An Open-label, Multinational, Multicenter, Follow-up Study to Evaluate the Long-term Safety and Efficacy of Brivaracetam Used at a Flexible Dose up to a Maximum of 200 mg/Day in Subjects Aged 16 Years or Older Suffering From Epilepsy.
Phase: PHASE3
Conditions: Epilepsy
Sponsor: UCB Pharma

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 1 of 89
1.
TITLE
Protocol of Study N01315
An open-label, multinational, multicenter, follow-up study to evaluate the long-term safety 
and efficacy of brivaracetam, used at a flexible dose up to a maximum of 200mg/day, in 
subjects aged 16 years or older suffering from epilepsy.
Sponsor:
UCB Biosciences, Inc
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Hereafter “UCB”
Brivaracetam - EudraCT Number: 2008-001433-98; IND Number: 70,205
Confidential Material
The information contained in this document is strictly confidential.  It is disclosed to you as a 
(potential) Investigator or (potential) consultant.  Acceptance of this document constitutes 
your agreement that the information contained herein will not be disclosed or in any way 
communicated to any third party without prior written approval of UCB (or it’s 
representative(s)) of the clinical study described therein except - to the extent necessary - to 
your staff, to members of appropriate review committee(s) and/or to persons to whom the 
investigational product may be administered or to their legal representative(s) to obtain their 
informed consent.
REDACTED COPY 
0
Y
0
ot be used to support any marketing authorization application and any extensions or variations thereof. 
y
t
y
in
ri
in
3
p
3-
pl
-98
plica
98; I
ca
; I
ation c
e us
ation c
al) Inve
ot be
al) Inve
This document cann
agreem
nnot
agreem
mmun
can
mmun
repres
ent c
repres
yo
me
yo
i

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 2 of 89
Principal Investigator
By my signature below, I acknowledge that I have read the protocol (RPCE08C0502) and 
agree that it contains all necessary details for carrying out the clinical study described therein.  
Furthermore, I agree to conduct this clinical study in compliance with said Protocol, the ICH 
Good Clinical Practice guideline, as well as with any and all applicable federal, state and/or 
local laws and regulations and with my contractual obligations towards UCB or its 
representatives(s).
Signature:
___________________________________________
Date:
______________
Printed Name:
______________________________________________________________________
Address:
______________________________________________________________________
______________________________________________________________________
Phone:
____________________________________
Site 
Number:
______________
REDACTED COPY 
____
D 
____
____
AC
____
____
RE
____
ation application and any extensions or variations thereof. 
2
s
2) and
s or 
) and
ribed t
ions
ribed t
rotocol
ensio
rotocol
deral, s
exte
deral, s
UCB
y e
UCB
x
y marketing authorizat
_____
at
_____
_____
tho
_____
_____
ng
_____
_____
rk
_____
This document cannot be used to support any 
_____
y
_____

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 3 of 89
2.
CONTACT INFORMATION
Sponsor
UCB Biosciences, Inc
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
UCB Contributors:
Study Physician 
Name:
, MD
Phone:
Mobile:
Fax:
Clinical Project Manager (CPM)
Name:
Phone:
Fax:
Trial Statistician 
Name:
Phone:
Fax:
SAEs Reporting (24h/24)

Fax:
Europe and Rest of the World: 
+32-2-386-2421
USA: 
+1-800-880-6949
Canada: 
+1-877-582-8842

Email:
Global
DSICT@ucb.com
Investigator(s)
The complete and updated list of Investigators is maintained in the Trial Master File (TMF) 
at UCB.
Signatory Coordinating Investigator(s)
The signatory coordinating Investigator will be designated by UCB.
REDACTED COPY 
P
Y
P
Fa
PY
Fa
R
used to support any marketing authorization application and any extensions or variations thereof. 
e:
pl
e:
ax:
a
ax:
ng
est of t
ma
est of t
ar
al
p
al
ort
s
This document cannot be 
s)
s
s)
ete and
be us
ete and
gnator
can
gnator
The si
ent c
The si
ny ex
nd a

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 4 of 89
3.
TABLE OF CONTENTS
1.
TITLE..............................................................................................................................1
2.
CONTACT INFORMATION .......................................................................................3
3.
TABLE OF CONTENTS...............................................................................................4
4.
LIST OF ABBREVIATIONS........................................................................................9
5.
PROTOCOL SUMMARY...........................................................................................11
5.1
Study Schedule of Assessments.......................................................................16
5.2
Schematic Diagram ..........................................................................................19
6.
BACKGROUND INFORMATION............................................................................21
6.1
Background and epidemiology of targeted disease..........................................21
6.2
Background information regarding product.....................................................22
6.3
Efficacy with BRV in fixed-dose Phase II/III studies in POS .........................23
6.4
Conversion to monotherapy .............................................................................23
6.5
Safety with BRV ..............................................................................................24
6.6
Study Rationale ................................................................................................24
6.6.1
Dose Selection....................................................................................24
6.6.2
Subject Population .............................................................................24
6.6.3
Treatment Duration............................................................................25
6.6.4
Statement............................................................................................25
7.
STUDY OBJECTIVES ................................................................................................26
7.1
Primary Objective ............................................................................................26
7.2
Secondary Objective ........................................................................................26
7.3
Exploratory Objectives.....................................................................................26
8.
STUDY DESIGN ..........................................................................................................27
8.1
Type/Design .....................................................................................................27
8.2
Subjects/Sites Numbers....................................................................................27
8.3
Measures to Minimize/Avoid Bias...................................................................27
8.3.1
Blinding..............................................................................................27
8.3.2
Randomization ...................................................................................27
8.3.3
Subject Identifier................................................................................27
8.4
Study Duration .................................................................................................28
8.5
End of Study.....................................................................................................28
9.
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................29
9.1
Subject Inclusion Criteria.................................................................................29
9.2
Subject Exclusion Criteria................................................................................30
9.3
Subject Withdrawal..........................................................................................30
REDACTED COPY 
...
PY
......
PY
...
......
CO
......
......
D
......
n
CT
n ....
TE
....
CT
ation
ACT
ation
DA
......
ED
......
y marketing authorization application and any extensions or variations thereof. 
3
tio
3
tio
.......4
aria
.......4
..........
or v
..........
..........
ions
..........
........
en
........
.
e
.........
exte
........
........
any
........
.......
nd
.......
.......
n a
.......
tudies
tion
tudies
ati
.......
lic
.......
........
pp
........
.......
n
.......
.......
ati
.......
........
riz
........
.......
th
.......
........
a
........
........
eti
........
.......
ark
.......
ctive
y ma
ctive
y m
Objecti
any 
Objecti
port an
j
an
j
nnot be used to sup
an
.......
po
.......
Design
upp
Design
up
bjects/S
to su
bjects/S
to
Measur
d to
Measur
ed
8.3.1
use
8.3.1
us
This document cann
8
u
8
8.4
anno
8.4
an
8
a
8
9.
me
9.
m

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 5 of 89
10.
TREATMENT OF SUBJECTS (INVESTIGATIONAL PRODUCT AND
CONCOMITANT MEDICATIONS) .........................................................................32
10.1
Study Investigational Products.........................................................................32
10.1.1
Description of all Investigational Products........................................32
10.1.1.1
Dosing Schedule ...............................................................32
10.1.2
Packaging...........................................................................................33
10.1.3
Labeling..............................................................................................33
10.1.4
Storage Requirements ........................................................................33
10.1.5
Monitoring of Subject Compliance....................................................34
10.1.6
Investigational Products Accountability ............................................34
10.2
Concomitant Treatments and Rescue Medications ..........................................35
10.2.1
Permitted Concomitant Treatments (Medications and Therapies) ....35
10.2.2
Prohibited Concomitant Treatments (Medications and
Therapies)...........................................................................................35
11.
STUDY PROCEDURES..............................................................................................36
11.1
Description of Procedures................................................................................36
11.1.1
Informed Consent...............................................................................36
11.1.2
Subject Study Card.............................................................................36
11.1.3
Eligibility Criteria Assessment ..........................................................36
11.1.4
Demography.......................................................................................36
11.1.5
Childbearing Potential and Birth Control ..........................................37
11.1.6
Medical and Procedure History..........................................................37
11.1.7
Epilepsy History.................................................................................37
11.1.8
Antiepileptic Medication History.......................................................37
11.1.9
Vital Signs..........................................................................................37
11.1.10 Body Weight and Height....................................................................37
11.1.11 Physical Examination.........................................................................38
11.1.12 Neurological Examination .................................................................38
11.1.13 ECG....................................................................................................38
11.1.14 Daily Record Card..............................................................................38
11.1.15 Laboratory Assessments and Study Medication/AED(s)
Plasma Levels ...................................................................................39
11.1.16 Adverse Events (AEs)........................................................................40
11.1.17 Assessment of Suicidality ..................................................................40
11.1.18 Medical Procedures............................................................................40
11.1.19 Non-Antiepileptic and Antiepileptic Concomitant Medications........41
11.1.20 Patient Reported Outcomes................................................................41
11.1.20.1 Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)41
11.1.20.2 Hospital Anxiety and Depression Scale (HADS) .............42
11.1.20.3 EQ-5D Questionnaire........................................................42
11.1.21 Hospital Stay......................................................................................42
11.1.22 Healthcare Provider Consultations not foreseen by the Protocol.......42
11.1.23 Socio-professional Data .....................................................................43
REDACTED COPY
......
PY 
......
smen
COPY
smen
CO
........
D C
........
ntial
TED
ntial a
D
a
TE
ocedu
ACT
ocedu
AC
tory
EDA
tory
ED
tic
RE
tic M
RE
M
R
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
33
tio
33
tio
...33
riat
...33
ri
........3
r va
........3
..........
s or
..........
.....
ion
.........
ns
....
........
ns
........
nd
xt
nd The
xte
The
ex
ns
ny
ns and
y ex
and
ny
........
d a
........
y
.......
a
.......
........
tio
........
....
ica
.......
ca
...
.......
pp
.......
nt
n
nt .....
n a
.....
n
..........
atio
..........
and
riza
and Bir
za
Bir
riz
re
th
re His
hor
His
th
.......
au
.......
Medicat
ing a
Medicat
ting
.......
ke
.......
eight
mark
eight an
k
an
ma
al
y
al Ex
y m
Exa
y 
urologi
t any
urologi
t a
ECG
ort
ECG.
po
4 Dail
upp
Dail
up
.15
o s
.15 L
u
L
to
11.1
used
11.1
us
1
u
1

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 6 of 89
11.1.24 End of Study.......................................................................................43
11.2
Description Visit by Visit.................................................................................43
11.2.1
Entry Visit..........................................................................................44
11.2.2
Full Evaluation Visit ..........................................................................45
11.2.3
Minimal Evaluation Visit...................................................................45
11.2.4
Yearly Evaluation Visit (replaces the first FEV of each year)...........46
11.2.5
Early Discontinuation Visit................................................................47
11.2.6
Down-Titration Phone Call................................................................48
11.2.7
Final Visit (FV following a Study Drug Free Period after an
EDV or FV initiated upon Sponsor request at the end of the
program).............................................................................................48
11.2.8
Additional Visit..................................................................................48
11.3
Handling of Biological Samples ......................................................................49
11.4
Other Supplies..................................................................................................49
12.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................50
12.1
Adverse Events.................................................................................................50
12.1.1
Definition of Adverse Event (AE) .....................................................50
12.1.2
Procedures for Reporting and Recording Adverse Events.................50
12.1.3
Description of AEs.............................................................................50
12.1.4
Follow-up on Adverse Events............................................................53
12.1.5
Rule for Repetition of an AE .............................................................53
12.1.6
Pregnancy...........................................................................................53
12.1.7
Overdose of Investigational Product..................................................54
12.1.8
Safety Signal Detection in Ongoing Clinical Studies ........................54
12.2
Serious Adverse Events....................................................................................54
12.2.1
Definition of Serious Adverse Event (SAE)......................................54
12.2.2
Procedures for Reporting Serious Adverse Events (SAEs) ...............55
12.2.3
Follow-up of Serious Adverse Events................................................56
12.2.4
Anticipated Serious Adverse Events..................................................56
13.
STATISTICS.................................................................................................................58
13.1
Statistical and Analytical Plans........................................................................58
13.1.1
Study Population(s)............................................................................58
13.1.2
Safety, Efficacy, and Other Variables................................................58
13.1.2.1
Primary Safety Variables ..................................................58
13.1.2.2
Other Safety Variables......................................................58
13.1.2.3
Secondary Efficacy Variables...........................................58
13.1.2.4
Other Efficacy Variables...................................................58
13.1.2.5
Pharmacoeconomic Variables...........................................59
13.1.2.6
Pharmacokinetic Variables................................................59
13.1.3
Statistical Evaluation..........................................................................59
13.1.3.1
Evaluation of Safety..........................................................59
13.1.3.2
Evaluation of Efficacy.......................................................60
REDACTED COPY
nd
PY
nd R
Y 
R
PY
......
CO
......
e
D
e Eve
D CO
Eve
D
n
T
n of
TED
of a
D
a
TE
......
AC
......
Inves
EDA
Inves
ED
nal
RE
nal D
RE
D
R
t any marketing authorization application and any extensions or variations thereof. 
46
tio
46
tio
...47
riat
...47
ri
........4
r va
........4
n
the
ion
the
io
..........
nsio
..........
.......
xt
.......
.......
y
.......
..
d
........
d a
......
NTS
an
NTS
n a
........
tio
........
.......
ica
.......
ecordin
pplic
ecordin
pp
........
n a
........
nts
tio
nts..
o
..
ati
n
ri
n AE
riza
AE
ririz
.......
tho
.......
stigatio
aut
stigatio
a
Detectio
ing a
Detectio
ting
nts
ket
nts...
e
...
ke
n
m
n of
mark
of Se
rk
Se
ma
dures fo
y m
dures fo
y 
ow
t an
ow-up
any
-up
rt a
d to suppo t a
Anticip
port 
Anticip
po
.......
su
.......
atistica
to s
atistica
d to
This document cannot be used
13.1.1
ed 
13.1.1
se
13.
us
13.
u

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 7 of 89
13.2
Determination of the Sample Size....................................................................60
13.3
Changes in the Conduct of the Study or the Planned Analyses .......................60
13.4
Statistical and Analytical Issues.......................................................................61
13.4.1
Adjustments for Covariates and Interactions.....................................61
13.4.2
Handling of Dropouts of Missing Data..............................................61
13.4.3
Interim Analysis.................................................................................61
13.4.4
Multi-center Studies...........................................................................61
13.4.5
Multiple Treatment Comparisons/Multiple Endpoints ......................61
13.4.6
Examination of Subgroups.................................................................61
13.5
Pre-Analysis Review of Data ...........................................................................61
13.6
Criteria for Un-blinding the Results.................................................................62
13.7
Dictionaries ......................................................................................................62
14.
ETHICS AND REGULATORY REQUIREMENTS................................................63
14.1
Approval...........................................................................................................63
14.2
Subject Information and Consent.....................................................................64
14.3
Subject Confidentiality.....................................................................................65
14.4
Informing the General Practitioner ..................................................................65
15.
STUDY MANAGEMENT AND ADMINISTRATION ............................................66
15.1
Monitoring........................................................................................................66
15.2
Direct Access to Source Data/Documents .......................................................66
15.3
Audit and Inspection ........................................................................................67
15.4
Case Report Forms (CRF) and Screen Failures ...............................................68
15.5
Adherence to Protocol......................................................................................68
15.6
Investigator Site File ........................................................................................69
15.7
Data Handling ..................................................................................................69
15.8
Termination of Study .......................................................................................69
15.9
Clinical Study Report.......................................................................................70
15.10
Insurance and Liability.....................................................................................70
15.11
Archiving and Data Retention..........................................................................71
15.12
Allocation of Responsibilities..........................................................................71
15.13
Curriculum Vitae (CV).....................................................................................71
15.14
Financial Disclosure.........................................................................................71
15.15
Good Clinical Practice .....................................................................................72
15.16
Disclosure of Clinical Study Information ........................................................72
15.17
Publication........................................................................................................72
16.
REFERENCES .............................................................................................................73
17.
APPENDICES...............................................................................................................75
17.1
Health related Quality of Life Questionnaire (QOLIE-31-P) (Version 2).......75
17.2
Hospital Anxiety and Depression Scale (HADS) ............................................85
17.3
EQ-5D ..............................................................................................................86
REDACTED COPY
ISTR
OPY 
ISTR
OP
......
CO
......
/Docu
ED C
/Docu
ED
......
CT
......
RF)
DAC
RF) an
AC
an
DA
ol
RE
ol...
RE
...
RE
R
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
61
tio
61
tio
...61
riat
...61
ri
........6
r va
........6
........
s o
........
......
ion
.........
ns
...
........
ns
........
.......
xt
.......
........
any
........
........
d 
........
.....
an
.......
a
..
........
tio
........
.......
ica
.......
RATIO
app
RATIO
ap
........
on
........
ument
zatio
ument
za
........
or
........
nd
ut
nd Scre
utho
Scre
ut
ut
.......
g a
.......
........
tin
........
.......
rk
.......
Study
mar
Study
m
y
a
y Repo
any m
Repo
any
nd
rt
nd Lia
an
Lia
rt
ng
pp
ng and
ppor
and
pp
pp
ation
supp
ation
p
su
rriculu
to s
rriculu
d to
Financ
ed 
Financ
se
Go
use
Go
u
16
t b
16
D
t b
15.17
not 
15.17
nn
6.
t
6.
RE
a
RE
t
17.
men
17.
m

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 8 of 89
List of Tables
Table 5:1
Study Flowchart...........................................................................................16
Table 5:2
Visit Schematic Diagram.............................................................................19
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 9 of 89
4.
LIST OF ABBREVIATIONS
AE
Adverse event
AED(s)
Antiepileptic Drug(s)
ALT(ALAT/SGPT)
Alanine Aminotransferase
AST (ASAT/SGOT) Aspartate Aminotransferase
b.i.d.
Twice daily
BRV
brivaracetam
CNS
Central Nervous System
CPM
Clinical Project Manager
Cr Cl
Creatinine Clearance
CRF
Case Report Form
CRO
Clinical Research Organization
C-SSRS
Columbia Suicide Severity Rating Scale
CTM
Clinical Trial Manager
CTS
Clinical Trials Supplies
CV
Curriculum Vitae
CYP
Cytochrome P450
DRC
Daily Record Card
ECG
Electrocardiogram
EDV
Early Discontinuation Visit
EEG
Electroencephalogram
EQ-5D
EuroQoL-5 Dimensions
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GP
General Practitioner
HADS
Hospital Anxiety and Depression Scale
HDL
High Density Lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
LTFU
Long-term Follow-up
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
PBO
Placebo
PK
Pharmacokinetic(s)
REDACTED COPY 
ation 
ACTE
ation 
alogra
DAC
alogra
Dime
RED
Dime
cal
R
cal
ort any marketing authorization application and any extensions or variations thereof. 
Visit
horiz
Visit
ram
auth
ram
ension
g au
ension
Practi
eting
Practi
ufactur
arke
ufactur
Practi
ma
Practi
pital An
any 
pital An
igh De
ort a
igh De
t cannot be used to supp
Health
ppo
Health
Int
up
Int
U
nn
U
MCH
can
MCH
This document 
MCH
ent c
MCH
M
e
M

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 10 of 89
POS
Partial onset seizure(s)
PRO
Patient Reported Outcome
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy Questionnaire
RBC
Red Blood Cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV2A
Synaptic vesicle protein 2A
TEAE
Treatment-emergent adverse event
TMF
Trial Master File
V
Visit
WBC
White Blood Cell
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 11 of 89
5.
PROTOCOL SUMMARY
TITLE OF THE STUDY
An open-label, multinational, multicenter, follow-up study to evaluate the long-term safety 
and efficacy of brivaracetam used at a flexible dose up to a maximum of 200mg/day in 
subjects aged 16 years or older suffering from epilepsy.
STUDY TYPE/PHASE
Phase III
STUDY OBJECTIVES
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.
Secondary Objective
To evaluate the maintenance of efficacy over time of BRV.
Exploratory Objectives

To explore impact on health-related quality of life, anxiety and depression.

To obtain a description of patient’s self-reported health status.

To collect data on medical resources used and on indirect cost parameters.
STUDY VARIABLES
Primary Safety Variables

Occurrence of a treatment-emergent adverse event (TEAE)

Withdrawal due to AE

Occurrence of a serious adverse event (SAE)
Other Safety Variables

Laboratory tests (blood chemistry, hematology, and urinalysis)

Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate)
and body weight

Electrocardiogram (ECG)

Physical and neurological examination
REDACTED COPY 
e 
O
e of 
OPY
of B
Y
B
ed qua
ACTE
ed qua
nt’s se
DAC
nt’s se
esourc
RED
esourc
to support any marketing authorization application and any extensions or variations thereof. 
(BRV)
and 
(BRV)
m epile
on a
m epile
BRV
app
BRV.
p
.
alit
ho
ality of
oriz
y of
elf
aut
elf-
ut
-f-f
ut
f-f rep
uth
rep
ces use
ng a
ces use
a treat
ppo
a treat
due to
o sup
due to
This document cannot be used 
nce of 
d to
nce of 
fety Va
be u
fety Va
Lab
nno
Lab

m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 12 of 89

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
Secondary Efficacy Variables

Percentage of subjects on continuous BRV monotherapy for at least 3 months, at least 
6 months, and at least 12 months of the Evaluation Period
Other Efficacy Variables

Partial onset seizure (POS) (type I) frequency per 28 days during the Evaluation 
Period

Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period

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

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

EuroQoL-5 Dimensions (EQ-5D) questionnaire response for each assessment for the 
first 2 years for the Evaluation Period and for the last assessment during the first 
2 years of the Evaluation Period
Pharmacoeconomic Variables

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

Indirect costs (workdays or schooldays lost by the subject and days subject received 
help from a caregiver) 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
Pharmacokinetic Variables

Brivaracetam (parent compound only) plasma levels

Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels
STUDY DESIGN
This is a Phase III, long-term follow-up (LTFU), multinational, multicenter, 
non-comparative, open-label and single arm study.
REDACTED COPY
e in E
PY 
e in E
he pre
COPY
he pre
Perio
D CO
Perio
questi
TED
questi
Period
ACT
Period
iod
EDA
iod
d to support any marketing authorization application and any extensions or variations thereof. 
least
ariat
least
he Eva
exte
he Eva
m Base
d an
m Base
l seizu
tion 
l seizu
aluatio
cati
aluatio
pilepsy
pplic
pilepsy
evious 
n ap
evious 
od asse
tion
od asse
ionnair
riza
ionnair
d and f
thor
d and f
re prov
ny m
re prov
proced
t any
proced
m [ER] 
port 
m [ER] 
(work
supp
(work
a careg
to su
a careg
This document cannot be used
professi
ed to
professi
ssment
use
ssment
macoki
not b
macoki

me


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 13 of 89
The visits will be scheduled as follows:

First year:

First 3 months:  1 visit/month:  Full Evaluation Visit (FEV) alternating with 
Minimal Evaluation Visit (MEV).

Next 9 months:  1 visit/3 months:  FEV alternating with MEV.

Second and subsequent years:

1 visit/3 months:  FEV alternating with MEV.

The Yearly Evaluation Visit (YEV) will be performed in replacement of the first 
FEV of each year.
PLANNED STUDY PERIOD
This 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 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 requirements in addition to legal and regulatory guidelines, or until BRV
development is stopped by the Sponsor.
PLANNED NUMBER OF SUBJECTS AND SITES:
It was estimated that approximately 300-600 subjects were to enter the study. However, the 
number of subjects entered will be reduced due to the premature discontinuation of N01276 
and N01306.
This study will include as many sites as required (initially, 120-180 sites are foreseen).
REGIONS AND COUNTRIES
The study is planned to be performed worldwide.
MAIN INCLUSION AND EXCLUSION CRITERIA
Before any study procedures are initiated for any subject in this study, an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) approved written informed consent form 
will be properly executed and documented.
Subject Inclusion Criteria:

An IEC/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.
REDACTED COPY
gram
PY 
gram
ccess 
COPY
ccess 
egal a
D CO
egal a
CTS A
EDA
CTS A
y
R
y 30
RE
30
y
R
y
0
E
0
port any marketing authorization application and any extensions or variations thereof. 
ent of t
sion
ent of t
ment pe
nd a
ment pe
Health A
n and
Health A
y
ti
y POS
tion 
POS
y
ti
y
the stu
licati
the stu
named
pplic
named
s progra
n ap
s progra
and reg
ation
and reg
AND 
aut
AND 
0-600
ng a
0-600
reduced
ketin
reduced
many
t any
many
not be used to sup
si
ny
si
y
ny
y
UNTR
uppo
UNTR
ed to b
to su
ed to b
LUSIO
used
LUSIO
y stud
be u
y stud
ittee (I
ot b
ittee (I
This document can
be pro
anno
be pro
Subj
ment
Subj

m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 14 of 89

Male/female subjects from 16 years or older.  Subjects under 18 years may only be 
included where legally permitted and ethically accepted. In 
 all subjects must 
be older than 18 years.

Subjects with epilepsy who participated in previous BRV studies which allow access to 
the present study.

Subjects from whom the Investigator believes a reasonable potential benefit from the 
long-term administration of BRV may be expected. 

Female subjects without childbearing potential (premenarcheal; 2 years 
postmenopausal, bilateral oophorectomy or ovariectomy, bilateral salpingectomy, 
complete hysterectomy, congenital sterility) are eligible.  Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive 
method for the duration of the study (Intra Uterine Device, diaphragm with spermicide, 
male or female condom with spermicide; oral hormonal contraceptive, non-oral 
hormonal contraceptive medication, bilateral tubal ligation, bilateral tubal implant, 
monogamous relationship with vasectomized partner).  Oral or depot contraceptive 
treatment with at least 30µg [or 50µg if associated with other antiepileptic drugs known 
as inducers] ethinylestradiol per intake must be used in conjunction with a barrier 
method.  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. Sexual inactivity might be accepted on a case-by-case basis.

Subject/legally acceptable representative considered as reliable and capable of adhering 
to the protocol (e.g. able to understand and complete diaries and questionnaires), visit 
schedule or medication intake according to the judgment of the Investigator.
Subject Exclusion Criteria:

Severe medical, neurological and psychiatric disorders, including current suicidal 
ideation or behaviour, or laboratory values which may have an impact on the safety of 
the subject, as determined by the Investigator.

Poor compliance with the visit schedule or medication intake in the previous BRV 
study.

Participation in any clinical study of another investigation drug or device during the 
study.

Pregnant or lactating woman.
INVESTIGATIONAL PRODUCT
Oral tablets of 10mg and 25mg BRV, packaged in bottles containing 200 oral tablets.
Subjects will begin at a recommended dose of BRV 100mg/day. The daily dose should be 
divided into 2 equal intakes (morning and evening), taken with or without food.  The first 
intake will be in the evening of the day of the dispensation of the study medication.
Subjects will continue BRV treatment at a dose up to a maximum of 200mg/day in twice 
daily (b.i.d.) administration. Up- and down-titration steps should be performed in steps of 
REDACTED COPY
nseq
PY 
nseq
educat
COPY
educat
e to in
D CO
e to in
ight b
TED 
ight b
entativ
ACT
entativ
derstan
EDA
derstan
e acc
RE
e acc
marketing authorization application and any extensions or variations thereof. 
tomy,
ns o
tomy,
s with 
sion
s with 
tracept
tens
tracept
gm with
exte
gm with
ptive, n
ny e
ptive, n
lateral 
d an
lateral 
al or de
and
al or de
other a
tion 
other a
in conj
icatio
in conj
uences a
pplic
uences a
ated ab
n app
ated ab
nform 
tion
nform 
be acce
rizat
be acce
ve con
thori
ve con
and and
auth
and and
cording
ing a
cording
cannot be used to support any
gical a
y m
gical a
,
t
, or lab
t any
or lab
ermine
port 
ermine
ce with
upp
ce with
tion in 
ed to
tion in 
gnant o
be u
gnant o
VESTI
ann
VESTI
This document 
Oral tab
nt ca
Oral tab
Su
m
Su

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 15 of 89
maximum 50mg/day on a weekly basis. Full down-titration should include a 1-week step on 
20mg/day.
The doses administered in this study must comply with doses that can be administered with 
either BRV 10mg tablets, 25mg tablets, or a combination of these 2 strengths in a total daily 
dose that can be administered in 2 equal doses.  Daily dose prescriptions that do not respect 
these limitations should not be administered.
Each subject will be informed on how to take the drug and that there might be an excess of 
drug dispensed at each visit.
STATISTICAL METHODS
Population for Analysis
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
The Efficacy Population 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.
Safety Variables Analyses
All safety analyses will be summarized descriptively. Changes from Baseline will be 
calculated from the Baseline of the preceding study.
Efficacy Variables Analyses
No hypothesis testing will be performed.
All efficacy analyses will be summarized descriptively. The Baseline of an efficacy variable 
will be the Baseline from the initial study.
Sample Size Calculation
For this open-label, LTFU study, no sample size calculation has been performed.  The sample 
size will depend upon recruitment into and completion of preceding studies; approximately 
300 - 600 subjects were expected.
REDACTED COPY 
wh
Y
wh
during
OPY
during
descrip
ACTE
descrip
ecedin
DAC
ecedin
y marketing authorization application and any extensions or variations thereof. 
xcess o
s or 
xcess o
t 1
an
t 1 dos
nd 
dos
took at
plica
took at
g the E
app
g the E
iptively
horiz
iptively
ing stud
autho
ing stud
ormed.
arke
ormed.
d to support an
 summ
any 
 summ
the ini
ort a
the ini
lation
sup
lation
el, 
d to
el, 
use
LT
to 
LT
nd upo
sed 
nd upo
This document cannot be 
ubjects
e us
ubjects

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 16 of 89
5.1
Study Schedule of Assessments
Table 5:1
Study Flowchart
Entry Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit (AV)
Early 
Discontinuation 
Visit (EDV)(l)
Down-Titration 
Phone Call 
(DTP)(a) 
Final Visit 
(FV)
Reference 
to Section
ASSESSMENTS
Written Informed Consent
X
11.1.1
Clinical Study Subject Card 
Dispensing
X
11.1.2
Verification Inclusion/
Exclusion Criteria
X
11.1.3
Demographic Data
X
11.1.4
Childbearing Potential
X
11.1.5
Medical and Procedures 
History
X(b) 
11.1.6
Epilepsy History
X(b) 
11.1.7
AED History
X(b) 
11.1.8
Vital Signs
X(c) 
X
X
X
X
X
X
11.1.9
Weight and Height(d) 
X(c) 
X
X
X
X
11.1.10
Physical Examination
X(c) 
X
X
X
X
11.1.11
Neurological Examination
X(c) 
X
X
X
X
11.1.12
ECG(e) 
X(c) 
X
X
X
11.1.13
Daily Record Card Dispensed
X(c) 
X
X
X
X
11.1.14
Daily Record Card Retrieval
X
X
X
X
X
11.1.14
Seizure Counts
X
X
X
X
X
X
11.1.14
Recording of Seizures
X(c) 
X
X
X
X
X
11.1.14
QOLIE-31-P(f) 
X
X
X
11.1.20.1
HADS(f) 
X
X
X
11.1.20.2
EQ-5D(f) 
X
X
X
11.1.20.3
REDACTED COPY 
Y
CO
ED
TE
CT
DA
R
nnot be used to support any marketing authorization application and any extensions or variations thereof. 
Final
r va
Final
nal
a
nal
(AV)
on a
(AV)
D
d a
nd
tio
ica
p
pp
on
iza
ho
uth
uth
uth
uth
ut
ng
ke
ma
m
X
y
X
ort
X
t a
X
o
X
po
up
su
c
d
c) 
d
) 
to
ed
X
s
X
us
e
This document cannot t b
ot
nn
t c
en

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 17 of 89
Table 5:1
Study Flowchart
Entry Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit (AV)
Early 
Discontinuation 
Visit (EDV)(l)
Down-Titration 
Phone Call 
(DTP)(a) 
Final Visit 
(FV)
Reference 
to Section
ASSESSMENTS
Workdays and schooldays lost / 
Days with caregiver’s help (k)
X
X
X
X
X
X
Hospital stay (k)
X
X
X
X
X
X
11.1.21
Healthcare Provider 
Consultations not foreseen by 
the protocol (k)
X
X
X
X
X
X
11.1.22
Socio-professional data(g) 
X
X
X
11.1.23
Laboratory Assessments(h) 
X(c) 
X
X
X
X
11.1.15
Recording of Adverse Events
X
X
X
X
X
X
X
X
11.1.16
C-SSRS(j)
X
X
X
X
X
X
11.1.17
Medical Procedures
X
X
X
X
X
X
X
11.1.6
Concomitant AED
X
X
X
X
X
X
X
11.1.19
Concomitant Non-AED
X
X
X
X
X
X
X
11.1.19
Drug Dispensing
X
X
X
X
X
Drug Return/Accountability
X
X
X
X
X
End of Study Status(i) 
X
11.1.24
AED=antiepileptic drug; AV=Additional Visit; BRV=brivaracetam; CRF=Case Report Form; C-SSRS=Columbia Suicide Severity Rating Scale; DTP=Down-Titration Phone 
Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EQ-5D=EuroQoL-5 Dimensions; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final Visit; 
HADS=Hospital Anxiety and Depression Scale; IEC=Independent Ethics Committee; IRB=Institutional Review Board; MEV=Minimal Evaluation Visit; QOLIE-31-P=Patient 
Weighted Quality of Life in Epilepsy Questionnaire; YEV=Yearly Evaluation Visit
(a) Down-Titration Phone Call at the end of the Down-Titration Period is mandatory in case the subjects discontinue from more than 20mg/day BRV.
(b) The following data will be obtained from the database of the Baseline Visit of the previous study and should not be recorded into the CRF:  General Medical and Procedure 
History, AED History, and Epilepsy History.
(c) The following data will be obtained from the database of the final visit of the previous study and should not be recorded in the CRF:  Vital Signs, Weight, Physical 
Examination, Neurological Examination, ECG, Recording of seizures, Laboratory Assessment including Safety (blood chemistry, hematology, and urinalysis), concomitant 
AED plasma levels and BRV plasma levels.
(d) Height will be recorded at Visit 1.  Height will also be measured at each YEV and the FV for those subjects who are still potentially growing. 
REDACTED COPY 
X
PY
X
CO
ED
ED
ED
ED
ED
X
A
X
CT
X
DA
X
AC
ED
R
t any marketing authorization application and any extensions or variations thereof. 
Final
r va
Final
arly
xte
arly
ontinua
ex
ontinua
Visit (E
ny 
Visit (E
en
an
d
nd
X
atio
X
on
ca
pp
X
tio
X
on
X
a
X
at
or
th
th
th
th
uth
X
n
X
a
X
etin
X
ng
X
e
X
ket
ark
m
y 
This document cannot be used to support a
V=brivar
ort 
V=brivar
ontinuati
ppo
ontinuati
e; IEC=
supp
e; IEC=
ionnaire
to su
ionnaire
end of 
sed
end of th
d
th
ined
e us
ined fro
us
fro
Epilepsy
t be 
Epilepsy
e
o
e obtain
ot b
obtain
ogical Ex
nno
ogical Ex
s and 
can
s and BR
an
BR
corded a
nt c
corded a
t a

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 18 of 89
Table 5:1
Study Flowchart
Entry Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit (AV)
Early 
Discontinuation 
Visit (EDV)(l)
Down-Titration 
Phone Call 
(DTP)(a) 
Final Visit 
(FV)
Reference 
to Section
ASSESSMENTS
(e) At FV, ECG is mandatory except if FV follows an EDV where ECG results were normal.
(f) QOLIE-31-P, EQ-5D, and HADS are to be completed at the beginning of the visit by all subjects who are not mentally impaired during the first 2 years.
(g) Socio-professional data (to be collected during the first 2 years) will not be collected in 
(h) Laboratory assessment includes blood chemistry, hematology, and urinalysis; where applicable (women of childbearing potential), a serum pregnancy test will be done.  
Laboratory is mandatory at FV except if FV follows an EDV where laboratory results were normal.  Concomitant AED plasma levels and BRV plasma levels up to approval 
of Protocol Amendment 2.  
(i) 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).
(j) The C-SSRS assessment will be implemented by site per IRB/IEC approval upon completion of required training. As of the time of Protocol Amendment 2, all subjects had 
completed their EV. Thus, the C-SSRS was not assessed for any subjects at their EV.
(k) Procedures only performed during the first 2 years of subject participation in the study or EDV/FV in case the subject discontinues participation within the first 2 years.
(l) For subjects that may transition to another BRV study or a managed access program or similar type of program, the EDV will need to be completed, however down- titration
and FV may not be applicable.
REDACTED COPY 
s w
Y
s w
n EDV
COP
n EDV
al upon 
ED 
al upon 
cts at th
CTE
cts at th
pation i
ACT
pation i
ed acce
EDA
ed acce
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
Final
r va
Final
arly
xte
arly
ontinua
ex
ontinua
Visit (E
ny 
Visit (E
en
an
o are not
n a
o are not
(women
cati
(women
normal. 
plic
normal. 
(discon
n ap
(discon
complet
zati
complet
heir 
ori
heir EV
oriz
EV
n the stu
tho
n the stu
ess progr
auth
ess progr
d

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 19 of 89
5.2
Schematic Diagram

First year:

First 3 months:  1 visit/month:  FEV alternating with MEV

Next 9 months:  1 visit/3 months:  FEV alternating with MEV

Second and subsequent years:

1 visit/3months:  FEV alternating with MEV

The YEV will be performed in replacement of the first FEV of each year.
Table 5:2
Visit Schematic Diagram
1st, 2nd and subsequent years 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
M12
V7
YEV
M15
V8
MEV
M18
V9
FEV
M21
V10
MEV
M24
V11
YEV
M…
V…
…
In case the subject will not continue with the study drug, the Investigator will first plan an 
Early Discontinuation Visit (EDV) followed by the progressive down-titration of the study 
drug.  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 will be
included prior to the drug free period.
REDACTED COPY 
PY
OP
CO
ED
CT
DA
RE
RE
RE
RE
RE
ent cannot be used to support any marketing authorization application and any extensions or variations thereof. 
year.
ns o
ear.
a
up
a
up
nd
f Visit
tion 
f Visit
n a
Visit
icati
Visit (
tio
MEV
ppli
MEV
lic
F
p
F
app
on
at
za
or
V5
aut
V5
uth
g a
tin
rk
rk
rk
rk
rk
M10
ny
M10
m
M11
rt an
M11
any
M
or
M
rt
pp
su
s
case th
can
case th
This documen
Earl
ent c
Early
c
y
dru
me
dru

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 20 of 89
At the end of the down-titration period, a phone call will be given to subjects having down-
titrated from doses higher than 20mg/day.  The down-titration period will be followed by a 
period free of study drug of a minimum of 2 weeks and a maximum of 4 weeks and 
subsequently, the Final Visit (FV) will occur.
When the time point is reached at which the study will be terminated by the Sponsor (as 
defined in Section 8.4), subjects will discontinue the study drug, following the Investigator’s 
instructions for down-titration if necessary. 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
tor’s 
ariat
tor’s 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 21 of 89
6.
BACKGROUND INFORMATION
6.1
Background and epidemiology of targeted disease
Epilepsy is 1 of the most common and challenging neurological disorders.  It has been 
estimated that over 50 million people are affected worldwide (Engel and Pedley, 1998; 
Hauser et al, 1993; Loiseau et al, 1990; Sander and Shorvon, 1996). The prevalence of 
epilepsy is around 1%.  The annual incidence in developed countries is around 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 for epilepsy remains 
difficult, and there is ongoing medical need for new AEDs.  For considerable proportions of 
patients, seizure freedom can still not be reached with currently available AEDs (Nasreddine 
et al, 2010; Kwan and Brodie, 2001).
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 (i.e., 
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 International 
League Against Epilepsy ([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 (EEGs) 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).
REDACTED COPY 
A
Y
A
with c
OPY
with c
curren
ACTE
curren
due to
DAC
due to
mplica
RED
mplica
ep
R
ep
t cannot be used to support any marketing authorization application and any extensions or variations thereof. 
of 
r
of 
o
s
o 70 ca
s or
70 ca
bstetric
ions
bstetric
dence 
ensio
dence 
els in e
xte
els in e
le, part
ny ex
le, part
will ha
d any
will ha
ng cau
and 
ng cau
to
on
to 5 pe
n a
5 pe
he treat
catio
he treat
Ds.  For
plica
Ds.  For
curren
app
curren
nce of s
horiz
nce of s
to gene
autho
to gene
ations 
ng au
ations 
psy
keti
psy is th
eting
is th
y
eti
y
n), whi
arke
n), whi
cases,
y ma
cases,
all epi
any 
all epi
or the c
rt a
or the c
f epilep
sup
f epilep
First p
d to s
First p
psies (
sed 
psies (
ainst E
e us
ainst E
s that, f
ot be
s that, f
[
n
[http:
nnot
http:
This documen
ng
c
ng-
ca
-term
can
term
imagin
ent c
imagin
clas
me
clas
i

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 22 of 89
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).
6.2
Background information regarding product 
Brivaracetam is a 2-pyrrolidone derivative.  Brivaracetam displays a high and selective 
interaction with a novel brain-specific binding site, SV2A (synaptic vesicle protein 2A).  This 
binding site appears to be the major target for its pharmacological activity.  Brivaracetam 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.
Brivaracetam is rapidly and completely absorbed throughout the gastrointestinal tract.  The 
extent of BRV absorption is not affected by food.  The pharmacokinetics (PK) are 
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 2C19 (CYP2C19) (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 
REDACTED COPY 
duc
Y
duc
rivara
CO
rivara
ing sit
ED C
ing sit
et for 
ACTE
et for 
urrents
DAC
urrents
n gam
RED
n gam
oliz
R
oliz
nnot be used to support any marketing authorization application and any extensions or variations thereof. 
ll
t
ll
s,
ar
s,
eizure
r va
eizure
e other 
s or 
e other 
nd at
ions
nd atyp
s
yp
atonic
ensio
atonic
ed from
exte
ed from
LAE, 1
ny ex
LAE, 1
ccordin
and 
ccordin
logy
on a
logy o
a
o
a
cetam
ion a
cetam
ite, SV
izatio
ite, SV
its pha
horiz
its pha
s.  Briv
autho
s.  Briv
mma
ng a
mma-
a
-am
au
am
ized, bu
keting
ized, bu
comple
any 
comple
n is not
ort a
n is not
eas
pp
east fro
ppo
t fro
he volu
sup
he volu
 plasm
d to s
 plasm
main me
sed 
main me
ing car
e us
ing car
me
t b
me P4
be
P4
ination
nnot
ination
This document c
etabolit
can
etabolit
BRV. 
ent c
BRV. 
Mo
me
Mo
7

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 23 of 89
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, levetiracetam, oxcarbazepine metabolite, phenobarbital, 
phenytoin, topiramate, valproate, and zonisamide.  Carbamazepine epoxide was moderately 
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.
6.3
Efficacy with BRV in fixed-dose Phase II/III studies in POS 
Following completion of the Phase II studies (N01114, UCB protocol reference code 
RPCE02K0301; N01193, UCB protocol reference code RPCE05C2201), clinical results 
supported further development of BRV for the adjunctive treatment of POS.  Two adequate 
and well-controlled fixed-dose studies (N01252, UCB protocol reference code 
RPCE06G0704; N01253, UCB protocol reference code RPCE06G0705) were conducted to 
assess BRV across a dose range of 5 to 100mg/day.
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 the primary efficacy endpoint (for 
BRV 50mg/day) of N01252 was not positive, it provided supporting evidence for the efficacy 
of BRV 100mg/day in subjects with epilepsy. An additional confirmatory study (N01358) in 
subjects with POS is ongoing and will assess the doses of BRV 100mg/day, to replicate and 
confirm the treatment effect observed in N01252, and BRV 200mg/day, at the 
recommendation of regulatory authorities in order to explore the upper end of the 
dose-response curve.
6.4
Conversion to monotherapy
Two Phase III studies (N01276 and N01306) were initiated to evaluate the efficacy, safety 
and tolerability of BRV (at doses of 50 and 100mg/day in b.i.d. regimen) in the conversion to 
monotherapy, in subjects with POS, whether or not secondarily generalized, when compared 
to a historical pseudo-placebo control group.
REDACTED COPY 
e
O
e II/II
OPY
II/II
es (N0
ED C
es (N0
refere
ACTE
refere
V
DA
V for 
DAC
for 
dies (N
RED
dies (N
toc
R
toc
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
ive 
ari
ive 
ubjects
r va
ubjects
ifampi
s or 
ifampi
s.  No s
exte
s.  No s
ma conc
ny ex
ma conc
e, phen
d any
e, phen
e epox
and 
e epox
ay
on
ay, nea
on a
, nea
g/day
catio
g/day
II stud
app
II stud
01114,
izatio
01114,
ence c
horiz
ence c
r the ad
autho
r the ad
N0125
ng au
N0125
ocol ref
keting
ocol ref
f 5
ark
f 5 to 
rke
to 1
s of 5, 
any 
s of 5, 
idence 
ort a
idence 
00mg/d
ppo
00mg/d
N0125
sup
N0125
day in s
d to s
day in s
POS
sed
POS is
d 
is
e treatm
e us
e treatm
endatio
ot be
endatio
respon
nno
respon
6.4
ent
6.4
T

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 24 of 89
A decision was taken to stop the N01276 and N01306 studies after an interim analysis and 
independent unblinded review of study data by a Data Monitoring Committee identified that 
pre-defined criteria for stopping the studies had been met. It was determined the probability 
that both studies together would demonstrate a positive outcome for the efficacy analysis at 
completion was too low.
6.5
Safety with BRV 
In Phase II/III studies, a favorable safety and tolerability profile has been demonstrated for 
BRV.  The discontinuation rate and the discontinuation rate due to 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 SAEs was low and similar to 
PBO.  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 (UCB reference code RXCE06E2216).
6.6
Study Rationale
The Sponsor wishes to develop BRV as a monotherapy antiepileptic treatment in subjects 
16 years and older suffering from epilepsy.  N01315 will give subjects, who have participated 
in a previous BRV monotherapy study in epilepsy, the opportunity to continue BRV
treatment under the present protocol.
The study will explore the long-term safety and efficacy of BRV in such a population and 
potentially populations from other future studies.
6.6.1
Dose Selection
In this study, the recommended starting dose is 100mg/day. Afterwards the daily dose can be 
individualized up to a maximum of 200mg/day. Twice daily dosing is deemed necessary to 
ensure more regular exposure over the 24-hour interval.
A maximum dose of 200mg/day was chosen following consultation with regulatory 
authorities and is to be evaluated in more recent BRV studies (e.g., N01358 and N01379). 
According to available data, 200mg/day doses have been well tolerated.
6.6.2
Subject Population
Male and female subjects, with a clinical diagnosis of epilepsy with POS, are allowed to 
participate in this study from the age of 16 (where legally permitted and ethically accepted). 
REDACTED COPY 
a mon
ACTE
a mon
leps
DAC
lepsy.
AC
y.
ud
RE
udy in
RED
y in
l
R
l
y marketing authorization application and any extensions or variations thereof. 
strated
ions
strated
ere
n
ere low
nsio
low
AEs we
exte
AEs we
low a
y ex
low a
s, vital 
d any
s, vital 
ease ref
catio
ease ref
nothera
horiz
nothera
.  N013
autho
.  N013
n ep
ng a
n epile
au
ile
term s
ma
term s
t cannot be used to support an
m other 
any 
m other 
n
p
n
r
d
recom
d to s
ecom
d up to 
sed 
d up to 
re regul
e us
re regul
aximum
nnot
aximum
thoritie
can
thoritie
This documen
Accor
ent c
Accor

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 25 of 89
Indeed epilepsy features in the range of 16 to 18 years do not differ from the ones of older 
subjects, and efficacy of the AEDs seems to be comparable (N01236; CPMP/EWP/566/98 
rev 1, 2000). In 
 however the minimal age to enter the study will be 18.
Depending on country-specific regulations, those subjects may be considered as adolescents 
or adults (N01125; CPMP/ICH/2711/99, 2000). In case they are considered as adolescents, 
parent(s) or legal representative will sign the informed consent form.  The consent form or a 
specific assent form, where required, will be signed and dated by the minor.
6.6.3
Treatment Duration
The study is planned to begin in Q3 2008.
This 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 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.
6.6.4
Statement
The present study will be conducted in accordance with:

This protocol.

Code of Federal Regulations Title 21 Parts, 50, 54, 56, 312, and 314.

International Conference on Harmonization: ICH E6 Note for Guidance on Good
Clinical Practice (CPMP/ICH/135/95).

The principles that have their origin in the Declaration of Helsinki.

All applicable laws and regulations.
REDACTED COPY 
ram
Y
ram
cess p
OPY
cess p
gal and
D CO
gal and
d i
R
d i
port any marketing authorization application and any extensions or variations thereof. 
or a
ariat
or a
ent per
d any
ent per
ealth A
and 
ealth A
y POS, 
on a
POS, 
y
he stud
catio
he stud
named 
plica
named 
program
app
program
d regu
tion a
d regu
in acco
keting
in acco
ions Ti
y ma
ions Ti
nce on 
any
nce on 
CPMP/
ort a
CPMP/
This document cannot be used to sup
hat hav
uppo
hat hav
e laws
o sup
e laws

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 26 of 89
7.
STUDY OBJECTIVES
7.1
Primary Objective
To evaluate the long-term safety and tolerability of BRV at individualized doses with a 
maximum of 200mg/day in subjects suffering from epilepsy.
7.2
Secondary Objective
To evaluate the maintenance of efficacy over time of BRV.
7.3
Exploratory Objectives

To explore impact on health-related quality of life, anxiety and depression.

To obtain a description of patient’s self-reported health status.

To collect data on medical resources used and on indirect cost parameters.
REDACTED COPY 
tion and any extensions or variations thereof. 
and dep
and
and dep
status.
ion a
status.
This document cannot be used to support any marketing authorization applica
irect co
icatio
irect co

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 27 of 89
8.
STUDY DESIGN
8.1
Type/Design
This is a Phase III, LTFU, multinational, multicenter, non-comparative, open-label and single 
arm study.
The visits will be scheduled as follows:

First year:

First 3 months:  1 visit/month:  FEV alternating with MEV.

Next 9 months:  1 visit/3 months:  FEV alternating with MEV.

Second and subsequent years:

1 visit/3months:  FEV alternating with MEV.

The YEV will be performed in replacement of the first FEV of each year.
8.2
Subjects/Sites Numbers
It was estimated that approximately 300 - 600 subjects were to enter the study. However, the 
number of subjects entered will be reduced due to the premature discontinuation of N01276 
and N01306.
This study will include as many sites as required (initially, 120-180 sites are foreseen).
8.3
Measures to Minimize/Avoid Bias
8.3.1
Blinding
This is a single arm open-label LTFU study.
8.3.2
Randomization
Not applicable.
8.3.3
Subject Identifier
Each subject will be identified by initials (3 letters; corresponding either to the subject’s 
actual initials, or “dummy” initials, as preferred by the Investigator and according to country 
regulatory requirements) and a unique identifier including the study number, a 3-digit center 
number and a 4-digit sequential number, starting by 1 at each site (e.g. 1st subject at site 025: 
N01315/025/0001).
REDACTED COPY 
ubject
COPY
ubject
ue to t
D CO
ue to t
as re
EDA
as re
nt cannot be used to support any marketing authorization application and any extensions or variations thereof. 
gle
ti
gle
rst FEV
n and
rst FEV
ts
n
ts were
n ap
were
the pre
ation
the pre
equired
auth
equired
oid Bi
ketin
oid Bi
n
p
n-
o
-label
port 
label
zation
o su
zation
le.
us
le.
Subj
ot b
Subj
Each su
t ca
Each su
This documen
actua
ment
actua
re
m
re

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 28 of 89
8.4
Study Duration
This 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 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.
8.5
End of Study
The end of study is defined as the date of the last visit of the last subject in the study.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
n
t
n
ed per 
r va
ed per 
BRV
s or
BRV
ject in 
d any
ject in 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 29 of 89
9.
SELECTION AND WITHDRAWAL OF SUBJECTS
Before any study procedures are initiated for any subject in this study, an Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) approved written informed consent form 
will be properly executed and documented.
9.1
Subject Inclusion Criteria
To be eligible to participate in this study, all of the following criteria must be met:

An IEC/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.

Male/female subjects from 16 years or older.  Subjects under 18 years may only be 
included where legally permitted and ethically accepted. In 
 subjects must be 
older than 18 to enter the study.

Subjects with epilepsy who participated in previous BRV studies which allow access to 
the present study.

Subjects from whom the Investigator believes a reasonable potential benefit from the 
long-term administration of BRV may be expected.

Female subjects without childbearing potential (premenarcheal; 2 years 
postmenopausal bilateral oophorectomy or ovariectomy, bilateral salpingectomy, 
complete hysterectomy, congenital sterility) are eligible.  Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive 
method for the duration of the study (Intra Uterine Device, diaphragm with spermicide, 
male or female condom with spermicide; oral hormonal contraceptive, non-oral 
hormonal contraceptive medication, bilateral tubal ligation, bilateral tubal implant, 
monogamous relationship with vasectomized partner).  Oral or depot contraceptive 
treatment with at least 30µg [or 50µg if associated with other antiepileptic drugs known 
as inducers] ethinylestradiol per intake must be used in conjunction with a barrier 
method.  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. Sexual inactivity might be accepted on a case-by-case basis

Subject/legally acceptable representative considered as reliable and capable of adhering 
to the protocol (e.g. able to understand and complete diaries and questionnaires), visit 
schedule or medication intake according to the judgment of the Investigator.
REDACTED COPY 
ves a 
COPY
ves a 
be exp
D CO
be exp
g pote
TED
g pote
ctom
ACT
ctom
T
nital s
EDA
nital s
gible
RE
gible
d any extensions or variations thereof. 
et:
io
et:
he subje
ensi
he subje
a speci
exte
a speci
18
d
18 ye
d an
yea
n
a
This document cannot be used to support any marketing authorization 
RV
cati
RV stu
tio
stu
 reason
n app
 reason
pected.
tion
pected.
ential (
rizat
ential (
y or ov
thori
y or ov
sterility
auth
sterility
e if the
ing a
e if the
study
ketin
study
th sperm
mark
th sperm
medica
y ma
medica
nship w
t any
nship w
east 30
port a
east 30
iny
upp
inylest
ppo
lest
e subjec
o sup
e subjec
el
d
ely pro
d to
y pro
racepti
used
racepti
nge in s
be u
nge in s
ubject/
ot b
ubject/
to the
anno
to the
sc
a
sc
application and 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 30 of 89
9.2
Subject Exclusion Criteria
Subjects must be excluded if they meet any of the following criteria:

Severe medical, neurological and psychiatric disorders, including current suicidal 
ideation or behaviour, or laboratory values which may have an impact on the safety of 
the subject, as determined by the Investigator.

Poor compliance with the visit schedule or medication intake in the previous BRV
study.

Participation in any clinical study of another investigation drug or device during the 
study.

Pregnant or lactating woman.
If the Investigator has any medically valid reason to doubt the eligibility of a subject, the 
subject should not be included into the study.  If, however, the Investigator has any other kind 
of doubts concerning the subject’s eligibility, he/she should consult the UCB Study Physician 
or representative for clarification.
9.3
Subject Withdrawal
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
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, liver enzymes significant increase, and any 
other significant safety reason.

Subject and/or Investigator does not think that the investigational drug is effective (i.e., 
lack or loss of efficacy).

Lost to follow-up.

Withdrawal of consent for personal reasons; not related to AE or lack/loss of efficacy.

Other reason that has to be specified in the CRF.
Withdrawal criteria for already enrolled subjects who did not complete a Columbia Suicide 
Severity Rating Scale (C-SSRS) assessment at Screening:

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 
REDACTED COPY 
dy
TE
dy at a
TED
at a
y
TE
y
crite
RED
crite
marketing authorization application and any extensions or variations thereof. 
f 
at
f 
RV
r v
RV
during
sions
during
bility
d an
bility o
an
o
y
an
y
vestiga
and
vestiga
onsult t
tion 
onsult t
any
riza
any tim
zat
 tim
y y
za
y y
eria for
ing a
eria for
by
keti
by the
etin
 the
y y
eti
y y
re t
ma
re t
to support any 
ype 
ark
ype 
eason
y m
eason
igat
t an
igator 
any
or 
cacy
port
cacy).
rt 
).
up.
up
up.
of con
to su
of con
This document cannot be used
son tha
ed to
son tha
al crit
be u
al crit
ty
no
ty Rati
not b
Rati
y y
no
y y
Subj
ann
Subj
a
a
a

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 31 of 89
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 decision of subject’s discontinuation, the Investigator will provide the subject with 
information about available alternative treatments.
Investigators should attempt to obtain information on subjects, in case of withdrawal or 
discontinuation.  The Investigator should make every effort, and document his/her effort, to 
complete the EDV and preferably also the Down-Titration Phone Call and 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 also attempt to minimize the number of subjects lost to follow-up and to 
obtain a maximum of information on such subjects.  The Investigator should make every 
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.
COPY 
e numb
OPY
e numb
ACTED C
bjects. 
D CO
bjects. 
messag
TED 
messag
d copy
ACTE
d copy
RED
aluati
EDAC
aluati
n application and any extensions or variations thereof. 
t with 
s or
t with 
withdra
exte
withdra
ment his
ny e
ment his
ll and 
d any
ll and 
escripti
and
escripti
ments. 
ion a
ments. 
discon
atio
discon
mber of 
app
mber of 
This document cannot be used to support any marketing authorizatio
.  The I
tion 
.  The I
ge to th
izati
ge to th
y
h
y of the
horiz
of the
y
h
y
ion.
auth
ion.

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 32 of 89
10.
TREATMENT OF SUBJECTS (INVESTIGATIONAL PRODUCT AND 
CONCOMITANT MEDICATIONS)
10.1
Study Investigational Products
10.1.1
Description of all Investigational Products
Oral tablets of 10 and 25mg BRV will be used in this study. 
Investigational product (study drug) is prepared and stored at the UCB Clinical Trial Supplies
(CTS) Operations or designee prior to shipment to the sites.
An Interactive Voice Response System (IVRS) will be used during this study. A telephone 
call to the system will be made:

At the EV: for assignment of the study subject number and dispensing of initial 
medication 
and 

At subsequent visits: for dispensing study medication

To update the status of the subject when the subject leaves the study
The IVRS will also be applied for the ordering of the drug shipments to the sites via the 
UCB CTS Operations or designee, using a “trigger and re-supply” method of medication 
management specified in a separate document.
10.1.1.1 Dosing Schedule
The suggested individual starting dose of each subject will be 100mg/day.
The daily dose should be divided into 2 equal intakes (morning and evening), taken with or 
without food.  The first intake will be in the evening of the day of the dispensation of the 
study medication.
At each subject visit, if necessary, the dosage can be adapted:

Up-titration can be made by increments of a maximum 50mg/day on a weekly basis and 
up to a maximum dose of 200mg/day.

Dose decreases can be made by steps of maximum 50mg/day on a weekly basis.  In 
case of study drug discontinuation, a last down-titration step at 20mg/day for 1 week 
will be included prior to the study-drug free period.
The doses administered in this study must comply with doses that can be administered with 
either BRV 10mg tablets, 25mg tablets, or a combination of these 2 strengths in a total daily 
dose that can be administered in 2 equal doses.  Daily dose prescriptions that do not respect 
these limitations should not be administered.
REDACTED COPY 
medic
OPY
medic
n the s
D CO
n the s
rderin
ACTE
rderin
using a
EDAC
using a
te doc
RED
te doc
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
al Tria
ensio
al Tria
his stud
d any
his stud
nd disp
ion a
nd disp
cation
n app
cation
subject
tion 
subject
ng of th
thoriz
ng of th
a “trigg
auth
a “trigg
cumen
ng a
cumen
arting d
any
arting d
 divide
ort a
 divide
st intak
uppo
st intak
ect
us
ect visit
sed
visit
titration
be us
titration
p to a m
ot be
p to a m
Dose
nno
Dose
ca
an
ca

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 33 of 89
The supplies needed by the subject in terms of the number of bottles of each dosage (10mg 
and 25mg tablets) according to the dose prescribed and the possibility to down-titrate/up-
titrate by a maximum of 50mg/day step, will be evaluated, as closely as possible at each visit.
In case the subject will not continue with BRV, the Investigator will plan the progressive 
down-titration of the study drug as described above.  The down-titration period will be 
followed by a period free of study drug of minimum 2 weeks and a maximum of 4 weeks and 
subsequently the FV will occur.
At the time of study termination by the Sponsor (as defined in Section 8.4), subjects will 
discontinue the study drug following the described down-titration process or 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 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.
10.1.2
Packaging
Oral tablets of 10mg and 25mg BRV tablets will be packaged in bottles of 200 tablets.  The 
Investigator will be supplied with a sufficient number of bottles and each bottle will have a 
unique, pre-printed identification number. 
The Investigator will inform each subject on how to take the drug and that a possible excess 
of drug might be dispensed at each visit.
10.1.3
Labeling
Clinical drug supplies will be labeled in accordance with the current ICH guidelines on Good 
Clinical Practice (GCP) and Good Manufacturing Practice (GMP) and will include any
locally required statements.
The labels will be adapted to local regulatory requirements and the size of the investigational 
product package and will be translated as appropriate.
The label will consist of 2 parts.  The first is a tear-off sticker which must be attached to the 
Case Report Form at the time of visit and the second remains fixed to the investigational 
product package.  The subject number, subject initials and dispensation date will be added 
manually by the Investigator before dispensing.
10.1.4
Storage Requirements
REDACTED COPY 
s
E
s will 
ED C
will 
cient 
CTE
cient 
mber.
DAC
mber.
ub
R
ub
keting authorization application and any extensions or variations thereof. 
eks an
r va
eks an
ubjects
ensio
ubjects
or
ex
or will
xte
will
re avai
ny ex
re avai
initiate
d any
initiate
am, co
and 
am, co
ntry-
on a
ntry-sp
a
sp
b
z
be pac
zatio
e pac
numbe
horiz
numbe
bject on
keting
bject on
nnot be used to support any mar
h visit.
arke
h visit.
will be
ppo
will be
CP
su
CP)
sup
) an
p
an
stateme
d to s
stateme
will be
e us
will be
packag
ot be
packag
This document ca
e label
can
e label
Case R
ent c
Case R
pro
me
pro

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 34 of 89
Investigational product packages should be stored in a secured limited access area and 
maintained at the storage temperature specified on the investigational product package label.  
A recording of this controlled temperature should be done on site.  If the storage conditions 
are not controlled (with recording), a temperature log should be completed at least once a 
week with the minimal and the maximal temperatures reached in the week preceding the 
record.  Any excursion from the allowed temperature range will be communicated to the 
Sponsor or representative.
Storage should be in a pharmacy or in a locked facility.  Supplies for this study will be stored 
in such a way that they may not be mixed up with supplies being used for another study.  A 
standard storage statement will appear on each investigational product package label of study
medication.
The Investigator or the hospital pharmacist is responsible for the appropriate storage and 
documentation of investigational product package at the site.  The Investigator will instruct 
the subject/legally acceptable representative to store the medication at the storage 
temperature specified on the investigational product package label, in a secure place out of 
the reach of children.
10.1.5
Monitoring of Subject Compliance
At each visit after drug is dispensed, subjects must return all unused medication and the 
original investigational product package (even if empty).  Drug reconciliation must be done 
in the subject’s presence in order to obtain explanations regarding discrepancies in 
compliance with the dosing regimen.
The number of tablets as well as explanations of non-compliance must all be recorded on the 
CRF.
The Investigator will assess compliance during the study. Compliance with study medication 
is defined as investigational product consumption by the subject within 80% to 120% of the 
prescribed dosage.
10.1.6
Investigational Products Accountability
The Sponsor or its representatives will supply a Drug Accountability Form to be kept up-to-
date by recording all study drug received during the course of the study and study drug 
released for subject use.  Details of any drug lost (due to breakage or wastage), not used, 
disposed of at the study site or returned must also be recorded.  All supplies and pharmacy 
documentation must be made available throughout the study for the Sponsor or designee to 
review.
The Drug Accountability Form should include the following:
REDACTED COPY 
jects m
ACTE
jects m
age (ev
DAC
age (ev
o obta
RED
o obta
n
R
n
used to support any marketing authorization application and any extensions or variations thereof. 
be sto
s or 
be sto
er
io
er stud
ons
stud
ge labe
ensio
ge labe
propriat
d any
propriat
e Invest
and 
e Invest
ation a
on a
ation a
e label
catio
e label
must r
horiz
must r
ven if 
autho
ven if 
ain exp
ng au
ain exp
as expla
y ma
as expla
assess c
ppo
assess c
gation
sup
gation
e.
d t
e.
t cannot be 
nvestiga
be us
nvestiga
Sponso
nnot
Sponso
te b
can
te by r
an
y r
This documen
release
ent c
release
disp
me
disp
d

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 35 of 89

Number of tablets dispensed to and return by each subject, with the subject’s number 
bottle number.

Initials of the person who actually dispensed and/or received the return tablets.

Dates of the above.

Explanations for non-compliance. 
Periodically and after completion of the study, all used (including empty bottles) and unused 
investigational product package must be reconciled and returned (preferably in their original 
package) to the Sponsor or designee according to a procedure to be defined at the time.  
Clinical drug supplies designated for the study cannot be used for any other purpose than that 
described in this protocol.
10.2
Concomitant Treatments and Rescue Medications
Should any treatment other than BRV be used, an accurate record must be kept in the clinic 
chart (source documentation) and the Case Report Form.  This record should include the 
brand name of the drug, the dose, frequency, route, the indication for use and the date(s) of 
administration.
10.2.1
Permitted Concomitant Treatments (Medications and Therapies)
Subjects entering the present study in BRV monotherapy may require re-conversion from 
BRV monotherapy treatment to adjunctive treatment with BRV and another AED.
In this case, as well as for subjects entering the study in add-on, the Investigator may adapt 
the concomitant AED drug/dosage for safety or efficacy reasons.
In case of excellent efficacy and tolerability of BRV, withdrawal of concomitant AED(s) 
resulting in monotherapy with BRV may be re-attempted by the Investigator.
Benzodiazepines (BZD) are allowed. If taken more than once a week (for any indication)
BZDs will be considered as a concomitant AED.
Use of phenobarbital and primidone is allowed. 
Use of felbamate is permitted if continuous exposure is at least 18 months before Visit 1.
Use of VNS is also allowed.
10.2.2
Prohibited Concomitant Treatments (Medications and Therapies)
Vigabatrin.
REDACTED COPY 
(Med
D CO
(Med
RV m
ACTE
RV m
nctive
EDAC
nctive
enter
RED
enter
f
R
f
upport any marketing authorization application and any extensions or variations thereof. 
used 
aria
used 
origina
or va
origina
time. 
ns o
time. 
rpose th
sion
rpose th
d must 
and
d must 
s record
tion 
s record
cation 
icatio
cation 
dicatio
tion
dicatio
monoth
thori
monoth
e treatm
auth
e treatm
ring th
ing a
ring th
for s
keti
for safe
tin
afe
nd toler
y ma
nd toler
ith BR
any
ith BR
D)
up
D)
annot be used to s
are 
ppo
are 
dered 
sup
dered 
barbita
used
barbita
felbam
ot be
felbam
This document c
se of V
t can
se of V
10
me
10

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 36 of 89
11.
STUDY PROCEDURES
11.1
Description of Procedures
11.1.1
Informed Consent
Prior to any study activities, subjects will be asked to read and sign an informed consent form 
that has been approved by an IEC/IRB and which complies with regulatory requirements.  
Subjects 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, subjects 
will be given the opportunity to ask the Investigator any questions regarding potential risks 
and benefits of participation in the study.
Where legally acceptable, a Partner Pregnancy Consent Form will be issued in case the 
partner of a male subject becomes pregnant (Section 12.1.6).
11.1.2
Subject Study Card
The Sponsor will provide to each Investigator an appropriate quantity of subject study cards 
that contains the Investigator’s contact information in case of emergency.  These subject 
cards will be in the language of the subject.  The Investigator will fill in each card with 
his/her contact details (name and telephone number) and the subject’s identifier.  This card 
will be distributed to the subject at the EV.  The Investigator will instruct the subject to keep 
the card with them all times.
11.1.3
Eligibility Criteria Assessment
The subject’s eligibility will be assessed based on the eligibility criteria defined in the 
protocol. 
11.1.4
Demography
At the EV, the subject’s date of birth, gender, racial group and ethnicity will be recorded. 
Genetic differences among different racial groups in terms of hepatic enzymes, receptors and 
other factors might result in different pharmacokinetic, pharmacodynamic and/or drug 
responses.  These differences may result in different dosing recommendations for different 
races.  Therefore race designation will be collected for potential future compound labeling.  
In some countries, such as 
 recording the complete date of birth is not permitted.
REDACTED COPY 
an ap
D CO
an ap
rmatio
ED C
rmatio
ect.  T
ACTE
ect.  T
phone
DAC
phone
the
RED
the E
ED
E
marketing authorization application and any extensions or variations thereof. 
ent form
r va
ent form
ments.
s or 
ments.
e stud
ions
e study
s
y
cedure,
ensio
cedure,
ng pote
exte
ng pote
l be iss
and 
l be iss
ppropri
tion a
ppropri
on in c
izatio
on in c
The Inv
horiz
The Inv
e numb
autho
e numb
V
g
V. 
g
. 
t cannot be used to support any m
Th
au
Th
sessme
y ma
sessme
will be 
ort a
will be 
raphy
d to 
raphy
the sub
e us
the sub
differe
ot be
differe
factor
nnot
factor
sponse
can
sponse
This documen
races. 
ent c
races. 
In s
me
In s

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 37 of 89
11.1.5
Childbearing Potential and Birth Control
At the first visit, information on childbearing potential and contraceptive method used by 
female subjects will be collected.  During the course of the study, the Investigator should 
make sure that birth control remains optimal should the subject’s status change.  A pregnancy 
test will be performed as specified in the Study Flowchart (see Table 5:1).
11.1.6
Medical and Procedure History
The General Medical and Procedure History will be obtained from the database of the 
previous study in which the subject was participating.
11.1.7
Epilepsy History
The history of epilepsy reported in the previous study in which the subject was enrolled will 
be considered as the history of epilepsy for the present study, and will be obtained from the 
database of the previous study.
11.1.8
Antiepileptic Medication History
The AED medication history will be obtained from the database of the previous study in 
which the subject was participating. The AED being used concurrently, at the current dose, 
will be recorded on the concomitant AED medication page of the CRF.
11.1.9
Vital Signs
At every office visit, 5 minutes supine or sitting pulse rate and blood pressure will be 
obtained followed by a standing pulse rate and blood pressure.
Vital signs for the EV will be obtained from the database of the last Evaluation Visit of the 
previous study. 
11.1.10 Body Weight and Height
Body weight (subject wearing light clothing without shoes) will be obtained at the following 
visits:  EV, each FEV, each YEV, EDV, and at the FV.  
Body weight for the EV will be obtained from the database of the last Evaluation Visit of the 
previous study.
Height will be obtained at the EV.  For subjects who are still potentially growing, height will 
also be measured at each YEV and the FV.
REDACTED COPY 
ained
CTE
ained
The AE
DAC
The AE
nt AED
RED
nt AED
ot be used to support any marketing authorization application and any extensions or variations thereof. 
cy
tio
cy
se of 
nsio
se of th
o
th
the su
on a
the su
y
c
y,
c
, and
atio
and
from t
horiz
from t
AED be
autho
AED be
ED med
ng au
ED med
tes sup
any 
tes sup
anding
ort a
anding
V 
s
V 
This document cann
will
sup
will
ody
be u
ody We
us
We
y weigh
nnot
weigh
its:  
can
its:  E
n
E
Bod
me
Bod

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 38 of 89
11.1.11 Physical Examination
A standard physical examination will be performed at the following visits: FEV, each YEV, 
EDV and at the FV.  This examination may include investigation of skin, eyes, ear, nose, 
throat, cardiovascular system, respiratory system, gastro-intestinal system, musculoskeletal 
system and optionally genitourinary system. 
The physical examination for the EV will be obtained from the database of the last 
Evaluation Visit of the previous study.
11.1.12 Neurological Examination
A standard neurological examination will be performed at the following visits:  FEV, each 
YEV, EDV and at the FV.  This examination will consist of a brief review of cortical 
functions, cranial nerves, motor function, reflex function, sensory function, gait and stance.  
Psychiatric and mental status will be reported by recording the presence or absence of 
psychiatric symptoms, mental impairments and behavioral symptoms. 
The neurological examination for the EV will be obtained from the database of the last 
Evaluation Visit of the previous study.
11.1.13 ECG
Following ethical approval of Protocol Amendment 2 and once the subject has signed the 
updated Informed Consent, the number of standard 12-lead ECGs will be reduced to once per 
year at each YEV and at the following visits: EDV and FV (in case the FV follows an EDV
and the EDV ECG is normal, no additional ECG has to be performed at the FV). 
At the EV, the ECG will be obtained electronically from the last Evaluation Visit of the 
previous study and should not be recorded in the CRF. 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.  
11.1.14 Daily Record Card 
At the EV, every FEV, every MEV, YEV, and the EDV, the subject will receive a Daily 
Record Card (DRC) and will be asked to come back at the next visit with the completed 
DRC.
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 
REDACTED COPY 
avi
Y
avi
b
C
be 
C
e ob
CO
ob
oco
R
oco
y marketing authorization application and any extensions or variations thereof. 
wing vis
d any
wing vis
f revie
and 
f revie
ory
on
ory fun
on a
fun
on
the pre
catio
the pre
al s
pli
al sym
plic
ym
tained
ion a
tained
ol
et
ol A
eting
Ame
ng
me
mber o
arke
mber o
llowing
y ma
llowing
t cannot be used to support an
l, no ad
any 
l, no ad
ill be o
ppo
ill be o
shou
sup
should
p
ld
lts of th
d to s
lts of th
ities.  T
sed 
ities.  T
r and r
e us
r and r
14
nn
14
This documen
Da
not
Da
At the
ent c
At the
Rec
me
Rec
D

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 39 of 89
epileptic seizures according to the ILAE codes and record the seizure types and frequency on 
the CRF; he/she will also confirm the presence of adverse events (if applicable). The 
concomitant medication changes and adverse events will be reported by the Investigator on 
the specific pages of the CRF.
The DRC will be considered source documentation. The subject should be educated to 
complete the DRC on a regular basis (each time that a seizure, an undesirable event, a 
modification of medication or investigational product, or a medical visit occurs).
Information on the following assessments collected in the DRC and transcribed to the 
appropriate CRF page are to be collected during the first 2 years:

Healthcare provider consultations not foreseen by the protocol 

Workdays or schooldays lost by the subject 

Days subject received help from a caregiver (paid or not) at home
11.1.15
Laboratory Assessments and Study Medication/AED(s) Plasma Levels
At the following visits, FEV, YEV, EDV, and FV, laboratory assessments will be conducted 
using standard methods at a central laboratory.  At the EV, data will be obtained from the last 
Evaluation Visit of the previous study and should not be recorded on the CRF.  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 back to the central laboratory. 
Results for hematology, chemistry, urinalysis and pregnancy tests will be provided by fax to 
the Investigator. 
The total blood volume drawn for the clinical laboratory assessments will be a maximum of 
20mL/sampling.  The subject should preferably be fasting.  Study medication intake must not
be delayed.
The following laboratory assessments will be conducted:

Blood chemistry:  glucose, urea, creatinine, sodium, potassium, calcium, phosphorus 
(inorganic), total protein, albumin, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase (ASAT/SGOT), alanine 
aminotransferase/serum glutamic pyruvic transaminase (ALAT/SGPT),
gamma-glutamyltranspeptidase, and uric acid.

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.
EDACTED COPY 
V
O
V,
O
, lab
OPY
lab
y
D
y. 
D C
. At t
CO
At t
shoul
TED 
shoul
with d
ACTE
with d
pecifi
EDAC
pecifi
R
the s
RED
the s
authorization application and any extensions or variations thereof. 
to the
ions
to the
col
ny
col
not) at 
and
not) at 
ation
catio
ation/A
io
/A
borator
n app
borator
the 
tion
the EV
on 
EV
d not b
izat
d not b
dedica
thoriz
dedica
fic lab
auth
fic labo
h
o
not be used to support any marketing
sample
ng a
sample
y, urina
arke
, urina
drawn f
ort a
drawn f
subjec
uppo
subjec
g labor
used
g labor
od chem
be us
od chem
norgan
ot be
norgan
This document cann
amin
nno
amin
am
an
am

m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 40 of 89

Hematology:  white blood cells (WBC), red blood cells (RBC), hemoglobin, 
hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), platelet count, lymphocytes 
(number, %), monocytes (number, %), neutrophils (number, %), eosinophils (number, 
%), basophils (number, %).

Urinalysis:  specific gravity, pH, glucose, bilirubin, ketones, occult blood, protein, 
nitrites, leukocytes.  If the test for protein, blood or leukocytes shows a trace or is 
positive, sediment and microscopic analyses (erythrocyte cast, leukocyte casts, 
hemoglobin casts, uric acid crystals, bihydrate calcium oxalate crystals, monohydrate 
calcium oxalate crystals, triple phosphate crystals and bacteria) will be conducted.

Where applicable (women of childbearing potential), a serum pregnancy test will be 
conducted. 
Cholesterol testing and plasma samples to analyze BRV and concomitant AED 
concentrations will be collected up to approval of Protocol Amendment 2.
11.1.16 Adverse Events (AEs)
At the EV, the Investigator will record any AE that was still ongoing at the end of the 
previous study in the source documentation.  From the EV onwards, adverse events will be 
assessed at each visit and recorded in the CRF and in the source documents.  The study 
participant will be given the opportunity to report AEs spontaneously.  A general prompt will 
also be given to detect AEs, e.g., “Did you notice anything unusual about your health (since 
your last visit)?”  In addition, the Investigator should review any self-assessment procedures 
(e.g. DRCs) used in the study.
11.1.17 Assessment of Suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS. This scale will be 
used to assess suicidal ideation and behavior that may occur during the study. The C-SSRS 
will be completed according to the tabular schedule of assessments (see Section 5.1).
11.1.18 Medical Procedures
From the EV onwards, collection of data on medical procedures (surgery, therapeutic and/or 
diagnostic, hospitalizations) undertaken during the study will be obtained.  ECGs 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.
ACTED COPY 
hat wa
OPY
hat wa
From 
D CO
From 
RF an
TED 
RF an
y to rep
ACTE
y to rep
EDA
d
ED
d
R
you
EDAC
you
nvest
RED
nvest
thorization application and any extensions or variations thereof. 
ohy
ns o
ohydra
or
dra
nducte
sions
nducte
cy
te
cy test
ens
test
y
e
y
mitant A
d an
mitant A
dment
and
dment
as still 
n app
as still 
the 
tion
the EV
n 
EV
nd in t
izat
nd in t
eport A
thoriz
eport A
t be used to support any marketing au
u notice
auth
u notice
tigator
ng a
tigator
ality
y ma
ality
ed by
ort a
ed by t
a
t
y
a
y
l ideati
uppo
l ideati
accordi
o sup
accordi
ical Pr
sed
ical Pr
t cannot be
e
ot
e EV 
ot be
EV 
e
nostic, 
nno
nostic, 
is 
c
is stud
can
stud
This documen
specif
ent 
specif

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 41 of 89
11.1.19 Non-Antiepileptic and Antiepileptic Concomitant Medications
At the EV, the Investigator will record all Non-Antiepileptic and Antiepileptic Concomitant 
Medications that were still ongoing at the end of the previous study.  All medications 
(including over-the-counter preparations) taken during the course of the study must be 
documented in the CRF (brand name, indication, dosage, and the dates of start and 
discontinuation).
At each visit, a complete listing of all medications currently being taken will be obtained.  
Any changes, additions or deletions in the administration of non-antiepileptic concomitant 
medications must be recorded on the Non-Antiepileptic Concomitant Medications page of the 
CRF.  In case of intake of forbidden concomitant medication (see Section 10.2) during the 
study period, the Investigator will contact the monitor immediately.
Changes, additions or deletions in the administration of antiepileptic concomitant 
medications must be recorded on the Antiepileptic Concomitant Medications page of the 
CRF.
11.1.20 Patient Reported Outcomes
A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as 
well as for EDV.  The assessment of the PROs will be limited to the first 2 years after study 
entry.  These booklets will include, in order of appearance:  The Patient Weighted Quality of 
Life in Epilepsy Inventory-- 31 item form (QOLIE-31-P - Version 2), the Hospital Anxiety 
and Depression Scale (HADS), and the EQ-5D self-report questionnaire.  The PRO booklet is 
to be provided to subjects who are not mentally impaired, at the very beginning of the study 
visit.  The subject will be asked to complete the questionnaires on his/her own.  Once 
completed, the subject will hand back the booklet to the Investigator who will check that all 
questions have been answered.
The PRO booklets will be considered as part of the CRF as well as source documentation.
11.1.20.1
Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)
QOLIE-31-P (Cramer and Van Hammée, 2003) (see Appendix17.1) is an adaptation of the 
original QOLIE-31 instrument (Cramer et al, 1998) that includes 7 subscales (seizure worry, 
overall quality of life, emotional well-being, energy-fatigue, cognitive functioning, 
medication effects, social function) and the health status item.  Subscale scores as well as 
Total score range from 0 to 100 with higher scores indicating better health related quality of 
life.  In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking 
the subjects to grade his or her overall "distress" related to the topic of each subscale.  The 
QOLIE-31-P also contains an item asking about the relative importance of each subscale 
REDACTED COPY 
oklet p
ACTE
oklet p
he
DA
he PR
AC
PR
, in or
RED
, in or
m f
R
m f
marketing authorization application and any extensions or variations thereof. 
obtain
ions
obtain
 conco
ensio
 conco
ication
exte
ication
on 
ny
on 10.2
y e
10.2
leptic c
on a
leptic c
itant M
catio
itant M
per vis
horiz
per vis
ROs 
uth
ROs w
ho
w
rder of
ng au
rder of
form (
keting
form (
d 
a
d the E
arke
the E
nnot be used to support any m
are not
ma
are not
ked to 
any 
ked to 
ll hand
ort a
ll hand
nswere
ppo
nswere
ts will 
d to s
ts will 
Qu
us
Qu
IE
nn
IE-31-
nnot
-31-
This document c
riginal 
can
riginal 
overal
ent c
overal
me
me
me
T

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 42 of 89
topic. The subjects will complete the QOLIE-31-P at every FEV and YEV for the first 
2 years, and at the EDV if the EDV occurs within the first 2 years.
11.1.20.2
Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) (Herrmann, 1997) (see Appendix 17.2) 
will be used to evaluate anxiety and depression/depressed feelings.  The HADS was 
developed as a self-administered scale to assess the presence and severity of both anxiety and 
depression simultaneously.  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) will be calculated as 
recommended by the authors with each score ranging from 0 to 21 and higher scores 
indicating higher depression/anxiety.  The subjects will complete the HADS at every FEV 
and YEV for the first 2 years, and at the EDV if the EDV occurs within the first 2 years.
11.1.20.3
EQ-5D Questionnaire
The EQ-5D (EuroQol Group, 2000) (see Appendix 17.3) is a self-administered questionnaire 
designed to measure health status.  EQ-5D defines health in terms of 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression).  Each dimension is 
divided into 3 levels:

no problem = 1

some or moderate problems = 2

extreme problems = 3
EQ-5D also captures a self-rating of health status on a 20cm vertical visual analogue scale, 
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) 
at the bottom.
The EQ-5D questionnaire will be assessed at every FEV and YEV for the first 2 years, and at 
the EDV if the EDV occurs within the first 2 years.
11.1.21 Hospital Stay
After the EV onwards, the collection of data on hospital stay will be assessed in the CRF.  It 
includes the reason of hospitalization, the admission wards, transfer and length of stay.  
Hospital stays will be assessed at every FEV, MEV, YEV, and Additional Visit (AV) for the 
first 2 years, and at the EDV and the FV if these visits occur within the first 2 years.
11.1.22 Healthcare Provider Consultations not foreseen by the Protocol
After the EV onwards, healthcare provider consultations not foreseen by the protocol will be 
assessed and recorded in the CRF. This includes the type of provider (general practitioner, 
specialist physician, nurse), site of care (offsite vs private, office vs hospital, home, ER), and 
REDACTED COPY 
hea
Y
hea
xiety/
OPY
xiety/
f h
R
f h
t any marketing authorization application and any extensions or variations thereof. 
)
t
)
iety
r va
iety an
va
 an
y y
va
y y
erity
s or
erity sc
or 
sc
y
or
y
ated as 
ions
ated as 
r s
en
r score
ns
core
DS at ev
exte
DS at ev
the fir
y ex
the fir
a self
catio
a self
in term
plica
in term
/depres
app
/depres
health
keting
health
health
arke
health
This document cannot be used to suppo
e will b
ort a
e will b
ccurs w
ppo
ccurs w
al Stay
d to 
al Stay
V 
e
V onw
e us
onw
s the re
ot be
s the re
pital sta
nno
pital sta
st 2
ca
st 2 y
a
y
11
me
11

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 43 of 89
the reason leading to the consultation. Healthcare provider consultations not foreseen by the 
protocol will be assessed at every FEV, MEV, YEV, and AV for the first 2 years, and at the 
EDV and the FV if these visits occur within the first 2 years.
11.1.23 Socio-professional Data
Socio-professional data will be collected at the YEV for the first 2 years and at the EDV and 
the FV if these visits occur within the first 2 years.  This module collects information such as
education level, housing status, employment status, need for caregiver and driving license. In 
countries such as 
 collection of these data is not permitted; therefore they will not be 
collected. 
11.1.24 End of Study
The end of the subject’s participation in the study will be confirmed on the subject’s status 
evaluation section of the CRF.  All data about the subject’s status (study completion or reason 
for early study termination) will be recorded.  It will be specified:

Whether the subject completed (participated until the study was stopped) or 
prematurely discontinued from the study.
A subject will be considered lost to follow-up following 2 unsuccessful documented attempts 
to contact the subject (e.g. by telephone).
If a subject will not continue with the study drug, the Investigator will first schedule an EDV 
which will be followed by a progressive down-titration of the study drug.  The dose decrease 
can be made by steps of a maximum of 50mg/day on a weekly basis.  A last down-titration 
step at 20mg/day for 1 week will be included prior to the study drug free period.  At the end 
of the down-titration period, a phone call will be given to subjects having down-titrated from 
doses higher than 20mg/day.  The Down-Titration Period will be followed by a period free of 
study drug at the minimum of 2 weeks and a maximum of 4 weeks and subsequently the FV 
will occur.
When the time point is reached at which the study will be terminated by the Sponsor (as 
defined in Section 8.4), subjects will discontinue the study drug, following the above 
described down-titration process or will be converted without down-titration to commercial 
BRV if, when and where available. Alternatively, subjects may transition to 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.
11.2
Description Visit by Visit
REDACTED COPY 
unti
Y
unti
up fol
TED 
up fol
).
AC
).
the
RE
the stu
ED
stu
ssi
R
ssi
t cannot be used to support any marketing authorization application and any extensions or variations thereof. 
and 
riat
and 
such a
r va
such a
license
s or 
license
y will n
ions
will n
ed on t
and 
ed on t
tus (
on a
tus (stu
a
stu
cified:
catio
cified:
he
ppl
he stud
plic
stud
ollowin
izati
ollowin
tudy
ng a
tudy dr
a
dr
sive do
keting
sive do
um of 5
arke
um of 5
ill be in
y ma
ill be in
 a phon
any 
 a phon
day
ort
day.  Th
rt a
.  Th
mum o
ppo
mum o
e point
sed 
e point
Section
e us
Section
d dow
t be
d dow
if, wh
nnot
if, wh
udy
t ca
udy
This documen
or
can
or
y
ca
y
progra
ent c
progra
cou
me
cou

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 44 of 89
The EV will be performed on the same day as the last visit of the previous study in which the 
subject was enrolled.  Should an interval become necessary between the last visit of the 
previous study and the EV in the present study, the Sponsor’s Study Physician or
representative should be contacted for agreement.  The adverse events, medical procedures, 
non-antiepileptic and antiepileptic concomitant medication belonging to the interim period 
will be reported in the CRF, on specific pages.
Each visit will be planned within a “window” of ± 7 days from the previous visit.  When 
possible, out of window visits should be rescheduled with respect to the EV.
At any time, the subject may have an additional study visit/phone call if the Investigator of 
the subject deems it necessary.  All information, including the reason for the visit/phone call, 
any information on adverse events, etc., should be collected in the source documents and 
recorded in the appropriate section of the CRF.
11.2.1
Entry Visit

Signing and dating of written informed consent.

Dispensation of “clinical study subject card” (participation in the study).

Verification of the inclusion/exclusion criteria.

Demographic data.

Childbearing potential.

Body height.

Dispensation of subject DRC and instruction on proper completion.

Concomitant medications (AED and Non-AED) documentation.

Recording of adverse events.

Medical procedures.

Dispensation of study medication (only dispensed once all inclusion/exclusion criteria 
have been met).

Appointment for the next visit according to the schedule described in Section 5.2.
The following data will be obtained from the database of the Baseline Visit of the previous 
study and should not be recorded in the CRF:

General medical and procedure history.

AED history.

Epilepsy history.
The following data will be obtained from the database of the final Evaluation Visit of the 
previous study, and should not be recorded in the CRF/DRC:

Vital signs including blood pressure and pulse rate.

Body weight.

Physical examination.

Neurological examination.
REDACTED COPY 
(par
Y
(par
eria.
OPY
eria.
and in
EDA
and in
ED 
RE
ED 
be used to support any marketing authorization application and any extensions or variations thereof. 
hen
r v
hen
nvestig
ensio
nvestig
he visit
exte
he visit
ce docu
ny ex
ce docu
cipatio
pplic
cipatio
nstructi
aut
nstructi
and N
ting 
and N
medica
ny m
medica
the nex
pport
the nex
ta will
to s
ta will
ld not 
ed t
ld not 
ral med
e use
ral med
This document cannot b
ED hist
t be 
ED hist
Epilep
nnot
Epilep
The fo
ent c
The fo
prev
me
prev

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 45 of 89

ECG.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis).

Pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels.

Recording of seizures.
11.2.2
Full Evaluation Visit

Vital signs including blood pressure and pulse rate.

Body weight.

Physical and neurological examination.

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels
up to approval of Protocol Amendment 2.

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication.

Appointment for the next visit according to the schedule described in Section 5.2.
The following assessments will be performed during the first 2 years:

QOLIE-31-P questionnaire (except if subject is mentally impaired). The questionnaire 
should be filled in at the beginning of the visit.

HADS questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.
11.2.3
Minimal Evaluation Visit

Vital signs including blood pressure and pulse rate.

Retrieval of previous subject DRC.

Recording of seizures.
REDACTED COPY 
n
C
n-
C
-AED
COP
AED
study
ED C
study
on.
DA
on.
it acc
RED
it acc
support any marketing authorization application and any extensions or variations thereof. 
mistry
any
mistry
els and
nd a
els and
D) doc
ion a
D) doc
m
za
medic
zatio
edic
cording
ng a
cording
e perfo
arke
e perfo
ire (exc
y ma
ire (exc
he beg
any
he beg
ire (exc
ort a
ire (exc
e begin
uppo
e begin
nt cannot be used to 
rovider
o sup
rovider
g of wo
ed to
g of wo
ver (pai
used
ver (pai
pital st
be u
pital st
EQ
not
EQ-
ot
-5D
ot b
5D
be fi
anno
be fi
This documen
11.2.
ment
11.2.

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 46 of 89

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication.

Appointment for the next visit according to the schedule described in Section 5.2.
The following assessments will be performed during the first 2 years:

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.
11.2.4
Yearly Evaluation Visit (replaces the first FEV of each year)

Vital signs including blood pressure and pulse rate.

Body weight and height (only for those subjects still potentially growing).

Physical and neurological examination.

ECG.

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels
up to approval of Protocol Amendment 2.

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication.

Appointment for the next visit according to the schedule described in Section 5.2.
The following assessments will be performed during the first 2 years:

QOLIE-31-P questionnaire (except if subject is mentally impaired). The questionnaire 
should be filled in at the beginning of the visit.

HADS questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.
REDACTED COPY
lse ra
OPY 
lse ra
ubj
CO
ubjec
O
ec
n.
ED
n.
RC.
DAC
RC.
i
R
i
ny marketing authorization application and any extensions or variations thereof. 
.2
or
.2.
or
.
ved hel
y ex
ved hel
each ye
ation
each ye
te.
ap
te.
ts
o
ts still
on a
still
ng safe
keting
ng safe
);
a
); con
ark
con
to support any
l l A
m
Ame
ma
me
e
a
events
any
vents
cidality
ort a
cidality
ures.
uppo
ures.
t medic
to su
t medic
cannot be used
rn/acco
ed to
rn/acco
nsation
use
nsation
pensat
be u
pensat
Appoin
not b
Appoin
This document 
The fol
nt ca
The fol

m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 47 of 89

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Socio-professional data.
11.2.5
Early Discontinuation Visit

Vital signs including blood pressure and pulse rate.

Body weight.

Physical and neurological examination.

ECG.

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels
up to approval of Protocol Amendment 2.

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication with down-titration dosing schedule.

Appointment for the next visit according to the schedule described in Section 5.2.
Down-titration may not be  applicable to subjects who may transition to another BRV study 
or may be initiated in a managed access program or similar type of program.   
The following assessments will be performed only if the EDV occurs within the first 2 years:

QOLIE-31-P questionnaire (except if subject is mentally impaired). The questionnaire 
should be filled in at the beginning of the visit.

HADS questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.
REDACTED COPY
AED 
OPY 
AED 
S).
CT
S).
ED an
RED
ED an
clu
R
clu
not be used to support any marketing authorization application and any extensions or variations thereof. 
y, bloo
plica
y, bloo
plasma
app
plasma
nd Non
ng au
nd Non
uding 
keting
uding 
edicati
y ma
edicati
next vis
any
next vis
ot be  a
uppo
ot be  a
in a m
o sup
in a m
g asses
used
g asses
QOLIE
ot b
QOLIE
This document cann
shoul
anno
shoul
H
a
H

m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 48 of 89

EQ-5D questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Socio-professional data.
11.2.6
Down-Titration Phone Call

Recording of adverse events.

Reminder of appointment for the next visit according to the schedule described in
Section 5.2.
11.2.7
Final Visit (FV following a Study Drug Free Period after an EDV or FV initiated 
upon Sponsor request at the end of the program)

Vital signs including blood pressure and pulse.

Body weight and height (only for those subjects still potentially growing).

Physical and neurological examination.

ECG (except if the FV follows an EDV where ECG results were normal).

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels 
up to approval of Protocol Amendment 2 (except if the FV follows an EDV where 
laboratory results were normal).

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Completion of end of study status.

Retrieval of “Clinical Study Subject Card”.
The following assessments will be performed during the first 2 years:

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

Socio-professional data.
11.2.8
Additional Visit
REDACTED COPY 
y (hem
ED C
y (hem
omita
CTED
omita
dmen
ACT
dmen
al)
RE
al).
E
.
y marketing authorization application and any extensions or variations thereof. 
in
or
in
V or FV
tens
V or FV
tially
n and
tially g
nd
g
y
nd
y
results
licat
results
matolo
zatio
matolo
ant AED
oriza
ant AED
nt
t
nt 2
th
2 (ex
ho
(ex
SSRS
arket
SSRS
This document cannot be used to support an
ons (AE
any 
ons (AE
tability
ort a
tability
nd of 
ppo
nd of s
Clinic
sup
Clinic
g asses
sed
g asses
ealthca
ot be
ealthca
Reco
nno
Reco
ca
an
ca

e


m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 49 of 89
At any time, the subject may have an additional study visit/phone call if the Investigator or 
the subject deems it necessary.  All information, including reason for visit/phone call, any 
information on AEs, etc., should be collected in the source documents and recorded in the 
appropriate section of the CRF. Study medication can be dispensed if required.
If an additional office visit is conducted due to safety or efficacy reasons, a C-SSRS 
assessment will be performed with the subject during the office visit. If an additional office 
visit is conducted for reasons other than safety or efficacy concerns (e.g., 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 office visits.
11.3
Handling of Biological Samples
The safety samples (hematology, biochemistry, urinalysis, pregnancy test) will be routinely 
assayed and the results sent by fax and letter to the Investigators as specified in 
Section 11.1.15.
11.4
Other Supplies
Not applicable.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
ice
ari
ice
of lost
r va
of lost
sis issu
s or 
is issu
y
d
y test) w
d any
test) w
y
d
y
as spec
and 
as spec

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 50 of 89
12.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
12.1
Adverse Events
12.1.1
Definition of Adverse Event (AE)
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment.  An adverse event 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.
In order to ensure complete safety data collection, all AEs or undesirable experiences 
occurring during the study (i.e., after signature of the Informed Consent), including any pre-
and post-treatment periods required by the protocol, must be reported in the CRF even if no 
investigational product was taken but specific study procedures were conducted.  These 
include 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.
12.1.2
Procedures for Reporting and Recording Adverse Events
The study participant will be given the opportunity to report adverse events spontaneously.  A 
general prompt will also be given to detect adverse events, e.g.
Did you notice anything unusual about your health (since your last visit)?
In addition, the Investigator should review any self-assessment procedures (e.g., diary cards) 
employed in the study.
12.1.3
Description of AEs
The following guidelines and definitions should be used by the Investigator for the 
description of an AE when reporting information:
Nature of the AE:
Preferably an overall diagnosis or syndrome, rather 
than individual symptoms or signs.  The Investigator 
must report adverse events using standard medical 
REDACTED COPY 
pr
Y
pr
it and 
OPY
it and 
ase fo
ACTE
ase fo
ly if t
DAC
ly if t
a clin
RED
a clin
om
R
om
ng authorization application and any extensions or variations thereof. 
ation
r va
ation
ausal
s or
ausal
able an
ions
able an
ease te
ensio
ease te
r not re
exte
r not re
esirable
and 
esirable
d Conse
on a
d Conse
e repor
catio
e repor
edures 
plica
edures 
d all AE
app
d all AE
or whic
horiz
or whic
their na
autho
their na
nicall
ng au
nicall
This document cannot be used to support any market
y
au
y
m the s
keting
m the s
ting an
y ma
ting an
l be giv
ort a
l be giv
so be g
ppo
so be g
ou notic
d to s
ou notic
, the In
e us
, the In
ed in th
ot be
ed in th
1.3
can
1.3
The
me
The
d

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 51 of 89
terminology.  The CRF and source documents should 
be consistent.  Any discrepancies between the subject’s 
own words on his/her own records (e.g., diary card) 
and the corresponding medical terminology should be 
clarified in the source documentation.
Date of onset:
Date the AE started.
Intensity:
Mild
The subject is aware of the sign or symptom 
(syndrome), but it does not interfere with his/her usual 
activities and/or it is of no clinical consequence.
Moderate
The AE interferes with the usual activities of the 
subject or it is of some clinical consequence.
Severe
The subject is unable to work normally or to carry out 
his/her usual activities, or the AE is of definite clinical 
consequence.
Actions taken with investigational product:
Not applicable
For AEs occurring during the investigational product 
free period (pre and post-treatment periods and for 
single dose studies).
No change
Investigational product dosing remained the same in 
spite of the AE being present.
Dose increased
Investigational product dose was increased because of 
this AE.
Dose decreased
Investigational product dose was decreased because of 
this AE.
Temporarily 
discontinued
Investigational product was temporarily discontinued 
because of this AE, either because the subject chose to 
discontinue the investigational product or the physician 
felt it was in the subject’s best interest to temporarily 
discontinue the investigational product.
Permanently 
discontinued
Investigational product was permanently discontinued 
because of this AE, either because the subject chose to 
discontinue the investigational product or the physician 
felt it was in the subject’s best interest to discontinue 
the investigational product.
Other actions taken
None
No other action was taken for this AE.
Medication
The subject took a medication (either prescription or 
non-prescription) specifically for this AE or existing 
medication dosage was modified.
Hospitalization or 
prolongation of 
hospitalization
Subject was hospitalized for this AE or subject’s stay
in hospital was prolonged because of this AE.
REDACTED COPY 
an
Y
an
tudies
OPY
tudies
ional 
D CO
ional 
f the A
TED 
f the A
estigat
ACTE
estigat
his AE
DAC
his AE
Inve
RED
Inve
th
R
th
ing authorization application and any extensions or variations thereof. 
er usua
s or 
er usua
nce.
ions
nce.
s of th
ensi
s of th
quence.
exte
quence.
mall
ny
mally or
y e
y or
E is of 
d any
E is of 
ng the 
catio
ng the 
post
pplic
post-tre
ic
-tre
s).
a
s).
produ
tion 
produ
AE bei
izati
AE bei
tional p
horiz
tional p
E.
au
E.
estigat
ng a
estigat
ot be used to support any market
his AE
eting
his AE
Inve
arke
Inve
b
a
b
y
o
y
This document cann
nued
d to
nued
her act
nnot
her act
N

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 52 of 89
Therapeutic or diagnostic 
procedure
Subject used other therapeutic measures (e.g. ice, 
heating pad, brace, cast, etc.) or subject underwent a 
diagnostic procedure (e.g., additional lab test, x-ray, 
etc.) for this AE.
Date of outcome
Date the AE abated.  If the AE consists of several signs 
and symptoms (syndromes), the sign or symptom with 
the longest duration determines the duration of the AE. 
Outcome:
Resolved
The AE is no longer present at any intensity -
completely abated.
Resolved with sequelae
The AE is resolved but residual effects are still present.
Ongoing
The AE is still present at the last contact with the 
subject.
Worsened
The AE is still present but at a heightened intensity.  
The rule of repetition of AE reporting should be 
applied.
Fatal
This AE caused or directly contributed to the subject’s 
death.
Relationship to investigational product:
None
Only applicable when no investigational product was 
taken or when the subject is taking single-blind 
placebo, or when the AE can be ascribed with 
reasonable certainty to another cause.
Unlikely
There are good reasons to think that there is no 
relationship e.g., the AE is a known adverse drug 
reaction of a concomitant medication, or the same AE 
does not reappear after re-administration of the 
investigational product.
Possible
Equally valid arguments can be considered for or 
against an implication of the investigational product, 
For example, the AE:

follows a reasonable temporal sequence from the 
administration of the investigational product;

follows a known or expected response pattern to 
the investigational product;

but could readily have been produced by a 
number of other factors.
Probable
The relationship is likely.  For example, the AE:

follows a reasonable temporal sequence from 
administration of the investigational product;

follows a known or expected response pattern to 
the investigational product;

is confirmed by improvement on stopping or 
REDACTED COPY 
icable
D CO
icable
r whe
ED C
r whe
ebo, o
ACTE
ebo, o
easona
DAC
easona
Ther
RED
Ther
re
R
re
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
E. 
ri
E. 
re still 
ensio
re still 
act with
exte
act with
eighten
d any
eighten
eportin
and 
eportin
ctly
cati
ctly con
atio
con
y
ati
y
e 
ti
e when
tion a
when
en the s
izatio
en the s
or whe
horiz
or whe
able ce
autho
able ce
ere are 
ng au
ere are 
elation
keting
elation
react
arke
react
d
a
d

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 53 of 89
reducing the dosage of the investigational 
product;

could not be reasonably explained by the known 
characteristics of the subject’s clinical state.
Highly probable
There is a strong relationship.  For example, the AE:

follows a reasonable temporal sequence from 
administration of the investigational product or in 
which the investigational product level has been 
established in body fluids or tissues;

follows a known or expected response pattern to 
the investigational product;

is confirmed by improvement on stopping or 
reducing the dosage of the investigational 
product, and reappearance on repeated exposure 
(rechallenge).
12.1.4
Follow-up on Adverse Events
If an AE is still ongoing at the end of the study for a subject, a follow-up report should be 
provided until resolution/stable level of sequelae or the Investigator no longer feels it is 
clinically significant.  If no follow-up report is provided, the Investigator must provide a 
justification.  The follow-up will be continued for 30 days after the subject has completed the 
study or until the pre-analysis meeting, whatever is shorter.
12.1.5
Rule for Repetition of an AE
An increase in the intensity of an AE should lead to the repetition of the AE reporting 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,

the AE verbatim being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first 1.
12.1.6
Pregnancy
Should a subject become pregnant during the course of the study, UCB should be informed 
immediately.  The subject should be excluded from the study as soon as pregnancy is known 
(e.g. immediate start of down-titration of investigational product intake).  The Investigator 
must inform the subject about the potential risk of malformations that may be caused by any 
AED, and about the available alternatives, e.g. voluntary termination with medical indication.
The pregnancy will be documented in the AE section of the CRF.  The progression of the 
pregnancy and the eventual birth (if applicable) must be followed up using UCB Investigator 
Pregnancy Report form in which the Investigator has to report on the health of the mother and
REDACTED COPY 
for a su
COPY
for a su
elae or
D CO
elae or
rt is p
TED 
rt is p
ntinued
ACTE
ntinued
ng, wh
EDAC
ng, wh
A
R
A
support any marketing authorization application and any extensions or variations thereof. 
r in 
aria
r in 
been
or va
been
e patter
sions
e patter
n stopp
exte
n stopp
nvestiga
ny e
nvestiga
e on rep
d an
e on rep
subject
n app
subject
r the In
tion
r the In
provide
rizat
provide
d for 3
thori
d for 3
hatever
auth
hatever
AE
ket
AE
an AE
y ma
an AE
he first
any
he first
the star
port a
the star
m being
uppo
m being
nt cannot be used to 
y
t
y identi
to su
identi
y
t
y
gnancy
used
gnancy
a subj
ot b
a subj
mediate
anno
mediate
e.g. imm
t ca
e.g. imm
This documen
must
ment
must
AE
m
AE

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 54 of 89
of the offspring.  The health of the child must 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. A pregnancy is also potentially a SAE if it is the consequence 
of a hormonal birth control method failure.
In cases where the partner of a currently enrolled male subject 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 where legally acceptable. If the partner agrees to 
provide additional information, the UCB Investigator Pregnancy Report form will be 
forwarded to the subject’s partner for completion.
12.1.7
Overdose of Investigational Product
Any daily intake of BRV beyond 200mg, the maximum dose used in this study, will be 
considered as overdose.  Only symptomatic overdoses need to be recorded as AEs.  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.  Excessive dosing (beyond that 
prescribed and including overdose) should be recorded in the study medication module.
12.1.8
Safety Signal Detection in Ongoing Clinical Studies
A regular monitoring of safety data collected during clinical studies will be performed as 
described in the Safety Signal Detection in Ongoing Clinical Trials Charter for BRV.
This ongoing monitoring of safety data will be performed at the product level.
Safety data including SAEs, AEs, vital signs, laboratory results and ECG data will be 
periodically reviewed by UCB on an ongoing basis.
The data from all studies with BRV will be scrutinized to detect as early as possible any 
safety concern related to the investigational product so that the Investigators, the clinical 
study subjects, the Regulatory Authorities and the Ethics Committees would be informed in 
the most appropriate manner.
12.2
Serious Adverse Events
12.2.1
Definition of Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that at any dose

results in death;
REDACTED COPY 
ses
Y
ses
e dosin
OPY
e dosin
e a sy
D CO
e a sy
be rec
ED C
be rec
Ongoin
DAC
Ongoin
co
R
co
ny marketing authorization application and any extensions or variations thereof. 
ce
ti
ce
UCB w
s or 
UCB w
consen
ions
consen
agrees 
ensio
agrees 
orm
ext
orm wil
te
wil
e used 
catio
e used 
ed to b
plica
ed to b
ng resu
app
ng resu
y
t
ymptom
tion a
mptom
y
t
y
corded
izatio
corded
ing
aut
ing Cli
th
Cli
ollecte
keting
ollecte
ection 
arke
ection 
be used to support an
safet
any
safety
y 
y
SAEs, A
ppo
SAEs, A
ed b
sup
ed by 
up
y U
p
U
all stu
sed 
all stu
cern rel
e us
cern rel
This document cannot 
bjects,
ot be
bjects,
most app
nnot
most app
12.2
ent c
12.2
1

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 55 of 89

is life threatening;

requires in-subject hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect.
In this context, the term life threatening refers to an event in which the subject was at 
immediate risk of death at the time of the event; it does NOT refer to an event which might 
have caused death if it would have been more severe.
Any important medical event that may not be immediately life threatening or result in death 
or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject 
or may require medical or surgical intervention to prevent 1 of the other outcomes listed in 
the definition above should also be reported as a SAE.  Examples of such events are intensive 
treatment in an ER or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
Cases of cancer should be reported as SAE following the criteria “Important medical event”.
Hospitalization criteria are met anytime a subject is formally admitted to hospital, regardless 
of duration, or if a subject is kept in hospital overnight and it is not clear if a formal 
admission took place.  If a subject is taken to a hospital and neither of the above apply (e.g. 
an ER visit), an event may still be considered serious, meeting the criteria of medically 
important.
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated 
adverse event will not be considered as a SAE, except when otherwise required by 
Regulatory Authorities. If a hospitalization is planned prior to the subjects receiving the first 
dose of investigational product (at week 0), it will not be classified as either an AE or SAE. 
This also applies to situation of scheduled elective surgery where no AE is present.  Non-
complicated, preplanned elective surgery will not be considered an AE or SAE even if it 
involves hospitalization.  However, if a hospitalization is unplanned or is a result of an 
adverse event, this will be considered an SAE.  
Any event reported by the Investigator to the local authorities will follow the same reporting 
procedures as an SAE.
12.2.2
Procedures for Reporting Serious Adverse Events (SAEs)
If a SAE is reported, UCB or its representative must be informed within 24 hours of receipt 
of this information by the site (see contact information for SAEs reporting listed in Section 
2).  The Investigator must forward to UCB (or its representatives) 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.
REDACTED COPY 
t is fo
COPY
t is fo
overni
D CO
overni
to a h
TED 
to a h
dered
ACTE
dered
R
keting authorization application and any extensions or variations thereof. 
ght 
ari
ght 
esult in
sion
esult in
rdize th
tens
rdize th
utcom
exte
utcom
uch eve
ny e
uch eve
crasias
d an
crasias
ndency
and
ndency
riteria “
icatio
riteria “
ormally
n app
ormally
ight an
tion
ight an
hospita
rizat
hospita
d seriou
thori
d seriou
rapeuti
ketin
rapeuti
This document cannot be used to support any ma
red as 
marke
red as 
ospital
y ma
ospital
duct (at
any
duct (at
tion of
ort a
tion of
ned elec
uppo
ned elec
ation.  
o sup
ation.  
his will
d to
his will
report
be us
report
ures 
ot b
ures as
b
as
2.2.2
t can
2.2.2
If 
me
If 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 56 of 89
A copy of the Investigator SAE report form and the completion guide will be provided to the 
Investigator. The Investigator SAE report form has to be completed in English.
Additional information (e.g. autopsy or lab reports) received by the Investigator must be 
provided within 24 hours.  All documents in 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.
UCB (or its representatives) will communicate safety information (Suspected Unexpected 
Serious Adverse Reactions - SUSAR) 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 representatives with evidence of such IEC/IRB 
notification.
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 after the end of the study for each subject and to 
inform the participating subjects of the need to inform the Investigator of any SAE within this 
period.  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.
The reference document for the assessment of the expectedness of the SAEs is the 
Investigator’s Brochure. 
12.2.3
Follow-up of Serious Adverse Events
A SAE should be followed-up until it has resolved/has a stable of sequelae or the Investigator 
no longer feels it is clinically significant.
Information on SAEs obtained after clinical database lock will be captured through the 
Global Drug Safety database without limitation of time.
12.2.4
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.
ACTED COPY 
and
Y
and
they
OPY
they a
Y
a
y
Y
y
e end 
D CO
e end 
d to in
ED C
d to in
ator th
ACTE
ator th
REDA
ardles
DAC
ardles
thorization application and any extensions or variations thereof. 
e e 
nexpe
ions
nexpec
s
c
es
n
es and
nsio
and
approp
exte
approp
ecified
ny ex
ecified
r
d
re appl
d any
e appl
h evide
and 
h evide
eport to
plica
eport to
are in n
app
are in n
d of the
tion a
d of the
nform 
izatio
nform 
hinks m
horiz
hinks m
This document cannot be used to support any marketing au
ss of th
autho
ss of th
sessme
arke
sessme
rious A
ort a
rious A
llowed
sup
llowed
is clin
d to s
is clin
n on SA
e us
n on SA
Drug S
ot be
Drug S
.2.4
can
.2.4
The
me
The

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 57 of 89
The list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 12.2.2.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 58 of 89
13.
STATISTICS
13.1
Statistical and Analytical Plans
A description of statistical methods is presented below and will be described in more detail in
the Statistical Analysis Plan (SAP).
13.1.1
Study Population(s)
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
The Efficacy Population 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.
13.1.2
Safety, Efficacy, and Other Variables
13.1.2.1 Primary Safety Variables

Occurrence of a TEAE

Withdrawal due to AE

Occurrence of an SAE
13.1.2.2 Other Safety Variables

Laboratory tests (blood chemistry, hematology, and urinalysis)

Vital signs (SBP, DBP, pulse rate) and body weight

Electrocardiogram 

Physical and neurological examination

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
13.1.2.3 Secondary Efficacy Variables

Percentage of subjects on continuous BRV monotherapy for at least 3 months, at least 
6 months, and at least 12 months of the Evaluation Period  
13.1.2.4 Other Efficacy Variables

Partial onset seizure (type I) frequency per 28 days during the Evaluation Period
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
in
tio
in
study
ensio
study
t 1 dose
d any
t 1 dose
ation P
and 
ation P
chemis
y ma
chemis
P, puls
t any
P, puls
eurolog
upp
eurolog
HADS s
to su
HADS s
 y
ed
 years 
d to
ears 
Second
be u
Second
P
ann
Perc
nn
erc
6
a
6
13
m
13

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 59 of 89

Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period

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

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

EuroQoL-5 Dimensions questionnaire response for each assessment for the first 2 years 
for the Evaluation Period and for the last assessment during the first 2 years of the 
Evaluation Period
13.1.2.5 Pharmacoeconomic Variables

Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and ER visits) during 
the first 2 years of the Evaluation Period

Indirect costs (workdays or schooldays lost by the subject and days subject received 
help from a caregiver) 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
13.1.2.6 Pharmacokinetic Variables

Brivaracetam (parent compound only) plasma levels

Concomitant AED (and/or relevant metabolites) plasma levels
13.1.3
Statistical Evaluation
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.
For the purpose of statistical analysis, the following periods are considered: 

Evaluation Period (V1 until the last Evaluation Visit)

Down-Titration Period

Post-Treatment Period
13.1.3.1 Evaluation of Safety
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
REDACTED COPY
for t
PY 
for t
Evalua
COPY
Evalua
nd onl
EDA
nd onl
eleva
RE
eleva
support any marketing authorization application and any extensions or variations thereof. 
rs
ti
rs
ye
vari
years
aria
ars
he 
r v
he 
he proto
any e
he proto
s, and 
nd an
s, and 
ct and 
tion 
ct and 
Evalua
icati
Evalua
he first 
ppli
he first 
ation P
n ap
ation P
nly
a
nly) pla
aut
) pla
ant me
ting 
ant me
as the 
t any
as the 
lue, an
port 
lue, an
gorical 
supp
gorical 
This document cannot be used to
ummary
to su
ummary
ose of 
use
ose of 
aluation
t be u
aluation
Down
not 
Down
Pos
ann
Pos
13.1
men
13.1

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 60 of 89
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.
Changes in laboratory values, vital signs, and weight will be summarized by visit. Possibly
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and
weight will be listed and summarized by analysis period. Electrocardiogram abnormalities, as 
well as physical and neurological abnormalities, will be presented in subject data listings.
13.1.3.2 Evaluation of Efficacy
13.1.3.2.1
Efficacy Analyses
All efficacy analyses will be based on the Efficacy Population. All efficacy variables will be 
analyzed descriptively. The Baseline of an efficacy variable will be the Baseline from the 
previous study.
The secondary efficacy variables for the cumulative proportion of subjects remaining on 
BRV monotherapy from the start of the study through 3, 6, and 12 months will be estimated 
using Kaplan-Meier methods.
13.1.3.2.2
Other Efficacy Analyses
The percentage reduction in 28-day POS frequency relative to Baseline will be summarized 
using descriptive statistics. Baseline will be defined as the Baseline value from the previous
study. Additionally, the number and percentage of subjects continuously seizure-free during 
the Evaluation Period will be presented. Descriptive statistics for the change in QOLIE-31-P 
and EQ-5D from Baseline of the previous study to each visit during the first 2 years of the 
study and the last Evaluation Period Visit will also be presented.  
13.2
Determination of the Sample Size
For this open-label, LTFU study, no sample size calculation has been performed.  The sample 
size will depend upon recruitment into and completion of proceeding studies; approximately 
300 - 600 subjects were expected.
13.3
Changes in the Conduct of the Study or the Planned Analyses
An SAP will be developed and approved prior to the database lock.  The full details of the 
statistical analyses will be provided in the SAP.  Any deviations from the SAP as well as 
changes from the protocol will be discussed in the Clinical Study Report.
REDACTED COPY 
pr
Y
pr
ough
OPY
ough
y
R
y POS
RED
POS
e w
R
e w
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
d
t
d
es
es, as 
aria
, as 
ngs.
r va
ngs.
fficacy
d any
fficacy
be the 
and
be the B
ortion 
plica
ortion 
3, 6, 
app
3, 6, a
p
a
S frequ
ng au
frequ
will be
keting
will be
nd perc
arke
nd perc
resente
y ma
resente
f the 
any
f the pr
y 
pr
tion Pe
ort a
tion Pe
ation o
sup
ation o
label
sed
label L
epend u
e us
epend u
0
t
0 subje
ot be
subje
.3
can
.3
An
me
An

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 61 of 89
13.4
Statistical and Analytical Issues
13.4.1
Adjustments for Covariates and Interactions
No adjustment for covariates is foreseen.
13.4.2
Handling of Dropouts of Missing Data
Safety and efficacy variables will be analyzed insofar as they are available.  Days with 
missing information will be ignored in the calculation of the seizure frequency per week.
Since subjects will drop out at different times from the study, the results will be presented by 
categories of duration of exposure where applicable.
13.4.3
Interim Analysis
Due to the single-arm open-label nature of this study, no interim analysis as such will be 
performed.  However, interim database locks will have to 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, SDR) 
applying to the entire BRV program is organized.
13.4.4
Multi-center Studies
No analysis by center is planned.
13.4.5
Multiple Treatment Comparisons/Multiple Endpoints
Not applicable.
13.4.6
Examination of Subgroups
No inferential analyses are planned. Only descriptive summaries will be made on sub-groups 
of subjects with similar exposure.
13.5
Pre-Analysis Review of Data
A pre-analysis review will take place:

before starting analysis. 

after all the data have been verified / coded / entered into the database.
REDACTED COPY 
y
Y
y, n
Y
, n
l have
OPY
l have
ivities
D CO
ivities
oing m
ED C
oing m
rganiz
ACTE
rganiz
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
ys with
ions
s with
y
e
y per w
ensio
per w
y
e
y
s will b
ny ex
s will b
interim
plica
interim
e to be 
app
e to be 
s or to
tion a
s or to
medica
izatio
medica
zed.
horiz
zed.
t Comp
any 
t Comp
nation o
d to 
nation o
ial ana
e us
ial ana
cts wit
ot be
cts wit
.5
c
.5
A p
me
A p

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 62 of 89
The review will be performed to decide how to deal with problems in subject’s data (missing 
values, withdrawals, protocol deviation).
After the pre-analysis review and documentation of all decisions concerning the subjects with 
problems, the database will be locked. 
The analysis will start after the approval and locking of the database, and approval of the 
final SAP.
13.6
Criteria for Un-blinding the Results
Not applicable
13.7
Dictionaries
Adverse events and concomitant procedures will be coded according to MedDRA dictionary 
(latest available version).
Medications will be coded according to World Health Organization Drug dictionary (latest 
available version).
REDACTED COPY 
ealth O
OPY
ealth O
pplication and any extensions or variations thereof. 
ording 
on a
ording 
This document cannot be used to support any marketing authorization a
Organ
app
Organ

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 63 of 89
14.
ETHICS AND REGULATORY REQUIREMENTS
14.1
Approval
The final protocol and any amendments must be signed by the Principal Investigator of the 
site and by appropriate representative(s) of UCB.
The final protocol must be submitted to and approved by:

a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB).

the relevant Regulatory Authorities, according to local regulations.
If any alterations to the protocol are required by these bodies, they can be implemented only 
with the written agreement of the Investigator and the Sponsor’s approver(s) before further
submission to the requesting body.
A copy of the IEC/IRB’s written approval with clear identification of the submitted 
document(s) and a list of members attending the meeting (listed by function and affiliation) 
should be forwarded by the Investigator to the Clinical Trial Manager (CTM).
The usual composition of the IRB/IEC (or DHHS number) along with an IRB/IEC Statement 
of Compliance should also be forwarded to the CTM.
Before submission to an IRB/IEC, the consent form and any other written information to be 
provided to subjects (e.g., advertisement) must be submitted for internal Sponsor approval.  
The study is not allowed to start until the protocol and related documents (informed consent, 
advertisement, etc.) have received written approval from the IEC/IRB and Regulatory 
Authorities, if applicable, as well as until other GCP prerequisites are fulfilled.  
If new information becomes available, it should be communicated without delay to the 
subject, the Investigator, the IEC/IRB, and regulatory authorities, wherever required.
The IEC/IRB must be notified promptly by the Investigator (or Sponsor, if applicable) in 
writing of the following:

Deviations from, or changes to the protocol to eliminate immediate hazards to all the 
study subjects.

Significant changes to the conduct of the study.  Significant changes to the protocol can 
only be affected by a formal protocol amendment that must be submitted to the 
IEC/IRB and approved prior to implementation at the site.

New information that may adversely affect subject safety or the conduct of the study.
REDACTED COPY 
ar id
Y
ar id
meeti
OPY
meeti
Clini
D CO
Clini
or DH
ACTE
or DH
ded to
EDAC
ded to
h
R
h
o support any marketing authorization application and any extensions or variations thereof. 
eview B
ions
eview B
an be i
d any
an be i
approv
and
approv
ntificat
pplic
ntificat
ing
n a
ing (lis
app
(lis
nical Tr
tion 
nical Tr
HHS nu
horiz
HHS nu
o the C
auth
o the C
he cons
keting
he cons
sement
arke
sement
rt until
y ma
rt until
ceived 
any 
ceived 
, as we
ort a
, as we
becom
sup
becom
This document cannot be used 
stigato
d to 
stigato
RB mu
be us
RB mu
of the 
ot be
of the 
Devia
nno
Devia
stu
an
stu

e


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 64 of 89
The Investigator (or Sponsor, if applicable) should comply with the applicable regulatory 
requirements related to the reporting of safety information to the IEC/IRB and Regulatory 
Authorities.
14.2
Subject Information and Consent
Adequate information will be provided to the subject in both oral and written form and 
consent will be obtained in writing prior to performance of any study specific procedure.  
Where required, the consent form or a specific Assent Form will be signed and dated by 
minors. The content and process of obtaining informed consent will be in accordance with all 
applicable regulatory and IEC/IRB requirements.
UCB may provide a sample informed consent form and a subject information sheet.  The 
final consent form must be approved by the IEC/IRB and should contain the applicable ICH-
GCP elements in a language readily understood by the subject (i.e., lay terminology) and/or 
subject’s legally representative(s).
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 IEC/IRB and use of the amended form.
For 
 centers, a separate Health Insurance Portability and Accountability Act (HIPAA)
agreement may be used if required by the IRB or institution.
Subjects and/or subjects’ legally acceptable representatives will be informed of the purpose 
of the study in unambiguous language they easily understand.  Their participation is 
voluntary and they can at any time decide to stop their participation without any influence on 
their future care or treatment.  The subjects and/or subject’s legally acceptable representatives 
must be informed about the main procedures used to guarantee their anonymity, especially 
during the analysis of their personal data.  Subjects and/or subjects’ legally acceptable 
representatives should be able to ask any questions about the study and to receive relevant 
answers.  They will receive complete written information in the Subject Information Sheet or 
Informed Consent Form.
After having received extensive information about the purpose and risks of the study and 
having had enough time to consider participation in the study, the subject and/or subject’s 
legally acceptable representative(s) must give their written consent by signing and dating the 
Informed Consent Form.  This form will also be signed and dated by the person who obtained 
the informed consent and then retained by the Investigator.  Obtaining of consent will be 
confirmed in the subject’s medical records.  The subject and/or subject’s legally acceptable 
representative(s) will receive a copy of the signed and dated consent form and the original 
will be filed in the Investigator’s Study File.
REDACTED COPY 
stu
Y
stu
requir
OPY
requir
C/IRB
D CO
C/IRB
nce Po
ACTE
nce Po
y the IR
DAC
y the IR
ce
R
ce
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
ure. 
r va
ure. 
ed b
s o
ed by 
o
y 
dance w
ions
dance w
mation
y ex
mation
ntain th
d any
ntain th
e., lay
and
e., lay t
d 
t
y
d
y
y, the
plica
, the I
a
I
iremen
app
iremen
B and u
tion a
B and u
Portabil
horiz
Portabil
IRB or 
autho
IRB or 
eptable
keting
eptable
uage th
arke
uage th
ime de
y ma
ime de
t.  The 
any 
t.  The 
he mai
ort a
he mai
their pe
ppo
their pe
uld be a
sup
uld be a
will rec
d to s
will rec
sent Fo
sed 
sent Fo
ving re
ot be
ving re
ng had 
nnot
ng had 
gally
can
gally ac
an
ac
y
an
y
In
nt
Inform
nt c
form
the
me
the

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 65 of 89
If the signature of a witness is required, the witness should sign and personally date the 
consent form after the subject and/or subject’s legally acceptable representative(s) has signed.  
By signing the consent form, the witness attests that the information in the consent form and 
in any other written information was accurately explained to, and apparently understood by, 
the subject and/or subject’s legally acceptable representative(s)and that informed consent was 
freely given.
The subject and/or subject’s legally acceptable representative(s) may withdraw their consent 
to participate in the study at any time.  A subject is considered as enrolled in the study when 
he/she and/or his/her legally acceptable representative(s) have signed the informed consent 
form.  A Case Report Form must not be started, nor may any study specific procedure be 
performed for a given subject, without having obtained his/her and/or his/her legally 
acceptable representative(s)written consent to participate in the study.
If any new information that could influence the subject and/or subject’s legally acceptable 
representative(s) decision to stay in the study becomes available, this information will be 
transmitted to the subject and/or subject’s legally acceptable representative(s) without delay.  
In addition, the informed consent form must be amended accordingly or a separate consent 
form be created and submitted to the IEC/IRB for approval prior to being implemented for 
re-consent of all ongoing subjects and/or subjects’ legally acceptable representative(s) in the 
study and for use in consenting all subjects entering the study from that point forward.
14.3
Subject Confidentiality
Subject confidentiality will be maintained at all times.  Personnel from UCB (or its 
representative), from Regulatory Authorities and members of the IEC/IRB may inspect 
medical records and Case Report Forms for verification of the accuracy of data.  These 
groups are obliged to respect medical secrecy and to refrain from divulging the subject’s 
identity or any other personal information.  Sites will be required to obliterate any possibly 
identifying information (e.g., name, social security number, address, etc.) on any materials, 
forms, or report prior to sending them to the Sponsor or its designee.
Medical records will be handled by professional standards and existing local laws.
14.4
Informing the General Practitioner 
If the subject agrees, the Investigator may inform the subject’s regular physician of his/her 
participation in the study, by sending him/her the letter to the General Practitioner (GP).  A 
template letter will be proposed by UCB.
REDACTED COPY 
nd
Y
nd
r appr
OPY
r appr
ects’ le
D CO
ects’ le
enteri
ED C
enteri
nta
R
nta
marketing authorization application and any extensions or variations thereof. 
consent
r va
consent
udy
s o
udy wh
or 
wh
y
o
y
med con
ions
med con
rocedu
ensio
rocedu
her leg
exte
her leg
bject’s 
and 
bject’s 
e, this 
on a
e, this 
e repres
catio
e repres
accord
plica
accord
roval p
app
roval p
legally
tion a
legally
a
ring the
izatio
ring the
ained a
keting
ained a
Author
arke
Author
t cannot be used to support any m
ort Form
y ma
ort Form
t medic
any 
t medic
onal in
ort a
onal in
n (e.g.,
ppo
n (e.g.,
or to se
sup
or to se
ds will
sed 
ds will
Infor
ot be
Infor
the sub
can
the sub
This documen
partici
ent c
partici
tem
me
tem

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 66 of 89
15.
STUDY MANAGEMENT AND ADMINISTRATION
15.1
Monitoring
Monitoring of the study is the responsibility of UCB and may be delegated to a Clinical 
Research Organization (CRO) or a contract monitor.  The Monitor (the individual responsible 
for monitoring) will advise the Investigator regarding the practical conduct of the study and 
maintaining compliance with the protocol, GCP, and all applicable regulatory requirements.
The Investigator will allow UCB or its representatives to review periodically, at mutually 
convenient times during the study and after the study has been completed, all CRFs and 
corresponding source documents (e.g., portions of office, hospital and laboratory records for 
each study participant).  Therefore, the monitor will have direct access to these records.  The 
monitoring visits provide UCB or its representatives with the opportunity to evaluate the 
progress of the study, to 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.
15.2
Direct Access to Source Data/Documents
The Investigator(s)/Institution(s) will permit study-related monitoring, audits by or on behalf 
of UCB, IEC/IRB review, and regulatory inspection(s), providing direct access to source 
data/documents.
Source documents are original records in which raw data are first recorded.  These may be:  
hospital/clinic/GP records, charts, diaries, x-rays, laboratory results, printouts, pharmacy 
records, care records, ECG or other printouts, completed scales, Quality of Life 
Questionnaires, etc.  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:

Demographic data

Childbearing potential and birth control

Vital signs

Body weight and height

Physical and neurological examinations

Socio-professional data

Number of school/workdays lost
Original laboratory results, ECG, will be inserted in the CRF and are also to be considered as 
source data.  Original DRCs, QOLIE-31-P, EQ-5D, and HADS questionnaires will be 
retrieved. The site will keep a copy in the CRF and this copy will considered as source data.
REDACTED COPY 
he s
Y
he s
ments
CO
ments
rmit s
ACTE
rmit s
tory
DAC
tory in
AC
in
y
AC
y
used to support any marketing authorization application and any extensions or variations thereof. 
nsible
ariat
nsible
dy
r
dy and 
r va
and 
y
r
y
iremen
s or 
iremen
at mu
ensio
at mu
all CR
exte
all CR
aborato
ny ex
aborato
ss to th
d any
ss to th
ortunit
and 
ortunit
of CRF
on a
of CRF
d I
cat
d Inves
catio
nves
dy
pl
dy reco
plica
reco
y
pl
y
s
i
s
study
horiz
study-r
z
r
nspecti
autho
nspecti
ords in
arke
ords in
rts, dia
y ma
rts, dia
or other
any 
or other
rce doc
ort a
rce doc
ded in 
sup
ded in 
irectly
d to s
irectly
raphic 
sed 
raphic 
This document cannot be
dbearin
be us
dbearin
ital sig
ot be
ital sig
Bod
nno
Body
o
y
Ph
a
Ph

e


m


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 67 of 89
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 correcting fluid or have temporary 
attachments (such as removable self-stick notes).  Photocopies of case report forms are not 
considered acceptable source documents.  Photocopies will only be considered as acceptable 
source documents when used to establish permanent documentation of data captured on non-
permanent media.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (e.g. 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.
For subjects exposed to investigational product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study related identifiers (such as subject/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.  
Information recorded in the CRF must be consistent with entries in the source documents.  
The monitor will perform 100% source documents verification.
15.3
Audit and Inspection
The Investigator will permit study-related audits by auditors 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 (i.e. signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of 
the investigational product have been processed and reported in compliance with the planned 
arrangements, the protocol, facility and IEC/IRB 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.
REDACTED COPY 
num
Y
num
study
OPY
study
Y
ing of
D CO
ing of
dical h
ED C
dical h
ptive 
ACTE
ptive 
provid
DAC
provid
marketing authorization application and any extensions or variations thereof. 
e 
t
e 
non-
ariat
non-
e printe
ions
e printe
be sign
ensio
be sign
urce do
exte
urce do
he print
ny ex
he print
m requ
on a
m requ
ain the 
catio
ain the 
er, CRF
plica
er, CRF
and id
app
and id
f conse
tion a
f conse
history
izatio
history
treatm
horiz
treatm
ide evid
autho
ide evid
must be
arke
must be
nnot be used to support any m
% sourc
ma
% sourc
ection
ort a
ection
ll perm
sup
ll perm
omestic
d to s
omestic
n audit 
sed 
n audit 
ave bee
e us
ave bee
ocedur
ot be
ocedur
nvestig
nnot
nvestig
This document c
rangem
can
rangem
requir
ent c
requir
rec
me
rec
I

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 68 of 89
15.4
Case Report Forms (CRF) and Screen Failures
Data reflecting participant experience with the drug(s) under investigation will be reported to 
UCB.  These data will be recorded on the Case Report Forms (CRF). The CRF is essentially 
a data entry form and may not routinely constitute the original (or source) medical record.  
CRF should be kept in a secure, limited access area.
The CRF will be organized in yearly books. CRFs will be signed and dated by the Principal 
Investigator or a Co-Investigator designated by the Principal Investigator.  The Investigator’s 
or Co-Investigator’s signature on the CRF attests to its accuracy and completeness.  Paper 
CRFs will be completed in dark ballpoint pen, and must be legible.  If an entry in a CRF 
needs to be changed, the correction will be made as follows:

Cross-out the initial entry (must still be legible).

Write the correct entry next to it together with your initials, the date and justification if 
necessary.  Correcting fluid, erasure or any form of obliteration of data in CRFs is not 
permitted except to obliterate information that could specifically identify a subject (i.e., 
a name written on a subject diary).
UCB cannot interpret a blank answer as NONE or NA (not applicable); therefore, all fields 
must be completed.  Please mark data which could not be recorded as follow: ND for “Not 
Done”, NA for “Not Applicable”, UN for “Unknown”.
Data reported in the CRF, which are derived from source documents, should be consistent 
with the source documents or the discrepancies should be explained in those source 
documents.
The Investigator will keep a subject screening log to document identification of subjects who 
entered pre-study screening.
All supportive documentation submitted to UCB in addition to the Case Report Form, such as 
laboratory results or hospitalization records, must be clearly identified with the study number, 
study participant number, and study participant initials; any personal information, including 
the study participant’s name, must be removed or rendered illegible to preserve individual 
confidentiality.  All original lab reports will remain at the study site.  
15.5
Adherence to Protocol
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 IEC/IRB.  The Investigator/institution and the Sponsor will sign the 
protocol to confirm agreement.
REDACTED COPY 
E or N
D CO
E or N
ch cou
TED 
ch cou
or “Un
ACTE
or “Un
re der
RED
re der
R
o support any marketing authorization application and any extensions or variations thereof. 
Princip
s or 
Princip
Investig
ions
Investig
eness. 
ensio
eness. 
entry
exte
entry in
e
in
y
e
y
the da
and
the da
eration
on a
eration
specific
catio
specific
NA (no
tion 
NA (no
uld not 
izati
uld not 
nknow
horiz
nknow
rived f
ng a
rived f
crepan
keting
crepan
 subjec
any 
 subjec
ng.
ort
ng.
umenta
o sup
umenta
This document cannot be used 
s or ho
d to 
s or ho
ant num
sed
ant num
particip
be us
particip
ntiality
ot be
ntiality
.5
c
.5
Th
me
Th

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 69 of 89
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 CPM 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 IEC/IRB and the appropriate regulatory authorities, if 
applicable prior to being implemented.  
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.
15.6
Investigator Site File
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring, auditing by UCB or its designee and/or inspection.
15.7
Data Handling
UCB will be responsible for data processing and may delegate this responsibility to a CRO.
CRF data will be entered in a validated electronic database using a clinical data management 
system.  Computerized data cleaning checks will be used in addition to manual review to 
check for discrepancies and to ensure consistency of the data.  An electronic audit trail 
system will be used to track all data changes in the database subsequent to the reconciliation 
of the double-entered data.  The SAS system will be used for the statistical analysis of the 
data.  Regular back-ups of the electronic data will be performed.
15.8
Termination of 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;
TED COPY 
the stu
ED C
the stu
REDAC
n an or
ACTE
n an or
esigne
DAC
esigne
rization application and any extensions or variations thereof. 
t 
t
t 
ents.
ariat
ents.
col an
r va
col an
if 
s o
if 
l may
exte
l may o
y
essmen
ny ex
essmen
overag
d any
overag
he Inve
on a
he Inve
nal Clin
catio
nal Clin
udy
izat
udy as 
atio
as 
y
at
y
upport any marketing autho
rderly
horiz
rderly
z
ee and/
autho
ee and/
ta proc
y ma
ta proc
in a va
ort a
in a va
d data c
ppo
d data c
t cannot be used to s
cies an
sup
cies an
sed to t
d to s
sed to t
entered
sed 
entered
ular bac
e us
ular bac
This documen
Te
not
Te
Upon 
ent c
Upon 
con
me
con

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 70 of 89

accountability, reconciliation and arrangements for used and unused investigational 
products;

review of site study records for completeness;

If applicable - return of treatment codes to UCB or its representatives;

discussion/reminder on archiving responsibilities;

discussion of IEC/IRB requirements for study termination;

arrangements for unused CRFs, lab supplies and any other study related supplies.
In addition, 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, non-
compliance, or unsatisfactory quality.
If the study is prematurely terminated or suspended, UCB or its representatives 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 IEC/IRB 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.
15.9
Clinical Study Report
UCB will prepare a clinical study report, in accordance with the relevant ICH guidelines.  
The report will include a thorough description of the clinical and laboratory methods, a 
discussion of the results and a list of all measurements as specified in the SAP.  This report 
may be included in submissions to government drug regulatory authorities worldwide, or 
used for whatever reason considered appropriate by UCB.  No information contained in the 
report may be used without written approval of UCB.
The coordinating Investigator(s) designated by UCB to sign the report (see Section 2) will 
have an opportunity to comment on the draft version.  He/she must give his/her comments 
within 7 days of receiving the report.  In addition, he/she will sign the report for approval 
within 7 days of receipt of the revised version or a satisfactory reply to these comments.
15.10
Insurance and Liability
UCB has taken out an insurance policy, for the total duration of the study, covering the 
subjects, in respect of the risks involved in this study according to this protocol.  In the case 
of injury or disability deriving from participation in the study, the subject is requested to 
inform the treating physician responsible for the study without delay.  
REDACTED COPY
Spon
PY 
Spon
ment(
COPY
ment(
nal pr
D CO
nal pr
port any marketing authorization application and any extensions or variations thereof. 
tinue th
ns o
tinue th
includ
sion
includ
ng, non
tens
ng, non
resenta
d a
resenta
f the ter
n and
f the ter
n, in ac
tion 
n, in ac
formed
licati
formed
sor or b
pplic
sor or b
(s).  In
n ap
(s).  In
roducts
ation
roducts
eport, in
ketin
eport, in
gh desc
mark
gh desc
list of 
y m
list of 
sions to
t any
sions to
n consi
ort 
n consi
t be used to sup
ithout 
uppo
ithout 
ng Inve
ed to
ng Inve
rtunit
used
rtunit
d
day
be
days of 
be u
s of 
This document cannot b
7 day
ot b
days
b
s
5.10
t ca
5.10
UC
m
UC

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 71 of 89
15.11
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 (ICH-GCP Guideline-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.
15.12
Allocation of Responsibilities
The Investigator is responsible for the implementation of the protocol but can delegate tasks 
to the research team.  The Investigator remains responsible for coordinating and informing 
his/her staff about the protocol and any possible changes made to it.  The Investigator should 
maintain a site signature and delegation of responsibility log.  The list should be kept up to 
date.
15.13
Curriculum Vitae (CV)
A signed and dated FDA Form 1572, in addition to required local forms, and recent (updated 
every 2 years) CV (in English) are required from each Investigator showing a current 
affiliation with the research center.  All sub-Investigators listed on the FDA Form 1572 
should also date and sign a recent English version of their CVs.  Any changes to the site 
personnel should be updated on a new FDA Form 1572.
15.14
Financial Disclosure
A financial disclosure statement must be obtained for everyone listed on the FDA form 1572. 
These must be collected before subject enrollment. The sites must inform the Sponsor if 
information related to financial disclosure changes during the course of the study and/or up to 
1 year after study completion/end of the study.
REDACTED COPY 
ud
Y
ud
mplem
ACTE
mplem
r rema
DAC
r rema
d an
RED
d any p
ED
y p
atio
R
atio
ng authorization application and any extensions or variations thereof. 
fter th
s or 
fter th
pendin
ions
pendin
e elaps
ensio
e elaps
roduct
exte
roduct
y the a
ny ex
y the a
Guidel
d any
Guidel
estruct
and 
estruct
study r
on a
study r
move t
catio
move t
master 
plica
master 
mentatio
horiz
mentatio
mains re
autho
mains re
possib
ng au
possib
ot be used to support any market
ion of r
keting
ion of r
(CV)
any 
(CV)
DA For
ppo
DA For
in Eng
sup
in Eng
he rese
d to s
he rese
te
se
te and
ed 
and
should 
e us
should 
This document cann
Fin
nnot
Fin
A
n
A f
nt
fina
t c
ina
fif
t
fif
The
me
The
i

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 72 of 89
15.15
Good Clinical Practice
Non-compliance 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 non-compliance may result in the 
termination of the participants’ involvement in the study.
15.16
Disclosure of Clinical Study Information
UCB alone shall be responsible for the registration of clinical studies in a public studies 
registry and for the disclosure of study results on a publicly accessible website.
15.17
Publication
Authorship of planned manuscripts for submission to medical journals shall be determined in 
accordance with the International Committee of Medical Journal Editors (ICMJE) Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals.  
The Site and its Investigators agree that if the Site is part of a multi-center Study, Site and
Investigator(s) shall coordinate in advance any intended disclosure of the results of the study 
with UCB to ensure that the results of individual sites are not published or presented before
those of the multi-centre Study, unless otherwise agreed by in writing by UCB.
Subject to the following paragraph, the authors have the final responsibility for the content of 
their own publication(s) and the decision to submit it/them for publication.  
Any planned manuscript, presentation, abstract or other intended disclosure of the results of 
the study or otherwise originating from the study shall be made available for review to UCB 
at least thirty (30) days before submission for publication or any other means of disclosure in 
order to allow UCB to protect its intellectual property.
In the rare event that such disclosure would affect the patentability of any invention to which 
UCB has rights, UCB shall have the right to request an additional delay to the proposed 
disclosure of no more than ninety (90) days so as to allow UCB to preserve its intellectual 
property.
REDACTED COPY 
dic
Y
dic
Site is
D CO
Site is
an
ED
any in
ED C
y in
dividu
ACTE
dividu
s othe
DAC
s othe
th
R
th
any marketing authorization application and any extensions or variations thereof. 
blic
ens
blic stu
sio
stu
site.
xte
site.
ournal
on a
ournal
urnal E
catio
urnal E
Jou
pli
Journal
plica
rnal
s part o
tion a
s part o
ntende
izatio
ntende
ual site
horiz
ual site
erwise 
autho
erwise 
he auth
keting
he auth
ecisi
arke
ecision
ke
on
esentat
any 
esentat
This document cannot be used to suppor
ginatin
ort a
ginatin
bef
ppo
befor
po
or
fo
f
po
fo
f
 to pro
sup
 to pro
ent that
sed 
ent that
ights, U
e us
ights, U
re of n
ot be
re of n
ert
nn
erty.
nno
y.

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 73 of 89
16.
REFERENCES
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised 
terminology and concepts for organization of seizures and epilepsies: report of the ILAE 
Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-85.
Commission on Classification and Terminology of the International League Against
Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia. 1981;22:489-501.
Commission on Classification and Terminology of the International League Against 
Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 
1989;30:389-99.
CPMP/EWP/566/98 rev 1 Note for guidance on clinical investigation of medicinal products 
in the treatment of epileptic disorders (European Medicines Agency) 16 Nov 2000.
CPMP/ICH/135/95 Note for guidance on good clinical practice (European Medicines 
Agency) Jul 2002.
CPMP/ICH/2711/99 Note for guidance on clinical investigation of medicinal products in the 
paediatric population (European Medicines Agency) 27 Jul 2000.
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;39:81-8.
Cramer JA, Van Hammée G. Maintenance of improvement in health-related quality of life 
during long-term treatment with levetiracetam. Epilepsy Behav. 2003;4:118-23.
Engel J Jr. Report of the ILAE classification core group. Epilepsia. 2006;47:1558-68.
Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-
Raven; 1998.
EuroQol Group. EQ-5D. A measure of health-related quality of life developed by the 
EuroQol group. User guide. 8th issue. April 2000.
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1948. Epilepsia. 1993;34:453-68.
REDACTED COPY 
inical
OPY
inical
on clin
ACTE
on clin
cines
DAC
cines
B
R
B
any marketing authorization application and any extensions or variations thereof. 
f epile
s or 
f epile
ue Aga
exte
ue Aga
s
n
syn
ny e
yndro
y ex
dro
igation
on a
igation
A
a
Agenc
catio
genc
l practi
app
l practi
nical in
horiz
nical in
A
uth
Agen
uth
gen
Bry
ketin
Bryant
ting
ant
anslati
arke
anslati
This document cannot be used to suppor
e G. M
ort a
e G. M
ment w
ppo
ment w
rt of th
d to s
rt of th
Pedley
e us
Pedley
1998.
t be
1998.
uroQol 
can
uroQol 
EuroQ
ent c
EuroQ
H

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 74 of 89
Herrmann C. International experiences with the Hospital Anxiety and Depression Scale-a 
review of validation data and clinical results. J Psychosom Res. 1997;42:17-41.
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255-60.
Loiseau J, Loiseau P, Guvot M, Duche B, Dartigues JF, Aublet B. Survey of seizure disorders 
in the French southwest. I. Incidence of epileptic syndromes. Epilepsia. 1990;31:391-6.
Lüders HO, Acharya J, Alexopoulos A, Baumgartner C, Bautista J, Burgess R, et al. Are 
epilepsy classifications based on epileptic syndromes and seizure types outdated? Epileptic 
Disord. 2006;8:81-5.
Nasreddine W, Beydoun A, Atweh S, Abou-Khalil B. Emerging drugs for partial onset 
seizures. Expert Opin Emerg Drugs. 2010;15:415-31.
Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 
1996;61:433-43.
REDACTED COPY 
and any extensions or variations thereof. 
rs
tio
rs
l. Are
s or 
l. Are
d? Epile
ions
d? Epile
for par
ny ex
for par
This document cannot be used to support any marketing authorization application
urol Ne
on a
urol Ne

Thefollowinginformation(eg,ƋƵĞƐƚŝŽŶŶĂŝƌĞ)iscopyrightedandUCBdoesnothavepermissionto
disclosethecontents.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 89 of 89
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. 









(/(&7521,&6,*1$785(6

6LJQHGE\
0HDQLQJRI6LJQDWXUH
6HUYHU$SSURYDO'DWH
GGPRQ\\\\
++PP

























































13URWRFRO$PHQGPHQW,QWHJUDWHG
&OLQLFDO$SSURYDO
0DU*07
&OLQLFDO$SSURYDO
0DU*07
REDACTED COPY 
ED
DA
DO
O
DO
authorization application and any extensions or variations thereof. 
n an
any 
6HUYHU
any
6HUYHU
nd a
an
upport any marketing au
y
n a
au
ke
an
This document cannot be used to sup
up
se