An Open-label, Multicenter, Follow-up Trial to Evaluate Long-term Safety and Efficacy of Brivaracetam Used as Adjunctive Treatment 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

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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 1 of 77
1.
TITLE
An open-label, multi-center, follow-up trial to evaluate long-term safety and efficacy of
brivaracetam (ucb 34714) used as adjunctive treatment at a flexible dose up to a maximum of 
200 mg/day in subjects aged 16 years or older suffering from epilepsy
Sponsor: UCB Pharma SA
Chemin du Foriest
B-1420 Braine l’Alleud
BELGIUM
With registered office:
Allée de la Recherche 60
B-1070 Brussels
BELGIUM
Brivaracetam - EudraCT Number: 2004 - 002140-10
IND Number: 75,898
General Substantial Amendment 1 approved 1st April 2005: limitation of the maximal dose to 150 mg/day.
General Non-Substantial Amendment 2 approved 20th May 2005: clarification of several sections of the 
protocol
Country Specific - Germany- Substantial Amendment 3 approved 30th May 2005: only subjects aged 18 years 
or more can be included
Country Specific - The Netherlands – Substantial Amendment 4 approved 2nd December 2005: only subjects 
aged 18 years or more can be included
General Substantial Amendment 5 approved 07th April 2006: compliance with Central EC and Sponsor 
requirements. Clarification of several sections of the protocol
Specific Substantial Amendment 6 approved 05th May 2006: specifications for subjects with ULD
General Substantial Amendment 7 approved 02nd February 2007: specifications for subjects with POS
General Substantial Amendment 8 approved 01st June 2007: specifications for subjects with POS
Specific Substantial Amendment 9 approved 01st June 2007: specifications for subjects with ULD
Specific Substantial Amendment 10 approved 26th October 2007: specifications for subjects with ULD
Country Specific – Austria – Amendment 11/C3 approved 20-Nov-2007: addition of a monthly urine pregnancy 
test in female subjects of childbearing potential
Country Specific – France – Amendment 12/C4 approved 11-Feb-2008: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug
Country Specific – Norway – Amendment 13/C5 approved 13-Mar-08: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug and only subjects aged 
18 years or more can be included
Country Specific – Spain – Amendment 14/C6 approved 04-Apr-08: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug
Site Specific – Site # 
 – Amendment 15/S1 approved 04-Apr-08: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug
Country Specific – Turkey – Amendment 16/C7 approved 04-Apr-08: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 2 of 77
Site Specific – Site # 
 – Amendment 17/S2 approved 04-Apr-08: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug
This amendment applies to all sites (with Partial Onset Seizures subjects) participating in the study
Specific Substantial Amendment 18 approved 04-April-2008: clarification of several sections of the protocol 
and FDA warning for suicidality and suicidal thoughts for subjects with POS
Site Specific – Site #
 – Amendment 19/S3 approved 29-May-2008: subjects are not allowed to convert to 
brivaracetam monotherapy in case of excellent efficacy and tolerability of the study drug
Country Specific – France – Amendment 20/C8 approved 09-Jun-2008: subjects are not allowed to enter the 
study if they are sexually inactive with childbearing potential
Country Specific – Czech Republic – Amendment 21/C9 approved 21-Jan-09: study entry of the N01258 
subjects allowed
Country Specific – Germany – Amendment 22/C10 approved 21-Jan-09: study entry of the N01258 subjects
allowed
Country Specific – Poland – Amendment 23/C11 approved 21-Jan-09: study entry of the N01258 subjects
allowed
Specific Substantial Amendment 24 dated 03 Jan 2011: clarification of several sections of the Integrated 
Protocol Amendment 18
Specific Substantial Amendment 25 dated 03 Jan 2011: clarification of several sections of the Integrated 
Protocol Amendment 10
Integrated Substantial Amendment 25 dated 03 Jan 2011 includes the changes to the previous Integrated 
Amendment 10 and to the Integrated Amendment 18 and applies to all subjects enrolled in N01125.
Integrated Substantial Amendment 26 dated 25 Oct 2011: addition of the suicidality assessment and the 
requirements per the FDA Final Rule and update of the study variables
Integrated Substantial Amendment 27 dated 12 Mar 2015: updated contact information, addition of procedures 
for subjects enrolling from another study (N01315), deletion of outdated exposure numbers, addition of 
language allowing all subjects to enroll into a managed access program (or similar), updated protocol adherence 
language, added Sponsor declaration page
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 anyway 
communicated to any third party without prior written approval of the Sponsor (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.”
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 3 of 77
Principal Investigator
“By my signature below, I acknowledge that I have read the protocol RPCE03D0801 
Integrated Amendment 27 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 the Sponsor of the clinical study or its representatives(s).”
Signature:
Date:
Printed Name:
Address:
Phone:
Site Number:
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 4 of 77
2.
CONTACT INFORMATION
Sponsor
Global address:
UCB Pharma SA 
Chemin du Foriest
B-1420 Braine l’Alleud Belgium
With registered office:
Allée de la Recherche 60
B-1070 Brussels, Belgium
Study Physician
Name:
, MD
Phone:
Fax:
Clinical Trial Manager
Name:
 PhD
Phone:
Fax:
Contract Research Organization (CRO)
PPD Development
Kleine Kloosterstraat 23
1932 St-Stevens-Woluwe
Belgium
During working hours:
Phone:
+32 2 723 26 26
Fax:
+32 2 723 26 00
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 5 of 77
SAE Reporting (24h/24), Safety Related Issues and Emergency Unblinding (GCSP)
Email:
Global
DSICT@ucb.com
Fax:
Europe and Rest of the World 
+32 2 386 24 21
USA:
+1 800 880 6949
Canada:
+1 877 582 8842
Central Laboratories:
Eurofins Medinet BV
Bergschot 71 
P.O. Box 5510
4801 DM Breda
The Netherlands
During working hours:
Phone:
+31(0)76 573 73 73
Fax:
+31(0)76 573 77 78
Quintiles Laboratories North America
1600 Terrell Mill Road
Marietta, GA 30067
USA
Phone:
+1 770 373 3900
Fax:
+1 770 373 3598
Investigator(s)
The complete and updated list of Investigators is maintained in the Trial Master File (TMF) 
at UCB.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 6 of 77
3.
TABLE OF CONTENTS
1.
TITLE..............................................................................................................................1
2.
CONTACT INFORMATION .......................................................................................4
3.
TABLE OF CONTENTS...............................................................................................6
3.1
List of Abbreviations........................................................................................10
4.
PROTOCOL SUMMARY...........................................................................................13
4.1
Schedule of Assessments .................................................................................18
4.2
Schematic Diagram ..........................................................................................22
5.
BACKGROUND INFORMATION............................................................................25
5.1
Background and epidemiology of targeted disease..........................................25
5.2
Background information regarding product.....................................................26
5.3
Efficacy with brivaracetam in fixed-dose Phase II/III studies in POS.............27
5.4
Safety with brivaracetam..................................................................................27
5.5
Efficacy and safety in subjects with Unverricht-Lundborg disease.................27
5.6
Study Rationale ................................................................................................28
5.6.1
Dose Selection....................................................................................28
5.6.2
Subjects Population............................................................................29
5.6.2.1
Minimal Age...............................................................29
5.6.3
Duration of Treatment........................................................................29
6.
STUDY OBJECTIVES AND PURPOSE...................................................................30
6.1
Primary Objective ............................................................................................30
6.2
Secondary Objective ........................................................................................30
6.3
Exploratory Objectives.....................................................................................30
7.
STUDY DESIGN ..........................................................................................................31
7.1
Type/Design .....................................................................................................31
7.2
Subjects/Sites Numbers....................................................................................32
7.3
Measures to Minimize/Avoid Bias...................................................................32
7.3.1
Randomization ...................................................................................32
7.3.2
Blinding..............................................................................................32
7.4
Study Duration .................................................................................................32
7.5
End of Study.....................................................................................................32
8.
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................32
8.1
Subject Inclusion Criteria.................................................................................32
8.2
Subject Exclusion Criteria................................................................................34
8.3
Subject Withdrawal Criteria.............................................................................34
8.3.1
Withdrawal Criteria............................................................................35
8.3.2
Subject Replacement Policy...............................................................35
9.
TREATMENT OF SUBJECT (INVESTIGATIONAL PRODUCTS AND
CONCOMITANT MEDICATIONS) .........................................................................35
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 7 of 77
9.1
Study Investigational Products.........................................................................35
9.1.1
Description of Investigational Products.............................................35
9.1.1.1
Dosing Schedule.........................................................36
9.1.2
Packaging...........................................................................................36
9.1.3
Labeling..............................................................................................37
9.1.4
Storage Requirements ........................................................................37
9.1.5
Monitoring of Subject Compliance....................................................37
9.1.6
Investigational Products Accountability ............................................38
9.1.7
Maintenance of Study Treatment Randomization Codes and
Procedures for Blind Breaking...........................................................38
9.2
Concomitant Treatments ..................................................................................38
9.2.1
Permitted Concomitant Treatments (Medications and Therapies) ....39
9.2.2
Not Permitted Concomitant Treatments (Medications and
Therapies)...........................................................................................39
10.
STUDY PROCEDURES..............................................................................................39
10.1
Subject Identifier..............................................................................................39
10.2
Description of Procedures ................................................................................39
10.2.1
Informed Consent...............................................................................39
10.2.2
Demography.......................................................................................40
10.2.3
Childbearing Potential and Birth Control ..........................................40
10.2.4
General Medical and Procedures History ..........................................40
10.2.5
Epilepsy History/Disease History ......................................................40
10.2.6
Antiepileptic/Antimyoclonic Medication History .............................40
10.2.7
Vital Signs..........................................................................................40
10.2.8
Body Weight and Height....................................................................41
10.2.9
Physical Examination.........................................................................41
10.2.10 Neurological Examination .................................................................41
10.2.11 ECG....................................................................................................41
10.2.12 Daily Record Card (DRC)..................................................................42
10.2.13 Patient Reported Outcomes................................................................43
10.2.14 Health Related Quality of Life Questionnaire (QOLIE-31-P)...........43
10.2.15 Hospital Anxiety and Depression Scale (HADS) ..............................44
10.2.16 Laboratory Assessments.....................................................................44
10.2.17 Adverse Events...................................................................................45
10.2.18 Assessment of Suicidality ..................................................................45
10.2.19 Medical Procedures............................................................................45
10.2.20 Health Care Provider Consultations not Foreseen by the
Protocol ..............................................................................................46
10.2.21 Hospital Stay......................................................................................46
10.2.22 Non-Antiepileptic and Antiepileptic Concomitant
Medications/Non-Antimyoclonic and Antimyoclonic
Concomitant Medications ..................................................................46
10.2.23 EQ-5D Questionnaire.........................................................................47
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 8 of 77
10.2.24 Socio-professional Data .....................................................................47
10.2.25 End of Study.......................................................................................47
10.3
Study Conduct..................................................................................................48
10.3.1
Entry Visit..........................................................................................48
10.3.2
Full Evaluation Visit ..........................................................................49
10.3.3
Minimal Evaluation Visit...................................................................50
10.3.4
Yearly Evaluation Visit (replaces the FEV of each year)..................50
10.3.5
Early Discontinuation Visit................................................................51
10.3.6
Down-Titration Phone Call................................................................52
10.3.7
Final Visit (FV following a Study Drug-free Period after an
EDV or FV initiated upon Sponsor request at the End of the
program).............................................................................................52
10.3.8
Additional Visit..................................................................................53
10.4
Handling of Biological Samples ......................................................................53
10.5
Other Supplies..................................................................................................53
11.
ASSESSMENT OF EFFICACY .................................................................................53
11.1
Specifications of Efficacy Variables................................................................54
11.2
Methods and Timing for Assessing, Recording, and Analyzing the
Efficacy Variables............................................................................................54
12.
ASSESSMENT OF SAFETY ......................................................................................54
12.1
Specifications of Safety Variables ...................................................................54
12.2
Methods and Timing for Assessing, Recording, and Analyzing the
Safety Variables ...............................................................................................54
12.3
Adverse Events.................................................................................................54
12.3.1
Definition of Adverse Event (AE) .....................................................54
12.3.2
Procedures for Reporting and Recording Adverse Events.................55
12.3.2.1
Recording/Collection of AEs .....................................55
12.3.2.2
Description of AEs .....................................................55
12.3.3
Follow-up of Adverse Events.............................................................58
12.3.4
Rule for Repetition of an AE .............................................................58
12.3.5
Pregnancy...........................................................................................59
12.3.6
Overdose of Investigational Product..................................................59
12.4
Serious Adverse Events....................................................................................59
12.4.1
Definition of Serious Adverse Event (SAE)......................................59
12.4.2
Procedures for Reporting Serious Adverse Events (SAE).................60
12.4.3
Anticipated Serious Adverse Events..................................................61
13.
STATISTICS.................................................................................................................61
13.1
Statistical and Analytical Plans........................................................................61
13.1.1
Study Population(s)............................................................................61
13.1.2
Study variables...................................................................................62
13.1.2.1
Safety Variables..........................................................62
13.1.2.2
Efficacy Variables ......................................................62
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 9 of 77
13.1.2.3
Pharmacoeconomic Variables ....................................63
13.1.3
Statistical Evaluation..........................................................................64
13.2
Determination of the Sample Size....................................................................65
13.3
Statistical and Analytical Issues.......................................................................65
13.3.1
Handling of Dropouts or Missing Data..............................................65
13.3.2
Interim Analysis and Data Monitoring ..............................................66
13.3.3
Use of an Efficacy Subset of Subjects ...............................................66
13.3.4
Examination of Subgroups.................................................................66
13.4
Criteria for Starting the Analysis .....................................................................66
13.5
Dictionaries ......................................................................................................66
14.
ETHICS.........................................................................................................................67
14.1
Approval...........................................................................................................67
14.2
Subject Information and Consent.....................................................................67
14.2.1
Information.........................................................................................68
14.2.2
Informed Consent...............................................................................68
14.3
Subject Confidentiality.....................................................................................69
14.4
Informing the General Practitioner ..................................................................69
15.
STUDY MANAGEMENT AND ADMINISTRATION ............................................69
15.1
Monitoring........................................................................................................69
15.2
Direct Access to Source Data/Documents .......................................................70
15.3
Audit and Inspection ........................................................................................70
15.4
Case Report Forms (CRF)................................................................................71
15.5
Adherence to Protocol......................................................................................71
15.6
Termination of the Study..................................................................................72
15.7
Investigator Site File ........................................................................................72
15.8
Data Handling and Record Keeping.................................................................73
15.9
Clinical Study Report.......................................................................................73
15.10
Subject Insurance .............................................................................................73
15.11
Archiving and Data Retention..........................................................................73
15.12
Allocation of Responsibilities..........................................................................74
15.13
Curriculum Vitae..............................................................................................74
15.14
Financial Disclosure.........................................................................................74
16.
REFERENCES .............................................................................................................75
17.
SPONSOR DECLARATION ......................................................................................77
List of Tables
Table 4:1
Study Flowchart...........................................................................................18
Table 4:2
Schematic Diagram......................................................................................23
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 10 of 77
3.1
List of Abbreviations
AE
Adverse Event
AED(s)
Antiepileptic Drug(s)
ALAT/SGPT
Alanine Aminotransferase/Serum Glutamic Pyruvic Transaminase
ALP
Alkaline Phosphatase
ASAT/SGOT
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase
AMD(s)
Antimyoclonic Drug(s)
AUC
Area Under the Curve
AUC(o-t)
Area Under the Curve from time 0 to infinity
b.i.d.
Twice Daily
BRV
Brivaracetam
CBZ
Carbamazepine
CBZE
Carbamazepine-10,11-epoxide
CDMS
Clinical Data Management System
cDNA
Copy-deoxyribonucleic Acid
CLB
Clobazam
Cmax
Highest Drug Concentration Observed in Plasma following Administration 
of an Extravascular Dose (= peak plasma level)
CNS
Central Nervous System
CPMP
Committee for Proprietary Medicinal Product
Cr Cl
Creatinine Clearance
CRF
Case Report Form
CRO
Clinical Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CTA
Clinical Trial Application
CTM
Clinical Trial Manager
CV
Curriculum Vitae
CZP
Clonazepam
dl
Deciliter
DRC
Daily Record Card
DTP
Down-titration Phone Call
ECG
Electrocardiogram
ED50
Effective Dose
EDV
Early Discontinuation Visit
EEG
Electroencephalogram
EQ-5D
EuroQol 5 Dimensions Questionnaire
ESM
Ethosuximide
EV
Entry Visit
FBM
Felbamate
FEV
Full Evaluation Visit
FSH
Follicle-stimulating Hormone
GAERS
Genetic Absence Epilepsy Rats from Strasbourg
GBP
Gabapentin
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 11 of 77
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
gamma-glutamyltranspeptidase
GMP
Good Manufacturing Practices
GP
General Practitioner
HADS
Hospital Anxiety and Depression Scale
HIPAA
Health Insurance Portability and Accountability Act Authorization
HRQOL
Health-related Quality of Life
β-hCG
Human Chorionic Gonadotropin
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intention-to-treat
ITT PGS
Intention-to-treat Population for Primary Generalized Epilepsy
ITT POS
Intention-to-treat Population for Localization Related Epilepsy
kg
Kilogram
L
Liter
LBS
Levetiracetam Binding Site
LEV
Levetiracetam
LH
Luteinizing Hormone
LTFU
Long-term Follow-up
LTG
Lamotrigine
M
Month
MAD
Minimum Active Dose
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA®
Medical Dictionary for Regulatory Activities
MEV
Minimal Evaluation Visit
μg
Microgram
mg
Milligram
min
Minute
mL
Milliliter
μM
Micromole
ms
Millisecond
Na
Natrium
NOAEL
No-observed-adverse-effect Level
NOEL
No-observed-effect Level
OC
Oral Contraceptive
OXC
Oxcarbazepine
PB
Phenobarbital
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 12 of 77
PBO
Placebo
PGB
Pregabalin
PGS
Primary Generalized Seizures
PHT
Phenytoin
PK
Pharmacokinetics
POS
Partial Onset Seizures
PP
Per Protocol
PRO
Patient Reported Outcomes
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy Questionnaire
QTc
QT Interval Corrected
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Source Documents or Standard Deviation
SDR
Safety Data Review
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV2A
Synaptic Vesicle Protein 2A
t ½
Half-life
TEAE
Treatment-emergent adverse event
TGB
Tiagabine
TMF
Trial Master File
TPM
Topiramate
UDP-GT
Uridine 5’-diphosphate Glucuronyl Transferase
ULD
Unverricht-Lundborg Disease
V
Visit
VGB
Vigabatrin
VPA
Valproate
W
Week
WBC
White Blood Cell
WHO
World Health Organization
YEV
Yearly Evaluation Visit
ZNS
Zonisamide
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 13 of 77
4.
PROTOCOL SUMMARY
Study Number: N01125
Title of the study: An open-label, multi-center, follow-up trial to evaluate long-term safety 
and efficacy of brivaracetam (ucb 34714) used as adjunctive treatment at a flexible dose up to 
a maximum of 200 mg/day in subjects aged 16 years or older suffering from epilepsy.
Study Objectives
For all subjects:
•
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized 
doses with a maximum of 200 mg/day in subjects suffering from epilepsy
For subjects with partial onset seizures (POS)/primary generalized seizures (PGS):
•
To evaluate the maintenance of efficacy over time of brivaracetam
•
To explore direct medical resource use and indirect cost parameters for the first 2 years
•
To obtain a description of the subject’s self-reported health status for the first 2 years
•
To explore the effects of BRV on the subject’s Health-related Quality of Life, anxiety, 
and depression for the first 2 years
•
To explore any change in the subject’s socio-professional status for the first 2 years
This open-label long-term follow-up (LTFU) study will give subjects suffering from epilepsy, 
for whom the Investigator believes a reasonable benefit from the long-term administration 
may be expected, the opportunity to access adjunctive brivaracetam treatment. Conversion to 
monotherapy is not permitted anymore, however, subjects already on monotherapy are 
allowed to continue BRV monotherapy. The access to the study will be limited to the subjects
having completed a previous brivaracetam study as listed in Section 5.6. 
Methodology:
Multi-center, open-label, single arm study.
The individual starting dose of each subject will be the one recommended at the end of the 
previous study. Dose adjustment of study drug and/or concomitant antiepileptic drugs 
(AEDs) or antimyoclonic drug (AMDs) is allowed at any time during the study if seizure 
control is insufficient, or in case of safety or tolerability issue.
Study Type/Phase:
Therapeutic study/long-term follow-up.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 14 of 77
Diagnosis and Main Criteria for Inclusion:
•
Male/female subjects from 16 years (where legally permitted and ethically accepted) or 
18 years onwards suffering from epilepsy and having completed a previous study with 
brivaracetam as adjunctive treatment, which allowed access to this study.
•
Subjects for whom the Investigator believes a reasonable benefit from long-term 
administration of brivaracetam may be expected.
Study Period (years):
This study will run throughout the duration of the clinical development period of 
brivaracetam, and will continue until a marketing authorization is granted by any Health 
Authority in an indication for the adjunctive treatment in adults with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, until a managed 
access program, named patient program, compassionate use program, or similar type of 
access program is established as allowed per country-specific requirements in addition to 
legal and regulatory guidelines, or until brivaracetam development is stopped by the Sponsor.
Number of Subjects (planned):
500-1000 subjects, based upon the assumption that 90% of subjects having completed a 
previous study with brivaracetam as adjunctive treatment in epilepsy will roll over into the 
present study.
Number of Sites (planned):
As many sites as required and estimated between 150-200 sites.
Countries (planned):
This will be a worldwide protocol.
Investigational Product (dose, mode of administration):
brivaracetam - oral tablets containing 10 mg or 25 mg of brivaracetam.
Reference Product: Not applicable
Study Duration per Subject:
For each subject, the study will last from study entry until either regulatory approval of 
brivaracetam has been granted by any Health Authority in an indication of adjunctive 
treatment of partial onset seizures; or until the Sponsor decides to close the study; 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 the investigational product development is 
stopped by the Sponsor.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 15 of 77
Safety Variables
Note: Assessments specified as performed within the first 2 years of the Evaluation Period 
are not applicable to subjects coming from N01315.
•
Primary safety variables
o
Occurrence of a treatment-emergent adverse event (TEAE)
o
Withdrawal due to adverse event (AE)
o
Occurrence of a serious adverse event (SAE)
•
Other safety variables
o
Laboratory tests (blood chemistry, hematology, urinalysis)
o
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) and body 
weight
o
Electrocardiogram (ECG)
o
Physical and neurological examinations
o
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
Efficacy variables
Note: Assessments specified as performed within the first 2 years of the Evaluation Period 
are not applicable to subjects coming from N01315.
•
Secondary efficacy variables
For subjects with focal-onset epilepsy:
o
Partial onset seizure (type I) frequency per 28 days during the Evaluation Period.
o
Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period.
o
Responder rate for POS (type I) frequency over the Evaluation Period. A responder is 
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline 
Period of the previous study.
No secondary efficacy variables are defined for subjects with generalized epilepsy,
subjects with Unverricht-Lundborg Disease (ULD), or subjects coming from N01315.
•
Other efficacy variables
For subjects with focal-onset epilepsy:
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 16 of 77
o
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period.
For subjects with generalized epilepsy:
o
Generalized (type II) seizure days per 28 days during the Evaluation Period.
o
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of 
the previous study to the Evaluation Period.
o
Responder rate for generalized (type II) seizure days over the Evaluation Period. 
A responder is defined as a subject with a ≥50% reduction in seizure days from the 
Baseline Period of the previous study.
o
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period.
The following will be evaluated separately for subjects with focal-onset epilepsy and 
subjects with generalized epilepsy:
o
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.
o
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.
No other efficacy variables are defined for subjects with ULD or coming from N01315.
Pharmacoeconomic variables
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
•
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
visits) during the first 2 years of the Evaluation Period
•
Indirect costs (work days or school days 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
No pharmacoeconomic variables are defined for subjects with ULD or for subjects coming 
from N01315.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 17 of 77
The periods considered are:
•
Evaluation Period (V1 until the last Evaluation Visit).
•
Down-Titration Period.
•
Post-treatment Period.
Statistical Methods:
All safety and efficacy variables will be analyzed using descriptive statistical methods.
COPY 
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 18 of 77
4.1
Schedule of Assessments
Table 4:1
Study Flowchart
Entry 
Visit 
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit 
(AV)
Early 
Discontinuation 
Visit (EDV)
Down-Titration 
Phone Call 
(DTP)(j)
Drug-free
Period Final 
Visit (FV)
Reference 
to Section
Assessments
Written Informed Consent
X
10.2.1
Clinical Trial Subject Card 
dispensing
X
10.5
Verification incl./excl. criteria
X
8.1/8.2
Demographic data
X
10.2.2
Childbearing potential
X
10.2.3
Medical and procedures history
(X)(a)
10.2.4
Epilepsy history/disease history(h)
(X)(a)
10.2.5
AED/AMD history(h)
(X)(a)
10.2.6
Vital signs
(X)(a)
X
X
X
X
X
10.2.7
Body weight and height(c)
X
X
X
X
X
10.2.8
Physical examination
(X)(a)
X
X
X
X
10.2.9
Neurological examination
(X)(a)
X
X
X
X
10.2.10
ECG(d)
(X)(a)
X
X
X
10.2.11
Daily record card dispense
X
X
X
X
X
10.2.12
Daily record card retrieval
X
X
X
X
X
10.2.12
Recording of seizures
(X)(a)
X
X
X
X
X
10.2.12
QOLIE-31-P(f) (k)
X(i)
M3(e)
X
X
10.2.14
HADS(f) (i) (k)
X
X
X
10.2.15
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 19 of 77
Table 4:1
Study Flowchart
Entry 
Visit 
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit 
(AV)
Early 
Discontinuation 
Visit (EDV)
Down-Titration 
Phone Call 
(DTP)(j)
Drug-free
Period Final 
Visit (FV)
Reference 
to Section
Assessments
Laboratory assessments(g)
(X)(a)
X
X
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X
10.2.16
Recording of Adverse Events
X(b)
X
X
X
X
X
X
X
10.2.17
C-SSRS(l)
X
X
X
X(m)
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X
10.2.18
Medical procedures
X(b)
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X
X
X
X
X
10.2.19
Healthcare provider consultation 
not foreseen by protocol(f)
X
X
X
X
X
10.2.20
Workdays and schooldays lost due 
to inability to perform an usual 
activity and days with caregiver’s 
help (excluding paid work)(f)
X
X
X
X
X
10.2.12
Hospital stay(f)
X
X
X
X
X
10.2.21
EQ-5D Questionnaire(f) (n)
X
X
X
10.2.23
Socio-professional Data(f) (o)
X
X
10.2.24
Concomitant AED/AMD(h)
X(b)
X
X
X
X
X
X
9.2
Concomitant non AED/AMD(h)
X(b)
X
X
X
X
X
X
9.2
Drug dispensing
X
X
X
X
(X)
X
9.1.1
Drug return/accountability
X
X
X
X
X
9.1.6
Down-titration
X
9.1.1.1
End of study status
X(p)
10.2.25
Clinical Trial Patient Card return
X
10.5
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 20 of 77
Table 4:1
Study Flowchart
Entry 
Visit 
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit 
(AV)
Early 
Discontinuation 
Visit (EDV)
Down-Titration 
Phone Call 
(DTP)(j)
Drug-free
Period Final 
Visit (FV)
Reference 
to Section
Assessments
AED=antiepileptic drug; AMD=antimyoclonic drug; AV=Additional Visit; CRF=Case Report Form; C-SSRS=Columbia-Suicide Severity Rating 
Scale; DTP=Down-Titration Phone Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Visit; 
FV=Final Visit; HADS=Hospital Anxiety and Depression Scale; IEC=Independent Ethics Committee; IRB=Institutional Review Board; 
MEV=Minimal Evaluation Visit; QOLIE=Patient Weighted Quality of Life in Epilepsy Questionnaire; ULD=Unverricht-Lundborg disease; 
YEV=Yearly Evaluation Visit
(a)
The following data (in parentheses) will be transferred electronically from the previous study and should not be recorded in the CRF:
From the First Visit: General Medical and Procedure history, epilepsy history, disease history (for ULD subjects only), AED history and 
AMD history (for ULD subjects only).
From the last Evaluation Visit: vital signs, physical and neurological examinations, ECG, recording of seizures, laboratory assessment.
(b)
Ongoing AE, procedures and medications at the end of previous study have to be recopied into the N01125 CRF appropriate sections (except 
subjects from N01315).
(c)
Height will only be recorded at Visit 1 (EV). Height will also be measured at each YEV and FV for subject still in growing period.
(d)
If an ECG has not been performed within the year, an ECG has to be scheduled once a year at the YEV. As well, an ECG shall be performed at 
the EDV and at the FV (if applicable). An ECG is mandatory at FV except if FV follows an EDV where ECG results were normal.
(e)
For subjects coming from study N01114 and for ULD subjects.
(f)
Procedures only performed during the first 2 years of subject participation in the study (eg. till last scheduled visit (YEV-Y3) or EDV/FV in 
case the subject discontinues participation within the first 2 years). 
(g)
Laboratory assessment includes blood chemistry, hematology and urine analysis; where applicable (women with childbearing potential), a urine 
pregnancy test will be done. 
(h)
Disease history, AMD history, concomitant AMD and concomitant nonAMD are collected only for ULD subjects.
(i)
Procedure not to be performed for ULD or N01315 subjects.
(j)
Down-Titration Phone call at the end of the Down-Titration Period is mandatory for all subjects in case the subjects discontinue from more than 
20 mg/day brivaracetam. This phone call will also replace the previous Down-Titration Visit for ULD subjects.
(k)
QOLIE-31-P and HADS (not for ULD and N01315 subjects) are to be completed at the beginning of the visit by all subjects who are not 
mentally impaired. 
(l)
The C-SSRS assessment will be implemented by site per IRB/IEC approval and upon completion of required training. As of the time of Protocol 
Amendment 26, all subjects had completed their EV. Thus, the C-SSRS was not assessed for any subjects at their EV.
(m)
The C-SSRS will be done at the AV in case the AV is conducted for safety and efficacy reasons.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 21 of 77
Table 4:1
Study Flowchart
Entry 
Visit 
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
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Early 
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Down-Titration 
Phone Call 
(DTP)(j)
Drug-free
Period Final 
Visit (FV)
Reference 
to Section
Assessments
(n)
EQ-5D questionnaire is to be completed only by subjects coming from N01252 and N01254, and if not mentally impaired.
(o)
Socio-professional status is to be completed only by subjects coming from N01252 and N01254.
(p)
End of study status will be completed at the FV for subjects having performed an EDV (discontinued subjects) and for subjects leaving the study 
at the end of the program (completed subjects).
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 22 of 77
4.2
Schematic Diagram
For subjects coming from the therapeutic exploratory study (N01114): 
•
First year:
First 6 months: 1 visit/month: 1 Full Evaluation Visit (FEV) alternating with 1 Minimal 
Evaluation Visit (MEV).
Next 6 months: 1 visit/3months: 2 Full Evaluation Visits (at V7 and V8).
•
Second and subsequent years:
1 visit/3months: 1 Full Evaluation Visit alternating with 1 Minimal Evaluation Visit.
Yearly Evaluation Visit (YEV) will be performed in replacement of the first Full 
Evaluation Visit of each year.
For subjects coming from confirmatory studies (N01252 and N01254):
•
First year:
First 3 months: 1 visit/month: Full Evaluation Visit alternating with Minimal
Evaluation Visit
Next 9 months: 1 visit/3 months: Full Evaluation Visit alternating with Minimal 
Evaluation Visit.
•
Second and subsequent years:
1 visit/3 months: Full Evaluation Visit alternating with Minimal Evaluation Visit.
Yearly Evaluation Visit will be performed in replacement of the first Full Evaluation 
Visit of each year.
For subjects coming from ULD confirmatory studies (N01187 and N01236):
•
First year:
First 3 months: 1 visit/month: 1 Full Evaluation Visit alternating with 1 Minimal 
Evaluation Visit.
Next 9 months: 1 visit/3months: Full Evaluation Visit alternately with Minimal 
Evaluation Visit.
•
Second and subsequent years:
1 visit/3months: 1 Full Evaluation Visit alternating with 1 Minimal Evaluation Visit.
Yearly Evaluation Visit will be performed in replacement of the first Full Evaluation 
Visit of each year.
For subjects coming from long-term follow up study N01315:
•
Subjects will perform their Last Visit in N01315 and perform at the same time their First 
Visit in N01125. They will follow the schedule of 1 visit/3 months: 1 Full Evaluation 
Visit alternating with 1 Minimal Evaluation Visit. Yearly Evaluation Visit will be 
performed in replacement of the first Full Evaluation Visit of each year.
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Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 23 of 77
Table 4:2
Schematic Diagram
Subjects coming from Exploratory Studies
(N01114)
Subjects coming from Confirmatory Studies
(N01252, N01254)
Month
Visit
Type of Visit
Month
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Type of Visit
1st year Follow-up
1st year Follow-up
MO
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MO
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M1
V2
MEV
M1
V2
MEV
M2
V3
FEV
M2
V3
FEV
M3
V4
MEV
M3
V4
MEV
M4
V5
FEV
M4
M5
V6
MEV
M5
M6
V7
FEV
M6
V5
FEV
M7
M7
M8
M8
M9
V8
FEV
M9
V6
MEV
M10
M10
M11
M11
2nd and subsequent years Follow-up
2nd and subsequent years Follow-up
M12
V9
YEV
M12
V7
YEV
M15
V10
MEV
M15
V8
MEV
M18
V11
FEV
M18
V9
FEV
M21
V12
MEV
M21
V10
MEV
FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; V=Visit; YEV=Yearly Evaluation 
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 24 of 77
Subjects coming from ULD Confirmatory Studies
(N01187, N01236)
Month
Visit
Type of Visit
1st year Follow-up
M0
V1
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M1
V2
MEV
M2
V3
FEV
M3
V4
MEV
M4
M5
M6
V5
FEV
M7
M8
M9
V6
MEV
M10
M11
2nd and subsequent years Follow-up
M12
V7
YEV
M15
V8
MEV
M18
V9
FEV
M21
V10
MEV
...
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FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; 
M=month; ULD=Unverricht-Lundborg disease; V=Visit; 
YEV=Yearly Evaluation Visit
In case the subject will not continue with the study drug, the Investigator will first plan an 
Early Discontinuation Visit followed by the progressive down-titration of the study drug. 
During the down-titration, dose decrease can be made by steps of a maximum of 50 mg/day 
on a weekly basis. A last down-titration step at 20 mg/day for one 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 20 mg/day. The Down-titration 
Period will be followed by a study drug-free period and subsequently the Final Visit will 
occur.
At the time of study termination by the Sponsor (as defined in Section 7.4), subjects will 
discontinue the study drug following the above described down titration process or will be 
converted without titration to commercial BRV where available, alternatively subjects may 
be initiated without down-titration in a managed access program, named patient program, 
compassionate use program, or similar type of access program as allowed per country-
specific requirements in addition to legal and regulatory guidelines.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 25 of 77
5.
BACKGROUND INFORMATION
5.1
Background and epidemiology of targeted disease
Epilepsy is one of the most common and challenging neurological disorders. It has been 
estimated that over 50 million people are affected worldwide(1, 2, 3, 4). The prevalence of 
epilepsy is around 1%. The annual incidence in developed countries is approximately 
50 to 70 cases per 100,000. In developing countries, the figure is higher due to more limited 
obstetric services and the greater likelihood of cerebral infection and trauma. The incidence 
varies greatly with age, with high rates occurring in childhood, falling to low levels in early 
adult life, but with a second peak in those aged over 65 years. In many people, particularly 
children, the condition may remit, although a significant proportion will have epilepsy 
lifelong. The disease duration is often determined by the underlying cause. Sudden 
unexpected death, a complication of great concern, occurs in 1 to 5 per 1000 patient years, 
particularly if the seizure disorder remains uncontrolled. The treatment for epilepsy remains 
difficult, and there is an ongoing medical need for new antiepileptic drugs (AEDs). For a 
considerable proportion of patients, seizure freedom can still not be reached with currently 
available AEDs(5, 6).
Diagnosis of epilepsy is based on the recurrence of seizures. Seizures may be caused by an 
underlying brain disorder or lesion or due to genetic conditions. Characterization of the 
epileptic syndrome has profound implications for treatment and prognosis. The major 
dichotomy for the diagnosis of epilepsy is the differentiation between focal epilepsies (ie, 
related to a focal brain dysfunction), which are the most frequent and account for 
approximately 60 to 70% of all cases, and generalized epilepsy syndromes, which represent 
approximately 25 to 30% of all epilepsy syndromes. In about 10% of cases, other specific 
syndromes are classified or the classification remains uncertain.
The classification of epileptic syndromes and seizure types is - and always was - a matter of 
ongoing debate. First published in 1960 and last updated officially in 1981 for seizures and 
1989 for epilepsies (Commission on Classification and Terminology of the 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(7) ILAE
[http://www.ilae-epilepsy.org]). The availability of these modern techniques, like long-term 
video electroencephalograms (EEG) and high-resolution magnetic resonance imaging (MRI), 
providing much more precise knowledge in regard to seizure type classifications and epileptic 
syndromes, led some epilepsy groups and scientists towards introducing competing 
classification systems (like the Cleveland Clinic Epilepsy Classification) and even debating 
how useful the currently used ILAE classification system is at all(8). 
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 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 26 of 77
(Classification Task Force) which proposes a thoroughly revised terminology and concept for 
the diagnosis of epilepsy syndromes and also to some extent seizure types(9).
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(10) (Commission on Classification and Terminology of the ILAE, 1981).
Likewise, the classification of epilepsy syndromes will be used according to the 1989 
ILAE-publication(11) (Commission on Classification and Terminology of the ILAE, 1989).
5.2
Background information regarding product
Brivaracetam is a chemical relative of the AED levetiracetam (LEV) (Keppra®). Like LEV, 
brivaracetam displays a high and selective interaction with a novel brain-specific binding site 
SV2A (synaptic vesicle protein 2A). However, the binding affinity of brivaracetam for SV2A 
is approximately 10-fold higher. This binding site appears to be the major target for its 
pharmacological activity. Unlike LEV, 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 brivaracetam absorption is not affected by food. The pharmacokinetics (PK) is 
dose-proportional (at least from 10 mg to 600 mg). Brivaracetam is weakly bound to plasma 
proteins (≤20%). The volume of distribution is 0.5 L/kg, a value that is close to that of total 
body water. The plasma half-life of brivaracetam is approximately 8 hours in young healthy 
male adults. The main metabolic pathway of brivaracetam is by hydrolysis of the acetamide 
group to the corresponding carboxylic acid, while a second pathway is the ω1-hydroxylation 
mediated by 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 brivaracetam. 
Brivaracetam is eliminated primarily by metabolism and by excretion in the urine. More than 
95% of the dose, with less than 9% as unchanged brivaracetam, 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 brivaracetam compared to that in healthy subjects, while the elimination 
of the metabolites was markedly slowed down. A PK study in subjects with hepatic 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
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impairment showed a 50% increase in exposure to brivaracetam associated with decreased 
hydroxylation.
Brivaracetam does not impair the efficacy of oral contraceptives containing 
ethinylestradiol 30 μg and levonorgestrel 150 μg. Brivaracetam does not induce CYP3A4 
using midazolam as a marker probe. Brivaracetam has no interaction on lamotrigine and 
topiramate. Brivaracetam plasma concentration is not increased by gemfibrozil, a selective 
CYP2C8/9 inhibitor but is increased in a nonclinically relevant manner in Japanese subjects 
possessing defective CYP2C19 mutations. Brivaracetam clearance is doubled by rifampicin, 
a potent CYP inducer.
Trough levels of concomitant AEDs were monitored in all efficacy studies. No significant 
change from Baseline nor dose-related trend was observed for the plasma concentrations of: 
carbamazepine, lamotrigine, LEV, oxcarbazepine metabolite, phenobarbital, phenytoin, 
topiramate, valproate, zonisamide. Carbamazepine epoxide was significantly increased from 
Baseline at all brivaracetam doses greater than 20 mg/day, nearly reaching the upper limit of 
normal (3.0 μg/mL) at brivaracetam doses of 100 and 150 mg/day.
5.3
Efficacy with brivaracetam in fixed-dose Phase II/III studies in POS
Following completion of the Phase II studies (N01114(12) and N01193(13)), clinical results 
supported further development of brivaracetam for the adjunctive treatment of POS. Two 
adequate and well-controlled fixed-dose studies (N01252(14) and N01253(15)) were conducted 
to assess brivaracetam across a dose range of 5 to 100 mg/day. 
N01253 assessed brivaracetam doses of 5, 20, and 50 mg/day and provided statistically 
significant and clinically relevant evidence of the efficacy of brivaracetam 50 mg/day. 
N01252 assessed brivaracetam doses of 20, 50, and 100 mg/day. Although N01252 was not 
positive, it provided supporting evidence for the efficacy of brivaracetam 100 mg/day in 
subjects with epilepsy.
5.4
Safety with brivaracetam
In Phase II/III studies, a favorable safety and tolerability profile has been demonstrated for 
brivaracetam. 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.
5.5
Efficacy and safety in subjects with Unverricht-Lundborg disease
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Two Phase III studies (N01187(16) and N01236(17)) were conducted to evaluate the efficacy 
and safety of brivaracetam (5, 50, and 150 mg/day) used as adjunctive treatment in adult 
subjects with genetically ascertained ULD. In both studies, primary efficacy endpoints failed 
to reach statistical significance. In N01187, the most frequently reported TEAEs were 
headache, somnolence, and dizziness. In N01236, the most frequently reported TEAEs were 
headache, myoclonus, and somnolence. There were no deaths or clinically relevant changes 
from Baseline observed for any vital sign parameters. Results indicate that in this population 
of ULD subjects, brivaracetam administered for 16 weeks was well tolerated. 
For additional details on safety and efficacy of BRV, please refer to the Investigator’s 
Brochure(18).
5.6
Study Rationale
The Sponsor wishes to develop brivaracetam as an antiepileptic treatment in subjects 16 years 
and older suffering from epilepsy. This N01125 study will give subjects who have 
participated in a previous brivaracetam adjunctive treatment study in epilepsy, the 
opportunity to access adjunctive brivaracetam treatment under the present protocol.
Conversion to monotherapy is not permitted anymore, however, subjects already on 
monotherapy are allowed to continue BRV monotherapy.
The subjects allowed to enter the study will mainly suffer from partial onset seizure (subjects 
coming from N01114, N01252, N01254(19), and N01315), while a minority will present with 
generalized epilepsy (subjects coming from N01254 and N01315). The study will explore the 
long-term safety and efficacy of brivaracetam in such a population.
It is to be noted that subjects suffering from Unverricht-Lundborg disease (ULD) and having 
participated in a previous UCB brivaracetam study (N01187 or N01236) are also allowed to 
participate in N01125. 
5.6.1
Dose Selection
In this study individualized doses up to a maximum of 200 mg/day will be used. Twice daily 
dosing is deemed necessary to ensure more regular exposure over the 24-hour interval. A 
maximum dose of 200 mg/day was chosen following consultation with regulatory authorities 
and is evaluated in more recent brivaracetam studies (eg, N01358 and N01379). According to 
available data, 200 mg/day doses have been well tolerated.
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Brivaracetam / N01125
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Protocol RPCE03D0801 Integrated Amendment 27
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5.6.2
Subjects Population
5.6.2.1 Minimal Age
Subjects are allowed to participate in this study from the age of 16 where legally permitted 
and ethically accepted. Indeed epilepsy features in the range of 16 to 18 years do not differ 
from the ones of older subjects, and efficacy of AEDs seems to be comparable(20).
Depending on country-specific regulations, those subjects may be considered as adolescents 
or adults(21). 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.
5.6.3
Duration of Treatment
For each subject, the study will run throughout the duration of the clinical development 
period of brivaracetam, and will continue until a marketing authorization is granted by any 
Health Authority in an indication for the adjunctive treatment in adults with refractory POS, 
whether or not secondarily generalized, until the Sponsor decides to close the study, until a 
managed access program, named patient program, compassionate use program, or similar 
type of access program established as allowed per country-specific requirements in addition 
to legal and regulatory guidelines, or until brivaracetam development is stopped by the 
Sponsor.
Statement
The present study will be conducted in accordance with:
•
This protocol.
•
International Conference on Harmonization (ICH): ICH E6 Note for Guidance on Good 
Clinical Practice [CPMP/ICH/135/95](22).
•
The principles that have their origin in the Declaration of Helsinki.
•
Code of Federal Regulations on Good Clinical Practice Title 21 Parts 50, 54, 56, 312, 
and 314.
•
All applicable local laws and regulations.
It is planned that approximately 30 sites enrolling ULD subjects will be involved in the US, 
Canada, Finland, France, Italy, The Netherlands, Sweden, Tunisia, and India. For the sites 
having participated in the previous ULD study N01236, this study will be conducted under 
the Investigational New Drug (IND) regulation in the US, in Finland, Tunisia, and in France.
For the sites having participated in the previous ULD study N01187, this study will not be 
conducted under IND/CTA. This study will not be conducted under the IND for all sites that
enrolled only POS/PGS subjects. For the sites having participated in the study N01315 
conducted under IND regulation, this study will not be conducted under IND/CTA as N01315 
enrolled only POS subjects.  
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 30 of 77
6.
STUDY OBJECTIVES AND PURPOSE
This open long-term follow-up study will give subjects suffering from epilepsy, for whom the 
Investigator believes a reasonable benefit from the long-term administration may be 
expected, the opportunity to access adjunctive brivaracetam treatment. Conversion to 
monotherapy is not permitted anymore, however, subjects already on monotherapy are 
allowed to continue BRV monotherapy. The maximum dose was increased to align with more 
recent LTFU studies. The access to the study will be limited to the subjects having completed 
a previous brivaracetam study as listed in Section 5.6.
6.1
Primary Objective
•
To evaluate the long-term safety and tolerability of brivaracetam at individualized doses 
with a maximum of 200 mg/day in subjects suffering from epilepsy
6.2
Secondary Objective
•
To evaluate the maintenance of efficacy over time of brivaracetam (for POS/PGS 
subjects)
No efficacy objectives are defined for ULD subjects or subjects coming from N01315.
6.3
Exploratory Objectives
Exploratory objectives for POS/PGS subjects:
•
To explore direct medical resource use and indirect cost parameters for the first 2 years
•
To obtain a description of the subject’s self-reported health status for the first 2 years
•
To explore the effects of BRV on the subject’s Health-related Quality of Life, anxiety, 
and depression for the first 2 years
•
To explore any change in the subject’s socio-professional status for the first 2 years
No exploratory objectives are defined for ULD or N01315 subjects.
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 31 of 77
7.
STUDY DESIGN
7.1
Type/Design
This is a therapeutic long-term follow-up, multinational, multi-center, noncomparative, 
open-label and single arm study.
This long-term follow-up study will run throughout the duration of the clinical development 
period of brivaracetam, and will thus include therapeutic exploratory studies in the early stage 
of development as well as therapeutic confirmatory studies, in the later stage of the 
development. For this reason, the study design and in particular the frequency of study visits 
is adapted to the 3 types of study, as described below:
For subjects coming from the therapeutic exploratory study (N01114):
•
First year:
First 6 months: 1 visit/month: 1 FEV alternately with 1 MEV.
Next 6 months: 1 visit/3months: 2 FEV (at V7 and V8).
•
Second and subsequent years: 
1 visit/3months: 1 FEV alternately with 1 MEV.
Yearly Evaluation Visit will be performed in replacement of the first FEV of each year.
For subjects coming from confirmatory studies (N01252 and N01254):
•
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.
Yearly Evaluation Visit will be performed in replacement of the first FEV of each year.
For subjects coming from ULD confirmatory studies (N01187 and N01236):
•
First year:
First 3 months: 1 visit/month: 1 FEV alternating with 1 MEV.
Next 9 months: 1 visit/3months: FEV alternately with MEV.
•
Second and subsequent years:
1 visit/3months: 1 FEV alternating with 1 MEV.
YEV will be performed in replacement of the first FEV of each year.
For subjects coming from long-term follow up study (N01315):
•
Subjects will perform their Last Visit in N01315 and perform at the same time their First 
Visit in N01125. They will follow the schedule of 1 visit/3 months: 1 Full Evaluation 
Visit alternating with 1 Minimal Evaluation Visit. Yearly Evaluation Visit will be 
performed in replacement of the first Full Evaluation Visit of each year.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 32 of 77
7.2
Subjects/Sites Numbers
A 90% switch over rate is estimated as compared to the number of subjects completing the 
previous brivaracetam studies.
Approximately 500-1000 subjects may enter the study.
7.3
Measures to Minimize/Avoid Bias
7.3.1
Randomization
Not applicable.
7.3.2
Blinding
Open-label.
7.4
Study Duration
This study will run throughout the duration of the clinical development period of 
brivaracetam, and will continue until a marketing authorization is granted by any Health 
Authority in an indication for the adjunctive treatment in adults with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, until a managed 
access program, named patient program, compassionate use program, or similar type of 
access program is established as allowed per country-specific requirement in addition to legal 
and regulatory guidelines, or until brivaracetam development is stopped by the Sponsor.
7.5
End of Study
The end of the study is defined as the date of the last visit of the last subject in the study.
8.
SELECTION AND WITHDRAWAL OF SUBJECTS
Before any study procedures are initiated for any subject in this study, an Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) approved written Informed Consent 
Form will be properly executed and documented.
8.1
Subject Inclusion Criteria
•
An IEC/IRB approved written informed consent signed and dated by the subject or 
legally acceptable representative(s). The consent form or a specific assent form will be 
signed and dated by minors, according to country-specific regulations.
•
Male/female subjects from 16 years or older. Subjects under 18 years may only be 
included where legally permitted and ethically accepted.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 33 of 77
•
Subjects with POS/PGS: inpatients or outpatients with epilepsy who participated in 
previous brivaracetam studies / programs which allow access to the present study.
Subjects with ULD: inpatients or outpatients with epilepsy who were treated with 
brivaracetam in previous studies / programs which allow access to the present study.
•
Subjects for whom the Investigator believes a reasonable benefit from the long-term 
administration of brivaracetam may be expected.
•
Female subjects with childbearing potential:
o
POS/PGS subjects: 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 participation (Intra Uterine Device;
diaphragm with spermicide; male or female condom with spermicide; oral hormonal 
contraceptive; non-oral hormonal contraceptive medication; bilateral tubal ligation;
monogamous relationship with vasectomized partner). In particular, oral or depot 
contraceptive treatment with at least 30 μg [or 50 μg if associated with carbamazepine 
(CBZ) or other strong enzyme inducing drugs] 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 according to the judgment of the 
Investigator.
o
ULD subjects: Female ULD subjects without childbearing potential (premenarcheal, 
postmenopausal for at least 2 years, bilateral oophorectomy or tubal ligation, 
complete hysterectomy) are eligible. Female subjects with childbearing potential are 
eligible if they use a medically accepted contraceptive method. Oral or depot 
contraceptive treatment with at least 30 μg [or 50 μg ethinylestradiol per intake if 
associated with carbamazepine (or other strong enzyme inducers e.g. phenobarbital, 
primidone, oxcarbazepine)] must be used in conjunction with a barrier method. 
Monogamous relationship with vasectomized partner or double-barrier contraception 
are acceptable methods. The subject must understand the consequences and potential 
risks of inadequately protected sexual activity, be educated about and understand the 
proper use of contraceptive methods, and undertake to inform the Investigator of any 
potential change in status. 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 (eg, able to understand and complete diaries and questionnaires), visit 
schedule or medication intake according to the judgment of the Investigator.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 34 of 77
8.2
Subject Exclusion Criteria
•
Severe medical, neurological and psychiatric disorders, or laboratory values which may 
have an impact on the safety of the subject.
•
Poor compliance with visit schedule or medication intake in previous brivaracetam study.
•
Participation in any clinical study of another investigational 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 eligibility, he/she should consult the Sponsor’s Clinical Study
Physician or representative for clarification.
8.3
Subject Withdrawal Criteria
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 Early Discontinuation Visit and preferably also the Down-Titration Phone Call 
and Final Visits. 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.
The study medication will be progressively down-titrated until a study drug-free state is 
reached. After a period of free of study medication, the subject will attend the Final Visit.
After decision of subject’s discontinuation, the Investigator will provide the subject with 
information about alternative treatments.
The Sponsor could decide to discontinue or prematurely terminate the study for reasons 
related to safety and/or efficacy of the Investigational Product or, decide to stop the 
development of brivaracetam.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 35 of 77
8.3.1
Withdrawal Criteria
•
Withdrawal for safety reasons by the Investigator.
•
Subject and/or Investigator does not think that the investigational drug is effective.
•
Lost to follow-up.
•
Withdrawal of consent by the subject for any reason, at any time.
•
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 the Entry Visit:
•
Subject has a lifetime history (prior to study entry or since study start) of suicide attempt 
(including an active attempt, interrupted attempt, or aborted attempt) of the “Already 
Enrolled Subjects” version of the C-SSRS. The Investigator must withdraw the subject 
from the study and immediately refer the subject to a Mental Healthcare Professional.
•
Subject had active suicidal ideation prior to study entry or since study start as indicated 
by a positive response (“Yes”) to either Question 4 or Question 5 of the “Already 
Enrolled Subjects” version of the C-SSRS. The Investigator must immediately refer the 
subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the subject from the study.
•
Subject has active suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study.
8.3.2
Subject Replacement Policy
Not applicable.
9.
TREATMENT OF SUBJECT (INVESTIGATIONAL PRODUCTS AND 
CONCOMITANT MEDICATIONS)
9.1
Study Investigational Products
9.1.1
Description of Investigational Products
The investigational product (tablets containing 10 mg or 25 mg of brivaracetam) will be 
supplied under the responsibility of the Sponsor Clinical Trial Supply Department for all 
subjects.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 36 of 77
The frequency at which investigational product will be supplied to each individual center will 
be adapted to the recruitment capacity of that center and to the expiry date of the 
investigational product.
9.1.1.1 Dosing Schedule
Subjects coming from brivaracetam studies have the opportunity to access brivaracetam 
treatment at a flexible dose up to a maximum of 200 mg/day in b.i.d administration. It is 
recommended that the daily dose will be divided into two equal intakes, taken with or without 
food and that the first intake will be in the evening of the day of the dispensation of the 
medication.
The individual starting dose of each subject will be the one recommended at the end of the 
previous study.
At each subject visit, if necessary, the dosage can be adapted:
•
Up-titration can be made by increments of 50 mg/day on a weekly basis and this to a 
maximum of 200 mg/day.
•
Dose decreases can be made by steps of 50 mg/day on a weekly basis. A last 
down-titration step at 20 mg/day for one week will be included prior to the study drug-
free period.
At each visit, the Investigator will evaluate, as closely as possible, the supplies needed by the 
subject in terms of number of containers (200 tablets per container) of each dosage (10 mg or 
25 mg tablets) according to the dose prescribed and the possibility to down-titrate/up-titrate 
by a maximum of 50 mg/day steps. 
In case the subject will not continue with the study drug, the Investigator will plan the 
progressive down-titration of the study drug. The Down-Titration Period will be followed by 
a period free of study drug of minimum two weeks and a maximum of four weeks and 
subsequently the Final Visit will occur.
9.1.2
Packaging
Tablets of brivaracetam (10 mg or 25 mg) will be packaged in containers of 200 tablets. 
Containers of 80 tablets have been removed. On request, the Investigator will be supplied 
with a sufficient number of containers. Each container will have a unique, pre-printed 
identification number.
The Investigator will inform each subject included on how to take the drug and that an excess 
of drug is present in the investigational product container.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 37 of 77
9.1.3
Labeling
Each type of container will be distinguished, per dosage, by colored labels.
The label consists of two 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.
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 label will be adapted to local regulatory requirements and to the size of the 
investigational product package, and translated as appropriate.
Subject number, subject initials, dispensation date and name of Investigator will be added 
manually by the Investigator before dispensing. Dosage instructions will be specified in the 
dispensing card.
9.1.4
Storage Requirements
Investigational product packages should be stored in a secured limited access area and 
maintained at controlled temperature (as specified on the label of the investigational product 
packages). A recording of the 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.
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 package label of study medication.
The Investigator or the hospital pharmacist is responsible for the appropriate storage of 
investigational product packages at the research site.
The Investigator will instruct the subject/legally acceptable representative to store the 
medication at controlled temperature (as specified on the label) in a secure place out of the 
reach of children.
9.1.5
Monitoring of Subject Compliance
Containers of study drug will be supplied to each subject at each Visit. Subjects will be 
instructed to ingest the study drug in the morning and in the evening (approximately 12 hours 
between doses).
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 38 of 77
The Investigator will instruct the subject to bring back at each visit, the original containers 
(even empty) dispensed at the previous visit and containing all the remaining tablets of the 
study medication. Drug reconciliation must be done in the subject’s presence in order to 
obtain explanations regarding discrepancies in compliance with the dosing regime. This 
information will be documented on the drug accountability form (see also Section 9.1.6).
The number of tablets returned must be recorded in the CRF. Compliance with study
medication is defined as investigational product consumption by the subject within 80% -
120% of the prescribed dosage.
9.1.6
Investigational Products Accountability
The Sponsor or its representative will supply a drug accountability form, to be kept 
up-to-date. Study medication disposition records, such as shipping, dispensing and returned 
drug records, inventory logs, must be kept at the site.
Drug accountability form should include at least:
•
Number of tablets dispensed to and returned by each subject, with the subject’s number 
and container number.
•
Initials of the person who actually dispensed and/or received returned study medication.
•
Dates of the above.
•
Explanations for non-compliance.
After completion of the study, all used (including empty bottles) and unused investigational 
product containers must be reconciled and returned (preferably in their original package) to 
the Sponsor, according to a procedure to be defined at the time.
9.1.7
Maintenance of Study Treatment Randomization Codes and Procedures for Blind 
Breaking
Not applicable.
9.2
Concomitant Treatments 
For any treatment other than the investigational product, 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, the date(s) of administration, 
and the indication for use.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 39 of 77
9.2.1
Permitted Concomitant Treatments (Medications and Therapies)
The Investigator may adapt the AED/AMD drug/dosage for safety or efficacy reasons. 
Benzodiazepines taken more than once a week will be considered as AED/AMD.
9.2.2
Not Permitted Concomitant Treatments (Medications and Therapies)
Felbamate and vigabatrin are not permitted for all subjects. Phenytoin is not permitted for
ULD subjects.
10.
STUDY PROCEDURES
Note: Entry Visit procedures for N01315 subjects were already conducted and will not be 
repeated in N01125. Assessments specified as performed within the first 2 years of the 
Evaluation Period are not applicable to subjects coming from N01315.
10.1
Subject Identifier
Each subject will be identified by initials (only letters preferably 4, without spaces or any 
punctuation signs like coma, slash, hyphen, etc.) and subject number. The subject number 
will be different from the previous study in which the subject was participating and it 
includes a newly assigned site number and a sequential enrollment number per site.
At the level of the database, the Master CRF number (from CRFs Yearly Book one) will be 
used as additional identifier to the subject numbers. Subjects coming from N01315 will retain 
their current subject numbers.
10.2
Description of Procedures
For N01315 subjects, ongoing procedures will be transferred electronically from the previous 
study and should not be recorded again in N01125 CRF.
10.2.1
Informed Consent
Before any study-related procedures are performed, an IEC/IRB approved informed consent 
will be properly executed and documented.
For subjects already ongoing in the study, an IEC approved addendum will also be signed 
covering the increased risk of suicidality or suicidal thoughts to comply with the warning 
issued by FDA subsequent to an analysis performed on marketed antiepileptic drugs. 
Although data from brivaracetam studies were not included in FDA's analysis, this risk 
cannot be ruled out because brivaracetam belongs to this class of medications.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 40 of 77
Where legally acceptable, a Partner Pregnancy Consent Form will be issued in case the 
partner of a male subject becomes pregnant (Section 12.3.5). 
10.2.2
Demography
At the first visit, date of birth, gender and racial group will be recorded.
10.2.3
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 a subject’s status change. A pregnancy 
test will be performed as specified in the flow chart (Section 4.1).
10.2.4
General Medical and Procedures History
The General Medical and Procedure History will be transferred electronically from the 
previous study in which the subject was participating.
10.2.5
Epilepsy History/Disease History
The history of epilepsy reported at the first visit of the previous study the subject was 
participating, will be considered as history of epilepsy in this study and will be directly 
electronically transferred from this study.
Similarly, a disease history will be recorded for ULD subjects only.
10.2.6
Antiepileptic/Antimyoclonic Medication History
The AED medication history and the AMD medication history (for ULD subjects) will be 
transferred electronically from first visit of the previous study in which the subject was 
participating. The AED and AMD being used concurrently at the current dose will be 
recorded on the concomitant AED/AMD medication page of the CRF.
10.2.7
Vital Signs
At every visit, after five minutes supine or sitting, pulse rate and blood pressure will be 
obtained, followed by standing pulse rate and blood pressure. At the Entry Visit, vital signs 
will be obtained electronically from the last Evaluation Visit of the previous study and should 
not be recorded in the CRF.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 41 of 77
10.2.8
Body Weight and Height
At Entry Visit, at each Full Evaluation Visit, at each Yearly Evaluation Visit, and at the Final 
Visit, body weight (subject wearing light clothing without shoes and rounded to the nearest 
kilogram) will be obtained. Height will be obtained only at the Entry Visit. For a subject still 
potentially growing, height will also be measured at each Yearly Evaluation visit and Final 
Visit.
10.2.9
Physical Examination
Physical examination will be performed at every Full Evaluation Visit, Yearly Evaluation 
Visit, Early Discontinuation Visit and Final Visit. At the Entry Visit, the physical 
examination will be obtained electronically from the last Evaluation Visit of the previous 
study and should not be recorded in the CRF. The standard physical examination will include 
investigation of skin, eyes, ear, nose, throat, cardiovascular system, respiratory system, 
gastro-intestinal system, musculoskeletal system, endocrine, metabolic and nutritional 
system, blood and blood-forming organs and immune system and optionally genitourinary 
system.
10.2.10 Neurological Examination
At every Full Evaluation Visit, Yearly Evaluation Visit, Early Discontinuation Visit and Final 
Visit a standard neurological examination will be performed, consisting of a brief review of 
cortical functions, cranial nerves, motor function, reflex function, sensory function, gait and 
stance. At the Entry Visit, the neurological examination will be obtained electronically from 
the last Evaluation Visit of the previous study and should not be recorded in the CRF. 
Psychiatric and mental status will be reported by recording the presence or absence of 
psychiatric symptoms, mental impairments and behavioral symptoms.
10.2.11 ECG
Once the subject has signed the updated Informed Consent, the number of standard 12-lead 
ECGs will be reduced to once per year at the following visits: at the Yearly Evaluation Visit, 
Early Discontinuation Visit and at the Final Visit (in case the FV follows an EDV and the 
EDV ECG is normal, no additional ECG has to be performed at FV). At the Entry Visit, 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. 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 42 of 77
10.2.12 Daily Record Card (DRC)
At the Entry Visit, every Full Evaluation Visit, every Minimal Evaluation Visit, Yearly 
Evaluation Visit, and the Early Discontinuation Visit, 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 following information will be recorded on the DRC:
•
Date and the number (where possible) of epileptic seizures 
•
Type of seizure (according to individual description of epileptic seizures) 
•
Occurrence of seizure clusters 
•
All unusual events concerning the subject’s health
•
Changes in concomitant medication (dosage and/or product) 
•
Changes in investigational product (dosage)
A new DRC designed according to these protocol amendment requirements, to reflect the 
update of the assessments and to enhance the subjects’ compliance will be used by all 
subjects from the visit following the IEC/IRB approval and after the subject has signed the 
N01125 Informed Consent.
Due to the nature of their disease, some ULD subjects may be unable or have physical 
difficulty in writing down their answers. These subjects may be helped by asking the 
subject’s legally acceptable representative/care giver/study nurse/study physician to write 
down their answers; the helping person should preferably be the same during the course of 
the study.
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 
epileptic seizures according to the ILAE codes and record the seizure types and frequency on 
the CRF (except for ULD subjects); 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 part of the CRF as well as 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).
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 43 of 77
10.2.13 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 Patient Reported Outcomes will be limited to the first 
2 years after study entry which includes the YEV of year 3. Subjects coming from the 
N01114 will not have to complete the EQ-5D questionnaire and ULD and N01315 subjects 
will not have to complete the EQ-5D questionnaire and the HADS.
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 that 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.
10.2.14 Health Related Quality of Life Questionnaire (QOLIE-31-P)
The QOLIE-31-P(23) will be only completed by subjects coming from studies during which 
Health-related Quality of Life (HRQOL) was a part of the assessment.
The subjects will complete the QOLIE-31-P (Version 2) at Month 3 (for subjects coming 
from N01114 and ULD subjects only), at every Full Evaluation Visit (for POS and PGS
subjects only), at every Yearly Discontinuation Visit for the first 2 years, and at the Early 
Discontinuation Visit if the Early Discontinuation Visit occurs within the first 2 years.
Subjects coming from N01315 will not complete the QOLIE-31-P (Version 2) in this study.
The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument(24) that includes seven 
subscales (seizure worry, overall quality of life, emotional well-being, energy-fatigue, 
cognitive functioning, medication effects, and social function) and the health status item. In 
addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains seven 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 
topic. The questionnaire will be completed by the subject, provided he/she is not mentally 
impaired.
It will be considered as part of the CRF as well as source documentation.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 44 of 77
10.2.15 Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) will be used to evaluate anxiety and 
depression/depressed feelings. The HADS will not be assessed in subjects with ULD or from 
N01315. 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 Full Evaluation Visit and Yearly Evaluation Visit for the first 2 years, and at the Early 
Discontinuation Visit if the Early Discontinuation Visit occurs within the first 2 years.
10.2.16 Laboratory Assessments 
At the following visits: Full Evaluation Visit, Yearly Evaluation Visit, Early Discontinuation 
Visit, and Final Visit, laboratory assessments will be conducted using standard methods at a 
central laboratory. At the Entry Visit, data will be transferred electronically 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 serum pregnancy tests (if the local urine pregnancy test 
was positive) will be provided by fax to the Investigator within 72 hours after sample receipt.
Total blood volume drawn for clinical laboratory assessments will be maximum 
11 mL/sampling. 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 (GGT), and uric acid.
•
The creatinine clearance (Cr Cl) will be calculated by the Cockroft’s formula (only at 
Entry Visit):
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•
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 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 45 of 77
(number, %), monocytes (number, %), neutrophils (number, %), eosinophils (number, %), 
basophils (number, %), other cells (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, haemoglobin casts, 
uric acid crystals, bihydrate calcium oxalate crystals, monohydrate calcium oxalate 
crystals, triple phosphate crystals and bacteria) will be conducted.
•
Where applicable (women with childbearing potential), a local urine pregnancy test 
(human chorionic gonadotropin [β-hCG] levels) will be conducted. In case of a positive 
outcome, a serum pregnancy test will be performed by the central laboratory. If 
pregnancy is suspected at any time during the study, an interim test should be performed.
Plasma samples to analyze brivaracetam and concomitant AED/AMD plasma concentrations 
have been collected up to Protocol Amendment 25, dated 03 Jan 2011, but will no longer be 
obtained.
10.2.17 Adverse Events
At Entry Visit, the Investigator will record all the adverse events that were still ongoing at the 
end of the previous study. From Entry Visit 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 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. 
daily record cards) used in the study.
10.2.18 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 (Section 4.1).
10.2.19 Medical Procedures
At Entry Visit, the Investigator will record all the medical procedures that were still ongoing 
at the end of the previous study. From Entry Visit onwards, collection of data on medical 
procedures (surgery, therapeutic and/or diagnostic, hospitalizations) undertaken during the 
study will be obtained. ECGs required by protocol will not be recorded on the Medical 
Procedures page of the CRF, but on the ECG module.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 46 of 77
10.2.20 Health Care Provider Consultations not Foreseen by the Protocol
From Entry Visit onwards, health care provider consultations not foreseen by the protocol 
will be assessed in the CRF. It includes the type of provider [General practitioner (GP), 
specialist physicians, nurses...], the site of care (office-private, office-hospital, home, 
emergency room) and the reason. Healthcare provider consultations not foreseen by the 
protocol will be assessed at every Full Evaluation Visit, Minimal Evaluation Visit, and 
Yearly Evaluation Visit for the first 2 years, and at the Early Discontinuation Visit and the 
Final Visit if these visits occur within the first 2 years. Health care provider consultations not 
foreseen by the protocol will not be assessed for N01315 subjects.
10.2.21 Hospital Stay
From Entry Visit onwards, the collection of data on hospital stay will be assessed in the CRF.  
It includes the reason of hospitalization, the admission wards, transfers and length of stay.
Hospital stays will be assessed at every Full Evaluation Visit, Minimal Evaluation Visit, and 
Yearly Evaluation Visit for the first 2 years, and at the Early Discontinuation Visit and the 
Final Visit if these visits occur within the first 2 years. Hospital stay will not be assessed for 
N01315 subjects.
10.2.22 Non-Antiepileptic and Antiepileptic Concomitant Medications/Non-Antimyoclonic 
and Antimyoclonic Concomitant Medications
At Entry Visit, the Investigator will record all the non-antiepileptic/non-antimyoclonic and 
antiepileptic/antimyoclonic 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/
non-antimyoclonic concomitant medications must be recorded on the Non-Antiepileptic/
Non-Antimyoclonic Concomitant Medications page of the CRF. In case of intake of 
forbidden concomitant medication (Section 9.2.2) during the study period, the Investigator 
will contact the monitor immediately.
Changes, additions or deletions in the administration of antiepileptic/antimyoclonic
concomitant medications must be recorded on the Antiepileptic/Antimyoclonic Concomitant 
Medications page of the CRF.
Antimyoclonic and non-antimyoclonic medication will only be recorded for ULD subjects.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 47 of 77
10.2.23 EQ-5D Questionnaire
The EQ-5D(25) 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
•
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EQ-5D also captures a self-rating of health status on a 20 cm 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 not be completed by subjects with ULD and by 
subjects coming from N01114 or N01315. The EQ-5D questionnaire will be assessed at every 
Full Evaluation Visit and Yearly Evaluation Visit for the first 2 years, or at the Early 
Discontinuation Visit if the Early Discontinuation Visit occurs within the first 2 years.
10.2.24 Socio-professional Data
Socio-professional data will be collected at the Yearly Evaluation Visit for the first 2 years 
and/or at the Early Discontinuation Visit if the Early Discontinuation Visit occurs within the 
first 2 years in the CRF for subjects coming from N01252 and N01254 only. It collects 
information such as education level, housing status, employment status, need for caregiver 
and driving license.
10.2.25 End of Study
In case the subject will not continue with the study drug, the Investigator will first plan an 
Early Discontinuation Visit followed by the progressive down-titration of the study drug 
dose. Dose decreases can be made by steps of 50 mg/day on a weekly basis. A last 
down-titration step at 20 mg/day for one week will be included prior to the study drug-free
period. At the end of the Down-Titration Period, a Down-Titration Phone Call will occur for
subjects having down-titrated from doses higher than 20 mg/day. The Down-titration Period 
will be followed by a study drug-free period and subsequently the Final Visit will occur.
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 final status (study completion or 
reason for early study termination) will be recorded. It will be specified:
•
Whether the subject completed (participated until the study is stopped) or prematurely 
discontinued the study.
A subject will be considered lost to follow-up following two documented unsuccessful 
attempts to contact the subject by telephone.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 48 of 77
10.3
Study Conduct
Conduct of the visits is described in Flow chart (Section 4.1). Detailed description of 
assessments done during different type of visits is described in this section and in Procedures 
(Section 10.2).
The Entry Visit 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 
entry visit in the present study, the Sponsor’s Clinical study physician or representative 
should be contacted for agreement. The Adverse Events, medical procedures, non-
antiepileptic/non-antimyoclonic and antiepileptic/antimyoclonic 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 Entry Visit.
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 adverse events, etc., should be collected in the source documents and recorded 
in the appropriate section of the CRF.
For subjects coming from therapeutic exploratory studies during the early stage of 
development, visits will be organized on a monthly basis during the first 6 months, afterwards 
subjects’ visits will be scheduled once every three months.
Coming from confirmatory studies at a later stage of the drug development, subjects will 
have monthly clinic visits during the first 3 months, afterwards subjects’ visits will be 
scheduled on a-three-monthly basis (Section 4.2). Subjects coming from N01315 will be 
scheduled on a three-monthly basis.
Note: Procedures performed within the first 2 years are not applicable to subjects coming 
from N01315.
10.3.1
Entry Visit
•
Signing and dating of written informed consent.
•
Dispensation of “clinical trial subject card” (participation in the study).
•
Verification inclusion/exclusion criteria.
•
Demography data: date of birth, gender and racial group.
•
Childbearing potential.
•
Body weight and height.
•
Dispensation of “daily record card”.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 49 of 77
•
Recording of Adverse Events.
•
Medical procedures.
•
Concomitant medications (AED and nonAED) documentation.
•
Concomitant medications (AMD and nonAMD) documentation (for ULD subjects).
•
Dispensation of study medication: subject will receive study medication at Entry Visit 
once all inclusion/exclusion criteria have been met.
•
Appointment for the next visit according to schedule described in Section 4.2.
The following data will be transferred electronically from the first visit of the previous study
and should not be recorded in the CRF:
•
General medical and procedures history.
•
Epilepsy history.
•
Disease history (for ULD subjects).
•
AED history.
•
AMD history (for ULD subjects).
The following data will be transferred electronically from the last Evaluation Visit of the 
previous study and should not be recorded in the CRF:
•
Vital signs including blood pressure, pulse rate.
•
Physical and neurological examinations.
•
ECG.
•
Recording of epileptic seizures.
•
Laboratory assessment includes safety: blood chemistry, hematology and urinalysis. 
Urine pregnancy test (β-hCG levels) for women with childbearing potential.
10.3.2
Full Evaluation Visit
•
Vital signs including blood pressure, pulse rate.
•
Body weight.
•
Physical and neurological examinations.
•
Retrieval of previous and dispensation of new daily record card.
•
Recording of epileptic seizures.
•
Laboratory assessment includes safety: blood chemistry, hematology and urinalysis. 
Urine pregnancy test (β-hCG levels) for women with childbearing potential.
•
Recording of Adverse Events.
•
Assessment of suicidality (C-SSRS).
•
Medical procedures.
•
Concomitant medications (AED and nonAED) documentation.
•
Concomitant medications (AMD and nonAMD) documentation (for ULD subjects only).
•
Drug return/accountability include study medication intake and compliance check.
•
Dispensation of study medication.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 50 of 77
•
Appointment for the next visit according to schedule described in Section 4.2.
The following assessments will be performed during the first 2 years which includes the YEV
in year 3
•
QOLIE-31-P assessment: the questionnaire should be filled in at the beginning of the 
Visit (not for ULD subjects).
•
HADS: the questionnaire should be filled in at the beginning of the Visit, after the 
QOLIE-31-P (not for ULD subjects).
•
Health care provider consultation not foreseen by 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 for subjects coming from N01252 and N01254.
10.3.3
Minimal Evaluation Visit
•
Vital signs including blood pressure, pulse rate.
•
Retrieval of previous and dispensation of new daily record card.
•
Recording of epileptic seizures.
•
QOLIE-31-P assessment: the questionnaire should be filled in at the beginning of the 
Visit at the MEV in Month 3 (for ULD subjects and subjects coming from N01114).
•
Recording of Adverse Events.
•
Assessment of suicidality (C-SSRS).
•
Medical procedures.
•
Health care provider consultation not foreseen by protocol during the first 2 years.
•
Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home during the first 2 years.
•
Hospital stay during the first 2 years.
•
Concomitant medications (AED and nonAED) documentation.
•
Concomitant medications (AMD and nonAMD) documentation (for ULD subjects only).
•
Drug return/accountability include study medication intake and compliance check.
•
Dispensation of study medication.
•
Appointment for the next visit according to schedule described in Section 4.2.
10.3.4
Yearly Evaluation Visit (replaces the FEV of each year)
•
Vital signs including blood pressure, pulse rate.
•
Body weight.
•
Height for subject still in growing period.
•
Physical and neurological examination.
•
ECG.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 51 of 77
•
Retrieval of previous and dispensation of new daily record card.
•
Recording of epileptic seizures.
•
Laboratory assessment includes safety: blood chemistry, hematology and urinalysis. 
Urine pregnancy test (β-hCG levels) for women with childbearing potential.
•
Recording of Adverse Events.
•
Assessment of suicidality (C-SSRS).
•
Medical procedures.
•
Concomitant medications (AED and nonAED) documentation.
•
Concomitant medications (AMD and nonAMD) documentation (for ULD subjects only).
•
Drug return/accountability include study medication intake and compliance check.
•
Dispensation of study medication.
•
Appointment for the next visit according to schedule described in Section 4.2.
The following assessments will be performed during the first 2 years which includes the YEV
in year 3
•
QOLIE-31-P assessment. The questionnaire should be filled in at the beginning of the 
Visit.
•
HADS: the scale should be filled in at the beginning of the Visit (except for ULD 
subjects).
•
Health care provider consultation not foreseen by 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 for subjects coming from N01252 and N01254.
•
Socio-professional data for subjects coming from N01252 and N01254.
10.3.5
Early Discontinuation Visit
•
Vital signs including blood pressure, pulse rate.
•
Body weight.
•
Physical and neurological examination.
•
ECG.
•
Retrieval of previous and dispensation of new daily record card.
•
Recording of epileptic seizures.
•
Laboratory assessment includes safety: blood chemistry, hematology and urinalysis. 
Urine pregnancy test (β-hCG levels) for women with childbearing potential.
•
Recording of Adverse Events.
•
Assessment of suicidality (C-SSRS).
•
Medical procedures.
•
Concomitant medications (AED and nonAED) documentation.
•
Concomitant medications (AMD and nonAMD) documentation (for ULD subjects only).
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 52 of 77
•
Drug return/accountability include study medication intake and compliance check.
•
Dispensation of study medication with down-titration dosing schedule.
•
Appointment for the next visit according to schedule described in Section 4.2.
•
Down-titration.
The following assessments will be performed only if the EDV occurs within the first 2 years.
•
QOLIE-31-P assessment: the questionnaire should be filled in at the beginning of the 
Visit.
•
HADS: the scale should be filled in at the beginning of the Visit (except for 
ULD subjects). 
•
Health care provider consultation not foreseen by 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 for subjects coming from N01252 and N01254. 
•
Socio-professional data for subjects coming from N01252 and N01254.
10.3.6
Down-Titration Phone Call
•
Recording of Adverse Events.
•
Remind appointment for the next visit according to schedule described in Section 4.2.
10.3.7
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, pulse rate.
•
Body weight.
•
Height for subject still in growing period.
•
Physical examination.
•
Neurological examination.
•
ECG (except after an EDV when EDV ECG results were normal).
•
Retrieval of previous daily record card.
•
Recording of epileptic seizures.
•
Laboratory assessment has to be scheduled (except after an EDV when EDV laboratory 
results were normal). Laboratory assessment includes safety: blood chemistry, 
hematology and urinalysis. Urine pregnancy test (β-hCG levels) for women with 
childbearing potential.
•
Recording of Adverse Events.
•
Assessment of suicidality (C-SSRS).
•
Medical procedures.
•
Health care provider consultation not foreseen by protocol during the first 2 years.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 53 of 77
•
Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home during the first 2 years.
•
Hospital stay during the first 2 years.
•
Concomitant medications (AED and nonAED) documentation.
•
Concomitant medications (AMD and nonAMD) documentation (for ULD subjects only).
•
Drug return/accountability including study medication intake and compliance check.
•
End of study status
•
Return of “Clinical Trial Patient Card”.
10.3.8
Additional Visit
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, medical procedures, concomitant AEDs and nonAEDs, concomitant 
AMDs and nonAMDs (for ULD subjects only), 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 Visit is conducted for safety or efficacy reasons, a C-SSRS assessment will 
be performed during this visit. If an Additional Visit is conducted for reasons other than 
safety or efficacy issues (eg, replacement of lost medication, repeated collection of a 
laboratory specimen due to collection or analysis issues), a C-SSRS will not be required at 
this visit.
10.4
Handling of Biological Samples
The safety samples (hematology, biochemistry, urinalysis, pregnancy test) will be routinely 
assayed and the results sent by fax to the Investigators as specified in Section 10.2.16.
Urine samples must be collected under hygienic conditions and transferred by study site staff 
in vacutainer tubes.
10.5
Other Supplies
At Entry Visit (or First Visit for subjects coming from N01315), each subject will receive a 
study card that will mention his/her participation in the study, indicating the name and phone 
number of the Investigator to be contacted in case of emergency and the name of the study
product concerned. Participation in the study will be mentioned in the subject’s clinical 
records.
11.
ASSESSMENT OF EFFICACY
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 54 of 77
11.1
Specifications of Efficacy Variables 
The procedures for obtaining the data of the efficacy variables are found in Section 10.2.
The complete list of variables to be analyzed is found in Section 13.1.2.1.
11.2
Methods and Timing for Assessing, Recording, and Analyzing the Efficacy 
Variables
The methods and timing for assessing and recording the efficacy variables are found in 
Section 4.2 and in Section 10.3.
The analysis methods are found in Section 13.1.3.
12.
ASSESSMENT OF SAFETY
12.1
Specifications of Safety Variables
Safety assessments will be made using adverse events, laboratory tests (including blood and 
urine), electrocardiogram (ECG), physical and neurological examinations, vital signs, and 
body weight.
The procedures for obtaining the data of the safety variables are found in Section 10.2.
The complete list of variables to be analyzed is found in Section 13.1.2.1.
12.2
Methods and Timing for Assessing, Recording, and Analyzing the Safety 
Variables
The methods and timing for assessing and recording the safety variables are found in 
Section 4.2 and in Section 10.3. The analysis methods are found in Section 13.1.3.
12.3
Adverse Events
12.3.1
Definition of Adverse Event (AE)
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and 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 
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 55 of 77
pre- and post-treatment periods required by the protocol, must be reported 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.  In the event subjects terminate study participation after signing 
informed consent but prior to any study procedures being conducted, adverse events will not 
be recorded on the CRFs.
Signs or symptoms of epilepsy 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.
12.3.2
Procedures for Reporting and Recording Adverse Events
12.3.2.1 Recording/Collection of AEs
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.
12.3.2.2 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 
terminology.
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 of AE started.
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A
Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 56 of 77
Pattern:
Intermittent
The AE recurs with the same intensity at various 
intervals throughout the entire time period specified.  
There were intervals within the specified time period 
when the AE was not present.
Continuous:
The AE is present at the same intensity for the entire 
time period specified.  There was no time at which the 
event abated or was not present during the time period 
specified.
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.
Action taken with investigational product:
Not applicable
For AEs occurring during the study drug-free period.
No charge
Investigational product dosing remained the same in 
spite of AE being present. 
Dosage changed
Investigational product dose was increased or 
decreased because of this AE.
Temporarily discontinued
Investigational product was temporarily discontinued 
because of this AE, either because the subject chose to 
discontinue the study drug 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 study drug 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.
Concomitant medication
Drug treatment: the subject took a concomitant 
medication (either prescription or non-prescription) 
specifically for this AE 
OR existing concomitant medication dosage was 
modified as a result of this AE.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 57 of 77
Hospitalization or 
prolongation of 
hospitalization
The subject was hospitalized for this AE or subject’s 
stay in hospital was prolonged because of this AE.
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 (and time) the AE abated.  If the AE consists of 
several signs and symptoms (syndrome), the sign or 
symptom with the longest duration determines the 
duration of the AE.
If the AE is marked “ongoing”, the outcome date 
should be blank.
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.
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 subject’s 
death.
Ongoing
The AE is still present at the last contact with the 
subject.
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.
Possible
equally valid arguments can be considered for or 
against an implication of the investigational product, 
e.g. 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.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 58 of 77
Probable
the relationship is likely, e.g. 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 
reducing the dosage of the investigational product;
•
could not be reasonably explained by the known 
characteristics of the subject’s clinical
Highly probable
there is a strong relationship, e.g.  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 of the AE on repeated exposure 
(rechallenge).
12.3.3
Follow-up of Adverse Events
If an AE is still ongoing at the time the last CRF is being collected, a follow-up report should 
be provided at a later date.
If no follow-up report is being provided, the Investigator must provide a justification.
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplementary measurements and/or evaluations (e.g. rechallenge procedure).
A serious AE or an AE leading to premature discontinuation from the study must always be 
followed up until it has resolved/has a stable level of sequelae or the Investigator no longer 
feels it is clinically significant.
12.3.4
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 being the same as the start date of the repeated AE,
•
the Investigator’s original description of the AE being the same for the first and repeated 
AE, so that they code to the same dictionary term.
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12.3.5
Pregnancy
Should a subject become pregnant during the course of the study, the Clinical Study 
Physician of the Sponsor should be informed immediately and the pregnancy will be 
documented in the AE section of the CRF. The subject should be excluded from the study as 
soon as pregnancy is known (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/AMD, and about the available alternatives, e.g., voluntary 
termination with medical indication.
The progression of the pregnancy and eventual birth must be followed up using the Sponsor’s 
standard Pregnancy & Delivery form in which the Investigator reports on the health of the 
mother and of the offspring.
In cases where the partner of a male subject enrolled 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 Pregnancy Report and Outcome form will be forwarded to the 
subject’s partner for completion.
12.3.6
Overdose of Investigational Product
For this protocol, any daily intake of more than 200 mg/day will be considered as an 
overdose.
Symptoms associated with an overdose must be recorded as AEs.
Overdose without signs or symptoms will be documented in the “Trial Medication Intake” 
section of the CRF.
12.4
Serious Adverse Events
12.4.1
Definition of Serious Adverse Event (SAE)
A Serious Adverse Event is any untoward medical occurrence that at any dose:
•
Results in death.
•
Is life threatening.
•
Requires in-patient hospitalization or prolongation of existing hospitalization.
•
Results in persistent or significant disability/incapacity, or.
•
Is a congenital anomaly/birth defect.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 60 of 77
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 intervention to prevent one 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 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.
Any event reported by the Investigator to the local authorities will follow the same reporting 
procedure as a “Serious Adverse Event”.
Cases involving cancer as an Adverse Event could be reported as serious using the criterion 
“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. This also applies to situation of scheduled elective surgery where no 
AE is present.
12.4.2
Procedures for Reporting Serious Adverse Events (SAE)
If a SAE is reported, the Sponsor or its representative must be informed within 24 hours of 
receipt of this information by the site (see emergency contact information on front page). The 
Investigator must promptly forward to the Sponsor or its representative a duly filled in 
“Investigator SAE report form” provided by the Sponsor, even if the data are incomplete or if 
it is obvious that more data will be needed in order to draw any conclusions.
The SAE report form and the completion guide will be provided by the monitor to the 
Investigator. The SAE report form has to be completed in English.
Additional information (e.g. autopsy or lab reports…) should be provided to the Sponsor in a 
timely fashion to ensure accurate follow-up of each case. 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 SAE report form.
The Sponsor or its representatives will communicate safety information (Suspected 
Unexpected Serious Adverse Reaction – SUSARs) to the appropriate Regulatory Authorities
and all active Investigators, in accordance with applicable regulatory requirements. The 
appropriate IEC/IRB will also be informed by the Investigator or by the Sponsor, as specified 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 61 of 77
by the applicable regulatory requirements in each concerned country. Investigators are to 
provide the Sponsor or its representatives with evidence of such IEC/IRB notification.
A copy of the Investigator SAE report form and the completion guide will be provided by the 
monitor.
If known by the Investigator, Serious Adverse Events up to 30 days after withdrawal of study
medication must be reported to the Sponsor, even if the Investigator is certain that they are in 
no way associated with the study drug. Adverse Events that the Investigator thinks may be 
associated with the study medication must be reported to the Sponsor 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.
12.4.3
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. 
This list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 12.4.2.
13.
STATISTICS
A general description of statistical methods is presented below. Additional detail will be 
described in the Statistical Analysis Plan (SAP). Statistical analyses of data for subjects 
transferring from N01315 will be handled as described in the SAP.
13.1
Statistical and Analytical Plans
13.1.1
Study Population(s)
•
Subpopulations
There are 3 mutually exclusive subpopulations. They are defined based upon enrollment.
1. Partial onset seizure: Subjects enrolled from prior studies N01114, N01252, and subjects 
from N01254 with a diagnosis of POS at N01254 study entry
2. Primary generalized seizure: Subjects enrolled from prior study N01254 with a diagnosis 
of PGS at N01254 study entry
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Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 62 of 77
3. Unverricht-Lundborg disease: Subjects enrolled from prior studies N01187 and N01236
The Efficacy Population will consist of all subjects who took at least 1 dose of study 
medication and have at least 1 seizure diary during the Evaluation Period.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
13.1.2
Study variables
13.1.2.1 Safety Variables
•
Primary safety variables
o
Occurrence of a TEAE
o
Withdrawal due to AE
o
Occurrence of an SAE
•
Other safety variables
o
Laboratory tests (blood chemistry, hematology, urinalysis)
o
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate) and body 
weight
o
ECG
o
Physical and neurological examinations
o
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
13.1.2.2 Efficacy Variables
•
Secondary efficacy variables
For subjects with focal-onset epilepsy:
o
Partial onset seizure (type I) frequency per 28 days during the Evaluation Period.
o
Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period.
o
Responder rate for POS (type I) frequency over the Evaluation Period. A responder is 
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline 
Period of the previous study.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 63 of 77
No secondary efficacy variables are defined for subjects with generalized epilepsy or 
subjects with ULD.
•
Other efficacy variables
For subjects with focal-onset epilepsy:
o
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period.
For subjects with generalized epilepsy:
o
Generalized (type II) seizure days per 28 days during the Evaluation Period.
o
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of 
the previous study to the Evaluation Period.
o
Responder rate for generalized (type II) seizure days over the Evaluation Period. 
A responder is defined as a subject with a ≥50% reduction in seizure days from the 
Baseline Period of the previous study.
o
Percentage of subjects continuously seizure free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period.
The following will be evaluated separately for subjects with focal-onset epilepsy and 
subjects with generalized epilepsy:
o
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.
o
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.
13.1.2.3 Pharmacoeconomic Variables
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
•
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
visits) during the first 2 years of the Evaluation Period
•
Indirect costs (work days or school days lost by the subject and days subject received help 
from a caregiver) during the first 2 years of the Evaluation Period
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 64 of 77
•
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
No pharmacoeconomic variables are defined for subjects with ULD.
13.1.3
Statistical Evaluation
•
General considerations:
Summary statistics will consist of frequency tables for categorical variables and descriptive 
statistics (number of available observations, mean, median, standard deviation, minimum, 
maximum, 25th and 75th percentiles) for continuous variables.
The periods considered are:
•
Evaluation Period (V1 until the last Evaluation Visit).
•
Down-Titration Period.
•
Post-treatment Period.
Efficacy summaries will be created separately for the POS and PGS subpopulations within 
the efficacy population, and safety summaries will be created for the safety population and 
separately for the POS, PGS, and ULD subpopulations within the safety population. 
•
Baseline:
Baseline, whether efficacy or safety, will always refer to the original prior study pretreatment 
Baseline value. Baselines created and validated, as part of the prior study SAPs, will be 
copied and used by this study for all change from Baseline analyses.
•
Study entry/disposition:
Subjects will be sufficiently described to enable a clear understanding of the populations and 
subpopulations and relevant demographics, disease, medical history, current treatment(s), as 
well as disposition. Historical and Baseline data will be copied from the prior study as 
required by the SAP.
•
Seizure efficacy variables:
Analyses will be based upon the Efficacy Population. Summaries will be over the entire 
Evaluation Period and by 3-month periods over the Evaluation Period. The ULD
subpopulation seizure diary data will not be summarized.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 65 of 77
•
QOLIE-31-P and EQ-5D efficacy variables:
Analyses will be based upon the Efficacy Population and summarized by data collection 
scheduled visits and for the last Evaluation Period assessment during the first 2 years. Data 
collected after year 2 are not planned to be summarized. The ULD subpopulation 
QOLIE-31-P and EQ-5D data will not be summarized.
•
Pharmacoeconomic variables:
Analyses will be based upon the Efficacy Population and summarized by 3-month periods. 
Data collected after year 2 are not planned to be summarized. The ULD subpopulation 
pharmacoeconomic data will not be summarized.
•
Safety variables:
Analyses will be based upon the Safety Population. Summary tables will be presented over 
the Evaluation Period by time windows, by periods, and by categories of total duration of 
exposure.
Treatment-emergent adverse events will be summarized by categories of total duration of 
exposure, period, and Medical Dictionary for Regulatory Activities (MedDRA®) Primary 
System Organ Class and Preferred Term in incidence tables. Separate tables will be provided, 
by categories of total duration of exposure, for AEs leading to withdrawal from the study and 
SAEs. 
Laboratory values, vital signs, and weight will be summarized by period and visit. Possibly 
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and 
weight will be listed and summarized by period and visit. Electrocardiogram abnormalities, 
as well as physical and neurological abnormalities, will also be listed by period and visit.
Hospital anxiety and depression scales will be analyzed for the POS/PGS subpopulation only.
13.2
Determination of the Sample Size
No sample size calculation has been made. Sample size will depend upon recruitment into 
and completion of preceding studies; approximately 500-1000 subjects are expected.
13.3
Statistical and Analytical Issues
13.3.1
Handling of Dropouts or Missing Data
Safety and efficacy variables will be analyzed as they are available. Days with missing 
information will be ignored in the calculation of the seizure frequency and seizure days. 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 66 of 77
Since subjects will drop out at different times from the study, results will be presented by 
categories of duration of exposure.
13.3.2
Interim Analysis and Data Monitoring
Due to the single-arm open-label nature of this study, no interim analysis as such will be 
performed. However, interim database snapshots may be performed to allow safety and 
efficacy analyses in support of submission activities or to allow optimization of the 
development program. In addition, an ongoing medical review (Safety Data Review) 
applying to the entire BRV program is organized.
13.3.3
Use of an Efficacy Subset of Subjects
The efficacy population will be a subset of the safety population. The efficacy population will 
be divided into two mutually exclusive groups, the POS and PGS subpopulations. 
Additionally, as needed, the POS and the PGS subjects may be subset into categories that 
group subjects and subject data according to similar BRV exposure times.
13.3.4
Examination of Subgroups
Subgroup analyses, if performed, will be specified in the SAP.
13.4
Criteria for Starting the Analysis
A pre-analysis data review will take place before starting any formal analysis. A pre-analysis 
data review will follow pertinent UCB Standard Operating Procedures.
13.5
Dictionaries
Adverse events and medical and surgical history will be coded according to the MedDRA 
dictionary. Coding of indications of concomitant medication has been stopped during the 
course of the study.
Medications will be coded according to the World Health Organization (WHO) Drug 
dictionary.
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Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 67 of 77
14.
ETHICS 
14.1
Approval
When finalized, the protocol must be signed by the Principal Investigator of the site, the 
Sponsor Clinical Study Physician, the Sponsor Clinical Program Director, the Sponsor 
Statistician, and the Sponsor Clinical Trial Manager (CTM). The final version must be 
submitted to and approved by:
•
a duly constituted IEC/IRB.
•
the relevant 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, the Clinical Study Physician, the Clinical 
Program Director, the Statistician, the CTM, and the Sponsor approval committee(s) and this 
before further submission to the requesting body.
A copy of the written IEC/IRB 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 CTM. In addition, for the sites under IND:
The usual composition of the IEC/IRB (or DHHS number) along with an IEC/IRB statement 
of compliance should also be forwarded to the CTM. 
The study is not allowed to start until the protocol and related documents (Subject 
Information Sheet/Informed Consent, advertisements if any, …) have received written 
approval/favorable opinion from the IEC and Regulatory Authorities, wherever required as 
well as until other GCP prerequisites are fulfilled.
If relevant new information becomes available, it should be communicated without delay to 
the subject, the Investigator, the IEC/IRB and the Regulatory authorities wherever required.
14.2
Subject Information and Consent
Adequate information will be provided to the subject and parent(s) or legal representative, if 
applicable, in both oral and written form and consent will be obtained in writing prior to the 
performance of any study specific procedure. The content and process of obtaining informed 
consent will be in accordance with all applicable regulatory requirements.
The Sponsor may provide a sample Informed Consent Form/subject information sheet.  The 
final form must be agreed by the IEC/IRB and must contain all ICH-GCP (4.8.10) elements 
in a language readily understood by the subject.
The original Informed Consent Form can be amended as appropriate. If the Informed Consent 
Form is amended during the study, the Investigator (or the Sponsor, if applicable) must 
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 68 of 77
follow all applicable regulatory requirements pertaining to the approval of the amended 
Informed Consent Form by the IRB/IEC and use of the amended form.
All studies conducted at centers in the United States must include the use of a Health 
Insurance Portability and Accountability Act Authorization form.
14.2.1
Information
The Investigator, or a person designated by the Investigator, should fully inform the subject 
or, if the subject is unable to provide informed consent, the parent(s) or legal representative, 
of all pertinent aspects of the study, including the fact that the protocol has been granted, the 
approval of the IEC/IRB and local regulatory authorities if required.
The subject will be informed of the nature of the study in an unambiguous, easily 
understandable language. The subject’s participation is voluntary. The subject can at any time 
withdraw consent without any influence on future care or treatment. The subject must be 
informed about the main procedures used to guarantee anonymity, especially during the 
analysis of personal data. The subject should be able to ask all the questions about the study
and to receive relevant answers. The subject will receive complete written information in the 
“Subject Information Sheet”.
14.2.2
Informed Consent
After having received extensive information about the nature, significance, implementation 
and risks of the study and having had enough time to consider, the subject must give his/her 
written consent by signing and dating the Informed Consent Form. For minors, the informed 
consent must be signed by the parent(s) or legal representative, in accordance with local 
regulations. The consent form or a specific assent form, where required, will be signed and 
dated by minors. For mentally retarded subjects, the Informed Consent Form must be signed 
by the legal representative.
If the signature of a witness is required, the witness should sign and personally date the 
consent form after the subject 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 that informed consent was freely 
given by the subject.
This form will also be dated and signed 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 chart and in the CRF.
Two copies of the Informed Consent Form will be signed. The subject will receive one and 
the other will be filed in the Investigator’s Site File.
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Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 69 of 77
The subject may withdraw his/her consent to his/her participation in the study at any time.
A subject is considered as enrolled in the study when he/she has signed the Informed Consent 
Form. A CRF must not be started, nor may any study specific procedure be performed for a 
given subject, without having obtained his/her written consent to participate in the study.
If any relevant new information that could influence the subject’s decision to stay in the study
becomes available, this will be transmitted without delay to the subject and the Investigator.
The Investigator will keep up to date a Subject Identification List, i.e. a log of all subjects 
having entered the study by signing an Informed Consent Form. This log is to be filed in the 
Investigator Site File.
14.3
Subject Confidentiality
Subject confidentiality will be maintained at all times.
Personnel from the Sponsor, from the CRO, from Regulatory Authorities, independent 
auditors and members of IEC/IRB are obliged to respect medical secrecy and to refrain from 
divulging the subject's identity or any other personal information they might fortuitously be 
aware of. Medical records will be handled by professional standards and existing local laws.
14.4
Informing the General Practitioner
If the subject agrees, the Investigator will inform the subject’s regular physician of his/her 
participation in the study.
15.
STUDY MANAGEMENT AND ADMINISTRATION
15.1
Monitoring
The monitoring of the study is the responsibility of the Sponsor. The monitor (the individual 
responsible for monitoring) will help the Investigator with the practical conduct of the study
and assist him/her in working according to the protocol, Good Clinical Practice (GCP), and 
the regulatory requirements.
The Investigator will allow the Sponsor or its representatives to periodically monitor at 
mutually convenient times during and after the study, all CRFs and the corresponding 
portions of source documents (e.g. office, hospital, and laboratory records for each study
participant). Therefore, the monitor will have direct access to these records. The monitoring 
visits provide the Sponsor or its representatives with the opportunity to evaluate the progress 
of the study, to verify the accuracy and completeness of CRFs, to ensure that all protocol 
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 70 of 77
requirements, applicable local Authority regulations and Investigator's obligations are being 
fulfilled, and to 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 the Sponsor, IEC/IRB review, and regulatory inspection(s), providing direct access to 
source data/documents.
Source documents (SD) are original records in which raw data are first recorded. These may 
be: hospital/clinic/general practitioner (GP) records, charts, diaries, x-rays, laboratory results, 
printouts, ECG tracing and reports and EEG tracing and reports, pharmacy records, care 
records, etc.
Original laboratory results, ECG tracing and reports, DRC, PRO booklets, etc. will be 
inserted in the CRF and are also to be considered as source data.
All source documents must be, accurate, clear, unambiguous, permanent and capable of being 
audited. They should be made using a permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correcting fluid or have temporary attachments 
(such as "post-it" notes).
Source documents that are computer generated and stored on magnetic support media must 
be printed. The Investigator will sign and date the print-out and the monitor will counter-sign 
these print outs after monitoring. The Investigator will authorize the monitor to compare the 
content of the print-out and the data stored in the computer to ensure all data are consistent.
The minimum requirements for source data in the medical records used in clinical studies are 
that they should contain: the identity of the subject and a study related identifiers (such as 
treatment number, CRF number or similar), a note of the subject's participation in the study
and identification of that study (protocol/study title or number), the date of obtaining signed 
informed consent, the subject's medical history, the treatments that the subject received, AEs 
and SAEs and the dates of the visits. The source documents should also provide evidence that 
inclusion/exclusion criteria were evaluated and met. Information recorded in the CRF must 
be consistent with entries in the source document. The monitor will verify 100% of the source 
documents against the CRFs.
15.3
Audit and Inspection
The Investigator will permit study-related audits by auditors mandated by the Sponsor, 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, and that all data relevant for the evaluation of the 
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 71 of 77
investigational product have been processed and reported in compliance with the planned 
arrangements, GCP and applicable regulatory requirements. The Investigator will provide 
direct access to all study documents, source records and source data. If an inspection by 
Health Authorities is announced, the Investigator will immediately inform the Sponsor.
15.4
Case Report Forms (CRF)
Data reflecting participant experience with the drugs under investigation will be reported to 
the Sponsor. These data will be recorded on the CRF. The CRF is essentially a data entry 
form and may not routinely constitute the original (or source) medical record.
The CRF will be organized in Yearly Books and general section workbooks. CRFs will be 
signed and dated by the Principal Investigator as indicated.
The CRF will be adapted to reflect the changes in the study assessments. It will be used after 
the approval of the Ethics Committee and after the subjects have signed the new Informed 
Consent Form.
The Principal Investigator’s signature on the CRF attests to its accuracy and completeness. 
The CRFs will be completed in black ink, and must be legible.
Data reported in the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained in these source documents.
The Investigator must submit to the Sponsor or its representatives a completed CRF for each 
participant exposed to the investigational product.
All supportive documentation submitted to the Sponsor in addition to the CRF, such as 
laboratory 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.
15.5
Adherence to Protocol
The Investigator/Institution should conduct the study in compliance with the protocol agreed 
to by the Sponsor and, if required, by the Regulatory Authority(ies) and for which an 
approval/favorable opinion by the IEC/IRB was given. The Investigator/Institution and the 
Sponsor should sign the protocol to confirm agreement.
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 
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 72 of 77
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 in or deviations from the protocol will ONLY be made as an amendment 
to the protocol and must be approved by the Sponsor and the IEC/IRB prior to being 
implemented. Unless the Sponsor has consented to any such deviations or changes in writing, 
they cannot be implemented and the Sponsor will not assume any resulting responsibility or 
liability for implementation of unapproved deviations or change.
Any significant protocol deviation will be documented and explained by the Investigator or 
the person designated by the Investigator and will be included in the final Study Report.
15.6
Termination of the Study
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator, as appropriate:
•
Return of all study data to the Sponsor or its representative.
•
Data clarification and/or resolution.
•
Accountability, reconciliation and arrangements for used and unused study drugs.
•
Review of site study records for completeness.
•
Discussion/reminder on archiving responsibilities.
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue 
this study either at a single site or at all sites at any time for reasons including, but not limited 
to, safety or ethical issues, severe non-compliance, recurrent non-compliance, with respect to 
quality or quantity.
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators/Institutions, and the regulatory authority(s) of the termination or suspension and 
the reason(s) for the termination or suspension.  The IEC/IRB should also be informed 
promptly and provided with the 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 all unused study drugs in accordance with the 
Sponsor procedures for the study.
15.7
Investigator Site File
The content of the Investigator file is structured in a manner that aids in the filing, retrieval, 
and/or auditing of study-related documents. All documents will be filed according to 
Standard File Categories that identify specific aspects of the study.
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 73 of 77
15.8
Data Handling and Record Keeping
The Sponsor will be responsible for data processing.
CRF data will be entered in an electronic database using a clinical data management system 
(CDMS). Computerized data cleaning checks will be used in addition to manual review to 
check for discrepancies and to ensure consistency of the data. An electronic audit trail system 
will be used to track all data changes in the database subsequent to the reconciliation of the 
interactive double data entry. The SAS system will be used for the statistical analysis of the 
data. Regular back-ups of the electronic data will be carried out.
15.9
Clinical Study Report
A clinical study report, conforming to the relevant ICH guidelines, will be prepared by the 
Sponsor. The report will include a thorough description of the clinical and laboratory 
methods, a discussion of the results and a list of all measurements.
This report may be included in submissions to government Drug Regulatory Authorities 
world-wide, or used for whatever reason considered appropriate by the Sponsor. No use 
should be made of the report before approval by the Sponsor.
The coordinating Investigator (designated by the Sponsor) will sign the report and will have 
an opportunity to comment on the draft version. He/she must give his/her comments within 
seven (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
Subject Insurance
The Sponsor declares that it has taken out an insurance, for the total duration of the study, 
covering the subjects (and for US sites only: Investigators, employees or co-workers of 
Investigators assisting with the study), in respect of the risks involved in this study according 
to this protocol. In case of injury or disability deriving from participation in the study, the 
subject is requested to inform without delay the treating physician responsible for the study.
15.11
Archiving and Data Retention
The Investigator will maintain adequate records for the study including CRFs, medical 
records, laboratory reports, informed consent documents, drug disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data.
All records 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 
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CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 74 of 77
should be retained for a longer period however if required by the applicable regulatory 
requirement(s) or by an agreement with the Sponsor (ICH-GCP Guideline-Section 4.9.5). The 
Investigator will contact the Sponsor 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 the Sponsor should he/she relocate or move the study related files 
to a location other than that specified in the Sponsor’s Trial 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. He/she remains responsible for coordinating and informing his/her staff 
about the protocol and the possible changes made to it.
The Investigator should maintain a list of appropriately qualified persons to whom he/she has 
delegated significant study-related duties ("authorized signatures" document with name, 
function, signature, initials, dates of participation in the study and type of delegated tasks). 
This list should be kept up to date.
15.13
Curriculum Vitae
The Investigators should supply their updated curriculum vitae (CV) (English translation),
dated and signed, together with a list of their collaborators responsible for the practical 
conduct of the study. These collaborators should also provide a recent English version of 
their CV, dated and signed.
In addition, for ULD sites under IND, a signed and dated FDA Form 1572 (Qualified 
Investigator Undertaking and Clinical Trial Site Information forms in Canada) and recent 
(updated every 2 years) CV (in English) are required from each Investigator showing a 
current affiliation with the research center.
15.14
Financial Disclosure
A financial disclosure statement must be obtained from each clinical site for every 
Investigator and co-Investigator participating in the study. This must be collected before 
subject enrollment. They must inform the Sponsor if information related to financial 
disclosure changes during the course of the study and/or after study completion/end of study.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 75 of 77
16.
REFERENCES
1.
Engel J, Pedley TA. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-
Raven; 1998.
2.
Sander JW, Shorvon S. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry.
1996;61:433-43.
3.
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures
in Rochester, Minnesota: 1935-1948. Epilepsia. 1993; 34:453-68.
4.
Loiseau J, Loiseau P, Guvot M, Duche B, Dartigues JF, Aublet B. Survey of seizures 
disorders in the French southwest. Incidence of Epileptic Syndromes. Epilepsia 
1990;31:391-6.
5.
Nasreddine W, Beydoun A, Atweh S, Abou-Khalil B. Emerging drugs for partial onset 
seizures. Expert Opin Emerg Drugs. 2010;15:415-31. 
6.
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 
2001;42:1255-60.
7.
Engel J. Report of the ILAE classification core group. Epilepsia. 2006;47:1558-68.
8.
Lüders HO, Acharya J, Alexopoulos A, Baumgartner C, Bautista J, Burgess R, et al. 
Are epilepsy classifications based on epileptic syndromes and seizures types outdated? 
Epileptic Disord. 2006;8:81-5.
9.
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.
10.
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.
11.
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.
12.
A multicenter, double-blind, randomized, placebo-controlled, 3 parallel groups, 
dose-ranging trial evaluating the efficacy and safety of ucb 34714 used as adjunctive 
treatment at doses of 50 and 150 mg/day in b.i.d. administration (oral capsules of 25 
mg) for a maximum of 12 weeks in subjects from 16 to 65 years with refractory 
epilepsy suffering from partial onset seizures whether or not secondarily generalized. 
UCB study number N01114. UCB protocol reference code RPCE02K0301.
13.
A multicenter, double-blind, randomized, placebo-controlled, 4 parallel groups, 
dose-ranging trial evaluating the efficacy and safety of brivaracetam used as adjunctive 
treatment at doses of 5, 20 and 50 mg/day in b.i.d. administration (oral tablets of 2.5 or 
10 mg) for a maximum of 7 weeks in subjects from 16 to 65 years with refractory 
epilepsy suffering from partial onset seizures whether or not secondarily generalized. 
UCB study number N01193. UCB protocol reference code RPCE05C2201.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 76 of 77
14.
A multi-center, double-blind, parallel-group, placebo-controlled, randomized study: 
evaluation of the efficacy and safety of brivaracetam in subjects (≥ 16 to 70 years old) 
with Partial Onset Seizures. UCB study number N01252. UCB protocol reference code 
RPCE06G0704.
15.
An international, double-blind, parallel-group, placebo-controlled, randomized study: 
evaluation of the efficacy and safety of brivaracetam in subjects (≥ 16 to 70 years old) 
with Partial Onset Seizures UCB study number N01253. UCB protocol reference code 
RPCE06G0705.
16.
A multicenter, randomized, double-blind, placebo-controlled, parallel study to evaluate 
the efficacy and safety of brivaracetam used as adjunctive treatment for 12 weeks in 
adolescent and adult patients (≥16 years) with genetically ascertained 
Unverricht-Lundborg disease. UCB study number N01187. UCB protocol reference 
code RPCE06C2321.
17.
A multicenter, randomized, double-blind, placebo-controlled, parallel study to evaluate 
the efficacy and safety of brivaracetam used as adjunctive treatment for 12 weeks in 
adolescent and adult patients (≥16 years) with genetically ascertained 
Unverricht-Lundborg disease. UCB study number N01236. UCB protocol reference 
code RPCE06C2320.
18.
UCB Investigator’s brochure: brivaracetam. UCB reference code RXCE06E2216. 
2010.
19.
An international, randomized, double-blind, parallel-group, placebo-controlled, flexible 
dose study: evaluation of the safety and efficacy of brivaracetam in subjects (≥ 16 to 
70 years old) suffering from localization-related or generalized epilepsy. UCB study 
number N01254. UCB protocol reference code RPCE06G0706.
20.
EMEA. Note for guidance on clinical investigation of medicinal products in the 
treatment of epileptic disorders. CPMP/EWP/566/98 rev 1, 16-Nov-2000.
21.
EMEA. Note for guidance on clinical investigation of medicinal products in the 
paediatric population. CPMP/ICH/2711/99, 27-Jul-2000.
22.
CPMP/ICH/135/95 Note for guidance on good clinical practice (EMEA). Jul 2002.
23.
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.
24.
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;39:81-9.
25.
EuroQol Group. EQ-5D. A measure of health-related quality of life developed by the 
EuroQol group. User guide. 8th issue. April 2000.
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Brivaracetam / N01125
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 77 of 77
17.
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 
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