Conditions: Epilepsy
Keywords: Epilepsy Brivaracetam Partial Onset Seizures Adjunctive treatment
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 767
Healthy volunteers: no

Brief summary:
This is a Phase 3, open label, long term follow-up (LTFU), multicenter, noncomparative, and single arm study of brivaracetam (BRV).

Detailed description:
The primary objective is to evaluate the long term safety and tolerability of BRV at individualized doses up to a maximum of 200 mg/day in epilepsy subjects.

Arms:
arm 1: Brivaracetam with a maximum of 200 mg/day

Interventions: intervention 1: Brivaracetam
Intervention descriptions: intervention 1: Tablet, Flexible dosing up to 200 mg/day, twice daily.

The study will continue until either regulatory approval of brivaracetam has been granted by any Health Authority in an indication of adjunctive treatment of partial onset seizures or until the Sponsor decides to close the study, or until the investigational product development is stopped by the Sponsor.

Protocol document:
Prot_000.pdf: 
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 
This document cannot be used to support any marketing authorization application and any extensions 
sio
or r variations 
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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
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Brivaracetam
N01379
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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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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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UCB
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 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
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Month
M0
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M18…
M1, M3, M9, 
M15, M21…
M12…
NA
NA
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5.3
ASSESSMENTS
Written Informed Consent
X
13.1
Written Informed Consent for 
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N01358)
X
13.1
Subject identification card 
dispensing
X
13.2
Verification inclusion/ exclusion 
criteria
X
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Childbearing potential
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8.1
General medical and procedures 
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Epilepsy history
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AED history
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Vital signs
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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 
(or Early 
Discontinuation 
Visit [EDV])
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Phone Call 
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Final 
Visit
(FV)
Reference 
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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
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5.3
Weight and heightd
X
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X
X
X
10.6.3
Physical examination
Xc
X
X
X
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10.6.4
Neurological examination
Xc
X
X
X
X
10.6.5
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Xc
X
X
X
X
10.6.1
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X
X
X
X
X
X
7.10
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X
X
X
X
X
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Daily record card retrieved
X
X
X
X
X
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Recording of seizures
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X
X
X
X
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X
X
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X
X
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X
X
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X
X
X
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X
X
X
9.1.4
Laboratory safety assessmentsh
Xc
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Xi
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X
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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 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Last Evaluation 
Period Visit 
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Visit
V1
V3, V5, 
V9…
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V8, V10…
V7…
NA
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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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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)
∀
Laboratory safety assessments: hematology, blood chemistry, urinalysis, and urine
pregnancy test (if applicable)
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Medical procedures
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∀
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∀
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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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UCB
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
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Medical procedures
∀
Concomitant AED
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Concomitant non-AED
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∀
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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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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UCB
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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UCB
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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UCB
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
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terminology and concepts for organization of seizures and epilepsies: report of the ILAE 
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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
application
nfiden
nfiden
fied
fied on
on
esig
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and any extensions
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UCB
15 May 2015
Clinical Study Protocol 
Brivaracetam
N01379
Confidential
Page 55 of 129
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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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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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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:
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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.
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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
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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 
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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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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
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M3
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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
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-
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M11
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Second year follow-upa
Month
Visit
Type of visit
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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.
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
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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
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DRC retrieved
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Recording of seizures
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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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UCB
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, %)
Albumin
Monocytes (number, %)
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Alkaline phosphatase
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Basophils (number, %)
ALT (SGPT)
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Uric acid
Urea
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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; 
GGT=gamma-glutamyltransferase; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
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
TSHa
β-hCG
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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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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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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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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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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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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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UCB
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 
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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
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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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SAP_001.pdf: 
UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 1 of 46
STATISTICAL ANALYSIS PLAN (SAP) 
Study: N01379
Product: Brivaracetam
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
SAP/Amendment Number
Date
Final SAP
SAP Amendment 1
27 January 2014
28 January 2019
Confidentiality Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB.
REDACTED 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 2 of 46
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS..............................................................................................6 
1 
INTRODUCTION .......................................................................................................8 
2 
PROTOCOL SUMMARY...........................................................................................8 
2.1 
Study objectives.................................................................................................8 
2.1.1 
Primary objective.....................................................................................8 
2.1.2 
Secondary objective.................................................................................8 
2.1.3 
Exploratory objectives .............................................................................8 
2.2 
Study variables...................................................................................................8 
2.2.1 
Safety variables........................................................................................8 
2.2.1.1 
Primary safety variables.................................................................8 
2.2.1.2 
Other safety variables.....................................................................8 
2.2.2 
Efficacy variables ....................................................................................9 
2.2.2.1 
Secondary efficacy variables .........................................................9 
2.2.2.2 
Other efficacy variables .................................................................9 
2.2.2.3 
Pharmacoeconomic variables.........................................................9 
2.3 
Study Design and Conduct...............................................................................10 
2.4 
Determination of Sample Size .........................................................................12 
3 
DATA ANALYSIS CONSIDERATIONS................................................................12 
3.1 
General presentation of summaries and analyses ............................................12 
3.2 
Analysis time points.........................................................................................12 
3.2.1 
First and last dose of BRV.....................................................................12 
3.2.2 
Relative day ...........................................................................................12 
3.2.3 
Study Entry Visit ...................................................................................12 
3.2.4 
Study periods .........................................................................................13 
3.2.5 
Monthly time intervals...........................................................................14 
3.2.6 
Last Value on BRV Treatment ..............................................................15 
3.2.7 
Exposure duration and exposure duration cohorts.................................15 
3.2.8 
Study visit cohorts .................................................................................15 
3.3 
Definition of Baseline Values..........................................................................16 
3.4 
Protocol deviations...........................................................................................16 
3.5 
Analysis populations........................................................................................16 
3.5.1 
Safety Population...................................................................................16 
3.5.2 
Efficacy populations ..............................................................................16 
3.6 
Treatment Assignment and Treatment Groups................................................16 
3.7 
Coding dictionaries ..........................................................................................17 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 3 of 46
3.8 
Definitions of study-specific derived variables ...............................................17 
3.8.1 
Calculation of seizure frequency/days...................................................17 
3.8.1.1 
Initial seizure data processing......................................................17 
3.8.1.2 
Calculation of adjusted seizure frequency ...................................17 
3.8.1.3 
Calculation of adjusted seizure days............................................17 
3.8.2 
QOLIE-31-P...........................................................................................18 
3.8.3 
HADS.....................................................................................................19 
4 
STATISTICAL/ANALYTICAL ISSUES.................................................................19 
4.1 
Adjustments for covariates ..............................................................................19 
4.2 
Handling of dropouts or missing data..............................................................19 
4.3 
Interim analyses and data monitoring..............................................................20 
4.4 
Multicenter studies...........................................................................................20 
4.5 
Multiple comparisons/multiplicity...................................................................20 
4.6 
Use of an “Efficacy Subset” of subjects ..........................................................20 
4.7 
Active-control studies intended to show equivalence......................................20 
4.8 
Examination of subgroups ...............................................................................20 
5 
STUDY POPULATION CHARACTERISTICS.......................................................21 
5.1 
Subject disposition...........................................................................................21 
5.2 
Protocol Deviations..........................................................................................23 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..................23 
6.1 
Demographics ..................................................................................................23 
6.2 
Medical and procedure history.........................................................................24 
6.2.1 
Medical history diseases ........................................................................24 
6.2.2 
Procedure history and concomitant procedures.....................................24 
6.3 
History of epilepsy...........................................................................................24 
6.3.1 
Etiology of epilepsy...............................................................................24 
6.3.2 
Epileptic seizure profile.........................................................................24 
6.3.3 
Classification of epileptic syndrome......................................................25 
6.3.4 
Focus localization ..................................................................................25 
6.3.5 
History of epileptic seizures ..................................................................25 
6.3.6 
Seizure types experienced during baseline of the prior study ...............25 
6.4 
Medications......................................................................................................25 
6.4.1 
Non-AEDs taken at study entry.............................................................26 
6.4.2 
Number of previous AEDs ....................................................................26 
6.4.3 
History of previous AED use.................................................................26 
6.4.4 
AEDs taken at study entry .....................................................................26 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 4 of 46
7 
MEASUREMENTS OF TREATMENT COMPLIANCE.........................................26 
8 
EFFICACY ANALYSES ..........................................................................................27 
8.1 
Statistical analyses of secondary efficacy variables ........................................27 
8.1.1 
Partial onset seizure frequency ..............................................................27 
8.1.2 
Percent reduction in POS frequency......................................................27 
8.1.3 
Responder outcome for POS frequency.................................................28 
8.2 
Analysis of other efficacy variables.................................................................28 
8.2.1 
Subjects with partial onset seizures .......................................................28 
8.2.2 
Subjects with Primary Generalized Seizures.........................................29 
8.2.2.1 
All type seizure days....................................................................29 
8.2.2.2 
Percent reduction in all type seizure days....................................29 
8.2.2.3 
Responder outcome for all type seizure days...............................29 
8.2.2.4 
Specified month seizure freedom.................................................29 
8.2.3 
QOLIE-31-P...........................................................................................29 
8.2.4 
Direct cost parameters ...........................................................................30 
8.2.6 
Socio-professional data..........................................................................30 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS ....................................30 
10 IMMUNOLOGICAL PROCEDURES......................................................................30 
11 SAFETY ANALYSES...............................................................................................30 
11.2 
Adverse events.................................................................................................31 
11.2.1 
Definition of treatment-emergent AE....................................................31 
11.2.2 
General summaries of TEAEs ...............................................................32 
11.3 
Clinical laboratory evaluations ........................................................................33 
11.3.1 
Hematology and blood chemistry parameters .......................................33 
11.3.3 
Endocrinology parameters .....................................................................34 
11.4 
Vital signs, physical findings, and other observations related to safety..........35 
11.4.1 
Vital signs ..............................................................................................35 
11.4.2 
Electrocardiograms ................................................................................36 
11.4.3 
Physical examination .............................................................................36 
11.4.4 
Neurological examination......................................................................36 
11.4.5 
HADS.....................................................................................................36 
11.4.6 
Columbia-Suicide Severity Rating Scale...............................................37 
12 REFERENCES ..........................................................................................................37 
13 APPENDICES ...........................................................................................................38 
13.1 
QOLIE-31-P total and subscale score calculations..........................................38 
13.2 
Subject site transfers ........................................................................................40 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 5 of 46
13.3 
PCST Criteria...................................................................................................41 
13.3.1 
Hematology parameters .........................................................................41 
13.3.2 
Hematology parameters .........................................................................42 
13.3.3 
Urinalysis...............................................................................................44 
13.3.4 
Vital signs and body weight...................................................................44 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 6 of 46
LIST OF ABBREVIATIONS 
AE
adverse event
AED
antiepileptic drug
ALP
Alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Class
BMI
body mass index
bpm
Beats per minute
BRV
brivaracetam
BUN
blood urea nitrogen
CHMP
Committee for Medicinal Products for Human Use
CR CL
creatinine clearance
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
DBP
diastolic blood pressure
ECG
electrocardiogram
EDV
Early Discontinuation Visit
ER
emergency room
EU
European Union
F
Female
FDA
Food and Drug Administration
FEV
Full Evaluation Visit
FV
Final Visit
GGT
Gamma-glutamyl transpeptidase 
HADS
Hospital Anxiety and Depression Scale
HDL
High-density lipoprotein 
HRQoL
Health-Related Quality of Life
ILAE
International League Against Epilepsy
LDL
low-density lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
M
Male
MEV
Minimal Evaluation Visit
N/A
Not applicable
PBO
placebo
PCST
potentially clinically significant treatment-emergent
PGS
primary generalized seizures
POS
partial onset seizure
PT
preferred term 
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy 
Questionnaire
RBC 
Red Blood Cell
SAE
serious adverse event
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 7 of 46
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
Upper Limit of Normal
V
Visit
VAS
visual analog scale
WBC
White Blood Cell
WHO-DRL
World Health Organization Drug Reference List
YEV
Yearly Evaluation Visit
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 8 of 46
1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report for N01379.
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized
doses with a maximum of 200mg/day in subjects suffering from epilepsy
2.1.2 
Secondary objective 
To evaluate the maintenance of efficacy over time of BRV (for subjects with partial onset 
seizures [POS] and subjects with primary generalized seizures [PGS])
2.1.3 
Exploratory objectives 
Exploratory objectives for subjects with POS/PGS:
x To explore the effects of BRV on subjects’ Health-Related Quality of Life (HRQoL)
x To explore direct medical resource use
x To explore any change in socio-professional status
x To assess the role of gene variants of synaptic vesicle protein 2 (SV2) in affecting 
response to BRV (as part of a DNA analysis at the program level)
2.2 
Study variables 
2.2.1 
Safety variables 
2.2.1.1 
Primary safety variables 
x Occurrence of a treatment-emergent adverse event (TEAE)
x Withdrawal due to adverse event (AE)
x Occurrence of a serious adverse event (SAE)
2.2.1.2 
Other safety variables 
x Laboratory tests (blood chemistry, hematology, urinalysis, and endocrinology)
x Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and 
body weight
x Electrocardiogram (ECG)
x Physical and neurological examinations
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 9 of 46
x Change in Hospital Anxiety and Depression Scale (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
2.2.2 
Efficacy variables 
2.2.2.1 
Secondary efficacy variables 
For subjects with focal-onset epilepsy:
x POS (type I) frequency per 28 days during the Evaluation Period
x Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period
x Responder rate for 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
2.2.2.2 
Other efficacy variables 
For subjects with focal-onset epilepsy:
x 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:
x Generalized (type II) seizure days per 28 days during the Evaluation Period
x Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period
x 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.
x 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:
x Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (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
2.2.2.3 
Pharmacoeconomic variables 
Due to the inconsistencies in data captured and collection forms across LTFU studies, the 
following variables will be provided in subject data listings only, but will not be evaluated or 
descriptive summarized:
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 10 of 46
x 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
x 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
2.3 
Study Design and Conduct 
This is an open-label, long-term follow-up, multicenter, noncomparative, single-arm study of
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 subjects with epilepsy. The 
secondary objective is to evaluate the maintenance of efficacy of BRV. Exploratory
objectives are to assess the effects of BRV on subjects’ HRQoL, obtain information on the 
direct costs, explore changes in socio-professional status, and assess the role of gene variants 
of SV2. DNA analysis will only be done for those subjects coming from N01358.
Study N01379 enrolled subjects 16 years of age and older who had completed N01358 or 
N01258. Study N01358 enrolled subjects with refractory partial onset seizures (POS) whether 
or not secondarily generalized and N01258 enrolled subjects with localization-related or 
generalized epilepsy (designated as “PGS subjects”).
Subjects from N01258 were 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. Subjects from N01358 were 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 was unable 
to tolerate treatment.
Subjects who enroll in the study entered an Evaluation Period during which treatment with 
BRV was initiated. The dose of BRV can be adjusted based on the individual subject’s 
seizure control and tolerability. Dose increases can be made in increments of 50mg/day on a 
weekly basis up to a maximum of 200mg/day; dose decreases can be made in steps of 
50mg/day on a weekly basis. Subjects who discontinue treatment with BRV enter a Down-
Titration Period during which the dose of BRV is decreased in steps of 50mg/day on a 
weekly basis with a last down-titration step at 20mg/day for 1 week. Subjects who have 
completed the Down-Titration Period or subjects who discontinue during the Evaluation 
Period without entering the Down-Titration Period enter a Post-Treatment Period for a 
minimum of 2 weeks and a maximum of 4 weeks.
The maximum allowable daily dose for this study is 200mg/day based on the protocol. It is 
recommended that the daily dose be administered in 2 equal intakes.
Dose adjustment to concomitant AEDs may be made at any time during the study and 
subjects may start new AEDs. Concomitant AEDs may also be discontinued.
The visit schedule for this study is the same without regard to the subject’s previous study. 
Study visits at Months 2, 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 11 of 46
or Yearly Evaluation Visits (YEVs) at which a greater number of assessments are performed. 
Study visits at Months 1, 3, 9, 15, 21, and so forth are Minimal Evaluation Visits (MEVs). In 
addition, a phone call is scheduled at the end of the Down-Titration Period and a Drug-Free
Final Visit (FV) is scheduled at the end of the Post-Treatment Period. The study schedule, as 
just described, is shown in Table 2‒1.
Table 2‒1: 
Study Schedule 
1st Year Follow-up
Month
Visit
Type of Visit
M0
V1
Entry Visit (EV)
M1
V2
MEV
M2
V3
FEV
M3
V4
MEV
M4
M5
M6
V5
FEV
M7
M8
M9
V6
MEV
M10
M11
2nd and subsequent years follow-up
M12
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YEV
M15
V8
MEV1
M18
V9
FEV
M21
V10
MEV2
...
...
...
FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month, V=Visit, YEV=Yearly Evaluation 
Visit
All subjects should have a Visit 1 at the start of N01379. Visit 1 will correspond to the last 
visit from the previous study and should be the visit at which study drug is dispensed for 
N01379.
This study will run throughout the duration of the clinical development period of
brivaracetam, and will continue until a marketing authorization is granted by any Health 
Authority in an indication for the adjunctive treatment in adults with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the 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 brivaracetam development is stopped by the Sponsor.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 12 of 46
2.4 
Determination of Sample Size 
No sample size calculation was done. Sample size was dependent upon recruitment into and 
completion of preceding studies.
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical 
output will be carried out using SAS® Version 9.1 or higher.
Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 75th
percentile, minimum value, and maximum value for quantitative variables, and counts and 
percentages for categorical variables, will be provided. Denominators for percentages will 
generally be based on the set of subjects with at least 1 assessment at the time point or at least 
1 assessment during the time interval being summarized.
All summaries will be descriptive; no statistical hypothesis testing is planned.
Unless otherwise noted, summaries will present BRV overall, which will include all subjects 
exposed to BRV during the study.
Subject data listings will be provided and will present source data and key derived variables 
for statistical analyses.
3.2 
Analysis time points 
3.2.1 
First and last dose of BRV 
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first 
dose of BRV during N01379 (ie, not the first dose of BRV from the previous study in which 
subjects participated in prior to N01379). Unless otherwise noted, all references to the last 
known dose of BRV in this SAP refer to the last dose of BRV taken across any study periods
(ie, not necessarily the last dose of BRV during the Evaluation Period).
3.2.2 
Relative day 
Relative day will be calculated with Day 1 representing the day of first dose of BRV, the 
previous day is Day -1 and each day prior to that is Day -2, Day -3, etc. Subsequent relative 
days to Day 1 will be Day 2, Day 3, etc. For days after the last dose of BRV, relative day will 
be calculated as the current date minus the date of last dose of BRV and including a ‘+’ to 
denote post treatment days (eg, the day after the last dose of BRV will be Day +1). Relative 
day will not be calculated for partial or missing dates.
3.2.3 
Study Entry Visit 
The study Entry Visit (EV) corresponds to assessments performed at the time of entry into 
N01379. Subjects will not have any interruption in study drug dosing during the transition to 
N01379. Selected assessments from the following visits from the previous study will be 
summarized at EV:
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 13 of 46
Study
Visit (Time Point)
N01258
Visit 7 (at Week 2)
N01358
Visit 7 (at Week 20)
The following assessments are to be performed for all subjects at the above time points: 
laboratory parameters, vital signs, and ECGs; the results for these assessments will be 
summarized at EV. For study N01258, the following selected assessments will be used for 
summary at EV for laboratory parameters, vital signs, and ECGs
Assessment
Visit (Time Point)
Laboratory
Laboratory assessment done on AM at Visit 7
Vital signs
60 minutes after IV dose on AM at Visit 7
ECGs
12 hours after IV dose on AM at Visit 7
Body weight is not recorded at Visit 1 for N01379. The body weight recorded at the above 
study visits for the previous studies will be summarized for EV.
3.2.4 
Study periods 
The Baseline Period for N01379 corresponds to the Baseline Period of the previous studies, 
and is defined for seizure outcomes and direct cost parameters. The Baseline Period is 
defined as study days on or after the date of Visit 1 and prior to the date of Visit 2 for 
N01258 and study days on or after the date of Visit 1 and prior to the date of Visit 3 for 
N01358.
The study is divided into 3 periods: Evaluation Period, Down-Titration Period, and Post-
Treatment Period. A subject is classified as “discontinued” if the subject has a termination 
case report form (CRF) or has an early discontinuation visit (EDV). A subject is classified as 
“completed” if this subject completes the full extent of the study as defined in the protocol at 
database lock.  
A “discontinued” subject can be potentially slotted into the 3 periods of the study. The 
following algorithms will be used to slot the subject appropriately into the Evaluation Period, 
Down-Titration Period, and Post-Treatment Period.
x For Evaluation Period, the start date is the date of first dose of BRV, and the 
following algorithm is used to determine the end date:
x If the subject enters the Down-Titration Period, then the date of EDV is the 
end date;
x If the subject does not enter the Down-Titration Period but meets 1 of the 
following criteria, the Evaluation Period ends on date of last dose of BRV:
x Without an EDV but having a termination CRF,
x With an EDV and having a termination CRF,
x With an EDV and the date of EDV prior to the database lock date and 
having no termination CRF.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 14 of 46
x A subject is considered entering Down-Titration Period only if the subject has an 
EDV and at least 1 dose of study drug after the date of EDV, the start date of Down-
Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period 
ends on date of last dose of BRV. A subject without an EDV but having a termination 
CRF or with an EDV but without any dosing of study drug after the EDV will not 
have the Down-Titration Period, and no artificial Down-Titration Period will be 
created for analysis.
x A subject is considered entering the Post-Treatment Period if the subject has at least 1 
contact (scheduled visit, unscheduled visit, or telephone contact) after the date of last 
dose of BRV. The Post-Treatment Period starts 1 day after date of last dose of BRV 
irrespective of entering the Down-Titration Period, and there is no end date.
A “completed” subject can potentially have Evaluation Period, Down-Titration Period, and 
Post-Treatment Period. At the time of study termination by the Sponsor, subjects will 
discontinue the study drug following the down titration process or will be converted without 
titration to commercial BRV where available; alternatively, subjects may 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 requirements in 
addition to legal and regulatory guidelines.
3.2.5 
Monthly time intervals 
A month is defined as 30 days and time intervals based on monthly durations are defined as a 
multiple of 30 days (eg, 12 months is defined as 360 days). The following definitions of 
3-month and 6-month intervals are based on 30-day months where the date of first dose of 
BRV is Day 1:
Interval
Duration Definition
Months 1-3
Days 1-90
Months 4-6
Days 91-180
Months 7-9
Days 181-270
Months 10-12
Days 271-360
Months 1-6
Days 1-180
Months 7-12
Days 181-360
Months 13-18
Days 361-540
Months 19-24
Days 541-720
Subsequent 3- and 6-month intervals are defined in a similar manner. 
Six-month intervals are defined for the evaluation of direct and indirect cost parameters. 
Statistical summaries for direct and indirect cost parameters will only present results through 
the first 2 years of treatment. Three-month intervals will be used for analysis of efficacy 
outcomes and AEs.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 15 of 46
For the analysis of efficacy outcomes, a subject is included in the analysis for a 3-month 
interval if the end date is on or after the last day of the 3-month interval and the subject diary 
was completed for at least 1 day during the 3-month interval.
For the analysis of AEs, a subject is included in the analysis for a 3-month interval if the end 
date is on or after the first day of the 3-month interval.
3.2.6 
Last Value on BRV Treatment 
Last Value for QOLIE-31-P, HADS, and socio-professional data is the last assessment 
strictly after the date of first dose of BRV and up to and including the YEV at the end of the 
second year and any EDVs for subjects who did not complete through the YEV at the end of 
the second year.
Last Value for clinical laboratory parameters, vital signs, and ECGs is the last available result 
obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All 
scheduled and unscheduled assessments within this time period will be considered. Last 
Value will be determined separately for each laboratory parameter for hematology, 
chemistry, urinalysis, and endocrinology assessments. 
3.2.7 
Exposure duration and exposure duration cohorts 
At the final analysis, the overall duration of exposure (or On Treatment Period) will be 
calculated as the date of last dose of BRV minus the date of first dose of BRV plus 1 day.
Each subject will be classified into one or more of the following exposure duration cohorts 
based on the duration of BRV exposure as calculated above: 
All subjects 
≥1 day
≥3 months
≥90 days
≥6 months
≥180 days
≥12 months
≥360 days
This categorization will continue in 6-month increments past 12 months up to a time point 
that will be determined based on cumulative exposure at the time of the database lock.
3.2.8 
 Study visit cohorts 
Study visit cohorts are defined for summaries of QOLIE-31-P and HADS. Six-month, 
12-month, 18-month, and 24-month cohorts are defined. Subjects will be classified into a 
study visit cohort if they attend the scheduled visit at the time point defined by the cohort. For 
example, subjects will be included in the 18-month study visit cohort if they attend the 
scheduled visit at 18 months (ie, FEV at Month 18). Subjects may be classified in more than 
1 cohort. Generally, subjects included in a cohort for a later visit will be included in all earlier 
study visit cohorts (eg, 6-month and 12-month study visit cohorts for subjects in the 
18-month study visit cohort), although this may not be the case in the event of a missed visit 
or if an unscheduled visit is conducted in lieu of a scheduled visit. 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 16 of 46
3.3 
Definition of Baseline Values 
Baseline for all study outcomes will be based on baseline from the previous studies. For
assessments performed at scheduled and unscheduled visits, Baseline will generally be the 
last result obtained or prior to the randomization visit of the previous study. Baseline will be 
defined separately for each hematology, blood chemistry, urinalysis, and endocrinology 
parameter.
Baseline for the evaluation of seizure frequency and seizure days will be calculated from the 
core study seizure diary based on the rules defined in Section 3.8.1.
3.4 
Protocol deviations 
The criteria for identifying important protocol deviations and the classification of important 
protocol deviations will be defined separately in the Specification of Protocol Deviations 
document. Whenever possible, criteria for identifying important protocol deviations will be 
implemented algorithmically to ensure consistency in the classification of important protocol 
deviations across all subjects.
3.5 
Analysis populations 
3.5.1 
Safety Population 
The Safety Population will consist of all subjects who took at least 1 dose of study drug.
Summaries of demographics and baseline characteristics, medical history, AEDs, non-AEDs, 
HADS, study drug exposure, and safety outcomes will be provided for the Safety Population.
3.5.2 
Efficacy populations 
Efficacy Populations will consist of all subjects who took at least 1 dose of study drug and 
have at least 1 seizure diary day during the Evaluation Period. Separate Efficacy Populations 
are defined for subjects with focal epilepsy from N01358 and N01258 and subjects with 
generalized epilepsy from N01258.
A subject will be excluded from the Efficacy Analysis Set for POS or PGS if either they did 
not receive at least 1 dose of BRV, or the clinical database indicates that the daily seizure 
diary was not completed for any days on or after the first dose of BRV and on or prior to the 
end date of the Evaluation Period (see Section 8). Subjects were assigned to a POS 
population or a PGS population in the previous study, based on diagnosis or medical history.
Seizure outcomes will be summarized for either the Efficacy Population for POS of the 
Efficacy Population for PGS. Summaries of epilepsy history and QOLIE-31-P will be 
provided for the Efficacy Populations for both POS and PGS.
3.6 
Treatment Assignment and Treatment Groups 
This is an uncontrolled study in which all subjects receive BRV in doses that are optimally 
adjusted for each subject. Generally, statistical summaries will present all subjects combined 
as a single treatment arm unless otherwise indicated.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 17 of 46
3.7 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory
Activities (MedDRA). Medications will be coded using the World Health Organization Drug 
Reference List (WHO-DRL). Prior and concomitant medical procedures will not be coded.
3.8 
Definitions of study-specific derived variables 
3.8.1 
Calculation of seizure frequency/days 
3.8.1.1 
Initial seizure data processing 
Each seizure code in the clinical database will be reported as 1 of the following codes based 
on the 1981 International League Against Epilepsy (ILAE) classification: I, IA, IA1, IA2, 
IA3, IA4, IB, IB1, IB2, IC, II, IIA, IIB, IIC, IID, IIE, IIF, or III. Seizures identified as type III 
seizures will be reviewed prior to database lock to ensure that such seizures were not 
misclassified.
With regard to cluster seizures, investigator sites are to report the number of cluster episodes 
rather than reporting the estimated number of individual seizures. Therefore, no imputation 
will be applied for the seizure counts corresponding to reports of cluster seizures.
3.8.1.2 
Calculation of adjusted seizure frequency 
The following derivations apply only to subjects with Partial Onset Seizures.
Baseline POS frequency for seizure types I, IA, IB, IC, and for all seizure types (I+II+III) 
will be obtained from the Baseline Period of the previous double-blind study.
The total number of seizures for seizure types I, IA, IB, and IC and the total number of 
seizures for all seizure types (I+II+III) will be calculated overall, by 3-month time intervals, 
and over the cohort interval for each exposure duration cohort. 
All seizure diary during evaluation period will be considered for these calculations.
Twenty-eight day adjusted seizure frequency for seizure types I, IA, IB, and IC, and for all 
seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and 
over each exposure duration cohort interval by dividing the total number of seizures for each 
seizure type by the number of days for which the diary was completed overall, within each 
3-month interval, and within each exposure duration cohort interval, and multiplying the 
resulting value by 28.
3.8.1.3 
Calculation of adjusted seizure days 
The following derivations apply only to subjects with Primary Generalized Seizures, based 
on the 1981 ILAE classification, Primary Generalized Seizures include the generalized 
seizure types and unclassified seizure types. 
Baseline seizure days for seizure types II, IIA through IIF, and for all seizure types (I+II+III) 
will be obtained from the Baseline Period of the previous study.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 18 of 46
The total number of seizure days for seizure types II, IIA through IIF, and the total number of 
seizure days for all seizure types (I+II+III) will be calculated overall, by 3 month time 
intervals, and over the cohort interval for each exposure duration cohort. The same seizure 
diary data defined in the Section 3.8.1.2 for POS frequency will be considered.
Twenty-eight day adjusted seizure days for seizure types II, IIA through IIF, and for all 
seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and 
over each exposure duration cohort interval by dividing the total number of seizure days for 
each seizure type by the number of days for which the diary was completed overall (ie, over 
the periods defined in the Section 3.8.1.2), within each 3-month interval, and within each 
exposure duration cohort interval, and multiplying the resulting value by 28.
3.8.2 
QOLIE-31-P 
The QOLIE-31-P is an adaptation of the original QOLIE-31 (Cramer et al, 1998). The 
QOLIE-31-P 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], and social function [5 items]) 
and a health status item. The QOLIE-31-P total score, subscale scores, and health status item 
score are calculated according to the scoring algorithm described below, with scores ranging 
from 0 to 100 and higher scores indicating better functioning. In addition to these 31 items, 
the QOLIE-31-P includes 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).
Subscale Scores
As a first step to calculating the subscale scores, the individual responses for the 30 subscale 
items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the 
rescaled values for each item are defined in Section 13.1. Each subscale score is then 
calculated by summing the rescaled responses for that subscale and dividing by the number of 
items without a missing response. A subscale score will be calculated only if at least 50% of 
the items within the subscale are present.
Total Score
Total score is calculated as a weighted sum of the subscale scores based on the weighting in 
Section 13.1. Total score will be missing if at least 1 subscale score is missing. Total score 
will range from 0 to 100 with a higher score reflecting better functioning.
Health Status Item
Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher 
score corresponding to a better health status. The health status item response is analyzed 
without rescaling.
Distress Items
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 19 of 46
Each subscale includes 1 distress item. The response for each distress item is an integer 
ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale 
(ie, 0, 25, 50, 75, and 100) with a higher score corresponding to greater distress.
Prioritization Item
The response for each subscale for the prioritization item is an integer ranging from 1 to 7. 
The prioritization ranking is analyzed without rescaling.
3.8.3 
HADS 
The HADS assessment consists of 14 items that are each scored on a 4-point scale ranging 
from 0 to 3, with a higher score corresponding to worse anxiety or depression. The 
depression and anxiety scores will be calculated by summing the scores for the items 
corresponding to each subscale, as described in the Hospital Anxiety and Depression Scale 
Manual (Snaith and Zigmond, 1994): the depression score is calculated as the sum of all 
even-numbered items; the anxiety score is calculated as the sum of all odd-numbered items. 
Scores for each subscale range from 0 to 21, with higher scores corresponding to a greater 
level of anxiety or depression.
Missing items will be replaced by the mean of non missing items from the same subscale 
when calculating the above, provided at least 50% of the items (ie, at least 4 of 7 items) 
within the subscale are present. A subscale score will not be calculated if more than 50% of 
the items are missing within a subscale. This rule applies separately to the subscale scores for 
anxiety and depression; for example, it may be possible to calculate the depression score in 
cases where the anxiety score is not calculated due to non response.
3.9 
Subject site transfers 
Subjects may have transferred from one site to another through the course of participation in 
the study. Subjects that transferred from one site to another site, for whatever reason, have 
generally retained their subject number. However, in some cases, the subject number 
changed. When this is true, the most recently assigned subject number will be used for 
analyses and subject data listings. A record of any change in subject numbers will be 
presented in the Section 13.2.
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No statistical testing is planned; therefore, this section is not applicable.
4.2 
Handling of dropouts or missing data 
Seizure frequency (subjects with POS) and seizure days (subjects with PGS) will be 
calculated over non missing diary days during each study period or time interval as described 
in Section 3.2.4 and Section 3.2.5; diary days for which seizure data were not obtained will 
not be considered in the calculation of seizure frequency or seizure days. Because the 
evaluation of efficacy is not the primary objective of this study, and because this is an 
uncontrolled study in a variable setting, which allows individualized optimization of dosing 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 20 of 46
of BRV and concomitant AEDs, no summaries assessing the impact of missing seizure diary 
days are planned.
For subjects who prematurely discontinue during the Evaluation Period, the calculation of 
POS frequency and PGS seizure days will be based on available seizure diary while the 
subject was receiving BRV. The presence of such dropouts may influence the evaluation of 
the long-term outcomes for subjects who either do not discontinue or do not discontinue early 
in the study. Therefore, as described below, selected summaries will be produced by exposure 
duration cohorts to allow an assessment of long-term outcomes without the potentially 
confounding influence of earlier discontinuations.
4.3 
Interim analyses and data monitoring 
Interim summaries were produced to support regulatory submissions for marketing 
authorization while this study is ongoing. There are no statistical concerns with such interim 
assessments for this study design.
4.4 
Multicenter studies 
Efficacy and safety outcomes will not be assessed for individual investigator sites due to the 
low expected number for enrollment within each investigator site.
4.5 
Multiple comparisons/multiplicity 
No statistical testing is planned; therefore, this section is not applicable.
4.6 
Use of an “Efficacy Subset” of subjects 
All subjects who receive at least 1 dose of study drug and have at least 1 diary record during 
the Evaluation Period will be included in efficacy summaries. No additional efficacy subsets 
are defined for this study.
4.7 
Active-control studies intended to show equivalence 
This section is not applicable for this study.
4.8 
Examination of subgroups 
Selected summaries will be provided for the following subgroups as specified within each of 
the following sections:
x Two mappings of countries to regions are defined, 1 based on the classification requested 
by Food and Drug Administration (FDA), and 1 based on the regional classification for 
the CHMP (Committee for Medicinal Products for Human Use).
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 21 of 46
Countries will be mapped to geographic regions as follows for the FDA:
Geographic Region (FDA)
Country
North America
Canada, United States, Puerto Rico
Latin America
Brazil, Mexico
Western Europe
Austria, Belgium, Finland, France, Germany, Ireland, 
Italy, Netherlands, Norway, Réunion, Spain, Sweden, 
United Kingdom, Switzerland
Eastern Europe
Bulgaria, Czech Republic, Estonia, Latvia, Hungary, 
Lithuania, Poland, Romania, Russia, Serbia and 
Montenegro, Turkey, Ukraine
Asia/Pacific/Other
Australia, Hong Kong, India, Israel, Japan, Singapore, 
South Africa, Republic of Korea, Taiwan, Tunisia
Countries will be mapped to geographic regions as follows for the CHMP:
Geographic Region 
(CHMP)
Country
North America
Canada, United States, Puerto Rico
Latin America
Brazil, Mexico
Europe (European Union
[EU] member states) *
Austria, Belgium, Bulgaria, Czech Republic, Estonia, 
Finland, France, Germany, Hungary, Ireland, Italy, 
Latvia, Lithuania, Netherlands, Norway, Poland, 
Réunion, Romania, Spain, Sweden, United Kingdom
Europe (non-EU member 
states)
Russia, Serbia and Montenegro, Switzerland, Turkey, 
Ukraine
Asia/Pacific/Other
Australia, Hong Kong, India, Israel, Japan, Singapore, 
South Africa, Republic of Korea, Taiwan, Tunisia
* EU member states plus Norway.
x Seizure type (Partial Onset Seizures, Primary Generalized Seizures)
x Randomized treatment in the previous study (placebo [PBO], BRV) (TEAEs only)
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
Due to differences in data format across studies, in order to facilitate summary of subject 
disposition, the reasons for discontinuation for individual studies will be collapsed as follows 
for summaries:
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 22 of 46
LTFU Category
CRF Reason
ADVERSE EVENT
ADVERSE EVENT
LACK OF EFFICACY
LACK OF EFFICACY
LOSS OF EFFICACY
LOST TO FOLLOW-UP
LOST TO FOLLOW-UP
SUBJECT CHOICE
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REASONS NOT RELATED TO AES OR LACK OF 
EFFICACY
OTHER
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OTHER REASON
OTHER
MISSING
If subject discontinued the study and the termination CRF is 
not available
Only 1 primary reason for discontinuation should have been reported. In the event that more 
than 1 reason is specified in the clinical database, both reasons will be summarized and a 
footnote will be added to the summary table to indicate that at least 1 subject is counted for 
multiple reasons for discontinuation. 
An overall summary of disposition will be provided for all enrolled subjects (ie, all subjects 
who signed informed consent). The following will be summarized:
x The number of subjects in the Safety Analysis Set
x The number of subjects excluded from the Safety Analysis Set 
x The number of subjects completed the study
x The number of subjects discontinued from the study, including the reason for 
discontinuation. If subject discontinued the study and the termination CRF is not 
available, the reason for discontinuation will be reported as “MISSING”.
Additionally, an overall summary of disposition will present the following for subjects in the 
Safety Analysis Set:
x The number of subjects completed the study 
x The overall number of subjects discontinued and the number of subjects discontinued by 
primary reason for discontinuation. If subject discontinued the study and the termination 
CRF is not available, the reason for discontinuation will be reported as “MISSING”.
Overall subject disposition will also be summarized by geographic region and seizure type
for the Safety Analysis Set.
The number of subjects within each geographic region and the number of subjects within
each seizure type will be summarized for the Safety Analysis Set.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 23 of 46
Kaplan-Meier estimates of the percentage of subjects completing 3, 6, 12, 24, 36, 48, and 
60 months of treatment with BRV will be provided. This analysis will be based on the 
duration of exposure to BRV as defined in Section 3.2.7. Subjects who have permanently 
discontinued will be analyzed as events on the last day of treatment with study drug; subjects 
who complete the study will be censored on the last day of treatment with study drug. 
The date of first subject in (date of earliest Visit 1), date of last subject out (date of last 
scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in 
each analysis set or seizure type will be summarized overall and by investigator site. Subjects 
who transferred sites will be summarized according to their original site.
5.2 
Protocol Deviations 
The number and percentage of subjects with at least 1 important protocol deviation will be 
summarized overall and by category of protocol deviation for the Safety Analysis Set.
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
Demographics summaries will be based on demographic data from follow-up studies for 
subjects who enrolled in a follow-up study that collected demographic data. Otherwise, 
demographics summaries will be based on demographic data collected in the previous 
double-blind study. 
Age, age category (<17, 17 to <65, and ≥65 years), gender, racial group and overall racial 
group (see below), body weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI 
category (<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40) will be summarized for the Safety 
Analysis Set. Demographic data will be summarized overall and by subgroup for seizure type
and geographic region.
Racial group was not collected in a consistent manner across studies. For this reason, racial 
group will be collapsed as follows for statistical summaries:
Category
CRF Racial Group
American Indian/Alaskan 
Native
American Indian/Alaskan Native
Asian
Asian, Asian/Pacific Islander, Indian/Pakistani
Black
Black, African-American
Native Hawaiian or Other 
Pacific Islander
Native Hawaiian or Other Pacific Islander
White
White, Caucasian, Hispanic
Other/Mixed
Other, Other/Mixed, Mixed Race
moreover, the overall racial group will be collapsed as follows for statistical summaries:
Category
Racial Group from Previous Study
White
White, Caucasian, Hispanic
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 24 of 46
Black
Black, African-American
Asian 
Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, 
Indian/Pakistani
Other
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All subjects should be classified into one of the above categories.
Racial group, ethnicity (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup 
(Indian/Pakistani, Japanese, Other) were not collected in a consistent manner across all 
studies; these variables will be provided in subject data listings if available in the clinical data 
from the previous study but will not be summarized.
6.2 
Medical and procedure history 
6.2.1 
Medical history diseases 
The summary of medical history will be based on the medical history at the time of entry into 
the previous study. 
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions at the time of entry into the previous study, will be 
summarized overall and by primary MedDRA system organ class (SOC) and preferred term 
(PT) for the Safety Analysis Set.
6.2.2 
Procedure history and concomitant procedures 
Medical procedures are not coded and will only be provided in subject data listings.
6.3 
History of epilepsy 
All of the following are summarized using data collected at the time of entry into the previous 
studies or from the Baseline Period of the previous studies.
6.3.1 
Etiology of epilepsy 
The number and percentage of subjects with each type of etiology as specified on the CRF 
(genetic, congenital, etc) from the previous studies will be summarized for the Efficacy 
Analysis Sets for POS and PGS. A subject will be counted as having a particular etiology if 
that etiology was either confirmed or suspected based on the investigator's assessment. 
Etiology of epilepsy is not collected for subjects from previous study N01258.
6.3.2 
Epileptic seizure profile 
The number and percentage of subjects experiencing each seizure type at any time prior to 
study entry will be summarized for the Efficacy Analysis Sets for POS and PGS. The 
following seizure types will be summarized: I, IA, IA1 through IA4, IB, IB1, IB2, IC, II, IIA 
through IIF, III. A subject with a history of a more specific seizure type will be counted in all 
higher levels of seizure types (eg, a subject with a history of IB1 seizures will be counted for 
seizure types I, IB, and IB1).
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 25 of 46
6.3.3 
Classification of epileptic syndrome 
The number and percentage of subjects with each epileptic syndrome will be summarized for 
the Efficacy Analysis Sets for POS and PGS. This summary will include the number and 
percentage of subjects within the following categories: localization-related epilepsy; 
idiopathic, symptomatic, and cryptogenic localization-related epilepsy; generalized epilepsy; 
and idiopathic, symptomatic, and cryptogenic generalized epilepsy.
6.3.4 
Focus localization 
The number and percentage of subjects with each category of focus localization (unknown,
frontal, temporal, parietal, occipital) will be summarized for the Efficacy Analysis Set for 
POS. Subjects may be counted in more than 1 category of focus localization. A category for 
no available data will be included in the summary to account for subjects from N01258 since 
focus localization was not obtained for subjects from N01258. Percentages will still be out of 
the full POS Efficacy Analysis Set, including subjects from N01258.
6.3.5 
History of epileptic seizures 
History of epileptic seizures, including the number and percentage of subjects with a history 
of status epilepticus and quantitative summaries of epilepsy duration, age at onset of first 
seizure, and percent of life with epilepsy, will be summarized for the Efficacy Populations for 
POS and PGS.
6.3.6 
Seizure types experienced during baseline of the prior study 
The number and percentage of subjects experiencing each seizure type during the Baseline 
Period will be summarized for the Efficacy Analysis Sets for POS and PGS based on the 
Baseline seizure diary data from the previous studies. The following seizure types will be 
summarized: I, IA, IB, IC, II, and IIA through IIF, and III as well.
Subjects will be counted for all higher levels of seizure type categories corresponding to the 
seizure types or seizure sub-types reported on the CRF.
6.4 
Medications 
Medications recorded on the Concomitant Medications CRF and the Concomitant 
Medications (AEDs only) CRF will be classified as either AEDs or non-AEDs based on the 
preferred drug name search criteria, which are documented outside of the SAP.
x The medication is not an AED if it does not meet the search criteria based on preferred 
drug name, regardless of which CRF is used for reporting the medication. However, 
further review will be performed for medications that are recorded on the Concomitant 
Medications (AEDs only) CRF but are not included in the AEDs search criteria;
x For non-benzodiazepine medications, if the medication meets the search criteria for an 
AED based on preferred drug name, then the medication will be classified as an AED 
regardless of indication and regardless of which CRF the medication is recorded on;
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 26 of 46
x For benzodiazepines (identified using the search criteria), if the benzodiazepine is 
recorded on the Concomitant Medications (AEDs only) CRF, then the benzodiazepine 
will be classified as an AED;
x For benzodiazepines (identified using the search criteria), if the benzodiazepine is 
recorded on the Concomitant Medications CRFs, then the benzodiazepine will not be 
classified as an AED.
After medications are classified as AEDs or non-AEDs, the standard date imputation 
algorithms for start and stop date of the medication and first dose and last dose of BRV in the 
study will be applied. If an AED was taken at any time during dosing with BRV, then the 
AED is classified as a concomitant AED.
6.4.1 
Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AED medications at study entry for the 
previous double-blind study will be summarized by WHO-DRL primary therapeutic group 
(Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and 
preferred drug name for the Safety Analysis Set.
6.4.2 
Number of previous AEDs 
The number and percentage of subjects taking an AED prior to entry into the previous study 
will be summarized by WHO-DRL preferred drug name for the POS and PGS Efficacy 
Analysis Sets based on the following categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.
6.4.3 
History of previous AED use 
The number and percentage of subjects who had taken at least 1 AED prior to entry into the
previous study will be summarized overall and by WHO-DRL preferred drug name for the 
POS and PGS Efficacy Analysis Sets.
6.4.4 
AEDs taken at study entry 
The number and percentage of subjects taking AEDs at study entry for the previous double-
blind study will be summarized by WHO-DRL preferred drug name for the POS and PGS 
Efficacy Analysis Sets.
6.4.5 
Concomitant AEDs 
A concomitant AED is an AED which was taken during administration of BRV in N01379 
study, regardless of the start and stop date of the AED. The number and percentage of 
subjects taking concomitant AEDs will be summarized by WHO-DRL preferred drug name 
for the POS and PGS Efficacy Analysis Sets.
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Study drug compliance will not be assessed due to the complexities associated with the 
calculation and interpretation of study drug compliance for this study. Study drug dosing will 
be provided in subject data listings.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 27 of 46
8 
EFFICACY ANALYSES 
In general, all study outcomes based on seizure frequency will be summarized for the 
Efficacy Analysis Set for POS and all study outcomes based on seizure days will be 
summarized for the Efficacy Analysis Set for PGS. 
The derivations of 28-day adjusted seizure frequency and 28-day adjusted seizure days are 
described in detail in Section 3.8.1.2 and Section 3.8.1.3, respectively.
All summaries of efficacy data are descriptive; no statistical testing will be performed.
Because study N01258 was a safety study, subjects were not required to meet seizure 
frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 
days). Therefore, subjects from N01258, whether subjects with POS or PGS, will be excluded 
from efficacy summaries in the variables of percent reduction in POS frequency and 
responder rates, but subjects from N01258 will be included in the efficacy summary in the 
variable of the percent of subjects continuously seizure free as this variable is independent 
from baseline. 
8.1 
Statistical analyses of secondary efficacy variables 
The following variables are summarized for the Efficacy Population for POS.
8.1.1 
Partial onset seizure frequency 
Twenty-eight day adjusted POS frequency will be summarized with quantitative descriptive 
statistics for all subjects for the Baseline Period, the On Treatment Period, and by 3-month 
time intervals over the On Treatment Period. The summary over the On Treatment Period 
will include all subjects in the POS Efficacy Analysis Set. Similar summaries will be 
provided for the full cohort interval and by 3-month time intervals for each exposure duration 
cohort.
8.1.2 
Percent reduction in POS frequency 
Percent reduction in POS frequency from Baseline to the On Treatment Period will be 
calculated as follows, where On Treatment Period Frequency is the 28-day adjusted POS 
frequency during On Treatment Period and Baseline Period Frequency is the 28-day adjusted 
POS frequency during the Baseline Period of the previous study.
Frequency
 
Period
 
Baseline
Frequency
 
Period
Treatment 
On 
Frequency
 
Period
 
Baseline
100
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A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort.
Percent reduction from Baseline for POS frequency will be summarized with quantitative 
descriptive statistics for the On Treatment Period, and by 3-month time intervals over the On 
Treatment Period. The summary over the On Treatment Period will include all subjects in the 
POS Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 28 of 46
and by 3-month time intervals for each exposure duration cohort. Percent reduction from 
Baseline for POS frequency will be summarized in the same manner by geographic region.
8.1.3 
Responder outcome for POS frequency 
Responders over the On Treatment Period are defined as subjects with a 50% or greater 
reduction in 28-day adjusted POS frequency from Baseline to the On Treatment Period. 
A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort.
The number and percentage of responders for POS frequency will be summarized for the On 
Treatment Period, and by 3-month time intervals over the On Treatment Period. The 
summary over the On Treatment Period will include all subjects in the POS Efficacy Analysis 
Set. Similar summaries will be provided over the full cohort interval and by 3-month time 
intervals for each exposure duration cohort. Responder rates for POS frequency will be 
summarized in the same manner by geographic region.
8.2 
Analysis of other efficacy variables 
8.2.1 
Subjects with partial onset seizures 
All of the following variables are summarized for the Efficacy Population for POS.
8.2.1.1 
Specified Month seizure freedom 
The numbers and percentages of subjects who are seizure free for all seizure types for any 
continuous 6-month interval, 12-month interval, 18-month interval, and so forth will be 
summarized overall for the period of time that subjects are being treated with BRV and by 
Exposure Duration Cohort. The overall summary will present the number and percentage of 
subjects who reported no seizures for the specified duration of seizure freedom and the 
seizure diary was completed for at least 90% of days within the seizure-free interval. Subjects 
whose duration of BRV treatment was less than the specified duration of seizure freedom will 
be considered failures for seizure-freedom. Summaries by exposure duration cohort will 
present the number and percentage of subjects who reported no seizures for the specified 
duration of seizure freedom at any time during the cohort interval (eg, through the end of 
Month 6 for the 6-month cohort) and the seizure diary was completed for at least 90% of days 
within the seizure-free interval. Percentages are relative to the number of subjects within each 
Exposure Duration Cohort. 
A subject is seizure free for a 6-month interval if the subject did not report any seizures in the 
6-month interval and the seizure diary was completed for at least 90% of days within the 
seizure-free interval. The percentage of days for which seizure diary was completed within a 
given 6-month interval will be calculated as follows based on a 30-day month:
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A similar calculation applies for 12-month seizure freedom based on 360 days, 18-month 
seizure freedom based on 540 days, and so forth.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 29 of 46
8.2.2 
Subjects with Primary Generalized Seizures 
The following variables are summarized for the Efficacy Population for PGS.
8.2.2.1 
All type seizure days 
Twenty-eight day adjusted all other type seizure days will be summarized with quantitative 
descriptive statistics in the same manner as 28-day adjusted POS frequency.
8.2.2.2 
Percent reduction in all type seizure days 
Percent reduction in all other type seizure days from Baseline will be calculated in the same 
manner as percent reduction in POS frequency as described in Section 8.1.2. This variable 
will be summarized in the same manner as percent reduction in POS frequency.
8.2.2.3 
Responder outcome for all type seizure days 
Responder outcome for all other type seizure days will be derived in a manner similar to the 
responder outcome for POS frequency as described in Section 8.1.3. This variable will be 
summarized in the same manner as 50% responder outcome for POS frequency.
8.2.2.4 
Specified month seizure freedom 
Specified month seizure freedom for subjects in the PGS Efficacy Analysis Set will be 
derived in a manner similar to specified month seizure freedom for the POS Efficacy 
Analysis Set as described in Section 8.2.1.1. This variable will be summarized in the same 
manner as specified month seizure freedom for subjects in the POS Efficacy Analysis Set.
8.2.3 
QOLIE-31-P 
The scoring algorithm for QOLIE-31-P is described in Section 13.1. QOLIE-31-P will be 
summarized for the POS and PGS Efficacy Analysis Sets. QOLIE-31-P is assessed at the 
following time points for subjects with POS and subjects with PGS: Month 2, Month 6, 
Month 12, Month 18, and Month 24. QOLIE-31-P is also assessed at EDVs for subjects who 
discontinue prior to the YEV at the end of the second year.
Observed values for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life, and Health Status will be summarized for 
Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. 
For each time point, summary statistics will be presented for the baseline scores for subjects 
with a change from baseline at the time point in addition to summaries of the observed values 
and changes from baseline at each time point. Only subjects with a non-missing change from 
baseline will be summarized at each time point.
The above scores will be also summarized for the 6-Month, 12-Month, 18-Month, and 
24-Month Study Visit Cohorts, including summaries of the baseline scores for all subjects 
within each study visit cohort and summaries of observed values and changes from baseline 
for each time point for each study visit cohort.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 30 of 46
Similar summaries will be provided for QOLIE-31-P distress items Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life. Only subjects with a non-missing change from 
baseline will be summarized at that time point.
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Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, and Overall 
Quality of Life) will be summarized at the same time points as above and for all subjects and 
by study visit cohort as defined above. Changes from baseline will not be summarized, and 
only the numbers of subjects and sample means will be presented
8.2.4 
Direct cost parameters 
Direct costs data are collected based on concurrent medical procedures, healthcare provider 
consultations not foreseen by protocol, hospital stays, and ER visits
Direct cost parameters will not be summarized but will be provided in subject data listings.
8.2.5 
Indirect cost parameters 
The number of school or working days lost will not be summarized but will be provided in 
subject data listings.
8.2.6 
Socio-professional data 
Socio-professional data are collected at the following time points: Month 12 and Month 24. 
Socio-professional data are also collected at EDVs for subjects who discontinue prior to the 
YEV at the end of the second year.  These additional assessments will not be summarized but 
will be provided in subject data listings.
9 
PHARMACOKINETICS AND PHARMACODYNAMICS 
Plasma samples to analyze BRV or concomitant AED plasma concentrations are not 
collected. As such, this section is not applicable.
10 
IMMUNOLOGICAL PROCEDURES 
This section is not applicable for this study.
11 
SAFETY ANALYSES 
Safety is assessed with AEs, laboratory tests (blood chemistry, hematology, urinalysis, 
endocrinology, and pregnancy test), vital signs, body weight, ECGs, physical examination, 
and neurological examination. Summary tables will be provided for AEs; blood chemistry, 
hematology, urinalysis, and endocrinology; vital signs; body weight; and ECGs. No summary 
tables will be provided for pregnancy testing, physical examination, and neurological 
examination.
All safety summaries will be based on the Safety Population.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 31 of 46
11.1 
Extent of exposure 
A daily dose will be calculated for each study day from the day of first dose of BRV to the 
day of last dose of BRV for the purposes of calculating modal dose. Daily dose will be 
calculated as the sum of the AM and PM dose for each day.
Modal daily doses will be calculated across all study days on or after the day of first dose of 
BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during this period. In the event of a tie, the modal dose will be set 
to the lower of the tied doses. Modal daily dose will be categorized as follows:
Category
Definition
5 mg/day
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≥50mg/day to <100mg/day
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150mg/day
≥150mg/day to <200mg/day
200mg/day
≥200mg/day
Subject years of exposure will be calculated by summing the exposure duration in days for all 
subjects being summarized, and dividing the resulting value by 365.25.
Subject years of exposure will be presented overall and by modal dose for the Safety 
Analysis Set. The subject years of exposure presented by modal dose will be the total subject 
years of exposure of subjects with that modal dose.
The number and percentage of subjects exposed to BRV will be summarized overall and by 
modal dose category. The number and percentage of subjects in each Exposure Duration 
Cohort (≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.
The number and percentage of subjects within each modal dose category will be summarized 
for each Exposure Duration Cohorts; percentages will be relative to the total number of 
subjects in each Exposure Duration Cohort.
In addition to the overall summaries of the above, the above will also be summarized by 
subgroup for region (North America, Europe [EU member states], Europe [non-EU member 
states], Asia/Pacific/Other), and seizure type (Partial Onset Seizures, Primary Generalized 
Seizures).
11.2 
Adverse events 
11.2.1 
Definition of treatment-emergent AE 
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined 
as AEs which had onset prior to the date of the first dose of BRV. TEAEs are defined as AEs 
that had onset on or after the day of first BRV dose. AEs with an incomplete onset date will 
be classified as TEAEs if the month and year of onset (when only the month and year are 
specified) is the same as the month and year of the first BRV dose or the year of onset (when 
only year is specified) is the same as the year of first BRV dose.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 32 of 46
11.2.2 
General summaries of TEAEs 
Pre-treatment AEs will be provided in a subject data listing; no summaries of pre treatment 
AEs are planned.
An overall summary of AEs will provide the overall number of TEAEs and the numbers and 
percentages of subjects with at least 1 TEAE, with a TEAE that led to permanent 
discontinuation of study drug, with a drug-related TEAE, with a severe TEAE, with a 
treatment-emergent SAE, and with a drug-related treatment-emergent SAE. The number and 
percentage of subjects who died will also be summarized. This summary will be provided for 
all subjects in the Safety Analysis Set and also by subgroup for geographic region and seizure 
type.
The following summaries of TEAEs will be provided by MedDRA SOC and PT. All 
summaries are for the combined Evaluation, Down-Titration, and Post-Treatment Periods 
unless otherwise indicated.
Overall Incidence Summaries
x Incidence of TEAEs
x Incidence of TEAEs by 3-month time interval
x Incidence of TEAEs by study period (Evaluation, Down-Titration, Post-Treatment)
x Incidence of TEAEs for TEAEs occurring in at least 5% of subjects
x Incidence of TEAEs by 3-month time intervals for TEAEs occurring in at least 5% of 
subjects overall
x Incidence of non-serious TEAEs occurring in at least 5% of subjects
The incidence of TEAEs occurring in at least 5% of subjects will be summarized overall as 
noted above and also by subgroup for geographic region, seizure type, and randomized 
treatment from the previous double-blind study.
A subject is included in a 3-month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above. TEAEs which had onset prior to or on the date of the last dose of BRV) are 
included in summaries by 3-month time intervals.
Maximum Intensity and Causality
x Incidence of TEAEs by maximum intensity
x Incidence of drug-related TEAEs
Serious Adverse Events
x Incidence of treatment-emergent SAEs
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 33 of 46
Discontinuations due to TEAE
x Incidence of TEAEs leading to permanent discontinuation of study drug
TEAEs of interest
AEs of interest will be identified based on MedDRA search criteria, which are documented 
outside of the SAP.  The following summaries will be provided for AEs of interest:
x Incidence of TEAEs of interest
x Incidence of TEAEs of interest by 3-month time interval
For the summary by maximum intensity, each subject will be counted at most once per SOC 
or PT according to the maximum intensity of all AEs within that SOC or PT. Severe intensity 
will be assumed for AEs for which intensity is not specified.
Drug-related AEs are AEs for which the relationship to study drug is specified as Related or 
AEs for which relationship is not specified.
11.3 
Clinical laboratory evaluations 
Clinical laboratory parameters (blood chemistry, hematology, urinalysis, and endocrinology) 
are assessed at all FEVs, YEVs, EDVs, and at FV and may also be assessed at Unscheduled 
Visits.
11.3.1 
Hematology and blood chemistry parameters 
Observed values for each planned hematology and blood chemistry parameter will be 
summarized for Baseline, Study Entry, and each scheduled visit during the Evaluation Period 
for which laboratory parameters were assessed, Last Value, EDV, and FV. Change from 
Baseline will be summarized for all post-Baseline time points including EV. Only laboratory 
parameters planned per protocol will be summarized; results for laboratory parameters not 
planned per the protocol will only be provided in subject data listings.
The number and percentage of subjects with an on-treatment potentially clinically significant 
treatment-emergent (PCST) value, PCST low value, and PCST high value will be 
summarized. This summary will consider all assessments after the first dose of BRV and 
prior to or on the date of the last dose of BRV. Percentages will be relative to the number of 
subjects with an on-treatment assessment.
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for Baseline, Study Entry, each visit during the 
Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last 
Value, and FV. Percentages for each parameter and time point will be relative to the number 
of subjects with a value at that time point.
PCST criteria (Sections 13.3 and 13.3.2) are based on FDA Division of Neuropharmacologic 
Drug Products guidelines with some UCB-defined additions.
Creatinine clearance, when available from the central laboratory, will be provided in subject 
data listings only and will not be summarized.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 34 of 46
11.3.2 
Macroscopic urinalysis 
Quantitative urinalysis parameters will be summarized in the same manner as hematology 
and blood chemistry parameters. Response categories are negative, 1+, 2+, and 3+ for the 
qualitative urinalysis parameters occult blood, leukocytes, glucose, protein, and ketones and 
negative and positive for nitrates. Outcome values for these parameters are mapped to the 
levels Negative, 1+, 2+, and 3+ as follows for purposes of summary tables and the 
determination of PCST:
Category
Definition
Negative
“Negative”, “NEGATIVE”, or other outcomes that clearly reflect a negative 
finding
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“1+”, “+” , “Trace”, “TRACE”, or other outcomes that clearly reflect trace 
amount
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For qualitative urinalysis parameters (occult blood, leukocytes, glucose, protein, ketones, and 
nitrates), the number and percentage of subjects with each response category will be 
summarized for Baseline, Study Entry, each scheduled visit during the Evaluation Period for 
which urinalysis parameters were scheduled to be assessed, Last Value, EDV, and FV. 
Percentages for each parameter will be relative to the number of subjects with a result at each 
time point.
For occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and 
percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high 
value will be summarized. This summary will consider all assessments after the first dose of 
BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the 
number of subjects with an on-treatment assessment.
Additionally, for occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number 
and percentage of subjects with a PCST value, PCST low value, and PCST high value will be 
summarized for Baseline, Study Entry, each visit during the Evaluation Period for which 
laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages 
for each parameter and time point will be relative to the number of subjects with a value at 
that time point.
11.3.3 
Endocrinology parameters 
Endocrinology parameters will be summarized in the same manner as hematology and blood 
chemistry parameters.
Observed values for each planned endocrinology parameter will be summarized for Baseline, 
EV, each scheduled visit during the Evaluation Period for which the parameter was assessed, 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 35 of 46
Last Value, EDV, and FV. Change from Baseline will be summarized for all post-Baseline 
time points including EV.
The number and percentage of subjects with an on-treatment potentially clinically significant 
treatment-emergent (PCST) value, PCST low value, and PCST high value will be 
summarized for each planned endocrinology parameter. All scheduled and unscheduled 
endocrinology assessments after the day of first dose of BRV and prior to or on the day of 
last dose of BRV across all study periods will be considered. Percentages for each parameter 
will be relative to the number of subjects with at least 1 result within this time period.
Additionally, the number and percentage of subjects with PCST value, PCST low value, and 
PCST high value will be summarized for endocrinology parameters for EV, each visit during 
the Evaluation Period for which endocrinology parameters were scheduled to be assessed, 
EDV, and Last Value. Percentages for each parameter and time point will be relative to the 
number of subjects with a result at that time point.
11.3.4 
Microscopic urinalysis 
In microscopic urinalysis, a small sample of urine is centrifuged to remove the liquid. The 
sediment is then examined under a microscope. The number and percentage of subjects with 
a microscopic urinalysis finding will be summarized. All scheduled and unscheduled 
assessments after the day of first dose of BRV will be considered. Percentages will be relative 
to the number of subjects with at least 1 on-treatment microscopic assessment. 
Additionally, the number and percentage of subjects with a microscopic finding will be 
summarized for Baseline, Study Entry, and each visit during the Evaluation Period for which 
urinalysis parameters were scheduled to be assessed, Last Value, EDV, and FV. Percentages 
for each parameter and time point will be relative to the number of subjects who had a
microscopic assessment at that time point.
11.4 
Vital signs, physical findings, and other observations related 
to safety 
11.4.1 
Vital signs 
Vital signs are assessed at all FEVs, MEVs, YEVs, EDVs, and at FV, and may also be 
assessed at Unscheduled Visits. Body weight is assessed at all FEVs, YEVs, EDVs, and at 
FV, and may also be assessed at Unscheduled Visits.
Observed values for SBP, DBP, pulse rate, and body weight will be summarized for Baseline, 
Study Entry, each visit during the Evaluation Period for which vital signs or body weight 
were assessed, EDV, Last Value, and FV. Changes from Baseline for SBP, DBP, pulse rate, 
and body weight will be summarized for all post-Baseline time points.
The number and percentage of subjects with an on-treatment PCST value, PCST low value, 
and PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV. Percentages will be relative to the number of subjects with an on-
treatment assessment.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 36 of 46
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for the above parameters for Study Entry, each visit 
during the Evaluation Period for which vital signs or body weight were scheduled to be 
assessed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects 
with a value at each time point.
PCST criteria (Section 13.3.3) are based on FDA Division of Neuropharmacologic Drug 
Products guidelines with some UCB-defined additions.
11.4.2 
Electrocardiograms 
ECGs are assessed at all YEVs, EDVs, and at FV, and may also be assessed at Unscheduled 
Visits.
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding will be summarized overall. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV. Percentages will be relative to the number of subjects with an on-
treatment assessment.
Additionally, the number and percentage of subjects with no abnormality, an abnormal but 
not clinically significant finding, and a clinically significant finding will be summarized for 
Baseline, Study Entry, each visit during the Evaluation Period for which an ECG is scheduled 
to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of 
subjects with an ECG assessment at each time point. Subjects are counted at most once at 
each time point based on the worst observed outcome across all abnormalities reported at that 
time point.
A subject number listing will be provided that identifies subjects with a clinically significant 
finding after the first dose of BRV for each type of ECG abnormality.
11.4.3 
Physical examination 
Physical examination findings were not recorded on the CRF; no summaries of physical 
examination findings are planned.
11.4.4 
Neurological examination 
A listing of visits where the neurological examination was not done will be; no summaries of 
neurological examination findings are planned.
11.4.5 
HADS 
The scoring algorithm for HADS is described in Section 3.8.3.
HADS is assessed at the following time points: Month 2, Month 6, Month 12, Month 18, and 
Month 24. HADS is also assessed at EDVs for subjects who discontinue prior to the YEV at 
the end of the second year.
Observed values for HADS depression and anxiety scores will be summarized for Baseline 
and Last Value for the Safety Analysis Set. Additionally, observed values will be 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 37 of 46
summarized for Baseline and by visit for each study visit cohort. Change from Baseline will 
be summarized at each visit during the Evaluation Period.
For summaries of observed values at each time point, only subjects with a change from 
Baseline value at that time point will be summarized. Additionally, the mean and SD for each 
Baseline score will be provided at each post-Baseline time point for subjects included in the 
summary of change from Baseline.
11.4.6 
Columbia-Suicide Severity Rating Scale 
With global amendment 2 to the protocol, the Columbia-Suicide Severity Rating Scale 
(C-SSRS) was added as an assessment at all study visits. Specific rules are provided to the 
study sites with regard to the identification of AEs or SAEs based on the outcome of this 
assessment. Because clinical events of interest will be recorded as AEs or SAEs, no study 
variable is defined for this assessment and no analyses are planned for the C-SSRS within the 
context of this study. However, subject data listings of the data for the C-SSRS will be 
provided. Additional listings will be provided for the subset of subjects with suicidal ideation 
and the subset of subject with actual suicide attempts.
Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions:
 
 
 
 
 
Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt 
questions:
 
 
 
12 
REFERENCES 
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. 
Epilepsia 1998, 39(1): 81-88.
Snaith RP, Zigmond AS. The hospital anxiety and depression scale manual. London; 
nferNelson Publishing Company Ltd. 1994.
This document cannot b
mer J
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 38 of 46
13 
APPENDICES 
13.1 
QOLIE-31-P total and subscale score calculations 
The following outlines the calculation of the subscale scores for the QOLIE-31-P. The 
rescaled responses are provided for each item. The subscale scores are calculated by 
summing the rescaled responses for that subscale and dividing by the number of items with a 
non-missing response. Note that the divisors shown assume that all items for each subscale 
have a response; the divisor will differ if there are missing responses. A subscale score will 
be calculated only if at least 50% of the items within the subscale are present.
Response
Final Score
Scale/Item Numbers
1
2
3
4
5
6
Subtotal
0-100 point scale 
Seizure Worry
30.
0
20
40
60
80
100
_____
31.
0
33.3
66.7
100
––
––
_____
32.
0
50
100
––
––
_____
33.
0
33.3
66.7
100
––
––
_____
34.
100
75
50
25
0
––
_____
TOTAL :  
_____
÷ 5 = _____
Overall Quality of Life
1.
Multiply each response by 10
_____
36.
100
75
50
25
0
––
_____
TOTAL :
_____
÷ 2 = _____
Emotional Well-Being
7.
0
20
40
60
80
100
_____
8.
0
20
40
60
80
100
_____
9.
100
80
60
40
20
0
_____
10.
0
20
40
60
80
100
_____
11.
100
80
60
40
20
0
_____
TOTAL :
_____
÷ 5 = _____
Energy/Fatigue
2.
100
80
60
40
20
0
_____
3.
100
80
60
40
20
0
_____
4.
0
20
40
60
80
100
_____
5.
0
20
40
60
80
100
_____
TOTAL :
_____
÷ 4 = _____ 
Cognitive Functioning
19.
0
20
40
60
80
100
_____
20.
0
33.3
66.7
100
––
––
_____
21.
0
20
40
60
80
100
_____
22.
0
20
40
60
80
100
_____
by 10
by 10
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 39 of 46
23.
0
20
40
60
80
100
_____
24.
100
75
50
25
0
––
_____
TOTAL :
_____
÷ 6 = _____
Medication Effects
28.
0
33.3
66.7
100
––
––
_____
26.
100
75
50
25
0
––
_____
27.
100
75
50
25
0
––
_____
                                                                                     
TOTAL :
_____
÷ 3 = _____
Daily Activities/Social Functioning
13.
0
20
40
60
80
100
_____
14.
0
25
50
75
100
––
_____
15.
0
25
50
75
100
––
_____
16.
100
75
50
25
0
––
_____
17.
100
75
50
25
0
––
_____
TOTAL :
_____
÷ 5 = _____
Total score is calculated as a weighted sum of the subscale scores based on the weighting 
shown below. Total score will be missing if at least 1 subscale score is missing. Total score 
will range from 0 to 100 with a higher score reflecting better functioning.
QOLIE-31-P Scale
Final Scale 
Score
Weight
Subtotal
Seizure worry
(a)
____
u
0.08
=
____
Overall quality of life
(b)
____
u
0.14
=
____
Emotional well-being
(c)
____
u
0.15
=
____
Energy/fatigue
(d)
____
u
0.12
=
____
Cognitive functioning
(e)
____
u
0.27
=
____
Medication effects
(f)
____
u
0.03
=
____
Daily activities/Social functioning
(g)
____
u
0.21
=
____
TOTAL SCORE: Sum subtotals (a) through (g)
____
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 40 of 46
13.2 
Subject site transfers 
CRF#
Initial Site Subject #
Transfer Site Subject #
REDACTED COPY 
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 41 of 46
13.3 
PCST Criteria 
13.3.1 
Hematology parameters 
Parameter
UCB Conventional Units
SI Units
CF
Hematocrit
For 1 m to < 6 m:  d 25%
For 1 m to < 6 m:  d 0.25
0.01
For 6 m to < 2 y:  d 27%
For 6 m to < 2 y:  d 0.27
For 2 y to < 4 y:  
d 29%
For 2 y to < 4 y:  
d 0.29
For 4 y to < 12 y:  d 32% (Female[F]); d 35% (Male [M])
For 4 y to < 12 y:  d 0.32 (F); d 0.35 (M)
For t 12 y:  
d 32% (F); d 37% (M)
For t 12 y:  
d 0.32 (F); d 0.37 (M)
Hemoglobin
For  6 m:  
d 9.7 g/dL
For  6 m:  
d 97 g/L
10
For 6 m to < 12 y:  d 10.0 g/dL
For 6 m to < 12 y:  d 100 g/L
For t 12 y:  
d 9.5 g/dL (F); d 11.5 g/dL (M)
For t 12 y:  
d 95 g/L (F); d 115 g/L (M)
Platelets
d 75 x 109/L or t 700 x 109/L
d 75 x 109/L or t 700 x 109/L
Not applicable (N/A)
White Blood 
Cell (WBC)
For  17 y:  
< 3.0 x 109/L or > 20 x 109/L; 
For  17 y:  
< 3.0 x 109/L or > 20 x 109/L; 
N/A
For t 17 y:  
< 2.8 x 109/L or > 16 x 109/L;
For t 17 y:  
< 2.8 x 109/L or > 16 x 109/L;
Red Blood 
Cell (RBC)
For  17 y:  < 2.5 x 106/mm3
For  17 y:  
< 2.5 x 1012/L
1
For t 17 y:  < 2.0 x 106/mm3 (F); < 2.5 x 106/mm3 (M)
For t 17 y:  
< 2.0 x 1012/L (F); < 2.5 x 1012/L (M)
Eosinophils
t 10% or t 0.7 x 109/L
t 0.10 or t 0.7 x 109/L
0.01 or N/A
Neutrophils
d 15% or d 1.0 x 109/L
d 0.15 or d 1.0 x 109/L
0.01 or N/A
Basophils
t 5% or t 0.4 x 109/L
t 0.05 or t 0.4 x 109/L
0.01 or N/A
Monocytes
t 20% or t 1.5 x 109/L
t 0.20 or t 1.5 x 109/L
0.01 or N/A
Lymphocytes
For 1 m to < 6 m:  d 22% or t 80%
For 1 m to < 6 m:  d 0.22 or t 0.80 
0.01
d 2.1 x 109/L or t 8.5 x 109/L
d 2.1 x 109/L or t 8.5 x 109/L
N/A
For 6 m to < 2 y:  d 15% or t 80% 
For 6 m to < 2 y:  d 0.15 or t 0.80 
0.01
d 1.5 x 109/L or t7.5 x 109/L
d 1.5 x 109/L or t7.5 x 109/L
N/A
For 2 y to < 12 y:  d 12% or t 80% 
For 2 y to < 12 y:  d 0.12 or t 0.80 
0.01
d 1.0 x 109/L or t 7.5 x 109/L
d 1.0 x 109/L or t 7.5 x 109/L
N/A
For 12 y to  17 y:  d 10% or t 80% 
For 12 y to  17 y:  d 0.10 or t 0.80 
0.01
d 0.5 x 109/L or t 5.5 x 109/L
d 0.5 x 109/L or t 5.5 x 109/L
N/A
For t 17 y:  
d 10% or t 80% 
For t 17 y:  
d 0.10 or t 0.80 
0.01
d 0.5 x 109/L or t 4.5 x 109/L
d 0.5 x 109/L or t 4.5 x 109/L
N/A
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 42 of 46
13.3.2 
Hematology parameters 
Parameter
UCB Conventional Units
SI Units
CF
AST (SGOT)
> 3 times of  ULN
> 3 times of  ULN
N/A
ALT (SGPT)
> 3 times of  ULN
> 3 times of  ULN
N/A
ALP
For  17 y:  
> 2 times of  ULN, if normal range
adjusted to the age range; 
For  17 y:  
> 2 times of  ULN, if normal range
adjusted to the age range; 
N/A
For t 17 y:  
> 3 times of  ULN
For t 17 y:
> 3 times of  ULN
GGT
> 3 times of  ULN, if baseline value < 3 times of  ULN
> 3 times of  ULN, if baseline value < 3 times of  ULN
N/A
BUN
> 30 mg/dL
> 10.71 mmol/L
0.357
Urea
> 60 mg/dL
> 10.02 mmol/L
0.167
Creatinine
For  17 y: 
> 1.5 mg/dL; 
For  17 y:  
> 132.6 umol/L; 
88.4
For t 17 y:  
> 2.0 mg/dL
For t 17 y:  
> 176.8 umol/L
Creatinine 
clearance 
(calc)
For  12 y:  
 70 ml/min (Schwartz)(a)
For  12 y:  
 70 ml/min (Schwartz)(a)
N/A
For t 12 y:  
 70 ml/min (Cockroft)(b)
For t 12 y:  
 70 ml/min (Cockroft)(b)
Total 
bilirubin
> 2.0 mg/dL
> 34.2 umol/L
17.1
Glucose
d 50 mg/dL or t 180 mg/dL
d 2.775 mmol/L or t 9.99 mmol/L
0.0555
Total Protein
For t 1 m to  6 m:
d 3.6 g/dL or t 7.8 g/dL
For t 1 m to  6 m:
d 36 g/L or t 78 g/L
10
For t 6 m to  17 y:  d 4.7 g/dL or t 9.5 g/dL
For t 6 m to  17 y:  d 47 g/L or t 95 g/L
For t 17 y: 
d 4.5 g/dL or t 9.0 g/dL
For t 17 y: 
d 45 g/L or t 90 g/L
Albumin
For  17 y:  
d 2.4 g/dL or t 6.5 g/dL
For  17 y:  
d 24 g/L or t 65 g/L
10
For t 17 y: 
d 2.5 g/dL or t 6.5 g/dL
For t 17 y: 
d 25 g/L or t 65 g/L
Globulin
For  17 y: 
d 1.2 g/dL or t 5.0 g/dL
For  17 y:
d 12 g/L or t 50 g/L
10
For t 17 y: 
d 1.5 g/dL or t 5.0 g/dL
For t 17 y: 
d 15 g/L or t 50 g/L
Sodium
For  17 y:  
d 120 mEq/L or t 155 mEq/L
For  17 y:  
d 120 mmol/L or t 155 mmol/L
1
For t 17 y: 
d 115 mEq/L or t 155 mEq/L
For t 17 y: 
d 115 mmol/L or t 155 mmol/L
Potassium
For  17 y:  
d 3.0 mEq/L or t 6.5 mEq/L
For  17 y:  
d 3.0 mmol/L or t 6.5 mmol/L
1
For t 17 y: 
d 3.0 mEq/L or t 5.8 mEq/L
For t 17 y: 
d 3.0 mmol/L or t 5.8 mmol/L
Calcium
For  17 y:  
d 7 mg/dL or t 11.5 mg/dL
For  17 y:  
d 1.75 mmol/L or t 2.875 mmol/L
0.25
For t 17 y:  
d 7 mg/dL or t 15.5 mg/dL
For t 17 y:  
d 1.75 mmol/L or t 3.875 mmol/L
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 43 of 46
Uric Acid
For < 12 y:  
t 8 mg/dL
For < 12 y:  
t 475.84 umol/L
59.48
For t 12 y:  
t 8 mg/dL (F); t 9.5 mg/dL (M)
For t 12 y:  
t 475.84 umol/L (F); t 565.06 umol/L 
(M)
Cholesterol
t 300 mg/dL
t 7.77 mmol/L
0.0259
HDL
d 25 mg/dL
d 0.65 mmol/L
0.0259
LDL
t 200 mg/dL
t 5.18 mmol/L
0.0259
Triglycerides
t 300 mg/dL
t 3.42 mmol/L
0.0114
(a) Schwartz equation (patients <12): 
Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine 
(b) Cockroft equation (patients >12):
Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine),
                      Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85
ALT=alanine aminotransferase; ALP=Alkaline phosphatase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CR CL=creatinine clearance; 
GGT=Gamma-glutamyl transpeptidase; HDL=High-density lipoprotein; LDL=low-density lipoprotein; SGOT=serum glutamic oxaloacetic transaminase; 
SGPT=serum glutamic pyruvic transaminase; ULN=Upper Limit of Normal.
REDACTED COPY
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 44 of 46
13.3.3 
Urinalysis 
Qualitative urine parameters are generally reported by a descriptive score, which differs 
among laboratories. For data analysis purpose, a four-point scale is used. Five-point, six-
point, or seven-point scales will be collapsed into a four-point scale first. A value is 
considered possibly clinically significant treatment emergent abnormal if an upward shift of 
at least 2 degrees from the baseline occurs under investigational treatment.  To collapse the 
results in a five-point scale into a four-point scale, the lowest two positive results will be 
combined (see example below). For results reported with a scale of more than five-point, 
please consult your study physician for how to collapse into four-point scale.
Original Five-point Scale
Four-point Scale
Negative/None
Negative/None
Trace/Rare/Mild/A Few
Trace/1+/Rare/Mild/A Few
1+
2+/Mod
2+/Mod
3+/Sev
3+/Sev
13.3.4 
Vital signs and body weight 
Pulse rate
For 1 m to  12 m: <110 bpm and a decrease of > 20 bpm from 
baseline or > 180 bpm and an increase of > 20 bpm from 
baseline
For 12 m to  3 y: < 90 bpm and a decrease of > 20 bpm from 
baseline or > 150 bpm and an increase of > 20 bpm from 
baseline
For 3 y to  12 y: < 65 bpm and a decrease of > 20 bpm from 
baseline or > 130 bpm and an increase of > 20 bpm from 
baseline
For 12 y to  17 y:  < 60 bpm and a decrease of > 20 bpm from 
baseline or > 120 bpm and an increase of > 20 bpm from 
baseline
For t 17 y:  < 50 bpm and a decrease of > 30 bpm from 
baseline or > 120 bpm and an increase of > 30 bpm from 
baseline
bpm=Beats per minute.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 45 of 46
Systolic blood pressure
For 1 m to  12 m:  < 60 mmHg and a decrease of > 20 mmHg 
from baseline or > 110 mmHg and an increase of 
> 30 mmHg from baseline
For 12 m to  6 y:  < 70 mmHg and a decrease of > 20 mmHg 
from baseline or > 120 mmHg and an increase of 
> 30 mmHg from baseline
For 6 y to  13 y:  < 70 mmHg and a decrease of > 20 mmHg 
from baseline or > 130 mmHg and an increase of 
> 30 mmHg from baseline
For 13 y and  17 y:  < 90 mmHg and a decrease of > 20 
mmHg from baseline or > 140 mmHg and an increase of 
> 30 mmHg from baseline
For t 17 y:  < 90 mmHg and a decrease of > 30 mmHg from 
baseline or > 180 mmHg and an increase of > 40 mmHg from 
baseline
Diastolic blood pressure
For 1 m to  12 m:  < 40 mmHg and a decrease of > 15 mmHg 
from baseline or > 60 mmHg and an increase of 
> 20 mmHg from baseline
For 12 m to  6 y:  < 45 mmHg and a decrease of > 15 mmHg 
from baseline or > 80 mmHg and an increase of 
> 20 mmHg from baseline
For 6 y to  13 y:  < 50 mmHg and a decrease of > 15 mmHg 
from baseline or > 85 mmHg and an increase of 
> 20 mmHg from baseline
For 13 y to  17 y:  < 55 mmHg and a decrease of > 20 mmHg 
from baseline or > 90 mmHg and an increase of 
> 30 mmHg from baseline
For t 17 y:  < 50 mmHg and a decrease of > 20 mmHg from 
baseline or > 105 mmHg and an increase of > 30 mmHg from 
baseline
Weight
For  17 y:  < 3% or ! 97% of the normal body weight growth 
curve ranges for the age at date of weight assessment (a) and 
gender;
For t 17 y:  change of t 7% of baseline weight
(a) Once the subject reaches 17 years of age use the body curve criteria of a 17 year old 
regardless of their age in the study.
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UCB                                                                                                                                                 28 January 2019
Statistical Analysis Plan                                          Brivaracetam                                                           
N01379
Page 46 of 46
14 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
Rational for the amendment
The primary purpose for the amendment is (1) remove rules and definitions based on data 
cutoffs for interim analyses; (2) remove the summary analysis for direct cost parameter and 
indirect cost parameters, and as well as Socio-professional data.
Change #1 (global)
Removed all rules and definitions based on data cutoffs for interim analyses throughout SAP.
Change #2
Section 8.2.4 Direct cost parameters, Section 8.2.5 Indirect cost parameters, Section 
8.2.6 Socio-professional data
Removed all direct/indirect cost parameters and socio-professional data summary analysis.
Change #3
Removed signature page. Using e-signature approval process through Source Submission.
REDACTED COPY 
This document cannot be used to support any marketing authorization application
throug
throu
and any
a sum
a sum
extensions 
ers, Se
rs, S
or 
ut 
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SA
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Approval Signatures
Name:
N01379 - SAP-Amendment-1
Version:
3. 0
Document Number:
CLIN-000130604
Title:
N01379 - SAP-Amendment-1
Approved Date:
04 Feb 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 04-Feb-2019 16:47:48 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 04-Feb-2019 17:24:54 GMT+0000
Y
App
App
DACTED CO
CO
REDA
DA
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
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