1
27 Jan 2011
Substantial
Protocol Amendment 2
14 Sep 2011
Substantial
Protocol Amendment 3
15 May 2015
Substantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed 
on, reproduced, published or otherwise used without the express permission of UCB.
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 2 of 129
STUDY CONTACT INFORMATION
Sponsor
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Sponsor Study Physician
Name:
, MD
Address:
8010 Arco Corporate Drive, Suite 100
Raleigh, NC  27617
United States
Phone:
Fax:
Clinical Project Manager
Name:
, PhD
Address:
Alfred-Nobel-Str. 10
40789 Monheim am Rhein
Germany
Phone:
Fax:
Clinical Trial Biostatistician 
Name:
 PhD
Address:
8010 Arco Corporate Drive, Suite 100
Raleigh, NC  27617
United States
Phone:
Fax:
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 3 of 129
Clinical Monitoring Contract Research Organization
Name:
PRA HEALTHSCIENCES
Address:
4130 Park Lake Avenue, Suite 400 
Raleigh, NC  27612 
United States
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions s or
or r variations thereof. 

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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 4 of 129
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Email
Global: DSICT@ucb.com
Fax
Europe and Rest of the World: +32 2 386 2421
USA: +1 800 880 6949
Canada: +1 877 582 8842
REDACTED COPY 
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 5 of 129
TABLE OF CONTENTS
STUDY CONTACT INFORMATION .....................................................................................2
SERIOUS ADVERSE EVENT REPORTING..........................................................................4
LIST OF ABBREVIATIONS....................................................................................................9
1
SUMMARY.....................................................................................................................11
2
INTRODUCTION ...........................................................................................................12
2.1 Background and epidemiology of targeted disease..........................................................12
2.2 Background information regarding product.....................................................................13
2.3 Efficacy of BRV in fixed-dose Phase 2/3 studies in POS................................................14
2.4 Safety of BRV..................................................................................................................15
2.5 Study rationale .................................................................................................................15
3
STUDY OBJECTIVES....................................................................................................15
3.1 Primary objective.............................................................................................................15
3.2 Secondary objective.........................................................................................................15
3.3 Exploratory objectives .....................................................................................................15
4
STUDY VARIABLES.....................................................................................................16
4.1 Safety variables................................................................................................................16
4.1.1
Primary safety variables ......................................................................................16
4.1.2
Other safety variables ..........................................................................................16
4.2 Efficacy variables.............................................................................................................16
4.2.1
Secondary efficacy variables ...............................................................................16
4.2.2
Other efficacy variables.......................................................................................16
4.3 Pharmacoeconomic variables...........................................................................................17
5
STUDY DESIGN.............................................................................................................17
5.1 Study description .............................................................................................................17
5.1.1
Study duration per subject ...................................................................................18
5.1.2
Planned number of subjects and sites ..................................................................18
5.1.3
Anticipated regions and countries .......................................................................18
5.2 Schedule of study assessments.........................................................................................19
5.3 Visit schedule...................................................................................................................24
5.4 Rationale for study design and selection of dose.............................................................25
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................26
6.1 Inclusion criteria ..............................................................................................................26
6.2 Exclusion criteria .............................................................................................................27
6.3 Withdrawal criteria ..........................................................................................................27
7
STUDY TREATMENTS.................................................................................................29
7.1 Description of investigational medicinal product(s)........................................................29
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
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7.2 Treatments to be administered.........................................................................................29
7.3 Packaging.........................................................................................................................29
7.4 Labeling ...........................................................................................................................29
7.5 Handling and storage requirements..................................................................................29
7.6 Drug accountability..........................................................................................................30
7.7 Procedures for monitoring subject compliance................................................................31
7.8 Concomitant medication(s)/treatment(s)..........................................................................31
7.8.1
Permitted concomitant treatments (medications and therapies) ..........................31
7.8.2
Prohibited concomitant treatments (medications and therapies).........................31
7.9 Blinding............................................................................................................................31
7.10 Randomization and numbering of subjects......................................................................32
8
STUDY PROCEDURES BY VISIT ...............................................................................32
8.1 Entry Visit........................................................................................................................32
8.2 Full Evaluation Visit........................................................................................................33
8.3 Minimal Evaluation Visit.................................................................................................34
8.4 Yearly Evaluation Visit....................................................................................................35
8.5 Unscheduled Visit............................................................................................................36
8.6 Last Evaluation Period Visit or Early Discontinuation Visit...........................................36
8.7 Down-Titration Phone Call..............................................................................................37
8.8 Final Visit.........................................................................................................................37
9
ASSESSMENT OF EFFICACY......................................................................................38
9.1 Additional efficacy and pharmacoeconomic assessments ...............................................38
9.1.1
QOLIE-31-P scores .............................................................................................38
9.1.2
Socio-professional data........................................................................................39
9.1.3
Medical procedures..............................................................................................39
9.1.4
Healthcare provider consultations not foreseen by the protocol..........................39
9.1.5
Hospital stays.......................................................................................................39
10
ASSESSMENT OF SAFETY..........................................................................................39
10.1 Adverse events.................................................................................................................39
10.1.1
Definition of adverse event..................................................................................39
10.1.2
Procedures for reporting and recording adverse events.......................................40
10.1.3
Description of adverse events..............................................................................40
10.1.4
Follow-up on adverse events ...............................................................................40
10.1.5
Rule for repetition of an adverse event................................................................40
10.1.6
Pregnancy ............................................................................................................41
10.1.7
Overdose of investigational medicinal product ...................................................41
10.1.8
Safety signal detection.........................................................................................41
10.2 Serious adverse events .....................................................................................................41
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 7 of 129
10.2.1
Definition of serious adverse event .....................................................................41
10.2.2
Procedures for reporting serious adverse events .................................................42
10.2.3
Follow-up of serious adverse events....................................................................43
10.3 Immediate reporting of adverse events............................................................................43
10.4 Anticipated serious adverse events ..................................................................................43
10.5 Laboratory measurements................................................................................................43
10.5.1
Safety laboratory assessments .............................................................................43
10.5.2
DNA analysis.......................................................................................................45
10.6 Other safety measurements..............................................................................................45
10.6.1
Electrocardiogram................................................................................................45
10.6.2
Vital signs ............................................................................................................46
10.6.3
Body weight and height.......................................................................................46
10.6.4
Physical examination...........................................................................................46
10.6.5
Neurological examination....................................................................................46
10.6.6
Assessment of suicidality ....................................................................................46
10.6.7
HADS scores .......................................................................................................46
11
STUDY MANAGEMENT AND ADMINISTRATION.................................................46
11.1 Adherence to protocol......................................................................................................46
11.2 Monitoring .......................................................................................................................47
11.2.1
Definition of source data .....................................................................................47
11.2.2
Source data verification .......................................................................................48
11.3 Data handling...................................................................................................................48
11.3.1
Case Report Form completion.............................................................................48
11.3.2
Database entry and reconciliation........................................................................49
11.3.3
Subject Enrollment log/Subject Identification Code list .....................................49
11.4 Termination of the study..................................................................................................49
11.5 Archiving and data retention............................................................................................50
11.6 Audit and inspection ........................................................................................................50
11.7 Good Clinical Practice .....................................................................................................50
12
STATISTICS ...................................................................................................................50
12.1 Definition of analysis populations ...................................................................................50
12.2 General statistical considerations.....................................................................................51
12.3 Planned safety analyses....................................................................................................51
12.4 Planned efficacy analyses ................................................................................................51
12.5 Planned pharmacoeconomic analyses..............................................................................52
12.6 Handling of protocol deviations.......................................................................................52
12.7 Handling of dropouts or missing data..............................................................................52
12.8 Planned interim analysis and data monitoring.................................................................52
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 8 of 129
12.9 Determination of sample size...........................................................................................52
13
ETHICS AND REGULATORY REQUIREMENTS......................................................52
13.1 Informed consent .............................................................................................................52
13.2 Subject identification cards..............................................................................................53
13.3 Institutional Review Boards and Independent Ethics Committees..................................53
13.4 Subject privacy.................................................................................................................54
13.5 Protocol amendments.......................................................................................................54
14
FINANCE, INSURANCE, AND PUBLICATION.........................................................54
15
REFERENCES ................................................................................................................54
16
APPENDICES .................................................................................................................56
16.1 Appendix 1: Patient Weighted Quality Of Life in Epilepsy: QOLIE-31-P (Version 
2.0, US – English)............................................................................................................56
16.2 Appendix 2: Hospital Anxiety and Depression Scale (HADS) .......................................66
16.3 Protocol Amendment 1 ....................................................................................................67
16.4 Protocol Amendment 2 ..................................................................................................100
16.5 Protocol Amendment 3 ..................................................................................................113
17
DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................128
18
SPONSOR DECLARATION ........................................................................................129
LIST OF TABLES
Table 5‒1:
Schedule of study assessments.........................................................................19
Table 5‒2:
Visit schedule...................................................................................................25
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 9 of 129
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
!-hCG
beta-human chorionic gonadotropin
BRV
brivaracetam
CDMS
clinical data management system
Cr Cl
creatinine clearance
CRF
Case Report Form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DRC
daily record card
DRM
data review meeting
DTP
Down-Titration Phone Call
ECG
electrocardiogram
EDV
Early Discontinuation Visit
EEG
electroencephalogram
EV
Entry Visit
FDA
Food and Drug Administration
FEV
Full Evaluation Visit
FV
Final Visit
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
HADS
Hospital Anxiety and Depression Scale
HRQoL
Health-related Quality of Life
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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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 10 of 129
iv
intravenous
IVRS
interactive voice response system
LEV
levetiracetam
LTFU
long-term follow-up
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA®
Medical Dictionary for Regulatory Activities
MEV
Minimal Evaluation Visit
MRI
magnetic resonance imaging
NA
not applicable
PBO
placebo
PK
pharmacokinetics
POS
partial onset seizure
PRN
pro re nata (as needed)
PS
Patient Safety
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy Inventory 
RBC
red blood cells
SAE
serious adverse event
SDV
source data verification
SOP
Standard Operating Procedure
SV2
synaptic vesicle protein 2
SV2A
synaptic vesicle protein 2A
TEAE
treatment-emergent adverse event
UV
Unscheduled Visit
TSH
thyroid-stimulating hormone
V
Visit
WBC
white blood cells
YEV
Yearly Evaluation Visit
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 11 of 129
1
SUMMARY
This is a Phase 3, open-label, long-term follow-up (LTFU), multicenter, noncomparative, and 
single-arm study of brivaracetam (BRV). The primary objective is to evaluate the long-term 
safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day in 
epilepsy subjects. The secondary objective is to evaluate the maintenance of efficacy of BRV 
over time. Exploratory objectives are to assess the effects of BRV on subjects’ Health-related 
Quality of Life (HRQoL), obtain information on the direct medical resource use, explore any 
change in socio-professional status, and assess the role of gene variants of SV2 in affecting 
response to BRV (as part of a DNA analysis at the program level).
This study will enroll subjects (≥16 years) from N01358 with refractory partial onset seizures 
(POS) whether or not secondarily generalized and subjects (≥16 years) from N01258 with 
localization-related or generalized epilepsy. Subjects under 18 years may only be included 
where legally permitted and ethically accepted. Subjects have to complete the Treatment 
Period of N01358 or the Evaluation Period of N01258 prior to enrollment into N01379. 
Subjects from N01358 will be started on a BRV dose of 150mg/day at study entry and should 
be maintained at this dose for at least 2 weeks unless the subject is unable to tolerate 
treatment. Subjects from N01258 will start at a dose of BRV 200mg/day and should be 
maintained at this dose for at least 2 weeks unless the subject is unable to tolerate treatment. 
The BRV dose can be adjusted based on the individual subject’s seizure control and 
tolerability. However, the BRV dose may not exceed 200mg/day during the study. During the 
Evaluation Period, subjects will be invited to visit the clinical site monthly in the first 
3 months and every 3 months thereafter. The completion of the Evaluation Period or early 
discontinuation from N01379 is followed by a Down-Titration Period of up to 4 weeks and 
by a subsequent Posttreatment Period (between 2 and 4 weeks) during which the subject does 
not receive study drug, or subjects will be converted without down-titration to commercial 
BRV if, when, and where available. Alternatively, subjects may transition into another BRV 
study, or be initiated without down-titration into a managed access program, named patient 
program, compassionate use program, or similar type of access program as allowed per 
country-specific legal and regulatory requirements.
This LTFU study will run throughout the duration of the clinical development period of 
BRV, and will continue until a marketing authorization is granted by any Health Authority in 
an indication for the adjunctive treatment in adults (≥16 years) with refractory POS, whether 
or not secondarily generalized; until the Sponsor decides to close the study; until subjects 
transition to another BRV study; until a managed access program, named patient program, 
compassionate use program, or similar type of access program is established as allowed per 
country-specific requirement in addition to legal and regulatory guidelines; or until BRV 
development is stopped by the Sponsor.
The primary efficacy variable is the POS (type I) seizure frequency standardized to a 28-day 
duration. Seizure types are coded according to the Commission on Classification and 
Terminology of the International League Against Epilepsy (ILAE), 1981. The primary 
efficacy variable will be summarized by 3-month periods over the Evaluation Period.
Secondary efficacy variables include the seizure frequency per 28 days for all seizure 
types (I+II+III), the proportion of seizure-free days for all seizure types (I+II+III), the 
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 12 of 129
proportion of continuously seizure-free subjects for all seizure types (I+II+III), and the 
responder rate in POS (type I). A responder is defined as a subject with a ≥50% reduction in 
seizure frequency from the Baseline Period for the double-blind study N01358. Responder 
rates will not be evaluated for subjects from N01258 due to the short duration of the Baseline 
Period for this study.
Other efficacy variables for subjects from N01258 with generalized epilepsy include the 
generalized (type II) seizure days, seizure days per 28 days for all seizure types (I+II+III), 
proportion of seizure-free days for all seizure types (I+II+III), and proportion of continuously 
seizure-free subjects for all seizure types (I+II+III) by 3-month periods over the Evaluation 
Period. Some variables may not be assessed if the number of subjects with generalized 
epilepsy is insufficient.
Other efficacy and pharmacoeconomic variables include the Patient Weighted Quality of Life 
in Epilepsy Inventory (QOLIE-31-P) scores, medical resources use, and socio-professional 
data during the first 2 years of the Evaluation Period.
Safety variables include adverse events (AEs), laboratory tests (hematology, blood chemistry,
urinalysis, endocrinology, and pregnancy test), electrocardiogram (ECG), vital signs, physical 
and neurological examinations, the Hospital Anxiety and Depression Scale (HADS) scores, 
and body weight.
It is estimated that approximately 650 to 720 subjects from N01358 will enter the study,
based on the assumption that at least 90% of randomized subjects from N01358 will complete 
N01358 and enroll in N01379. Up to 100 subjects from N01258 may also be eligible. It is 
estimated that approximately 120 sites from N01358 and up to 25 sites from N01258 will 
participate in the study.
2
INTRODUCTION
2.1
Background and epidemiology of targeted disease
Epilepsy is one of the most common and challenging neurological disorders. It has been 
estimated that over 50 million people are affected worldwide (Engel and Pedley, 1998; 
Sander and Shorvon, 1996; Hauser et al, 1993; Loiseau et al, 1990). The prevalence of
epilepsy is around 1%. The annual incidence in developed countries is approximately 
50 to 70 cases per 100,000. In developing countries, the figure is higher due to more limited 
obstetric services and the greater likelihood of cerebral infection and trauma. The incidence 
varies greatly with age, with high rates occurring in childhood, falling to low levels in early 
adult life, but with a second peak in those aged over 65 years. In many people, particularly 
children, the condition may remit, although a significant proportion will have epilepsy 
lifelong. The disease duration is often determined by the underlying cause. Sudden 
unexpected death, a complication of great concern, occurs in 1 to 5 per 1000 patient years, 
particularly if the seizure disorder remains uncontrolled. The treatment of epilepsy remains 
difficult, and there is an ongoing medical need for new antiepileptic drugs (AEDs). For a 
considerable proportion of patients, seizure freedom can still not be reached with the 
currently available AEDs (Nasreddine et al, 2010, Kwan and Brodie, 2001).
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 13 of 129
Diagnosis of epilepsy is based on the recurrence of seizures. Seizures may be caused by an 
underlying brain disorder or lesion or due to genetic conditions. Characterization of the 
epileptic syndrome has profound implications for treatment and prognosis. The major 
dichotomy for the diagnosis of epilepsy is the differentiation between focal epilepsies 
(ie, related to a focal brain dysfunction), which are the most frequent and account for 
approximately 60 to 70% of all cases, and generalized epilepsy syndromes, which represent 
approximately 25 to 30% of all epilepsy syndromes. In about 10% of cases, other specific 
syndromes are classified or the classification remains uncertain.
The classification of epileptic syndromes and seizure types is - and always was - a matter of 
ongoing debate. First published in 1960 and last updated officially in 1981 for seizures and 
1989 for epilepsies (Commission on Classification and Terminology of the ILAE, 1981 and 
1989), these ILAE classifications were based on concepts that, for the most part, predate 
modern technologies and concepts (Engel, 2006; ILAE [http://www.ilae-epilepsy.org]). The 
availability of these modern techniques, like long-term video electroencephalograms (EEG) 
and high-resolution magnetic resonance imaging (MRI), providing much more precise 
knowledge in regard to seizure type classifications and epileptic syndromes, led some 
epilepsy groups and scientists towards introducing competing classification systems (like the 
Cleveland Clinic Epilepsy Classification) and even debating how useful the currently used 
ILAE classification system is at all (Lüders et al, 2006). 
This ongoing debate regarding the classification systems for epilepsies and seizures is also 
reflected within the latest Report of the Commission on Classification and Terminology 
(Classification Task Force) which proposes a thoroughly revised terminology and concept for 
the diagnosis of epilepsy syndromes and also to some extent seizure types (Berg et al, 2010).
Despite this ongoing debate, for the purpose of this study the seizure type classification will 
follow the 1981 ILAE classification of epileptic seizures, which speaks of partial seizures, 
classified as simple partial seizures (no alteration of consciousness), complex partial seizures 
(with alteration of consciousness), and secondarily generalized seizures, and on the other 
hand defines generalized seizure types, referred to as absence seizures (typical and atypical), 
myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. 
Apart from myoclonic seizures, consciousness is almost invariably impaired from the onset 
of the seizure (Commission on Classification and Terminology of the ILAE, 1981).
Likewise, the classification of epilepsy syndromes will be used according to the 1989 
ILAE publication (Commission on Classification and Terminology of the ILAE, 1989).
2.2
Background information regarding product
Brivaracetam is a chemical relative of the AED levetiracetam (LEV) (Keppra®). Like LEV, 
BRV displays a high and selective interaction with a novel brain-specific binding site SV2A 
(synaptic vesicle protein 2A). However, the binding affinity of BRV for SV2A is 
approximately 10-fold higher. This binding site appears to be the major target for its 
pharmacological activity. Unlike LEV, BRV also reduces voltage-dependent sodium currents. 
Brivaracetam also reverses the inhibitory effects of negative allosteric modulators on 
gamma-aminobutyric acid- and glycine-induced currents. Brivaracetam is extensively
metabolized, but seizure protection appears to be associated with the parent compound.
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 14 of 129
Brivaracetam is rapidly and completely absorbed throughout the gastrointestinal tract. The 
extent of BRV absorption is not affected by food. The pharmacokinetics (PK) is 
dose-proportional (at least from 10mg to 600mg). Brivaracetam is weakly bound to plasma 
proteins (≤20%). The volume of distribution is 0.5L/kg, a value that is close to that of total 
body water. The plasma half-life of BRV is approximately 8 hours in young healthy male 
adults. The main metabolic pathway of BRV is by hydrolysis of the acetamide group to the 
corresponding carboxylic acid, while a second pathway is the ω1-hydroxylation mediated by 
cytochrome P450 (CYP)2C19 (with contributions of several other isoenzymes). The
combination of these 2 pathways results in the hydroxyacid terminal metabolite. These 
metabolites are not pharmacologically active. There is no evidence of chiral inversion of 
BRV. Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. 
More than 95% of the dose, with less than 9% as unchanged BRV, is excreted in urine within 
72 hours after dosing. 
Pharmacokinetic studies in elderly subjects and in subjects with renal impairment showed a 
similar PK profile of BRV compared to that in healthy subjects, while the elimination of the 
metabolites was markedly slowed down. A PK study in subjects with hepatic impairment 
showed a 50% increase in exposure to BRV associated with decreased hydroxylation.
Brivaracetam does not impair the efficacy of oral contraceptives containing 
ethinylestradiol 30μg and levonorgestrel 150μg. Brivaracetam does not induce CYP3A4 
using midazolam as a marker probe. Brivaracetam has no interaction on lamotrigine and 
topiramate. Brivaracetam plasma concentration is not increased by gemfibrozil, a selective 
CYP2C8/9 inhibitor, but is increased in a nonclinically relevant manner in Japanese subjects 
possessing defective CYP2C19 mutations. Brivaracetam clearance is doubled by rifampicin, 
a potent CYP inducer.
Trough levels of concomitant AEDs were monitored in all efficacy studies. No significant 
change from Baseline nor dose-related trend was observed for the plasma concentrations of: 
carbamazepine, lamotrigine, LEV, oxcarbazepine metabolite, phenobarbital, phenytoin, 
topiramate, valproate, zonisamide. Carbamazepine epoxide was significantly increased from 
Baseline at all BRV doses greater than 20mg/day, nearly reaching the upper limit of normal 
(3.0μg/mL) at BRV doses of 100 and 150mg/day.
There is increasing research to assess the role of genetic variation on response to medicines, 
including antiepileptics (Goldstein et al, 2007). Preliminary research with BRV has suggested 
a possible role for variants in synaptic vesicle protein (SV2) genes in modulating response to 
the medicine. To explore this observation further and to broaden the pharmacogenetic 
information available for BRV, deoxyribonucleic acid (DNA) sampling is included in the 
study for subjects coming from N01358. 
2.3
Efficacy of BRV in fixed-dose Phase 2/3 studies in POS
Following completion of the Phase 2 studies (N01114 and N01193), clinical results supported 
further development of BRV for the adjunctive treatment of POS. Two adequate and 
well-controlled fixed-dose studies (N01252 and N01253) were conducted to assess BRV 
across a dose range of 5 to 100mg/day. 
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15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 15 of 129
N01253 assessed BRV doses of 5, 20, and 50mg/day and provided statistically significant 
and clinically relevant evidence of the efficacy of BRV 50mg/day. N01252 assessed BRV 
doses of 20, 50, and 100mg/day. Although N01252 was not positive, it provided supporting 
evidence for the efficacy of BRV 100mg/day in subjects with epilepsy.
2.4
Safety of BRV
In Phase 2/3 studies, a favorable safety and tolerability profile has been demonstrated for 
BRV. The discontinuation rate and the discontinuation rate due to treatment-emergent 
adverse events (TEAEs) were low for all studies. The most frequently reported TEAEs were 
headache, somnolence, dizziness, and fatigue. The overall incidence of serious adverse events 
(SAEs) was low. There were no clinically relevant changes in laboratory values, vital signs,
or ECG abnormalities.
For additional details on the safety and efficacy of BRV, please refer to the Investigator’s 
Brochure.
2.5
Study rationale
UCB is developing BRV as an adjunctive antiepileptic treatment in subjects 16 years and 
older suffering from epilepsy. N01379 will give subjects who have completed N01358 or 
N01258 the opportunity to access BRV under the present protocol. N01358 is an adequate 
and well-controlled study to provide additional data confirming the efficacy and safety of 
BRV as an AED in adults (≥16 years) with refractory POS whether or not secondarily 
generalized. N01258 is a multicenter, 4-arm, randomized, parallel-group study evaluating the 
safety and tolerability of adjunctive BRV treatment administered as intravenous (iv) infusion 
or iv bolus in subjects with localization-related or generalized epilepsy from 16 to 70 years 
old.
N01379 will explore the long-term safety and efficacy of BRV in subjects with epilepsy
while providing access to BRV for subjects who may benefit from open-label treatment with 
BRV.
3
STUDY OBJECTIVES
3.1
Primary objective
The primary objective is to evaluate the long-term safety and tolerability of BRV at 
individualized doses up to a maximum of 200mg/day in epilepsy subjects.
3.2
Secondary objective
∀
To evaluate the maintenance of efficacy of BRV over time
3.3
Exploratory objectives
∀
To explore the effects of BRV on subjects’ HRQoL
∀
To explore direct medical resource use
∀
To explore any change in socio-professional status
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 16 of 129
∀
To assess the role of gene variants of SV2 in affecting response to BRV (as part of a 
DNA analysis at the program level)
4
STUDY VARIABLES
4.1
Safety variables
4.1.1
Primary safety variables
∀
Occurrence of a TEAE
∀
Withdrawal due to AE
∀
Occurrence of an SAE
4.1.2
Other safety variables
∀
Laboratory tests (blood chemistry, hematology, urinalysis, endocrinology)
∀
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) and body weight
∀
ECG
∀
Physical and neurological examinations
∀
Change in HADS scores from the Baseline of the previous study to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
4.2
Efficacy variables
4.2.1
Secondary efficacy variables
For subjects with focal-onset epilepsy:
∀
POS (type 1) frequency per 28 days during the Evaluation Period
∀
Percent reduction in POS (type 1) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period
∀
Responder rate in POS (type I) frequency over the Evaluation Period. A responder is 
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline Period 
of the previous study. 
No secondary efficacy variables are defined for subjects with generalized epilepsy.
4.2.2
Other efficacy variables
For subjects with focal-onset epilepsy:
∀
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period
For subjects with generalized epilepsy:
∀
Generalized (type II) seizure days per 28 days during the Evaluation Period
∀
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 17 of 129
∀
Responder rate for generalized (type II) seizure days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure days from the Baseline 
Period of the previous study.
∀
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
∀
Change in QOLIE-31-P scores from Baseline of the previous study to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
4.3
Pharmacoeconomic variables
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
∀
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
visits) during the first 2 years of the Evaluation Period
∀
Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
5
STUDY DESIGN
5.1
Study description
This is a Phase 3, open-label, LTFU, multicenter, noncomparative, and single-arm study. The 
subject population will be adults (≥16 years) with refractory POS whether or not secondarily 
generalized from N01358 and subjects with localization-related or generalized epilepsy from 
N01258. Subjects under 18 years may be included only where legally permitted and ethically 
accepted. Subjects must complete the Treatment Period of N01358 or the Evaluation Period 
of N01258 prior to enrollment into N01379. Upon completion of the Evaluation Period or 
early discontinuation from N01379 there will be a Down-Titration Period followed by a 
Posttreatment Period during which the subject does not receive study drug, or subjects will be 
converted without down-titration to commercial BRV if, when, and where available. 
Alternatively, subjects may transition into another BRV study, or be initiated without 
down-titration into a managed access program, named patient program, compassionate use 
program, or similar type of access program as allowed per country-specific legal and 
regulatory requirements.
Subjects from N01358 will be started on oral BRV at a dose of 150mg/day (2 equally divided 
doses administered twice daily) at study entry and should be maintained at this dose for at 
least 2 weeks unless the subject is unable to tolerate treatment. Subjects from N01258 will be
started at an oral dose of BRV 200mg/day (2 equally divided doses administered twice daily)
and should be maintained at this dose for at least 2 weeks unless the subject is unable to 
tolerate treatment. The BRV dose can be adjusted based on the individual subject’s seizure 
control and tolerability. However, the BRV dose may not exceed 200mg/day during the study
and must always be administered as a symmetrical morning and evening dose.
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 18 of 129
5.1.1
Study duration per subject
Subject recruitment for the study will begin in approximately Q2 2011. For each subject, the 
study will last from study entry until either regulatory approval of BRV has been granted by 
any Health Authority in an indication of adjunctive treatment of POS, until the Sponsor 
decides to close the study; until subjects transition to another BRV study; until a managed 
access program, named patient program, compassionate use program, or similar type of 
access program is established as allowed per country-specific requirement in addition to legal 
and regulatory guidelines; or until BRV development is stopped by the Sponsor.
The following study periods are defined:
∀
Evaluation Period (Visit 1 until the Last Evaluation Period Visit or Early Discontinuation 
Visit [EDV]): Subjects who enroll in N01379 will immediately enter the Evaluation 
Period.
∀
Down-Titration Period (up to 4 weeks)
#
If the subject is discontinuing study drug, the Investigator will first plan an EDV 
followed by the progressive down-titration of study drug. 
#
During the Down-Titration Period, the BRV dose may be decreased in steps of a 
maximum of 50mg/day on a weekly basis. A last down-titration step at 20mg/day for 
1 week should be included prior to the Posttreatment Period.
∀
Posttreatment Period (2 to 4 weeks): After completion of the Down-Titration Period, or
for those subjects who for extenuating circumstances do not complete a Down-Titration 
Period, the subject will be required to enter a Posttreatment Period for a minimum of 
2 weeks and a maximum of 4 weeks, followed by a Final Visit (FV).
∀
The end of the study is defined as the date of the last visit of the last subject in the study.
For subjects who transition to another BRV study or a managed access program or similar 
type of program or who will be converted to commercial BRV if, when, and where available, 
the Down-Titration Period and FV are not applicable.
5.1.2
Planned number of subjects and sites 
It is estimated that approximately 650 to 720 subjects from N01358 will enter the study,
based on the assumption that at least 90% of randomized subjects from N01358 will complete 
N01358 and enroll in N01379. Up to 100 subjects from N01258 may also be eligible for 
enrollment.
It is estimated that 120 sites from N01358 and up to 25 sites from N01258 will participate in 
the study.
5.1.3
Anticipated regions and countries
The regions and countries for enrollment will be the same as in the previous studies, N01358
and N01258. N01358 is planned to be performed in North America (Canada and USA), 
Western Europe, Latin America, Eastern Europe, Asia, and Africa, and N01258 is planned to 
be performed in the USA and Europe, with possible extension to other countries or regions
for both studies. 
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 19 of 129
5.2
Schedule of study assessments
Table 5‒1:
Schedule of study assessments
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
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Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
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5.3
ASSESSMENTS
Written Informed Consent
X
13.1
Written Informed Consent for 
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N01358)
X
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Subject identification card 
dispensing
X
13.2
Verification inclusion/ exclusion 
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X
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Childbearing potential
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General medical and procedures 
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AED history
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 20 of 129
Table 5‒1:
Schedule of study assessments
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
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Discontinuation 
Visit [EDV])
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Visit
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Reference 
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Visit
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V9…
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V8, V10…
V7…
NA
NA
NA
5.3
Month
M0
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M18…
M1, M3, M9, 
M15, M21…
M12…
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5.3
Weight and heightd
X
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10.6.3
Physical examination
Xc
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X
X
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10.6.4
Neurological examination
Xc
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X
X
X
10.6.5
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X
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X
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Recording of seizures
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X
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X
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X
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X
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9.1.4
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Xc
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Xi
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 21 of 129
Table 5‒1:
Schedule of study assessments
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
(or Early 
Discontinuation 
Visit [EDV])
Down-Titration 
Phone Call 
(DTP)a
Final 
Visit
(FV)
Reference 
to Section
Visit
V1
V3, V5, 
V9…
V2, V4, V6, 
V8, V10…
V7…
NA
NA
NA
5.3
Month
M0
M2, M6, 
M18…
M1, M3, M9, 
M15, M21…
M12…
NA
NA
NA
5.3
Blood sampling for the DNA 
analysisj
X
10.5.2
Recording of AEs
Xk
X
X
X
X
X
X
10.1
C-SSRS
X
X
X
X
X
X
10.6.6
Medical procedures
X
X
X
X
X
X
9.1.3
Concomitant AED
Xl
X
X
X
X
X
7.8
Concomitant non-AED
Xl
X
X
X
X
X
7.8
Drug dispensing
X
X
X
X
X
7
Drug return/accountability
X
X
X
X
X
7
End of study statusm
X
X
8.8
AE=adverse event; AED=antiepileptic drug; CRF=Case Report Form; C-SSRS=Columbia-Suicide Severity Rating Scale; DNA=deoxyribonucleic acid; 
DTP=Down-Titration Phone Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final Visit; 
HADS=Hospital Anxiety and Depression Scale; IVRS=interactive voice response system; M=Month; MEV=Minimal Evaluation Visit; NA=not applicable;
QOLIE-31-P=Patient Weighted Quality of Life in Epilepsy Inventory; V=Visit; YEV=Yearly Evaluation Visit
Note: Months and visit numbers are displayed for the first 2 years. The visit schedule described in Section 5.3 will be applied.
Note: At the EV, the IVRS call will be part of the N01358 or N01258 final visit.
a    The Down-Titration Phone Call at the end of the Down-Titration Period is mandatory.
b    General medical and procedures history, AED history, recording of seizures, and epilepsy history will be obtained from the Baseline of N01358 or N01258 
and do not need to be recorded on the CRF for this study.
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 22 of 129
Table 5‒1:
Schedule of study assessments
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
(or Early 
Discontinuation 
Visit [EDV])
Down-Titration 
Phone Call 
(DTP)a
Final 
Visit
(FV)
Reference 
to Section
Visit
V1
V3, V5, 
V9…
V2, V4, V6, 
V8, V10…
V7…
NA
NA
NA
5.3
Month
M0
M2, M6, 
M18…
M1, M3, M9, 
M15, M21…
M12…
NA
NA
NA
5.3
c    The following will be obtained from the last visit of N01358 or N01258 and do not need to be recorded on the CRF for this study: physical and neurological 
examination, vital signs, hospital stays, healthcare provider consultations not foreseen by the protocol, ECG, and laboratory assessments (hematology, blood 
chemistry, and urinalysis).
d    Height will be obtained at Visit 1 in N01358 or N01258.
e    At the FV, an ECG is mandatory, except if the FV follows an EDV where ECG results were normal.
f    QOLIE-31-P and HADS are to be completed at the beginning of the visit by all subjects who are able to complete the assessments on their own. These will be
collected only for the first 2 years.
g    Socio-professional data, hospital stays, and healthcare provider consultations not foreseen by the protocol will be collected for all subjects for the first 2 years. 
h    Laboratory safety assessment includes hematology, blood chemistry, and urinalysis; where applicable (women with childbearing potential), a urine pregnancy 
test will be done. Endocrinology will be assessed at each YEV. In addition, liver function tests as described in Section 10.5.1 will be performed at the MEV in 
M3 and M9. Laboratory assessment is mandatory at the FV, except if the FV follows an EDV where laboratory results were normal. The result of the 
calculated creatinine clearance will be provided by the central laboratory.  
i    Liver function tests are the only laboratory assessments done at the MEV in M3 and M9 (see Section 10.5.1).
j    The DNA analysis is part of N01379 and will be performed only in adult subjects from N01358 after signing an additional Informed Consent form and where 
ethically accepted and authorized by regulatory agencies. Mentally impaired subjects will be excluded from the DNA analysis.
k
Ongoing AEs at the time of subject completion of N01358 or N01258 will be obtained from the database for N01358 or N01258 and should not be recorded 
on the CRF for N01379 unless there is a change in intensity or seriousness. In this event, the AE should be recorded on the CRF for N01379 with the onset 
date corresponding to the date of change in condition.
l    Ongoing medications (AEDs and non-AEDs) at the time of subject completion of N01358 or N01258 will be obtained from the database for N01358 or 
N01258 and should not be recorded on the CRF for N01379 unless there is a change regarding the administration of the medication. In this event, the 
medication should be recorded on the CRF for N01379 with the start date corresponding to the date of change in administration.
m
End of study status will be completed at the FV for subjects having performed an EDV and down-titration of BRV (discontinued subjects) and for subjects 
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UCB
15 May 2015
Clinical Study Protocol
Brivaracetam
N01379
Confidential
Page 23 of 129
Table 5‒1:
Schedule of study assessments
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
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Visit (MEV)
Yearly 
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Last Evaluation 
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Visit
V1
V3, V5, 
V9…
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V7…
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NA
5.3
Month
M0
M2, M6, 
M18…
M1, M3, M9, 
M15, M21…
M12…
NA
NA
NA
5.3
leaving the study at the end of the program (completed subjects). Alternatively, end of study status will be completed at the EDV for subjects who may 
transition into another BRV study, or be initiated without down-titration in a managed access program, named patient program, compassionate use program, 
or similar type of access program as allowed per country-specific legal and regulatory requirements, or for subjects who will be converted without 
down-titration to commercial BRV if, when, and where available.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 24 of 129
5.3
Visit schedule
Visits to the clinical site will be scheduled as follows:
∀
First year:
#
First 3 months: 1 visit every month: Minimal Evaluation Visit (MEV) alternating with 
the Full Evaluation Visit (FEV)
#
Next 9 months: 1 visit every 3 months: FEV alternating with MEV
∀
Second and subsequent years:
#
1 visit every 3 months: MEV alternating with FEV/Yearly Evaluation Visit (YEV)
#
The YEV will be performed every 12 months
A full visit schedule is presented in the following table.
REDACTED COPY 
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or variations thereof. 

UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 25 of 129
Table 5‒2:
Visit schedule
First year follow-up
Month
Visit
Type of visit
M0
V1
EV
M1
V2
MEV
M2
V3
FEV
M3
V4
MEVb
M4
-
-
M5
-
-
M6
V5
FEV
M7
-
-
M8
-
-
M9
V6
MEVb
M10
-
-
M11
-
-
Second year follow-upa
Month
Visit
Type of visit
M12
V7
YEV
M15
V8
MEV
M18
V9
FEV
M21
V10
MEV
EV=Entry Visit; FEV=Full Evaluation Visit; M=month; MEV=Minimal Evaluation Visit; V=Visit; 
YEV=Yearly Evaluation Visit
Note: “-“ denotes that no visit is scheduled in that month.
a    Subsequent years will follow the same visit schedule.
b
Liver function tests will be performed in addition to the assessments described in Section 8.3
5.4
Rationale for study design and selection of dose
In the previous study N01358, subjects will be randomized to an oral dose of 
BRV 100mg/day, BRV 200mg/day, or to matching PBO. In the previous study N01258,
subjects will receive either a 60-second iv bolus or a 15-minute iv infusion at a dose of 
BRV 100mg twice daily (200mg/day). Previous Phase 2/3 clinical studies in POS and 
dose-response modeling suggest that optimal seizure frequency requires BRV doses of 
50 to 100mg/day, with BRV 150mg/day possibly providing some additional benefit. 
Following consultation with regulatory authorities, it was recommended to also explore 
BRV 200mg/day to obtain data on the upper end of the dose response curve in N01358. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 26 of 129
The starting doses in N01379 will be BRV 150mg/day for subjects from N01358 and 
BRV 200mg/day for subjects from N01258. The study entry doses will be taken as 2 equally 
divided oral doses administered twice daily. In Phase 2/3 studies for POS with BRV doses up 
to 150mg/day, the overall discontinuation rate and the discontinuation rate due to TEAEs was 
low and similar to PBO. The most frequently reported TEAEs at BRV doses up to 150mg/day 
were headache, somnolence, dizziness, and fatigue. The BRV dose can be adjusted based on 
the individual subject’s seizure control and/or tolerability after the first 2 weeks, up to a 
maximum dose of BRV 200mg/day.
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. An Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved 
written informed consent signed and dated by the subject or by parent(s) or legally
acceptable representative. The consent form or a specific assent form, where required, 
will be signed and dated by minors. In countries and sites where a DNA analysis is 
accepted, an additional Informed Consent form will have to be signed by subjects coming 
from N01358. Deoxyribonucleic acid analysis will be performed only in adults, and the 
subject can withdraw consent to the use of the sample at any time. Mentally impaired 
subjects will be excluded. In case the consent is withdrawn, the site must request the 
destruction of the sample.
2. Male/female subject from 16 years or older. Subject under 18 years may only be included 
where legally permitted and ethically accepted.
3. Subject completed the Treatment Period of N01358 or the Evaluation Period of N01258. 
4. Subject for whom the Investigator believes a reasonable benefit from the long-term 
administration of BRV may be expected.
5. Female subject without childbearing potential (premenarcheal, postmenopausal for at 
least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are 
eligible. Female subject with childbearing potential are eligible if they use a medically 
accepted contraceptive method. Oral or depot contraceptive treatment with at least 
ethinylestradiol 30μg per intake (or ethinylestradiol 50μg per intake if associated with any 
strong enzyme inducer [eg, carbamazepine, phenobarbital, primidone, phenytoin, 
oxcarbazepine, St. John’s Wort, rifampicin]), monogamous relationship with 
vasectomized partner, or double-barrier contraception are acceptable methods. The 
subject must understand the consequences and potential risks of inadequately protected 
sexual activity, be educated about and understand the proper use of contraceptive 
methods, and undertake to inform the Investigator of any potential change in status. 
Abstinence will be considered as an acceptable method of contraception if the 
Investigator can document that the subject agrees to be compliant.
6. Subject/legally acceptable representative considered as reliable and capable of adhering to 
the protocol (eg, able to understand and complete diaries and questionnaires), visit 
schedule, or medication intake according to the judgment of the Investigator.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 27 of 129
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject has developed hypersensitivity to any components of the investigational 
medicinal product (IMP) or comparative drugs as stated in this protocol during the course 
of the core studies
2. Severe medical, neurological, or psychiatric disorders, or laboratory values which may 
have an impact on the safety of the subject
3. Poor compliance with the visit schedule or medication intake in the previous BRV studies
4. Planned participation in any other clinical study of another investigational drug or device 
during this study
5. Pregnant or lactating woman
6. Any medical condition which, in the Investigator’s opinion, warrants exclusion 
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the Entry Visit
6.3
Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Subjects who have signed an additional Informed Consent form for DNA analysis may 
withdraw their consent to the DNA analysis at any time and may continue their participation
in the N01379 study.
Investigators should attempt to obtain information on subjects, in case of withdrawal or 
discontinuation. 
For subjects considered as lost to follow-up, the Investigator should make an effort (at least 
1 phone call and 1 written message to the subject), and document his/her effort (date and 
summary of the phone call and copy of the written message in the source documents) to 
complete the final evaluation.
The Investigator should make an effort, and document his/her effort, to complete the EDV
and preferably also the FV. 
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 Case 
Report Form (CRF) must document the primary reason for withdrawal or discontinuation.
Investigators should contact the Medical Monitor whenever possible to discuss the 
withdrawal in advance.
When possible, the study medication will be progressively down-titrated in the case of 
discontinuation. During the Down-Titration Period, the dose may be decreased in steps of a 
maximum of 50mg/day on a weekly basis. A last down-titration step at 20mg/day for 1 week 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 28 of 129
will be included prior to the Posttreatment Period. The Down-Titration Period will be 
followed by a Posttreatment Period of a minimum of 2 weeks and a maximum of 4 weeks.
Stopping rules and discontinuation criteria for individual subjects may be, for example:
∀
Withdrawal for safety reasons by the Investigator: occurrence of status epilepticus, 
appearance of a more severe type of seizure, significant increase in liver enzymes, and 
any other significant safety reason, or if the subject develops an illness that would 
interfere with his/her continued participation.
∀
Subject and/or Investigator does not think that the investigational drug is effective (ie, 
lack or loss of efficacy).
∀
Lost to follow-up.
∀
Withdrawal of consent for personal reasons not related to AEs or lack/loss of efficacy.
∀
Other reason that has to be specified in the CRF.
∀
There is confirmation of a pregnancy during the study, as evidenced by a positive 
pregnancy test.
∀
The Sponsor or a regulatory agency requests withdrawal of the subject.
∀
Withdrawal criterion for subjects who completed a C-SSRS assessment at the Entry Visit:
#
Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or 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.
∀
Withdrawal criteria for already enrolled subjects who did not complete a C-SSRS 
assessment at the Entry Visit:
#
Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must withdraw 
the subject from the study and immediately refer the subject to a Mental Healthcare 
Professional.
#
Subject had active suicidal ideation prior to study entry or since study start as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
immediately refer the subject to a Mental Healthcare Professional and use clinical 
judgment as to whether to withdraw the subject from the study.
#
Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or 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.
After the decision of the subject’s discontinuation, the Investigator will provide the subject 
with information about available alternative treatments.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 29 of 129
7
STUDY TREATMENTS
7.1
Description of investigational medicinal product(s)
-coated tablets of BRV 10mg, BRV 25mg, and BRV 50mg will be used in this 
study. The tablets of BRV will be packaged in bottles. 
The BRV 10mg dose (20mg/day) will be used only for down-titration.
7.2
Treatments to be administered
Subjects from N01358 will be started on a BRV dose of 150mg/day (2 equally divided doses 
administered twice daily) at study entry and should be maintained at this dose for at least 
2 weeks, unless the subject is not able to tolerate treatment. Subjects from N01258 will be 
started at a BRV dose of 200mg/day (2 equally divided doses administered twice daily) and 
should be maintained at this dose for at least 2 weeks, unless the subject is not able to tolerate 
treatment. The BRV dose can subsequently be adjusted based on the individual subject’s 
seizure control and/or tolerability. However, the BRV dose should not exceed 200mg/day 
during the study. 
The first intake of study medication should occur in the evening of the day of the Entry 
Visit (EV). Subjects should take tablets according to instructions provided by the 
Investigator.
During the Down-Titration Period, the BRV dose may be decreased in steps of a maximum of 
50mg/day on a weekly basis. A last down-titration step at 20mg/day for 1 week should be 
included prior to the Posttreatment Period.
7.3
Packaging
Oral tablets of BRV 25mg and 50mg will be packaged in high density polyethylene bottles of 
200 tablets, and the 10mg tablets will be packaged in bottles containing 38 tablets. Each 
container will have a unique, preprinted identification number. 
The Investigator will inform each subject on how to take the drug and that an excess of drug 
is present in the bottle.
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Conference 
on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good 
Manufacturing Practice and will include any locally required statements. If necessary, labels 
will be translated into the local language.
The label will be adapted to the size of the investigational product package.
7.5
Handling and storage requirements
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the 
site. Investigational medicinal product stored by the Investigator is to be kept in a secured 
area with limited access. Storage conditions will be specified on the labels.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 30 of 129
Appropriate storage conditions must be ensured either by controlled room temperature, or by 
completing a temperature log in accordance with local requirements on a regular basis (eg, 
once a week), showing minimum and maximum temperatures reached over the time interval.
In case an out-of-range temperature is noted, it must be immediately communicated to the 
Clinical Project Manager (or designee) before further use of the IMP.
The Clinical Project Manager (or designee) will transmit the out-of-range temperature (copy 
of the temperature log, duration of the out-of-range temperature, if available) to the Clinical 
Supply Coordinator. Based on discussion with Quality Assurance, the Clinical Supply 
Coordinator will then provide the Clinical Project Manager (or designee) with instructions for 
the site regarding use of the IMP.
The Investigator (or designee) will instruct the subject to store the IMP following the 
instructions on the label.
7.6
Drug accountability 
A Drug Accountability form will be provided and kept up-to-date to record IMP dispensing 
and return information on a by-subject basis and will serve as source documentation during 
the course of the study. The study medication disposition records, such as shipping, 
dispensing, and return records, and inventory logs, must be kept at the site, preferably in the 
pharmacy. Details of any IMP lost (due to breakage or wastage), not used, disposed of at the 
study site, or returned to the Sponsor or designee must also be recorded on the appropriate 
forms. All supplies and pharmacy documentation must be made available throughout the 
study for UCB (or designee) to review.
The Drug Accountability form should include at least:
∀
Number of tablets dispensed to and returned by each subject, with the visit number, kit 
number, and subject’s number
∀
Initials of the person who actually dispensed and/or received returned study medication
∀
Dates of the above
∀
Explanation of noncompliance
Investigational medicinal product intended for the study cannot be used for any other purpose 
than that described in this protocol
The Investigator may assign some of the Investigator’s duties for drug accountability at the 
study site to an appropriate pharmacist/designee.
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed.
The Investigator must ensure that the IMP is used only in accordance with the protocol.
Periodically, and/or after completion of the study, all used (including empty boxes and 
bottles) and unused visit boxes and bottles must be reconciled and returned (preferably in 
their original package) to the Sponsor or its representative.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 31 of 129
7.7
Procedures for monitoring subject compliance
The IMP (kits) will be supplied to the subjects at EV, FEV, MEV, YEV, Last Evaluation 
Period Visit, or EDV in case of early discontinuation. 
The Investigator will instruct the subject to bring back at each visit, the kits with all original 
bottles (even empty) dispensed at the previous visit and containing all the remaining tablets 
of study medication.
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.
Compliance with investigational product is defined as investigational product consumption 
by the subject within 80% and 120% of the prescribed dosage. If a subject is found to be 
persistently noncompliant (<80% or >120%), the Sponsor in conjunction with the 
Investigator will make a decision as to whether the subject should be withdrawn from the 
study.
The number of tablets dispensed and returned must be recorded in the source document.
7.8
Concomitant medication(s)/treatment(s)
For any treatment other than the investigational product, including over-the-counter products, 
an accurate record must be kept in the clinic chart (source documentation) and in the CRF.
This record should include the name of the drug (preferably the brand name), the dose, the 
date(s) of administration, and the indication for use.
7.8.1
Permitted concomitant treatments (medications and therapies)
All concomitant AEDs except the ones specified in Section 7.8.2 are permitted during the 
study.
Benzodiazepines are allowed. If taken more than once a week, for any indication, a 
benzodiazepine will be considered as an AED. Each intake for PRN use must be listed 
individually in the CRF, either on the concomitant AED medication page or on the 
concomitant non-AED medication page, according to the indication.
Vagal nerve stimulation is allowed. Vagal nerve stimulation will be counted as a concomitant 
AED. Vagal nerve stimulation implantation must be recorded on the medical and procedures 
history CRF page. 
7.8.2
Prohibited concomitant treatments (medications and therapies)
The following concomitant AED medications are prohibited during the study:
∀
Felbamate (except if on stable dose during previous studies N01358 and N01258)
∀
Vigabatrin
7.9
Blinding
This is an open-label LTFU study of the preceding double-blind study N01358 and of the 
open-label randomized study N01258.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 32 of 129
7.10
Randomization and numbering of subjects 
Since N01379 is an open-label LTFU study for N01358 and N01258, subjects will not be
randomized to any treatment groups. Subjects from N01358 will start with a dose of 
BRV 150mg/day and will be maintained on that dose for at least 2 weeks, unless they are 
unable to tolerate the dose. Subjects from N01258 will start at a dose of BRV 200mg/day and 
should be maintained on that dose for at least 2 weeks, unless they are unable to tolerate the 
dose.
Subjects will continue with the 5-digit subject numbers assigned by the interactive voice 
response system (IVRS) in the preceding studies.
8
STUDY PROCEDURES BY VISIT 
Prior to any study activities, the subject or legal representative will be asked to read and sign 
an Informed Consent form that has been approved by an IRB/IEC and which complies with 
regulatory requirements. Subjects from N01358 agreeing to the DNA analysis will have to 
sign an additional Informed Consent form. The subject or legal representative will be given 
adequate time to consider any information concerning the study, given to them by the 
Investigator or designee. As part of the informed consent procedure, the subject or legal 
representative will be given the opportunity to ask the Investigator any questions regarding 
potential risks and benefits of participation in the study. Additionally, if applicable (according 
to the subject’s age and local requirements), the subject will sign an IRB/IEC assent form.
8.1
Entry Visit
∀
Written Informed Consent
∀
Additional written Informed Consent for subjects agreeing to DNA analysis
∀
Subject identification card dispensing
∀
Verification inclusion/exclusion criteria
∀
Demographic data
∀
Childbearing potential
∀
Weight
∀
IVRS call
∀
Daily record card (DRC) dispensed
∀
Medical procedures
∀
Blood sampling for the DNA analysis for consenting subjects coming from N01358. The 
DNA analysis will be performed in adult subjects where ethically accepted and authorized 
by regulatory agencies.
∀
Concomitant AED
∀
Concomitant non-AED
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 33 of 129
Ongoing medications (AEDs and non-AEDs) at the time of subject completion of N01358 or 
N01258 will be obtained from the database for N01358 or N01258 and should not be 
recorded on the CRF for N01379 unless there is a change regarding the administration of the 
medication. In this event, the medication should be recorded on the CRF for N01379 with the 
start date corresponding to the date of change in administration.
∀
Recording of AEs
Ongoing AEs at the time of subject completion of N01358 or N01258 will be obtained from 
the database for N01358 or N01258 and should not be recorded on the CRF for N01379 
unless there is a change in intensity or seriousness. In this event, the AE should be recorded 
on the CRF for N01379 with the onset date corresponding to the date of change in condition.
∀
Drug dispensing
∀
Appointment for the next visit according to the schedule described in Section 5.3
The following data will be obtained from the Baseline of N01358 or N01258 and do not need 
to be recorded on the CRF for this study.
∀
General medical and procedures history
∀
AED history 
∀
Recording of seizures
∀
Epilepsy history
The following data will be obtained from the last visit of N01358 or N01258 and do not need 
to be recorded on the CRF for this study.
∀
Vital signs
∀
Neurological examination
∀
Physical examination
∀
ECG
∀
Laboratory safety assessments: hematology, blood chemistry, urinalysis, and urine
pregnancy test (if applicable)
∀
Hospital stays
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol
Height will be obtained from Visit 1 in N01358 or N01258.
8.2
Full Evaluation Visit
∀
QOLIE-31-P (for the first 2 years)
∀
HADS (for the first 2 years)
∀
Vital signs
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 34 of 129
∀
Weight
∀
Physical examination
∀
Neurological examination
∀
ECG
∀
IVRS call
∀
DRC dispensed
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (for the first 2 years)
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol (for the first 2 years)
∀
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8.3
Minimal Evaluation Visit
∀
Vital signs
∀
IVRS call
∀
DRC dispensed
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (for the first 2 years)
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol (for the first 2 years)
∀
Liver function tests will be performed in Month 3 (V4) and Month 9 (V6) as described in 
Section 10.5.1
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 35 of 129
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing
∀
Drug return/accountability
∀
Appointment for the next visit according to the schedule described in Section 5.3
8.4
Yearly Evaluation Visit
∀
QOLIE-31-P (for the first 2 years)
∀
HADS (for the first 2 years)
∀
Vital signs
∀
Weight
∀
Physical examination
∀
Neurological examination
∀
ECG
∀
IVRS call
∀
DRC dispensed
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (for the first 2 years)
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol (for the first 2 years)
∀
Socio-professional data (for the first 2 years)
∀
Laboratory safety assessments, including thyroid-stimulating hormone (TSH)
assessments: hematology, blood chemistry, urinalysis, and urine pregnancy test (if 
applicable)
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 36 of 129
∀
Drug return/accountability
∀
Appointment for the next visit according to the schedule described in Section 5.3
8.5
Unscheduled Visit
At any time, the subject may have an Unscheduled Visit (UV) if the Investigator or the 
subject and/or the legal representative consider it necessary. All information, including the 
reason for the UV, should be recorded in the appropriate sections of the CRF.
∀
Vital signs
∀
Recording of AEs
∀
Suicidality assessment (C-SSRS)
#
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.
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
8.6
Last Evaluation Period Visit or Early Discontinuation Visit
For subjects who transition to another BRV study or a managed access program or similar 
type of program or who convert to commercial BRV (if, when, and where available), the 
EDV will need to be completed; however, down-titration and FV are not applicable.
∀
QOLIE-31-P (if the EDV occurs within the first 2 years)
∀
HADS (if the EDV occurs within the first 2 years)
∀
Vital signs
∀
Weight
∀
Physical examination
∀
Neurological examination
∀
ECG
∀
IVRS call
∀
DRC dispensed (if applicable; DRC not dispensed if subject will not down-titrate)
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (if the EDV occurs within the first 2 years)
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 37 of 129
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol (if the EDV occurs within
the first 2 years)
∀
Socio-professional data (if the EDV occurs within the first 2 years)
∀
Laboratory safety assessments: hematology, blood chemistry, urinalysis, and urine
pregnancy test (if applicable)
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing (if applicable; drug not dispensed if subject will not down-titrate) 
∀
Drug return/accountability
∀
End of study status (if the subject will not down-titrate)
8.7
Down-Titration Phone Call
∀
Recording of AEs
The Down-Titration Phone Call at the end of the Down-Titration Period is mandatory.
Down-titration is not applicable to subjects who transition to another BRV study or a 
managed access program or similar type of program or who convert to commercial BRV (if, 
when, and where available).  
8.8
Final Visit
∀
Vital signs
∀
Weight
∀
Physical examination
∀
Neurological examination
∀
ECG (mandatory, except if the FV follows an EDV where ECG results were normal)
∀
IVRS call
∀
DRC retrieved
∀
Recording of seizures
∀
Laboratory safety assessments (mandatory, except if the FV follows an EDV where 
laboratory results were normal): hematology, blood chemistry, urinalysis, and urine
pregnancy test (if applicable)
∀
Recording of AEs
∀
Suicidality assessment (C-SSRS)
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 38 of 129
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug return/accountability
∀
End of study status
The FV is not applicable to subjects who transition to another BRV study or a managed 
access program or similar type of program or who convert to commercial BRV (if, when, and 
where available).
9
ASSESSMENT OF EFFICACY 
Efficacy variables will be assessed using the seizure count information recorded on the DRC. 
At each visit, the subject will receive a DRC, to be filled in on days on which a seizure 
occurs, and to be returned at the next visit. No DRC will be dispensed at the UV or the FV.
The date and the number (where possible) of epileptic seizures will be recorded on the DRC, 
as well as the type of seizure (according to individual description of seizures), occurrence of 
clusters, intake of concomitant AEDs, undesirable events with start and end dates, healthcare
provider consultations not foreseen per protocol, and changes in concomitant medication, if 
applicable.
The written information will be discussed with the subject 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 on the CRF; 
he/she will also confirm the presence of AEs (if applicable). The concomitant medication 
changes, healthcare provider consultations not foreseen per protocol, and AEs will be 
reported by the Investigator on the specific pages of the CRF.
The DRC will be considered as source documentation. The subject should be educated to 
complete the DRC on all days with seizures (eg, when taking evening tablets). Substantial 
noncompliance with diary completion (seizures recording) may result in subject 
discontinuation from the study at any time by the Investigator or the Sponsor.
9.1
Additional efficacy and pharmacoeconomic assessments
9.1.1
QOLIE-31-P scores
The QOLIE-31-P - Version 2.0 (see Section 16.1) will be used to evaluate the HRQoL of 
study subjects (Cramer and Van Hammée, 2003).
The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument (Cramer et al, 1998) 
that includes 30 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), social function (5 items), and a health 
status item. The subscale scores, the total score, and the health status item score are 
calculated according to the scoring algorithm defined by the author, with scores ranging from 
0 to 100 and higher scores indicating better function. In addition to these 31 items, the 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 39 of 129
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 by subjects who 
are able to complete the assessments on their own, during the first 2 years at the FEV, YEV, 
Last Evaluation Period Visit, and EDV.
9.1.2
Socio-professional data 
Socio-professional data, such as highest level of education, current professional status, 
housing status, regular assistance, and ability to drive, will be collected at the YEV, Last 
Evaluation Period Visit, and EDV during the first 2 years.
9.1.3
Medical procedures
Data on medical procedures (surgery, therapeutic and/or diagnostic, hospitalizations) 
undertaken during the study will be collected and recorded in the CRF. Electrocardiograms 
specific to this study will not be recorded on the medical procedures page of the CRF, but in 
the modules specifically designed for this purpose. Medical procedures will be recorded at
the EV, FEV, MEV, YEV, Last Evaluation Period Visit, EDV, and FV during the entire 
study, but only the first 2 years of recording will be included in the outcome evaluation. 
9.1.4
Healthcare provider consultations not foreseen by the protocol
At the FEV, MEV, YEV, Last Evaluation Period Visit, and EDV, healthcare provider 
consultations not foreseen by the protocol will be recorded in the CRF. It will include 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. At the EV, data will be obtained from the last visit of the previous study,
N01358 or N01258, and do not need to be recorded on the CRF for this study. Healthcare 
provider consultations not foreseen by the protocol will be recorded for the first 2 years.
9.1.5
Hospital stays
At the FEV, MEV, YEV, Last Evaluation Period Visit, and EDV, data on hospital stays will 
be collected in the CRF. It will include the reason leading to the hospitalization, the 
admission ward, transfers, and length of stay. At the EV, data will be obtained from the last 
visit of the previous study, N01358 or N01258, and do not need to be recorded on the CRF
for this study. Hospital stays will be recorded for the first 2 years.
10
ASSESSMENT OF SAFETY
10.1
Adverse events
10.1.1
Definition of adverse event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 40 of 129
In order to ensure complete safety data collection, all AEs occurring during the study (ie, 
after signing the Informed Consent form), including any pretreatment and posttreatment 
periods required by the protocol, must be reported in the CRF even if no investigational 
product was taken but specific study procedures were conducted. This includes all AEs not 
present prior to the initial visit and all AEs which recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the investigational product is being 
studied should be recorded as AEs only if their nature changes considerably or their 
frequency or intensity increases in a clinically significant manner as compared to the clinical 
profile known to the Investigator from the subject’s history or the Baseline Period.
10.1.2
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.
10.1.3
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 CRF 
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 CRF (including judgment of relationship to 
study medication) are described in the CRF Completion Guidelines.
10.1.4
Follow-up on adverse events
An AE should be followed until it has resolved, has a stable sequelae, the Investigator
determines that it is no longer clinically significant, or the subject is lost to follow-up. 
If an AE is still ongoing at the end of the study for a subject, follow-up should be provided 
until resolution/stable level of sequelae, 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 their IMP. 
10.1.5
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported 
with:
∀
The outcome date of the first AE that is not related to the natural course of the disease 
being the same as the start date of the repeated AE, and the outcome of “worsening” 
∀
The AE verbatim term being the same for the first and repeated AE, so that the repeated 
AE can be easily identified as the worsening of the first one 
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 41 of 129
10.1.6
Pregnancy
Should a subject become pregnant after the first intake of any IMP, UCB’s Patient Safety 
(PS) department should be informed immediately. The subject should be withdrawn from the
study as soon as pregnancy is known and the following should be completed:
∀
The subject should return for an EDV.
∀
The subject should immediately stop the intake of the IMP or be down-titrated as 
instructed at the EDV. 
∀
A Safety Follow-Up Visit should be scheduled 2 weeks after the subject has discontinued 
their IMP.
The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, 
UCB will ask the Investigator or designee to contact the subject and his partner to request 
consent via the Partner Pregnancy Consent form. If the partner agrees to provide additional 
information, the Pregnancy Report and Outcome form will be forwarded to the subject’s 
partner for completion.
Any 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. The health of the child may be followed 
for 12 months after birth for any significant medical issues.
A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or 
anomaly/birth defect of the child. Those SAEs must be additionally reported using the 
Investigator SAE Report form.
10.1.7
Overdose of investigational medicinal product
Excessive dosing (2 times of maximum dose beyond that is prescribed in the protocol and 
including overdose) should be recorded in the study drug dosing module of the CRF. Any 
SAE or nonserious AE associated with excessive dosing must be followed as any other 
serious or nonserious AE. These events may be symptomatic, in that the excessive dosing 
results in clinical signs and symptoms, or the excessive intake may itself be a symptom.
10.1.8
Safety signal detection
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible.
10.2
Serious adverse events
10.2.1
Definition of serious adverse event
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 42 of 129
∀
Death
∀
Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred
in a more severe form.)
∀
Significant or persistent disability/incapacity
∀
Congenital anomaly/birth defect (including that occurring in a fetus)
∀
Important medical event that, based upon appropriate medical judgment, may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of 
the other outcomes listed in the definition of serious
(Important medical events may include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.)
∀
Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if released on the same day, meets the criteria for 
the initial inpatient hospitalization. An emergency room visit that results in admission to 
the hospital would also qualify for the initial inpatient hospitalization criteria. However, 
emergency room visits that do not result in admission to the hospital would not qualify 
for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or 
manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For 
example, if a subject has a condition recorded on his/her medical history and later has a 
preplanned surgery for this condition, it is not appropriate to record the surgery or 
hospitalization as an SAE since there is no AE upon which to assess the serious criterion. 
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.)
10.2.2
Procedures for reporting serious adverse events
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information 
by the site (see contact details for SAE reporting listed in the Serious Adverse Event 
Reporting section at the front of the protocol). The Investigator must forward to UCB (or its 
representative) a duly completed Investigator SAE Report form provided by UCB, even if the 
data are incomplete, or if it is obvious that more data will be needed in order to draw any 
conclusions. Information recorded on this form will be entered into the global safety 
database.
An Investigator SAE Report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English.
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 43 of 129
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 
investigational product), up to 30 days from the end of the study for each subject, and to also 
inform participating subjects of the need to inform the Investigator of any SAE within this 
period. Serious adverse events that the Investigator thinks may be associated with the 
investigational product must be reported to UCB regardless of the time between the event and 
the end of the study.
Upon receipt of the SAE form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure.
10.2.3
Follow-up of serious adverse events
An SAE should be followed until it has resolved, has a stable sequelae, the Investigator
determines that it is no longer clinically significant, or the subject is lost to follow-up. 
Information on SAEs obtained after clinical database lock will be captured through the PS
database without limitation of time.
10.3
Immediate reporting of adverse events
The following AEs must be reported immediately:
∀
SAE: AE that the Investigator classifies as serious by the above definitions regardless of 
causality
∀
Suspected transmission of an infectious agent via a medicinal product
10.4
Anticipated serious adverse events
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure: convulsion. This original list will remain in effect for the duration of the protocol. 
The list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 10.2.2.
10.5
Laboratory measurements
10.5.1
Safety laboratory assessments
Laboratory assessments (including hematology, blood chemistry, endocrinology, and 
urinalysis) 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.
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 44 of 129
The total blood volume drawn for clinical laboratory assessments will be a maximum of 
11mL per sampling, which includes 3mL for hematology and 8mL for blood chemistry. In 
addition, a 10mL blood sample for the DNA analysis will be collected at the EV in 
consenting adult subjects from N01358.
The subject must be preferably fasting, but study medication intake must not be delayed.  
The following laboratory assessments will be conducted:
Hematology
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aminotransferase (serum glutamic oxaloacetic transaminase); β-hCG=beta-human chorionic gonadotropin; 
GGT=gamma-glutamyltransferase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; MEV=Minimal Evaluation Visit; RBC=red 
blood cells; TSH=thyroid-stimulating hormone; WBC=white blood cells; YEV=Yearly Evaluation Visit
a    Thyroid-stimulating hormone will be assessed at each YEV.
b    Including bacteria, cells, casts, and crystals will be performed for all samples.
c    Liver function tests will be assessed at MEVs (Visit 4 and Visit 6) during the first year in addition to the 
full laboratory assessments described in Section 8.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 45 of 129
The creatinine clearance (Cr Cl) will be calculated by the Cockroft’s formula:
∀
Male: Cr Cl mL/min=[(140-age) x body weight] / [72 x serum creatinine (mg/dL)]
∀
Female: Cr Cl mL/min=([(140-age) x body weight] / [72 x serum creatinine (mg/dL)]) x 
0.85
The result of the calculated creatinine clearance will be provided by the central laboratory.
Urine pregnancy tests should be used at any time during the study if a pregnancy is 
suspected.
Laboratory safety assessments at the EV will be taken from the last visit of N01358 or 
N01258 and do not need to be recorded on the CRF. Thereafter, laboratory safety 
assessments will be performed at the FEV, YEV, Last Evaluation Period Visit, and EDV. In 
addition, liver function tests will be performed at MEVs (Visit 4 and Visit 6) during the first 
year. Endocrinology (TSH) measurements will be performed at YEVs only. Laboratory 
assessments will also be mandatory at the FV, except if the FV follows an EDV where 
laboratory results were normal.
Results for hematology, blood chemistry, urinalysis, endocrinology, and pregnancy tests will 
be provided by fax to the Investigator within 72 hours after sample receipt. Results will be 
reported by the central laboratory to the Investigator as exact values, with a flag to those 
values that are outside the therapeutic range. 
10.5.2
DNA analysis
For subjects coming from N01358, a blood sample for DNA analysis will be collected at the 
EV in order to explore a possible correlation between the SV2 gene variations and the 
subject’s response to BRV. Blood samples for DNA analysis will be collected only in adults 
where ethically accepted and authorized by legal authorities. The DNA analysis will be done 
in a separate report at the program level.
Samples will be split into 2 aliquots and will be initially stored at the central laboratory and 
will then be shipped to the genotyping facility for DNA extraction and genotyping. Samples 
will be stored at -20°C for a period of up to 20 years. 
10.6
Other safety measurements
10.6.1
Electrocardiogram
A standard 12-lead ECG will be performed at the FEV, YEV, Last Evaluation Period Visit, 
EDV, and the FV. At the EV, data will be obtained from the last visit of the previous study 
and should not be recorded in the CRF. At the FV, an ECG is mandatory, except if the FV 
follows an EDV where ECG results were normal. The Investigator will determine whether 
the results of the ECG are normal or abnormal and assess the clinical significance of any 
abnormalities.
The original ECG tracing will be signed or initialed and dated by the Investigator and 
retained as part of the source data. Copies of all ECG tracings will be retrieved for all 
subjects presenting treatment-emergent clinically significant abnormalities during the study.
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 46 of 129
10.6.2
Vital signs
At each visit, supine or sitting pulse rate and blood pressure after 5 minutes rest will be 
measured. At the EV, data will be obtained from the last visit of the previous study and 
should not be recorded in the CRF.
10.6.3
Body weight and height
Body weight (subject wearing light clothing without shoes and rounded to the nearest 
kilogram or pound) will be measured at the EV, FEV, YEV, Last Evaluation Period Visit, 
EDV, and FV. Height will be obtained from Visit 1 in N01358 or N01258. 
10.6.4
Physical examination
A standard physical examination will be performed at the FEV, YEV, Last Evaluation Period 
Visit, EDV, and FV. At the EV, data will be obtained from the last visit of the previous study 
and should not be recorded in the CRF. Clinically significant new or worsened abnormalities 
will have to be reported as AEs.
10.6.5
Neurological examination
A standard neurological examination will be performed at the FEV, YEV, Last Evaluation 
Period Visit, EDV, and FV. At the EV, data will be obtained from the last visit of the 
previous study and should not be recorded in the CRF. Clinically significant new or worsened 
abnormalities will have to be reported as AEs.
10.6.6
Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS. This scale will be 
used for screening as well as to assess suicidal ideation and behavior that may occur during 
the study. The C-SSRS will be completed according to the tabular schedule of study 
procedures, Section 5.2.
10.6.7
HADS scores
The HADS (see Section 16.2) will be used to evaluate anxiety and depression/depressed 
mood of study subjects (Zigmond and Snaith, 1983). The HADS is an instrument that
assesses the presence and severity of anxiety and depressed mood. It consists of 14 items that 
are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension (anxiety, 
depression) is calculated as recommended by the authors, ranging from 0 to 21 with higher 
scores indicating higher depression/anxiety. The HADS will be completed by subjects who 
are able to complete the assessments on their own, during the first 2 years at the FEV, YEV, 
Last Evaluation Period Visit, and EDV.
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 
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 47 of 129
Clinical Project Manager of the sponsor within 24 hours and follow any local regulatory 
requirements. 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 appropriate regulatory 
authorities, if applicable, prior to being implemented.
The Investigator/institution should conduct the study in compliance with the protocol agreed 
to by the Sponsor and, if applicable, by the appropriate regulatory authority(ies) and which 
has been approved by the IRB/IEC. The Investigator/institution and the Sponsor should sign 
the protocol to confirm agreement.
In exceptional circumstances, subject-specific deviations from the protocol may occur. All 
deviations should be recorded on an ongoing basis to allow regular assessment for the need of 
an amendment. Protocol deviations could invalidate the insurance coverage. 
Any protocol deviation will be documented and explained by the Investigator or the person 
designated by the Investigator and will be included in the final Clinical Study Report.
11.2
Monitoring
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring Standard 
Operating Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, 
and to ensure that study initiation, conduct, and closure are adequate. Monitoring of the study 
may be delegated by UCB to a contract research organization (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 CRFs 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 CRFs, 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). Photocopies of CRFs are not considered acceptable 
source documents. 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 CRF and will therefore be considered as source data:
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 48 of 129
∀
Healthcare provider consultations not foreseen by the protocol
∀
Socio-professional data
Original laboratory results and ECG reports will be inserted in the CRF and are also to be 
considered as source data. Original QOLIE-31-P and HADS questionnaires will be retrieved. 
The site will keep a copy in the CRF and this copy will considered as source data.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and 
dated by the Investigator and become a permanent part of the subject’s source documents. 
The Investigator will authorize the monitor to compare the content of the printout and the 
data stored in the computer to ensure all data are consistent.
Electronic data records such as Holter monitor records or EEG records must be saved and 
stored as instructed by UCB (or designee).
For subjects receiving investigational product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study-related identifiers (such as treatment number, CRF number, or similar), they should 
mention the subject’s participation in the study and identification of that study (study title or 
number), they should record the obtaining of consent (date of consent), the exposure to 
investigational product, the subject’s medical history, the concomitant medication treatments 
and dates (including contraceptive treatment), AEs and SAEs, and the 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, recordings from automated instruments, 
tracings [ECG], x-ray films, laboratory notes). All data reported on the CRF should be 
supported by source documents, unless otherwise specified in Section 11.2.1.
Information recorded in the CRF must be consistent with entries in the source documents. 
The monitor will perform 100% SDV.
11.3
Data handling
11.3.1
Case Report Form completion
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in 
the CRFs and in all required reports. 
Any change or correction to the CRF should be dated, initialed, and explained (if necessary) 
and should not obscure the original entry. Use of correction fluid is not permitted.
Corrections made after the Investigator’s review and signature of the completed CRF will be 
resigned and dated by the Investigator.
The Investigator should maintain a list of personnel authorized to enter data into the CRF. 
Detailed instructions will be provided in the CRF Completion Guidelines.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 49 of 129
11.3.2
Database entry and reconciliation
Case Report Forms/external electronic data will be entered/loaded in a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning 
checks will be used in addition to manual review to check for discrepancies and to ensure 
consistency of the data. Case Report Form data are entered into the clinical database using 
independent, double-data entry, with the exception of comment fields, which are verified by a 
second person. 
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.
11.3.3
Subject Enrollment log/Subject Identification Code list
The subject’s enrollment will be recorded in the Subject Enrollment Log. The Investigator 
will keep a Subject Identification Code list. This list remains with the Investigator and is used 
for unambiguous identification of each subject. The subject’s consent and enrollment in the 
study must be recorded in the subject’s medical record. These data should identify the study 
and document the dates of the subject’s participation.
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 investigational products and other material in accordance with 
UCB procedures for the study.
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator, as appropriate:
∀
Return of all study data to UCB or its representatives while maintaining original source 
documents.
∀
Data clarification and/or resolution.
∀
Accountability, reconciliation, and arrangements for used and unused investigational 
products.
∀
Review of site study records for completeness.
∀
Discussion/reminder on archiving responsibilities.
∀
Discussion of IRB/IEC requirements for study termination.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 50 of 129
∀
Arrangements for unused CRFs, laboratory supplies, and any other study-related supplies.
11.5
Archiving and data retention
The Investigator will maintain adequate records for the study including CRFs, 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 investigational product. 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 and inspections by 
domestic or foreign regulatory authorities, after reasonable notice.
The main purposes of an audit or inspection are to confirm that the rights and well-being of 
the subjects enrolled have been protected, that enrolled subjects (ie, signing consent and 
undergoing study procedures) are appropriate for the study, and that all data relevant for the 
evaluation of the IMP have been processed and reported in compliance with the planned 
arrangements, the protocol, investigational site, and IRB/IEC SOPs, ICH/GCP, and 
applicable regulatory requirements.
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will 
immediately inform UCB (or designee).
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 is presented below and will be described in more detail in 
the Statistical Analysis Plan.
12.1
Definition of analysis populations
Efficacy Populations will consist of all subjects who took at least 1 dose of study medication 
and have at least 1 seizure diary day during the Evaluation Period. Separate Efficacy 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 51 of 129
Populations will be defined for subjects with focal epilepsy and subjects with generalized 
epilepsy.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
12.2
General statistical considerations
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 
75th percentile, 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 for all subjects combined. 
12.3
Planned safety analyses
The long-term safety of BRV at individualized doses will be evaluated by means of the safety 
analyses. Summary tables will be presented over the Evaluation Period for all subjects and by 
categories of total duration of exposure.
All safety variables will be analyzed by descriptive methods on the Safety Population. 
Treatment-emergent adverse events will be summarized in incidence tables by categories of 
total duration of exposure and by Medical Dictionary for Regulatory Activities (MedDRA®)
Primary System Organ Class and Preferred Term. Separate tables will be provided for AEs
leading to withdrawal from the study and SAEs.
Laboratory values, vital signs, and weight will be summarized by period and visit. Possibly 
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and 
weight will be listed and summarized by period and visit. Electrocardiogram abnormalities,
as well as physical and neurological abnormalities, will also be listed by period and visit.
12.4
Planned efficacy analyses
All efficacy outcomes will be summarized with descriptive statistics only. Separate 
summaries will be provided for subjects with focal epilepsy and subjects with generalized 
epilepsy.
For subjects with focal epilepsy, 28-day adjusted seizure frequency will be calculated by 
dividing the number of partial seizures by the number of days for which the diary was 
completed, and multiplying the resulting value by 28. For subjects with generalized epilepsy, 
28-day adjusted seizure days will be calculated by dividing the number of days with a 
generalized seizure by the number of days for which the diary was completed, and 
multiplying the resulting value by 28.
Responder rates will not be evaluated for subjects from N01258 due to the short duration of 
the Baseline Period for this study.
Some variables for subjects with generalized epilepsy may not be assessed if the number of 
subjects with generalized epilepsy is insufficient.
Change in QOLIE-31-P scores from Baseline of the previous study will be summarized with 
descriptive statistics for the first 2 years of the Evaluation Period.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 52 of 129
12.5
Planned pharmacoeconomic analyses
Direct cost parameters and socio-professional data will be summarized with descriptive 
statistics for the first 2 years of the Evaluation Period.
12.6
Handling of protocol deviations
After all CRFs have been retrieved and entered and queries addressed, and prior to locking 
the clinical database, a data review meeting (DRM) will be held. The purpose of this DRM 
will be to assess the quality of the data for subsequent database lock, identify protocol 
deviations, and finalize analysis sets.
12.7
Handling of dropouts or missing data
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.
12.8
Planned interim analysis and data monitoring
Due to the single-arm open-label nature of this study, no interim analysis as such will be 
performed. However, interim database snapshots may be performed to allow safety and 
efficacy analyses in support of submission activities or to allow optimization of the 
development program. In addition, an ongoing medical review (Safety Data Review) 
applying to the entire BRV program is organized.
12.9
Determination of sample size
For this open-label LTFU, no sample size calculation will be performed. The sample size will 
depend upon recruitment into and completion of the previous studies. It is estimated that 
approximately 650 to 720 subjects from N01358 will enter the study based on the assumption 
that at least 90% of randomized subjects from N01358 will complete N01358 and enroll in 
N01379. Up to 100 subjects from N01258 may also be eligible.
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 written Informed Consent form 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). An additional written 
Informed Consent form should be signed and dated for adult subjects from N01358 (without 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 53 of 129
mental impairment) giving their consent to blood sampling for DNA analysis. The subject or 
his/her legal representative must receive a copy of the signed and dated Informed Consent 
form. 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 Informed Consent form 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 Informed Consent form 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 their consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent form. A 
CRF 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 name of the study and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with them 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, Informed Consent form(s), Investigator’s Brochure, Investigator’s curriculum vitae 
(if applicable), advertisement (if applicable), and all other subject-related documents to be 
used for the study to the IRB/IEC for its review and approval.
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol.
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol 
deviations, to eliminate immediate hazards to subjects.
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. 
For minor changes to a previously approved protocol during the period covered by the 
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 54 of 129
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 the Committee’s 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 Screening.
The Investigator agrees that representatives of UCB, its designee, representatives of the 
relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that 
portion of the subject’s primary medical records that directly concerns this study (including, 
but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries 
for hospital admissions occurring during a subject’s study participation, and autopsy reports 
for deaths occurring during the study).
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.
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements as applicable.
15
REFERENCES
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised 
terminology and concepts for organization of seizures and epilepsies: report of the ILAE 
Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-85.
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e leg
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marketing 
su
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men
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authorization
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author
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hat d
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ubje
ubje
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nfiden
nfiden
fied
fied on
on
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 55 of 129
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Cramer JA, Van Hammée G. Maintenance of improvement in health-related quality of life 
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Engel J. Report of the ILAE classification core group. Epilepsia. 2006;47:1558-68.
Engel J, Pedley TA. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 
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Goldstein DB, Need AC, Singh R, Sisodiya SM. Potential genetic causes of heterogeneity of 
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Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34:453-68.
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255-60.
Loiseau J, Loiseau P, Guyot M, Duche B, Dartigues JF, Aublet B. Survey of seizure disorders 
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Lüders HO, Acharya J, Alexopoulos A, Baumgartner C, Bautista J, Burgess R, et al. Are 
epilepsy classifications based on epileptic syndromes and seizure types outdated? Epileptic 
Disord. 2006;8(1):81-5.
Nasreddine W, Beydoun A, Atweh S, Abou-Khalil B. Emerging drugs for partial onset 
seizures. Expert Opin Emerg Drugs. In press (2010).
Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 
1996;61:433-43.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67:361-70.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 67 of 129
16.3
Protocol Amendment 1
Rationale for the amendment
This protocol amendment is issued to include a DNA analysis in order to assess the role of 
gene variants of SV2 in affecting response to BRV. The DNA analysis applies to adult 
subjects from N01358 without mental impairment and where legally acceptable and 
authorized by regulatory agencies. All related sections were updated accordingly. 
Furthermore, subjects coming from N01258 will also have the option to enroll in N01379 in 
addition to subjects from N01358 and the respective sections were revised. The laboratory 
section and the impacted study visits were updated to include assessments of liver function at 
3-monthly intervals during the first year and a yearly TSH measurement in response to a 
regulatory agency request. Administrative changes include the update of the Sponsor 
company name and of the contact details. A few changes of editorial nature are not listed in 
the specific changes section.
Modifications and changes
Global changes
∀
The following changes were made throughout the protocol:
∀
Procedures related to the DNA analysis and respective blood samplings have been added 
to various sections. 
∀
N01379 will now include subjects coming from N01358 and from N01258. A reference 
to N01258 has been added to various impacted sections. As a consequence of the 
inclusion of subjects from N01258, various paragraphs relating to the study entry dose, 
efficacy variables, and analysis of efficacy variables were updated. 
∀
The laboratory section and the impacted study visits were updated as follows:
#
Liver function tests will be performed in 3-month intervals during the first year.
#
Thyroid-stimulating hormone will be assessed at all YEVs.
Specific changes
Change #1
TITLE PAGE, SPONSOR NAME
Original text
SCHWARZ BIOSCIENCES, INC.
A Member of the UCB Group of Companies
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 68 of 129
UCB BIOSCIENCES, INC.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Change #2
SPONSOR DECLARATION
Original text
Clinical Project Manager
 MPH, MBA
_____________________________
Date/Signature
Clinical Trial Biostatistician
, MS
_____________________________
Date/Signature
Study Physician
Dr. 
, MD, MBA
_____________________________
Date/Signature
Clinical Program Director 
, MD, PhD
_____________________________
Date/Signature
Has been changed to:
Clinical Project Manager
, MPH, MBA
_____________________________
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, MS
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 69 of 129
Clinical Program Director 
, MD, PhD
_____________________________
Date/Signature
Change #3
STUDY CONTACT INFORMATION
Original text
Sponsor
SCHWARZ BIOSCIENCES, INC.
A Member of the UCB Group of Companies
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Has been changed to:
Sponsor
UCB BIOSCIENCES, INC.
8010 Arco Corporate Drive
Raleigh, NC  27617
UNITED STATES
Change #4
STUDY CONTACT INFORMATION, Sponsor Study Physician
Original text
Name:
Dr. 
, MD, MBA
Address:
Alfred-Nobel-Straße 10
40789 Monheim
Germany
Phone:
Fax:
Has been changed to:
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 70 of 129
Address:
8010 Arco Corporate Drive, Suite 100
Raleigh, NC  27617
United States
Phone:
Fax:
Change #5
LIST OF ABBREVIATIONS
The following explanations have been added to the list of abbreviations:
DNA
deoxyribonucleic acid
iv
Intravenous
SV2
synaptic vesicle protein 2
TSH
thyroid-stimulating hormone
Change #6
Section 1 SUMMARY
Original text
This is a Phase 3, open-label, long-term follow-up (LTFU), multicenter, noncomparative, and 
single-arm study of brivaracetam (BRV). The primary objective is to evaluate the long-term 
safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day in 
focal epilepsy subjects. The secondary objective is to evaluate the maintenance of efficacy of 
BRV over time. Exploratory objectives are to assess the effects of BRV on subjects’ 
Health-related Quality of Life (HRQoL), obtain information on the direct medical resource 
use, and explore any change in socio-professional status.
This study will enroll adults (≥16 years) with refractory partial onset seizures (POS) whether 
or not secondarily generalized. Subjects under 18 years may only be included where legally 
permitted and ethically accepted. Subjects have to complete the Treatment Period of N01358 
prior to enrollment into N01379. They will be started on a BRV dose of 150mg/day at study 
entry and should be maintained at this dose for at least 2 weeks unless the subject is unable to 
tolerate treatment. The BRV dose can be adjusted based on the individual subject’s seizure 
control and tolerability. However, the BRV dose may not exceed 200mg/day during the 
study. During the Evaluation Period, subjects will be invited to visit the clinical site monthly 
in the first 3 months and every 3 months thereafter. The completion of the Evaluation Period 
or early discontinuation from N01379 is followed by a Down-Titration Period of up to 
4 weeks and by a subsequent Posttreatment Period (between 2 and 4 weeks) during which the 
subject does not receive study drug.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 71 of 129
This LTFU study will run throughout the duration of the clinical development period of 
BRV, and will continue until a marketing authorization is granted by any Health Authority in 
an indication for the adjunctive treatment in adults (≥16 years) with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, or until BRV 
development is stopped by the Sponsor.
The primary efficacy variable is the POS (type I) seizure frequency standardized to a 28-day 
duration. Seizure types are coded according to the Commission on Classification and 
Terminology of the International League Against Epilepsy (ILAE), 1981. The primary 
efficacy variable will be summarized by 3-month periods over the Evaluation Period. 
Secondary efficacy variables include the seizure frequency per 28 days for all seizure types 
(I+II+III), the proportion of seizure-free days for all seizure types (I+II+III), the proportion of 
continuously seizure-free subjects for all seizure types (I+II+III), and the responder rate in 
POS (type I). A responder is defined as a subject with a ≥50% reduction in seizure frequency
from the Baseline Period for the double-blind study N01358. 
Other efficacy variables include the Patient Weighted Quality of Life in Epilepsy Inventory 
(QOLIE-31-P) scores, the Hospital Anxiety and Depression Scale (HADS) scores, medical 
resources use, and socio-professional data during the first 2 years of the Evaluation Period.
Safety variables include adverse events (AEs), laboratory tests (hematology, blood chemistry, 
urinalysis, and pregnancy test), electrocardiogram (ECG), vital signs, physical and 
neurological examinations, and body weight.
It is estimated that approximately 650 to 720 subjects will enter the study, based on the 
assumption that at least 90% of randomized subjects from N01358 will complete N01358 and 
enroll in N01379. It is estimated that approximately 120 sites will participate in the study.
Has been changed to:
This is a Phase 3, open-label, long-term follow-up (LTFU), multicenter, noncomparative, and 
single-arm study of brivaracetam (BRV). The primary objective is to evaluate the long-term 
safety and tolerability of BRV at individualized doses up to a maximum of 200mg/day in 
epilepsy subjects. The secondary objective is to evaluate the maintenance of efficacy of BRV 
over time. Exploratory objectives are to assess the effects of BRV on subjects’ Health-related 
Quality of Life (HRQoL), obtain information on the direct medical resource use, explore any 
change in socio-professional status, and assess the role of gene variants of SV2 in affecting 
response to BRV (as part of a DNA analysis at the program level).
This study will enroll subjects (≥16 years) from N01358 with refractory partial onset 
seizures (POS) whether or not secondarily generalized and subjects (≥16 years) from 
N01258 with localization-related or generalized epilepsy. Subjects under 18 years may 
only be included where legally permitted and ethically accepted. Subjects have to complete 
the Treatment Period of N01358 or the Evaluation Period of N01258 prior to enrollment 
into N01379. Subjects from N01358 will be started on a BRV dose of 150mg/day at study 
entry and should be maintained at this dose for at least 2 weeks unless the subject is unable to 
tolerate treatment. Subjects from N01258 will start at a dose of BRV 200mg/day and 
should be maintained at this dose for at least 2 weeks unless the subject is unable to 
tolerate treatment. The BRV dose can be adjusted based on the individual subject’s seizure 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 72 of 129
control and tolerability. However, the BRV dose may not exceed 200mg/day during the 
study. During the Evaluation Period, subjects will be invited to visit the clinical site monthly 
in the first 3 months and every 3 months thereafter. The completion of the Evaluation Period 
or early discontinuation from N01379 is followed by a Down-Titration Period of up to 
4 weeks and by a subsequent Posttreatment Period (between 2 and 4 weeks) during which the 
subject does not receive study drug.
This LTFU study will run throughout the duration of the clinical development period of 
BRV, and will continue until a marketing authorization is granted by any Health Authority in 
an indication for the adjunctive treatment in adults (≥16 years) with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, or until BRV 
development is stopped by the Sponsor.
The primary efficacy variable is the POS (type I) seizure frequency standardized to a 28-day 
duration. Seizure types are coded according to the Commission on Classification and 
Terminology of the International League Against Epilepsy (ILAE), 1981. The primary 
efficacy variable will be summarized by 3-month periods over the Evaluation Period. 
Secondary efficacy variables include the seizure frequency per 28 days for all seizure 
types (I+II+III), the proportion of seizure-free days for all seizure types (I+II+III), the 
proportion of continuously seizure-free subjects for all seizure types (I+II+III), and the 
responder rate in POS (type I). A responder is defined as a subject with a ≥50% reduction in 
seizure frequency from the Baseline Period for the double-blind study N01358. Responder 
rates will not be evaluated for subjects from N01258 due to the short duration of the 
Baseline Period for this study.
Other efficacy variables for subjects from N01258 with generalized epilepsy include the 
generalized (type II) seizure days, seizure days per 28 days for all seizure 
types (I+II+III), proportion of seizure-free days for all seizure types (I+II+III), and 
proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period. Some variables may not be assessed if the 
number of subjects with generalized epilepsy is insufficient.
Other nonseizure-related efficacy variables include the Patient Weighted Quality of Life in 
Epilepsy Inventory (QOLIE-31-P) scores, the Hospital Anxiety and Depression Scale 
(HADS) scores, medical resources use, and socio-professional data during the first 2 years of 
the Evaluation Period.
Safety variables include adverse events (AEs), laboratory tests (hematology, blood chemistry, 
urinalysis, endocrinology, and pregnancy test), electrocardiogram (ECG), vital signs, 
physical and neurological examinations, and body weight.
It is estimated that approximately 650 to 720 subjects from N01358 will enter the study, 
based on the assumption that at least 90% of randomized subjects from N01358 will complete 
N01358 and enroll in N01379. Up to 100 subjects from N01258 may also be eligible. It is 
estimated that approximately 120 sites from N01358 and up to 25 sites from N01258 will 
participate in the study.
Change #7
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 73 of 129
Section 2.2
Background information regarding product
The following paragraph has been added to the original text.
There is increasing research to assess the role of genetic variation on response to medicines, 
including antiepileptics (Goldstein et al, 2007). Preliminary research with BRV has suggested 
a possible role for variants in synaptic vesicle protein (SV2) genes in modulating response to 
the medicine. To explore this observation further and to broaden the pharmacogenetic 
information available for BRV, deoxyribonucleic acid (DNA) sampling is included in the 
study for subjects coming from N01358. 
Change #8
Section 2.5
Study rationale
Original text
UCB is developing BRV as an adjunctive antiepileptic treatment in subjects 16 years and 
older suffering from focal epilepsy. N01379 will give subjects who have completed N01358 
the opportunity to access BRV under the present protocol. N01358 is an adequate and 
well-controlled study to provide additional data confirming the efficacy and safety of BRV as 
an AED in adults (≥16 years) with refractory POS whether or not secondarily generalized. 
N01379 will explore the long-term safety and efficacy of BRV in subjects with POS whether 
or not secondarily generalized while providing access to BRV for subjects who may benefit 
from open-label treatment with BRV.
Has been changed to:
UCB is developing BRV as an adjunctive antiepileptic treatment in subjects 16 years and 
older suffering from epilepsy. N01379 will give subjects who have completed N01358 or 
N01258 the opportunity to access BRV under the present protocol. N01358 is an adequate 
and well-controlled study to provide additional data confirming the efficacy and safety of 
BRV as an AED in adults (≥16 years) with refractory POS whether or not secondarily 
generalized. N01258 is a multicenter, 4-arm, randomized, parallel-group study
evaluating the safety and tolerability of adjunctive BRV treatment administered as 
intravenous (iv) infusion or iv bolus in subjects with localization-related or generalized 
epilepsy from 16 to 70 years old.
N01379 will explore the long-term safety and efficacy of BRV in subjects with epilepsy 
while providing access to BRV for subjects who may benefit from open-label treatment with 
BRV.
Change #9
Section 3.1
Primary objective
Original text
The primary objective is to evaluate the long-term safety and tolerability of BRV at 
individualized doses up to a maximum of 200mg/day in focal epilepsy subjects.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 74 of 129
Has been changed to:
The primary objective is to evaluate the long-term safety and tolerability of BRV at 
individualized doses up to a maximum of 200mg/day in epilepsy subjects.
Change #10
Section 3.3
Exploratory objectives
Original text
∀
To explore the effects of BRV on subjects’ HRQoL
∀
To explore direct medical resource use
∀
To explore any change in socio-professional status
Has been changed to:
∀
To explore the effects of BRV on subjects’ HRQoL
∀
To explore direct medical resource use
∀
To explore any change in socio-professional status
∀
To assess the role of gene variants of SV2 in affecting response to BRV (as part of a 
DNA analysis at the program level)
Change #11
Section 4.1.2 Secondary efficacy variables
Original text
Secondary efficacy variables are as follows:
∀
Seizure frequency per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
∀
Responder rate in POS (type I) by 3-month periods over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from the 
Baseline Period for the double-blind study N01358. 
Has been changed to:
Secondary efficacy variables are as follows:
∀
Seizure frequency per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 75 of 129
∀
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
∀
Responder rate in POS (type I) by 3-month periods over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from the 
Baseline Period for the double-blind study N01358. 
Responder rates will not be evaluated for subjects from N01258 due to the short 
duration of the Baseline Period for this study.
Change #12
Section 4.1.3 Other efficacy variables
Original text
The other efficacy variables are as follows:
∀
Change in QOLIE-31-P scores from the Baseline of N01358 to each assessment for the 
first 2 years and to the last Evaluation Period assessment during the first 2 years 
∀
Change in HADS scores from the Baseline of N01358 to each assessment for the first 
2 years and to the last Evaluation Period assessment during the first 2 years
∀
Medical resources use during the first 2 years of the Evaluation Period
∀
Change in socio-professional data from the Baseline of N01358 to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years 
Has been changed to:
4.1.3.1
Seizure-related other efficacy variables
For subjects from N01258 with generalized epilepsy:
∀
Generalized (type II) seizure days standardized to a 28-day duration by 3-month 
periods over the Evaluation Period
∀
Seizure days per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
Some variables may not be assessed if the number of subjects with generalized epilepsy 
is insufficient.
4.1.3.2
Nonseizure-related other efficacy variables
The other efficacy variables are as follows:
∀
Medical resources use during the first 2 years of the Evaluation Period
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 76 of 129
∀
Change in QOLIE-31-P scores from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years 
∀
Change in HADS scores from the Baseline of N01358 or N01258 to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
∀
Change in socio-professional data from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years 
Change #13
Section 4.2
Safety variables
Original text
∀
AEs
∀
Laboratory tests (including hematology, blood chemistry, urinalysis, and pregnancy test)
∀
ECG
∀
Physical examination 
∀
Neurological examination
∀
Vital signs
∀
Body weight
Has been changed to:
∀
AEs
∀
Laboratory tests (including hematology, blood chemistry, urinalysis, and pregnancy test, 
and additional endocrinology once a year)
∀
ECG
∀
Physical examination 
∀
Neurological examination
∀
Vital signs
∀
Body weight
Change #14
Section 5.1
Study description, paragraph 1
Original text
This is a Phase 3, open-label, LTFU, multicenter, noncomparative, and single-arm study. The 
subject population will be adults (≥16 years) with refractory POS whether or not secondarily 
generalized. Subjects under 18 years may be included only where legally permitted and 
ethically accepted. Subjects must complete the Treatment Period of N01358 prior to 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 77 of 129
enrollment into N01379. Upon completion or early discontinuation from N01379, there will 
be a Down-Titration Period, followed by a Posttreatment Period during which the subject will 
not receive study drug.
Has been changed to:
This is a Phase 3, open-label, LTFU, multicenter, noncomparative, and single-arm study. The 
subject population will be adults (≥16 years) with refractory POS whether or not secondarily 
generalized from N01358 and subjects with localization-related or generalized epilepsy 
from N01258. Subjects under 18 years may be included only where legally permitted and 
ethically accepted. Subjects must complete the Treatment Period of N01358 or the 
Evaluation Period of N01258 prior to enrollment into N01379. Upon completion or early 
discontinuation from N01379, there will be a Down-Titration Period, followed by a 
Posttreatment Period during which the subject will not receive study drug.
Change #15
Section 5.1
Study description, paragraph 3
Original text
Subjects will be started on oral BRV at a dose of 150mg/day (2 equally divided doses 
administered twice daily) at study entry and should be maintained at this dose for at least 
2 weeks unless the subject is unable to tolerate treatment. The BRV dose can be adjusted 
based on the individual subject’s seizure control and tolerability. However, the BRV dose 
may not exceed 200mg/day during the study and must always be administered as a 
symmetrical morning and evening dose.
Has been changed to:
Subjects from N01358 will be started on oral BRV at a dose of 150mg/day (2 equally divided 
doses administered twice daily) at study entry and should be maintained at this dose for at 
least 2 weeks unless the subject is unable to tolerate treatment. Subjects from N01258 will 
be started at an oral dose of BRV 200mg/day (2 equally divided doses administered 
twice daily) and should be maintained at this dose for at least 2 weeks unless the subject 
is unable to tolerate treatment. The BRV dose can be adjusted based on the individual 
subject’s seizure control and tolerability. However, the BRV dose may not exceed 200mg/day
during the study and must always be administered as a symmetrical morning and evening 
dose.
Change #16
Section 5.1.1 Study duration per subject 
Original text
Subject recruitment for the study will begin in approximately Q1 2011. For each subject, the 
study will last from study entry until either regulatory approval of BRV has been granted by 
any Health Authority in an indication of adjunctive treatment of POS, until the Sponsor 
decides to close the study, or until BRV development is stopped by the Sponsor.
Has been changed to:
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 78 of 129
Subject recruitment for the study will begin in approximately Q2 2011. For each subject, the 
study will last from study entry until either regulatory approval of BRV has been granted by 
any Health Authority in an indication of adjunctive treatment of POS, until the Sponsor 
decides to close the study, or until BRV development is stopped by the Sponsor.
Change #17
Section 5.1.2 Planned number of subjects and sites 
Original text
It is estimated that approximately 650 to 720 subjects will enter the study, based on the 
assumption that at least 90% of randomized subjects from N01358 will complete N01358 and 
enroll in N01379.
It is estimated that 120 sites will participate in the study.
Has been changed to:
It is estimated that approximately 650 to 720 subjects from N01358 will enter the study, 
based on the assumption that at least 90% of randomized subjects from N01358 will complete 
N01358 and enroll in N01379. Up to 100 subjects from N01258 may also be eligible for 
enrollment.
It is estimated that 120 sites from N01358 and up to 25 sites from N01258 will participate in 
the study.
Change #18
Section 5.1.3 Anticipated regions and countries 
Original text
The regions and countries for enrollment will be the same as the core study, N01358. The 
study is planned to be performed in North America (Canada and USA), Western Europe, 
Latin America, Eastern Europe, Asia, and Africa, with possible extension to other countries 
or regions. 
Has been changed to:
The regions and countries for enrollment will be the same as in the previous studies, N01358
and N01258. N01358 is planned to be performed in North America (Canada and USA), 
Western Europe, Latin America, Eastern Europe, Asia, and Africa, and N01258 is planned 
to be performed in the USA and Europe, with possible extension to other countries or 
regions for both studies. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 79 of 129
Change #19
Section 5.2
Schedule of study assessments, Table 5:1.
The following rows have been added
Written Informed 
Consent for DNA 
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from N01358)
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 80 of 129
Change #20
Section 5.2
Schedule of study assessments, Table 5:1., abbreviations
Original text
AE=adverse event; AED=antiepileptic drug; CRF=Case Report Form; DTP=Down-Titration 
Phone Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EV=Entry Visit; 
FEV=Full Evaluation Visit; FV=Final Visit; HADS=Hospital Anxiety and Depression Scale; 
IVRS=interactive voice response system; M=Month; MEV=Minimal Evaluation Visit; 
NA=not applicable; QOLIE-31-P=Patient Weighted Quality of Life in Epilepsy Inventory; 
V=Visit; YEV=Yearly Evaluation Visit
Has been changed to:
AE=adverse event; AED=antiepileptic drug; CRF=Case Report Form; 
DNA=deoxyribonucleic acid; DTP=Down-Titration Phone Call; ECG=electrocardiogram; 
EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final 
Visit; HADS=Hospital Anxiety and Depression Scale; IVRS=interactive voice response 
system; M=Month; MEV=Minimal Evaluation Visit; NA=not applicable; QOLIE-31-
P=Patient Weighted Quality of Life in Epilepsy Inventory; V=Visit; YEV=Yearly Evaluation 
Visit
Change #21
Section 5.2
Schedule of study assessments, Table 5:1., footnotes
Original text
Note: Months and visit numbers are displayed for the first 2 years. The visit schedule 
described in Section 5.3 will be applied.
Note: At the EV, the IVRS call will be part of the N01358 final visit.
a.
The Down-Titration Phone Call at the end of the Down-Titration Period is mandatory.
b.
General medical and procedures history, AED history, recording of seizures, and epilepsy 
history will be obtained from the Baseline of N01358 and do not need to be recorded on the 
CRF for this study.
c.
The following will be obtained from the last visit of N01358 and do not need to be 
recorded on the CRF for this study: physical and neurological examination, vital signs, 
hospital stays, healthcare provider consultations not foreseen by the protocol, ECG, and 
laboratory assessments (hematology, blood chemistry, and urinalysis).
d.
Height will be obtained at Visit 1 in N01358.
e.
At the FV, an ECG is mandatory, except if the FV follows an EDV where ECG results 
were normal.
f.
QOLIE-31-P and HADS are to be completed at the beginning of the visit by all subjects 
who are able to complete the assessments on their own. These will be collected only for the 
first 2 years.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 81 of 129
g.
Socio-professional data, hospital stays, and healthcare provider consultations not foreseen 
by the protocol will be collected for all subjects for the first 2 years. 
h.
Laboratory assessment includes hematology, blood chemistry, and urinalysis; where 
applicable (women with childbearing potential), a urine pregnancy test will be done. 
Laboratory assessment is mandatory at the FV, except if the FV follows an EDV where 
laboratory results were normal. The result of the calculated creatinine clearance will be 
provided by the central laboratory.  
i.
Ongoing AEs at the time of subject completion of N01358 will be obtained from the 
database for N01358 and should not be recorded on the CRF for N01379 unless there is a 
change in intensity or seriousness. In this event, the AE should be recorded on the CRF for 
N01379 with the onset date corresponding to the date of change in condition.
j.
Ongoing medications (AEDs and non-AEDs) at the time of subject completion of N01358 
will be obtained from the database for N01358 and should not be recorded on the CRF for 
N01379 unless there is a change regarding the administration of the medication. In this event, 
the medication should be recorded on the CRF for N01379 with the start date corresponding 
to the date of change in administration.
k.
End of study status will be completed at the FV for subjects having performed an EDV 
(discontinued subjects) and for subjects leaving the study at the end of the program 
(completed subjects).
Has been changed to:
Note: Months and visit numbers are displayed for the first 2 years. The visit schedule 
described in Section 5.3 will be applied.
Note: At the EV, the IVRS call will be part of the N01358 or N01258 final visit.
a.
The Down-Titration Phone Call at the end of the Down-Titration Period is mandatory.
b.
General medical and procedures history, AED history, recording of seizures, and epilepsy 
history will be obtained from the Baseline of N01358 or N01258 and do not need to be 
recorded on the CRF for this study.
c.
The following will be obtained from the last visit of N01358 or N01258 and do not need 
to be recorded on the CRF for this study: physical and neurological examination, vital signs, 
hospital stays, healthcare provider consultations not foreseen by the protocol, ECG, and 
laboratory assessments (hematology, blood chemistry, and urinalysis).
d.
Height will be obtained at Visit 1 in N01358 or N01258.
e.
At the FV, an ECG is mandatory, except if the FV follows an EDV where ECG results 
were normal.
f.
QOLIE-31-P and HADS are to be completed at the beginning of the visit by all subjects 
who are able to complete the assessments on their own. These will be collected only for the 
first 2 years.
g.
Socio-professional data, hospital stays, and healthcare provider consultations not foreseen 
by the protocol will be collected for all subjects for the first 2 years. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 82 of 129
h.
Laboratory assessment includes hematology, blood chemistry, and urinalysis; where 
applicable (women with childbearing potential), a urine pregnancy test will be done. 
Endocrinology will be assessed at each YEV. In addition, liver function tests as 
described in Section 10.5.1 will be performed at the MEV in M3 and M9. Laboratory 
assessment is mandatory at the FV, except if the FV follows an EDV where laboratory results 
were normal. The result of the calculated creatinine clearance will be provided by the central 
laboratory.  
i.
The DNA analysis is part of N01379 and will be performed only in adult subjects 
from N01358 after signing an additional Informed Consent form and where ethically 
accepted and authorized by regulatory agencies. Mentally impaired subjects will be 
excluded from the DNA analysis. 
j.
Ongoing AEs at the time of subject completion of N01358 or N01258 will be obtained 
from the database for N01358 or N01258 and should not be recorded on the CRF for N01379 
unless there is a change in intensity or seriousness. In this event, the AE should be recorded 
on the CRF for N01379 with the onset date corresponding to the date of change in condition.
k.
Ongoing medications (AEDs and non-AEDs) at the time of subject completion of N01358 
or N01258 will be obtained from the database for N01358 or N01258 and should not be 
recorded on the CRF for N01379 unless there is a change regarding the administration of the 
medication. In this event, the medication should be recorded on the CRF for N01379 with the 
start date corresponding to the date of change in administration.
l.
End of study status will be completed at the FV for subjects having performed an EDV 
(discontinued subjects) and for subjects leaving the study at the end of the program 
(completed subjects).
Change #22
Section 5.3
Visit schedule, Table 5:2.
Original text
A full visit schedule is presented in the following table.
Table 5:2.
Visit schedule
First year follow-up
Month
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Type of visit
M0
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 83 of 129
Table 5:2.
Visit schedule
First year follow-up
Month
Visit
Type of visit
M7
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M8
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M9
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EV=Entry Visit; FEV=Full Evaluation Visit; M=month; MEV=Minimal Evaluation Visit; V=Visit; 
YEV=Yearly Evaluation Visit
Note: “-“ denotes that no visit is scheduled in that month.
a.
Subsequent years will follow the same visit schedule.
Has been changed to:
A full visit schedule is presented in the following table.
Table 5:2.
Visit schedule
First year follow-up
Month
Visit
Type of visit
M0
V1
EV
M1
V2
MEV
M2
V3
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M3
V4
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 84 of 129
Table 5:2.
Visit schedule
First year follow-up
M9
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MEVb
M10
-
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M11
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Second year follow-upa
Month
Visit
Type of visit
M12
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M21
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MEV
EV=Entry Visit; FEV=Full Evaluation Visit; M=month; MEV=Minimal Evaluation Visit; V=Visit; 
YEV=Yearly Evaluation Visit
Note: “-“ denotes that no visit is scheduled in that month.
a    Subsequent years will follow the same visit schedule.
b    Liver function tests will be performed in addition to the assessments described in Section 8.3
Change #23
Section 5.4
Rationale for study design and selection of dose
Original text
In the prerequisite study (N01358) for inclusion in N01379, subjects will be randomized to 
BRV 100mg/day, BRV 200mg/day or to matching PBO. Previous Phase 2/3 clinical studies 
in POS and dose-response modeling suggest that optimal seizure frequency requires BRV 
doses of 50 to 100mg/day, with BRV 150mg/day possibly providing some additional benefit. 
Following consultation with regulatory authorities, it was recommended to also explore 
BRV 200mg/day to obtain data on the upper end of the dose response curve in N01358. 
Subjects will enter N01379 at a dose of BRV 150mg/day (2 equally divided doses 
administered twice daily). In Phase 2/3 studies for POS with BRV doses up to 150mg/day, 
the overall discontinuation rate and the discontinuation rate due to TEAEs was low and 
similar to PBO. The most frequently reported TEAEs at BRV doses up to 150mg/day were 
headache, somnolence, dizziness, and fatigue. The BRV dose can be adjusted based on the 
individual subject’s seizure control and/or tolerability after the first 2 weeks, up to a 
maximum dose of BRV 200mg/day.
Has been changed to:
In the previous study N01358, subjects will be randomized to an oral dose of
BRV 100mg/day, BRV 200mg/day, or to matching PBO. In the previous study N01258, 
subjects will receive either a 60-second iv bolus or a 15-minute iv infusion at a dose of 
BRV 100mg twice daily (200mg/day). Previous Phase 2/3 clinical studies in POS and 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 85 of 129
dose-response modeling suggest that optimal seizure frequency requires BRV doses of 
50 to 100mg/day, with BRV 150mg/day possibly providing some additional benefit. 
Following consultation with regulatory authorities, it was recommended to also explore 
BRV 200mg/day to obtain data on the upper end of the dose response curve in N01358. 
The starting doses in N01379 will be BRV 150mg/day for subjects from N01358 and 
BRV 200mg/day for subjects from N01258. The study entry doses will be taken as
2 equally divided oral doses administered twice daily. In Phase 2/3 studies for POS with 
BRV doses up to 150mg/day, the overall discontinuation rate and the discontinuation rate due 
to TEAEs was low and similar to PBO. The most frequently reported TEAEs at BRV doses 
up to 150mg/day were headache, somnolence, dizziness, and fatigue. The BRV dose can be 
adjusted based on the individual subject’s seizure control and/or tolerability after the first 
2 weeks, up to a maximum dose of BRV 200mg/day.
Change #24
Section 6.1
Inclusion criteria, bullets 1 and 3
Original text
1. An Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved 
written informed consent signed and dated by the subject or by parent(s) or legally 
acceptable representative. The consent form or a specific assent form, where required, 
will be signed and dated by minors. 
2. Subject completed the Treatment Period of N01358. 
Has been changed to:
1. An Independent Ethics Committee (IEC)/Institutional Review Board (IRB) approved 
written informed consent signed and dated by the subject or by parent(s) or legally 
acceptable representative. The consent form or a specific assent form, where required, 
will be signed and dated by minors. In countries and sites where a DNA analysis is 
accepted, an additional Informed Consent form will have to be signed by subjects 
coming from N01358. Deoxyribonucleic acid analysis will be performed only in 
adults, and the subject can withdraw consent to the use of the sample at any time. 
Mentally impaired subjects will be excluded. In case the consent is withdrawn, the 
site must request the destruction of the sample.
2. Subject completed the Treatment Period of N01358 or the Evaluation Period of N01258. 
Change #25
Section 6.2
Exclusion criteria, bullets 1 and 3
Original text
1. Subject has developed hypersensitivity to any components of the investigational 
medicinal product (IMP) or comparative drugs as stated in this protocol during the course 
of the core study
2. Poor compliance with the visit schedule or medication intake in the previous BRV study
Has been changed to:
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 86 of 129
1. Subject has developed hypersensitivity to any components of the investigational 
medicinal product (IMP) or comparative drugs as stated in this protocol during the course 
of the core studies
2. Poor compliance with the visit schedule or medication intake in the previous BRV studies
Change #26
Section 6.3
Withdrawal criteria, paragraph 1
Original text
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
Has been changed to:
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care. Subjects who have signed an additional Informed Consent form for DNA analysis 
may withdraw their consent to the DNA analysis at any time and may continue their 
participation in the N01379 study.
Change #27
Section 7.2
Treatments to be administered, paragraph 1
Original text
Subjects will be started on a BRV dose of 150mg/day (2 equally divided doses administered 
twice daily) at study entry and should be maintained at this dose for at least 2 weeks, unless 
the subject is not able to tolerate treatment. The BRV dose can subsequently be adjusted 
based on the individual subject’s seizure control and/or tolerability. However, the BRV dose 
should not exceed 200mg/day during the study. 
Has been changed to:
Subjects from N01358 will be started on a BRV dose of 150mg/day (2 equally divided doses 
administered twice daily) at study entry and should be maintained at this dose for at least 
2 weeks, unless the subject is not able to tolerate treatment. Subjects from N01258 will be 
started at a BRV dose of 200mg/day (2 equally divided doses administered twice daily) 
and should be maintained at this dose for at least 2 weeks, unless the subject is not able 
to tolerate treatment. The BRV dose can subsequently be adjusted based on the individual 
subject’s seizure control and/or tolerability. However, the BRV dose should not exceed 
200mg/day during the study. 
Change #28
Section 7.3
Packaging, paragraph 1
Original text
Oral tablets of BRV 10mg, 25mg, and 50mg will be packaged in high density polyethylene 
bottles of 200 tablets. Each container will have an unique, preprinted identification number. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 87 of 129
Has been changed to:
Oral tablets of BRV 25mg and 50mg will be packaged in high density polyethylene bottles of 
200 tablets, and the 10mg tablets will be packaged in bottles containing 38 tablets. Each 
container will have a unique, preprinted identification number. 
Change #29
Section 7.8.2 Prohibited concomitant treatments (medications and therapies)
Original text
The following concomitant AED medications are prohibited during the study:
∀
Felbamate (except if on stable dose during previous double-blind study N01358)
∀
Vigabatrin
Has been changed to:
The following concomitant AED medications are prohibited during the study:
∀
Felbamate (except if on stable dose during previous studies N01358 and N01258)
∀
Vigabatrin
Change #30
Section 7.9
Blinding
Original text
This is an open-label LTFU study of the preceding double-blind study N01358.
Has been changed to:
This is an open-label LTFU study of the preceding double-blind study N01358 and of the 
open-label randomized study N01258.
Change #31
Section 7.10
Randomization and numbering of subjects
Original text
Since N01379 is an open-label LTFU study of the preceding double-blind study N01358, 
subjects will not be randomized to any treatment groups. All subjects enrolled will start with 
a dose of BRV 150mg/day and will be maintained on that dose for at least 2 weeks, unless 
they are unable to tolerate the dose. 
Subjects will continue with the 5-digit subject numbers assigned by the interactive voice 
response system (IVRS) in the preceding double-blind study N01358.
Has been changed to:
Since N01379 is an open-label LTFU study for N01358 and N01258; subjects will not be 
randomized to any treatment groups. Subjects from N01358 will start with a dose of BRV 
150mg/day and will be maintained on that dose for at least 2 weeks, unless they are unable to 
tolerate the dose. Subjects from N01258 will start at a dose of BRV 200mg/day and
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 88 of 129
should be maintained on that dose for at least 2 weeks unless they are unable to tolerate 
the dose.
Subjects will continue with the 5-digit subject numbers assigned by the interactive voice 
response system (IVRS) in the preceding studies.
Change #32
Section 8 STUDY PROCEDURES BY VISIT
Original text
Prior to any study activities, the subject or legal representative will be asked to read and sign 
an Informed Consent form that has been approved by an IRB/IEC and which complies with 
regulatory requirements. The subject or legal representative will be given adequate time to 
consider any information concerning the study, given to them by the Investigator or designee. 
As part of the informed consent procedure, subject or legal representative will be given the 
opportunity to ask the Investigator any questions regarding potential risks and benefits of 
participation in the study. Additionally, if applicable (according to subject’s age and local 
requirements), the subject will sign an IRB/IEC assent form.
Has been changed to:
Prior to any study activities, the subject or legal representative will be asked to read and sign 
an Informed Consent form that has been approved by an IRB/IEC and which complies with 
regulatory requirements. Subjects from N01358 agreeing to the DNA analysis will have to 
sign an additional Informed Consent form. The subject or legal representative will be 
given adequate time to consider any information concerning the study, given to them by the 
Investigator or designee. As part of the informed consent procedure, the subject or legal 
representative will be given the opportunity to ask the Investigator any questions regarding 
potential risks and benefits of participation in the study. Additionally, if applicable (according 
to the subject’s age and local requirements), the subject will sign an IRB/IEC assent form.
Change #33
Section 8.1
Entry Visit
Original text
∀
Written Informed Consent
∀
Subject identification card dispensing
∀
Verification inclusion/exclusion criteria
∀
Demographic data
∀
Childbearing potential
∀
Weight
∀
IVRS call
∀
Daily record card (DRC) dispensed
∀
Medical procedures
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 89 of 129
∀
Concomitant AED
∀
Concomitant non-AED
Ongoing medications (AEDs and non-AEDs) at the time of subject completion of N01358 
will be obtained from the database for N01358 and should not be recorded on the CRF for 
N01379 unless there is a change regarding the administration of the medication. In this event, 
the medication should be recorded on the CRF for N01379 with the start date corresponding 
to the date of change in administration.
∀
Recording of AEs
Ongoing AEs at the time of subject completion of N01358 will be obtained from the database 
for N01358 and should not be recorded on the CRF for N01379 unless there is a change in 
intensity or seriousness. In this event, the AE should be recorded on the CRF for N01379 
with the onset date corresponding to the date of change in condition.
∀
Drug dispensing
∀
Appointment for the next visit according to the schedule described in (Section 5.3)
The following data will be obtained from the Baseline of N01358 and do not need to be 
recorded on the CRF for this study.
∀
General medical and procedures history
∀
AED history 
∀
Recording of seizures
∀
Epilepsy history
The following data will be obtained from the last visit of N01358 and do not need to be 
recorded on the CRF for this study.
∀
Vital signs
∀
Neurological examination
∀
Physical examination
∀
ECG
∀
Laboratory assessments 
∀
Hospital stays
∀
Healthcare provider consultations not foreseen by the protocol
Height will be obtained from Visit 1 in N01358.
Has been changed to:
∀
Written Informed Consent
∀
Additional written Informed Consent for subjects agreeing to DNA analysis
∀
Subject identification card dispensing
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 90 of 129
∀
Verification inclusion/exclusion criteria
∀
Demographic data
∀
Childbearing potential
∀
Weight
∀
IVRS call
∀
Daily record card (DRC) dispensed
∀
Medical procedures
∀
Blood sampling for the DNA analysis for consenting subjects coming from N01358. 
The DNA analysis will be performed in adult subjects where ethically accepted and 
authorized by regulatory agencies. 
∀
Concomitant AED
∀
Concomitant non-AED
Ongoing medications (AEDs and non-AEDs) at the time of subject completion of N01358 or
N01258 will be obtained from the database for N01358 or N01258 and should not be 
recorded on the CRF for N01379 unless there is a change regarding the administration of the 
medication. In this event, the medication should be recorded on the CRF for N01379 with the 
start date corresponding to the date of change in administration.
∀
Recording of AEs
Ongoing AEs at the time of subject completion of N01358 or N01258 will be obtained from 
the database for N01358 or N01258 and should not be recorded on the CRF for N01379 
unless there is a change in intensity or seriousness. In this event, the AE should be recorded 
on the CRF for N01379 with the onset date corresponding to the date of change in condition.
∀
Drug dispensing
∀
Appointment for the next visit according to the schedule described in (Section 5.3)
The following data will be obtained from the Baseline of N01358 or N01258 and do not need 
to be recorded on the CRF for this study.
∀
General medical and procedures history
∀
AED history 
∀
Recording of seizures
∀
Epilepsy history
The following data will be obtained from the last visit of N01358 or N01258 and do not need 
to be recorded on the CRF for this study.
∀
Vital signs
∀
Neurological examination
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 91 of 129
∀
Physical examination
∀
ECG
∀
Laboratory assessments 
∀
Hospital stays
∀
Healthcare provider consultations not foreseen by the protocol
Height will be obtained from Visit 1 in N01358 or N01258.
Change #34
Section 8.3
Minimal Evaluation Visit
Original text
∀
Vital signs
∀
IVRS call
∀
DRC dispensed
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (for the first 2 years)
∀
Healthcare provider consultations not foreseen by the protocol (for the first 2 years)
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing
∀
Drug return/accountability
∀
Appointment for the next visit according to the schedule described in Section 5.3
Has been changed to:
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Vital signs
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IVRS call
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DRC dispensed
∀
DRC retrieved
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Recording of seizures
∀
Hospital stays (for the first 2 years)
∀
Healthcare provider consultations not foreseen by the protocol (for the first 2 years)
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 92 of 129
∀
Liver function tests will be performed in Month 3 (V4) and Month 9 (V6) as 
described in Section 10.5.1
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing
∀
Drug return/accountability
∀
Appointment for the next visit according to the schedule described in Section 5.3
Change #35
Section 8.4
Yearly Evaluation Visit, bullet on laboratory assessments
Original text
∀
Laboratory assessments
Has been changed to:
∀
Laboratory assessments, including thyroid-stimulating hormone (TSH) assessments
Change #36
Section 9.1.1 QOLIE-31-P scores, paragraph 1
Original text
The QOLIE-31-P - Version 2.0 US - English (see Section 16.1) will be used to evaluate the 
HRQoL of study subjects (Cramer and Van Hammée, 2003).
Has been changed to:
The QOLIE-31-P - Version 2.0 (see Section 16.1) will be used to evaluate the HRQoL of 
study subjects (Cramer and Van Hammée, 2003).
Change #37
Section 9.1.5 Healthcare provider consultations not foreseen by the protocol
Original text
At the FEV, MEV, YEV, Last Evaluation Period Visit, and EDV, healthcare provider 
consultations not foreseen by the protocol will be recorded in the CRF. It will include 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. At the EV, data will be obtained from the last visit of the previous study, 
N01358 and do not need to be recorded on the CRF for this study. Healthcare provider 
consultations not foreseen by the protocol will be recorded for the first 2 years.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 93 of 129
Has been changed to:
At the FEV, MEV, YEV, Last Evaluation Period Visit, and EDV, healthcare provider 
consultations not foreseen by the protocol will be recorded in the CRF. It will include 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. At the EV, data will be obtained from the last visit of the previous study,
N01358 or N01258, and do not need to be recorded on the CRF for this study. Healthcare 
provider consultations not foreseen by the protocol will be recorded for the first 2 years.
Change #38
Section 9.1.6 Hospital stays
Original text
At the FEV, MEV, YEV, Last Evaluation Period Visit, and EDV, data on hospital stays will 
be collected in the CRF. It will include the reason leading to the hospitalization, the 
admission ward, transfers, and length of stay. At the EV, data will be obtained from the last 
visit of the previous study, N01358 and do not need to be recorded on the CRF for this study. 
Hospital stays will be recorded for the first 2 years.
Has been changed to:
At the FEV, MEV, YEV, Last Evaluation Period Visit, and EDV, data on hospital stays will 
be collected in the CRF. It will include the reason leading to the hospitalization, the 
admission ward, transfers, and length of stay. At the EV, data will be obtained from the last 
visit of the previous study, N01358 or N01258, and do not need to be recorded on the CRF 
for this study. Hospital stays will be recorded for the first 2 years.
Change #39
Section 10.4
Laboratory measurements
Original text
Laboratory assessments (including hematology, blood chemistry, and urinalysis) 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 total blood volume drawn for clinical laboratory assessments will be a maximum of 
11mL per sampling, which includes 3mL for hematology and 8mL for blood chemistry. 
The subject must be preferably fasting, but study medication intake must not be delayed.  
The following laboratory assessments will be conducted:
Hematology
Blood chemistry
Urinalysis
Pregnancy
WBC
Glucose
Glucose
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 94 of 129
Hematology
Blood chemistry
Urinalysis
Pregnancy
Hemoglobin
Potassium
Occult blood
Hematocrit
Calcium
Protein
MCV
Chloride
Nitrites
MCH
Bicarbonate
Leukocytes
MCHC
Phosphorus (inorganic)
Microscopic exama
Platelet count
Total protein
Lymphocytes (number, %)
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ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); β-hCG=beta-human chorionic gonadotropin; 
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hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cells; WBC=white blood cells
a.
Including bacteria, cells, casts, and crystals will be performed for all samples.
Has been changed to:
10.4.1 Safety laboratory assessments
Laboratory assessments (including hematology, blood chemistry, endocrinology, and 
urinalysis) 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 total blood volume drawn for clinical laboratory assessments will be a maximum of 
11mL per sampling, which includes 3mL for hematology and 8mL for blood chemistry. In 
addition, a 10mL blood sample for the DNA analysis will be collected at the EV in 
consenting adult subjects from N01358.
The subject must be preferably fasting, but study medication intake must not be delayed.  
The following laboratory assessments will be conducted:
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 95 of 129
Hematology
Blood chemistry
Urinalysis
Endo-
crinology
Pregnancy
WBC
Glucose
Glucose
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hemoglobin concentration; MCV=mean corpuscular volume; MEV=Minimal Evaluation Visit; RBC=red 
blood cells; TSH=thyroid-stimulating hormone; WBC=white blood cells; YEV=Yearly Evaluation Visit
a    Thyroid-stimulating hormone will be assessed at each YEV.
b    Including bacteria, cells, casts, and crystals will be performed for all samples.
c    Liver function tests will be assessed at MEVs (Visit 4 and Visit 6) during the first year in addition to 
the full laboratory assessments described in Section 8.
Change #40
Section 10.4
Laboratory measurements, last 2 paragraphs
Original text
Laboratory safety assessments at the EV will be taken from the last visit of N01358 and do 
not need to be recorded on the CRF. Thereafter, laboratory safety assessments will be 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 96 of 129
performed at the FEV, YEV, Last Evaluation Period Visit, and EDV. Laboratory assessments 
will also be mandatory at the FV, except if the FV follows an EDV where laboratory results 
were normal.
Results for hematology, blood chemistry, urinalysis, and pregnancy tests will be provided by 
fax to the Investigator within 72 hours after sample receipt. Results will be reported by the 
central laboratory to the Investigator as exact values, with a flag to those values that are 
outside the therapeutic range. 
Has been changed to:
10.4.1 Safety laboratory assessments
Laboratory safety assessments at the EV will be taken from the last visit of N01358 or 
N01258 and do not need to be recorded on the CRF. Thereafter, laboratory safety 
assessments will be performed at the FEV, YEV, Last Evaluation Period Visit, and EDV. In 
addition, liver function tests will be performed at MEVs (Visit 4 and Visit 6) during the first 
year. Endocrinology (TSH) measurements will be performed at YEVs only. Laboratory 
assessments will also be mandatory at the FV, except if the FV follows an EDV where 
laboratory results were normal.
Results for hematology, blood chemistry, urinalysis, endocrinology, and pregnancy tests will 
be provided by fax to the Investigator within 72 hours after sample receipt. Results will be 
reported by the central laboratory to the Investigator as exact values, with a flag to those 
values that are outside the therapeutic range. 
Change #41
The following paragraph has been added to Section 10.4.
Section 10.4.2DNA analysis
For subjects coming from N01358, a blood sample for DNA analysis will be collected at 
the EV in order to explore a possible correlation between the SV2 gene variations and 
the subject’s response to BRV. Blood samples for DNA analysis will be collected only in 
adults where ethically accepted and authorized by legal authorities. The DNA analysis 
will be done in a separate report at the program level.
Samples will be split into 2 aliquots and will be initially stored at the central laboratory and 
will then be shipped to the genotyping facility for DNA extraction and genotyping. Samples 
will be stored at -20°C for a period of up to 20 years. 
Change #42
Section 10.5.3Body weight and height
Original text
Body weight (subject wearing light clothing without shoes and rounded to the nearest 
kilogram or pound) will be measured at the EV, FEV, YEV, Last Evaluation Period Visit, 
EDV, and FV. Height will be obtained from Visit 1 in N01358. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 97 of 129
Has been changed to:
Body weight (subject wearing light clothing without shoes and rounded to the nearest 
kilogram or pound) will be measured at the EV, FEV, YEV, Last Evaluation Period Visit, 
EDV, and FV. Height will be obtained from Visit 1 in N01358 or N01258. 
Change #43
Section 12.1
Definition of analysis populations
Original text
The Efficacy Population will consist of all subjects who took at least 1 dose of study
medication and have at least 1 seizure diary during the Evaluation Period.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
Has been changed to:
Efficacy Populations will consist of all subjects who took at least 1 dose of study medication 
and have at least 1 seizure diary during the Evaluation Period. Separate Efficacy 
Populations will be defined for subjects with POS and subjects with generalized 
epilepsy.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
Change #44
Section 12.3.2 Analysis of the secondary efficacy variables
Original text
The following secondary efficacy variables will be summarized with descriptive statistics. 
∀
Seizure frequency per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
∀
Responder rate in POS (type I) by 3-month periods over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from the 
Baseline Period for the double-blind study N01358. 
Has been changed to:
The following secondary efficacy variables will be summarized with descriptive statistics. 
∀
Seizure frequency per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 98 of 129
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
∀
Responder rate in POS (type I) by 3-month periods over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from the 
Baseline Period for the double-blind study N01358. 
Responder rates will not be evaluated for subjects from N01258 due to the short 
duration of the Baseline Period for this study.
Change #45
Section 12.3.3 Analysis of the other efficacy variables
Original text
The following other efficacy variables will be summarized with descriptive statistics. 
∀
Change in QOLIE-31-P scores from the Baseline of N01358 to each assessment for the 
first 2 years and to the last Evaluation Period assessment during the first 2 years 
∀
Change in HADS scores from the Baseline of N01358 to each assessment for the first 
2 years and to the last Evaluation Period assessment during the first 2 years
∀
Medical resources use during the first 2 years of the Evaluation Period
∀
Change in socio-professional data from the Baseline of N01358 to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years 
Has been changed to:
12.3.3.1
Seizure-related other efficacy variables
For subjects from N01258 with generalized epilepsy:
∀
Generalized (type II) seizure days standardized to a 28-day duration by 3-month 
periods over the Evaluation Period
∀
Seizure days per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
Some variables may not be assessed if the number of subjects with generalized epilepsy 
is insufficient.
12.3.3.2
Nonseizure-related other efficacy variables
The following other efficacy variables will be summarized with descriptive statistics.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 99 of 129
∀
Medical resources use during the first 2 years of the Evaluation Period
∀
Change in QOLIE-31-P scores from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years 
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∀
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assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years 
Change #46
Section 12.8
Determination of sample size
Original text
For this open-label LTFU, no sample size calculation will be performed. The sample size will 
depend upon recruitment into and completion of the previous study. It is estimated that 
approximately 650 to 720 subjects will enter the study based on the assumption that at least 
90% of randomized subjects from N01358 will complete N01358 and enroll in N01379.
Has been changed to:
For this open-label LTFU, no sample size calculation will be performed. The sample size will 
depend upon recruitment into and completion of the previous studies. It is estimated that 
approximately 650 to 720 subjects from N01358 will enter the study based on the assumption 
that at least 90% of randomized subjects from N01358 will complete N01358 and enroll in 
N01379. Up to 100 subjects from N01258 may also be eligible.
Change #47
Section 13.1 Informed consent, paragraph 3
Original text
Prior to participation in the study, the written Informed Consent form 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 Informed Consent form. 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.
Has been changed to:
Prior to participation in the study, the written Informed Consent form 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). An additional written 
Informed Consent form should be signed and dated for adult subjects from N01358 
(without mental impairment) giving their consent to blood sampling for DNA analysis.
The subject or his/her legal representative must receive a copy of the signed and dated 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 100 of 129
Informed Consent form. 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.
Change #48
Section 15
REFERENCES
The following reference was added.
Goldstein DB, Need AC, Singh R, Sisodiya SM. Potential genetic causes of heterogeneity 
of treatment effects. T Am J Med. 2007;120(Suppl 1):S21-5.
16.4
Protocol Amendment 2
Rationale for the amendment
The main reasons for this protocol amendment are as follows:
∀
Procedures for reporting SAEs were updated to implement the Food and Drug 
Administration (FDA) Final Rule requirements.
∀
The C-SSRS was added to address the requirement of the FDA that prospective 
assessments for suicidality should be included in clinical studies involving all drugs for 
neurological indications.
∀
The study variables were rearranged to more appropriately show that the main purpose of 
N01379 is to evaluate long-term safety of BRV in this patient population. The HADS 
scores subsection was moved from Section 9 Assessment of Efficacy to Section 10 
Assessment of Safety and the statistical analysis section (Section 12) was updated to be 
consistent with the rearrangement of the study variables.
In addition, there were a few changes made to the protocol to update and clarify information, 
such as an update to the SAE reporting phone and fax numbers for the US and Canada.
Modifications and changes
Global changes
The following changes were made throughout the protocol:
∀
Inclusion of a suicidality assessment using the C-SSRS at each visit in response to the US 
FDA request. In addition, the exclusion and withdrawal criteria were updated to include 
the C-SSRS assessment.
∀
Inclusion of the list of Anticipated SAEs in Section 10.4 in response to the US FDA Final 
Rule. Due to this addition, subsequent sections within Section 10 were renumbered 
accordingly.
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 101 of 129
Specific changes
Change #1
Original title:
AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND EFFICACY OF BRIVARACETAM USED AS 
ADJUNCTIVE TREATMENT IN SUBJECTS AGED 16 YEARS OR OLDER WITH 
PARTIAL ONSET SEIZURES
Has been changed to:
AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND EFFICACY OF BRIVARACETAM USED AS 
ADJUNCTIVE TREATMENT IN SUBJECTS AGED 16 YEARS OR OLDER WITH 
EPILEPSY
Change #2
The clinical trial biostatistician was changed from 
 in both the 
SPONSOR DECLARATION and STUDY CONTACT INFORMATION sections.
Change #3
SERIOUS ADVERSE EVENT REPORTING
Original table:
Serious adverse event reporting (24h), safety related issues, and emergency 
unblinding
Fax
Europe and Rest of the World (except Japan): +32 2 386 24 21
USA and Canada: +1 800 880 6949 or +1 866 890 3175
Japan: +81 3 5283 1869
Phone
During business hours:
Outside business hours:
Europe and Rest of the World 
(except Japan): 
+32 2 386 24 68
USA and Canada: 
+1 919 767 2627 
Japan:
+81 3 5283 1814
Europe and Rest of the World 
(except Japan): 
+32 2 386 24 68
USA and Canada: 
+1 404 895 0794 
Japan:
+81 80 1100 5372
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 102 of 129
Has been changed to:
Serious adverse event reporting (24h), safety related issues, and emergency 
unblinding
Fax
Europe and Rest of the World (except Japan): +32 2 386 24 21
USA: +1 800 880 6949 
Canada: +1 877 582 8842
Japan: +81 3 5283 1869
Phone
During business hours:
Outside business hours:
Europe and Rest of the World 
(except Japan): 
+32 2 386 24 68
USA and Canada: 
+1 404 895 0794 
Japan:
+81 3 5283 1814
Europe and Rest of the World 
(except Japan): 
+32 2 386 24 68
USA and Canada: 
+1 404 895 0794 
Japan:
+81 80 1100 5372
Change #4
List of abbreviations
The following abbreviations were added to the list:
C-SSRS
Columbia-Suicide Severity Rating Scale
FDA
Food and Drug Administration
Change #5
Section 1 Summary
Original text:
Paragraphs 7 and 8:
Other nonseizure-related efficacy variables include the Patient Weighted Quality of Life in 
Epilepsy Inventory (QOLIE-31-P) scores, the Hospital Anxiety and Depression Scale 
(HADS) scores, medical resources use, and socio-professional data during the first 2 years of 
the Evaluation Period.
Safety variables include adverse events (AEs), laboratory tests (hematology, blood chemistry, 
urinalysis, endocrinology, and pregnancy test), electrocardiogram (ECG), vital signs, physical 
and neurological examinations, and body weight.
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 103 of 129
Has been changed to:
Other efficacy and pharmacoeconomic variables include the Patient Weighted Quality of 
Life in Epilepsy Inventory (QOLIE-31-P) scores, medical resources use, and 
socio-professional data during the first 2 years of the Evaluation Period.
Safety variables include adverse events (AEs), laboratory tests (hematology, blood chemistry, 
urinalysis, endocrinology, and pregnancy test), electrocardiogram (ECG), vital signs, physical 
and neurological examinations, the Hospital Anxiety and Depression Scale (HADS) 
scores, and body weight.
Change #6
Section 4 STUDY VARIABLES
Original Sections:
4.1 Efficacy variables
4.1.1
Primary efficacy variable
The primary efficacy variable is the POS (type I) seizure frequency standardized to a 28-day 
duration. This will be summarized by 3-month periods over the Evaluation Period.
4.1.2
Secondary efficacy variables
Secondary efficacy variables are as follows:
•
Seizure frequency per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
•
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
•
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
•
Responder rate in POS (type I) by 3-month periods over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from the 
Baseline Period for the double-blind study N01358.
Responder rates will not be evaluated for subjects from N01258 due to the short duration of 
the Baseline Period for this study.
4.1.3
Other efficacy variables
4.1.3.1 Seizure-related other efficacy variables
For subjects from N01258 with generalized epilepsy:
∀
Generalized (type II) seizure days standardized to a 28-day duration by 3-month periods 
over the Evaluation Period
∀
Seizure days per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 104 of 129
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
Some variables may not be assessed if the number of subjects with generalized epilepsy is 
insufficient.
4.1.3.2 Nonseizure-related other efficacy variables
The other efficacy variables are as follows:
∀
Medical resources use during the first 2 years of the Evaluation Period 
∀
Change in QOLIE-31-P scores from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years
∀
Change in HADS scores from the Baseline of N01358 or N01258 to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
∀
Change in socio-professional data from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years
4.2 Safety variables
∀
AEs
∀
Laboratory tests (including hematology, blood chemistry, urinalysis, and pregnancy test, 
and additional endocrinology once a year )
∀
ECG
∀
Physical examination
∀
Neurological examination
∀
Vital signs
∀
Body weight
Has been changed to:
4.1 Safety variables
4.1.1
Primary safety variables
∀
Occurrence of a TEAE
∀
Withdrawal due to AE
∀
Occurrence of an SAE
4.1.2
Other safety variables
∀
Laboratory tests (blood chemistry, hematology, urinalysis, endocrinology)
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 105 of 129
∀
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and 
body weight
∀
ECG
∀
Physical and neurological examinations
∀
Change in HADS scores from the Baseline of the previous study to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
4.2 Efficacy variables
4.2.1
Secondary efficacy variables
For subjects with focal-onset epilepsy:
∀
POS (type 1) frequency per 28 days during the Evaluation Period
∀
Percent reduction in POS (type 1) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period
∀
Responder rate in POS (type I) frequency over the Evaluation Period. A responder is 
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline Period 
of the previous study. 
No secondary efficacy variables are defined for subjects with generalized epilepsy.
4.2.2
Other efficacy variables
For subjects with focal-onset epilepsy:
∀
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period
For subjects with generalized epilepsy:
∀
Generalized (type II) seizure days per 28 days during the Evaluation Period
∀
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period
∀
Responder rate for generalized (type II) seizure days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure days from the Baseline 
Period of the previous study.
∀
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
∀
Change in QOLIE-31-P scores from Baseline of the previous study to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
4.3 Pharmacoeconomic variables
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 106 of 129
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
∀
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
[ER] visits) during the first 2 years of the Evaluation Period
∀
Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
Change #7
Section 5.2 Schedule of study assessments
Table 5:1 Schedule of study assessments
The “Laboratory assessments” row was renamed “Laboratory safety assessments,” and this 
row now includes an ‘Xi’ for the MEV column.  The corresponding ‘i’ footnote was added 
under the table and reads as follows:
i Liver function tests are the only laboratory assessments done at the MEV in M3 and M9 (see 
Section 10.5.1).
Subsequent footnotes were assigned sequential lettering due to the addition of new footnote.
A table row for C-SSRS was added and included this assessment at each study visit. In 
addition, the abbreviation C-SSRS and its definition were added to the table abbreviations.
Change #8
Section 6.2 Exclusion criteria
The following exclusion criterion was added:
7. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide 
Severity Rating Scale (C-SSRS) at the Entry Visit.
Change #9
Section 6.3 Withdrawal criteria
The following withdrawal criteria have been added to this section:
∀
Withdrawal criterion for subjects who completed a C-SSRS assessment at the Entry Visit:
#
Subject has active suicidal ideation as indicated by a positive response (“Yes”) to 
either Question 4 or 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.
∀
Withdrawal criteria for already enrolled subjects who did not complete a C-SSRS 
assessment at the Entry Visit:
#
Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of the 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 107 of 129
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must withdraw 
the subject from the study and immediately refer the subject to a Mental Healthcare 
Professional.
#
Subject had active suicidal ideation prior to study entry or since study start as 
indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must 
immediately refer the subject to a Mental Healthcare Professional and use clinical 
judgment as to whether to withdraw the subject from the study.
#
Subject has active suicidal ideation as indicated by a positive response (“Yes”) to
either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The 
subject should be referred immediately to a Mental Healthcare Professional and must 
be withdrawn from the study.
Change #10
Section 8 Study Procedures By Visit
The following C-SSRS assessment bullet was added to the lists for all study visits included in 
Section 8.1, Section 8.2, Section 8.3, Section 8.4, Section 8.6, and Section 8.8.
∀
Suicidality assessment (C-SSRS)
The laboratory safety assessment bullet in Section 8.1, Section 8.2, and Section 8.6 were 
updated as follows:
∀
Laboratory safety assessments: hematology, blood chemistry, urinalysis, and urine
pregnancy test (if applicable)
The laboratory safety assessment bullet in Section 8.4 was updated as follows:
∀
Laboratory safety assessments, including thyroid-stimulating hormone (TSH) 
assessments: hematology, blood chemistry, urinalysis, and urine pregnancy test (if 
applicable)
The laboratory safety assessment bullet in Section 8.8 was updated as follows:
∀
Laboratory safety assessments (mandatory, except if the FV follows an EDV where 
laboratory results were normal): hematology, blood chemistry, urinalysis, and urine 
pregnancy test (if applicable)
Change #11
Section 8.5 Unscheduled Visit
The C-SSRS suicidality assessment has been added to the bulleted list for an Unscheduled 
Visit as follows:
∀
Suicidality assessment (C-SSRS)
#
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 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 108 of 129
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.
Change #12
The title for Section 9.1 was changed.
Original title:
9.1 Additional efficacy assessments
Has been changed to:
9.1 Additional efficacy and pharmacoeconomic assessments
Change #13
The section describing the HADS scores assessment was moved from Section 9 Assessment 
of Efficacy to Section 10 Assessment of Safety to correspond with the realignment of 
variables in Section 4 Study Variables. No text in the section was changed, only the 
placement. After the deletion of the HADS scores section, the subsequent numbering of 
subsections within Section 9 changed accordingly.
Original section:
Section 9.1.2 HADS scores
The HADS (see Section 16.2) will be used to evaluate anxiety and depression/depressed 
mood of study subjects (Zigmond and Snaith, 1983). The HADS is an instrument that 
assesses the presence and severity of anxiety and depressed mood. It consists of 14 items that 
are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension (anxiety, 
depression) is calculated as recommended by the authors, ranging from 0 to 21 with higher 
scores indicating higher depression/anxiety. The HADS will be completed by subjects who 
are able to complete the assessments on their own, during the first 2 years at the FEV, YEV, 
Last Evaluation Period Visit, and EDV.
Has been changed to:
Section 10.6.7 HADS scores
The HADS (see Section 16.2) will be used to evaluate anxiety and depression/depressed 
mood of study subjects (Zigmond and Snaith, 1983). The HADS is an instrument that 
assesses the presence and severity of anxiety and depressed mood. It consists of 14 items that 
are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension (anxiety, 
depression) is calculated as recommended by the authors, ranging from 0 to 21 with higher 
scores indicating higher depression/anxiety. The HADS will be completed by subjects who 
are able to complete the assessments on their own, during the first 2 years at the FEV, YEV, 
Last Evaluation Period Visit, and EDV.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 109 of 129
Change #14
Section 10.1.6 Pregnancy
Original text:
Paragraph 4:
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. The health of the child must be 
followed for 12 months after birth for any significant medical issues.
Has been changed to:
Any 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. The health of the child may be followed 
for 12 months after birth for any significant medical issues.
Change #15
The following section was added to address the FDA Final Rule.  The subsequent section 
numbering within Section 10 was changed accordingly.
Section 10.4 Anticipated serious adverse events
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure: convulsion. This original list will remain in effect for the duration of the protocol. 
The list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 10.2.2.
Change #16
Due to the addition of Section 10.4 Anticipated serious adverse events, Section 10.4.1 Safety 
laboratory assessments was changed to Section 10.5.1 and the following change was made:
Section 10.5.1 Safety laboratory assessments
Original text:
Under laboratory assessments table:
The creatinine clearance (Cr Cl) will be calculated by the Cockroft’s formula:
∀
Male: Cr Cl mL/min=[(140-age) x body weight] / [72 x serum creatinine (mg/day)]
∀
Female: Cr Cl mL/min=([(140-age) x body weight] / [72 x serum creatinine (mg/day)]) x 
0.85 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 110 of 129
∀
Male: Cr Cl mL/min=[(140-age) x body weight] / [72 x serum creatinine (mg/dL)]
∀
Female: Cr Cl mL/min=([(140-age) x body weight] / [72 x serum creatinine (mg/dL)]) x 
0.85 
Change #17
Due to the addition of Section 10.4 Anticipated serious adverse events, Section 10.5 Other 
safety measurements was changed to Section 10.6.  The following subsection was added to 
this section:
Section 10.6.6 Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS. This scale will be 
used for screening as well as to assess suicidal ideation and behavior that may occur during 
the study. The C-SSRS will be completed according to the tabular schedule of study 
procedures, Section 5.2.
Change #18
Section 12 Statistics
Original sections:
A description of statistical methods is presented below and will be described in more detail in 
the Statistical Analysis Plan.
12.1
Definition of analysis populations
Efficacy Populations will consist of all subjects who took at least 1 dose of study medication 
and have at least 1 seizure diary during the Evaluation Period. Separate Efficacy Populations 
will be defined for subjects with POS and subjects with generalized epilepsy.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
12.2
General statistical considerations
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 75th 
percentile, 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 BRV dose. 
12.3
Planned efficacy analyses
12.3.1 Analysis of the primary efficacy variable
The following primary efficacy variable will be summarized with descriptive statistics. 
∀
The primary efficacy variable is the POS (type I) seizure frequency standardized to a 
28-day duration. The primary efficacy variable will be summarized by 3-month periods 
over the Evaluation Period.
12.3.2 Analysis of the secondary efficacy variables
The following secondary efficacy variables will be summarized with descriptive statistics. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 111 of 129
∀
Seizure frequency per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
∀
Responder rate in POS (type I) by 3-month periods over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure frequency from the 
Baseline Period for the double-blind study N01358. 
Responder rates will not be evaluated for subjects from N01258 due to the short duration of 
the Baseline Period for this study.
12.3.3 Analysis of the other efficacy variables
12.3.3.1
Seizure-related other efficacy variables
For subjects from N01258 with generalized epilepsy:
∀
Generalized (type II) seizure days standardized to a 28-day duration by 3-month periods 
over the Evaluation Period
∀
Seizure days per 28 days for all seizure types (I+II+III) by 3-month periods over the 
Evaluation Period
∀
Proportion of seizure-free days for all seizure types (I+II+III) by 3-month periods over 
the Evaluation Period
∀
Proportion of continuously seizure-free subjects for all seizure types (I+II+III) by 
3-month periods over the Evaluation Period
Some variables may not be assessed if the number of subjects with generalized epilepsy is 
insufficient.
12.3.3.2
Nonseizure-related other efficacy variables
The following other efficacy variables will be summarized with descriptive statistics.
∀
Medical resources use during the first 2 years of the Evaluation Period
∀
Change in QOLIE-31-P scores from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years 
∀
Change in HADS scores from the Baseline of N01358 or N01258 to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
∀
Change in socio-professional data from the Baseline of N01358 or N01258 to each 
assessment for the first 2 years and to the last Evaluation Period assessment during the 
first 2 years 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 112 of 129
12.4
Planned safety analyses
The long-term safety of BRV at individualized doses will be evaluated by means of the safety 
analyses. Summary tables will be presented over the Evaluation Period by time windows, by 
periods, and by categories of total duration of exposure.
All safety variables will be analyzed by descriptive methods on the Safety Population. 
Treatment-emergent adverse events will be summarized by categories of total duration of 
exposure, period, Medical Dictionary for Regulatory Activities (MedDRA®) Primary System 
Organ Class and Preferred Term in incidence tables. Separate tables will be provided, by 
categories of total duration of exposure, for AEs leading to withdrawal from the study and 
SAEs. 
Laboratory values, vital signs, and weight will be summarized by period and visit. Possibly 
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and 
weight will be listed and summarized by period and visit. ECG abnormalities, as well as 
physical and neurological abnormalities, will also be listed by period and visit.
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A description of statistical methods is presented below and will be described in more detail in 
the Statistical Analysis Plan.
12.1
Definition of analysis populations
Efficacy Populations will consist of all subjects who took at least 1 dose of study medication 
and have at least 1 seizure diary day during the Evaluation Period. Separate Efficacy 
Populations will be defined for subjects with focal epilepsy and subjects with generalized 
epilepsy.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
12.2
General statistical considerations
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 
75th percentile, 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 for all subjects combined. 
12.3
Planned safety analyses
The long-term safety of BRV at individualized doses will be evaluated by means of the safety 
analyses. Summary tables will be presented over the Evaluation Period for all subjects and 
by categories of total duration of exposure.
All safety variables will be analyzed by descriptive methods on the Safety Population. 
Treatment-emergent adverse events will be summarized in incidence tables by categories of 
total duration of exposure and by Medical Dictionary for Regulatory Activities (MedDRA®) 
Primary System Organ Class and Preferred Term. Separate tables will be provided for AEs 
leading to withdrawal from the study and SAEs. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 113 of 129
Laboratory values, vital signs, and weight will be summarized by period and visit. Possibly
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and 
weight will be listed and summarized by period and visit. Electrocardiogram abnormalities, 
as well as physical and neurological abnormalities, will also be listed by period and visit.
12.4
Planned efficacy analyses
All efficacy outcomes will be summarized with descriptive statistics only. Separate 
summaries will be provided for subjects with focal epilepsy and subjects with 
generalized epilepsy.
For subjects with focal epilepsy, 28-day adjusted seizure frequency will be calculated by 
dividing the number of partial seizures by the number of days for which the diary was 
completed, and multiplying the resulting value by 28. For subjects with generalized 
epilepsy, 28-day adjusted seizure days will be calculated by dividing the number of days 
with a generalized seizure by the number of days for which the diary was completed, 
and multiplying the resulting value by 28.
Responder rates will not be evaluated for subjects from N01258 due to the short 
duration of the Baseline Period for this study.
Some variables for subjects with generalized epilepsy may not be assessed if the number 
of subjects with generalized epilepsy is insufficient.
Change in QOLIE-31-P scores from Baseline of the previous study will be summarized 
with descriptive statistics for the first 2 years of the Evaluation Period.
12.5
Planned pharmacoeconomic analyses
Direct cost parameters and socio-professional data will be summarized with descriptive 
statistics for the first 2 years of the Evaluation Period.
16.5
Protocol Amendment 3
Rationale for the amendment
This protocol is being amended to align existing language with updated UCB Standard 
Operating Procedures (SOPs) and/or best practices as well as to allow for a named patient or 
compassionate use program (or similar) or for subjects to switch to another BRV study or to 
commercial BRV, if when, and where available.
Modifications and changes
Global changes
The following changes were made where applicable in this protocol:
∀
In accordance with new UCB SOP, the sponsor signature block was removed and 
replaced with a Sponsor Declaration (Section 18) and electronic signature.
∀
Outdated safety information was deleted from Section 2.4
∀
Update of the protocol contact information.
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15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 114 of 129
∀
The study duration language was revised to include the possibility of a named patient 
or compassionate use program (or similar) as a reason for ending the study duration.
∀
Language regarding Investigator deviation from the protocol in the event of a medical 
emergency (Section 11.1) was revised to align with current UCB standard language.
Specific changes
Change #1
Sponsor Declaration was moved from page 2 of protocol to Section 18. Signature block was 
deleted due to use of electronic signature.
Change #2
STUDY CONTACT INFORMATION
Original tables:
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 115 of 129
Have been changed to: 
Clinical Project Manager
Name:
, PhD
Address:
Alfred-Nobel-Str. 10
40789 Monheim am Rhein
Germany
Phone:
Fax:
Clinical Trial Biostatistician 
Name:
, PhD
Address:
8010 Arco Corporate Drive, Suite 100
Raleigh, NC  27617
United States
Phone:
Fax:
Clinical Monitoring Contract Research Organization
Name:
PRA HEALTHSCIENCES
Address:
4130 Park Lake Avenue, Suite 400 
Raleigh, NC  27612 
United States
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 116 of 129
Change #3
SERIOUS ADVERSE EVENT REPORTING
Original table:
Has been changed to:
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Email
Global: DSICT@ucb.com
Fax
Europe and Rest of the World: +32 2 386 2421
USA: +1 800 880 6949 
Canada: +1 877 582 8842
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 117 of 129
Change #4
List of Abbreviations
The following abbreviation was deleted: GCSP Global Clinical Safety and 
Pharmacovigilance.
The following abbreviation was added: PS
Patient Safety
Change #5
Section 1
Summary
Original text:
This study will enroll subjects (≥16 years) from N01358 with refractory partial onset seizures 
(POS) whether or not secondarily generalized and subjects (≥16 years) from N01258 with 
localization-related or generalized epilepsy. Subjects under 18 years may only be included 
where legally permitted and ethically accepted. Subjects have to complete the Treatment 
Period of N01358 or the Evaluation Period of N01258 prior to enrollment into N01379. 
Subjects from N01358 will be started on a BRV dose of 150mg/day at study entry and should 
be maintained at this dose for at least 2 weeks unless the subject is unable to tolerate 
treatment. Subjects from N01258 will start at a dose of BRV 200mg/day and should be 
maintained at this dose for at least 2 weeks unless the subject is unable to tolerate treatment. 
The BRV dose can be adjusted based on the individual subject’s seizure control and 
tolerability. However, the BRV dose may not exceed 200mg/day during the study. During the 
Evaluation Period, subjects will be invited to visit the clinical site monthly in the first 
3 months and every 3 months thereafter. The completion of the Evaluation Period or early 
discontinuation from N01379 is followed by a Down-Titration Period of up to 4 weeks and 
by a subsequent Posttreatment Period (between 2 and 4 weeks) during which the subject does 
not receive study drug. 
This LTFU study will run throughout the duration of the clinical development period of 
BRV, and will continue until a marketing authorization is granted by any Health Authority in 
an indication for the adjunctive treatment in adults (≥16 years) with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, or until BRV 
development is stopped by the Sponsor.
Has been changed to: 
This study will enroll subjects (≥16 years) from N01358 with refractory partial onset seizures 
(POS) whether or not secondarily generalized and subjects (≥16 years) from N01258 with 
localization-related or generalized epilepsy. Subjects under 18 years may only be included 
where legally permitted and ethically accepted. Subjects have to complete the Treatment 
Period of N01358 or the Evaluation Period of N01258 prior to enrollment into N01379. 
Subjects from N01358 will be started on a BRV dose of 150mg/day at study entry and should 
be maintained at this dose for at least 2 weeks unless the subject is unable to tolerate 
treatment. Subjects from N01258 will start at a dose of BRV 200mg/day and should be 
maintained at this dose for at least 2 weeks unless the subject is unable to tolerate treatment. 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 118 of 129
The BRV dose can be adjusted based on the individual subject’s seizure control and 
tolerability. However, the BRV dose may not exceed 200mg/day during the study. During the 
Evaluation Period, subjects will be invited to visit the clinical site monthly in the first 
3 months and every 3 months thereafter. The completion of the Evaluation Period or early 
discontinuation from N01379 is followed by a Down-Titration Period of up to 4 weeks and 
by a subsequent Posttreatment Period (between 2 and 4 weeks) during which the subject does 
not receive study drug, or subjects will be converted without down-titration to 
commercial BRV if, when, and where available. Alternatively, subjects may transition 
into another BRV study, or be initiated without down-titration into a managed access 
program, named patient program, compassionate use program, or similar type of access 
program as allowed per country-specific legal and regulatory requirements.
This LTFU study will run throughout the duration of the clinical development period of 
BRV, and will continue until a marketing authorization is granted by any Health Authority in 
an indication for the adjunctive treatment in adults (≥16 years) with refractory POS, whether 
or not secondarily generalized; until the Sponsor decides to close the study; until subjects 
transition to another BRV study; until a managed access program, named patient 
program, compassionate use program, or similar type of access program is established 
as allowed per country-specific requirement in addition to legal and regulatory 
guidelines; or until BRV development is stopped by the Sponsor.
Change #6
Section 2.4 Safety of BRV
Original text:
In Phase 2/3 studies, a favorable safety and tolerability profile has been demonstrated for 
BRV. The discontinuation rate and the discontinuation rate due to treatment-emergent 
adverse events (TEAEs) were low and similar to placebo (PBO) for all studies. The most 
frequently reported TEAEs were headache, somnolence, dizziness, and fatigue. The overall 
incidence of serious adverse events (SAEs) was low and similar to PBO. There were no 
clinically relevant changes in laboratory values, vital signs, or ECG abnormalities.
In addition, there are 2 ongoing open-label LTFU studies (N01125 and N01199) that include 
subjects with POS who completed one of the above Phase 2/3 well-controlled studies. As of 
05 Jan 2010, 1521 subjects have been enrolled into these studies and 1516 received study 
medication. The median duration of BRV exposure in LTFU studies was 52 weeks. The most 
frequently reported TEAEs based on interim safety monitoring review include headache, 
dizziness, nasopharyngitis, somnolence, convulsion, and fatigue. The most frequent TEAEs 
leading to premature discontinuation were convulsion, pregnancy, and depression. The only 
SAE occurring at a frequency >1% was convulsion (1.8%).
For additional details on the safety and efficacy of BRV, please refer to the Investigator’s 
Brochure.
Has been changed to: 
In Phase 2/3 studies, a favorable safety and tolerability profile has been demonstrated for 
BRV. The discontinuation rate and the discontinuation rate due to treatment-emergent 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 119 of 129
adverse events (TEAEs) were low for all studies. The most frequently reported TEAEs were 
headache, somnolence, dizziness, and fatigue. The overall incidence of serious adverse events 
(SAEs) was low. There were no clinically relevant changes in laboratory values, vital signs, 
or ECG abnormalities.
For additional details on the safety and efficacy of BRV, please refer to the Investigator’s 
Brochure.
Change #7
Section 5.1 Study description
Original text:
This is a Phase 3, open-label, LTFU, multicenter, noncomparative, and single-arm study. The 
subject population will be adults (≥16 years) with refractory POS whether or not secondarily 
generalized from N01358 and subjects with localization-related or generalized epilepsy from 
N01258. Subjects under 18 years may be included only where legally permitted and ethically 
accepted. Subjects must complete the Treatment Period of N01358 or the Evaluation Period 
of N01258 prior to enrollment into N01379. Upon completion or early discontinuation from 
N01379, there will be a Down-Titration Period, followed by a Posttreatment Period during 
which the subject will not receive study drug.
This LTFU study will run throughout the duration of the clinical development period of 
BRV, and will continue until a marketing authorization is granted by any Health Authority in 
an indication for the adjunctive treatment in adults (≥16 years) with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, or until BRV 
development is stopped by the Sponsor.
Subjects from N01358 will be started on oral BRV at a dose of 150mg/day (2 equally divided 
doses administered twice daily) at study entry and should be maintained at this dose for at 
least 2 weeks unless the subject is unable to tolerate treatment. Subjects from N01258 will be 
started at an oral dose of BRV 200mg/day (2 equally divided doses administered twice daily) 
and should be maintained at this dose for at least 2 weeks unless the subject is unable to 
tolerate treatment. The BRV dose can be adjusted based on the individual subject’s seizure 
control and tolerability. However, the BRV dose may not exceed 200mg/day during the study 
and must always be administered as a symmetrical morning and evening dose.
Has been changed to: 
This is a Phase 3, open-label, LTFU, multicenter, noncomparative, and single-arm study. The 
subject population will be adults (≥16 years) with refractory POS whether or not secondarily 
generalized from N01358 and subjects with localization-related or generalized epilepsy from 
N01258. Subjects under 18 years may be included only where legally permitted and ethically 
accepted. Subjects must complete the Treatment Period of N01358 or the Evaluation Period 
of N01258 prior to enrollment into N01379. Upon completion of the Evaluation Period or 
early discontinuation from N01379 there will be a Down-Titration Period followed by a 
Posttreatment Period during which the subject does not receive study drug, or subjects will 
be converted without down-titration to commercial BRV if, when, and where available. 
Alternatively, subjects may transition into another BRV study, or be initiated without 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 120 of 129
down-titration into a managed access program, named patient program, compassionate 
use program, or similar type of access program as allowed per country-specific legal 
and regulatory requirements.
Subjects from N01358 will be started on oral BRV at a dose of 150mg/day (2 equally divided 
doses administered twice daily) at study entry and should be maintained at this dose for at 
least 2 weeks unless the subject is unable to tolerate treatment. Subjects from N01258 will be 
started at an oral dose of BRV 200mg/day (2 equally divided doses administered twice daily) 
and should be maintained at this dose for at least 2 weeks unless the subject is unable to 
tolerate treatment. The BRV dose can be adjusted based on the individual subject’s seizure 
control and tolerability. However, the BRV dose may not exceed 200mg/day during the study 
and must always be administered as a symmetrical morning and evening dose.
Change #8
Section 5.1.1
Study duration per subject
Original text: 
Subject recruitment for the study will begin in approximately Q2 2011. For each subject, the 
study will last from study entry until either regulatory approval of BRV has been granted by 
any Health Authority in an indication of adjunctive treatment of POS, until the Sponsor 
decides to close the study, or until BRV development is stopped by the Sponsor.
The following study periods are defined:
•
Evaluation Period (Visit 1 until the Last Evaluation Period Visit or Early Discontinuation 
Visit [EDV]): Subjects who enroll in N01379 will immediately enter the Evaluation 
Period.
•
Down-Titration Period (up to 4 weeks)
◦
If the subject is discontinuing study drug, the Investigator will first plan an EDV 
followed by the progressive down-titration of study drug. 
◦
During the Down-Titration Period, the BRV dose may be decreased in steps of a 
maximum of 50mg/day on a weekly basis. A last down-titration step at 20mg/day 
for 1 week should be included prior to the Posttreatment Period.
•
Posttreatment Period (2 to 4 weeks): After completion of the Down-Titration Period, or
for those subjects who for extenuating circumstances do not complete a Down-Titration 
Period, the subject will be required to enter a Posttreatment Period for a minimum of 
2 weeks and a maximum of 4 weeks, followed by a Final Visit (FV).
•
The end of the study is defined as the date of the last visit of the last subject in the study.
Has been changed to: 
Subject recruitment for the study will begin in approximately Q2 2011. For each subject, the 
study will last from study entry until either regulatory approval of BRV has been granted by 
any Health Authority in an indication of adjunctive treatment of POS, until the Sponsor 
decides to close the study; until subjects transition to another BRV study; until a 
managed access program, named patient program, compassionate use program, or 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 121 of 129
similar type of access program is established as allowed per country-specific 
requirement in addition to legal and regulatory guidelines; or until BRV development is 
stopped by the Sponsor.
The following study periods are defined:
•
Evaluation Period (Visit 1 until the Last Evaluation Period Visit or Early Discontinuation 
Visit [EDV]): Subjects who enroll in N01379 will immediately enter the Evaluation 
Period.
•
Down-Titration Period (up to 4 weeks)
◦
If the subject is discontinuing study drug, the Investigator will first plan an EDV 
followed by the progressive down-titration of study drug. 
◦
During the Down-Titration Period, the BRV dose may be decreased in steps of a 
maximum of 50mg/day on a weekly basis. A last down-titration step at 20mg/day 
for 1 week should be included prior to the Posttreatment Period.
•
Posttreatment Period (2 to 4 weeks): After completion of the Down-Titration Period, or
for those subjects who for extenuating circumstances do not complete a Down-Titration 
Period, the subject will be required to enter a Posttreatment Period for a minimum of 
2 weeks and a maximum of 4 weeks, followed by a Final Visit (FV).
•
The end of the study is defined as the date of the last visit of the last subject in the study.
For subjects who transition to another BRV study or a managed access program or 
similar type of program or who will be converted to commercial BRV if, when, and 
where available, the Down-Titration Period and FV are not applicable.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 122 of 129
Change #9
Table 5-1: Schedule of study assessments
Original table:
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
(or Early 
Discontinuation 
Visit [EDV])
Down-Titration 
Phone Call 
(DTP)a
Final 
Visit
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Reference 
to Section
Visit 
V1
V3, V5, 
V9…
V2, V4, V6, 
V8, V10…
V7…
NA
NA
NA
5.3
Month 
M0
M2, M6, 
M18…
M1, M3, M9, 
M15, M21…
M12…
NA
NA
NA
5.3
ASSESSMENTS
End of study statusm
X
8.8
m    End of study status will be completed at the FV for subjects having performed an EDV (discontinued subjects) and for subjects leaving the study at the end of 
the program (completed subjects).
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 123 of 129
Has been changed to:
Entry 
Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
(or Early 
Discontinuation 
Visit [EDV])
Down-Titration 
Phone Call 
(DTP)a
Final 
Visit
(FV)
Reference 
to Section
Visit 
V1
V3, V5, 
V9…
V2, V4, V6, 
V8, V10…
V7…
NA
NA
NA
5.3
Month 
M0
M2, M6, 
M18…
M1, M3, M9, 
M15, M21…
M12…
NA
NA
NA
5.3
ASSESSMENTS
End of study statusm
X
X
8.8
m    End of study status will be completed at the FV for subjects having performed an EDV and down-titration of BRV (discontinued subjects) and for subjects 
leaving the study at the end of the program (completed subjects). Alternatively, end of study status will be completed at the EDV for subjects who may 
transition into another BRV study, or be initiated without down-titration in a managed access program, named patient program, compassionate use 
program, or similar type of access program as allowed per country-specific legal and regulatory requirements, or for subjects who will be converted 
without down-titration to commercial BRV if, when, and where available.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 124 of 129
Change #10
Section 8.6 Last Evaluation Period Visit or Early Discontinuation Visit
Original text:
∀
QOLIE-31-P (if the EDV occurs within the first 2 years)
∀
HADS (if the EDV occurs within the first 2 years)
∀
Vital signs
∀
Weight
∀
Physical examination
∀
Neurological examination
∀
ECG
∀
IVRS call
∀
DRC dispensed 
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (if the EDV occurs within the first 2 years)
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol (if the EDV occurs within 
the first 2 years)
∀
Socio-professional data (if the EDV occurs within the first 2 years)
∀
Laboratory safety assessments: hematology, blood chemistry, urinalysis, and urine 
pregnancy test (if applicable)
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing 
∀
Drug return/accountability
Has been changed to: 
For subjects who transition to another BRV study or a managed access program or 
similar type of program or who convert to commercial BRV (if, when, and where 
available), the EDV will need to be completed; however, down-titration and FV are not
applicable.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 125 of 129
∀
QOLIE-31-P (if the EDV occurs within the first 2 years)
∀
HADS (if the EDV occurs within the first 2 years)
∀
Vital signs
∀
Weight
∀
Physical examination
∀
Neurological examination
∀
ECG
∀
IVRS call
∀
DRC dispensed (if applicable; DRC not dispensed if subject will not down-titrate)
∀
DRC retrieved
∀
Recording of seizures
∀
Hospital stays (if the EDV occurs within the first 2 years)
∀
Suicidality assessment (C-SSRS)
∀
Healthcare provider consultations not foreseen by the protocol (if the EDV occurs within 
the first 2 years)
∀
Socio-professional data (if the EDV occurs within the first 2 years)
∀
Laboratory safety assessments: hematology, blood chemistry, urinalysis, and urine 
pregnancy test (if applicable)
∀
Recording of AEs
∀
Medical procedures
∀
Concomitant AED
∀
Concomitant non-AED
∀
Drug dispensing (if applicable; drug not dispensed if subject will not down-titrate)
∀
Drug return/accountability
∀
End of study status (if the subject will not down-titrate)
Change #11
Section 8.7 Down-Titration Phone Call
Original text:
∀
Recording of AEs
The Down-Titration Phone Call at the end of the Down-Titration Period is mandatory.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 126 of 129
Has been changed to:
∀
Recording of AEs 
The Down-Titration Phone Call at the end of the Down-Titration Period is mandatory.
Down-titration is not applicable to subjects who transition to another BRV study or a 
managed access program or similar type of program or who convert to commercial 
BRV (if, when, and where available).  
Change #12
Section 8.8 Final Visit
The following text was added after the list of Final Visit procedures: 
The FV is not applicable to subjects who transition to another BRV study or a managed 
access program or similar type of program or who convert to commercial BRV (if, 
when, and where available).
Change #13
Section 10.1.6 Pregnancy
Original text:
Should a subject become pregnant after the first intake of any IMP, UCB’s Global Clinical 
Safety and Pharmacovigilance (GCSP) department should be informed immediately. The 
subject should be withdrawn from the study as soon as pregnancy is known and the following 
should be completed:
Has been changed to:
Should a subject become pregnant after the first intake of any IMP, UCB’s Patient Safety 
(PS) department should be informed immediately. The subject should be withdrawn from the 
study as soon as pregnancy is known and the following should be completed:
Change #14
Section 10.2.2 Procedures for reporting serious adverse events
Original text:
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information 
by the site (see contact numbers for SAE reporting listed in the Serious Adverse Event 
Reporting section at the front of the protocol). The Investigator must forward to UCB (or its 
representative) a duly completed Investigator SAE Report form 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.
Has been changed to:
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information 
by the site (see contact details for SAE reporting listed in the Serious Adverse Event 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 127 of 129
Reporting section at the front of the protocol). The Investigator must forward to UCB (or its 
representative) a duly completed Investigator 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.
Change #15
Section 10.2.3 Follow-up of serious adverse events
Original text: 
An SAE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow-up. 
Information on SAEs obtained after clinical database lock will be captured through the GCSP 
database without limitation of time.
Has been changed to:
An SAE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow-up. 
Information on SAEs obtained after clinical database lock will be captured through the PS
database without limitation of time.
Change #16
Section 11.1
Adherence to protocol
Original text:
The Investigator should not deviate from the protocol. In medical emergencies, the 
Investigator may use his/her medical judgment and may remove a study participant from 
immediate hazard before notifying UCB (or its representative) and the IRB/IEC in writing 
regarding the type of emergency and the course of action taken. 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 appropriate regulatory authorities, if applicable, prior to being 
implemented.
Has been changed to:
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. 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 appropriate regulatory authorities, if applicable, prior to being 
implemented.
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 128 of 129
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 sub-Investigators and other staff members read and understand all 
aspects of this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be 
treated confidentially, and will not be made available to third parties without prior 
authorization by UCB.
All rights of publication of the results reside with UCB, unless other agreements were made 
in a separate contract.
Investigator:
__________________________________
Printed Name
__________________________________
Date/Signature
REDACTED 
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 129 of 129
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.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

ELECTRONIC SIGNATURES
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