Clinical trial NCT00761774
Conditions: Epilepsy
Keywords: Epilepsy Monotherapy Partial Onset Seizures
Sponsor: UCB Pharma
Start date: 2008-11-01; Completion date: 2017-03-01
Enrollment: 108 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The Sponsor wishes to develop brivaracetam as an anti-epileptic treatment in subjects 16 years and older with epilepsy. This study permits continued access to treatment for subjects who participated in a previous epilepsy study. The study will explore the long-term safety and efficacy of brivaracetam.

Detailed description:

Arms: arm 1: Brivaracetam at flexible dosing up to 200mg /day
Interventions: intervention 1: Brivaracetam
Intervention descriptions: intervention 1: Subjects will begin at a recommended dose of Brivaracetam 100 mg/day. Subjects will continue treatment at a dose up to a maximum of 200 mg/day with a twice per day administration. Up- and down-titration steps may be performed in steps of a maximum of 50 mg/day on a weekly basis. Full down-titration should include a one week step on 20 mg/day. The study medication will come in 10 mg and 25 mg tablet strengths.

Protocol documents:
Prot_000.pdf: 
Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 1 of 89
1.
TITLE
Protocol of Study N01315
An open-label, multinational, multicenter, follow-up study to evaluate the long-term safety 
and efficacy of brivaracetam, used at a flexible dose up to a maximum of 200mg/day, in 
subjects aged 16 years or older suffering from epilepsy.
Sponsor:
UCB Biosciences, Inc
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Hereafter “UCB”
Brivaracetam - EudraCT Number: 2008-001433-98; IND Number: 70,205
Confidential Material
The information contained in this document is strictly confidential.  It is disclosed to you as a 
(potential) Investigator or (potential) consultant.  Acceptance of this document constitutes 
your agreement that the information contained herein will not be disclosed or in any way 
communicated to any third party without prior written approval of UCB (or it’s 
representative(s)) of the clinical study described therein except - to the extent necessary - to 
your staff, to members of appropriate review committee(s) and/or to persons to whom the 
investigational product may be administered or to their legal representative(s) to obtain their 
informed consent.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 2 of 89
Principal Investigator
By my signature below, I acknowledge that I have read the protocol (RPCE08C0502) and 
agree that it contains all necessary details for carrying out the clinical study described therein.  
Furthermore, I agree to conduct this clinical study in compliance with said Protocol, the ICH 
Good Clinical Practice guideline, as well as with any and all applicable federal, state and/or 
local laws and regulations and with my contractual obligations towards UCB or its 
representatives(s).
Signature:
___________________________________________
Date:
______________
Printed Name:
______________________________________________________________________
Address:
______________________________________________________________________
______________________________________________________________________
Phone:
____________________________________
Site 
Number:
______________
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 3 of 89
2.
CONTACT INFORMATION
Sponsor
UCB Biosciences, Inc
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
UCB Contributors:
Study Physician 
Name:
, MD
Phone:
Mobile:
Fax:
Clinical Project Manager (CPM)
Name:
Phone:
Fax:
Trial Statistician 
Name:
Phone:
Fax:
SAEs Reporting (24h/24)

Fax:
Europe and Rest of the World: 
+32-2-386-2421
USA: 
+1-800-880-6949
Canada: 
+1-877-582-8842

Email:
Global
DSICT@ucb.com
Investigator(s)
The complete and updated list of Investigators is maintained in the Trial Master File (TMF) 
at UCB.
Signatory Coordinating Investigator(s)
The signatory coordinating Investigator will be designated by UCB.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 4 of 89
3.
TABLE OF CONTENTS
1.
TITLE..............................................................................................................................1
2.
CONTACT INFORMATION .......................................................................................3
3.
TABLE OF CONTENTS...............................................................................................4
4.
LIST OF ABBREVIATIONS........................................................................................9
5.
PROTOCOL SUMMARY...........................................................................................11
5.1
Study Schedule of Assessments.......................................................................16
5.2
Schematic Diagram ..........................................................................................19
6.
BACKGROUND INFORMATION............................................................................21
6.1
Background and epidemiology of targeted disease..........................................21
6.2
Background information regarding product.....................................................22
6.3
Efficacy with BRV in fixed-dose Phase II/III studies in POS .........................23
6.4
Conversion to monotherapy .............................................................................23
6.5
Safety with BRV ..............................................................................................24
6.6
Study Rationale ................................................................................................24
6.6.1
Dose Selection....................................................................................24
6.6.2
Subject Population .............................................................................24
6.6.3
Treatment Duration............................................................................25
6.6.4
Statement............................................................................................25
7.
STUDY OBJECTIVES ................................................................................................26
7.1
Primary Objective ............................................................................................26
7.2
Secondary Objective ........................................................................................26
7.3
Exploratory Objectives.....................................................................................26
8.
STUDY DESIGN ..........................................................................................................27
8.1
Type/Design .....................................................................................................27
8.2
Subjects/Sites Numbers....................................................................................27
8.3
Measures to Minimize/Avoid Bias...................................................................27
8.3.1
Blinding..............................................................................................27
8.3.2
Randomization ...................................................................................27
8.3.3
Subject Identifier................................................................................27
8.4
Study Duration .................................................................................................28
8.5
End of Study.....................................................................................................28
9.
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................29
9.1
Subject Inclusion Criteria.................................................................................29
9.2
Subject Exclusion Criteria................................................................................30
9.3
Subject Withdrawal..........................................................................................30
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 5 of 89
10.
TREATMENT OF SUBJECTS (INVESTIGATIONAL PRODUCT AND
CONCOMITANT MEDICATIONS) .........................................................................32
10.1
Study Investigational Products.........................................................................32
10.1.1
Description of all Investigational Products........................................32
10.1.1.1
Dosing Schedule ...............................................................32
10.1.2
Packaging...........................................................................................33
10.1.3
Labeling..............................................................................................33
10.1.4
Storage Requirements ........................................................................33
10.1.5
Monitoring of Subject Compliance....................................................34
10.1.6
Investigational Products Accountability ............................................34
10.2
Concomitant Treatments and Rescue Medications ..........................................35
10.2.1
Permitted Concomitant Treatments (Medications and Therapies) ....35
10.2.2
Prohibited Concomitant Treatments (Medications and
Therapies)...........................................................................................35
11.
STUDY PROCEDURES..............................................................................................36
11.1
Description of Procedures................................................................................36
11.1.1
Informed Consent...............................................................................36
11.1.2
Subject Study Card.............................................................................36
11.1.3
Eligibility Criteria Assessment ..........................................................36
11.1.4
Demography.......................................................................................36
11.1.5
Childbearing Potential and Birth Control ..........................................37
11.1.6
Medical and Procedure History..........................................................37
11.1.7
Epilepsy History.................................................................................37
11.1.8
Antiepileptic Medication History.......................................................37
11.1.9
Vital Signs..........................................................................................37
11.1.10 Body Weight and Height....................................................................37
11.1.11 Physical Examination.........................................................................38
11.1.12 Neurological Examination .................................................................38
11.1.13 ECG....................................................................................................38
11.1.14 Daily Record Card..............................................................................38
11.1.15 Laboratory Assessments and Study Medication/AED(s)
Plasma Levels ...................................................................................39
11.1.16 Adverse Events (AEs)........................................................................40
11.1.17 Assessment of Suicidality ..................................................................40
11.1.18 Medical Procedures............................................................................40
11.1.19 Non-Antiepileptic and Antiepileptic Concomitant Medications........41
11.1.20 Patient Reported Outcomes................................................................41
11.1.20.1 Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)41
11.1.20.2 Hospital Anxiety and Depression Scale (HADS) .............42
11.1.20.3 EQ-5D Questionnaire........................................................42
11.1.21 Hospital Stay......................................................................................42
11.1.22 Healthcare Provider Consultations not foreseen by the Protocol.......42
11.1.23 Socio-professional Data .....................................................................43
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 6 of 89
11.1.24 End of Study.......................................................................................43
11.2
Description Visit by Visit.................................................................................43
11.2.1
Entry Visit..........................................................................................44
11.2.2
Full Evaluation Visit ..........................................................................45
11.2.3
Minimal Evaluation Visit...................................................................45
11.2.4
Yearly Evaluation Visit (replaces the first FEV of each year)...........46
11.2.5
Early Discontinuation Visit................................................................47
11.2.6
Down-Titration Phone Call................................................................48
11.2.7
Final Visit (FV following a Study Drug Free Period after an
EDV or FV initiated upon Sponsor request at the end of the
program).............................................................................................48
11.2.8
Additional Visit..................................................................................48
11.3
Handling of Biological Samples ......................................................................49
11.4
Other Supplies..................................................................................................49
12.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................50
12.1
Adverse Events.................................................................................................50
12.1.1
Definition of Adverse Event (AE) .....................................................50
12.1.2
Procedures for Reporting and Recording Adverse Events.................50
12.1.3
Description of AEs.............................................................................50
12.1.4
Follow-up on Adverse Events............................................................53
12.1.5
Rule for Repetition of an AE .............................................................53
12.1.6
Pregnancy...........................................................................................53
12.1.7
Overdose of Investigational Product..................................................54
12.1.8
Safety Signal Detection in Ongoing Clinical Studies ........................54
12.2
Serious Adverse Events....................................................................................54
12.2.1
Definition of Serious Adverse Event (SAE)......................................54
12.2.2
Procedures for Reporting Serious Adverse Events (SAEs) ...............55
12.2.3
Follow-up of Serious Adverse Events................................................56
12.2.4
Anticipated Serious Adverse Events..................................................56
13.
STATISTICS.................................................................................................................58
13.1
Statistical and Analytical Plans........................................................................58
13.1.1
Study Population(s)............................................................................58
13.1.2
Safety, Efficacy, and Other Variables................................................58
13.1.2.1
Primary Safety Variables ..................................................58
13.1.2.2
Other Safety Variables......................................................58
13.1.2.3
Secondary Efficacy Variables...........................................58
13.1.2.4
Other Efficacy Variables...................................................58
13.1.2.5
Pharmacoeconomic Variables...........................................59
13.1.2.6
Pharmacokinetic Variables................................................59
13.1.3
Statistical Evaluation..........................................................................59
13.1.3.1
Evaluation of Safety..........................................................59
13.1.3.2
Evaluation of Efficacy.......................................................60
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 7 of 89
13.2
Determination of the Sample Size....................................................................60
13.3
Changes in the Conduct of the Study or the Planned Analyses .......................60
13.4
Statistical and Analytical Issues.......................................................................61
13.4.1
Adjustments for Covariates and Interactions.....................................61
13.4.2
Handling of Dropouts of Missing Data..............................................61
13.4.3
Interim Analysis.................................................................................61
13.4.4
Multi-center Studies...........................................................................61
13.4.5
Multiple Treatment Comparisons/Multiple Endpoints ......................61
13.4.6
Examination of Subgroups.................................................................61
13.5
Pre-Analysis Review of Data ...........................................................................61
13.6
Criteria for Un-blinding the Results.................................................................62
13.7
Dictionaries ......................................................................................................62
14.
ETHICS AND REGULATORY REQUIREMENTS................................................63
14.1
Approval...........................................................................................................63
14.2
Subject Information and Consent.....................................................................64
14.3
Subject Confidentiality.....................................................................................65
14.4
Informing the General Practitioner ..................................................................65
15.
STUDY MANAGEMENT AND ADMINISTRATION ............................................66
15.1
Monitoring........................................................................................................66
15.2
Direct Access to Source Data/Documents .......................................................66
15.3
Audit and Inspection ........................................................................................67
15.4
Case Report Forms (CRF) and Screen Failures ...............................................68
15.5
Adherence to Protocol......................................................................................68
15.6
Investigator Site File ........................................................................................69
15.7
Data Handling ..................................................................................................69
15.8
Termination of Study .......................................................................................69
15.9
Clinical Study Report.......................................................................................70
15.10
Insurance and Liability.....................................................................................70
15.11
Archiving and Data Retention..........................................................................71
15.12
Allocation of Responsibilities..........................................................................71
15.13
Curriculum Vitae (CV).....................................................................................71
15.14
Financial Disclosure.........................................................................................71
15.15
Good Clinical Practice .....................................................................................72
15.16
Disclosure of Clinical Study Information ........................................................72
15.17
Publication........................................................................................................72
16.
REFERENCES .............................................................................................................73
17.
APPENDICES...............................................................................................................75
17.1
Health related Quality of Life Questionnaire (QOLIE-31-P) (Version 2).......75
17.2
Hospital Anxiety and Depression Scale (HADS) ............................................85
17.3
EQ-5D ..............................................................................................................86
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 8 of 89
List of Tables
Table 5:1
Study Flowchart...........................................................................................16
Table 5:2
Visit Schematic Diagram.............................................................................19
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 9 of 89
4.
LIST OF ABBREVIATIONS
AE
Adverse event
AED(s)
Antiepileptic Drug(s)
ALT(ALAT/SGPT)
Alanine Aminotransferase
AST (ASAT/SGOT) Aspartate Aminotransferase
b.i.d.
Twice daily
BRV
brivaracetam
CNS
Central Nervous System
CPM
Clinical Project Manager
Cr Cl
Creatinine Clearance
CRF
Case Report Form
CRO
Clinical Research Organization
C-SSRS
Columbia Suicide Severity Rating Scale
CTM
Clinical Trial Manager
CTS
Clinical Trials Supplies
CV
Curriculum Vitae
CYP
Cytochrome P450
DRC
Daily Record Card
ECG
Electrocardiogram
EDV
Early Discontinuation Visit
EEG
Electroencephalogram
EQ-5D
EuroQoL-5 Dimensions
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GP
General Practitioner
HADS
Hospital Anxiety and Depression Scale
HDL
High Density Lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
LTFU
Long-term Follow-up
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
PBO
Placebo
PK
Pharmacokinetic(s)
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 10 of 89
POS
Partial onset seizure(s)
PRO
Patient Reported Outcome
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy Questionnaire
RBC
Red Blood Cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV2A
Synaptic vesicle protein 2A
TEAE
Treatment-emergent adverse event
TMF
Trial Master File
V
Visit
WBC
White Blood Cell
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 11 of 89
5.
PROTOCOL SUMMARY
TITLE OF THE STUDY
An open-label, multinational, multicenter, follow-up study to evaluate the long-term safety 
and efficacy of brivaracetam used at a flexible dose up to a maximum of 200mg/day in 
subjects aged 16 years or older suffering from epilepsy.
STUDY TYPE/PHASE
Phase III
STUDY OBJECTIVES
Primary Objective
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized 
doses with a maximum of 200mg/day in subjects suffering from epilepsy.
Secondary Objective
To evaluate the maintenance of efficacy over time of BRV.
Exploratory Objectives

To explore impact on health-related quality of life, anxiety and depression.

To obtain a description of patient’s self-reported health status.

To collect data on medical resources used and on indirect cost parameters.
STUDY VARIABLES
Primary Safety Variables

Occurrence of a treatment-emergent adverse event (TEAE)

Withdrawal due to AE

Occurrence of a serious adverse event (SAE)
Other Safety Variables

Laboratory tests (blood chemistry, hematology, and urinalysis)

Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate)
and body weight

Electrocardiogram (ECG)

Physical and neurological examination
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 12 of 89

Change in Hospital Anxiety and Depression Scale (HADS) scores from the Baseline 
of the previous study to each assessment for the first 2 years and to the last Evaluation 
Period assessment during the first 2 years
Secondary Efficacy Variables

Percentage of subjects on continuous BRV monotherapy for at least 3 months, at least 
6 months, and at least 12 months of the Evaluation Period
Other Efficacy Variables

Partial onset seizure (POS) (type I) frequency per 28 days during the Evaluation 
Period

Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period

Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period

Change in Patient Weighted Quality of Life in Epilepsy Questionnaire 
(QOLIE-31-P) scores from Baseline of the previous study to each assessment for the 
first 2 years and to the last Evaluation Period assessment during the first 2 years

EuroQoL-5 Dimensions (EQ-5D) questionnaire response for each assessment for the 
first 2 years for the Evaluation Period and for the last assessment during the first 
2 years of the Evaluation Period
Pharmacoeconomic Variables

Direct costs (healthcare provider consultations not foreseen by the protocol, 
concurrent medical procedures, concomitant medications, hospitalizations, and 
emergency room [ER] visits) during the first 2 years of the Evaluation Period

Indirect costs (workdays or schooldays lost by the subject and days subject received 
help from a caregiver) during the first 2 years of the Evaluation Period

Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
Pharmacokinetic Variables

Brivaracetam (parent compound only) plasma levels

Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels
STUDY DESIGN
This is a Phase III, long-term follow-up (LTFU), multinational, multicenter, 
non-comparative, open-label and single arm study.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 13 of 89
The visits will be scheduled as follows:

First year:

First 3 months:  1 visit/month:  Full Evaluation Visit (FEV) alternating with 
Minimal Evaluation Visit (MEV).

Next 9 months:  1 visit/3 months:  FEV alternating with MEV.

Second and subsequent years:

1 visit/3 months:  FEV alternating with MEV.

The Yearly Evaluation Visit (YEV) will be performed in replacement of the first 
FEV of each year.
PLANNED STUDY PERIOD
This study will run throughout the duration of the clinical development period of BRV, and 
will continue until a marketing authorization is granted by any Health Authority in an 
indication for the adjunctive treatment in adults with refractory POS, whether or not 
secondarily generalized, until the Sponsor decides to close the study, until subjects transition 
to another BRV study, until a managed access program, named patient program, 
compassionate use program, or similar type of access program is established as allowed per 
country-specific requirements in addition to legal and regulatory guidelines, or until BRV
development is stopped by the Sponsor.
PLANNED NUMBER OF SUBJECTS AND SITES:
It was estimated that approximately 300-600 subjects were to enter the study. However, the 
number of subjects entered will be reduced due to the premature discontinuation of N01276 
and N01306.
This study will include as many sites as required (initially, 120-180 sites are foreseen).
REGIONS AND COUNTRIES
The study is planned to be performed worldwide.
MAIN INCLUSION AND EXCLUSION CRITERIA
Before any study procedures are initiated for any subject in this study, an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB) approved written informed consent form 
will be properly executed and documented.
Subject Inclusion Criteria:

An IEC/IRB approved written informed consent signed and dated by the subject or by 
parent(s) or legally acceptable representative.  The consent form or a specific assent 
form, where required, will be signed and dated by minors.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 14 of 89

Male/female subjects from 16 years or older.  Subjects under 18 years may only be 
included where legally permitted and ethically accepted. In 
 all subjects must 
be older than 18 years.

Subjects with epilepsy who participated in previous BRV studies which allow access to 
the present study.

Subjects from whom the Investigator believes a reasonable potential benefit from the 
long-term administration of BRV may be expected. 

Female subjects without childbearing potential (premenarcheal; 2 years 
postmenopausal, bilateral oophorectomy or ovariectomy, bilateral salpingectomy, 
complete hysterectomy, congenital sterility) are eligible.  Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive 
method for the duration of the study (Intra Uterine Device, diaphragm with spermicide, 
male or female condom with spermicide; oral hormonal contraceptive, non-oral 
hormonal contraceptive medication, bilateral tubal ligation, bilateral tubal implant, 
monogamous relationship with vasectomized partner).  Oral or depot contraceptive 
treatment with at least 30µg [or 50µg if associated with other antiepileptic drugs known 
as inducers] ethinylestradiol per intake must be used in conjunction with a barrier 
method.  The subject must understand the consequences and potential risks of 
inadequately protected sexual activity, be educated about and understand the proper use 
of contraceptive methods, and undertake to inform the Investigator of any potential 
change in status. Sexual inactivity might be accepted on a case-by-case basis.

Subject/legally acceptable representative considered as reliable and capable of adhering 
to the protocol (e.g. able to understand and complete diaries and questionnaires), visit 
schedule or medication intake according to the judgment of the Investigator.
Subject Exclusion Criteria:

Severe medical, neurological and psychiatric disorders, including current suicidal 
ideation or behaviour, or laboratory values which may have an impact on the safety of 
the subject, as determined by the Investigator.

Poor compliance with the visit schedule or medication intake in the previous BRV 
study.

Participation in any clinical study of another investigation drug or device during the 
study.

Pregnant or lactating woman.
INVESTIGATIONAL PRODUCT
Oral tablets of 10mg and 25mg BRV, packaged in bottles containing 200 oral tablets.
Subjects will begin at a recommended dose of BRV 100mg/day. The daily dose should be 
divided into 2 equal intakes (morning and evening), taken with or without food.  The first 
intake will be in the evening of the day of the dispensation of the study medication.
Subjects will continue BRV treatment at a dose up to a maximum of 200mg/day in twice 
daily (b.i.d.) administration. Up- and down-titration steps should be performed in steps of 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 15 of 89
maximum 50mg/day on a weekly basis. Full down-titration should include a 1-week step on 
20mg/day.
The doses administered in this study must comply with doses that can be administered with 
either BRV 10mg tablets, 25mg tablets, or a combination of these 2 strengths in a total daily 
dose that can be administered in 2 equal doses.  Daily dose prescriptions that do not respect 
these limitations should not be administered.
Each subject will be informed on how to take the drug and that there might be an excess of 
drug dispensed at each visit.
STATISTICAL METHODS
Population for Analysis
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
The Efficacy Population will consist of all subjects who took at least 1 dose of study 
medication and have at least 1 seizure diary day during the Evaluation Period.
Safety Variables Analyses
All safety analyses will be summarized descriptively. Changes from Baseline will be 
calculated from the Baseline of the preceding study.
Efficacy Variables Analyses
No hypothesis testing will be performed.
All efficacy analyses will be summarized descriptively. The Baseline of an efficacy variable 
will be the Baseline from the initial study.
Sample Size Calculation
For this open-label, LTFU study, no sample size calculation has been performed.  The sample 
size will depend upon recruitment into and completion of preceding studies; approximately 
300 - 600 subjects were expected.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 16 of 89
5.1
Study Schedule of Assessments
Table 5:1
Study Flowchart
Entry Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit (AV)
Early 
Discontinuation 
Visit (EDV)(l)
Down-Titration 
Phone Call 
(DTP)(a) 
Final Visit 
(FV)
Reference 
to Section
ASSESSMENTS
Written Informed Consent
X
11.1.1
Clinical Study Subject Card 
Dispensing
X
11.1.2
Verification Inclusion/
Exclusion Criteria
X
11.1.3
Demographic Data
X
11.1.4
Childbearing Potential
X
11.1.5
Medical and Procedures 
History
X(b) 
11.1.6
Epilepsy History
X(b) 
11.1.7
AED History
X(b) 
11.1.8
Vital Signs
X(c) 
X
X
X
X
X
X
11.1.9
Weight and Height(d) 
X(c) 
X
X
X
X
11.1.10
Physical Examination
X(c) 
X
X
X
X
11.1.11
Neurological Examination
X(c) 
X
X
X
X
11.1.12
ECG(e) 
X(c) 
X
X
X
11.1.13
Daily Record Card Dispensed
X(c) 
X
X
X
X
11.1.14
Daily Record Card Retrieval
X
X
X
X
X
11.1.14
Seizure Counts
X
X
X
X
X
X
11.1.14
Recording of Seizures
X(c) 
X
X
X
X
X
11.1.14
QOLIE-31-P(f) 
X
X
X
11.1.20.1
HADS(f) 
X
X
X
11.1.20.2
EQ-5D(f) 
X
X
X
11.1.20.3
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 17 of 89
Table 5:1
Study Flowchart
Entry Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit (AV)
Early 
Discontinuation 
Visit (EDV)(l)
Down-Titration 
Phone Call 
(DTP)(a) 
Final Visit 
(FV)
Reference 
to Section
ASSESSMENTS
Workdays and schooldays lost / 
Days with caregiver’s help (k)
X
X
X
X
X
X
Hospital stay (k)
X
X
X
X
X
X
11.1.21
Healthcare Provider 
Consultations not foreseen by 
the protocol (k)
X
X
X
X
X
X
11.1.22
Socio-professional data(g) 
X
X
X
11.1.23
Laboratory Assessments(h) 
X(c) 
X
X
X
X
11.1.15
Recording of Adverse Events
X
X
X
X
X
X
X
X
11.1.16
C-SSRS(j)
X
X
X
X
X
X
11.1.17
Medical Procedures
X
X
X
X
X
X
X
11.1.6
Concomitant AED
X
X
X
X
X
X
X
11.1.19
Concomitant Non-AED
X
X
X
X
X
X
X
11.1.19
Drug Dispensing
X
X
X
X
X
Drug Return/Accountability
X
X
X
X
X
End of Study Status(i) 
X
11.1.24
AED=antiepileptic drug; AV=Additional Visit; BRV=brivaracetam; CRF=Case Report Form; C-SSRS=Columbia Suicide Severity Rating Scale; DTP=Down-Titration Phone 
Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EQ-5D=EuroQoL-5 Dimensions; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final Visit; 
HADS=Hospital Anxiety and Depression Scale; IEC=Independent Ethics Committee; IRB=Institutional Review Board; MEV=Minimal Evaluation Visit; QOLIE-31-P=Patient 
Weighted Quality of Life in Epilepsy Questionnaire; YEV=Yearly Evaluation Visit
(a) Down-Titration Phone Call at the end of the Down-Titration Period is mandatory in case the subjects discontinue from more than 20mg/day BRV.
(b) The following data will be obtained from the database of the Baseline Visit of the previous study and should not be recorded into the CRF:  General Medical and Procedure 
History, AED History, and Epilepsy History.
(c) The following data will be obtained from the database of the final visit of the previous study and should not be recorded in the CRF:  Vital Signs, Weight, Physical 
Examination, Neurological Examination, ECG, Recording of seizures, Laboratory Assessment including Safety (blood chemistry, hematology, and urinalysis), concomitant 
AED plasma levels and BRV plasma levels.
(d) Height will be recorded at Visit 1.  Height will also be measured at each YEV and the FV for those subjects who are still potentially growing. 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015 / Page 18 of 89
Table 5:1
Study Flowchart
Entry Visit
(EV)
Full 
Evaluation 
Visit (FEV)
Minimal 
Evaluation 
Visit (MEV)
Yearly 
Evaluation 
Visit (YEV)
Additional 
Visit (AV)
Early 
Discontinuation 
Visit (EDV)(l)
Down-Titration 
Phone Call 
(DTP)(a) 
Final Visit 
(FV)
Reference 
to Section
ASSESSMENTS
(e) At FV, ECG is mandatory except if FV follows an EDV where ECG results were normal.
(f) QOLIE-31-P, EQ-5D, and HADS are to be completed at the beginning of the visit by all subjects who are not mentally impaired during the first 2 years.
(g) Socio-professional data (to be collected during the first 2 years) will not be collected in 
(h) Laboratory assessment includes blood chemistry, hematology, and urinalysis; where applicable (women of childbearing potential), a serum pregnancy test will be done.  
Laboratory is mandatory at FV except if FV follows an EDV where laboratory results were normal.  Concomitant AED plasma levels and BRV plasma levels up to approval 
of Protocol Amendment 2.  
(i) End of study status will be completed at the FV for subjects having performed an EDV (discontinued subjects) and for subjects leaving the study at the end of the program 
(completed subjects).
(j) The C-SSRS assessment will be implemented by site per IRB/IEC approval upon completion of required training. As of the time of Protocol Amendment 2, all subjects had 
completed their EV. Thus, the C-SSRS was not assessed for any subjects at their EV.
(k) Procedures only performed during the first 2 years of subject participation in the study or EDV/FV in case the subject discontinues participation within the first 2 years.
(l) For subjects that may transition to another BRV study or a managed access program or similar type of program, the EDV will need to be completed, however down- titration
and FV may not be applicable.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 19 of 89
5.2
Schematic Diagram

First year:

First 3 months:  1 visit/month:  FEV alternating with MEV

Next 9 months:  1 visit/3 months:  FEV alternating with MEV

Second and subsequent years:

1 visit/3months:  FEV alternating with MEV

The YEV will be performed in replacement of the first FEV of each year.
Table 5:2
Visit Schematic Diagram
1st, 2nd and subsequent years follow-up
Month
Visit
Type of Visit
M0
V1
Entry Visit (EV)
M1
V2
MEV
M2
V3
FEV
M3
V4
MEV
M4
M5
M6
V5
FEV
M7
M8
M9
V6
MEV
M10
M11
M12
V7
YEV
M15
V8
MEV
M18
V9
FEV
M21
V10
MEV
M24
V11
YEV
M…
V…
…
In case the subject will not continue with the study drug, the Investigator will first plan an 
Early Discontinuation Visit (EDV) followed by the progressive down-titration of the study 
drug.  During the down-titration period, the dose may be decreased in steps of a maximum of
50mg/day on a weekly basis. A last down-titration step at 20mg/day for 1 week will be
included prior to the drug free period.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 20 of 89
At the end of the down-titration period, a phone call will be given to subjects having down-
titrated from doses higher than 20mg/day.  The down-titration period will be followed by a 
period free of study drug of a minimum of 2 weeks and a maximum of 4 weeks and 
subsequently, the Final Visit (FV) will occur.
When the time point is reached at which the study will be terminated by the Sponsor (as 
defined in Section 8.4), subjects will discontinue the study drug, following the Investigator’s 
instructions for down-titration if necessary. 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 21 of 89
6.
BACKGROUND INFORMATION
6.1
Background and epidemiology of targeted disease
Epilepsy is 1 of the most common and challenging neurological disorders.  It has been 
estimated that over 50 million people are affected worldwide (Engel and Pedley, 1998; 
Hauser et al, 1993; Loiseau et al, 1990; Sander and Shorvon, 1996). The prevalence of 
epilepsy is around 1%.  The annual incidence in developed countries is around 50 to 70 cases 
per 100,000.  In developing countries, the figure is higher due to more limited obstetric 
services and the greater likelihood of cerebral infection and trauma.  The incidence varies 
greatly with age, with high rates occurring in childhood, falling to low levels in early adult 
life, but with a second peak in those aged over 65 years.  In many people, particularly 
children, the condition may remit, although a significant proportion will have epilepsy 
lifelong.  The disease duration is often determined by the underlying cause.  Sudden 
unexpected death, a complication of great concern, occurs in 1 to 5 per 1000 patient years, 
particularly if the seizure disorder remains uncontrolled.  The treatment for epilepsy remains 
difficult, and there is ongoing medical need for new AEDs.  For considerable proportions of 
patients, seizure freedom can still not be reached with currently available AEDs (Nasreddine 
et al, 2010; Kwan and Brodie, 2001).
Diagnosis of epilepsy is based on the recurrence of seizures.  Seizures may be caused by an 
underlying brain disorder or lesion or due to genetic conditions.  Characterization of the 
epileptic syndrome has profound implications for treatment and prognosis.  The major 
dichotomy for the diagnosis of epilepsy is the differentiation between focal epilepsies (i.e., 
related to a focal brain dysfunction), which are the most frequent and account for 
approximately 60 to 70% of all cases, and generalized epilepsy syndromes, which represent 
approximately 25 to 30% of all epilepsy syndromes.  In about 10% of cases, other specific 
syndromes are classified or the classification remains uncertain.
The classification of epileptic syndromes and seizure types is – and always was – a matter of 
ongoing debate.  First published in 1960 and last updated officially in 1981 for seizures and 
1989 for epilepsies (Commission on Classification and Terminology of the International 
League Against Epilepsy ([ILAE], 1981 and 1989), these ILAE classifications were based on 
concepts that, for the most part, predate modern technologies and concepts (Engel, 2006;
ILAE [http://www.ilae-epilepsy.org]).  The availability of these modern techniques, like 
long-term video electroencephalograms (EEGs) and high-resolution magnetic resonance 
imaging (MRI), providing much more precise knowledge in regard to seizure type 
classifications and epileptic syndromes, led some epilepsy groups and scientists towards 
introducing competing classification systems (like the Cleveland Clinic Epilepsy 
Classification) and even debating how useful the currently used ILAE classification system is 
at all (Lüders et al, 2006).
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 22 of 89
This ongoing debate regarding the classification systems for epilepsies and seizures is also 
reflected within the latest Report of the Commission on Classification and Terminology 
(Classification Task Force) which proposes a thoroughly revised terminology and concept for 
the diagnosis of epilepsy syndromes and also to some extent seizure types (Berg et al, 2010).
Despite this ongoing debate, for the purpose of this study, the seizure type classification will 
follow the 1981 ILAE classification of epileptic seizures, which speaks of partial seizures, 
classified as simple partial seizures (no alteration of consciousness), complex partial seizures 
(with alteration of consciousness), and secondarily generalized seizures, and on the other 
hand defines generalized seizure types, referred to as absence seizures (typical and atypical), 
myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.  
Apart from myoclonic seizures, consciousness is almost invariably impaired from the onset 
of the seizure (Commission on Classification and Terminology of the ILAE, 1981).
Likewise, the classification of epilepsy syndromes will be used according to the 1989 
ILAE-publication (Commission on Classification and Terminology of the ILAE, 1989).
6.2
Background information regarding product 
Brivaracetam is a 2-pyrrolidone derivative.  Brivaracetam displays a high and selective 
interaction with a novel brain-specific binding site, SV2A (synaptic vesicle protein 2A).  This 
binding site appears to be the major target for its pharmacological activity.  Brivaracetam also 
reduces voltage-dependent sodium currents.  Brivaracetam also reverses the inhibitory effects 
of negative allosteric modulators on gamma-aminobutyric acid, and glycine-induced currents.  
Brivaracetam is extensively metabolized, but seizure protection appears to be associated with 
the parent compound.
Brivaracetam is rapidly and completely absorbed throughout the gastrointestinal tract.  The 
extent of BRV absorption is not affected by food.  The pharmacokinetics (PK) are 
dose-proportional (at least from 10mg to 600mg).  Brivaracetam is weakly bound to plasma 
proteins (≤20%).  The volume of distribution is 0.5L/kg, a value that is close to that of total 
body water.  The plasma half-life of BRV is approximately 8 hours in young healthy male 
adults.  The main metabolic pathway of BRV is by hydrolysis of the acetamide group to the 
corresponding carboxylic acid, while a second pathway is the ω1-hydroxylation mediated by 
cytochrome P450 2C19 (CYP2C19) (with contributions of several other isoenzymes).  The
combination of these 2 pathways results in the hydroxyacid terminal metabolite.  These 
metabolites are not pharmacologically active.  There is no evidence of chiral inversion of 
BRV.  Brivaracetam is eliminated primarily by metabolism and by excretion in the urine.  
More than 95% of the dose, with less than 9% as unchanged BRV, is excreted in urine within 
72 hours after dosing.
Pharmacokinetic studies in elderly subjects and in subjects with renal impairment showed a 
similar PK profile of BRV compared to that in healthy subjects, while the elimination of the 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 23 of 89
metabolites was markedly slowed down.  A PK study in subjects with hepatic impairment 
showed a 50% increase in exposure to BRV associated with decreased hydroxylation.
Brivaracetam does not impair the efficacy of oral contraceptives containing 
ethinylestradiol 30µg and levonorgestrel 150µg.  Brivaracetam does not induce CYP3A4 
using midazolam as a marker probe.  Brivaracetam has no interaction on lamotrigine and 
topiramate.  Brivaracetam plasma concentration is not increased by gemfibrozil, a selective 
CYP2C8/9 inhibitor, but is increased in a nonclinically relevant manner in Japanese subjects 
possessing defective CYP2C19 mutations.  Brivaracetam clearance is doubled by rifampicin, 
a potent CYP inducer.
Trough levels of concomitant AEDs were monitored in all efficacy studies.  No significant 
change from Baseline nor dose-related trend was observed for the plasma concentrations of 
carbamazepine, lamotrigine, levetiracetam, oxcarbazepine metabolite, phenobarbital, 
phenytoin, topiramate, valproate, and zonisamide.  Carbamazepine epoxide was moderately 
increased from Baseline at all BRV doses greater than 20mg/day, nearly reaching the upper 
limit of normal (3.0µg/mL) at BRV doses of 100 and 150mg/day.
6.3
Efficacy with BRV in fixed-dose Phase II/III studies in POS 
Following completion of the Phase II studies (N01114, UCB protocol reference code 
RPCE02K0301; N01193, UCB protocol reference code RPCE05C2201), clinical results 
supported further development of BRV for the adjunctive treatment of POS.  Two adequate 
and well-controlled fixed-dose studies (N01252, UCB protocol reference code 
RPCE06G0704; N01253, UCB protocol reference code RPCE06G0705) were conducted to 
assess BRV across a dose range of 5 to 100mg/day.
N01253 assessed BRV doses of 5, 20, and 50mg/day and provided statistically significant 
and clinically relevant evidence of the efficacy of BRV 50mg/day.  N01252 assessed BRV 
doses of 20, 50, and 100mg/day.  Although the primary efficacy endpoint (for 
BRV 50mg/day) of N01252 was not positive, it provided supporting evidence for the efficacy 
of BRV 100mg/day in subjects with epilepsy. An additional confirmatory study (N01358) in 
subjects with POS is ongoing and will assess the doses of BRV 100mg/day, to replicate and 
confirm the treatment effect observed in N01252, and BRV 200mg/day, at the 
recommendation of regulatory authorities in order to explore the upper end of the 
dose-response curve.
6.4
Conversion to monotherapy
Two Phase III studies (N01276 and N01306) were initiated to evaluate the efficacy, safety 
and tolerability of BRV (at doses of 50 and 100mg/day in b.i.d. regimen) in the conversion to 
monotherapy, in subjects with POS, whether or not secondarily generalized, when compared 
to a historical pseudo-placebo control group.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 24 of 89
A decision was taken to stop the N01276 and N01306 studies after an interim analysis and 
independent unblinded review of study data by a Data Monitoring Committee identified that 
pre-defined criteria for stopping the studies had been met. It was determined the probability 
that both studies together would demonstrate a positive outcome for the efficacy analysis at 
completion was too low.
6.5
Safety with BRV 
In Phase II/III studies, a favorable safety and tolerability profile has been demonstrated for 
BRV.  The discontinuation rate and the discontinuation rate due to TEAEs were low and 
similar to placebo (PBO) for all studies. The most frequently reported TEAEs were headache, 
somnolence, dizziness, and fatigue.  The overall incidence of SAEs was low and similar to 
PBO.  There were no clinically relevant changes in laboratory values, vital signs, or ECG 
abnormalities.
For additional details on the safety and efficacy of BRV, please refer to the Investigator’s 
Brochure (UCB reference code RXCE06E2216).
6.6
Study Rationale
The Sponsor wishes to develop BRV as a monotherapy antiepileptic treatment in subjects 
16 years and older suffering from epilepsy.  N01315 will give subjects, who have participated 
in a previous BRV monotherapy study in epilepsy, the opportunity to continue BRV
treatment under the present protocol.
The study will explore the long-term safety and efficacy of BRV in such a population and 
potentially populations from other future studies.
6.6.1
Dose Selection
In this study, the recommended starting dose is 100mg/day. Afterwards the daily dose can be 
individualized up to a maximum of 200mg/day. Twice daily dosing is deemed necessary to 
ensure more regular exposure over the 24-hour interval.
A maximum dose of 200mg/day was chosen following consultation with regulatory 
authorities and is to be evaluated in more recent BRV studies (e.g., N01358 and N01379). 
According to available data, 200mg/day doses have been well tolerated.
6.6.2
Subject Population
Male and female subjects, with a clinical diagnosis of epilepsy with POS, are allowed to 
participate in this study from the age of 16 (where legally permitted and ethically accepted). 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 25 of 89
Indeed epilepsy features in the range of 16 to 18 years do not differ from the ones of older 
subjects, and efficacy of the AEDs seems to be comparable (N01236; CPMP/EWP/566/98 
rev 1, 2000). In 
 however the minimal age to enter the study will be 18.
Depending on country-specific regulations, those subjects may be considered as adolescents 
or adults (N01125; CPMP/ICH/2711/99, 2000). In case they are considered as adolescents, 
parent(s) or legal representative will sign the informed consent form.  The consent form or a 
specific assent form, where required, will be signed and dated by the minor.
6.6.3
Treatment Duration
The study is planned to begin in Q3 2008.
This study will run throughout the duration of the clinical development period of BRV, and 
will continue until a marketing authorization is granted by any Health Authority in an 
indication for the adjunctive treatment in adults with refractory POS, whether or not 
secondarily generalized, until the Sponsor decides to close the study, until subjects transition 
to another BRV study, until a managed access program, named patient program, 
compassionate use program, or similar type of access program is established as allowed per 
country-specific requirement in addition to legal and regulatory guidelines, or until BRV 
development is stopped by the Sponsor.
6.6.4
Statement
The present study will be conducted in accordance with:

This protocol.

Code of Federal Regulations Title 21 Parts, 50, 54, 56, 312, and 314.

International Conference on Harmonization: ICH E6 Note for Guidance on Good
Clinical Practice (CPMP/ICH/135/95).

The principles that have their origin in the Declaration of Helsinki.

All applicable laws and regulations.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 26 of 89
7.
STUDY OBJECTIVES
7.1
Primary Objective
To evaluate the long-term safety and tolerability of BRV at individualized doses with a 
maximum of 200mg/day in subjects suffering from epilepsy.
7.2
Secondary Objective
To evaluate the maintenance of efficacy over time of BRV.
7.3
Exploratory Objectives

To explore impact on health-related quality of life, anxiety and depression.

To obtain a description of patient’s self-reported health status.

To collect data on medical resources used and on indirect cost parameters.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 27 of 89
8.
STUDY DESIGN
8.1
Type/Design
This is a Phase III, LTFU, multinational, multicenter, non-comparative, open-label and single 
arm study.
The visits will be scheduled as follows:

First year:

First 3 months:  1 visit/month:  FEV alternating with MEV.

Next 9 months:  1 visit/3 months:  FEV alternating with MEV.

Second and subsequent years:

1 visit/3months:  FEV alternating with MEV.

The YEV will be performed in replacement of the first FEV of each year.
8.2
Subjects/Sites Numbers
It was estimated that approximately 300 - 600 subjects were to enter the study. However, the 
number of subjects entered will be reduced due to the premature discontinuation of N01276 
and N01306.
This study will include as many sites as required (initially, 120-180 sites are foreseen).
8.3
Measures to Minimize/Avoid Bias
8.3.1
Blinding
This is a single arm open-label LTFU study.
8.3.2
Randomization
Not applicable.
8.3.3
Subject Identifier
Each subject will be identified by initials (3 letters; corresponding either to the subject’s 
actual initials, or “dummy” initials, as preferred by the Investigator and according to country 
regulatory requirements) and a unique identifier including the study number, a 3-digit center 
number and a 4-digit sequential number, starting by 1 at each site (e.g. 1st subject at site 025: 
N01315/025/0001).
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 28 of 89
8.4
Study Duration
This study will run throughout the duration of the clinical development period of BRV, and 
will continue until a marketing authorization is granted by any Health Authority in an 
indication for the adjunctive treatment in adults with refractory POS, whether or not 
secondarily generalized, until the Sponsor decides to close the study, until subjects transition 
to another BRV study, until a managed access program, named patient program, 
compassionate use program, or similar type of access program is established as allowed per 
country-specific requirement in addition to legal and regulatory guidelines, or until BRV
development is stopped by the Sponsor.
8.5
End of Study
The end of study is defined as the date of the last visit of the last subject in the study.
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Brivaracetam / Study N01315
Integrated Amendment 3
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Final / 25 Mar 2015/ Page 29 of 89
9.
SELECTION AND WITHDRAWAL OF SUBJECTS
Before any study procedures are initiated for any subject in this study, an Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) approved written informed consent form 
will be properly executed and documented.
9.1
Subject Inclusion Criteria
To be eligible to participate in this study, all of the following criteria must be met:

An IEC/IRB approved written informed consent signed and dated by the subject or by 
parent(s) or legally acceptable representative.  The consent form or a specific assent 
form, where required, will be signed and dated by minors.

Male/female subjects from 16 years or older.  Subjects under 18 years may only be 
included where legally permitted and ethically accepted. In 
 subjects must be 
older than 18 to enter the study.

Subjects with epilepsy who participated in previous BRV studies which allow access to 
the present study.

Subjects from whom the Investigator believes a reasonable potential benefit from the 
long-term administration of BRV may be expected.

Female subjects without childbearing potential (premenarcheal; 2 years 
postmenopausal bilateral oophorectomy or ovariectomy, bilateral salpingectomy, 
complete hysterectomy, congenital sterility) are eligible.  Female subjects with 
childbearing potential are eligible if they use a medically accepted contraceptive 
method for the duration of the study (Intra Uterine Device, diaphragm with spermicide, 
male or female condom with spermicide; oral hormonal contraceptive, non-oral 
hormonal contraceptive medication, bilateral tubal ligation, bilateral tubal implant, 
monogamous relationship with vasectomized partner).  Oral or depot contraceptive 
treatment with at least 30µg [or 50µg if associated with other antiepileptic drugs known 
as inducers] ethinylestradiol per intake must be used in conjunction with a barrier 
method.  The subject must understand the consequences and potential risks of 
inadequately protected sexual activity, be educated about and understand the proper use 
of contraceptive methods, and undertake to inform the Investigator of any potential 
change in status. Sexual inactivity might be accepted on a case-by-case basis

Subject/legally acceptable representative considered as reliable and capable of adhering 
to the protocol (e.g. able to understand and complete diaries and questionnaires), visit 
schedule or medication intake according to the judgment of the Investigator.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 30 of 89
9.2
Subject Exclusion Criteria
Subjects must be excluded if they meet any of the following criteria:

Severe medical, neurological and psychiatric disorders, including current suicidal 
ideation or behaviour, or laboratory values which may have an impact on the safety of 
the subject, as determined by the Investigator.

Poor compliance with the visit schedule or medication intake in the previous BRV
study.

Participation in any clinical study of another investigation drug or device during the 
study.

Pregnant or lactating woman.
If the Investigator has any medically valid reason to doubt the eligibility of a subject, the 
subject should not be included into the study.  If, however, the Investigator has any other kind 
of doubts concerning the subject’s eligibility, he/she should consult the UCB Study Physician 
or representative for clarification.
9.3
Subject Withdrawal
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
Stopping rules and discontinuation criteria for individual subjects may be for example:

Withdrawal for safety reasons by the Investigator:  occurrence of status epilepticus, 
appearance of a more severe type of seizure, liver enzymes significant increase, and any 
other significant safety reason.

Subject and/or Investigator does not think that the investigational drug is effective (i.e., 
lack or loss of efficacy).

Lost to follow-up.

Withdrawal of consent for personal reasons; not related to AE or lack/loss of efficacy.

Other reason that has to be specified in the CRF.
Withdrawal criteria for already enrolled subjects who did not complete a Columbia Suicide 
Severity Rating Scale (C-SSRS) assessment at Screening:

Subject has a lifetime history (prior to study entry or since study start) of suicide 
attempt (including an active attempt, interrupted attempt, or aborted attempt) of the 
“Already Enrolled Subjects” version of the C-SSRS. The Investigator must withdraw 
the subject from the study and immediately refer the subject to a Mental Healthcare 
Professional.

Subject had active suicidal ideation prior to study entry or since study start as indicated 
by a positive response (‘Yes’) to either Question 4 or Question 5 of the “Already 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 31 of 89
Enrolled Subjects” version of the C-SSRS. The Investigator must immediately refer the 
subject to a Mental Healthcare Professional and use clinical judgment as to whether to 
withdraw the subject from the study.

Subject has active suicidal ideation as indicated by a positive response (‘Yes’) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study.
After decision of subject’s discontinuation, the Investigator will provide the subject with 
information about available alternative treatments.
Investigators should attempt to obtain information on subjects, in case of withdrawal or 
discontinuation.  The Investigator should make every effort, and document his/her effort, to 
complete the EDV and preferably also the Down-Titration Phone Call and the FV.  All results 
of these evaluations and observations, together with a narrative description of the reason(s) 
for removing the subject, must be recorded in the source documents.  The Case Report Form 
(CRF) must document the primary reason for withdrawal or discontinuation.
Investigators should also attempt to minimize the number of subjects lost to follow-up and to 
obtain a maximum of information on such subjects.  The Investigator should make every 
effort (at least 1 phone call and 1 written message to the subject), and document his/her effort 
(date and summary of the phone call and copy of the written message in the source 
documents), to complete the Final Evaluation.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 32 of 89
10.
TREATMENT OF SUBJECTS (INVESTIGATIONAL PRODUCT AND 
CONCOMITANT MEDICATIONS)
10.1
Study Investigational Products
10.1.1
Description of all Investigational Products
Oral tablets of 10 and 25mg BRV will be used in this study. 
Investigational product (study drug) is prepared and stored at the UCB Clinical Trial Supplies
(CTS) Operations or designee prior to shipment to the sites.
An Interactive Voice Response System (IVRS) will be used during this study. A telephone 
call to the system will be made:

At the EV: for assignment of the study subject number and dispensing of initial 
medication 
and 

At subsequent visits: for dispensing study medication

To update the status of the subject when the subject leaves the study
The IVRS will also be applied for the ordering of the drug shipments to the sites via the 
UCB CTS Operations or designee, using a “trigger and re-supply” method of medication 
management specified in a separate document.
10.1.1.1 Dosing Schedule
The suggested individual starting dose of each subject will be 100mg/day.
The daily dose should be divided into 2 equal intakes (morning and evening), taken with or 
without food.  The first intake will be in the evening of the day of the dispensation of the 
study medication.
At each subject visit, if necessary, the dosage can be adapted:

Up-titration can be made by increments of a maximum 50mg/day on a weekly basis and 
up to a maximum dose of 200mg/day.

Dose decreases can be made by steps of maximum 50mg/day on a weekly basis.  In 
case of study drug discontinuation, a last down-titration step at 20mg/day for 1 week 
will be included prior to the study-drug free period.
The doses administered in this study must comply with doses that can be administered with 
either BRV 10mg tablets, 25mg tablets, or a combination of these 2 strengths in a total daily 
dose that can be administered in 2 equal doses.  Daily dose prescriptions that do not respect 
these limitations should not be administered.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 33 of 89
The supplies needed by the subject in terms of the number of bottles of each dosage (10mg 
and 25mg tablets) according to the dose prescribed and the possibility to down-titrate/up-
titrate by a maximum of 50mg/day step, will be evaluated, as closely as possible at each visit.
In case the subject will not continue with BRV, the Investigator will plan the progressive 
down-titration of the study drug as described above.  The down-titration period will be 
followed by a period free of study drug of minimum 2 weeks and a maximum of 4 weeks and 
subsequently the FV will occur.
At the time of study termination by the Sponsor (as defined in Section 8.4), subjects will 
discontinue the study drug following the described down-titration process or will be 
converted without down-titration to commercial BRV if, when and where available.  
Alternatively, subjects may transition into another BRV study, or be initiated without 
down-titration in a managed access program, named patient program, compassionate use 
program, or similar type of access program as allowed per country-specific legal and 
regulatory requirements.
10.1.2
Packaging
Oral tablets of 10mg and 25mg BRV tablets will be packaged in bottles of 200 tablets.  The 
Investigator will be supplied with a sufficient number of bottles and each bottle will have a 
unique, pre-printed identification number. 
The Investigator will inform each subject on how to take the drug and that a possible excess 
of drug might be dispensed at each visit.
10.1.3
Labeling
Clinical drug supplies will be labeled in accordance with the current ICH guidelines on Good 
Clinical Practice (GCP) and Good Manufacturing Practice (GMP) and will include any
locally required statements.
The labels will be adapted to local regulatory requirements and the size of the investigational 
product package and will be translated as appropriate.
The label will consist of 2 parts.  The first is a tear-off sticker which must be attached to the 
Case Report Form at the time of visit and the second remains fixed to the investigational 
product package.  The subject number, subject initials and dispensation date will be added 
manually by the Investigator before dispensing.
10.1.4
Storage Requirements
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 34 of 89
Investigational product packages should be stored in a secured limited access area and 
maintained at the storage temperature specified on the investigational product package label.  
A recording of this controlled temperature should be done on site.  If the storage conditions 
are not controlled (with recording), a temperature log should be completed at least once a 
week with the minimal and the maximal temperatures reached in the week preceding the 
record.  Any excursion from the allowed temperature range will be communicated to the 
Sponsor or representative.
Storage should be in a pharmacy or in a locked facility.  Supplies for this study will be stored 
in such a way that they may not be mixed up with supplies being used for another study.  A 
standard storage statement will appear on each investigational product package label of study
medication.
The Investigator or the hospital pharmacist is responsible for the appropriate storage and 
documentation of investigational product package at the site.  The Investigator will instruct 
the subject/legally acceptable representative to store the medication at the storage 
temperature specified on the investigational product package label, in a secure place out of 
the reach of children.
10.1.5
Monitoring of Subject Compliance
At each visit after drug is dispensed, subjects must return all unused medication and the 
original investigational product package (even if empty).  Drug reconciliation must be done 
in the subject’s presence in order to obtain explanations regarding discrepancies in 
compliance with the dosing regimen.
The number of tablets as well as explanations of non-compliance must all be recorded on the 
CRF.
The Investigator will assess compliance during the study. Compliance with study medication 
is defined as investigational product consumption by the subject within 80% to 120% of the 
prescribed dosage.
10.1.6
Investigational Products Accountability
The Sponsor or its representatives will supply a Drug Accountability Form to be kept up-to-
date by recording all study drug received during the course of the study and study drug 
released for subject use.  Details of any drug lost (due to breakage or wastage), not used, 
disposed of at the study site or returned must also be recorded.  All supplies and pharmacy 
documentation must be made available throughout the study for the Sponsor or designee to 
review.
The Drug Accountability Form should include the following:
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 35 of 89

Number of tablets dispensed to and return by each subject, with the subject’s number 
bottle number.

Initials of the person who actually dispensed and/or received the return tablets.

Dates of the above.

Explanations for non-compliance. 
Periodically and after completion of the study, all used (including empty bottles) and unused 
investigational product package must be reconciled and returned (preferably in their original 
package) to the Sponsor or designee according to a procedure to be defined at the time.  
Clinical drug supplies designated for the study cannot be used for any other purpose than that 
described in this protocol.
10.2
Concomitant Treatments and Rescue Medications
Should any treatment other than BRV be used, an accurate record must be kept in the clinic 
chart (source documentation) and the Case Report Form.  This record should include the 
brand name of the drug, the dose, frequency, route, the indication for use and the date(s) of 
administration.
10.2.1
Permitted Concomitant Treatments (Medications and Therapies)
Subjects entering the present study in BRV monotherapy may require re-conversion from 
BRV monotherapy treatment to adjunctive treatment with BRV and another AED.
In this case, as well as for subjects entering the study in add-on, the Investigator may adapt 
the concomitant AED drug/dosage for safety or efficacy reasons.
In case of excellent efficacy and tolerability of BRV, withdrawal of concomitant AED(s) 
resulting in monotherapy with BRV may be re-attempted by the Investigator.
Benzodiazepines (BZD) are allowed. If taken more than once a week (for any indication)
BZDs will be considered as a concomitant AED.
Use of phenobarbital and primidone is allowed. 
Use of felbamate is permitted if continuous exposure is at least 18 months before Visit 1.
Use of VNS is also allowed.
10.2.2
Prohibited Concomitant Treatments (Medications and Therapies)
Vigabatrin.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 36 of 89
11.
STUDY PROCEDURES
11.1
Description of Procedures
11.1.1
Informed Consent
Prior to any study activities, subjects will be asked to read and sign an informed consent form 
that has been approved by an IEC/IRB and which complies with regulatory requirements.  
Subjects will be given adequate time to consider any information concerning the study, given 
to them by the Investigator or designee.  As part of the informed consent procedure, subjects 
will be given the opportunity to ask the Investigator any questions regarding potential risks 
and benefits of participation in the study.
Where legally acceptable, a Partner Pregnancy Consent Form will be issued in case the 
partner of a male subject becomes pregnant (Section 12.1.6).
11.1.2
Subject Study Card
The Sponsor will provide to each Investigator an appropriate quantity of subject study cards 
that contains the Investigator’s contact information in case of emergency.  These subject 
cards will be in the language of the subject.  The Investigator will fill in each card with 
his/her contact details (name and telephone number) and the subject’s identifier.  This card 
will be distributed to the subject at the EV.  The Investigator will instruct the subject to keep 
the card with them all times.
11.1.3
Eligibility Criteria Assessment
The subject’s eligibility will be assessed based on the eligibility criteria defined in the 
protocol. 
11.1.4
Demography
At the EV, the subject’s date of birth, gender, racial group and ethnicity will be recorded. 
Genetic differences among different racial groups in terms of hepatic enzymes, receptors and 
other factors might result in different pharmacokinetic, pharmacodynamic and/or drug 
responses.  These differences may result in different dosing recommendations for different 
races.  Therefore race designation will be collected for potential future compound labeling.  
In some countries, such as 
 recording the complete date of birth is not permitted.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 37 of 89
11.1.5
Childbearing Potential and Birth Control
At the first visit, information on childbearing potential and contraceptive method used by 
female subjects will be collected.  During the course of the study, the Investigator should 
make sure that birth control remains optimal should the subject’s status change.  A pregnancy 
test will be performed as specified in the Study Flowchart (see Table 5:1).
11.1.6
Medical and Procedure History
The General Medical and Procedure History will be obtained from the database of the 
previous study in which the subject was participating.
11.1.7
Epilepsy History
The history of epilepsy reported in the previous study in which the subject was enrolled will 
be considered as the history of epilepsy for the present study, and will be obtained from the 
database of the previous study.
11.1.8
Antiepileptic Medication History
The AED medication history will be obtained from the database of the previous study in 
which the subject was participating. The AED being used concurrently, at the current dose, 
will be recorded on the concomitant AED medication page of the CRF.
11.1.9
Vital Signs
At every office visit, 5 minutes supine or sitting pulse rate and blood pressure will be 
obtained followed by a standing pulse rate and blood pressure.
Vital signs for the EV will be obtained from the database of the last Evaluation Visit of the 
previous study. 
11.1.10 Body Weight and Height
Body weight (subject wearing light clothing without shoes) will be obtained at the following 
visits:  EV, each FEV, each YEV, EDV, and at the FV.  
Body weight for the EV will be obtained from the database of the last Evaluation Visit of the 
previous study.
Height will be obtained at the EV.  For subjects who are still potentially growing, height will 
also be measured at each YEV and the FV.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 38 of 89
11.1.11 Physical Examination
A standard physical examination will be performed at the following visits: FEV, each YEV, 
EDV and at the FV.  This examination may include investigation of skin, eyes, ear, nose, 
throat, cardiovascular system, respiratory system, gastro-intestinal system, musculoskeletal 
system and optionally genitourinary system. 
The physical examination for the EV will be obtained from the database of the last 
Evaluation Visit of the previous study.
11.1.12 Neurological Examination
A standard neurological examination will be performed at the following visits:  FEV, each 
YEV, EDV and at the FV.  This examination will consist of a brief review of cortical 
functions, cranial nerves, motor function, reflex function, sensory function, gait and stance.  
Psychiatric and mental status will be reported by recording the presence or absence of 
psychiatric symptoms, mental impairments and behavioral symptoms. 
The neurological examination for the EV will be obtained from the database of the last 
Evaluation Visit of the previous study.
11.1.13 ECG
Following ethical approval of Protocol Amendment 2 and once the subject has signed the 
updated Informed Consent, the number of standard 12-lead ECGs will be reduced to once per 
year at each YEV and at the following visits: EDV and FV (in case the FV follows an EDV
and the EDV ECG is normal, no additional ECG has to be performed at the FV). 
At the EV, the ECG will be obtained electronically from the last Evaluation Visit of the 
previous study and should not be recorded in the CRF. The Investigator will determine 
whether the results of the ECG are normal or abnormal and assess the clinical significance of 
any abnormalities.  The original ECG tracing will be signed or initialed and dated by the 
Investigator and retained as part of the source data.  
11.1.14 Daily Record Card 
At the EV, every FEV, every MEV, YEV, and the EDV, the subject will receive a Daily 
Record Card (DRC) and will be asked to come back at the next visit with the completed 
DRC.
The written information will be discussed with the subject at each visit in order to ensure 
completeness and accuracy. As a result of the discussion, the Investigator will assess the 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 39 of 89
epileptic seizures according to the ILAE codes and record the seizure types and frequency on 
the CRF; he/she will also confirm the presence of adverse events (if applicable). The 
concomitant medication changes and adverse events will be reported by the Investigator on 
the specific pages of the CRF.
The DRC will be considered source documentation. The subject should be educated to 
complete the DRC on a regular basis (each time that a seizure, an undesirable event, a 
modification of medication or investigational product, or a medical visit occurs).
Information on the following assessments collected in the DRC and transcribed to the 
appropriate CRF page are to be collected during the first 2 years:

Healthcare provider consultations not foreseen by the protocol 

Workdays or schooldays lost by the subject 

Days subject received help from a caregiver (paid or not) at home
11.1.15
Laboratory Assessments and Study Medication/AED(s) Plasma Levels
At the following visits, FEV, YEV, EDV, and FV, laboratory assessments will be conducted 
using standard methods at a central laboratory.  At the EV, data will be obtained from the last 
Evaluation Visit of the previous study and should not be recorded on the CRF.  The central 
laboratory will provide the Investigator with dedicated, standardized sampling equipment 
(labels, needles, tubes), and a study-specific laboratory manual, which will explain how to 
use the equipment and how to ship the samples back to the central laboratory. 
Results for hematology, chemistry, urinalysis and pregnancy tests will be provided by fax to 
the Investigator. 
The total blood volume drawn for the clinical laboratory assessments will be a maximum of 
20mL/sampling.  The subject should preferably be fasting.  Study medication intake must not
be delayed.
The following laboratory assessments will be conducted:

Blood chemistry:  glucose, urea, creatinine, sodium, potassium, calcium, phosphorus 
(inorganic), total protein, albumin, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase (ASAT/SGOT), alanine 
aminotransferase/serum glutamic pyruvic transaminase (ALAT/SGPT),
gamma-glutamyltranspeptidase, and uric acid.

The creatinine clearance (Cr Cl) will be calculated by the Cockroft’s formula: 

male:  Cr Cl mL/min = [(140-age) x body weight] / (72 x serum creatinine 
(mg/dL)].

female:  Cr Cl mL/min = [(140-age) x body weight] / [72 x serum creatinine 
(mg/dL)] x 0.85.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 40 of 89

Hematology:  white blood cells (WBC), red blood cells (RBC), hemoglobin, 
hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), platelet count, lymphocytes 
(number, %), monocytes (number, %), neutrophils (number, %), eosinophils (number, 
%), basophils (number, %).

Urinalysis:  specific gravity, pH, glucose, bilirubin, ketones, occult blood, protein, 
nitrites, leukocytes.  If the test for protein, blood or leukocytes shows a trace or is 
positive, sediment and microscopic analyses (erythrocyte cast, leukocyte casts, 
hemoglobin casts, uric acid crystals, bihydrate calcium oxalate crystals, monohydrate 
calcium oxalate crystals, triple phosphate crystals and bacteria) will be conducted.

Where applicable (women of childbearing potential), a serum pregnancy test will be 
conducted. 
Cholesterol testing and plasma samples to analyze BRV and concomitant AED 
concentrations will be collected up to approval of Protocol Amendment 2.
11.1.16 Adverse Events (AEs)
At the EV, the Investigator will record any AE that was still ongoing at the end of the 
previous study in the source documentation.  From the EV onwards, adverse events will be 
assessed at each visit and recorded in the CRF and in the source documents.  The study 
participant will be given the opportunity to report AEs spontaneously.  A general prompt will 
also be given to detect AEs, e.g., “Did you notice anything unusual about your health (since 
your last visit)?”  In addition, the Investigator should review any self-assessment procedures 
(e.g. DRCs) used in the study.
11.1.17 Assessment of Suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS. This scale will be 
used to assess suicidal ideation and behavior that may occur during the study. The C-SSRS 
will be completed according to the tabular schedule of assessments (see Section 5.1).
11.1.18 Medical Procedures
From the EV onwards, collection of data on medical procedures (surgery, therapeutic and/or 
diagnostic, hospitalizations) undertaken during the study will be obtained.  ECGs specific to 
this study will not be recorded on the Medical Procedures page of the CRF but in the modules 
specifically designed for this purpose.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 41 of 89
11.1.19 Non-Antiepileptic and Antiepileptic Concomitant Medications
At the EV, the Investigator will record all Non-Antiepileptic and Antiepileptic Concomitant 
Medications that were still ongoing at the end of the previous study.  All medications 
(including over-the-counter preparations) taken during the course of the study must be 
documented in the CRF (brand name, indication, dosage, and the dates of start and 
discontinuation).
At each visit, a complete listing of all medications currently being taken will be obtained.  
Any changes, additions or deletions in the administration of non-antiepileptic concomitant 
medications must be recorded on the Non-Antiepileptic Concomitant Medications page of the 
CRF.  In case of intake of forbidden concomitant medication (see Section 10.2) during the 
study period, the Investigator will contact the monitor immediately.
Changes, additions or deletions in the administration of antiepileptic concomitant 
medications must be recorded on the Antiepileptic Concomitant Medications page of the 
CRF.
11.1.20 Patient Reported Outcomes
A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as 
well as for EDV.  The assessment of the PROs will be limited to the first 2 years after study 
entry.  These booklets will include, in order of appearance:  The Patient Weighted Quality of 
Life in Epilepsy Inventory-- 31 item form (QOLIE-31-P - Version 2), the Hospital Anxiety 
and Depression Scale (HADS), and the EQ-5D self-report questionnaire.  The PRO booklet is 
to be provided to subjects who are not mentally impaired, at the very beginning of the study 
visit.  The subject will be asked to complete the questionnaires on his/her own.  Once 
completed, the subject will hand back the booklet to the Investigator who will check that all 
questions have been answered.
The PRO booklets will be considered as part of the CRF as well as source documentation.
11.1.20.1
Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)
QOLIE-31-P (Cramer and Van Hammée, 2003) (see Appendix17.1) is an adaptation of the 
original QOLIE-31 instrument (Cramer et al, 1998) that includes 7 subscales (seizure worry, 
overall quality of life, emotional well-being, energy-fatigue, cognitive functioning, 
medication effects, social function) and the health status item.  Subscale scores as well as 
Total score range from 0 to 100 with higher scores indicating better health related quality of 
life.  In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking 
the subjects to grade his or her overall "distress" related to the topic of each subscale.  The 
QOLIE-31-P also contains an item asking about the relative importance of each subscale 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 42 of 89
topic. The subjects will complete the QOLIE-31-P at every FEV and YEV for the first 
2 years, and at the EDV if the EDV occurs within the first 2 years.
11.1.20.2
Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) (Herrmann, 1997) (see Appendix 17.2) 
will be used to evaluate anxiety and depression/depressed feelings.  The HADS was 
developed as a self-administered scale to assess the presence and severity of both anxiety and 
depression simultaneously.  It consists of 14 items that are scored on a 4-point severity scale 
ranging from 0 to 3.  A score per dimension (anxiety, depression) will be calculated as 
recommended by the authors with each score ranging from 0 to 21 and higher scores 
indicating higher depression/anxiety.  The subjects will complete the HADS at every FEV 
and YEV for the first 2 years, and at the EDV if the EDV occurs within the first 2 years.
11.1.20.3
EQ-5D Questionnaire
The EQ-5D (EuroQol Group, 2000) (see Appendix 17.3) is a self-administered questionnaire 
designed to measure health status.  EQ-5D defines health in terms of 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression).  Each dimension is 
divided into 3 levels:

no problem = 1

some or moderate problems = 2

extreme problems = 3
EQ-5D also captures a self-rating of health status on a 20cm vertical visual analogue scale, 
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) 
at the bottom.
The EQ-5D questionnaire will be assessed at every FEV and YEV for the first 2 years, and at 
the EDV if the EDV occurs within the first 2 years.
11.1.21 Hospital Stay
After the EV onwards, the collection of data on hospital stay will be assessed in the CRF.  It 
includes the reason of hospitalization, the admission wards, transfer and length of stay.  
Hospital stays will be assessed at every FEV, MEV, YEV, and Additional Visit (AV) for the 
first 2 years, and at the EDV and the FV if these visits occur within the first 2 years.
11.1.22 Healthcare Provider Consultations not foreseen by the Protocol
After the EV onwards, healthcare provider consultations not foreseen by the protocol will be 
assessed and recorded in the CRF. This includes the type of provider (general practitioner, 
specialist physician, nurse), site of care (offsite vs private, office vs hospital, home, ER), and 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 43 of 89
the reason leading to the consultation. Healthcare provider consultations not foreseen by the 
protocol will be assessed at every FEV, MEV, YEV, and AV for the first 2 years, and at the 
EDV and the FV if these visits occur within the first 2 years.
11.1.23 Socio-professional Data
Socio-professional data will be collected at the YEV for the first 2 years and at the EDV and 
the FV if these visits occur within the first 2 years.  This module collects information such as
education level, housing status, employment status, need for caregiver and driving license. In 
countries such as 
 collection of these data is not permitted; therefore they will not be 
collected. 
11.1.24 End of Study
The end of the subject’s participation in the study will be confirmed on the subject’s status 
evaluation section of the CRF.  All data about the subject’s status (study completion or reason 
for early study termination) will be recorded.  It will be specified:

Whether the subject completed (participated until the study was stopped) or 
prematurely discontinued from the study.
A subject will be considered lost to follow-up following 2 unsuccessful documented attempts 
to contact the subject (e.g. by telephone).
If a subject will not continue with the study drug, the Investigator will first schedule an EDV 
which will be followed by a progressive down-titration of the study drug.  The dose decrease 
can be made by steps of a maximum of 50mg/day on a weekly basis.  A last down-titration 
step at 20mg/day for 1 week will be included prior to the study drug free period.  At the end 
of the down-titration period, a phone call will be given to subjects having down-titrated from 
doses higher than 20mg/day.  The Down-Titration Period will be followed by a period free of 
study drug at the minimum of 2 weeks and a maximum of 4 weeks and subsequently the FV 
will occur.
When the time point is reached at which the study will be terminated by the Sponsor (as 
defined in Section 8.4), subjects will discontinue the study drug, following the above 
described down-titration process or will be converted without down-titration to commercial 
BRV if, when and where available. Alternatively, subjects may transition to another BRV 
study or be initiated without down-titration in a managed access program, named patient 
program, compassionate use program, or similar type of access program as allowed per 
country-specific legal and regulatory requirements.
11.2
Description Visit by Visit
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 44 of 89
The EV will be performed on the same day as the last visit of the previous study in which the 
subject was enrolled.  Should an interval become necessary between the last visit of the 
previous study and the EV in the present study, the Sponsor’s Study Physician or
representative should be contacted for agreement.  The adverse events, medical procedures, 
non-antiepileptic and antiepileptic concomitant medication belonging to the interim period 
will be reported in the CRF, on specific pages.
Each visit will be planned within a “window” of ± 7 days from the previous visit.  When 
possible, out of window visits should be rescheduled with respect to the EV.
At any time, the subject may have an additional study visit/phone call if the Investigator of 
the subject deems it necessary.  All information, including the reason for the visit/phone call, 
any information on adverse events, etc., should be collected in the source documents and 
recorded in the appropriate section of the CRF.
11.2.1
Entry Visit

Signing and dating of written informed consent.

Dispensation of “clinical study subject card” (participation in the study).

Verification of the inclusion/exclusion criteria.

Demographic data.

Childbearing potential.

Body height.

Dispensation of subject DRC and instruction on proper completion.

Concomitant medications (AED and Non-AED) documentation.

Recording of adverse events.

Medical procedures.

Dispensation of study medication (only dispensed once all inclusion/exclusion criteria 
have been met).

Appointment for the next visit according to the schedule described in Section 5.2.
The following data will be obtained from the database of the Baseline Visit of the previous 
study and should not be recorded in the CRF:

General medical and procedure history.

AED history.

Epilepsy history.
The following data will be obtained from the database of the final Evaluation Visit of the 
previous study, and should not be recorded in the CRF/DRC:

Vital signs including blood pressure and pulse rate.

Body weight.

Physical examination.

Neurological examination.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 45 of 89

ECG.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis).

Pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels.

Recording of seizures.
11.2.2
Full Evaluation Visit

Vital signs including blood pressure and pulse rate.

Body weight.

Physical and neurological examination.

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels
up to approval of Protocol Amendment 2.

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication.

Appointment for the next visit according to the schedule described in Section 5.2.
The following assessments will be performed during the first 2 years:

QOLIE-31-P questionnaire (except if subject is mentally impaired). The questionnaire 
should be filled in at the beginning of the visit.

HADS questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.
11.2.3
Minimal Evaluation Visit

Vital signs including blood pressure and pulse rate.

Retrieval of previous subject DRC.

Recording of seizures.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 46 of 89

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication.

Appointment for the next visit according to the schedule described in Section 5.2.
The following assessments will be performed during the first 2 years:

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.
11.2.4
Yearly Evaluation Visit (replaces the first FEV of each year)

Vital signs including blood pressure and pulse rate.

Body weight and height (only for those subjects still potentially growing).

Physical and neurological examination.

ECG.

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels
up to approval of Protocol Amendment 2.

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication.

Appointment for the next visit according to the schedule described in Section 5.2.
The following assessments will be performed during the first 2 years:

QOLIE-31-P questionnaire (except if subject is mentally impaired). The questionnaire 
should be filled in at the beginning of the visit.

HADS questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 47 of 89

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Socio-professional data.
11.2.5
Early Discontinuation Visit

Vital signs including blood pressure and pulse rate.

Body weight.

Physical and neurological examination.

ECG.

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels
up to approval of Protocol Amendment 2.

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Dispensation of new DRC.

Dispensation of study medication with down-titration dosing schedule.

Appointment for the next visit according to the schedule described in Section 5.2.
Down-titration may not be  applicable to subjects who may transition to another BRV study 
or may be initiated in a managed access program or similar type of program.   
The following assessments will be performed only if the EDV occurs within the first 2 years:

QOLIE-31-P questionnaire (except if subject is mentally impaired). The questionnaire 
should be filled in at the beginning of the visit.

HADS questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 48 of 89

EQ-5D questionnaire (except if subject is mentally impaired). The questionnaire should 
be filled in at the beginning of the visit, after the QOLIE-31-P.

Socio-professional data.
11.2.6
Down-Titration Phone Call

Recording of adverse events.

Reminder of appointment for the next visit according to the schedule described in
Section 5.2.
11.2.7
Final Visit (FV following a Study Drug Free Period after an EDV or FV initiated 
upon Sponsor request at the end of the program)

Vital signs including blood pressure and pulse.

Body weight and height (only for those subjects still potentially growing).

Physical and neurological examination.

ECG (except if the FV follows an EDV where ECG results were normal).

Retrieval of previous subject DRC.

Recording of seizures.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis);
pregnancy test (if applicable); concomitant AED plasma levels and BRV plasma levels 
up to approval of Protocol Amendment 2 (except if the FV follows an EDV where 
laboratory results were normal).

Recording of adverse events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.

Drug return/accountability including study medication intake and compliance check.

Completion of end of study status.

Retrieval of “Clinical Study Subject Card”.
The following assessments will be performed during the first 2 years:

Healthcare provider consultation not foreseen by the protocol.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

Socio-professional data.
11.2.8
Additional Visit
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 49 of 89
At any time, the subject may have an additional study visit/phone call if the Investigator or 
the subject deems it necessary.  All information, including reason for visit/phone call, any 
information on AEs, etc., should be collected in the source documents and recorded in the 
appropriate section of the CRF. Study medication can be dispensed if required.
If an additional office visit is conducted due to safety or efficacy reasons, a C-SSRS 
assessment will be performed with the subject during the office visit. If an additional office 
visit is conducted for reasons other than safety or efficacy concerns (e.g., replacement of lost 
medication, repeated collection of a laboratory specimen due to collection or analysis issues), 
a C-SSRS will not be required at these office visits.
11.3
Handling of Biological Samples
The safety samples (hematology, biochemistry, urinalysis, pregnancy test) will be routinely 
assayed and the results sent by fax and letter to the Investigators as specified in 
Section 11.1.15.
11.4
Other Supplies
Not applicable.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 50 of 89
12.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
12.1
Adverse Events
12.1.1
Definition of Adverse Event (AE)
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
In order to ensure complete safety data collection, all AEs or undesirable experiences 
occurring during the study (i.e., after signature of the Informed Consent), including any pre-
and post-treatment periods required by the protocol, must be reported in the CRF even if no 
investigational product was taken but specific study procedures were conducted.  These 
include all AEs not present prior to the initial visit and all AEs which recurred or worsened 
after the initial visit. 
Signs or symptoms of the condition/disease for which the investigational product is being 
studied should be recorded as AEs only if their nature changes considerably or their 
frequency or intensity increases in a clinically significant manner as compared to the clinical 
profile known to the Investigator from the subject’s history or the Baseline Period.
12.1.2
Procedures for Reporting and Recording Adverse Events
The study participant will be given the opportunity to report adverse events spontaneously.  A 
general prompt will also be given to detect adverse events, e.g.
Did you notice anything unusual about your health (since your last visit)?
In addition, the Investigator should review any self-assessment procedures (e.g., diary cards) 
employed in the study.
12.1.3
Description of AEs
The following guidelines and definitions should be used by the Investigator for the 
description of an AE when reporting information:
Nature of the AE:
Preferably an overall diagnosis or syndrome, rather 
than individual symptoms or signs.  The Investigator 
must report adverse events using standard medical 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 51 of 89
terminology.  The CRF and source documents should 
be consistent.  Any discrepancies between the subject’s 
own words on his/her own records (e.g., diary card) 
and the corresponding medical terminology should be 
clarified in the source documentation.
Date of onset:
Date the AE started.
Intensity:
Mild
The subject is aware of the sign or symptom 
(syndrome), but it does not interfere with his/her usual 
activities and/or it is of no clinical consequence.
Moderate
The AE interferes with the usual activities of the 
subject or it is of some clinical consequence.
Severe
The subject is unable to work normally or to carry out 
his/her usual activities, or the AE is of definite clinical 
consequence.
Actions taken with investigational product:
Not applicable
For AEs occurring during the investigational product 
free period (pre and post-treatment periods and for 
single dose studies).
No change
Investigational product dosing remained the same in 
spite of the AE being present.
Dose increased
Investigational product dose was increased because of 
this AE.
Dose decreased
Investigational product dose was decreased because of 
this AE.
Temporarily 
discontinued
Investigational product was temporarily discontinued 
because of this AE, either because the subject chose to 
discontinue the investigational product or the physician 
felt it was in the subject’s best interest to temporarily 
discontinue the investigational product.
Permanently 
discontinued
Investigational product was permanently discontinued 
because of this AE, either because the subject chose to 
discontinue the investigational product or the physician 
felt it was in the subject’s best interest to discontinue 
the investigational product.
Other actions taken
None
No other action was taken for this AE.
Medication
The subject took a medication (either prescription or 
non-prescription) specifically for this AE or existing 
medication dosage was modified.
Hospitalization or 
prolongation of 
hospitalization
Subject was hospitalized for this AE or subject’s stay
in hospital was prolonged because of this AE.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 52 of 89
Therapeutic or diagnostic 
procedure
Subject used other therapeutic measures (e.g. ice, 
heating pad, brace, cast, etc.) or subject underwent a 
diagnostic procedure (e.g., additional lab test, x-ray, 
etc.) for this AE.
Date of outcome
Date the AE abated.  If the AE consists of several signs 
and symptoms (syndromes), the sign or symptom with 
the longest duration determines the duration of the AE. 
Outcome:
Resolved
The AE is no longer present at any intensity -
completely abated.
Resolved with sequelae
The AE is resolved but residual effects are still present.
Ongoing
The AE is still present at the last contact with the 
subject.
Worsened
The AE is still present but at a heightened intensity.  
The rule of repetition of AE reporting should be 
applied.
Fatal
This AE caused or directly contributed to the subject’s 
death.
Relationship to investigational product:
None
Only applicable when no investigational product was 
taken or when the subject is taking single-blind 
placebo, or when the AE can be ascribed with 
reasonable certainty to another cause.
Unlikely
There are good reasons to think that there is no 
relationship e.g., the AE is a known adverse drug 
reaction of a concomitant medication, or the same AE 
does not reappear after re-administration of the 
investigational product.
Possible
Equally valid arguments can be considered for or 
against an implication of the investigational product, 
For example, the AE:

follows a reasonable temporal sequence from the 
administration of the investigational product;

follows a known or expected response pattern to 
the investigational product;

but could readily have been produced by a 
number of other factors.
Probable
The relationship is likely.  For example, the AE:

follows a reasonable temporal sequence from 
administration of the investigational product;

follows a known or expected response pattern to 
the investigational product;

is confirmed by improvement on stopping or 
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 53 of 89
reducing the dosage of the investigational 
product;

could not be reasonably explained by the known 
characteristics of the subject’s clinical state.
Highly probable
There is a strong relationship.  For example, the AE:

follows a reasonable temporal sequence from 
administration of the investigational product or in 
which the investigational product level has been 
established in body fluids or tissues;

follows a known or expected response pattern to 
the investigational product;

is confirmed by improvement on stopping or 
reducing the dosage of the investigational 
product, and reappearance on repeated exposure 
(rechallenge).
12.1.4
Follow-up on Adverse Events
If an AE is still ongoing at the end of the study for a subject, a follow-up report should be 
provided until resolution/stable level of sequelae or the Investigator no longer feels it is 
clinically significant.  If no follow-up report is provided, the Investigator must provide a 
justification.  The follow-up will be continued for 30 days after the subject has completed the 
study or until the pre-analysis meeting, whatever is shorter.
12.1.5
Rule for Repetition of an AE
An increase in the intensity of an AE should lead to the repetition of the AE reporting with:

the outcome date of the first AE that is not related to the natural course of the disease 
being the same as the start date of the repeated AE,

the AE verbatim being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first 1.
12.1.6
Pregnancy
Should a subject become pregnant during the course of the study, UCB should be informed 
immediately.  The subject should be excluded from the study as soon as pregnancy is known 
(e.g. immediate start of down-titration of investigational product intake).  The Investigator 
must inform the subject about the potential risk of malformations that may be caused by any 
AED, and about the available alternatives, e.g. voluntary termination with medical indication.
The pregnancy will be documented in the AE section of the CRF.  The progression of the 
pregnancy and the eventual birth (if applicable) must be followed up using UCB Investigator 
Pregnancy Report form in which the Investigator has to report on the health of the mother and
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 54 of 89
of the offspring.  The health of the child must be followed for 12 months after birth for any 
significant medical issues.
A pregnancy becomes an SAE in the following circumstances:  miscarriage, abortion or 
anomaly/birth defect of the child.  Those SAEs must be additionally reported using the 
Investigator SAE report form. A pregnancy is also potentially a SAE if it is the consequence 
of a hormonal birth control method failure.
In cases where the partner of a currently enrolled male subject becomes pregnant, UCB will 
ask the Investigator or designee to contact the subject and his partner to request consent via 
the Partner Pregnancy Consent Form where legally acceptable. If the partner agrees to 
provide additional information, the UCB Investigator Pregnancy Report form will be 
forwarded to the subject’s partner for completion.
12.1.7
Overdose of Investigational Product
Any daily intake of BRV beyond 200mg, the maximum dose used in this study, will be 
considered as overdose.  Only symptomatic overdoses need to be recorded as AEs.  These 
events may be symptomatic, in that the excessive dosing results in clinical signs and 
symptoms or the excessive intake may itself be a symptom.  Excessive dosing (beyond that 
prescribed and including overdose) should be recorded in the study medication module.
12.1.8
Safety Signal Detection in Ongoing Clinical Studies
A regular monitoring of safety data collected during clinical studies will be performed as 
described in the Safety Signal Detection in Ongoing Clinical Trials Charter for BRV.
This ongoing monitoring of safety data will be performed at the product level.
Safety data including SAEs, AEs, vital signs, laboratory results and ECG data will be 
periodically reviewed by UCB on an ongoing basis.
The data from all studies with BRV will be scrutinized to detect as early as possible any 
safety concern related to the investigational product so that the Investigators, the clinical 
study subjects, the Regulatory Authorities and the Ethics Committees would be informed in 
the most appropriate manner.
12.2
Serious Adverse Events
12.2.1
Definition of Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that at any dose

results in death;
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 55 of 89

is life threatening;

requires in-subject hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect.
In this context, the term life threatening refers to an event in which the subject was at 
immediate risk of death at the time of the event; it does NOT refer to an event which might 
have caused death if it would have been more severe.
Any important medical event that may not be immediately life threatening or result in death 
or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject 
or may require medical or surgical intervention to prevent 1 of the other outcomes listed in 
the definition above should also be reported as a SAE.  Examples of such events are intensive 
treatment in an ER or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
Cases of cancer should be reported as SAE following the criteria “Important medical event”.
Hospitalization criteria are met anytime a subject is formally admitted to hospital, regardless 
of duration, or if a subject is kept in hospital overnight and it is not clear if a formal 
admission took place.  If a subject is taken to a hospital and neither of the above apply (e.g. 
an ER visit), an event may still be considered serious, meeting the criteria of medically 
important.
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated 
adverse event will not be considered as a SAE, except when otherwise required by 
Regulatory Authorities. If a hospitalization is planned prior to the subjects receiving the first 
dose of investigational product (at week 0), it will not be classified as either an AE or SAE. 
This also applies to situation of scheduled elective surgery where no AE is present.  Non-
complicated, preplanned elective surgery will not be considered an AE or SAE even if it 
involves hospitalization.  However, if a hospitalization is unplanned or is a result of an 
adverse event, this will be considered an SAE.  
Any event reported by the Investigator to the local authorities will follow the same reporting 
procedures as an SAE.
12.2.2
Procedures for Reporting Serious Adverse Events (SAEs)
If a SAE is reported, UCB or its representative must be informed within 24 hours of receipt 
of this information by the site (see contact information for SAEs reporting listed in Section 
2).  The Investigator must forward to UCB (or its representatives) a duly completed 
“Investigator SAE report form” provided by UCB, even if the data are incomplete or if it is 
obvious that more data will be needed in order to draw any conclusions.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 56 of 89
A copy of the Investigator SAE report form and the completion guide will be provided to the 
Investigator. The Investigator SAE report form has to be completed in English.
Additional information (e.g. autopsy or lab reports) received by the Investigator must be 
provided within 24 hours.  All documents in local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE report form.
UCB (or its representatives) will communicate safety information (Suspected Unexpected 
Serious Adverse Reactions - SUSAR) to the appropriate Regulatory Authorities and all active 
Investigators, in accordance with applicable regulatory requirements.  The appropriate 
IRB/IEC will also be informed by the Investigator or the Sponsor, as specified by the 
applicable regulatory requirements in each concerned country.  Where applicable, 
Investigators are to provide the Sponsor or its representatives with evidence of such IEC/IRB 
notification.
The Investigator is specifically requested to collect and report to UCB or its representative 
any SAEs (even if the Investigator is certain that they are in no way associated with the 
investigational product), up to 30 days after the end of the study for each subject and to 
inform the participating subjects of the need to inform the Investigator of any SAE within this 
period.  Adverse events that the Investigator thinks may be associated with the investigational 
product must be reported to UCB regardless of the time between the event and the end of the 
study.
The reference document for the assessment of the expectedness of the SAEs is the 
Investigator’s Brochure. 
12.2.3
Follow-up of Serious Adverse Events
A SAE should be followed-up until it has resolved/has a stable of sequelae or the Investigator 
no longer feels it is clinically significant.
Information on SAEs obtained after clinical database lock will be captured through the 
Global Drug Safety database without limitation of time.
12.2.4
Anticipated Serious Adverse Events
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure: convulsion. This original list will remain in effect for the duration of the protocol.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 57 of 89
The list does not change the Investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 12.2.2.
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 58 of 89
13.
STATISTICS
13.1
Statistical and Analytical Plans
A description of statistical methods is presented below and will be described in more detail in
the Statistical Analysis Plan (SAP).
13.1.1
Study Population(s)
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
The Efficacy Population will consist of all subjects who took at least 1 dose of study 
medication and have at least 1 seizure diary day during the Evaluation Period.
13.1.2
Safety, Efficacy, and Other Variables
13.1.2.1 Primary Safety Variables

Occurrence of a TEAE

Withdrawal due to AE

Occurrence of an SAE
13.1.2.2 Other Safety Variables

Laboratory tests (blood chemistry, hematology, and urinalysis)

Vital signs (SBP, DBP, pulse rate) and body weight

Electrocardiogram 

Physical and neurological examination

Change in HADS scores from the Baseline of the previous study to each assessment for 
the first 2 years and to the last Evaluation Period assessment during the first 2 years
13.1.2.3 Secondary Efficacy Variables

Percentage of subjects on continuous BRV monotherapy for at least 3 months, at least 
6 months, and at least 12 months of the Evaluation Period  
13.1.2.4 Other Efficacy Variables

Partial onset seizure (type I) frequency per 28 days during the Evaluation Period
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 59 of 89

Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period

Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period

Change in QOLIE-31-P scores from Baseline of the previous study to each assessment 
for the first 2 years and to the last Evaluation Period assessment during the first 2 years

EuroQoL-5 Dimensions questionnaire response for each assessment for the first 2 years 
for the Evaluation Period and for the last assessment during the first 2 years of the 
Evaluation Period
13.1.2.5 Pharmacoeconomic Variables

Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and ER visits) during 
the first 2 years of the Evaluation Period

Indirect costs (workdays or schooldays lost by the subject and days subject received 
help from a caregiver) during the first 2 years of the Evaluation Period

Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
13.1.2.6 Pharmacokinetic Variables

Brivaracetam (parent compound only) plasma levels

Concomitant AED (and/or relevant metabolites) plasma levels
13.1.3
Statistical Evaluation
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 75th
percentile, minimum value, and maximum value for quantitative variables, and counts and
percentages for categorical variables, will be provided. Key supporting data will be provided
in data listings. Summary statistics will be presented by the overall BRV dose.
For the purpose of statistical analysis, the following periods are considered: 

Evaluation Period (V1 until the last Evaluation Visit)

Down-Titration Period

Post-Treatment Period
13.1.3.1 Evaluation of Safety
All safety variables will be analyzed by descriptive methods on the Safety Population.
Treatment-emergent adverse events will be summarized by categories of total duration of
exposure, period, Medical Dictionary for Regulatory Activities (MedDRA®) Primary System
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 60 of 89
Organ Class and Preferred Term in incidence tables. Separate tables will be provided, by
categories of total duration of exposure, for AEs leading to withdrawal from the study and
SAEs.
Changes in laboratory values, vital signs, and weight will be summarized by visit. Possibly
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and
weight will be listed and summarized by analysis period. Electrocardiogram abnormalities, as 
well as physical and neurological abnormalities, will be presented in subject data listings.
13.1.3.2 Evaluation of Efficacy
13.1.3.2.1
Efficacy Analyses
All efficacy analyses will be based on the Efficacy Population. All efficacy variables will be 
analyzed descriptively. The Baseline of an efficacy variable will be the Baseline from the 
previous study.
The secondary efficacy variables for the cumulative proportion of subjects remaining on 
BRV monotherapy from the start of the study through 3, 6, and 12 months will be estimated 
using Kaplan-Meier methods.
13.1.3.2.2
Other Efficacy Analyses
The percentage reduction in 28-day POS frequency relative to Baseline will be summarized 
using descriptive statistics. Baseline will be defined as the Baseline value from the previous
study. Additionally, the number and percentage of subjects continuously seizure-free during 
the Evaluation Period will be presented. Descriptive statistics for the change in QOLIE-31-P 
and EQ-5D from Baseline of the previous study to each visit during the first 2 years of the 
study and the last Evaluation Period Visit will also be presented.  
13.2
Determination of the Sample Size
For this open-label, LTFU study, no sample size calculation has been performed.  The sample 
size will depend upon recruitment into and completion of proceeding studies; approximately 
300 - 600 subjects were expected.
13.3
Changes in the Conduct of the Study or the Planned Analyses
An SAP will be developed and approved prior to the database lock.  The full details of the 
statistical analyses will be provided in the SAP.  Any deviations from the SAP as well as 
changes from the protocol will be discussed in the Clinical Study Report.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 61 of 89
13.4
Statistical and Analytical Issues
13.4.1
Adjustments for Covariates and Interactions
No adjustment for covariates is foreseen.
13.4.2
Handling of Dropouts of Missing Data
Safety and efficacy variables will be analyzed insofar as they are available.  Days with 
missing information will be ignored in the calculation of the seizure frequency per week.
Since subjects will drop out at different times from the study, the results will be presented by 
categories of duration of exposure where applicable.
13.4.3
Interim Analysis
Due to the single-arm open-label nature of this study, no interim analysis as such will be 
performed.  However, interim database locks will have to be performed to allow safety and 
efficacy analyses in support of submission activities or to allow optimization of the 
development program.  In addition, an ongoing medical review (Safety Data Review, SDR) 
applying to the entire BRV program is organized.
13.4.4
Multi-center Studies
No analysis by center is planned.
13.4.5
Multiple Treatment Comparisons/Multiple Endpoints
Not applicable.
13.4.6
Examination of Subgroups
No inferential analyses are planned. Only descriptive summaries will be made on sub-groups 
of subjects with similar exposure.
13.5
Pre-Analysis Review of Data
A pre-analysis review will take place:

before starting analysis. 

after all the data have been verified / coded / entered into the database.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 62 of 89
The review will be performed to decide how to deal with problems in subject’s data (missing 
values, withdrawals, protocol deviation).
After the pre-analysis review and documentation of all decisions concerning the subjects with 
problems, the database will be locked. 
The analysis will start after the approval and locking of the database, and approval of the 
final SAP.
13.6
Criteria for Un-blinding the Results
Not applicable
13.7
Dictionaries
Adverse events and concomitant procedures will be coded according to MedDRA dictionary 
(latest available version).
Medications will be coded according to World Health Organization Drug dictionary (latest 
available version).
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 63 of 89
14.
ETHICS AND REGULATORY REQUIREMENTS
14.1
Approval
The final protocol and any amendments must be signed by the Principal Investigator of the 
site and by appropriate representative(s) of UCB.
The final protocol must be submitted to and approved by:

a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB).

the relevant Regulatory Authorities, according to local regulations.
If any alterations to the protocol are required by these bodies, they can be implemented only 
with the written agreement of the Investigator and the Sponsor’s approver(s) before further
submission to the requesting body.
A copy of the IEC/IRB’s written approval with clear identification of the submitted 
document(s) and a list of members attending the meeting (listed by function and affiliation) 
should be forwarded by the Investigator to the Clinical Trial Manager (CTM).
The usual composition of the IRB/IEC (or DHHS number) along with an IRB/IEC Statement 
of Compliance should also be forwarded to the CTM.
Before submission to an IRB/IEC, the consent form and any other written information to be 
provided to subjects (e.g., advertisement) must be submitted for internal Sponsor approval.  
The study is not allowed to start until the protocol and related documents (informed consent, 
advertisement, etc.) have received written approval from the IEC/IRB and Regulatory 
Authorities, if applicable, as well as until other GCP prerequisites are fulfilled.  
If new information becomes available, it should be communicated without delay to the 
subject, the Investigator, the IEC/IRB, and regulatory authorities, wherever required.
The IEC/IRB must be notified promptly by the Investigator (or Sponsor, if applicable) in 
writing of the following:

Deviations from, or changes to the protocol to eliminate immediate hazards to all the 
study subjects.

Significant changes to the conduct of the study.  Significant changes to the protocol can 
only be affected by a formal protocol amendment that must be submitted to the 
IEC/IRB and approved prior to implementation at the site.

New information that may adversely affect subject safety or the conduct of the study.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 64 of 89
The Investigator (or Sponsor, if applicable) should comply with the applicable regulatory 
requirements related to the reporting of safety information to the IEC/IRB and Regulatory 
Authorities.
14.2
Subject Information and Consent
Adequate information will be provided to the subject in both oral and written form and 
consent will be obtained in writing prior to performance of any study specific procedure.  
Where required, the consent form or a specific Assent Form will be signed and dated by 
minors. The content and process of obtaining informed consent will be in accordance with all 
applicable regulatory and IEC/IRB requirements.
UCB may provide a sample informed consent form and a subject information sheet.  The 
final consent form must be approved by the IEC/IRB and should contain the applicable ICH-
GCP elements in a language readily understood by the subject (i.e., lay terminology) and/or 
subject’s legally representative(s).
If the informed consent form is amended during the study, the Investigator (or the Sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of 
the amended informed consent form by the IEC/IRB and use of the amended form.
For 
 centers, a separate Health Insurance Portability and Accountability Act (HIPAA)
agreement may be used if required by the IRB or institution.
Subjects and/or subjects’ legally acceptable representatives will be informed of the purpose 
of the study in unambiguous language they easily understand.  Their participation is 
voluntary and they can at any time decide to stop their participation without any influence on 
their future care or treatment.  The subjects and/or subject’s legally acceptable representatives 
must be informed about the main procedures used to guarantee their anonymity, especially 
during the analysis of their personal data.  Subjects and/or subjects’ legally acceptable 
representatives should be able to ask any questions about the study and to receive relevant 
answers.  They will receive complete written information in the Subject Information Sheet or 
Informed Consent Form.
After having received extensive information about the purpose and risks of the study and 
having had enough time to consider participation in the study, the subject and/or subject’s 
legally acceptable representative(s) must give their written consent by signing and dating the 
Informed Consent Form.  This form will also be signed and dated by the person who obtained 
the informed consent and then retained by the Investigator.  Obtaining of consent will be 
confirmed in the subject’s medical records.  The subject and/or subject’s legally acceptable 
representative(s) will receive a copy of the signed and dated consent form and the original 
will be filed in the Investigator’s Study File.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 65 of 89
If the signature of a witness is required, the witness should sign and personally date the 
consent form after the subject and/or subject’s legally acceptable representative(s) has signed.  
By signing the consent form, the witness attests that the information in the consent form and 
in any other written information was accurately explained to, and apparently understood by, 
the subject and/or subject’s legally acceptable representative(s)and that informed consent was 
freely given.
The subject and/or subject’s legally acceptable representative(s) may withdraw their consent 
to participate in the study at any time.  A subject is considered as enrolled in the study when 
he/she and/or his/her legally acceptable representative(s) have signed the informed consent 
form.  A Case Report Form must not be started, nor may any study specific procedure be 
performed for a given subject, without having obtained his/her and/or his/her legally 
acceptable representative(s)written consent to participate in the study.
If any new information that could influence the subject and/or subject’s legally acceptable 
representative(s) decision to stay in the study becomes available, this information will be 
transmitted to the subject and/or subject’s legally acceptable representative(s) without delay.  
In addition, the informed consent form must be amended accordingly or a separate consent 
form be created and submitted to the IEC/IRB for approval prior to being implemented for 
re-consent of all ongoing subjects and/or subjects’ legally acceptable representative(s) in the 
study and for use in consenting all subjects entering the study from that point forward.
14.3
Subject Confidentiality
Subject confidentiality will be maintained at all times.  Personnel from UCB (or its 
representative), from Regulatory Authorities and members of the IEC/IRB may inspect 
medical records and Case Report Forms for verification of the accuracy of data.  These 
groups are obliged to respect medical secrecy and to refrain from divulging the subject’s 
identity or any other personal information.  Sites will be required to obliterate any possibly 
identifying information (e.g., name, social security number, address, etc.) on any materials, 
forms, or report prior to sending them to the Sponsor or its designee.
Medical records will be handled by professional standards and existing local laws.
14.4
Informing the General Practitioner 
If the subject agrees, the Investigator may inform the subject’s regular physician of his/her 
participation in the study, by sending him/her the letter to the General Practitioner (GP).  A 
template letter will be proposed by UCB.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 66 of 89
15.
STUDY MANAGEMENT AND ADMINISTRATION
15.1
Monitoring
Monitoring of the study is the responsibility of UCB and may be delegated to a Clinical 
Research Organization (CRO) or a contract monitor.  The Monitor (the individual responsible 
for monitoring) will advise the Investigator regarding the practical conduct of the study and 
maintaining compliance with the protocol, GCP, and all applicable regulatory requirements.
The Investigator will allow UCB or its representatives to review periodically, at mutually 
convenient times during the study and after the study has been completed, all CRFs and 
corresponding source documents (e.g., portions of office, hospital and laboratory records for 
each study participant).  Therefore, the monitor will have direct access to these records.  The 
monitoring visits provide UCB or its representatives with the opportunity to evaluate the 
progress of the study, to verify the accuracy and completeness of CRFs, ensure that all 
protocol requirements, applicable authorities regulations and Investigator’s obligations are 
being fulfilled, and resolve any inconsistencies in the study records.
15.2
Direct Access to Source Data/Documents
The Investigator(s)/Institution(s) will permit study-related monitoring, audits by or on behalf 
of UCB, IEC/IRB review, and regulatory inspection(s), providing direct access to source 
data/documents.
Source documents are original records in which raw data are first recorded.  These may be:  
hospital/clinic/GP records, charts, diaries, x-rays, laboratory results, printouts, pharmacy 
records, care records, ECG or other printouts, completed scales, Quality of Life 
Questionnaires, etc.  Source documents should be kept in a secure, limited access area.
If they are not included in the clinical dossier/hospital file of the subjects, the following data 
may be written directly in the CRF and will therefore be considered as source data:

Demographic data

Childbearing potential and birth control

Vital signs

Body weight and height

Physical and neurological examinations

Socio-professional data

Number of school/workdays lost
Original laboratory results, ECG, will be inserted in the CRF and are also to be considered as 
source data.  Original DRCs, QOLIE-31-P, EQ-5D, and HADS questionnaires will be 
retrieved. The site will keep a copy in the CRF and this copy will considered as source data.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 67 of 89
All source documents must be, accurate, clear, unambiguous, permanent and capable of being 
audited.  They should be made using some permanent form of recording (ink, typing, 
printing, optical disc).  They should not be obscured by correcting fluid or have temporary 
attachments (such as removable self-stick notes).  Photocopies of case report forms are not 
considered acceptable source documents.  Photocopies will only be considered as acceptable 
source documents when used to establish permanent documentation of data captured on non-
permanent media.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (e.g. ECG reports).  Once printed, these copies should be signed and 
dated by the Investigator and become a permanent part of the subject’s source documents.  
The Investigator will authorize the monitor to compare the content of the printout and the 
data stored in the computer to ensure all data are consistent.
For subjects exposed to investigational product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study related identifiers (such as subject/treatment number, CRF number, or similar), they 
should mention the subject’s participation in the study and identification of that study (study 
title or number), they should record the obtaining of consent (date of consent), the exposure 
to investigational product, the subject’s medical history, the concomitant medication 
treatments and dates (including contraceptive treatment), AEs and SAEs and the dates of the 
visits.  The source documents should provide evidence that inclusion/exclusion criteria have 
been met.  
Information recorded in the CRF must be consistent with entries in the source documents.  
The monitor will perform 100% source documents verification.
15.3
Audit and Inspection
The Investigator will permit study-related audits by auditors mandated by UCB and 
inspections by domestic or foreign regulatory authorities, after reasonable notice.  The main 
purposes of an audit or inspection are to confirm that the rights and well-being of the subjects 
enrolled have been protected, that enrolled subjects (i.e. signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of 
the investigational product have been processed and reported in compliance with the planned 
arrangements, the protocol, facility and IEC/IRB SOPS, ICH/GCP and applicable regulatory
requirements.  The Investigator will provide direct access to all study documents, source 
records and source data.  If an inspection by a regulatory authority is announced, the 
Investigator will immediately inform UCB.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 68 of 89
15.4
Case Report Forms (CRF) and Screen Failures
Data reflecting participant experience with the drug(s) under investigation will be reported to 
UCB.  These data will be recorded on the Case Report Forms (CRF). The CRF is essentially 
a data entry form and may not routinely constitute the original (or source) medical record.  
CRF should be kept in a secure, limited access area.
The CRF will be organized in yearly books. CRFs will be signed and dated by the Principal 
Investigator or a Co-Investigator designated by the Principal Investigator.  The Investigator’s 
or Co-Investigator’s signature on the CRF attests to its accuracy and completeness.  Paper 
CRFs will be completed in dark ballpoint pen, and must be legible.  If an entry in a CRF 
needs to be changed, the correction will be made as follows:

Cross-out the initial entry (must still be legible).

Write the correct entry next to it together with your initials, the date and justification if 
necessary.  Correcting fluid, erasure or any form of obliteration of data in CRFs is not 
permitted except to obliterate information that could specifically identify a subject (i.e., 
a name written on a subject diary).
UCB cannot interpret a blank answer as NONE or NA (not applicable); therefore, all fields 
must be completed.  Please mark data which could not be recorded as follow: ND for “Not 
Done”, NA for “Not Applicable”, UN for “Unknown”.
Data reported in the CRF, which are derived from source documents, should be consistent 
with the source documents or the discrepancies should be explained in those source 
documents.
The Investigator will keep a subject screening log to document identification of subjects who 
entered pre-study screening.
All supportive documentation submitted to UCB in addition to the Case Report Form, such as 
laboratory results or hospitalization records, must be clearly identified with the study number, 
study participant number, and study participant initials; any personal information, including 
the study participant’s name, must be removed or rendered illegible to preserve individual 
confidentiality.  All original lab reports will remain at the study site.  
15.5
Adherence to Protocol
The Investigator/institution should conduct the study in compliance with the protocol agreed 
to by the Sponsor and, if applicable, by the appropriate regulatory authority(ies) and which 
has been approved by the IEC/IRB.  The Investigator/institution and the Sponsor will sign the 
protocol to confirm agreement.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 69 of 89
The Investigator should not deviate from the protocol.  . However, the investigator should 
take any measure necessary in deviation from or not defined by the protocol in order to 
protect clinical study subjects from any immediate hazard to their health and safety. In this 
case, this action should be taken immediately, without prior notification of the regulatory 
authority, IRB/IEC or sponsor. After implementation of such measure, the investigator must 
notify the CPM of the sponsor within 24 hours and follow any local regulatory requirements. 
Significant changes to the protocol will ONLY be made as an amendment to the protocol and 
must be approved by UCB, the IEC/IRB and the appropriate regulatory authorities, if 
applicable prior to being implemented.  
In exceptional circumstances, subject-specific deviations from the protocol may occur.  All 
deviations should be recorded on an ongoing basis to allow regular assessment for the need of 
an amendment. Protocol Deviations could invalidate the insurance coverage.
Any protocol deviation will be documented and explained by the Investigator or the person 
designated by the Investigator and will be included in the final Clinical Study Report.
15.6
Investigator Site File
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring, auditing by UCB or its designee and/or inspection.
15.7
Data Handling
UCB will be responsible for data processing and may delegate this responsibility to a CRO.
CRF data will be entered in a validated electronic database using a clinical data management 
system.  Computerized data cleaning checks will be used in addition to manual review to 
check for discrepancies and to ensure consistency of the data.  An electronic audit trail 
system will be used to track all data changes in the database subsequent to the reconciliation 
of the double-entered data.  The SAS system will be used for the statistical analysis of the 
data.  Regular back-ups of the electronic data will be performed.
15.8
Termination of Study
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the Investigator, as appropriate:

return of all study data to UCB or its representatives while maintaining original source 
documents;

data clarification and/or resolution;
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 70 of 89

accountability, reconciliation and arrangements for used and unused investigational 
products;

review of site study records for completeness;

If applicable - return of treatment codes to UCB or its representatives;

discussion/reminder on archiving responsibilities;

discussion of IEC/IRB requirements for study termination;

arrangements for unused CRFs, lab supplies and any other study related supplies.
In addition, UCB reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single site, multiple sites, or at all sites at any time for reasons including, but 
not limited to, safety or ethical issues, inaccurate or incomplete data recording, non-
compliance, or unsatisfactory quality.
If the study is prematurely terminated or suspended, UCB or its representatives will inform 
the Investigators/institutions, and the regulatory authority(ies) of the termination or 
suspension and the reason(s) for the termination or suspension, in accordance with applicable 
regulatory requirement(s).  The IEC/IRB should also be informed and provided with 
reason(s) for the termination or suspension by the Sponsor or by the Investigator/institution, 
as specified by the applicable regulatory requirement(s).  In addition, arrangements will be 
made for the return of all unused investigational products and other material in accordance 
with UCB procedures for the study.
15.9
Clinical Study Report
UCB will prepare a clinical study report, in accordance with the relevant ICH guidelines.  
The report will include a thorough description of the clinical and laboratory methods, a 
discussion of the results and a list of all measurements as specified in the SAP.  This report 
may be included in submissions to government drug regulatory authorities worldwide, or 
used for whatever reason considered appropriate by UCB.  No information contained in the 
report may be used without written approval of UCB.
The coordinating Investigator(s) designated by UCB to sign the report (see Section 2) will 
have an opportunity to comment on the draft version.  He/she must give his/her comments 
within 7 days of receiving the report.  In addition, he/she will sign the report for approval 
within 7 days of receipt of the revised version or a satisfactory reply to these comments.
15.10
Insurance and Liability
UCB has taken out an insurance policy, for the total duration of the study, covering the 
subjects, in respect of the risks involved in this study according to this protocol.  In the case 
of injury or disability deriving from participation in the study, the subject is requested to 
inform the treating physician responsible for the study without delay.  
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 71 of 89
15.11
Archiving and Data Retention
The Investigator will maintain adequate records for the study including CRFs, medical 
records, laboratory results, informed consent documents, drug dispensing and disposition 
records, safety reports, information regarding participants who discontinued, and other 
pertinent data.
All essential documents are to be retained by the Investigator until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period however if required by the applicable 
regulatory requirement(s) or by an agreement with UCB (ICH-GCP Guideline-section 4.9.5).  
The Investigator will contact UCB for authorization prior to the destruction of any study 
records or in the event of accidental loss or destruction of any study records.  The 
Investigator will also notify UCB should he/she relocate or move the study related files to a 
location other than that specified in the Sponsor’s study master file.
15.12
Allocation of Responsibilities
The Investigator is responsible for the implementation of the protocol but can delegate tasks 
to the research team.  The Investigator remains responsible for coordinating and informing 
his/her staff about the protocol and any possible changes made to it.  The Investigator should 
maintain a site signature and delegation of responsibility log.  The list should be kept up to 
date.
15.13
Curriculum Vitae (CV)
A signed and dated FDA Form 1572, in addition to required local forms, and recent (updated 
every 2 years) CV (in English) are required from each Investigator showing a current 
affiliation with the research center.  All sub-Investigators listed on the FDA Form 1572 
should also date and sign a recent English version of their CVs.  Any changes to the site 
personnel should be updated on a new FDA Form 1572.
15.14
Financial Disclosure
A financial disclosure statement must be obtained for everyone listed on the FDA form 1572. 
These must be collected before subject enrollment. The sites must inform the Sponsor if 
information related to financial disclosure changes during the course of the study and/or up to 
1 year after study completion/end of the study.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 72 of 89
15.15
Good Clinical Practice
Non-compliance with the protocol, ICH/GCP or local regulatory requirements by the 
Investigator, institution, institution staff or designees of the Sponsor will lead to prompt 
action by UCB to secure compliance.  Continued non-compliance may result in the 
termination of the participants’ involvement in the study.
15.16
Disclosure of Clinical Study Information
UCB alone shall be responsible for the registration of clinical studies in a public studies 
registry and for the disclosure of study results on a publicly accessible website.
15.17
Publication
Authorship of planned manuscripts for submission to medical journals shall be determined in 
accordance with the International Committee of Medical Journal Editors (ICMJE) Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals.  
The Site and its Investigators agree that if the Site is part of a multi-center Study, Site and
Investigator(s) shall coordinate in advance any intended disclosure of the results of the study 
with UCB to ensure that the results of individual sites are not published or presented before
those of the multi-centre Study, unless otherwise agreed by in writing by UCB.
Subject to the following paragraph, the authors have the final responsibility for the content of 
their own publication(s) and the decision to submit it/them for publication.  
Any planned manuscript, presentation, abstract or other intended disclosure of the results of 
the study or otherwise originating from the study shall be made available for review to UCB 
at least thirty (30) days before submission for publication or any other means of disclosure in 
order to allow UCB to protect its intellectual property.
In the rare event that such disclosure would affect the patentability of any invention to which 
UCB has rights, UCB shall have the right to request an additional delay to the proposed 
disclosure of no more than ninety (90) days so as to allow UCB to preserve its intellectual 
property.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 73 of 89
16.
REFERENCES
Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised 
terminology and concepts for organization of seizures and epilepsies: report of the ILAE 
Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-85.
Commission on Classification and Terminology of the International League Against
Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia. 1981;22:489-501.
Commission on Classification and Terminology of the International League Against 
Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 
1989;30:389-99.
CPMP/EWP/566/98 rev 1 Note for guidance on clinical investigation of medicinal products 
in the treatment of epileptic disorders (European Medicines Agency) 16 Nov 2000.
CPMP/ICH/135/95 Note for guidance on good clinical practice (European Medicines 
Agency) Jul 2002.
CPMP/ICH/2711/99 Note for guidance on clinical investigation of medicinal products in the 
paediatric population (European Medicines Agency) 27 Jul 2000.
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. 
Epilepsia. 1998;39:81-8.
Cramer JA, Van Hammée G. Maintenance of improvement in health-related quality of life 
during long-term treatment with levetiracetam. Epilepsy Behav. 2003;4:118-23.
Engel J Jr. Report of the ILAE classification core group. Epilepsia. 2006;47:1558-68.
Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-
Raven; 1998.
EuroQol Group. EQ-5D. A measure of health-related quality of life developed by the 
EuroQol group. User guide. 8th issue. April 2000.
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in 
Rochester, Minnesota: 1935-1948. Epilepsia. 1993;34:453-68.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 74 of 89
Herrmann C. International experiences with the Hospital Anxiety and Depression Scale-a 
review of validation data and clinical results. J Psychosom Res. 1997;42:17-41.
Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255-60.
Loiseau J, Loiseau P, Guvot M, Duche B, Dartigues JF, Aublet B. Survey of seizure disorders 
in the French southwest. I. Incidence of epileptic syndromes. Epilepsia. 1990;31:391-6.
Lüders HO, Acharya J, Alexopoulos A, Baumgartner C, Bautista J, Burgess R, et al. Are 
epilepsy classifications based on epileptic syndromes and seizure types outdated? Epileptic 
Disord. 2006;8:81-5.
Nasreddine W, Beydoun A, Atweh S, Abou-Khalil B. Emerging drugs for partial onset 
seizures. Expert Opin Emerg Drugs. 2010;15:415-31.
Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry. 
1996;61:433-43.
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Brivaracetam / Study N01315
Integrated Amendment 3
CONFIDENTIAL
Final / 25 Mar 2015/ Page 89 of 89
18.
SPONSOR DECLARATION
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice.
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SAP_001.pdf: 
UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 1 of 43
STATISTICAL ANALYSIS PLAN (SAP)
Study: N01315
Product: Brivaracetam
An open-label, multinational, multicenter, follow-up study to evaluate the long-term safety 
and efficacy of brivaracetam used at a flexible dose up to a maximum of 200mg/day in 
subjects aged 16 years or older suffering from epilepsy
SAP/Amendment Number
Date
Final SAP
SAP Amendment 1
27 January 2014
24 June 2016
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
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 2 of 43
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...........................................................................8
2.2.2
Efficacy variables ..........................................................................................8
2.2.2.1
Secondary efficacy variables ...............................................................8
2.2.2.2
Other efficacy variables .......................................................................9
2.2.3
Pharmacoeconomic variables ........................................................................9
2.2.4
Pharmacokinetic variables.............................................................................9
2.3
Study Design and Conduct.......................................................................................9
2.4
Determination of Sample Size ...............................................................................11
2.5
Changes from the Analysis Planned in the Protocol..............................................11
3
DATA ANALYSIS CONSIDERATIONS......................................................................11
3.1
General Presentation of Summaries and Analyses ................................................11
3.2
Analysis Time Points.............................................................................................12
3.2.1
First and last dose of BRV...........................................................................12
3.2.2
Relative day .................................................................................................12
3.2.3
Summaries at Study Entry ...........................................................................12
3.2.4
Study periods ...............................................................................................13
3.2.5
Monthly time intervals.................................................................................14
3.2.6
Last value on BRV treatment.......................................................................14
3.2.7
Exposure duration and exposure duration cohorts.......................................14
3.2.8
Study visit cohorts .......................................................................................15
3.3
Definition of Baseline Values................................................................................15
3.4
Protocol deviations.................................................................................................15
3.5
Analysis Sets..........................................................................................................15
3.5.1
Safety Analysis Set ......................................................................................15
3.5.2
Efficacy Analysis Set...................................................................................16
3.6
Treatment Assignment and Treatment Groups......................................................16
3.7
Coding dictionaries ................................................................................................16
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 3 of 43
3.8
Definitions of Study-specific Derived Variables...................................................16
3.8.1
Calculation of seizure frequency/days.........................................................16
3.8.1.1
Initial seizure data processing............................................................16
3.8.1.2
Calculation of adjusted seizure frequency .........................................16
3.8.2
QOLIE-31-P.................................................................................................17
3.8.3
HADS...........................................................................................................17
3.8.4
Subject site transfers ....................................................................................18
4
STATISTICAL/ANALYTICAL ISSUES.......................................................................18
4.1
Adjustments for Covariates....................................................................................18
4.2
Handling of Dropouts or Missing Data..................................................................18
4.3
Interim Analyses and Data Monitoring..................................................................18
4.4
Multicenter Studies................................................................................................18
4.5
Multiple Comparisons/Multiplicity .......................................................................19
4.6
Use of an “Efficacy Subset” of Subjects................................................................19
4.7
Active-Control Studies Intended to Show Equivalence.........................................19
4.8
Examination of Subgroups.....................................................................................19
5
STUDY POPULATION CHARACTERISTICS.............................................................20
5.1
Subject Disposition................................................................................................20
5.2
Protocol Deviations................................................................................................21
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................21
6.1
Demographics ........................................................................................................21
6.2
Medical and Procedure History .............................................................................22
6.2.1
Medical history diseases ..............................................................................22
6.2.2
Procedure history and concomitant procedures...........................................22
6.3
History of Epilepsy ................................................................................................22
6.3.1
Etiology of epilepsy.....................................................................................22
6.3.2
Epileptic seizure profile...............................................................................23
6.3.3
Classification of epileptic syndrome............................................................23
6.3.4
Focus localization ........................................................................................23
6.3.5
History of epileptic seizures ........................................................................23
6.3.6
Seizure types experienced during baseline of the previous study ...............23
6.4
Medications............................................................................................................23
6.4.1
Non-AEDs taken at study entry...................................................................24
6.4.2
Number of previous AEDs ..........................................................................24
6.4.3
History of previous AED use.......................................................................24
6.4.4
AEDs taken at study entry ...........................................................................24
7
MEASUREMENTS OF TREATMENT COMPLIANCE...............................................24
8
EFFICACY ANALYSES ................................................................................................25
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 4 of 43
8.1
Statistical Analysis of the Secondary Efficacy Variables......................................25
8.1.1
Percentage of subjects on continuous BRV monotherapy...........................25
8.2
Analyses of Other Efficacy Variables....................................................................25
8.2.1
Partial onset seizure frequency ....................................................................25
8.2.2
Percent reduction in POS frequency............................................................25
8.2.3
Specified Month seizure freedom................................................................25
8.2.4
QOLIE-31-P.................................................................................................26
8.2.5
EQ-5D..........................................................................................................27
8.2.6
Direct cost parameters .................................................................................27
8.2.7
Indirect cost parameters...............................................................................27
8.2.8
Socio-professional data................................................................................27
9
PHARMACOKINETICS AND PHARMACODYNAMICS..........................................27
10
IMMUNOLOGICAL PROCEDURES............................................................................27
11
SAFETY ANALYSES.....................................................................................................27
11.1
Extent of Exposure.................................................................................................28
11.1.1
Number of subjects exposed and subject-years of exposure .......................28
11.2
Adverse Events ......................................................................................................28
11.2.1
Definition of treatment-emergent AE..........................................................28
11.2.2
General summaries of TEAEs .....................................................................29
11.3
Clinical Laboratory Evaluations ............................................................................30
11.3.1
Hematology and blood chemistry parameters .............................................30
11.3.2
Macroscopic urinalysis ................................................................................31
11.3.3
Microscopic urinalysis.................................................................................31
11.4
Vital Signs, Physical Findings, and Other Observations Related to Safety...........32
11.4.1
Vital signs ....................................................................................................32
11.4.2
Electrocardiograms ......................................................................................32
11.4.3
Physical examination ...................................................................................32
11.4.4
Neurological examination............................................................................33
11.4.5
Psychiatric and mental status.......................................................................33
11.4.6
HADS...........................................................................................................33
11.4.7
Columbia-Suicide Severity Rating Scale.....................................................33
12
REFERENCES ................................................................................................................34
13
APPENDICES .................................................................................................................35
13.1
QOLIE-31-P Total and Subscale Score Calculations............................................35
13.2
Subject site transfers ..............................................................................................37
13.3
PCST criteria..........................................................................................................38
13.3.1
Hematology parameters ...............................................................................38
13.3.2
Blood chemistry parameters ........................................................................39
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24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 5 of 43
13.3.3
Urinalysis.....................................................................................................41
13.3.4
Vital signs and body weight.........................................................................41
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 6 of 43
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALP
Alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Class
BMI
body mass index
Bpm
Beats per minute
BRV
brivaracetam
BUN
blood urea nitrogen
CHMP
Committee for Medicinal Products for Human Use
CR CL
creatinine clearance
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
DBP
diastolic blood pressure
ECG
electrocardiogram
EDV
Early Discontinuation Visit
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
PCST
potentially clinically significant treatment-emergent
POS
partial onset seizure
PT
preferred term 
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy 
Questionnaire
RBC 
Red Blood Cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
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24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 7 of 43
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
Upper Limit of Normal
V 
Visit
VAS
visual analog scale
WBC
White Blood Cell
WHO-DRL
World Health Organization Drug Reference List
YEV
Yearly Evaluation Visit
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 8 of 43
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 N01315.
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.
2.1.3
Exploratory objectives

To explore impact on health-related quality of life, anxiety and depression.

To obtain a description of patient’s self-reported health status.

To collect data on medical resources used and on indirect cost parameters.
2.2
Study Variables
2.2.1
Safety variables
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)
2.2.1.2
Other safety variables

Laboratory tests (blood chemistry, hematology, and urinalysis)

Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and 
body weight

Electrocardiogram (ECG)

Physical and neurological examination

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

Percentage of subjects on continuous BRV monotherapy for at least 3 months, at least 6 
months, and at least 12 months of the Evaluation Period
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 9 of 43
2.2.2.2
Other efficacy variables

Partial onset seizure (POS) (type I) frequency per 28 days during the Evaluation Period

Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period

Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period

Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) 
scores from Baseline of the previous study to each assessment for the first 2 years and to
the last Evaluation Period assessment during the first 2 years

EuroQol-5 Dimensions (EQ-5D) questionnaire response for each assessment for the first 
2 years for the Evaluation Period and for the last assessment during the first 2 years of the 
Evaluation Period
2.2.3
Pharmacoeconomic variables

Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
[ER] visits) during the first 2 years of the Evaluation Period

Indirect costs (workdays or schooldays lost by the subject and days subject received help 
from a caregiver) during the first 2 years of the Evaluation Period

Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
2.2.4
Pharmacokinetic variables

Brivaracetam (parent compound only) plasma levels

Concomitant antiepileptic drugs (AEDs) (and/or relevant metabolites) plasma levels
2.3
Study Design and Conduct
This is an open-label, long-term follow-up, multicenter, multinational, 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 
suffering from epilepsy. The secondary objective is to evaluate the maintenance of efficacy
over time of BRV. Exploratory objectives are to assess the effects of BRV on subjects’ 
Health-Related Quality of Life (HRQoL), obtain information on the direct and indirect costs 
and subjects’ self-reported health status.
At the time of development of this SAP, the enrollment into N01315 had completed. Study 
N01315 enrolled subjects 16 years of age and older who had completed N01276 or N01306.
Subjects who enrolled in the study entered an Evaluation Period at a recommended starting 
dose of 100mg/day. The dose of BRV could then be adjusted based on the individual 
subject’s seizure control and tolerability. Dose increases could be made in increments of a 
maximum 50mg/day on a weekly basis and up to a maximum dose of 200mg/day; dose 
decreases could be made in steps of maximum 50mg/day on a weekly basis with a last down-
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 10 of 43
titration step at 20mg/day for 1 week. Subjects who completed the Down-Titration Period or 
subjects who discontinued during the Evaluation Period without entering the Down-Titration 
Period enter a Study Drug-Free 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 2 to the protocol. The daily dose should have 
been administered in 2 equal intakes (morning and evening), taken with or without food.
Subjects entering N01315 on BRV monotherapy could have converted to adjunctive BRV 
treatment during the N01315 study. In this case, as well as for subjects entering N01315 
taking BRV and a concomitant AED, the Investigator may have adapted the concomitant 
AED drug/dosage for safety or efficacy reasons. In case of excellent efficacy and tolerability 
of BRV, withdrawal of concomitant AED(s) resulting in monotherapy with BRV may have 
been re-attempted by the Investigator.
Study visits at Months 2, 6, 12, 18, 24, etc., are either Full Evaluation Visits (FEVs) or 
Yearly Evaluation Visits (YEVs) at which a greater number of assessments are performed. 
Study visits at Months 1, 3, 9, 15, 21, etc. are Minimal Evaluation Visits (MEVs) at which 
few assessments are performed. If a subject elected to end their study participation prior to 
study completion, then an Early Discontinuation Visit was conducted and subjects were
progressively down-titrated from study medication. Once study medication down-titration 
was completed, a telephone call was conducted for subjects who discontinued taking more 
than BRV 20 mg/day. A Study Drug Free Period was initiated after down titration of study 
medication was completed. The Final Visit was conducted after the Study Drug Free Period. 
The Visit schedule described is displayed in Table 2‒1.
Table 2‒1:
Visit Schematic Diagram
1st, 2nd and subsequent years follow-up
Month
Visit
Type of Visit
M0
V1
Entry Visit (EV)
M1
V2
MEV
M2
V3
FEV
M3
V4
MEV
M4
M5
M6
V5
FEV
M7
M8
Table 2‒1:
Visit Schematic Diagram (Continued)
1st, 2nd and subsequent years follow-up
Month
Visit
Type of Visit
M9
V6
MEV
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 11 of 43
1st, 2nd and subsequent years follow-up
Month
Visit
Type of Visit
M10
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FEV
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FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month; V=visit; YEV=Yearly Evaluation Visit
Visit 1 will correspond to the last visit from the previous study and should be the visit at 
which study drug is dispensed for N01315.
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, 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, the enrollment into 
this study has been completed and a total of 108 subjects have been enrolled into N01315.
2.5
Changes from the Analysis Planned in the Protocol
Percentage of subjects remaining on continuous BRV monotherapy from the start of the study 
through 3, 6, and 12 months will not be done because it would be limited to subjects entering 
on monotherapy and it was expected that this rate would be low due to the parent studies 
being stopped prematurely. Instead of this analysis, the cumulative proportion of subjects 
able to achieve BRV monotherapy for 3, 6, and 12 months during the Evaluation Period will 
be summarized
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 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 12 of 43
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 N01315. Unless otherwise noted, all references to the last known dose of 
BRV in this SAP refer to the last dose of BRV taken across any study periods (ie, not 
necessarily the last dose of BRV during the Evaluation Period).
3.2.2
Relative day
Relative day will be calculated 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 
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
The study Entry Visit (EV) corresponds to assessments performed at the time of entry into 
N01315. There are 2 groups of subjects to consider:
1. Subjects who immediately entered N01315 after completing the Evaluation Period or 
meeting the protocol defined exit criteria for N01276 and N01306
2. Subjects who did not immediately enter N01315 and had a gap in treatment with study 
drug between the previous study and N01315
Subjects in category 1 will generally not have any interruption in study drug dosing during 
the transition to N01315. Subjects in category 2 had minimal gaps in treatment, which will 
not change how the data are analyzed. For subjects in both categories, selected assessments 
from Visit 8 of the previous study will be summarized at EV. Subjects who met exit criteria 
in the prior study will have data from EDV used as EV for N01315.
For the assessments that were performed for all subjects at Visit 8/EDV of the previous study, 
the following assessments will be summarized at EV: vital signs, weight, physical 
examination, neurological examination, ECGs, recording of seizures, and laboratory 
parameters. 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 13 of 43
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;
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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,
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With an EDV and having a termination CRF,
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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.
A “completed” subject can potentially have Evaluation Period, Down-Titration Period, or 
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.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 14 of 43
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.
End date is the date of last dose of BRV.
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 
scheduled and unscheduled assessments within this time period will be considered. Last 
Value will be determined separately for each laboratory parameter for hematology, 
chemistry, and urinalysis assessments. 
3.2.7
Exposure duration and exposure duration cohorts
At the final analysis, the overall duration of exposure (or On Treatment Period) will be 
calculated as the date of last dose of BRV minus the date of first dose of BRV plus 1 day. 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 15 of 43
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
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≥12 months
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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.
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.
Summaries of demographics and baseline characteristics, medical history, AEDs, non-AEDs, 
HADS, direct and indirect cost parameters, socio-professional data, study drug exposure, and 
safety outcomes will be provided for the Safety Analysis Set.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 16 of 43
3.5.2
Efficacy Analysis Set
Efficacy Analysis Set 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.
Summaries of seizure outcomes, epilepsy history, QOLIE-31-P, and EQ-5D will be provided 
for the Efficacy Analysis Set.
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, AEs, and concurrent medical procedures 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 medical procedures will not be 
coded.
3.8
Definitions of Study-specific Derived Variables
3.8.1
Calculation of seizure frequency/days
3.8.1.1
Initial seizure data processing
Each seizure code in the clinical database will be 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.
Seizures reported as “too frequent to count” will not have a reported frequency; the count of 1 
will be used for analyses.
3.8.1.2
Calculation of adjusted seizure frequency
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 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. Allseizure 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.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 17 of 43
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.
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. 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 18 of 43
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.
3.8.4
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 will be calculated over non missing diary days during each study period or 
time interval as described in Section 3.8.1; diary days for which seizure data were not 
obtained will not be considered in the calculation of seizure frequency. 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 
seizure frequency will be based on available seizure diary data while the subject was 
receiving BRV. The presence of dropouts may influence the evaluation of the long-term 
outcomes for subjects who either do not discontinue or do not discontinue early in the study. 
Therefore, as described below, selected summaries will be produced by exposure duration 
cohorts to allow an assessment of long-term outcomes without the potentially confounding 
influence of earlier discontinuations.
4.3
Interim Analyses and Data Monitoring
Interim summaries may be 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.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
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Page 19 of 43
4.5
Multiple Comparisons/Multiplicity
No statistical testing is planned; therefore, this section is not applicable.
4.6
Use of an “Efficacy Subset” of Subjects
All subjects who receive at least 1 dose of study drug and have at least 1 diary record during 
the Evaluation Period will be included in efficacy summaries. No additional efficacy subsets 
are defined for the study.
4.7
Active-Control Studies Intended to Show Equivalence
This section is not applicable for this study.
4.8
Examination of Subgroups
Selected summaries will be provided for the following subgroups as specified within each of 
the following sections:

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
Countries will be mapped to geographic regions as follows for the CHMP:
Geographic Region 
(CHMP)
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 20 of 43
* 
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
Subject’s exit status in the prior trial (eg., =1 if met exit criteria in prior trial, =0 
otherwise)
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 
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 who have 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”.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 21 of 43
Additionally, an overall summary of disposition will present the following for subjects in the 
Safety Analysis Set:

The number of subjects completing the study The overall number of subjects 
discontinuing and the number of subjects discontinuing 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 for the Safety 
Analysis Set.
The number of subjects within each geographic region 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.
5.2
Protocol Deviations
The number and percentage of subjects with at least 1 important protocol deviation will be 
summarized overall and by category of protocol deviation for the Safety Analysis Set. 
6
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
6.1
Demographics
Demographics summaries will be based on demographic data from follow-up studies for 
subjects who enrolled in a follow-up study that collected demographic data. Otherwise, 
demographics summaries will be based on demographic data collected in the previous 
double-blind study. 
Age, age category (<17, 17 to <65, and ≥65 years), gender, racial group and overall racial 
group (see below), body weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI 
category (<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40) will be summarized for the Safety 
Analysis Set. Demographic data will be summarized overall and by subgroup for 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:
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 22 of 43
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) will be provided in subject data listings.
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 study, will be 
summarized overall and by primary MedDRA system organ class (SOC) and preferred term 
(PT) for the Safety Analysis Set.
6.2.2
Procedure history and concomitant procedures
Medical procedures are not coded and will only be provided in subject data listings.
6.3
History of Epilepsy
All of the following are summarized using data collected at the time of entry into the previous 
studies or from the Baseline Period of the previous studies.
6.3.1
Etiology of epilepsy
The number and percentage of subjects with each type of etiology as specified on the CRF 
(genetic, congenital, etc) from the previous studies will be summarized for the Efficacy 
Analysis Sets. A subject will be counted as having a particular etiology if that etiology was 
either confirmed or suspected based on the investigator's assessment.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 23 of 43
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. The following seizure types 
will be summarized: I, IA, IA1 through IA4, IB, IB1, IB2, IC, II, IIA through IIF, III, and IV. 
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. 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 (frontal, 
temporal, parietal, occipital) will be summarized for the Efficacy Analysis Set. Subjects may 
be counted in more than 1 category of focus localization.
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 Set.
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 Set 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;
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 24 of 43

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.
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 Efficacy Analysis Set 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 
Efficacy Analysis Set.
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 Efficacy Analysis 
Set. 
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 Efficacy 
Analysis Set.
7
MEASUREMENTS OF TREATMENT COMPLIANCE
Study drug compliance will not be assessed due to the complexities associated with the 
calculation and interpretation of study drug compliance for this study. Study drug dosing will 
be provided in subject data listings.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 25 of 43
8
EFFICACY ANALYSES
Unless otherwise noted, all efficacy outcomes will be summarized for the Efficacy Analysis 
Set. The derivations of 28-day adjusted seizure frequency are described in detail in Section 
3.8.1.2.
All summaries of efficacy data are descriptive; no statistical testing will be performed.
8.1
Statistical Analysis of the Secondary Efficacy Variables
8.1.1
Percentage of subjects on continuous BRV monotherapy
The cumulative proportion of subjects able to achieve BRV monotherapy for 3, 6, and 12 
months during the Evaluation Period will be summarized. BRV monotherapy is defined as 
continuous treatment with BRV only (ie, no treatment with another AED). Use of rescue 
AED medications for a duration of no more than 2 consecutive days will not disqualify a 
subject from being defined as on continuous monotherapy provided the use of rescue AED 
medication does not exceed more than 1 time per week.
8.2
Analyses of Other Efficacy Variables
8.2.1
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 Efficacy Analysis Set. Similar summaries will be provided for 
the full cohort interval and by 3-month time intervals for each exposure duration cohort.
8.2.2
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 
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100
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A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort.
Percent reduction from Baseline for POS frequency will be summarized with quantitative 
descriptive statistics for the On Treatment Period, and by 3-month time intervals over the On 
Treatment Period. The summary over the On Treatment Period will include all subjects in the 
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.
8.2.3
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 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 26 of 43
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.
8.2.4
QOLIE-31-P
The scoring algorithm for QOLIE-31-P is described in Section 3.8.2 and Section 13.1.
QOLIE-31-P is assessed at the following time points: Month 2, Month 6, Month 12, Month 
18, and Month 24. QOLIE-31-P is also assessed at EDVs for subjects who discontinue prior 
to the YEV at the end of the second year. 
Observed values for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life, and Health Status will be summarized for 
Baseline and Last Value for the Efficacy Analysis Set. Additionally, observed values will be 
summarized for Baseline, EV, and by visit for each study visit cohort. 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.
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, and Overall Quality of Life.
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 by visit for the first 2 years of the Evaluation Period, and 
for Last Value for the first 2 years of the Evaluation Period for the Efficacy Analysis Set. 
Only observed values will be summarized and only the number of non missing values and the 
means for each item will be presented.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 27 of 43
8.2.5
EQ-5D
EQ-5D (EuroQol Group, 2000) is assessed at the following time points: Month 2, Month 6, 
Month 12, Month 18, and Month 24. EQ-5D is also assessed at EDVs for subjects who 
discontinue prior to the YEV at the end of the second year.
Qualitative EQ-5D items will be summarized for Baseline and Last Value for the Efficacy 
Analysis Set. Additionally these parameters will be summarized for Baseline and by visit for 
each study visit cohort. Percentages will be relative to the number of subjects with a response 
to each item at each time point.
Observed values for the visual analog scale (VAS) score for general health state will be 
summarized for Baseline and Last Value for the Efficacy Analysis Set. Additionally observed 
values will be summarized for Baseline and by visit for each study visit cohort. Change from 
Baseline will be summarized at each visit during the Evaluation Period.
For summaries of observed values for VAS at each time point, only subjects with a change 
from Baseline value at that time point will be summarized.
8.2.6
Direct cost parameters
Direct costs will be assessed based on concurrent medical procedures, healthcare provider 
consultations not foreseen by protocol, hospital stays, and ER visits.
Direct cost parameters will not be summarized but will be provided in subject data listings.
8.2.7
Indirect cost parameters
The number of school or working days lost will not be summarized but will be provided in 
subject data listings.
8.2.8
Socio-professional data
Socio-professional data are collected at the following time points: Month 12 and Month 24. 
Socio-professional data are also collected at EDVs for subjects who discontinue prior to the 
YEV at the end of the second year. These additional assessments will not be summarized but 
will be provided in subject data listings.
9
PHARMACOKINETICS AND PHARMACODYNAMICS
Plasma samples to analyze BRV and concomitant AED plasma concentrations will no longer 
be obtained, as directed by the integrated protocol amendment 2.
No summaries of BRV or concomitant AED 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 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 28 of 43
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, or psychiatric and mental status.
All safety summaries will be based on the Safety Analysis Set.
11.1
Extent of Exposure
11.1.1
Number of subjects exposed and subject-years of exposure
A daily dose will be calculated for each study day from the day of first dose of BRV to the 
day of last dose of BRV for the purposes of calculating modal dose. Daily dose will be 
calculated as the sum of the AM and PM dose for each day.
Modal daily doses will be calculated across all study days on or after the day of first dose of 
BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during this period. In the event of a tie, the modal dose will be set 
to the lower of the tied doses. Modal daily dose will be categorized as follows:
Category
Definition
5 mg/day
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100mg/day
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150mg/day
≥150mg/day to <200mg/day
200mg/day
≥200mg/day
Subject years of exposure will be calculated by summing the exposure duration in days for all 
subjects being summarized, and dividing the resulting value by 365.25.
Subject years of exposure will be presented overall and by modal dose for the Safety 
Analysis Set. The subject years of exposure presented by modal dose will be the total subject 
years of exposure of subjects with that modal dose.
The number and percentage of subjects exposed to BRV will be summarized overall and by 
modal dose category. The number and percentage of subjects in each Exposure Duration 
Cohort (≥3 months, ≥6 months, ≥12 months, and so forth) will be summarized.
The number and percentage of subjects within each modal dose category will be summarized 
for each Exposure Duration Cohorts; percentages will be relative to the total number of 
subjects in each Exposure Duration Cohort.
In addition to the overall summaries of the above, the above will also be summarized by 
subgroup for region.
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 for N01315. TEAEs are 
defined as AEs that had onset on or after the day of first BRV dose. AEs with an incomplete 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 29 of 43
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.
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

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.
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 (or 
the date of last scheduled or unscheduled visit for subjects who are ongoing at the time of the 
clinical cutoff) 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
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 30 of 43
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
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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.
11.3.1
Hematology and blood chemistry parameters
Observed values for each planned hematology and blood chemistry parameter will be 
summarized for Baseline, Study Entry, and each scheduled visit during the Evaluation Period 
for which laboratory parameters were assessed, Last Value, EDV, and FV. Change from 
Baseline will be summarized for all post-Baseline time points including EV. Only laboratory 
parameters planned per protocol will be summarized; results for laboratory parameters not 
planned per the protocol will only be provided in subject data listings.
The number and percentage of subjects with an on-treatment potentially clinically significant 
treatment-emergent (PCST) value, PCST low value, and PCST high value will be 
summarized. This summary will consider all assessments after the first dose of BRV and 
prior to or on the date of the last dose of BRV. Percentages will be relative to the number of 
subjects with an on-treatment assessment.
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for Baseline, Study Entry, each visit during the 
Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last 
Value, and FV. Percentages for each parameter and time point will be relative to the number 
of subjects with a value at that time point.
PCST (Sections 13.3.1, 13.3.2, and 13.3.3) criteria are based on FDA Division of 
Neuropharmacologic Drug Products guidelines with some UCB-defined additions.
Creatinine clearance, when available from the central laboratory, will be provided in subject 
data listings only and will not be summarized.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 31 of 43
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 
which urinalysis parameters were scheduled to be assessed, Last Value, EDV, and FV. 
Percentages for each parameter will be relative to the number of subjects with a result at each 
time point.
For occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number and 
percentage of subjects with an on-treatment PCST value, PCST low value, and PCST high 
value will be summarized. This summary will consider all assessments after the first dose of 
BRV and prior to or on the date of the last dose of BRV. Percentages will be relative to the 
number of subjects with an on-treatment assessment.
Additionally, for occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number 
and percentage of subjects with a PCST value, PCST low value, and PCST high value will be 
summarized for Baseline, Study Entry, each visit during the Evaluation Period for which 
laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages 
for each parameter and time point will be relative to the number of subjects with a value at 
that time point.
11.3.3
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, Occult Blood, and Leukocytes, a listing of microscopic 
analysis parameters will be provided; no summaries of microscopic analysis findings are 
planned.  
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 32 of 43
11.4
Vital Signs, Physical Findings, and Other Observations 
Related to Safety
11.4.1
Vital signs
Vital signs are assessed at all FEVs, MEVs, YEVs, EDVs, and at FV, and may also be 
assessed at Unscheduled Visits. Body weight is assessed at all FEVs, YEVs, EDVs, and at 
FV, and may also be assessed at Unscheduled Visits.
Observed values for SBP, DBP, pulse rate, and body weight will be summarized for Baseline, 
Study Entry, each visit during the Evaluation Period for which vital signs or body weight 
were assessed, EDV, Last Value, and FV. Changes from Baseline for SBP, DBP, pulse rate, 
and body weight will be summarized for all post-Baseline time points.
The number and percentage of subjects with an on-treatment PCST value, PCST low value, 
and PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV. 
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for the above parameters for Study Entry, each visit 
during the Evaluation Period for which vital signs or body weight were scheduled to be 
assessed, Last Value, EDV, and FV. Percentages will be relative to the number of subjects 
with a value at each time point.
PCST criteria (Section 13.3.4) 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.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 33 of 43
11.4.4
Neurological examination
A listing of abnormal 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 Section 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 
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. 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 2 to the protocol, the Columbia-Suicide Severity Rating Scale 
(C-SSRS) was added as an assessment at all study visits. Specific rules are provided to the 
study sites with regard to the identification of AEs or SAEs based on the outcome of this 
assessment. Because clinical events of interest will be recorded as AEs or SAEs, no study 
variable is defined for this assessment and no analyses are planned for the C-SSRS within the 
context of this study. However, subject data listings of the data for the C-SSRS will be 
provided. Additional listings will be provided for the subset of subjects with suicidal ideation 
and the subset of subject with actual suicide attempts.
Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions:
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 34 of 43
Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt 
questions:
12
REFERENCES
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. 
Epilepsia 1998, 39(1): 81-88.
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
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 35 of 43
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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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 36 of 43
Medication Effects
28.
0
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66.7
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26.
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TOTAL :
_____
÷ 3 = _____
Daily Activities/Social Functioning
13.
0
20
40
60
80
100
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0
25
50
75
100
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0
25
50
75
100
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100
75
50
25
0
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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)
____
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 37 of 43
13.2
Subject site transfers
CRF#
Initial Site Subject #
Transfer Site Subject #
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
     24 June2016
Statistical Analysis Plan
                                                             Brivaracetam
         01315
Confidential
                                                         Page 38 of 43
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
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UCB
     24 June2016
Statistical Analysis Plan
                                                             Brivaracetam
         01315
Confidential
                                                         Page 39 of 43
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
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UCB
     24 June2016
Statistical Analysis Plan
                                                             Brivaracetam
         01315
Confidential
                                                         Page 40 of 43
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.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 41 of 43
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.
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 42 of 43
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. 
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UCB
24 June2016
Statistical Analysis Plan
Brivaracetam
         01315
Confidential
Page 43 of 43
14
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN
Rational for the amendment
The primary purpose for the amendment is (1) remove rules and definitions based on data 
cutoffs for interim analyses; (2) remove the summary analysis for direct cost parameter and 
indirect cost parameters, and as well as Socio-professional data.
Change #1 (global)
Removed all rules and definitions based on data cutoffs for interim analyses throughout SAP.
Change #2
Section 8.2.6 Direct cost parameters, Section 8.2.7 Indirect cost parameters, Section 
8.2.8 Socio-professional data
Removed all direct/indirect cost parameters and socio-professional data summary analysis.
Change #3
Removed signature page. Using e-signature approval process through Mikado.
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