Conditions: Epilepsy
Keywords: Brivaracetam Epilepsy long term
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 853
Healthy volunteers: no

Brief summary:
This trial, evaluating the long-term safety and tolerability of brivaracetam, will give subjects suffering from epilepsy, who may have benefited from brivaracetam, the opportunity to continue the treatment. The study will also evaluate the maintenance of efficacy over time of brivaracetam for subjects with partial onset seizures (POS)/primary generalized seizures (PGS).

Detailed description:

Arms:
arm 1: Flexible dosing, can up and down titrate as needed.

Interventions: intervention 1: Brivaracetam (ucb 34714)
Intervention descriptions: intervention 1: 10 mg and 25 mg tablets. Flexible dosing up to 200 mg/day, twice daily. 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.

Protocol document:
Prot_000.pdf: 
A
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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A
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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A
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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A
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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A
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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A
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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Protocol RPCE03D0801 Integrated Amendment 27
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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
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Protocol RPCE03D0801 Integrated Amendment 27
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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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A
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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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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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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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
X
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)
X
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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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 
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Yearly 
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Additional 
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Early 
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Reference 
to Section
Assessments
(n)
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(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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Brivaracetam / N01125
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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Brivaracetam / N01125
CONFIDENTIAL
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
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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
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M3
V4
MEV
M3
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MEV
M4
V5
FEV
M4
M5
V6
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M5
M6
V7
FEV
M6
V5
FEV
M7
M7
M8
M8
M9
V8
FEV
M9
V6
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M10
M10
M11
M11
2nd and subsequent years Follow-up
2nd and subsequent years Follow-up
M12
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YEV
M15
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MEV
M15
V8
MEV
M18
V11
FEV
M18
V9
FEV
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M21
V10
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FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; V=Visit; YEV=Yearly Evaluation 
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Brivaracetam / N01125
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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Brivaracetam / N01125
CONFIDENTIAL
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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
CONFIDENTIAL
Protocol RPCE03D0801 Integrated Amendment 27
12 Mar 2015 / Page 29 of 77
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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Brivaracetam / N01125
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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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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A
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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A
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):
o
male: Cr Cl mL/min= [(140-age) x body weight] / (72 x serum creatinine (mg/dl)),
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female: Cr Cl mL/min= [(140-age) x body weight] / (72 x serum creatinine (mg/dl))] 
x 0.85.
•
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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A
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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A
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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•
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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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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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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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Protocol RPCE03D0801 Integrated Amendment 27
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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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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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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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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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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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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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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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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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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
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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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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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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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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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Protocol RPCE03D0801 Integrated Amendment 27
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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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SAP_001.pdf: 
UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 1 of 50 
 
STATISTICAL ANALYSIS PLAN 
Study: N01125 
Product: Brivaracetam 
An open-label, multi-center, follow-up trial to evaluate the long-term safety and efficacy of 
brivaracetam (ucb 34714) used as adjunctive treatment at a flexible dose up to a maximum of 
200mg/day in subjects aged 16 years or older suffering from epilepsy 
 
SAP/Amendment Number 
Date 
Final SAP 
SAP Amendment 1 
27 January 2014 
11 February 2019 
Confidentiality Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB.  
 
 
REDACTED COPY 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 2 of 50 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 6 
1 
INTRODUCTION ....................................................................................................... 8 
2 
PROTOCOL SUMMARY ........................................................................................... 8 
2.1 
Study objectives ................................................................................................. 8 
2.1.1 
Primary objective ..................................................................................... 8 
2.1.2 
Secondary objectives ............................................................................... 8 
2.1.3 
Exploratory objectives ............................................................................. 8 
2.2 
Study variables ................................................................................................... 8 
2.2.1 
Safety variables ........................................................................................ 8 
2.2.1.1 
Primary safety variables ................................................................. 8 
2.2.1.2 
Other safety variables..................................................................... 9 
2.2.2 
Efficacy variables .................................................................................... 9 
2.2.2.1 
Secondary efficacy variables ......................................................... 9 
2.2.2.2 
Other efficacy variables ................................................................. 9 
2.2.3 
Pharmacoeconomic variables ................................................................ 10 
2.3 
Study Design and Conduct............................................................................... 10 
2.4 
Determination of Sample Size ......................................................................... 14 
3 
DATA ANALYSIS CONSIDERATIONS ................................................................ 14 
3.1 
General presentation of summaries and analyses ............................................ 14 
3.2 
Analysis time points ......................................................................................... 14 
3.2.1 
First and last dose of BRV ..................................................................... 14 
3.2.2 
Relative day ........................................................................................... 14 
3.2.3 
Summaries at Study Entry ..................................................................... 15 
3.2.4 
Study periods ......................................................................................... 16 
3.2.5 
Monthly time intervals ........................................................................... 17 
3.2.6 
Last Value on BRV Treatment .............................................................. 17 
3.2.7 
Exposure duration and exposure duration cohorts ................................. 18 
3.2.8 
Study visit cohorts ................................................................................. 18 
3.3 
Definition of Baseline Values .......................................................................... 18 
3.4 
Protocol deviations........................................................................................... 18 
3.5 
Analysis Sets .................................................................................................... 19 
3.5.1 
Safety Analysis Set ................................................................................ 19 
3.5.2 
Efficacy Analysis Sets ........................................................................... 19 
3.6 
Treatment Assignment and Treatment Groups ................................................ 19 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 3 of 50 
 
3.7 
Coding dictionaries .......................................................................................... 19 
3.8 
Definitions of study-specific derived variables ............................................... 20 
3.8.1 
Calculation of seizure frequency/days ................................................... 20 
3.8.1.1 
Initial seizure data processing ...................................................... 20 
3.8.1.2 
Calculation of adjusted seizure frequency ................................... 20 
3.8.1.3 
Calculation of adjusted seizure days ............................................ 20 
3.8.2 
QOLIE-31-P ........................................................................................... 21 
3.8.3 
HADS ..................................................................................................... 22 
3.9 
Subject site transfers ........................................................................................ 22 
4 
STATISTICAL/ANALYTICAL ISSUES ................................................................. 22 
4.1 
Adjustments for covariates .............................................................................. 22 
4.2 
Handling of dropouts or missing data .............................................................. 22 
4.3 
Interim analyses and data monitoring .............................................................. 23 
4.4 
Multicenter studies ........................................................................................... 23 
4.5 
Multiple comparisons/multiplicity ................................................................... 23 
4.6 
Use of an “Efficacy Subset” of subjects .......................................................... 23 
4.7 
Active-control studies intended to show equivalence ...................................... 23 
4.8 
Examination of subgroups ............................................................................... 23 
5 
STUDY POPULATION CHARACTERISTICS ....................................................... 24 
5.1 
Subject disposition ........................................................................................... 24 
5.2 
Protocol Deviations .......................................................................................... 25 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .................. 26 
6.1 
Demographics .................................................................................................. 26 
6.2 
Medical and procedure history......................................................................... 27 
6.2.1 
Medical history diseases ........................................................................ 27 
6.2.2 
Procedure history and concomitant procedures ..................................... 27 
6.3 
History of epilepsy ........................................................................................... 27 
6.3.1 
Etiology of epilepsy ............................................................................... 27 
6.3.2 
Epileptic seizure profile ......................................................................... 27 
6.3.3 
Classification of epileptic syndrome ...................................................... 27 
6.3.4 
Focus localization .................................................................................. 27 
6.3.5 
History of epileptic seizures .................................................................. 28 
6.3.6 
Seizure types experienced during baseline of the previous study ......... 28 
6.4 
Medications ...................................................................................................... 28 
6.4.1 
Non-AEDs taken at study entry ............................................................. 29 
6.4.2 
Number of previous AEDs .................................................................... 29 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 4 of 50 
 
6.4.3 
History of previous AED use ................................................................. 29 
6.4.4 
AEDs taken at study entry ..................................................................... 29 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ......................................... 29 
8 
EFFICACY ANALYSES .......................................................................................... 29 
8.1 
Statistical analyses of secondary efficacy variables ........................................ 29 
8.1.1 
Partial onset seizure frequency .............................................................. 30 
8.1.2 
Percent reduction in POS frequency ...................................................... 30 
8.1.3 
Responder outcome for POS frequency ................................................. 30 
8.2 
Analysis of other efficacy variables ................................................................. 30 
8.2.1 
Subjects with partial onset seizures ....................................................... 30 
8.2.1.1 
Specified Month seizure freedom ................................................ 31 
8.2.2 
Subjects with Primary Generalized Seizures ......................................... 31 
8.2.2.1 
All type seizure days .................................................................... 31 
8.2.2.2 
Percent reduction in all type seizure days .................................... 31 
8.2.2.3 
Responder outcome for all type seizure days............................... 31 
8.2.2.4 
Specified month seizure freedom ................................................. 31 
8.2.3 
QOLIE-31-P ........................................................................................... 32 
8.2.4 
EQ-5D .................................................................................................... 32 
8.2.5 
Direct cost parameters ........................................................................... 33 
8.2.6 
Indirect cost parameters ......................................................................... 33 
8.2.7 
The number of school or working days lost will not be summarized but 
will be provided in subject data listings. Socio-professional data ......... 33 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .................................... 33 
10 IMMUNOLOGICAL PROCEDURES ...................................................................... 34 
11 SAFETY ANALYSES ............................................................................................... 34 
11.1 
Extent of exposure ........................................................................................... 34 
11.2 
Adverse events ................................................................................................. 35 
11.2.1 
Definition of treatment-emergent AE .................................................... 35 
11.2.2 
General summaries of TEAEs ............................................................... 35 
11.3 
Clinical laboratory evaluations ........................................................................ 36 
11.3.1 
Hematology and blood chemistry parameters ....................................... 37 
11.3.2 
Macroscopic urinalysis .......................................................................... 37 
11.3.3 
Microscopic urinalysis ........................................................................... 38 
11.4 
Vital signs, physical findings, and other observations related to safety .......... 38 
11.4.1 
Vital signs .............................................................................................. 38 
11.4.2 
Electrocardiograms ................................................................................ 39 
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Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 5 of 50 
 
11.4.3 
Physical examination ............................................................................. 39 
11.4.4 
Neurological examination ...................................................................... 39 
11.4.5 
Psychiatric and mental status ................................................................. 39 
11.4.6 
HADS ..................................................................................................... 39 
11.4.7 
Columbia-Suicide Severity Rating Scale ............................................... 40 
12 REFERENCES .......................................................................................................... 41 
13 APPENDICES ........................................................................................................... 42 
13.1 
QOLIE-31-P total and subscale score calculations .......................................... 42 
13.2 
Subject site transfers ........................................................................................ 44 
13.3 
PCST criteria .................................................................................................... 45 
13.3.1 
Hematology parameters ......................................................................... 45 
13.3.2 
Blood chemistry parameters .................................................................. 46 
13.3.3 
Urinalysis ............................................................................................... 48 
13.3.4 
Vital signs and body weight ................................................................... 48 
 
 
 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 6 of 50 
 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
AMD 
antimyoclonic drug 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class 
BMI 
body mass index 
bpm 
Beats per minute 
BRV 
brivaracetam 
BUN 
blood urea nitrogen 
CHMP 
Committee for Medicinal Products for Human Use 
CR CL 
creatinine clearance 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
EDV 
Early Discontinuation Visit 
EQ-5D 
EuroQol 5 Dimensions 
ER 
emergency room 
EU 
European Union 
F 
Female 
FDA 
Food and Drug Administration 
FEV 
Full Evaluation Visit 
FV 
Final Visit 
GGT 
Gamma-glutamyl transpeptidase  
HADS 
Hospital Anxiety and Depression Scale 
HDL 
High-density lipoprotein  
HRQoL 
Health-Related Quality of Life 
ILAE 
International League Against Epilepsy 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
M 
Male 
MEV 
Minimal Evaluation Visit 
N/A 
Not applicable 
PBO 
placebo 
PCST 
potentially clinically significant treatment-emergent 
PGS 
primary generalized seizures 
POS 
partial onset seizure 
PT 
preferred term  
QOLIE-31-P 
Patient Weighted Quality of Life in Epilepsy 
Questionnaire 
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Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 7 of 50 
 
RBC  
Red Blood Cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SEV 
Supplemental Entry Visit 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULD 
Unverricht-Lundborg Disease 
ULN 
Upper Limit of Normal 
V  
Visit 
VAS 
visual analog scale 
WBC 
White Blood Cell 
WHO-DRL 
World Health Organization Drug Reference List 
YEV 
Yearly Evaluation Visit 
 
 
 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 8 of 50 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report for N01125. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized 
doses with a maximum of 200mg/day in subjects suffering from epilepsy 
2.1.2 
Secondary objectives 
To evaluate the maintenance of efficacy over time of BRV (for subjects with partial onset 
seizures [POS] and subjects with primary generalized seizures [PGS]) 
No secondary efficacy objectives are defined for subjects with Unverricht-Lundborg Disease 
(ULD) or subjects entering the study from N01315. 
2.1.3 
Exploratory objectives 
Exploratory objectives for subjects with POS/PGS: 
 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 (HRQoL), 
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 subjects or subjects entering the study from 
01315. 
2.2 
Study variables 
2.2.1 
Safety variables 
Note: Assessments specified as performed within the first 2 years of the Evaluation Period 
are not applicable to subjects entering the study from N01315. 
2.2.1.1 
Primary safety variables 
 Occurrence of a treatment-emergent adverse event (TEAE) 
 Withdrawal due to adverse event (AE) 
 Occurrence of a serious adverse event (SAE) 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 9 of 50 
 
2.2.1.2 
Other safety variables 
 Laboratory tests (hematology, blood chemistry, urinalysis) 
 Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and 
body weight 
 Electrocardiogram (ECG) 
 Physical and neurological examinations 
 Change in Hospital Anxiety and Depression Scale (HADS) scores from the Baseline of 
the previous study to each assessment for the first 2 years and to the last Evaluation 
Period assessment during the first 2 years 
2.2.2 
Efficacy variables 
2.2.2.1 
Secondary efficacy variables 
For subjects with focal-onset epilepsy: 
• POS (type I) frequency per 28 days during the Evaluation Period 
 Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period 
 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 or subjects 
with ULD or subjects entering the study from N01315. 
2.2.2.2 
Other efficacy variables 
For subjects with focal-onset epilepsy: 
 Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period 
For subjects with generalized epilepsy: 
 Generalized (type II) seizure days per 28 days during the Evaluation Period 
 Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period 
 Responder rate for generalized (type II) seizure days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure days from the Baseline 
Period of the previous study. 
 Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period 
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Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 10 of 50 
 
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy: 
 Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) 
scores from Baseline of the previous study to each assessment for the first 2 years and to 
the last Evaluation Period assessment during the first 2 years 
 EuroQol 5 Dimensions (EQ-5D) questionnaire response for each assessment for the first 
2 years for the Evaluation Period and for the last assessment during the first 2 years of the 
Evaluation Period 
2.2.3 
Pharmacoeconomic variables 
Due to the inconsistencies in data captured and collection forms across LTFU studies, the 
following variables will be provided in subject data listings only, but will not be evaluated or 
descriptive summarized: 
 Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
[ER] visits) during the first 2 years of the Evaluation Period 
 Indirect costs (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 ULD subjects or subjects entering the study 
from N01315. 
2.3 
Study Design and Conduct 
This is an open-label, long-term follow-up, multicenter, noncomparative, single-arm study of 
BRV. The primary objective is to evaluate the long-term safety and tolerability of BRV at 
individualized doses up to a maximum of 200mg/day in subjects with epilepsy. The 
secondary objective is to evaluate the maintenance of efficacy of BRV. Exploratory 
objectives are to assess the effects of BRV on subjects’ HRQoL, obtain information on the 
direct and indirect costs, and explore changes in socio-professional status. 
N01125 enrolled subjects 16 years of age and older who had completed N01114, N01252 
(non-Indian subjects only), N01254 (non-Indian subjects only), N01187, or N01236. N01114 
and N01252 enrolled subjects with focal-onset seizures with or without secondary 
generalization (designated as “POS subjects”). N01254 enrolled subjects with focal-onset 
epilepsy and a smaller number of subjects with generalized epilepsy (designated as “PGS 
subjects”). N01187 and N01236 enrolled subjects with ULD. Subjects entering the study 
from long-term follow-up study (N01315) were 16 years of age and older with from POS. 
Subjects from double-blind, placebo-controlled studies N01114, N01187, and N01236 were 
to enter N01125 at a dose of 100mg/day after completion of a blinded Conversion Period. 
Subjects from double-blind, placebo-controlled N01252 were to enter N01125 at a dose of 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 11 of 50 
 
50mg/day. The starting doses for subjects from double-blind, placebo-controlled, flexible-
dose study N01254 were based on the blinded dose levels achieved during the Maintenance 
Period of N01254 but were not to exceed 100mg/day; thus, starting doses for subjects from 
N01254 were 20mg/day, 50mg/day, or 100mg/day, with most subjects entering N01125 at a 
dose of 100mg/day. 
Subjects who enrolled in the study entered an Evaluation Period during which treatment with 
BRV was initiated. The dose of BRV can be adjusted based on the individual subject’s 
seizure control and tolerability. Dose increases can be made in increments of 50mg/day on a 
weekly basis up to a maximum of 200mg/day; dose decreases can be made in steps of 
50mg/day on a weekly basis. Subjects who discontinue treatment with BRV enter a Down-
Titration Period during which the dose of BRV is decreased in steps of 50mg/day with a last 
down-titration step at 20mg/day for 1 week. Subjects who have completed the Down-
Titration Period or subjects who discontinue during the Evaluation Period without entering 
the Down-Titration Period enter a Post-Treatment Period for a minimum of 2 weeks and a 
maximum of 4 weeks. 
The maximum allowable daily dose for this study was increased from 150mg/day to 
200mg/day based on integrated amendment 25 to the protocol. It is recommended that the 
daily dose be administered in 2 equal intakes. 
Dose adjustment to concomitant antiepileptic drugs (AEDs) may be made at any time during 
the study and subjects may start new AEDs. Concomitant AEDs may also be discontinued; 
however, special considerations apply if the discontinuation of such AEDs results in the 
subject receiving BRV monotherapy. Previously, in the event of excellent efficacy and 
tolerability of BRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may 
have been attempted by the Investigator for subjects with POS or PGS. With integrated 
amendment 25 to the protocol, conversion to monotherapy is no longer permitted; however, 
subjects already on BRV monotherapy are allowed to continue monotherapy treatment. No 
conversion to monotherapy is permitted for subjects with ULD. 
The visit schedule for this study depends on the previous study from which the subject was 
enrolled and the numbering of study visits differs depending on the previous study. Study 
visits at Months 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) or Yearly 
Evaluation Visits (YEVs) at which a greater number of assessments are performed for all 
subjects from previous studies. For subjects coming from N01114, study visits at Months 1, 
3, 5, 15, 21 are Minimal Evaluation Visits (MEVs) at which few assessments are generally 
performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from N01252, 
N01254, N01187, and N01236, study visits at Months 1, 3, 9, 15, and 21 are MEVs. The 
study visit at Month 2 is an FEV. In addition, a phone call is scheduled at the end of the 
Down-Titration Period and a Drug-Free Final Visit (FV) is scheduled at the end of the Post-
Treatment Period. The study schedule, as just described, is shown in Table 2‒1 and Table 2‒
2. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 12 of 50 
 
Table 2‒1: 
Study Schedule for Subjects from N01114, N01252, and 
N01254 
Subjects coming from Exploratory Studies 
(N01114) 
Subjects coming from Confirmatory Studies 
(N01252, N01254) 
Month 
Visit 
Type of Visit 
Month 
Visit 
Type of Visit 
1st year Follow-up 
1st year Follow-up 
MO 
V1 
Entry Visit 
MO 
V1 
Entry Visit 
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 Visit 
 
 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 13 of 50 
 
Table 2‒2: 
Study Schedule for Subjects from N01187 and N01236 
Subjects coming from ULD Confirmatory Studies 
(N01187, N01236) 
Month 
Visit 
Type of Visit 
1st year Follow-up 
M0 
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V3 
FEV 
M3 
V4 
MEV 
M4 
 
 
M5 
 
 
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M7 
 
 
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M9 
V6 
MEV 
M10 
 
 
M11 
 
 
2nd and subsequent years Follow-up 
M12 
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YEV 
M15 
V8 
MEV 
M18 
V9 
FEV 
M21 
V10 
MEV 
... 
... 
... 
FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; ULD=Unverricht-
Lundborg disease; V=Visit; YEV=Yearly Evaluation Visit 
All subjects should have a Visit 1 at the start of N01125. Visit 1 will typically correspond to 
the last visit from the previous study and should be the visit at which study drug is dispensed 
for N01125. However, some subjects had a delay in treatment with study drug after 
completion of the previous study. Such subjects may have had an additional Supplemental 
Entry Visit (SEV) at the time of entry into N01125. 
Subjects entering from N01315 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/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. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 14 of 50 
 
 
This study will run throughout the duration of the clinical development period of BRV, and 
will continue until a marketing authorization is granted by any Health Authority in an 
indication for the adjunctive treatment in adults with refractory POS, whether or not 
secondarily generalized, until the Sponsor decides to close the study, until a managed access 
program, named patient program, compassionate use program, or similar type of access 
program is established as allowed per country-specific requirement in addition to legal and 
regulatory guidelines, or until BRV development is stopped by the Sponsor. 
2.4 
Determination of Sample Size 
No sample size calculation was done. Sample size was dependent upon recruitment into and 
completion of preceding studies. At the time of development of this SAP amendment 1, the 
enrollment into this study has been completed; a total of 859 subjects were enrolled into 
N01125 including 6 subjects entering the study from N01315.  
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical 
output will be carried out using SAS® Version 9.1 or higher. 
Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 
75th percentile, minimum value, and maximum value for quantitative variables, and counts 
and percentages for categorical variables, will be provided. Denominators for percentages 
will generally be based on the set of subjects with at least 1 assessment at the time point or at 
least 1 assessment during the time interval being summarized. 
All summaries will be descriptive; no statistical hypothesis testing is planned. 
Unless otherwise noted, summaries will present BRV overall, which will include all subjects 
exposed to BRV during the study. 
Subject data listings will be provided and will present source data and key derived variables 
for statistical analyses. 
3.2 
Analysis time points 
3.2.1 
First and last dose of BRV 
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first 
dose of BRV during N01125 (ie, not the first dose of BRV from the previous study in which 
subjects participated in prior to N01125). Unless otherwise noted, all references to the last 
known dose of BRV in this SAP refer to the last dose of BRV taken across any study periods 
(ie, the last dose of BRV across both the Evaluation and Down-Titration Periods). 
3.2.2 
Relative day 
Relative day will be calculated as the current date minus the date of first dose of study drug 
for days prior to the first dose of study drug, and the current date minus the date of first dose 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 15 of 50 
 
of study drug plus 1 for days on or after the day first dose of study drug and prior to or on the 
day of last study drug dose (eg, the day of first dose will be Day 1 and the day prior to first 
dose will be Day -1), ie, Day 1 representing the day of first dose of BRV, the previous day is 
Day -1 and each day prior to that is Day -2, Day -3, etc; subsequent relative days to Day 1 
will be Day 2, Day 3, etc. For days after the last dose of BRV, relative day will be calculated 
as the current date minus the date of last dose of BRV and including a ‘+’ to denote post 
treatment days (eg, the day after the last dose of BRV will be Day +1). Relative day will not 
be calculated for partial or missing dates. 
3.2.3 
Summaries at Study Entry 
Study Entry denotes an analysis time point that will summarize assessments done at the last 
visit of the previous study for most subjects as described below, but may also include 
assessments that may have been performed at Supplemental Entry Visits (SEVs) for some 
subjects who did not immediately enter N01125. 
There are 4 groups of subjects to consider: 
1. Subjects who immediately entered N01125 after completing the Treatment Periods for 
N01252 and N01254 or the blinded Conversion Periods for N01114, N01187, and 
N01236 
2. Subjects who entered the Down-Titration Period of the previous study and entered 
N01125 during the Down-Titration Period 
3. Subjects who did not immediately enter N01125 and had a gap in treatment with 
study drug between the previous study and N01125Subjects  
4. Subjects entering the study from N01315 who entered after their N01315 study sites 
were closed 
Subjects in Categories 1 and 2 
Subjects in categories 1 and 2 will generally not have any interruption in study drug dosing 
during the transition to N01125. For such subjects, selected assessments from the following 
visits from the previous study will be summarized at Study Entry: 
 
 
 
Study  
 
 
 
Visit (Time Point) 
 
 
 
N01187/N01236  
Visit 9 (Week 16) 
 
 
 
N01114 
 
 
 
Visit 10 (Week 12) 
 
 
 
N01252 
 
 
 
Visit 7 (Week 12) 
 
 
 
N01254 
 
 
 
Visit 8 (Week 16) 
The following assessments were to be performed for all subjects at the above time points: 
laboratory parameters, vital signs, and ECGs; these assessments will be summarized at Study 
Entry. The following assessments were to be performed for all subjects from N01252 and 
N01254 at the above time points: QOLIE-31-P, HADS, EQ-5D and socio-professional data; 
however, these assessments will not be summarized at Study Entry. 
Subjects in Category 3 
Some subjects in category 3 have data available from an SEV at the time of entry into 
N01125. Laboratory parameters, vital signs, and ECGs collected at SEV will be summarized 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 16 of 50 
 
at Study Entry. If one or more of these assessments were not performed at SEV, or if a 
subject in category 3 does not have an SEV, then the subject will be excluded from 
summaries of Study Entry for the assessments that were not performed. 
Subjects in Category 4 
Subjects in category 4 will have their demographic data including date of birth, country, 
gender, race, and ongoing medication data transferred into N01125. Laboratory parameters, 
vital signs, and ECGs collected at SEV will be collected at Study Entry.  
3.2.4 
Study periods 
The study is divided into 3 periods: Evaluation Period, Down-Titration Period, and Post-
Treatment Period. A subject is classified as “discontinued” if the subject has a termination 
case report form (CRF) or has an early discontinuation visit (EDV). A subject is classified as 
“completed” if this subject completes the full extent of the study as defined in the protocol at 
database lock.   
A “discontinued” subject can be potentially slotted into the 3 periods of the study. The 
following algorithms will be used to slot the subject appropriately into the Evaluation Period, 
Down-Titration Period, and Post-Treatment Period. 
 For Evaluation Period, the start date is the date of first dose of BRV, and the 
following algorithm is used to determine the end date: 
 If the subject enters the Down-Titration Period, then the date of EDV is the 
end date; 
 If the subject does not enter the Down-Titration Period but meets 1 of the 
following criteria, the Evaluation Period ends on date of last dose of BRV, 
 Without an EDV but having a termination CRF, 
 With an EDV and having a termination CRF, 
 With an EDV and the date of EDV prior to the database lock date and 
having no termination CRF. 
 A subject is considered entering Down-Titration Period only if the subject has an 
EDV and at least 1 dose of study drug after the date of EDV, the start date of Down-
Titration Period is set as 1 day after the date of EDV, and the Down-Titration Period 
ends on date of last dose of BRV. A subject without an EDV but having a termination 
CRF or with an EDV but without any dosing of study drug after the EDV will not 
have the Down-Titration Period, and no artificial Down-Titration Period will be 
created for analysis. 
 A subject is considered entering the Post-Treatment Period if the subject has at least 1 
contact (scheduled visit, unscheduled visit, or telephone contact) after the date of last 
dose of BRV. The Post-Treatment Period starts 1 day after date of last dose of BRV 
irrespective of entering the Down-Titration Period, and there is no end date. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 17 of 50 
 
A “completed” subject can potentially have Evaluation Period, Down-Titration Period, and 
Post-Treatment Period. At the time of study termination by the Sponsor, subjects will 
discontinue the study drug following the down titration process or will be converted without 
titration to commercial BRV where available; alternatively, subjects may be initiated without 
down-titration in a managed access program, named patient program, compassionate use 
program, or similar type of access program as allowed per country specific requirements in 
addition to legal and regulatory guidelines. 
3.2.5 
Monthly time intervals 
A month is defined as 30 days and time intervals based on monthly durations are defined as a 
multiple of 30 days (eg, 12 months is defined as 360 days). The following definitions of 
3-month and 6-month intervals are based on 30-day months where the date of first dose of 
BRV is Day 1: 
 
Interval 
 
 
Duration Definition 
 
Months 1-3 
 
Days 1-90 
 
Months 4-6 
 
Days 91-180 
 
Months 7-9 
 
Days 181-270 
 
Months 10-12  
Days 271-360 
 
Months 1-6 
 
Days 1-180 
 
Months 7-12  
Days 181-360 
 
Months 13-18  
Days 361-540 
 
Months 19-24  
Days 541-720 
Subsequent 3- and 6-month intervals are defined in a similar manner.  
Six-month intervals are defined for the evaluation of direct and indirect cost parameters. 
Statistical summaries for direct and indirect cost parameters will only present results through 
the first 2 years of treatment. Three-month intervals will be used for analysis of efficacy 
outcomes and AEs. 
For the analysis of efficacy outcomes, a subject is included in the analysis for a 3-month 
interval if the end date is on or after the last day of the 3-month interval and the subject diary 
was completed for at least 1 day during the 3-month interval. 
For the analysis of AEs, a subject is included in the analysis for a 3-month interval if the end 
date is on or after the first day of the 3-month interval. 
3.2.6 
Last Value on BRV Treatment 
Last Value for QOLIE-31-P, HADS, EQ-5D, and socio-professional data is the last 
assessment strictly after the date of first dose of BRV and up to and including the YEV at the 
end of the second year and any EDVs for subjects who did not complete through the YEV at 
the end of the second year. 
Last Value for clinical laboratory parameters, vital signs, and ECGs is the last available result 
obtained after the first dose of BRV and prior to or on the date of last dose of BRV. All 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 18 of 50 
 
scheduled and unscheduled assessments within this time period will be considered. Last 
Value will be determined separately for each laboratory parameter.  
3.2.7 
Exposure duration and exposure duration cohorts 
At the final analysis, the overall duration of exposure (or On Treatment Period) will be 
calculated as the date of last dose of BRV minus the date of first dose of BRV plus 1 day. 
Each subject will be classified into one or more of the following exposure duration cohorts 
based on the duration of BRV exposure as calculated above:  
 
 
All subjects   
≥1 day 
 
 
≥3 months  
 
≥90 days 
 
 
≥6 months  
 
≥180 days 
 
 
≥12 months 
 
≥360 days 
This categorization will continue in 6-month increments past 12 months up to a time point 
that will be determined based on cumulative exposure at the time of the database lock. 
3.2.8 
Study visit cohorts 
Study visit cohorts are defined for summaries of QOLIE-31-P, HADS, and EQ-5D. Six-
month, 12-month, 18-month, and 24-month cohorts are defined. Subjects will be classified 
into a study visit cohort if they attend the scheduled visit at the time point defined by the 
cohort. For example, subjects will be included in the 18-month study visit cohort if they 
attend the scheduled visit at 18 months (ie, FEV at Month 18). Subjects may be classified in 
more than 1 cohort. Generally, subjects included in a cohort for a later visit will be included 
in all earlier study visit cohorts (eg, 6-month and 12-month study visit cohorts for subjects in 
the 18-month study visit cohort), although this may not be the case in the event of a missed 
visit or if an unscheduled visit is conducted in lieu of a scheduled visit.  
3.3 
Definition of Baseline Values 
Baseline for all study outcomes will be based on baseline from the previous studies. For 
assessments performed at scheduled and unscheduled visits, Baseline will generally be the 
last result obtained or prior to the randomization visit of the previous study. Baseline will be 
defined separately for each hematology, blood chemistry, and urinalysis parameter. 
Baseline for the evaluation of seizure frequency and seizure days will be calculated from the 
core study seizure diary based on the rules defined in Section 3.8.1 . 
3.4 
Protocol deviations 
The criteria for identifying important protocol deviations and the classification of important 
protocol deviations will be defined separately in the Specification of Protocol Deviations 
document. Whenever possible, criteria for identifying important protocol deviations will be 
implemented algorithmically to ensure consistency in the classification of important protocol 
deviations across all subjects. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 19 of 50 
 
3.5 
Analysis Sets 
3.5.1 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who took at least 1 dose of study drug but 
not including subjects entering the study from N01315. 
Summaries of demographics and baseline characteristics, medical history, AEDs, non-AEDs, 
HADS, study drug exposure, and safety outcomes will be provided for the Safety Analysis 
Set. 
A Modified Safety Analysis Set will also be defined to consist of all subjects who took at 
least 1 dose of study drug including subjects entering the study from N01315. Demographic, 
ongoing medication and safety assessment listings will be provided based on the Modified 
Safety Analysis Set. 
3.5.2 
Efficacy Analysis Sets 
Efficacy Analysis Sets will consist of all subjects who took at least 1 dose of study drug and 
have at least 1 seizure diary day during the Evaluation Period. Separate Efficacy Analysis 
Sets are defined for subjects with focal epilepsy from N01114, N01252, and N01254 and 
subjects with generalized epilepsy from N01254.  
A subject will be excluded from the Efficacy Analysis Set for POS or PGS if either they did 
not receive at least 1 dose of BRV, or the clinical database indicates that the daily seizure 
diary was not completed for any days on or after the first dose of BRV and on or prior to the 
end date of the Evaluation Period (see Section 8). 
Seizure outcomes will be summarized for either the Efficacy Analysis Set for POS or the 
Efficacy Analysis Set for PGS. Summaries of epilepsy history, QOLIE-31-P, and EQ-5D will 
be provided for the Efficacy Analysis Sets for both POS and PGS. No summaries of these 
outcomes will be provided for ULD subjects or subjects entering the study from N01315, but 
these data will only be provided in subject data listings. 
3.6 
Treatment Assignment and Treatment Groups 
This is an uncontrolled study in which all subjects receive BRV in doses that are optimally 
adjusted for each subject. Generally, statistical summaries will present all subjects combined 
as a single treatment arm unless otherwise indicated. 
3.7 
Coding dictionaries 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Medications will be coded using the World Health Organization Drug 
Reference List (WHO-DRL). Prior and concomitant medical procedures will not be coded. 
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UCB                                                                                                                                              11 February 2019 
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Page 20 of 50 
 
3.8 
Definitions of study-specific derived variables 
3.8.1 
Calculation of seizure frequency/days 
3.8.1.1 
Initial seizure data processing 
Each seizure code in the clinical database will be mapped to exactly 1 of the following codes 
based on the 1981 International League Against Epilepsy (ILAE) classification: I, IA, IA1, 
IA2, IA3, IA4, IB, IB1, IB2, IC, II, IIA, IIB, IIC, IID, IIE, IIF, or III. 
With regard to cluster seizures, investigator sites are to report the number of cluster episodes 
rather than reporting the estimated number of individual seizures. Therefore, no imputation 
will be applied for the seizure counts corresponding to reports of cluster seizures. 
3.8.1.2 
Calculation of adjusted seizure frequency 
The following derivations apply only to subjects with Partial Onset Seizures. 
Baseline POS frequency for seizure types I, IA, IB, IC, and for all seizure types (I+II+III) 
will be obtained from the Baseline Period of the previous double-blind study. 
The total number of seizures for seizure types I, IA, IB, and IC, and the total number of 
seizures for all seizure types (I+II+III) will be calculated overall, by 3-month time intervals, 
and over the cohort interval for each exposure duration cohort. All seizure diary on or after 
the date of first dose of BRV and prior to or on the date of last dose of BRV will be 
considered for these calculations. 
Twenty-eight day adjusted seizure frequency for seizure types I, IA, IB, and IC, and for all 
seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and 
over each exposure duration cohort interval by dividing the total number of seizures for each 
seizure type by the number of days for which the diary was completed overall, within each 
3-month interval, and within each exposure duration cohort interval, and multiplying the 
resulting value by 28. 
3.8.1.3 
Calculation of adjusted seizure days 
The following derivations apply only to subjects with Primary Generalized Seizures, based 
on the 1981 ILAE classification, Primary Generalized Seizures include the generalized 
seizure types and unclassified seizure types.  
Baseline seizure days for seizure types II, IIA through IIF, and for all seizure types (I+II+III) 
will be obtained from the Baseline Period of the previous study. 
The total number of seizure days for seizure types II, IIA through IIF, and the total number of 
seizure days for all seizure types (I+II+III) will be calculated overall, by 3-month time 
intervals, and over the cohort interval for each exposure duration cohort. The same seizure 
diary data defined in the Section 3.8.1.2 for POS frequency will be considered. 
Twenty-eight day adjusted seizure days for seizure types II, IIA through IIF, and for all 
seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and 
over each exposure duration cohort interval by dividing the total number of seizure days for 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 21 of 50 
 
each seizure type by the number of days for which the diary was completed overall (ie, over 
the periods defined in the Section 3.8.1.2), within each 3-month interval, and within each 
exposure duration cohort interval, and multiplying the resulting value by 28. 
3.8.2 
QOLIE-31-P 
The QOLIE-31-P is an adaptation of the original QOLIE-31 (Cramer et al, 1998). The 
QOLIE-31-P includes 30 items grouped into 7 multi-item subscales (seizure worry [5 items], 
overall quality of life [2 items], emotional well-being [5 items], energy/fatigue [4 items], 
cognitive functioning [6 items], medication effects [3 items], and social function [5 items]) 
and a health status item. The QOLIE-31-P total score, subscale scores, and health status item 
score are calculated according to the scoring algorithm described below, with scores ranging 
from 0 to 100 and higher scores indicating better functioning. In addition to these 31 items, 
the QOLIE-31-P includes 7 items assessing the degree of “distress” associated with the topic 
of each subscale (ie, distress items) and 1 item asking about the relative importance of each 
subscale topic (ie, prioritization item). 
Subscale Scores 
As a first step to calculating the subscale scores, the individual responses for the 30 subscale 
items are rescaled to a 0 to 100 scale with higher scores reflecting better functioning; the 
rescaled values for each item are defined in Section 13.1. Each subscale score is then 
calculated by summing the rescaled responses for that subscale and dividing by the number of 
items without a missing response. A subscale score will be calculated only if at least 50% of 
the items within the subscale are present. 
Total Score 
Total score is calculated as a weighted sum of the subscale scores based on the weighting in 
Section 13.1. Total score will be missing if at least 1 subscale score is missing. Total score 
will range from 0 to 100 with a higher score reflecting better functioning. 
Health Status Item 
Responses for the health status item is a multiple of 10 ranging from 0 to 100 with a higher 
score corresponding to a better health status. The health status item response is analyzed 
without rescaling. 
Distress Items 
Each subscale includes 1 distress item. The response for each distress item is an integer 
ranging from 1 to 5. The response for each distress item will be converted to a 0 to 100 scale 
(ie, 0, 25, 50, 75, and 100) with a higher score corresponding to greater distress. 
Prioritization Item 
The response for each subscale for the prioritization item is an integer ranging from 1 to 7. 
The prioritization ranking is analyzed without rescaling. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 22 of 50 
 
3.8.3 
HADS 
The HADS assessment consists of 14 items that are each scored on a 4-point scale ranging 
from 0 to 3, with a higher score corresponding to worse anxiety or depression. The 
depression and anxiety scores will be calculated by summing the scores for the items 
corresponding to each subscale, as described in the Hospital Anxiety and Depression Scale 
Manual (Snaith and Zigmond, 1994): the depression score is calculated as the sum of all 
even-numbered items; the anxiety score is calculated as the sum of all odd-numbered items. 
Scores for each subscale range from 0 to 21, with higher scores corresponding to a greater 
level of anxiety or depression. 
Missing items will be replaced by the mean of non-missing items from the same subscale 
when calculating the above, provided at least 50% of the items (ie, at least 4 of 7 items) 
within the subscale are present. A subscale score will not be calculated if more than 50% of 
the items are missing within a subscale. This rule applies separately to the subscale scores for 
anxiety and depression; for example, it may be possible to calculate the depression score in 
cases where the anxiety score is not calculated due to non-response. 
3.9 
Subject site transfers 
Subjects may have transferred from one site to another through the course of participation in 
the study. Subjects that transferred from one site to another site, for whatever reason, have 
generally retained their subject number. However, in some cases, the subject number 
changed. When this is true, the most recently assigned subject number will be used for 
analyses and subject data listings. A record of any change in subject numbers will be 
presented in the Section 13.2. 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
No statistical testing is planned; therefore, this section is not applicable. 
4.2 
Handling of dropouts or missing data 
Seizure frequency (subjects with POS) and seizure days (subjects with PGS) will be 
calculated over non missing diary days during each study period or time interval as described 
in Section 3.2.4 and Section 3.2.5; diary days for which seizure data were not obtained will 
not be considered in the calculation of seizure frequency or seizure days. Because the 
evaluation of efficacy is not the primary objective of this study, and because this is an 
uncontrolled study in a variable setting, which allows individualized optimization of dosing 
of BRV and concomitant AEDs, no summaries assessing the impact of missing seizure diary 
days are planned. 
For subjects who prematurely discontinue during the Evaluation Period, the calculation of 
POS frequency and PGS seizure days will be based on available seizure diary while the 
subject was receiving BRV. The presence of such dropouts may influence the evaluation of 
the long-term outcomes for subjects who either do not discontinue or do not discontinue early 
in the study. Therefore, as described below, selected summaries will be produced by exposure 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 23 of 50 
 
duration cohorts to allow an assessment of long-term outcomes without the potentially 
confounding influence of earlier discontinuations. 
4.3 
Interim analyses and data monitoring 
Interim summaries were produced to support regulatory submissions for marketing 
authorization while this study is ongoing. There are no statistical concerns with such interim 
assessments for this study design. 
4.4 
Multicenter studies 
Efficacy and safety outcomes will not be assessed for individual investigator sites due to the 
low expected number for enrollment within each investigator site. 
4.5 
Multiple comparisons/multiplicity 
No statistical testing is planned; therefore, this section is not applicable. 
4.6 
Use of an “Efficacy Subset” of subjects 
All subjects who receive at least 1 dose of study drug and have at least 1 seizure diary day 
during the Evaluation Period will be included in efficacy summaries. Separate Efficacy 
Analysis Sets are defined for subjects with focal epilepsy from N01114, N01252, and 
N01254 and subjects with generalized epilepsy from N01254. 
4.7 
Active-control studies intended to show equivalence 
This section is not applicable for this study. 
4.8 
Examination of subgroups 
Selected summaries will be provided for the following subgroups as specified within each of 
the following sections: 
 Two mappings of countries to regions are defined, 1 based on the classification requested 
by Food and Drug Administration (FDA), and 1 based on the regional classification for 
the CHMP (Committee for Medicinal Products for Human Use). 
Countries will be mapped to geographic regions as follows for the FDA: 
Geographic Region (FDA) Country 
North America 
Canada, United States, Puerto Rico 
Latin America 
Brazil, Mexico 
Western Europe 
Austria, Belgium, Finland, France, Germany, Ireland, 
Italy, Netherlands, Norway, Réunion, Spain, Sweden, 
United Kingdom, Switzerland 
Eastern Europe 
Bulgaria, Czech Republic, Estonia, Latvia, Hungary, 
Lithuania, Poland, Romania, Russia, Serbia and 
Montenegro, Turkey, Ukraine 
Asia/Pacific/Other 
Australia, Hong Kong, India, Israel, Japan, Singapore, 
South Africa, Republic of Korea, Taiwan, Tunisia 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 24 of 50 
 
Countries will be mapped to geographic regions as follows for the CHMP: 
Geographic Region 
(CHMP) 
Country 
North America 
Canada, United States, Puerto Rico 
Latin America 
Brazil, Mexico 
Europe (European Union 
[EU] member states) *  
Austria, Belgium, Bulgaria, Czech Republic, Estonia, 
Finland, France, Germany, Hungary, Ireland, Italy, 
Latvia, Lithuania, Netherlands, Norway, Poland, 
Réunion, Romania, Spain, Sweden, United Kingdom 
Europe (non-EU member 
states) 
Russia, Serbia and Montenegro, Switzerland, Turkey, 
Ukraine 
Asia/Pacific/Other 
Australia, Hong Kong, India, Israel, Japan, Singapore, 
South Africa, Republic of Korea, Taiwan, Tunisia 
* EU member states plus Norway. 
 Indication (Partial Onset Seizures, Primary Generalized Seizures, ULD) 
 Randomized treatment in the previous study (placebo [PBO], BRV)  
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
Due to differences in data format across studies, in order to facilitate summary of subject 
disposition, the reasons for discontinuation for individual studies will be collapsed as follows 
for summaries: 
LTFU Category 
CRF Reason 
ADVERSE EVENT 
ADVERSE EVENT 
LACK OF EFFICACY 
LACK OF EFFICACY 
LOSS OF EFFICACY 
LOST TO FOLLOW-UP 
LOST TO FOLLOW-UP 
SUBJECT CHOICE 
CONSENT WITHDRAWN 
WITHDRAWAL OF CONSENT FOR PERSONAL 
REASONS NOT RELATED TO AES 
WITHDRAWAL OF CONSENT FOR PERSONAL 
REASONS NOT RELATED TO AES OR LACK OF 
EFFICACY 
OTHER 
PROTOCOL VIOLATION 
OTHER REASON 
OTHER 
 
MISSING 
If subject discontinued the study and the termination CRF is 
not available 
Only 1 primary reason for discontinuation should have been reported. In the event that more 
than 1 reason is specified in the clinical database, both reasons will be summarized and a 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 25 of 50 
 
footnote will be added to the summary table to indicate that at least 1 subject is counted for 
multiple reasons for discontinuation. 
An overall summary of disposition will be provided for all enrolled subjects (ie, all subjects 
who signed informed consent). The following will be summarized: 
 The number of subjects in the Safety Analysis Set 
 The number of subjects excluded from the Safety Analysis Set  
 The number of subjects completed the study 
 The number of subjects discontinued from the study, including the reason for 
discontinuation. If subject discontinued the study and the termination CRF is not 
available, the reason for discontinuation will be reported as “MISSING”. 
Additionally, an overall summary of disposition will present the following for subjects in the 
Safety Analysis Set: 
 The number of subjects completed the study  
 The overall number of subjects discontinued and the number of subjects discontinued by 
primary reason for discontinuation. If subject discontinued the study and the termination 
CRF is not available, the reason for discontinuation will be reported as “MISSING”. 
Overall subject disposition will also be summarized by geographic region and indication for 
the Safety Analysis Set. 
The number of subjects within each geographic region and the number of subjects with each 
indication will be summarized for the Safety Analysis Set. 
Kaplan-Meier estimates of the percentage of subjects completing 3, 6, 12, 24, 36, 48, and 
60 months of treatment with BRV will be provided. This analysis will be based on the 
duration of exposure to BRV as defined in Section 3.2.7. Subjects who have permanently 
discontinued will be analyzed as events on the last day of treatment with study drug; subjects 
who complete the study will be censored on the last day of treatment with study drug.  
The date of first subject in (date of earliest Visit 1), date of last subject out (date of last 
scheduled or unscheduled visit), number of enrolled subjects, and the number of subjects in 
each analysis set or indication will be summarized overall and by investigator site. Subjects 
who transferred sites will be summarized according to their original site. 
Overall summary of disposition will be provided for safety analysis set, in addition, a 
separate overall summary will also be provided for modified safety analysis set. 
5.2 
Protocol Deviations 
The number and percentage of subjects with at least 1 important protocol deviation will be 
summarized overall and by category of protocol deviation for the Safety Analysis Set.  
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 26 of 50 
 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
For subjects entering the study from N01315, their demographics data including date of birth, 
country, gender, race, and ongoing medication will be transferred into N01125. These data 
will be provided in subject data listing only, but will not be summarized.  
6.1 
Demographics 
Demographics summaries will be based on demographic data from follow-up studies for 
subjects who enrolled in a follow-up study that collected demographic data. Otherwise, 
demographics summaries will be based on demographic data collected in the previous 
double-blind study.  
Age, age category (<17, 17 to <65, and ≥65 years), gender, racial group and overall racial 
group (see below), body weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI 
category (<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40) will be summarized for the Safety 
Analysis Set. Demographic data will be summarized overall and by subgroup for indication 
and geographic region. 
Racial group was not collected in a consistent manner across studies. For this reason, racial 
group will be collapsed as follows for statistical summaries: 
Category 
CRF Racial Group 
American Indian/Alaskan 
Native 
American Indian/Alaskan Native 
Asian 
Asian, Asian/Pacific Islander, Indian/Pakistani 
Black 
Black, African-American  
Native Hawaiian or Other 
Pacific Islander 
Native Hawaiian or Other Pacific Islander 
White 
White, Caucasian, Hispanic 
Other/Mixed 
Other, Other/Mixed, Mixed Race 
moreover, the overall racial group will be collapsed as follows for statistical summaries: 
Category  
Racial Group from Previous Study 
White  
 
White, Caucasian, Hispanic 
Black  
 
Black, African-American 
Asian  
Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, 
Indian/Pakistani 
Other  
 
American Indian/Alaskan Native, Other, Other/Mixed 
All subjects should be classified into one of the above categories. 
Racial group, ethnicity (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup 
(Indian/Pakistani, Japanese, Other) were not collected in a consistent manner across all 
studies; these variables will be provided in subject data listings if available in the clinical data 
from the previous study but will not be summarized. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 27 of 50 
 
6.2 
Medical and procedure history 
6.2.1 
Medical history diseases 
The summary of medical history will be based on the medical history at the time of entry into 
the previous studies.  
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions at the time of entry into the previous studies, will be 
summarized overall and by primary MedDRA system organ class (SOC) and preferred term 
(PT) for the Safety Analysis Set. 
6.2.2 
Procedure history and concomitant procedures 
Medical procedures are not coded and will only be provided in subject data listings. 
6.3 
History of epilepsy 
All of the following are summarized using data collected at the time of entry into the previous 
studies or from the Baseline Period of the previous studies. 
6.3.1 
Etiology of epilepsy 
The number and percentage of subjects with each type of etiology as specified on the CRF 
(genetic, congenital, etc) from the previous studies will be summarized for the Efficacy 
Analysis Sets for POS and PGS. A subject will be counted as having a particular etiology if 
that etiology was either confirmed or suspected based on the investigator's assessment. 
6.3.2 
Epileptic seizure profile 
The number and percentage of subjects experiencing each seizure type at any time prior to 
study entry will be summarized for the Efficacy Analysis Sets for POS and PGS. The 
following seizure types will be summarized: I, IA, IA1 through IA4, IB, IB1, IB2, IC, II, IIA 
through IIF, III. A subject with a history of a more specific seizure type will be counted in all 
higher levels of seizure types (eg, a subject with a history of IB1 seizures will be counted for 
seizure types I, IB, and IB1). 
6.3.3 
Classification of epileptic syndrome 
The number and percentage of subjects with each epileptic syndrome will be summarized for 
the Efficacy Analysis Sets for POS and PGS. This summary will include the number and 
percentage of subjects within the following categories: localization-related epilepsy; 
idiopathic, symptomatic, and cryptogenic localization-related epilepsy; generalized epilepsy; 
and idiopathic, symptomatic, and cryptogenic generalized epilepsy. 
6.3.4 
Focus localization 
The number and percentage of subjects with each category of focus localization (unknown, 
frontal, temporal, parietal, occipital) will be summarized for the Efficacy Analysis Set for 
POS. Subjects may be counted in more than 1 category of focus localization. A category for 
no available data will be included in the summary to account for subjects from N01114 since 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 28 of 50 
 
focus localization was not obtained for subjects from N01114. Percentages will still be out of 
the full POS Efficacy Analysis Set, including subjects from N01114. 
6.3.5 
History of epileptic seizures 
History of epileptic seizures, including the number and percentage of subjects with a history 
of status epilepticus and quantitative summaries of epilepsy duration, age at onset of first 
seizure, and percent of life with epilepsy, will be summarized for the Efficacy Analysis Sets 
for POS and PGS. 
6.3.6 
Seizure types experienced during baseline of the previous study 
The number and percentage of subjects experiencing each seizure type during the Baseline 
Period will be summarized for the Efficacy Analysis Sets for POS and PGS based on the 
Baseline seizure diary data from the previous studies. The following seizure types will be 
summarized: I, IA, IB, IC, II, and IIA through IIF. 
Subjects will be counted for all higher levels of seizure type categories corresponding to the 
seizure types or seizure sub-types reported on the CRF. 
6.4 
Medications 
Medications recorded on the Concomitant Medications CRF and the Concomitant 
Medications (AEDs only) CRF will be classified as either AEDs or non-AEDs based on the 
preferred drug name search criteria, which are documented outside of the SAP. 
 The medication is not an AED if it does not meet the search criteria based on preferred 
drug name, regardless of which CRF is used for reporting the medication. However, 
further review will be performed for medications that are recorded on the Concomitant 
Medications (AEDs only) CRF but are not included in the AEDs search criteria; 
 For non-benzodiazepine medications, if the medication meets the search criteria for an 
AED based on preferred drug name, then the medication will be classified as an AED 
regardless of indication and regardless of which CRF the medication is recorded on; 
 For benzodiazepines (identified using the search criteria), if the benzodiazepine is 
recorded on the Concomitant Medications (AEDs only) CRF, then the benzodiazepine 
will be classified as an AED; 
 For benzodiazepines (identified using the search criteria), if the benzodiazepine is 
recorded on the Concomitant Medications CRFs, then the benzodiazepine will not be 
classified as an AED.  
After medications are classified as AEDs or non-AEDs, the standard date imputation 
algorithms for start and stop date of the medication and first dose and last dose of BRV in the 
study will be applied. If an AED was taken at any time during dosing with BRV, then the 
AED is classified as a concomitant AED. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 29 of 50 
 
6.4.1 
Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AED medications at study entry for the 
previous double-blind study will be summarized by WHO-DRL primary therapeutic group 
(Anatomic Therapeutic Class [ATC] level 1), therapeutic subgroup (ATC level 2), and 
preferred drug name for the Safety Analysis Set. 
6.4.2 
Number of previous AEDs 
The number and percentage of subjects taking an AED prior to entry into the previous study 
will be summarized by WHO-DRL preferred drug name for the POS and PGS Efficacy 
Analysis Sets based on the following categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.
6.4.3 
History of previous AED use 
The number and percentage of subjects who had taken at least 1 AED prior to entry into the 
previous study will be summarized overall and by WHO-DRL preferred drug name for the 
POS and PGS Efficacy Analysis Sets. 
6.4.4 
AEDs taken at study entry 
The number and percentage of subjects taking AEDs at study entry for the previous double-
blind study will be summarized by WHO-DRL preferred drug name for the POS and PGS 
Efficacy Analysis Sets.  
6.4.5 
Concomitant AEDs 
A concomitant AED is an AED which was taken during administration of BRV, regardless of 
the start and stop date of the AED. The number and percentage of subjects taking 
concomitant AEDs will be summarized by WHO-DRL preferred drug name for the POS and 
PGS Efficacy Analysis Sets. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Study drug compliance will not be assessed due to the complexities associated with the 
calculation and interpretation of study drug compliance for this study. Study drug dosing will 
be provided in subject data listings. 
8 
EFFICACY ANALYSES 
In general, all study outcomes based on seizure frequency will be summarized for the 
Efficacy Analysis Set for POS and all study outcomes based on seizure days will be 
summarized for the Efficacy Analysis Set for PGS. No efficacy summaries are provided for 
ULD subjects or subjects entering the study from N01315. 
The derivations of 28-day adjusted seizure frequency and 28-day adjusted seizure days are 
described in detail in Section 3.8.1.2 and Section 3.8.1.3, respectively. 
All summaries of efficacy data are descriptive; no statistical testing will be performed. 
8.1 
Statistical analyses of secondary efficacy variables 
The following variables are summarized for the Efficacy Analysis Set for POS. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 30 of 50 
 
8.1.1 
Partial onset seizure frequency 
Twenty-eight day adjusted POS frequency will be summarized with quantitative descriptive 
statistics for all subjects for the Baseline Period, the On Treatment Period, and by 3-month 
time intervals over the On Treatment Period. The summary over the On Treatment Period 
will include all subjects in the POS Efficacy Analysis Set. Similar summaries will be 
provided for the full cohort interval and by 3-month time intervals for each exposure duration 
cohort.  
8.1.2 
Percent reduction in POS frequency 
Percent reduction in POS frequency from Baseline to the On Treatment Period will be 
calculated as follows, where On Treatment Period Frequency is the 28-day adjusted POS 
frequency during On Treatment Period and Baseline Period Frequency is the 28-day adjusted 
POS frequency during the Baseline Period of the previous study.  
 
Frequency
 
Period
 
Baseline
Frequency
 
Period
Treatment 
On 
Frequency
 
Period
 
Baseline
100
Reduction
 
%


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A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort. 
Percent reduction from Baseline for POS frequency will be summarized with quantitative 
descriptive statistics for the On Treatment Period, and by 3-month time intervals over the On 
Treatment Period. The summary over the On Treatment Period will include all subjects in the 
POS Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval 
and by 3-month time intervals for each exposure duration cohort. Percent reduction from 
Baseline for POS frequency will be summarized in the same manner by geographic region. 
8.1.3 
Responder outcome for POS frequency 
Responders over the On Treatment Period are defined as subjects with a 50% or greater 
reduction in 28-day adjusted POS frequency from Baseline to the On Treatment Period. 
A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort. 
The number and percentage of responders for POS frequency will be summarized for the On 
Treatment Period, and by 3-month time intervals over the On Treatment Period. The 
summary over the On Treatment Period will include all subjects in the POS Efficacy Analysis 
Set. Similar summaries will be provided over the full cohort interval and by 3-month time 
intervals for each exposure duration cohort. Responder rates for POS frequency will be 
summarized in the same manner by geographic region. 
8.2 
Analysis of other efficacy variables  
8.2.1 
Subjects with partial onset seizures 
All of the following variables are summarized for the Efficacy Analysis Set for POS.
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 31 of 50 
 
8.2.1.1 
Specified Month seizure freedom 
The numbers and percentages of subjects who are seizure free for all seizure types for any 
continuous 6-month interval, 12-month interval, 18-month interval, and so forth will be 
summarized overall for the period of time that subjects are being treated with BRV and by 
Exposure Duration Cohort. The overall summary will present the number and percentage of 
subjects who reported no seizures for the specified duration of seizure freedom and the 
seizure diary was completed for at least 90% of days within the seizure-free interval. Subjects 
whose duration of BRV treatment was less than the specified duration of seizure freedom will 
be considered failures for seizure-freedom. Summaries by exposure duration cohort will 
present the number and percentage of subjects who reported no seizures for the specified 
duration of seizure freedom at any time during the cohort interval (eg, through the end of 
Month 6 for the 6-month cohort) and the seizure diary was completed for at least 90% of days 
within the seizure-free interval. Percentages are relative to the number of subjects within each 
Exposure Duration Cohort.  
A subject is seizure free for a 6-month interval if the subject did not report any seizures in the 
6-month interval and the seizure diary was completed for at least 90% of days within the 
seizure-free interval. The percentage of days for which seizure diary was completed within a 
given 6-month interval will be calculated as follows based on a 30-day month: 
% of days diary was done = 100 × [180 −number of days diary was not done in the interval
180
]  
A similar calculation applies for 12-month seizure freedom based on 360 days, 18-month 
seizure freedom based on 540 days, and so forth. 
8.2.2 
Subjects with Primary Generalized Seizures 
The following variables are summarized for the Efficacy Analysis Set for PGS. 
8.2.2.1 
All type seizure days 
Twenty-eight day adjusted all other type seizure days will be summarized with quantitative 
descriptive statistics in the same manner as 28-day adjusted POS frequency. 
8.2.2.2 
Percent reduction in all type seizure days 
Percent reduction in all other type seizure days from Baseline will be calculated in the same 
manner as percent reduction in POS frequency as described in Section 8.1.2. This variable 
will be summarized in the same manner as percent reduction in POS frequency. 
8.2.2.3 
Responder outcome for all type seizure days 
Responder outcome for all other type seizure days will be derived in a manner similar to the 
responder outcome for POS frequency as described in Section 8.1.3. This variable will be 
summarized in the same manner as 50% responder outcome for POS frequency. 
8.2.2.4 
Specified month seizure freedom 
Specified month seizure freedom for subjects in the PGS Efficacy Analysis Set will be 
derived in a manner similar to specified month seizure freedom for the POS Efficacy 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 32 of 50 
 
Analysis Set as described in Section 8.2.1.1. This variable will be summarized in the same 
manner as specified month seizure freedom for subjects in the POS Efficacy Analysis Set. 
8.2.3 
QOLIE-31-P 
The scoring algorithm for QOLIE-31-P is described in Section 13.1. QOLIE-31-P will be 
summarized for the POS and PGS Efficacy Analysis Sets. No summaries of QOLIE-31-P will 
be provided for subjects with ULD. QOLIE-31-P was to be assessed at Months 2, 6, 12, 18, 
and 24 during the first 2 years of the Evaluation Period for subjects from N01252 and 
N01254, and assessments at Months 3, 6, 12, 18, and 24 during the first 2 years of the 
Evaluation Period for subjects from N01114. Additionally, QOLIE-31-P was to be assessed 
at EDVs. The limited number of assessments obtained at Month 3 for N01114 will not be 
summarized but will be provided in subject data listings. Prior to Protocol Amendment 25, 
QOLIE-31-P may have been assessed for more than 2 years after study entry for some 
subjects. These additional assessments will not be summarized but will be provided in subject 
data listings. 
Observed values for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life, and Health Status will be summarized for 
Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. 
For each time point, summary statistics will be presented for the baseline scores for subjects 
with a change from baseline at the time point in addition to summaries of the observed values 
and changes from baseline at each time point. Only subjects with a non-missing change from 
baseline will be summarized at each time point. 
The above scores will be also summarized for the 6-Month, 12-Month, 18-Month, and 
24-Month Study Visit Cohorts, including summaries of the baseline scores for all subjects 
within each study visit cohort and summaries of observed values and changes from baseline 
for each time point for each study visit cohort. 
Similar summaries will be provided for QOLIE-31-P distress items Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life. Only subjects with a non-missing change from 
baseline will be summarized at that time point. 
The rankings of prioritization items (Seizure Worry, Daily Activities/Social Function, 
Energy/Fatigue, Emotional Well-Being, Cognitive Function, Medication Effects, and Overall 
Quality of Life) will be summarized at the same time points as above and for all subjects and 
by study visit cohort as defined above. Changes from baseline will not be summarized, and 
only the numbers of subjects and sample means will be presented. 
8.2.4 
EQ-5D 
EQ-5D (EuroQol Group, 2000) will be summarized for the POS and PGS Efficacy Analysis 
Sets. No summaries of EQ-5D will be provided for subjects with ULD. EQ-5D was to be 
assessed at Months 2, 6, 12, 18, and 24 during the first 2 years of the Evaluation Period for 
subjects from N01252 and N01254. Additionally, QOLIE-31-P was to be assessed at EDVs. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 33 of 50 
 
EQ-5D was not routinely assessed for subjects from N01114. Prior to Protocol Amendment 
25, EQ-5D may have been assessed for more than 2 years after study entry for some subjects. 
These additional assessments will not be summarized but will be provided in subject data 
listings. 
EQ-5D dimensions will be summarized for Months 2, 6, 12, 18, and 24 and Last Value for 
the Efficacy Analysis Sets for POS and PGS. The number and percentage of subjects with 
each response will be summarized for each dimension and time point. Percentages will be 
relative to the number of subjects with a response to the dimension at that time point. 
Additionally, for each dimension and time point, the number and percentage of subjects with 
each response will be summarized for baseline for subjects with an observed response at that 
time point. Additionally, each dimension will be summarized for the 6-Month, 12-Month, 18-
Month, and 24-Month Study Visit Cohorts, including summaries for baseline for all subjects 
within each cohort and summaries of observed responses for all time points for each cohort.
Observed values for the EQ-5D visual analog scale (VAS) score will be summarized for 
Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. 
For each time point, summary statistics will be presented for the baseline VAS score for 
subjects with a change from baseline at the time point in addition to summaries of the 
observed values and changes from baseline at each time point. Only subjects with a non-
missing change from baseline will be summarized at each time point. 
EQ-5D VAS score will also summarized for the 6-Month, 12-Month, 18-Month, and 
24-Month Study Visit Cohorts, including summaries of the baseline scores for all subjects 
within each study visit cohort and summaries of observed values and changes from baseline 
for each time point for each study visit cohort. 
8.2.5 
Direct cost parameters 
Direct costs data are collected based on concurrent medical procedures, healthcare provider 
consultations not foreseen by protocol, hospital stays, and ER visits. All direct cost 
parameters will be not summarized but will be provided in subject data listings.  
8.2.6 
Indirect cost parameters 
8.2.7 
The number of school or working days lost will not be 
summarized but will be provided in subject data listings. Socio-
professional data 
Socio-professional data is collected at Month 12 and Month 24 and at EDVs. Prior to 
Protocol Amendment 25, socio-professional data may have been collected for more than 
2 years after study entry for some subjects. These additional assessments will not be 
summarized but will be provided in subject data listings. Socio-professional data are not 
collected for subjects from N01114 and subjects with ULD. 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS 
Plasma samples for BRV and concomitant AEDs and antimyoclonic drugs (AMDs) will no 
longer be obtained, as directed by the integrated protocol amendment 25. No summaries of 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 34 of 50 
 
BRV or concomitant AED/AMD plasma levels will be provided; plasma levels will only be 
provided in subject data listings. 
10 
IMMUNOLOGICAL PROCEDURES 
This section is not applicable for this study. 
11 
SAFETY ANALYSES 
Safety is assessed with AEs, laboratory tests (blood chemistry, hematology, urinalysis, and 
pregnancy test), vital signs, body weight, ECGs, physical examination, neurological 
examination, mental status, and psychiatric status. Summary tables will be provided for AEs; 
blood chemistry, hematology, and urinalysis; vital signs; body weight; and ECGs. No 
summary tables will be provided for pregnancy testing, physical examination, neurological 
examination, mental status, or psychiatric status. 
All safety summaries will be based on the Safety Analysis Set. 
For subjects entering from N01315, their ongoing AEs will be transferred into N01125, and 
their safety assessments will be provided in subject data listings only, no summaries will be 
presented. 
 
11.1 
Extent of exposure 
A daily dose will be calculated for each study day from the day of first dose of BRV to the 
day of last dose of BRV for the purposes of calculating modal dose. Daily dose will be 
calculated as the sum of the AM and PM dose for each day. 
Modal daily doses will be calculated across all study days on or after the day of first dose of 
BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during this period. In the event of a tie, the modal dose will be set 
to the lower of the tied doses. Modal daily dose will be categorized as follows: 
 
 
Category  
 
Definition 
5 mg/day  
 
<20mg/day 
20mg/day         
≥20mg/day to <50mg/day  
50mg/day  
 
≥50mg/day to <100mg/day 
100mg/day 
 
≥100mg/day to <150mg/day 
150mg/day 
 
≥150mg/day to <200mg/day 
200mg/day 
 
≥200mg/day 
Subject years of exposure will be calculated by summing the exposure duration in days for all 
subjects being summarized, and dividing the resulting value by 365.25. 
Subject years of exposure will be presented overall and by modal dose for the Safety 
Analysis Set. The subject years of exposure presented by modal dose will be the total subject 
years of exposure of subjects with that modal dose. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 35 of 50 
 
The number and percentage of subjects exposed to BRV will be summarized overall and by 
modal dose category. The number and percentage of subjects in each Exposure Duration 
Cohort (≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized. 
The number and percentage of subjects within each modal dose category will be summarized 
for each Exposure Duration Cohorts; percentages will be relative to the total number of 
subjects in each Exposure Duration Cohort. 
In addition to the overall summaries of the above, the above will also be summarized by 
subgroup for region (North America, Europe [EU member states], Europe [non-EU member 
states], Asia/Pacific/Other), and by indication (Partial Onset Seizures, Primary Generalized 
Seizures, ULD). 
11.2 
Adverse events 
11.2.1 
Definition of treatment-emergent AE 
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined 
as AEs which had onset prior to the date of the first dose of BRV. TEAEs are defined as AEs 
that had onset on or after the day of first BRV dose. AEs with an incomplete onset date will 
be classified as TEAEs if the month and year of onset (when only the month and year are 
specified) is the same as the month and year of the first BRV dose or the year of onset (when 
only year is specified) is the same as the year of first BRV dose. 
11.2.2 
General summaries of TEAEs 
Pre-treatment AEs will be provided in a subject data listing; no summaries of pre-treatment 
AEs are planned. 
An overall summary of AEs will provide the overall number of TEAEs and the numbers and 
percentages of subjects with at least 1 TEAE, with a TEAE that led to permanent 
discontinuation of study drug, with a drug-related TEAE, with a severe TEAE, with a 
treatment-emergent SAE, and with a drug-related treatment-emergent SAE. The number and 
percentage of subjects who died will also be summarized. This summary will be provided for 
all subjects in the Safety Analysis Set and also by subgroup for geographic region and 
indication. 
The following summaries of TEAEs will be provided by MedDRA SOC and PT. All 
summaries are for the combined Evaluation, Down-Titration, and Post-Treatment Periods 
unless otherwise indicated. 
Overall Incidence Summaries 
 Incidence of TEAEs 
 Incidence of TEAEs by 3-month time interval 
 Incidence of TEAEs by study period (Evaluation, Down-Titration, Post-Treatment) 
 Incidence of TEAEs for TEAEs occurring in at least 5% of subjects 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 36 of 50 
 
 Incidence of TEAEs by 3-month time intervals for TEAEs occurring in at least 5% of 
subjects overall 
 Incidence of non-serious TEAEs occurring in at least 5% of subjects 
The incidence of TEAEs occurring in at least 5% of subjects will be summarized overall as 
noted above and also by subgroup for geographic region, indication, and randomized 
treatment from the previous double-blind study. 
A subject is included in a 3-month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
as defined above. TEAEs which had onset prior to or on the date of the last dose of BRV are 
included in summaries by 3-month time intervals. 
Maximum Intensity and Causality 
 Incidence of TEAEs by maximum intensity 
 Incidence of drug-related TEAEs 
Serious Adverse Events 
 Incidence of treatment-emergent SAEs 
Discontinuations due to TEAE 
 Incidence of TEAEs leading to permanent discontinuation of study drug 
TEAEs of interest 
AEs of interest will be identified based on MedDRA search criteria, which are documented 
outside of the SAP.  The following summaries will be provided for AEs of interest: 
 Incidence of TEAEs of interest 
 Incidence of TEAEs of interest by 3-month time interval 
For the summary by maximum intensity, each subject will be counted at most once per SOC 
or PT according to the maximum intensity of all AEs within that SOC or PT. Severe intensity 
will be assumed for AEs for which intensity is not specified. 
Drug-related AEs are AEs for which the relationship to study drug is specified as Related or 
AEs for which relationship is not specified. 
11.3 
Clinical laboratory evaluations 
Clinical laboratory parameters (blood chemistry, hematology, urinalysis) are assessed at all 
FEVs, YEVs, EDVs, and at FV, and may also be assessed at Unscheduled Visits. 
For subjects entering the study from N01315, the clinical laboratory assessments will be 
provided in subject data listings only. The baseline assessment of these subjects will not be 
carried over from the previous studies. 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 37 of 50 
 
11.3.1 
Hematology and blood chemistry parameters 
Observed values for each planned hematology and blood chemistry parameter will be 
summarized for Baseline, Study Entry, and each scheduled visit during the Evaluation Period 
for which laboratory parameters were assessed, Last Value, EDV, and FV. Change from 
Baseline will be summarized for all post-Baseline time points including EV. Only laboratory 
parameters planned per protocol will be summarized; results for laboratory parameters not 
planned per the protocol will only be provided in subject data listings. 
The number and percentage of subjects with an on-treatment potentially clinically significant 
treatment-emergent (PCST) value, PCST low value, and PCST high value will be 
summarized. This summary will consider all assessments after the first dose of BRV and 
prior to or on the date of the last dose of BRV.  
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for Baseline, Study Entry, each visit during the 
Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last 
Value, and FV. Percentages for each parameter and time point will be relative to the number 
of subjects with a value at that time point. 
PCST criteria (Sections 13.3.1 and 13.3.2)  are based on FDA Division of 
Neuropharmacologic Drug Products guidelines with some UCB-defined additions. 
Creatinine clearance, when available from the central laboratory, will be provided in subject 
data listings only and will not be summarized. 
11.3.2 
Macroscopic urinalysis 
Quantitative urinalysis parameters will be summarized in the same manner as hematology 
and blood chemistry parameters. Response categories are negative, 1+, 2+, and 3+ for the 
qualitative urinalysis parameters occult blood, leukocytes, glucose, protein, and ketones and 
negative and positive for nitrates. Outcome values for these parameters are mapped to the 
levels Negative, 1+, 2+, and 3+ as follows for purposes of summary tables and the 
determination of PCST: 
Category 
Definition 
Negative 
“Negative”, “NEGATIVE”, or other outcomes that clearly reflect a negative 
finding 
1+ 
“1+”, “+” , “Trace”, “TRACE”, or other outcomes that clearly reflect trace 
amount 
2+ 
“2+” or “++” 
3+ 
“3+”, “+++”, or other outcomes that clearly reflect the data above 3+ (eg, 
“4+”, “5+” etc) or more than 4 plus signs (eg, “++++”, “+++++”etc) 
For qualitative urinalysis parameters (occult blood, leukocytes, glucose, protein, ketones, and 
nitrates), the number and percentage of subjects with each response category will be 
summarized for Baseline, Study Entry, each scheduled visit during the Evaluation Period for 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 38 of 50 
 
which urinalysis parameters were scheduled to be assessed, Last Value, EDV, and FV. 
Percentages for each parameter will be relative to the number of subjects with a result at each 
time point. 
For occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and 
percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high 
value will be summarized. This summary will consider all assessments after the first dose of 
BRV and prior to or on the date of the last dose of BRV.  
Additionally, for occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number 
and percentage of subjects with a PCST value, PCST low value, and PCST high value will be 
summarized for Baseline, Study Entry, each visit during the Evaluation Period for which 
laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages 
for each parameter and time point will be relative to the number of subjects with a value at 
that time point. 
11.3.3 
Microscopic urinalysis 
In microscopic urinalysis, a small sample of urine is centrifuged to remove the liquid. The 
sediment is then examined under a microscope. In the urinalysis laboratory test group, other 
than urinalysis parameters such as Bilirubin, Blood, Glucose, Ketone, Nitrite, pH, Protein, 
Specific Gravity, Total protein, Hemoglobin, Beta-HCG, Occult Blood, and Leukocytes, a 
listing of microscopic analysis parameters will be provided; no summaries of microscopic 
analysis findings are planned.   
11.4 
Vital signs, physical findings, and other observations related 
to safety 
For subjects entering the study from N01315, the vital signs, physical findings, and other 
observations related to safety assessments will be provided in subject data listings only. The 
baseline assessment from the previous studies of these subjects will not be presented. 
11.4.1 
Vital signs 
Vital signs are assessed at all FEVs, MEVs, YEVs, EDVs, and at FV, and may also be 
assessed at Unscheduled Visits. Body weight is assessed at all FEVs, YEVs, EDVs, and at 
FV, and may also be assessed at Unscheduled Visits. 
Observed values for SBP, DBP, pulse rate, and body weight will be summarized for Baseline, 
Study Entry, each visit during the Evaluation Period for which vital signs or body weight 
were assessed, EDV, Last Value, and FV. Changes from Baseline for SBP, DBP, pulse rate, 
and body weight will be summarized for all post-Baseline time points. 
The number and percentage of subjects with an on-treatment PCST value, PCST low value, 
and PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV.  
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for the above parameters for Study Entry, each visit 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 39 of 50 
 
during the Evaluation Period for which vital signs or body weight were scheduled to be 
assessed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects 
with a value at each time point. 
PCST criteria (Section 13.3.4) are based on FDA Division of Neuropharmacologic Drug 
Products guidelines with some UCB-defined additions. 
11.4.2 
Electrocardiograms 
ECGs are assessed at all YEVs, EDVs, and at FV, and may also be assessed at Unscheduled 
Visits. 
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding will be summarized overall. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV. 
Additionally, the number and percentage of subjects with no abnormality, an abnormal but 
not clinically significant finding, and a clinically significant finding will be summarized for 
Baseline, Study Entry, each visit during the Evaluation Period for which an ECG is scheduled 
to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of 
subjects with an ECG assessment at each time point. Subjects are counted at most once at 
each time point based on the worst observed outcome across all abnormalities reported at that 
time point. 
A subject number listing will be provided that identifies subjects with a clinically significant 
finding after the first dose of BRV for each type of ECG abnormality. 
11.4.3 
Physical examination 
A listing of abnormal physical examination findings will be provided; no summaries of 
physical examination findings are planned. 
11.4.4 
Neurological examination 
A listing of neurological examination findings will be provided; no summaries of 
neurological examination findings are planned. 
11.4.5 
Psychiatric and mental status 
A listing of abnormal Psychiatric and Mental Status findings will be provided; no summaries 
of Psychiatric and Mental Status findings are planned. 
11.4.6 
HADS 
The scoring algorithm for HADS is described in 3.8.3. 
During the first 2 years, HADS was assessed at Month 2, Month 6, Month 12, Month 18, and 
Month 24 and at EDV for subjects who discontinued the study prior to the YEV at the end of 
the second year for all subjects, and was also assessed at Month 4 and Month 9 for some 
subjects from N01114. HADS was not assessed for subjects from N01187 and N01236. Prior 
to integrated protocol amendment 25, HADS was being assessed for time points beyond the 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 40 of 50 
 
YEV at the end of the second year. These additional assessments will not be summarized but 
will be provided in subject data listings. 
Observed values for HADS depression and anxiety scores will be summarized for Baseline 
and Last Value for the Safety Analysis Set. Additionally, observed values will be 
summarized for Baseline and by visit for each study visit cohort. Summaries for each study 
visit cohort will only include scheduled visits up to the time of cutoff for the study visit 
cohort. Change from Baseline will be summarized at each visit during the Evaluation Period. 
For summaries of observed values at each time point, only subjects with a change from 
Baseline value at that time point will be summarized. Additionally, the mean and SD for each 
Baseline score will be provided at each post-Baseline time point for subjects included in the 
summary of change from Baseline. 
11.4.7 
Columbia-Suicide Severity Rating Scale 
With global amendment 25 to the protocol, the Columbia-Suicide Severity Rating Scale 
(C-SSRS) was added as an assessment at all study visits. Specific rules are provided to the 
study sites with regard to the identification of AEs or SAEs based on the outcome of this 
assessment. Because clinical events of interest will be recorded as AEs or SAEs, no study 
variable is defined for this assessment and no analyses are planned for the C-SSRS within the 
context of this study. However, subject data listings of the data for the C-SSRS will be 
provided. Additional listings will be provided for the subset of subjects with suicidal ideation 
and the subset of subject with actual suicide attempts. 
Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions: 





Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt 
questions: 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 41 of 50 
 
12 
REFERENCES 
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. 
Epilepsia 1998, 39(1): 81-88. 
EuroQol Group. EQ-5D. A measure of health-related quality of life developed by the 
EuroQol group. User guide. 8th issue. April 2000. 
Snaith RP, Zigmond AS. The hospital anxiety and depression scale manual. London: 
nferNelson Publishing Company Ltd. 1994. 
 
 
REDACTED COPY 
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 42 of 50 
 
13 
APPENDICES 
13.1 
QOLIE-31-P total and subscale score calculations 
The following outlines the calculation of the subscale scores for the QOLIE-31-P. The 
rescaled responses are provided for each item. The subscale scores are calculated by 
summing the rescaled responses for that subscale and dividing by the number of items with a 
non-missing response. Note that the divisors shown assume that all items for each subscale 
have a response; the divisor will differ if there are missing responses. A subscale score will 
be calculated only if at least 50% of the items within the subscale are present. 
 
Response 
Final Score 
Scale/Item Numbers 
1 
2 
3 
4 
5 
6 
Subtotal 
0-100 point scale  
 
Seizure Worry 
 
30. 
0 
20 
40 
60 
80 
100 
_____ 
 
31. 
0 
33.3 
66.7 
100 
–– 
–– 
_____ 
 
32. 
0 
50 
100 
 
–– 
–– 
_____ 
 
33. 
0 
33.3 
66.7 
100 
–– 
–– 
_____ 
 
34. 
100 
75 
50 
25 
0 
–– 
_____ 
 
 
 
 
 
 
 
 
TOTAL :   
_____ 
÷ 5 =  _____ 
Overall Quality of Life 
 
1. 
Multiply each response by 10 
 
 
_____ 
 
36. 
100 
75 
50 
25 
0 
–– 
_____ 
 
 
 
 
 
 
 
 
TOTAL : 
_____ 
÷ 2 =  _____ 
Emotional Well-Being 
 
7. 
0 
20 
40 
60 
80 
100 
_____ 
 
8. 
0 
20 
40 
60 
80 
100 
_____ 
 
9. 
100 
80 
60 
40 
20 
0 
_____ 
 
10. 
0 
20 
40 
60 
80 
100 
_____ 
 
11. 
100 
80 
60 
40 
20 
0 
_____ 
 
 
 
 
 
 
 
 
TOTAL : 
_____ 
÷ 5 =  _____ 
Energy/Fatigue 
 
2. 
100 
80 
60 
40 
20 
0 
_____ 
 
3. 
100 
80 
60 
40 
20 
0 
_____ 
 
4. 
0 
20 
40 
60 
80 
100 
_____ 
 
5. 
0 
20 
40 
60 
80 
100 
_____ 
 
 
 
 
 
 
 
 
TOTAL : 
_____ 
÷ 4 = _____  
Cognitive Functioning 
 
19. 
0 
20 
40 
60 
80 
100 
_____ 
 
20. 
0 
33.3 
66.7 
100 
–– 
–– 
_____ 
 
21. 
0 
20 
40 
60 
80 
100 
_____ 
 
22. 
0 
20 
40 
60 
80 
100 
_____ 
 
23. 
0 
20 
40 
60 
80 
100 
_____ 
 
24. 
100 
75 
50 
25 
0 
–– 
_____ 
 
 
 
 
 
 
 
 
TOTAL : 
_____ 
÷ 6 = _____ 
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t be used to support any marketing authorization application and any extensions or variations thereof. 
w
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UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 43 of 50 
 
Medication Effects 
 
28. 
0 
33.3 
66.7 
100 
–– 
–– 
_____ 
 
26. 
100 
75 
50 
25 
0 
–– 
_____ 
 
27. 
100 
75 
50 
25 
0 
–– 
_____ 
 
                                                                                      
 
TOTAL : 
_____ 
÷ 3 =  _____ 
Daily Activities/Social Functioning 
 
13. 
0 
20 
40 
60 
80 
100 
_____ 
 
14. 
0 
25 
50 
75 
100 
–– 
_____ 
 
15. 
0 
25 
50 
75 
100 
–– 
_____ 
 
16. 
100 
75 
50 
25 
0 
–– 
_____ 
 
17. 
100 
75 
50 
25 
0 
–– 
_____ 
 
 
 
 
 
 
 
 
TOTAL : 
_____ 
÷ 5 =  _____ 
 
Total score is calculated as a weighted sum of the subscale scores based on the weighting 
shown below. Total score will be missing if at least 1 subscale score is missing. Total score 
will range from 0 to 100 with a higher score reflecting better functioning. 
 
QOLIE-31-P Scale 
 
Final Scale 
Score 
 
 
Weight 
 
 
Subtotal 
 
 
 
 
 
 
 
Seizure worry 
(a) 
____ 
 
0.08 
= 
____ 
Overall quality of life 
(b) 
____ 
 
0.14 
= 
____ 
Emotional well-being 
(c) 
____ 
 
0.15 
= 
____ 
Energy/fatigue 
(d) 
____ 
 
0.12 
= 
____ 
Cognitive functioning 
(e) 
____ 
 
0.27 
= 
____ 
Medication effects 
(f) 
____ 
 
0.03 
= 
____ 
Daily activities/Social functioning 
(g) 
____ 
 
0.21 
= 
____ 
 
 
 
 
 
 
 
TOTAL SCORE: Sum subtotals (a) through (g) 
____ 
 
REDACTED COPY 
Y
_
C
_
(c)
CT
(c)
(d)
DAC
(d)
ny marketing authorization application and any extensions or variations thereof. 
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This document cannot be used to support a
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ubtota


UCB                                                                                                                                              11 February 2019 
Statistical Analysis Plan                                          Brivaracetam                                                                N01125 
 
Page 44 of 50 
 
13.2 
Subject site transfers 
 
RED
This document cannot be used to support any marketing au
nd any extensions or variations thereof. 


UCB 
 
19 May 2016 
Statistical Analysis Plan 
Brivaracetam 
N01125 
 
Confidential 
Page 45 of 50 
 
13.3 
PCST criteria 
13.3.1 
Hematology parameters 
Parameter 
UCB Conventional Units 
SI Units 
CF 
Hematocrit 
For 1 m to < 6 m:    25% 
For 1 m to < 6 m:    0.25 
0.01 
For 6 m to < 2 y:    27% 
For 6 m to < 2 y:    0.27 
For 2 y to < 4 y:    29% 
For 2 y to < 4 y:    0.29 
For 4 y to < 12 y:    32% (Female[F]);  35% (Male [M]) 
For 4 y to < 12 y:    0.32 (F);  0.35 (M) 
For  12 y:   
 32% (F);  37% (M) 
For  12 y:   
 0.32 (F);  0.37 (M) 
Hemoglobin 
For  6 m:   
 9.7 g/dL 
For  6 m:   
 97 g/L 
10 
For 6 m to < 12 y:    10.0 g/dL 
For 6 m to < 12 y:    100 g/L 
For  12 y:   
 9.5 g/dL (F);  11.5 g/dL (M) 
For  12 y:   
 95 g/L (F);  115 g/L (M) 
Platelets 
 75 x 109/L or  700 x 109/L 
 75 x 109/L or  700 x 109/L 
Not applicable (N/A) 
White Blood 
Cell (WBC) 
For  17 y:   
< 3.0 x 109/L or > 20 x 109/L;  
For  17 y:   
< 3.0 x 109/L or > 20 x 109/L;  
N/A 
For  17 y:   
< 2.8 x 109/L or > 16 x 109/L; 
For  17 y:   
< 2.8 x 109/L or > 16 x 109/L; 
Red Blood 
Cell (RBC) 
For  17 y:  < 2.5 x 106/mm3 
For  17 y:   
< 2.5 x 1012/L 
1 
For  17 y:  < 2.0 x 106/mm3 (F); < 2.5 x 106/mm3 (M) 
For  17 y:   
< 2.0 x 1012/L (F); < 2.5 x 1012/L (M) 
Eosinophils 
 10% or  0.7 x 109/L 
 0.10 or  0.7 x 109/L 
0.01 or N/A 
Neutrophils 
 15% or  1.0 x 109/L 
 0.15 or  1.0 x 109/L 
0.01 or N/A 
Basophils 
 5% or  0.4 x 109/L 
 0.05 or  0.4 x 109/L 
0.01 or N/A 
Monocytes 
 20% or  1.5 x 109/L 
 0.20 or  1.5 x 109/L 
0.01 or N/A 
Lymphocytes 
For 1 m to < 6 m:    22% or  80% 
For 1 m to < 6 m:    0.22 or  0.80  
0.01 
 
 2.1 x 109/L or  8.5 x 109/L 
 
 2.1 x 109/L or  8.5 x 109/L 
N/A 
For 6 m to < 2 y:    15% or  80%  
For 6 m to < 2 y:    0.15 or  0.80  
0.01 
 
 1.5 x 109/L or 7.5 x 109/L 
 
 1.5 x 109/L or 7.5 x 109/L 
N/A 
For 2 y to < 12 y:    12% or  80%  
For 2 y to < 12 y:    0.12 or  0.80  
0.01 
 
 1.0 x 109/L or  7.5 x 109/L 
 
 1.0 x 109/L or  7.5 x 109/L 
N/A 
For 12 y to  17 y:   10% or  80%  
For 12 y to  17 y:    0.10 or  0.80  
0.01 
 
 0.5 x 109/L or  5.5 x 109/L 
 
 0.5 x 109/L or  5.5 x 109/L 
N/A 
For  17 y:   
 10% or  80%  
For  17 y:   
 0.10 or  0.80  
0.01 
 
 0.5 x 109/L or  4.5 x 109/L 
 
 0.5 x 109/L or  4.5 x 109/L 
N/A 
EDACTED COPY 
For
Y
For
For 
OPY
For 
OP
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authorization application and any extensions or variations thereof. 
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an


UCB 
 
19 May 2016 
Statistical Analysis Plan 
Brivaracetam 
N01125 
 
Confidential 
Page 46 of 50 
 
13.3.2 
Blood chemistry parameters 
Parameter 
UCB Conventional Units 
SI Units 
CF 
AST (SGOT) 
> 3 times of  ULN 
> 3 times of  ULN 
N/A 
ALT (SGPT) 
> 3 times of  ULN 
> 3 times of  ULN 
N/A 
ALP 
For  17 y:   
> 2 times of  ULN, if normal range 
 
adjusted to the age range;  
For  17 y:   
> 2 times of  ULN, if normal range 
 
adjusted to the age range;  
N/A 
For  17 y:   
> 3 times of  ULN 
For  17 y: 
> 3 times of  ULN 
GGT 
> 3 times of  ULN, if baseline value < 3 times of  ULN 
> 3 times of  ULN, if baseline value < 3 times of  ULN 
N/A 
BUN 
> 30 mg/dL 
> 10.71 mmol/L 
0.357 
Urea 
> 60 mg/dL 
> 10.02 mmol/L 
0.167 
Creatinine 
For  17 y:  
> 1.5 mg/dL;  
For  17 y:   
> 132.6 umol/L;  
88.4 
For  17 y:   
 > 2.0 mg/dL 
For  17 y:   
> 176.8 umol/L 
Creatinine 
clearance 
(calc) 
For  12 y:   
 70 ml/min (Schwartz)(a) 
For  12 y:   
 70 ml/min (Schwartz)(a) 
N/A 
For  12 y:   
 70 ml/min (Cockroft)(b) 
For  12 y:   
 70 ml/min (Cockroft)(b) 
Total 
bilirubin 
> 2.0 mg/dL 
> 34.2 umol/L 
17.1 
Glucose 
 50 mg/dL or  180 mg/dL 
 2.775 mmol/L or  9.99 mmol/L 
0.0555 
Total Protein 
For  1 m to  6 m:    3.6 g/dL or  7.8 g/dL 
For  1 m to  6 m:    36 g/L or  78 g/L 
10 
For  6 m to  17 y:    4.7 g/dL or  9.5 g/dL 
For  6 m to  17 y:    47 g/L or  95 g/L 
For  17 y:  
 4.5 g/dL or  9.0 g/dL 
For  17 y:  
 45 g/L or  90 g/L 
Albumin 
For  17 y:   
 2.4 g/dL or  6.5 g/dL 
For  17 y:   
 24 g/L or  65 g/L 
10 
For  17 y:  
 2.5 g/dL or  6.5 g/dL 
For  17 y:  
 25 g/L or  65 g/L 
Globulin 
For  17 y:  
 1.2 g/dL or  5.0 g/dL 
For  17 y: 
 12 g/L or  50 g/L 
10 
For  17 y:  
 1.5 g/dL or  5.0 g/dL 
For  17 y:  
 15 g/L or  50 g/L 
Sodium 
For  17 y:   
 120 mEq/L or  155 mEq/L 
For  17 y:   
 120 mmol/L or  155 mmol/L 
1 
For  17 y:  
 115 mEq/L or  155 mEq/L 
For  17 y:  
 115 mmol/L or  155 mmol/L 
Potassium 
For  17 y:   
 3.0 mEq/L or  6.5 mEq/L 
For  17 y:   
 3.0 mmol/L or  6.5 mmol/L 
1 
For  17 y:  
 3.0 mEq/L or  5.8 mEq/L 
For  17 y:  
 3.0 mmol/L or  5.8 mmol/L 
Calcium 
For  17 y:   
 7 mg/dL or  11.5 mg/dL 
For  17 y:   
 1.75 mmol/L or  2.875 mmol/L 
0.25 
For  17 y:   
 7 mg/dL or  15.5 mg/dL 
For  17 y:   
 1.75 mmol/L or  3.875 mmol/L 
REDACTED COPY 
F
Y
F
Y
CO
CT
RE
R
annot be used to support any marketing authorization application and any extensions or variations thereof. 
Units
sion
Units
on
si
te
> 2
ny
2 time
y e
time
n
adjus
any
adjus
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>
 
>
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an
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For 
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ann
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This document can
an


UCB 
 
19 May 2016 
Statistical Analysis Plan 
Brivaracetam 
N01125 
 
Confidential 
Page 47 of 50 
 
Uric Acid 
 
For < 12 y:   
 8 mg/dL 
For < 12 y:   
 475.84 umol/L 
59.48 
For  12 y:   
 8 mg/dL (F);  9.5 mg/dL (M) 
For  12 y:   
 475.84 umol/L (F);  565.06 umol/L 
(M) 
Cholesterol 
 300 mg/dL 
 7.77 mmol/L 
0.0259 
HDL 
 25 mg/dL 
 0.65 mmol/L 
0.0259 
LDL 
 200 mg/dL 
 5.18 mmol/L 
0.0259 
Triglycerides 
 300 mg/dL 
 3.42 mmol/L 
0.0114 
(a)  Schwartz equation (patients <12):  
Cr Cl ml/min = [Height (cm) * 0.55] / serum creatinine  
(b)  Cockroft equation (patients >12): 
Male: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine), 
 
 
 
 
 
 
                      Female: Cr Cl ml/min = [(140-age) x body weight (kg)] / (72 x serum creatinine)] x 0.85 
ALT=alanine aminotransferase; ALP=Alkaline phosphatase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CR CL=creatinine clearance; 
GGT=Gamma-glutamyl transpeptidase; HDL=High-density lipoprotein; LDL=low-density lipoprotein; SGOT=serum glutamic oxaloacetic transaminase; 
SGPT=serum glutamic pyruvic transaminase; ULN=Upper Limit of Normal.  
COPY
mi
Y
mi
DL=low
OPY 
DL=low
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REDACTED CO
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nd any extensions or variations thereof. 
/L
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/L
or
mol/L (
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mol/L (
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kg)] / (7
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This document cannot be used to support any marketing authorization
nd
on


UCB 
 
19 May 2016 
Statistical Analysis Plan 
Brivaracetam 
N01125 
 
Confidential 
Page 48 of 50 
 
13.3.3 
Urinalysis 
Qualitative urine parameters are generally reported by a descriptive score, which differs 
among laboratories. For data analysis purpose, a four-point scale is used. Five-point, six-
point, or seven-point scales will be collapsed into a four-point scale first. A value is 
considered possibly clinically significant treatment emergent abnormal if an upward shift of 
at least 2 degrees from the baseline occurs under investigational treatment.  To collapse the 
results in a five-point scale into a four-point scale, the lowest two positive results will be 
combined (see example below). For results reported with a scale of more than five-point, 
please consult your study physician for how to collapse into four-point scale. 
Original Five-point Scale 
Four-point Scale 
 
 
Negative/None 
Negative/None 
Trace/Rare/Mild/A Few 
Trace/1+/Rare/Mild/A Few 
1+ 
 
2+/Mod 
2+/Mod 
3+/Sev 
3+/Sev 
13.3.4 
Vital signs and body weight 
Pulse rate 
For 1 m to  12 m:  <110 bpm and a decrease of > 20 bpm from 
baseline or > 180 bpm and an increase of > 20 bpm from 
baseline 
For 12 m to  3 y:  < 90 bpm and a decrease of > 20 bpm from 
baseline or > 150 bpm and an increase of > 20 bpm from 
baseline 
For 3 y to  12 y:  < 65 bpm and a decrease of > 20 bpm from 
baseline or > 130 bpm and an increase of > 20 bpm from 
baseline 
For 12 y to  17 y:  < 60 bpm and a decrease of > 20 bpm from 
baseline or > 120 bpm and an increase of > 20 bpm from 
baseline 
For  17 y:  < 50 bpm and a decrease of > 30 bpm from 
baseline or > 120 bpm and an increase of > 30 bpm from 
baseline 
bpm=Beats per minute. 
 
 
REDACTED COPY 
m
CO
m: 
COP
: <
OP
<1
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1
180 b
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180 b
m to
DAC
m to
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pplication and any extensions or variations thereof. 
int,
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110 bp
on ap
110 bp
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bpm an

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basel
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This document cannot be used to support an
app
nn
an
m=Bea
can
m=Bea


UCB 
 
19 May 2016 
Statistical Analysis Plan 
Brivaracetam 
N01125 
 
Confidential 
Page 49 of 50 
 
Systolic blood pressure 
For 1 m to  12 m:  < 60 mmHg and a decrease of > 20 mmHg 
from baseline or > 110 mmHg and an increase of  
> 30 mmHg from baseline 
For 12 m to  6 y:  < 70 mmHg and a decrease of > 20 mmHg 
from baseline or > 120 mmHg and an increase of  
> 30 mmHg from baseline 
For 6 y to  13 y:  < 70 mmHg and a decrease of > 20 mmHg 
from baseline or > 130 mmHg and an increase of  
> 30 mmHg from baseline 
For 13 y and  17 y:  < 90 mmHg and a decrease of > 20 
mmHg from baseline or > 140 mmHg and an increase of  
> 30 mmHg from baseline 
For  17 y:  < 90 mmHg and a decrease of > 30 mmHg from 
baseline or > 180 mmHg and an increase of > 40 mmHg from 
baseline 
Diastolic blood pressure 
For 1 m to  12 m:  < 40 mmHg and a decrease of > 15 mmHg 
from baseline or > 60 mmHg and an increase of  
> 20 mmHg from baseline 
For 12 m to  6 y:  < 45 mmHg and a decrease of > 15 mmHg 
from baseline or > 80 mmHg and an increase of  
> 20 mmHg from baseline 
For 6 y to  13 y:  < 50 mmHg and a decrease of > 15 mmHg 
from baseline or > 85 mmHg and an increase of  
> 20 mmHg from baseline 
For 13 y to  17 y:  < 55 mmHg and a decrease of > 20 mmHg 
from baseline or > 90 mmHg and an increase of  
> 30 mmHg from baseline 
For  17 y:  < 50 mmHg and a decrease of > 20 mmHg from 
baseline or > 105 mmHg and an increase of > 30 mmHg from 
baseline 
Weight 
For  17 y:  < 3% or  97% of the normal body weight growth 
curve ranges for the age at date of weight assessment (a) and 
gender; 
For  17 y:  change of  7% of baseline weight 
(a) Once the subject reaches 17 years of age use the body curve criteria of a 17-year old 
regardless of their age in the study.  
 
REDACTED COPY
60 m
OPY 
60 m
m bas
COP
m bas

TE
6 y
ED 
6 y
seline 
ACT
seline 
mm
EDA
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DAC
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ation and any extensions or variations thereof. 
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> 20 m
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> 20 m
Fo
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This document cannot be used to support an
at
an
ght
ot
ght
be
e


UCB 
 
19 May 2016 
Statistical Analysis Plan 
Brivaracetam 
N01125 
 
Confidential 
Page 50 of 50 
 
14 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
Rational for the amendment 
The primary purpose for the amendment is (1) include subjects entering the study from study 
N01315 into this statistical analysis plan; (2) remove rules and definitions based on data 
cutoffs for interim analyses; (3) remove the summary analysis for direct cost parameter and 
indirect cost parameters, and as well as Socio-professional data. 
Change #1 (global) 
Removed all rules and definitions based on data cutoffs for interim analyses throughout SAP. 
Change #2 (global)  
Added analysis plan for subjects entering the study from study N01315 throughout SAP. 
Change #3 (global) 
Section 8.2.5 Direct cost parameters, Section 8.2.6 Indirect cost parameters, Section 8.2.7 
Socio-professional data 
Removed all direct/indirect cost parameters and socio-professional data summary analysis. 
Change #4 
Section 2.4 Determination of Sample Size 
Changed the sample size to include subjects entering from N01315. 
Change #5 
Section 3.5.1 Safety Analysis Set 
Modified Safety Analysis Set and added a modified Safety Analysis Set. 
Change #6 
Section 13.2 Subject site transfers 
Removed subjects 
 
Change #7 
Removed signature page. Using e-signature approval process through Source Submission. 
 
 
REDACTED COPY 
cts en
CTED
cts en
keting authorization application and any extensions or variations thereof. 
ghout S
ns or
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and 
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Approval Signatures
Name:
N01125-SAP-Amendment-1
Version:
1. 0
Document Number:
CLIN-000130975
Title:
N01125-SAP-Amendment-1
Approved Date:
25 Feb 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 11-Feb-2019 14:05:58 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-Feb-2019 20:26:08 GMT+0000
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 
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