Conditions: Epilepsy
Keywords: Brivaracetam Epilepsy Partial Onset Seizures open label
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 668
Healthy volunteers: no

Brief summary:
This trial, evaluating the long-term safety and tolerability of brivaracetam will provide subjects suffering from epilepsy, who may have benefited from brivaracetam as adjunctive treatment, the opportunity to receive open label brivaracetam treatment.

Detailed description:
Study access was limited to subjects having completed one of the previous brivaracetam (BRV) studies: N01193 \[NCT00175825\], N01252 \[NCT00490035\], N01253 \[NCT00464269\], N01254 \[NCT00504881\].

Arms:
arm 1: Brivaracetam used as adjunctive treatment, flexible dosing up to 200 mg /day in b.i.d (twice daily) administration. Dose increase or decrease can be made in increments of maximum 50 mg/day on a weekly basis.

Interventions: intervention 1: Brivaracetam
Intervention descriptions: intervention 1: * Active Substance: Brivaracetam
* Pharmaceutical Form: Tablet
* Concentration: 10 mg and 25 mg
* Route of Administration: Oral

Protocol document:
Prot_000.pdf: 
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 1 of 72
1
TITLE
PROTOCOL N01199
An open-label, multicenter, follow-up trial to evaluate the long-term safety and efficacy of 
brivaracetam used as adjunctive treatment at a flexible dose up to a maximum of 200 mg/day 
in subjects aged 16 years or older suffering from epilepsy.
Sponsor:
UCB Pharma Inc.
1950 Lake Park Drive
USA - GA 30080
Smyrna
UNITED STATES
Hereafter “UCB”
Brivaracetam - 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 anyway 
communicated to any third party without prior written approval of the Sponsor (or its 
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 / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 2 of 72
Protocol Signatures:
Authorized signature on behalf of UCB:
Principal Investigator
“By my signature below, I acknowledge that I have read the protocol RPCE05C2110 and 
agree that it contains all necessary details for carrying out the clinical study described therein. 
Furthermore, I agree to conduct this clinical study in compliance with said Protocol, the ICH 
Good Clinical Practice guideline, as well as with any and all applicable federal, state and/or 
local laws and regulations and with my contractual obligations towards the Sponsor of the 
clinical study or its representatives(s).”
Signature:
__________________________________
Date:
_________
Printed Name:
__________________________________
Address:
__________________________________
__________________________________
Phone:
__________________________________
Site Number:
_________
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 3 of 72
2
CONTACT INFORMATION
Sponsor
UCB Pharma Inc.
1950 Lake Park Drive
USA - GA 30080
Smyrna
UNITED STATES
Study Physician
Name:
, MD
Phone:
Fax:
Clinical Project Manager
Name:
Phone:
Fax:
Safety Physician
Name:
, MB BCh 
BAO, MRCGP
Phone:
Fax:
Clinical Trial Statistician
Name:
Phone:
Fax:
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 4 of 72
SAE Reporting (24h/24), Safety Related Issues (GCSP)
Email:
Global:
DSICT@ucb.com
Fax:
Europe and Rest of the World:
USA: 
+32-2-386-2421+1-
800-880-6949
Canada:
+1-877-582-8842
Investigator(s)
The complete and updated list of Investigators is maintained in the Trial Master File (TMF) at 
the sponsor.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 5 of 72
3
TABLE OF CONTENTS
1
TITLE..............................................................................................................................1
2
CONTACT INFORMATION .......................................................................................3
3
TABLE OF CONTENTS...............................................................................................5
4
LIST OF ABBREVIATIONS........................................................................................9
5
PROTOCOL SUMMARY...........................................................................................12
5.1
Study Schedule of Assessments.......................................................................18
5.2
Schematic Diagram ..........................................................................................21
6
BACKGROUND INFORMATION............................................................................23
6.1
Background and epidemiology of targeted disease..........................................23
6.2
Background information regarding product.....................................................24
6.3
Efficacy with BRV in fixed-dose Phase II/III studies in POS .........................25
6.4
Safety with BRV ..............................................................................................25
6.5
Study Rationale ................................................................................................26
6.5.1
Dose Selection....................................................................................26
6.5.2
Subjects Population............................................................................26
6.5.2.1
Minimal Age...............................................................26
6.5.3
Duration of Treatment........................................................................26
7
STUDY OBJECTIVES ................................................................................................27
7.1
Primary Objective ............................................................................................27
7.2
Secondary Objectives.......................................................................................27
7.3
Exploratory Objectives.....................................................................................27
8
STUDY DESIGN ..........................................................................................................28
8.1
Type/Design .....................................................................................................28
8.2
Subjects/Sites Numbers....................................................................................29
8.3
Subject Identifier..............................................................................................29
8.4
Study Duration .................................................................................................29
8.5
End of Study.....................................................................................................29
9
SELECTION AND WITHDRAWAL OF SUBJECTS.............................................29
9.1
Subject Inclusion Criteria.................................................................................29
9.2
Subject Exclusion Criteria................................................................................30
9.3
Subject Withdrawal..........................................................................................30
9.3.1
Withdrawal Criteria............................................................................31
9.3.2
Subject Replacement Policy...............................................................32
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
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CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 6 of 72
10.1.2
Dosing Schedule ................................................................................32
10.1.3
Packaging...........................................................................................33
10.1.4
Labeling..............................................................................................33
10.1.5
Storage Requirements ........................................................................33
10.1.6
Monitoring of Subject Compliance....................................................34
10.1.7
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..............................................................................................35
11.1
Description of Procedures ................................................................................35
11.1.1
Informed Consent...............................................................................35
11.1.2
Subject Study Card.............................................................................36
11.1.3
Demography.......................................................................................36
11.1.4
Childbearing Potential and Birth Control ..........................................36
11.1.5
General Medical and Procedure History............................................36
11.1.6
Epilepsy History.................................................................................36
11.1.7
Antiepileptic Medication History.......................................................36
11.1.8
Vital Signs..........................................................................................36
11.1.9
Weight and Height .............................................................................37
11.1.10 Physical Examination.........................................................................37
11.1.11 Neurological Examination .................................................................37
11.1.12 ECG....................................................................................................37
11.1.13 Daily Record Card (DRC)..................................................................38
11.1.14 Laboratory Assessments.....................................................................38
11.1.15 Adverse Events (AEs)........................................................................39
11.1.16 Assessment of Suicidality ..................................................................39
11.1.17 Medical Procedures............................................................................40
11.1.18 Non-Antiepileptic and Antiepileptic Concomitant Medications........41
11.1.19 Patient Reported Outcomes................................................................41
11.1.20 Quality of Life in Epilepsy Questionnaire (QOLIE-31-P).................41
11.1.21 Hospital Anxiety and Depression Scale (HADS) ..............................42
11.1.22 EQ-5D Questionnaire.........................................................................42
11.1.23 Hospital Stay......................................................................................42
11.1.24 Healthcare Provider Consultation not Foreseen by Protocol.............43
11.1.25 Socio-professional Data .....................................................................43
11.1.26 End of Study.......................................................................................43
11.2
Description Visit by Visit.................................................................................44
11.2.1
Entry Visit..........................................................................................44
11.2.2
Full Evaluation Visit ..........................................................................45
11.2.3
Minimal Evaluation Visit...................................................................46
11.2.4
Yearly Evaluation Visit (replaces the first FEV of each year)...........46
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CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 7 of 72
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..................................................................................49
11.3
Handling of Biological Samples ......................................................................49
11.4
Other Supplies..................................................................................................49
12
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................49
12.1
Adverse Events.................................................................................................49
12.1.1
Definition of Adverse Event (AE) .....................................................49
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
12.2
Serious Adverse Events....................................................................................54
12.2.1
Definition of Serious Adverse Event (SAE)......................................54
12.2.2
Procedures for Reporting Serious Adverse Events (SAE).................55
12.2.3
Anticipated Serious Adverse Events..................................................56
13
STATISTICS.................................................................................................................56
13.1
Statistical and Analytical Plans........................................................................56
13.1.1
Study Population(s)............................................................................56
13.1.2
Efficacy and Safety Variables............................................................56
13.1.3
Statistical Evaluation..........................................................................58
13.2
Determination of the Sample Size....................................................................60
13.3
Statistical and Analytical Issues.......................................................................60
13.3.1
Handling of Dropouts of Missing Data..............................................60
13.3.2
Interim Analysis and Data Monitoring ..............................................60
13.3.3
Use of an Efficacy Subset of Subjects ...............................................60
13.3.4
Examination of Subgroups.................................................................60
13.4
Criteria for Starting the Analysis .....................................................................60
13.5
Dictionaries ......................................................................................................61
14
ETHICS AND REGULATORY REQUIREMENTS................................................61
14.1
Approval...........................................................................................................61
14.2
Subject Information and Consent.....................................................................62
14.3
Subject Confidentiality.....................................................................................63
14.4
Informing the General Practitioner (or Pediatrician) .......................................64
15
STUDY MANAGEMENT AND ADMINISTRATION ............................................64
15.1
Monitoring........................................................................................................64
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 8 of 72
15.2
Direct Access to Source Data/Documents .......................................................64
15.3
Audit and Inspection ........................................................................................65
15.4
Case Report Forms (CRF)................................................................................65
15.5
Adherence to Protocol......................................................................................66
15.6
Investigator Site File ........................................................................................67
15.7
Data Handling ..................................................................................................67
15.8
Termination of Study .......................................................................................67
15.8.1
Termination of Study by Sponsor ......................................................68
15.9
Clinical Study Report.......................................................................................68
15.10
Insurance and Liability.....................................................................................68
15.11
Archiving and Data Retention..........................................................................68
15.12
Allocation of Responsibilities..........................................................................69
15.13
Curriculum Vitae (CV).....................................................................................69
15.14
Financial Disclosure.........................................................................................69
15.15
Good Clinical Practice .....................................................................................70
15.16
Publication........................................................................................................70
16
REFERENCES .............................................................................................................70
17
SPONSOR DECLARATION ......................................................................................72
List of Tables
Table 5:1
Study Flowchart...........................................................................................18
Table 5:2
Visit Schematic Diagrams ...........................................................................22
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 9 of 72
4
LIST OF ABBREVIATIONS
AE(s)
Adverse Event(s)
AED(s)
Antiepileptic Drug(s)
ALT 
(ALAT/SGPT)
Alanine Aminotransferase
ASAT/SGOT
Aspartate Aminotransferase
ALP
Alkaline Phosphatase
AV
Additional Visit
b.i.d.
Twice Daily
BRV
Brivaracetam
BZD
Benzodiazepine
CBZ
Carbamazepine
CDMS
Clinical Data Management System
CPMP
Committee for Proprietary Medicinal Product
Cr Cl
Creatinine Clearance
CRF
Case Report Form
CRO
Clinical Research Organization
C-SSRS
Columbia Suicide Severity Rating Scale
CTM
Clinical Trial Manager
CV
Curriculum Vitae
CYP
Cytochrome
DBP
Diastolic blood pressure
DHHS
Department of Health and Human Services
dl
Deciliter
DRC
Daily Record Card
DTP
Down-titration Phone Call
ECG
Electrocardiogram
EDV
Early Discontinuation Visit
EQ-5D
EuroQoL 5 Dimensions Questionnaire
ER
Emergency room
EV
Entry Visit
FEV
Full Evaluation Visit
FDA
Food and Drug Administration
FV
Final Visit
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma-glutamyltranspeptidase
GMP
Good Manufacturing Practices
GP
General Practitioner
h
Hour
HADS
Hospital Anxiety and Depression Scale
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 10 of 72
HDPE
High Density Polyethylene
IB
Investigator Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ILAE
International League Against Epilepsy
IND
Investigational New Drug
IRB
Institutional Review Board
IVRS
Interactive voice response system
IWRS
Interactive web response system
kg
Kilogram
L
Liter
LTG
Lamotrigine
m
Meter
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MEV
Minimal Evaluation Visit
µg
Microgram
mg
Milligram
min
Minute
ml
Milliliter
µL
Microliter
µM
Micromol
PBO
Placebo
PGS
Primary Generalized Epilepsy
PK
Pharmacokinetics
POS
Partial Onset Seizure
PRO
Patient Reported Outcomes
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy Questionnaire
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SBP
Systolic blood pressure
SDV
Source Data Verification
SOC
System Organ Class
SOP
Standard Operating Procedure
SP
Study Physician
SV2A
Synaptic Vesicle Protein 2A
TMF
Trial Master File
WBC
White Blood Cell
WHO
World Health Organization
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 11 of 72
YEV
Yearly Evaluation Visit
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 12 of 72
5
PROTOCOL SUMMARY
Investigational Product:
Brivaracetam (BRV)
Objectives:
Primary Objective
To evaluate the long-term safety and tolerability of BRV at individualized doses with a 
maximum of 200 mg/day in subjects suffering from epilepsy.
Secondary Objective
To evaluate the maintenance of efficacy over time of BRV (for POS/PGS subjects).
Exploratory Objectives

To explore the effects of BRV on the subject’s Health-related Quality of Life, anxiety,
and depression for the first 2 years.

To explore medical resource use and indirect cost parameters for the first 2 years.

To obtain a description of the subject’s self-reported health status for the first 2 years.

To explore any change in the subject’s socio-professional status for the first 2 years.
This study will provide subjects suffering from epilepsy, who may benefit from BRV as 
adjunctive treatment, the opportunity to receive open label adjunctive BRV treatment.  
Conversion to monotherapy is not permitted anymore; however, subjects already on 
monotherapy are allowed to continue BRV monotherapy.  The access will be limited to the 
subjects having completed a previous BRV study as listed in Section 5.2.
Estimated Number of Subjects, Sites and Rationale:
It is estimated that approximately 500 - 1,000 subjects will enter the study based on the 
assumption that 90% of subjects having completed a previous study with BRV as adjunctive 
treatment in epilepsy will roll over into the present study.
It is estimated that between 100 - 200 sites will participate in this global protocol.
Subject Population and Diagnosis:
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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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 13 of 72

Male/female subjects from 16 years or older. Subjects under 18 years may only be 
included where legally permitted and ethically accepted.

Subjects with epilepsy who participated in previous BRV studies which allow access to 
the present study.

Subjects from whom the Investigator believes a reasonable 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 30 µg [or 50 µg if associated with 
other antiepileptic drugs (AEDs) 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. According to the judgment of the 
Investigator, 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 or laboratory values which may 
have an impact on the safety of the subject.

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.
Drug Administration: 
Subjects coming from BRV studies have the opportunity to access BRV treatment at a 
flexible dose of up to a maximum of 200 mg/day in b.i.d. administration. It is recommended 
that the daily dose be divided equally and be taken with or without food. The first intake will 
be in the evening of the day of the dispensation of the study medication. The individual 
starting dose of each subject will be the one defined/reached at the end of the previous study.
At each visit, an interactive voice response system (IVRS) /interactive web response system 
(IWRS) will be responsible for issuing subjects kits of study medication, as appropriate, 
according to the visit schedule and according to the supplies needed by the subject in terms of 
the number of tablets of each size (80 count or 200 count), and of each dosage (10 mg and 25 
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 14 of 72
mg tablets) according to the dose prescribed and the possibility to down-titrate/up-titrate by a 
maximum of 50 mg/day steps 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.  Containers of 80 tablets will be progressively removed.
Oral tablets of 10 mg and 25 mg BRV will be used in this study. Initially, BRV 2.5 mg and 
10 mg tablets were packaged in blister cards containing 20 tablets each. Visit cartons of 80 
(4 blister cards) and 200 (10 blister cards) tablets were provided and each visit carton had a 
unique, pre-printed identification number.
In November 2006, a transition from blister cards to HDPE (High Density Polyethylene) 
bottles was implemented. Brivaracetam 2.5 mg oral tablets were packaged in bottles of 200 
tablets and BRV 10 mg oral tablets were packaged in bottles of 80 and 200 tablets. Each 
bottle has a unique, pre-printed identification number. Containers of 80 tablets will be 
progressively removed.
HDPE bottles containing 80 and 200 oral tablets of BRV 25 mg will be available when 
subjects begin enrolling from BRV Phase III studies (N01252, N01253, and N01254).  
Containers of 80 tablets will be progressively removed.
Each subject will be informed on how to take the drug and that there is an excess of drug in 
the visit carton or bottle.
Methodology:
This is a Phase III, therapeutic long-term follow-up, multicenter, non-comparative, open-label 
and single arm study.
This study will run throughout the duration of the clinical development period of BRV and 
will thus include the therapeutic exploratory study completed during the early stage of 
development as well as therapeutic confirmatory studies which will be completed in the later 
stages of development.  For this reason, the study design of this study and in particular the 
frequency of study visits is adapted for the 2 types of phases as described below.
For those subjects coming from the therapeutic exploratory study, visits will be scheduled as 
follows:

First year:

During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit 
(FEV) alternating with 1 Minimal Evaluation Visit (MEV).

During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7
and V8).

Second and subsequent years:

1 visit every 3 months; 1 FEV alternating with 1 MEV.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 15 of 72

The Yearly Evaluation Visit (YEV) will be performed in replacement of the first 
FEV of each year.
For those subjects coming from therapeutic confirmatory studies:

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/3 months: FEV alternating with MEV.

The YEV will be performed in replacement of the first FEV of each year.
Variables and Assessments:
The efficacy variables will be assessed by using the seizure count information recorded on the 
DRC.  The subject will be asked to record the date and the number (where possible) of 
epileptic seizures he/she has experienced.  The type of seizure (according to individual 
description of seizures) will be defined by the Investigator by adding the ILAE codes.  The 
Investigator will also confirm on the DRC the number of seizures of each type experienced 
by the subject.
The periods considered in the definition of efficacy variables are the following:

3-month periods over the Evaluation Period (V1 until the last evaluation visit).
Primary safety variables:

Occurrence of a TEAE

Withdrawal due to an AE

Occurrence of an SAE
Other safety variables:

Laboratory tests (hematology, blood chemistry, urinalysis)

Vital signs (systolic blood pressure [SBP]), diastolic blood pressure [DBP], pulse rate) 
and body weight

Electrocardiogram (ECG)

Physical and neurological examinations
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 16 of 72

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
POS (type I) frequency per 28 days during the Evaluation Period
Percent reduction in POS (type I) frequency per 28 days from Baseline of the previous 
study to the Evaluation Period
Responder rate for POS (type I) frequency over the Evaluation Period. A responder is
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline 
Period of the previous study
Other efficacy variables
For subjects with focal-onset epilepsy:
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period
For subjects with generalized epilepsy:
Generalized (type II) seizure days per 28 days during the Evaluation Period
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period
Responder rate for generalized (type II) seizure days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure days from the 
Baseline Period of the previous study
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:
Change in 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
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final /15 Oct 2015 / Page 17 of 72
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
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects
with generalized epilepsy:
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
[ER] visits) during the first 2 years of the Evaluation Period
Indirect costs (work days or school days lost by the subject and days subject received 
help from a caregiver) during the first 2 years of the Evaluation Period
Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 18 of 72
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) (a) 
Down-Titration 
Phone Call
(DTP) (a) 
Final Visit
(FV)
Reference to 
Section
ASSESSMENTS
Written Informed Consent
X
11.1.1
Clinical Trial Subject Card 
Dispensing
X
11.1.2
Verification Inclusion/ 
Exclusion Criteria
X
9.1 and 9.2
Demographic Data
X
11.1.3
Childbearing Potential
X
11.1.4
Medical and Procedures History
X(b) 
11.1.5
Epilepsy History
X(b) 
11.1.6
AED History
X(b) 
11.1.7
Vital Signs
X(c) 
X
X
X
X
X
X
11.1.8
Weight and Height(d) 
X
X
X
X
X
11.1.9
Physical Examination
X(c) 
X
X
X
X
11.1.10
Neurological Examination
X(c) 
X
X
X
X
11.1.11
ECG(e) 
X(c) 
X
X
X
11.1.12
Daily Record Card Dispensed
X
X
X
X
X
11.1.13
Daily Record Card Retrieval
X
X
X
X
X
X
11.1.13
Recording of Seizures
X (c) 
X
X
X
X
X
11.1.13
QOLIE-31-P(f) (k)
X
X
X
11.1.20
HADS(f) (k)
X
X
X
11.1.21
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 19 of 72
Table 5:1
Study Flowchart (continued)
Entry 
Visit
(EV)
Full 
Evaluation 
Visit
(FEV)
Minimal 
Evaluation 
Visit 
(MEV)
Yearly 
Evaluation 
Visit
(YEV)
Additional 
Visit
(AV)
Early 
Discontinuation 
Visit(a) 
(EDV)
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Phone Call
(DTP) (a) 
Final Visit
(FV)
Reference to 
Section
EQ-5D(g) (k)
X
X
X
11.1.22
Workdays and schooldays lost / 
days with caregiver’s help (k)
X
X
X
X
X
X
11.1.13
Hospital Stay (k)
X
X
X
X
X
X
11.1.23
Heathcare Provider Consultations
not foreseen by the protocol (k)
X
X
X
X
X
X
11.1.24
Socio-professional Data(h) (k)
X
X
11.1.25
Laboratory Assessments(i) 
X(c) 
X
X
X
X
11.1.14
Recording of Adverse Events
X
X
X
X
X
X
X
X
11.1.15
C-SSRS(l)
X
X
X
X
X
X
11.1.16
Medical Procedures
X
X
X
X
X
X
X
11.1.17
Concomitant AED
X
X
X
X
X
X
X
11.1.18
Concomitant Non-AED
X
X
X
X
X
X
X
11.1.18
Drug Dispensing
X
X
X
X
X
10.1.2 and 
10.1.6
Drug Return/Accountability
X
X
X
X
X
10.1.6 and 
10.1.7
End of Study Status(j) 
X
11.1.26
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 20 of 72
Table 5:1
Study Flowchart (continued)
AED=antiepileptic drug; AV=Additional Visit; CRF=Case Report Form; C-SSRS=Columbia Suicide Severity Rating Scale; DTP=Down-titration Phone 
Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Visit; FV=Final Visit; HADS=Hospital Anxiety 
and Depression Scale; 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 transferred 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 transferred from the database of the last visit of the previous study and should not be recorded in the CRF:  Vital Signs, 
Physical Examination, Neurological Examination, ECG, Recording of seizures, Laboratory Assessment including Safety (blood chemistry, hematology 
and urinalysis) 
(d) Height will be recorded at Visit 1 (Entry Visit).  Height will also be measured at each YEV and the Final Visit for those subjects that are still potentially 
growing.
(e) At Final Visit, ECG is mandatory except if Final Visit follows an Early Discontinuation Visit where ECG results were normal.
(f) QOLIE-31-P and HADS are to be completed at the beginning of the visit by all subjects (except those coming from N01193) who are not mentally 
impaired.
(g) EQ-5D questionnaire is to be completed by all subjects (except those coming from N01193) who are not mentally impaired.
(h) Socio-professional data will be collected for all subjects except those coming from N01193.
(i) Laboratory assessment includes blood chemistry, hematology and urine analysis; where applicable (women of childbearing potential), a urine pregnancy 
test will be done. Laboratory assessment is mandatory at Final visit except if Final Visit follows an Early Discontinuation Visit where laboratory results 
were normal.
(j) 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).
(k) Procedures only performed during the first 2 years of subject participation in the study (eg, until last scheduled visit [Y3-YEV]) or EDV/FV in case the 
subject discontinues participation within the first 2 years).
(l) The C-SSRS assessment will be implemented by site per IRB/IEC approval and upon completion of required training.  As of the time of Protocol Amendment 6, all 
subjects had completed their Entry Visit.  Thus, the C-SSRS was not assessed for any subjects at their Entry Visit.
(m) 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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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 21 of 72
5.2
Schematic Diagram
For subjects coming from the therapeutic exploratory study (N01193), visits will be 
scheduled as follows:

First year:

During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit 
(FEV) alternating with 1 Minimal Evaluation Visit (MEV).

During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7
and V8).

Second and subsequent years:

1 visit every 3 months; 1 FEV alternating with 1 MEV.

The Yearly Evaluation Visit (YEV) will be performed in replacement of the first 
FEV of each year.
For those subjects coming from therapeutic confirmatory studies (N01252, N01253, and 
N01254):

First year:

First 3 months: 1 visit/month: FEV alternating with MEV.

Next 9 months: 1 visit/3 months: FEV alternating with MEV.

Second and subsequent years:
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1 visit/3months: FEV alternating with MEV.
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The YEV will be performed in replacement of the first FEV of each year.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 22 of 72
Table 5:2
Visit Schematic Diagrams
Subjects coming from Exploratory Study
(N01193)
Subjects coming from Confirmatory 
Studies (N01252, N01253, N01254)
1st Year Follow-up
1st Year Follow-up
Month
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Month
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Type of Visit
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2nd and subsequent years follow-up
M12
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V12
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In case the subject will not continue with the study drug, the Investigator will first plan an 
Early Discontinuation Visit followed by the progressive down-titration of the study drug.  
During the down-titration period, the dose may be decreased in steps of a maximum of
50 mg/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 20 mg/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 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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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 23 of 72
6
BACKGROUND INFORMATION
6.1
Background and epidemiology of targeted disease
Epilepsy is one of the most common and challenging neurological disorders.  It has been 
estimated that over 50 million people are affected worldwide (Engel and Pedley, 1998; 
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 approximately 50 to 
70 cases per 100.000.  In developing countries, the figure is higher due to more limited 
obstetric services and the greater likelihood of cerebral infection and trauma.  The incidence 
varies greatly with age, with high rates occurring in childhood, falling to low levels in early 
adult life, but with a second peak in those aged over 65 years.  In many people, particularly 
children, the condition may remit, although a significant proportion will have epilepsy 
lifelong.  The disease duration is often determined by the underlying cause.  Sudden 
unexpected death, a complication of great concern, occurs in 1 to 5 per 1000 patient years, 
particularly if the seizure disorder remains uncontrolled.  The treatment for epilepsy remains 
difficult, and there is ongoing medical need for new antiepileptic drugs (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 (ie, 
related to a focal brain dysfunction), which are the most frequent and account for 
approximately 60 to 70% of all cases, and generalized epilepsy syndromes, which represent 
approximately 25 to 30% of all epilepsy syndromes.  In about 10% of cases, other specific 
syndromes are classified or the classification remains uncertain.
The classification of epileptic syndromes and seizure types is – and always was – a matter of 
ongoing debate.  First published in 1960 and last updated officially in 1981 for seizures and 
1989 for epilepsies (Commission on Classification and Terminology of the International 
League Against Epilepsy ([ILAE], 1981 and 1989), these ILAE classifications were based on 
concepts that, for the most part, predate modern technologies and concepts (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).
This ongoing debate regarding the classification systems for epilepsies and seizures is also 
reflected within the latest Report of the Commission on Classification and Terminology 
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 24 of 72
(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. Like levetiracetam (LEV, Keppra®), BRV
displays a high and selective interaction with a novel brain-specific binding site, SV2A 
(synaptic vesicle protein 2A).  However, the binding affinity of BRV for SV2A is 
approximately 10-fold higher than with LEV.  This binding site appears to be the major target 
for its pharmacological activity.  Unlike LEV, BRV also reduces voltage-dependent sodium 
currents.  Brivaracetam also reverses the inhibitory effects of negative allosteric modulators 
on gamma-aminobutyric acid, and glycine-induced currents.  Brivaracetam is extensively 
metabolized, but seizure protection appears to be associated with the parent compound.
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 10 mg to 600 mg).  Brivaracetam is weakly bound to plasma 
proteins (≤20%).  The volume of distribution is 0.5 L/kg, a value that is close to that of total 
body water.  The plasma half-life of 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 
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 
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.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 25 of 72
Brivaracetam does not impair the efficacy of oral contraceptives containing ethinylestradiol 
30 µg and levonorgestrel 150 µg.  Brivaracetam does not induce CYP3A4 using midazolam 
as a marker probe.  Brivaracetam has no interaction on lamotrigine (LTG) 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 (CBZ), lamotrigine, LEV, oxcarbamazepine metabolite, phenobarbital, 
phenytoin, topiramate, valproate, and zonisamide. Carbamazepine epoxide was significantly 
increased from baseline at all BRV doses greater than 20 mg/day, nearly reaching the upper 
limit of normal (3.0 µg/mL) at BRV doses of 100 and 150 mg/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 100 mg/day.
N01253 assessed BRV doses of 5, 20, and 50 mg/day and provided statistically significant 
and clinically relevant evidence of the efficacy of BRV 50 mg/day.  N01252 assessed BRV
doses of 20, 50, and 100mg/day.  Although N01252 was not positive, it provided supporting 
evidence for the efficacy of BRV 100 mg/day in subjects with epilepsy.
6.4
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 treatment-emergent 
adverse events (TEAEs) were low and similar to placebo (PBO) for all studies. The most 
frequently reported TEAEs were headache, somnolence, dizziness, and fatigue.  The overall 
incidence of serious adverse events (SAEs) was low and similar to PBO.  There were no 
clinically relevant changes in laboratory values, vital signs, or ECG abnormalities.
For additional details on safety and efficacy of BRV, please refer to the Investigator’s 
Brochure (UCB reference code RXCE06E2216).
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 26 of 72
6.5
Study Rationale
The Sponsor wishes to develop BRV as an adjunctive antiepileptic treatment in subjects 
16 years and older suffering from epilepsy. N01199 will give subjects who have participated 
in previous BRV adjunctive treatment studies in epilepsy the opportunity to access adjunctive 
BRV treatment under the present protocol.  Conversion to monotherapy is not permitted
anymore; however, subjects already on monotherapy are allowed to continue BRV
monotherapy.
The subjects allowed to enter the study will mainly suffer from partial onset seizures (subjects 
coming from N01193, N01252, N01253, and N01254 [UCB protocol reference code 
RPCE06G0706]), while a minority will present with generalized epilepsy (subjects coming 
from N01254).  The N01252, N01253 and N01254 studies aimed to test the efficacy and 
tolerability of BRV in POS subjects as oral therapy. This study will explore the long-term 
safety and efficacy of BRV in such a population.
6.5.1
Dose Selection
In this study, individualized doses up to a maximum of 200 mg/day will be used. Twice daily 
dosing is deemed necessary to ensure more regular exposure over the 24-hour interval.
A maximum dose of 200 mg/day was chosen following consultation with regulatory 
authorities and is evaluated in more recent BRV studies (eg, N01358 and N01379).  
According to available data, 200 mg/day doses have been well tolerated.
6.5.2
Subjects Population
6.5.2.1
Minimal Age
Subjects are allowed to participate in this study from the age of 16 where legally permitted 
and ethically accepted. Indeed, epilepsy features in the range of 16 to 18 years do not differ 
from the ones of older subjects, and efficacy of the AEDs seems to be comparable
(CPMP/EWP/566/98 rev 1, 2000).
Depending on country-specific regulations, those subjects may be considered as adolescents 
or adults (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.
6.5.3
Duration of Treatment
For each subject, the 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 
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 27 of 72
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.
Statement
The present study will be conducted in accordance with:

This protocol.

International Conference on Harmonization (ICH): ICH E6 Note for Guidance on Good 
Clinical Practice [CPMP/ICH/135/95] and Code of Federal Regulations on Good Clinical 
Practice (GCP) Title 21 Parts 50, 54, 56, 312 and 314).

The principles that have their origin in the Declaration of Helsinki.

All applicable local laws and regulations.
7
STUDY OBJECTIVES
7.1
Primary Objective
To evaluate the long-term safety and tolerability of BRV at individualized doses with a 
maximum of 200 mg/day in subjects suffering from epilepsy.
7.2
Secondary Objectives
To evaluate the maintenance of efficacy over time of BRV (for POS/PGS subjects).
7.3
Exploratory Objectives

To explore the effects of BRV on the subject’s Health-related Quality of Life, anxiety,
and depression for the first 2 years.

To explore medical resource use and indirect cost parameters for the first 2 years.

To obtain a description of the subject’s self-reported health status for the first 2 years.

To explore any change in the subject’s socio-professional status for the first 2 years.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 28 of 72
8
STUDY DESIGN
8.1
Type/Design
This is a Phase III, therapeutic, long-term, follow-up, multicenter, 
noncomparative, open-label, and single arm study.
The study design of this study and in particular the frequency of study visits is adapted for the 
2 types of studies as described below.
For those subjects coming from the therapeutic exploratory study (N01193), visits will be 
scheduled as follows:

First year:

During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit 
(FEV) alternating with 1 Minimal Evaluation Visit (MEV).

During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7 
and V8).

Second and subsequent years:

1 visit every 3 months; 1 FEV alternating with 1 MEV.

The Yearly Evaluation Visit (YEV) will be performed in replacement of the first 
FEV of each year.
For those subjects coming from therapeutic confirmatory studies (N01252, N01253, 
N01254):

First year:

First 3 months:  1 visit/month: FEV alternating with MEV.

Next 9 months: 1 visit/3 months: FEV alternating with MEV.

Second and subsequent years:

1 visit/3months: FEV alternating with MEV.

The Yearly Evaluation Visit will be performed in replacement of the first FEV of 
each year.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 29 of 72
8.2
Subjects/Sites Numbers
It is estimated that approximately 500 - 1,000 subjects will enter the study based on the 
assumption that 90% of subjects having completed a previous study with BRV as adjunctive 
treatment in epilepsy will roll over into the present study.
It is estimated that between 100 - 200 sites will participate in the study.
8.3
Subject Identifier
Each subject will be identified by his/her initials and a subject identifier which include the 
study number, the site number and a sequential enrollment number.  The Master CRF number 
will be used as an additional identifier on laboratory reports and at the level of the database.
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 of 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 the study is defined as the date of the last visit of the last subject in the study.
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.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 30 of 72

Male/female subjects from 16 years or older. Subjects under 18 years may only be 
included where legally permitted and ethically accepted.

Subjects with epilepsy who participated in previous BRV studies which allow access to 
the present study.

Subjects from whom the Investigator believes a reasonable 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 30 µg [or 50 µg 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.  According to the judgment of the Investigator, 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.
9.2
Subject Exclusion Criteria
Subjects must be excluded if they meet any of the following criteria:

Severe medical, neurological and psychiatric disorders or laboratory values which may 
have an impact on the safety of the subject.

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
(SP) or representative for clarification.
9.3
Subject Withdrawal
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 
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 31 of 72
complete the Early Discontinuation Visit and preferably also the Down-Titration Phone Call 
and the Final Visit. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in the source 
documents. The Case Report Form (CRF) must document the primary reason for withdrawal 
or discontinuation.
The study medication will be progressively down-titrated. During the down-titration period, 
the dose may be decreased in steps of a maximum of 50 mg/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. 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 will occur.
9.3.1
Withdrawal Criteria
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 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 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.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 32 of 72
After decision of subject’s discontinuation, the Investigator will provide the subject with 
information about available alternative treatments.
9.3.2
Subject Replacement Policy
Not applicable.
10
TREATMENT OF SUBJECTS (INVESTIGATIONAL PRODUCT AND 
CONCOMITANT MEDICATIONS)
10.1
Study Investigational Products
10.1.1 Description of all Investigational Products
Active investigational product (tablets containing 10 or 25 mg BRV) will be supplied under 
the responsibility of the Sponsor Clinical Trial Supply Department for all subjects. The 
frequency at which investigational product will be supplied to each individual site will be 
adapted to the recruitment capacity of that site and to the expiry date of the investigational 
product.
10.1.2 Dosing Schedule
Subjects coming from BRV studies have the opportunity to access BRV treatment at a 
flexible dose of up to a maximum of 200 mg/day in b.i.d. administration.  It is recommended 
that the daily dose be divided equally, taken with or without food, and that the first intake will
be in the evening of the day of the dispensation of the study medication.
The individual starting dose of each subject will be the one defined/reached at the end of the 
previous study.  It is recommended that the dosing be done in even increments such as 20 mg, 
30 mg, 40 mg, etc. with the implementation of the IVRS/IWRS.  
At each subject visit, if necessary, the dosage can be adapted:

Up-titration can be made by increments of maximum 50 mg/day on a weekly basis and 
this to a maximum of 200 mg/day.

Dose decreases can be made by steps of maximum 50 mg/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 each visit, an IVRS/IWRS will be responsible for issuing subjects kits of study 
medication, as appropriate, according to the visit schedule and according to the supplies 
needed by the subject in terms of number of containers of each size (80 or 200) and of each 
dosage (10 mg or 25 mg tablets) according to the dose prescribed and the possibility to down-
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 33 of 72
titrate/up-titrate by a maximum of 50 mg/day steps.  Containers of 80 tablets will be 
progressively removed.
In case the subject will not continue with BRV, the Investigator will plan the progressive 
down-titration of the study drug. The down-titration period will be followed by a period free 
of study drug of minimum 2 weeks and a maximum of 4 weeks and subsequently the Final 
Visit 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, 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.
10.1.3 Packaging
Oral tablets of 10 mg and 25 mg BRV will be packaged in bottles of 80 and 200 tablets.
Containers of 80 tablets will be progressively removed.  On request via the IVRS/IWRS, the
Investigator will be supplied with a sufficient number of containers. Each container will have 
a unique, pre-printed identification number. 
The Investigator will inform each subject on how to take the drug and that an excess of drug 
is present in the investigational product container.
10.1.4 Labeling
Clinical drug supplies will be labeled in accordance with the current ICH guidelines on GCP 
and Good Manufacturing Practice (GMP) and will include any locally required statements.
The labels and the size of the investigational product package will be adapted to local 
regulatory requirements. The labels 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.
10.1.5 Storage Requirements
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 
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 34 of 72
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.
10.1.6 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.
Compliance with study medication is defined as investigational product consumption by the 
subject within 80% - 120% of the prescribed dosage.
10.1.7 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:

Number of tablets dispensed to and return by each subject, with the subject’s number and 
carton or bottle number.

Initials of the person who actually dispensed and/or received the return tablets.

Dates of the above.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 35 of 72

Explanations for non-compliance.
Periodically and after completion of the study, all used (including empty cartons and 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
For any treatment other than BRV, 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)
Investigator may adapt the AED drug/dosage for safety or efficacy reasons.  Benzodiazepines 
(BZD) taken more than once a week (for any indication) will be considered as a concomitant 
AED. 
10.2.2 Prohibited Concomitant Treatments (Medications and Therapies)
Vigabatrin
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).
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 36 of 72
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 Entry Visit. The Investigator will instruct the subject 
to keep the card with them at all times.
11.1.3 Demography
At the first visit, date of birth, gender and racial group will be recorded.
11.1.4 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).
11.1.5 General Medical and Procedure History
The General Medical and Procedure History will be transferred from the database of the 
previous study in which the subject was participating.
11.1.6 Epilepsy History
The history of epilepsy reported at the first visit of the previous study in which the subject 
was enrolled will be considered as the history of epilepsy for the present study and will be 
directly electronically transferred from this study.
11.1.7 Antiepileptic Medication History
The AED medication history will be transferred 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.
11.1.8 Vital Signs
At every visit, after 5 minutes supine or sitting, pulse rate and blood pressure will be obtained 
followed by a standing pulse rate and blood pressure. At the Entry Visit, vital signs will be 
obtained electronically from the last Evaluation Visit of the previous study and should not be 
recorded in the CRF.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 37 of 72
11.1.9 Weight and Height
Body weight (subject wearing light clothing without shoes and rounded to the nearest 
kilogram) will be obtained at the following visits: Entry Visit, each Full Evaluation Visit, 
each Yearly Evaluation Visit, Early Discontinuation Visit, and at the Final Visit. Height will 
be obtained at the Entry Visit. For subjects that are still potentially growing, height will also 
be measured at each Yearly Evaluation Visit and the Final Visit.
11.1.10 Physical Examination
A standard physical examination will be performed at the following visits: every Full 
Evaluation Visit, each Yearly Evaluation Visit, Early Discontinuation Visit and at the Final 
Visit. This examination may include investigation of skin, eyes, ear, nose, throat, 
cardiovascular system, respiratory system, gastro-intestinal system, musculoskeletal system 
and optionally genitourinary system. At the Entry Visit, the physical examination will be 
obtained electronically from the last Evaluation Visit of the previous study and should not be 
recorded in the CRF.
11.1.11 Neurological Examination
A standard neurological examination will be performed at the following visits: every Full 
Evaluation Visit, each Yearly Evaluation Visit, Early Discontinuation Visit and at the Final 
Visit. 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. At the Entry Visit, the neurological examination will 
be obtained electronically from the last Evaluation Visit of the previous study and should not 
be recorded in the CRF.
11.1.12 ECG
Once the subject has signed the updated Informed Consent, the number of standard 12-lead 
ECGs will be reduced to once per year at the following visits: Yearly Evaluation Visit, Early 
Discontinuation Visit, and Final Visit (in case the FV follows an EDV and the EDV ECG is 
normal, no additional ECG has to be performed at FV). At the Entry Visit, the ECG will be 
obtained electronically from the last Evaluation Visit of the previous study and should not be 
recorded in the CRF.  The Investigator will determine whether the results of the ECG are 
normal or abnormal and assess the clinical significance of any abnormalities.  The original 
ECG tracing will be signed or initialed and dated by the Investigator and retained as part of 
the source data.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 38 of 72
11.1.13 Daily Record Card (DRC)
At the Entry Visit, every Full Evaluation Visit, every Minimal Evaluation Visit, Yearly 
Evaluation Visit, and the Early Discontinuation Visit, the subject will receive a Daily Record 
Card (DRC) and will be asked to come back at the next visit with the completed DRC.
The following information will be recorded on the DRC:

Date and the number (where possible) of epileptic seizures

Type of seizure (according to individual description of epileptic seizures)

Occurrence of seizure clusters

All unusual events concerning the subject’s health

Changes in concomitant medication (dosage and/or product)

Changes in investigational product (dosage)
The written information will be discussed with the subject at each visit in order to ensure 
completeness and accuracy.  As a result of the discussion, the Investigator will assess the 
epileptic seizures according to the ILAE codes and record the seizure types and frequency on 
the CRF; he/she will also confirm the presence of adverse events (if applicable).  The 
concomitant medication changes and adverse events will be reported by the Investigator on 
the specific pages of the CRF.
The DRC will be considered part of the CRF as well as source documentation.  The subject 
should be educated to complete the DRC on a regular basis (each time that a seizure, an 
undesirable event, a modification of medication or investigational product, or a medical visit 
occurs).
11.1.14 Laboratory Assessments
At the following visits, Full Evaluation Visit, Yearly Evaluation Visit, Early Discontinuation 
Visit, and Final Visit, laboratory assessments will be conducted using standard methods at a 
central laboratory. At the Entry Visit, data will be transferred electronically from the last 
Evaluation Visit of the previous study and should not be recorded on the CRF.  The central 
laboratory will provide the Investigator with dedicated, standardized sampling equipment 
(labels, needles, tubes), and a study-specific laboratory manual, which will explain how to 
use the equipment and how to ship the samples back to the central laboratory. 
Results for hematology, chemistry, urinalysis and pregnancy tests will be provided by fax to 
the Investigator within 72 hours after sample receipt. 
The total blood volume drawn for the clinical laboratory assessments will be a maximum of 
20 ml/sampling. The subject should preferably be fasting. Study medication intake must not 
be delayed.
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 39 of 72
The following laboratory assessments will be conducted:

Blood chemistry: glucose, urea, creatinine, sodium, potassium, calcium, phosphorus 
(inorganic), total protein, albumin, total bilirubin, alkaline phosphatase (ALP), aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase (ASAT/SGOT), alanine 
aminotransferase/serum glutamic pyruvic transaminase (ALAT/SGPT), gamma-
glutamyltranspeptidase (GGT), and uric acid.

The creatinine clearance (Cr Cl) will be calculated by the Cockroft’s formula (only at the 
Entry Visit): 

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.

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 urine pregnancy test will be 
conducted. 
Plasma samples to analyze BRV and concomitant AED plasma concentrations will no longer 
be obtained.
11.1.15 Adverse Events (AEs)
At the Entry Visit, the Investigator will record any adverse event that was still ongoing at the 
end of the previous study. From the entry Visit onwards, adverse events will be assessed at 
each visit and recorded in the CRF and in the source documents. The study participant will 
be given the opportunity to report AEs spontaneously. A general prompt will also be given to 
detect 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. daily record 
cards) used in the study.
11.1.16 Assessment of Suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS.  This scale will be 
used to assess suicidal ideation and behavior that may occur during the study.  The C-SSRS 
will be completed according to the tabular schedule of assessments (Section 5.1).
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 40 of 72
11.1.17 Medical Procedures
From the Entry Visit 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 / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 41 of 72
11.1.18 Non-Antiepileptic and Antiepileptic Concomitant Medications
At the Entry Visit, 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 prohibited concomitant medication (see Section 10.2.2) 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.
11.1.19 Patient Reported Outcomes
A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as 
well as for EDV. The assessment of the Patient Reported Outcomes will be limited to the 
first 2 years after study entry, which includes the YEV of Year 3.  These booklets will 
include, in order of appearance: The Patient Weighted Quality of Life in Epilepsy Inventory -
31 item form (QOLIE-31-P - Version 2), the Hospital Anxiety and Depression Scale 
(HADS), and the EQ-5D self report questionnaire. The PRO booklet is to be provided to 
subjects that are not mentally impaired, at the very beginning of the study visit. The subject 
will be asked to complete the questionnaires on his/her own. Once completed, the subject 
will hand back the booklet to the Investigator who will check that all questions have been 
answered.
Subjects coming from N01193 will not have to complete the PRO booklet. All other subjects 
that are not mentally impaired will complete the PRO booklet at FEV, YEV and/or EDV for 
the first 2 years.
The PRO booklets will be considered as part of the CRF as well as source documentation.
11.1.20 Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)
QOLIE-31-P (Cramer and Van Hammée, 2003) 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 
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Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 42 of 72
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 topic. The subjects will complete 
the QOLIE-31-P at every Full Evaluation Visit and Yearly Evaluation Visit for the first 
2 years, and at the Early Discontinuation Visit if the Early Discontinuation Visit occurs 
within the first 2 years.
11.1.21 Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) (Herrmann, 1997) 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 Full Evaluation Visit and 
Yearly Evaluation Visit for the first 2 years, and at the Early Discontinuation Visit if the 
Early Discontinuation Visit occurs within the first 2 years.
11.1.22 EQ-5D Questionnaire
The EQ-5D (EuroQol Group, 2000) 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 20 cm vertical visual analogue scale, 
anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) 
at the bottom.
The EQ-5D questionnaire will be assessed at every Full Evaluation Visit and Yearly 
Evaluation Visit for the first 2 years, or at the Early Discontinuation Visit if the Early 
Discontinuation Visit occurs within the first 2 years.
11.1.23 Hospital Stay
From Entry Visit onwards, the collection of data on hospital stay will be assessed in the CRF. 
It includes the reason of hospitalization, the admission wards, transfer and length of stay.  
Hospital stays will be assessed at every Full Evaluation Visit, Minimal Evaluation Visit, and 
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 43 of 72
Yearly Evaluation Visit, for the first 2 years, and at the Early Discontinuation Visit and the 
Final Visit if these visits occur within the first 2 years.
11.1.24 Healthcare Provider Consultation not Foreseen by Protocol
From Entry Visit onwards, healthcare provider consultation not foreseen by protocol will be 
assessed and recorded in the CRF. It will include the type of provider [general practitioner 
(GP), specialist physician, nurse], site of care (office-private, office-hospital, home, 
emergency room) and the reason leading to the consultation.  Healthcare provider 
consultations not foreseen by the protocol will be assessed at every Full Evaluation Visit, 
Minimal Evaluation Visit, and Yearly Evaluation Visit for the first 2 years, and at the Early 
Discontinuation Visit and the Final Visit if these visits occur within the first 2 years.
11.1.25 Socio-professional Data
Socio-professional data will be collected at the Yearly Evaluation Visit for the first 2 years 
and/or at the Early Discontinuation Visit if the Early Discontinuation Visit occurs within the 
first 2 years in the CRF for subjects coming from N01252, N01253 and N01254 only. It
collects information such as education level, housing status, employment status, need for 
caregiver and driving license.
11.1.26 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 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 Early 
Discontinuation Visit 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 50 mg/day on a weekly 
basis. A last down-titration step at 20 mg/day for 1 week will be included prior to the study-
drug free period.  At the end of the down-titration period, a Down-Titration Phone Call will 
occur for subjects having down-titrated from doses higher than 20 mg/day. The Down-
Titration Period will be followed by a period free of study drug at the minimum of 2 weeks 
and a maximum of 4 weeks and subsequently the Final Visit 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 
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 44 of 72
described down-titration process or will be converted without down-titration to commercial 
BRV, 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
The Entry Visit will be performed on the same day as the last visit of the previous study in 
which the subject was enrolled.  Should an interval become necessary between the last visit of 
the previous study and the entry visit in the present study, the Sponsor’s 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.
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.

Demography data: date of birth, gender and racial group.

Childbearing potential.

Medical and procedure history.

Epilepsy history.

AED history.

Vital signs including blood pressure and pulse rate.

Body weight and height.

Physical and neurological examination.

ECG.

Dispensation of subject DRC and instruction on proper completion.

Recording of seizures.

Concomitant medications (AED and Non-AED) documentation.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis), 
pregnancy test (if applicable).

Recording of Adverse Events.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 45 of 72

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 transferred 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 transferred from the database of the last evaluation visit of the 
previous study and should not be recorded in the CRF/DRC:

Vital signs including blood pressure and pulse rate.

Physical examination.

Neurological examination.

ECG.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis).

Pregnancy test (if applicable).

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), 
urine pregnancy test (if applicable).

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 which includes the YEV 
in Year 3.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 46 of 72

QOLIE-31-P questionnaire (except if subject mentally impaired and except for all 
subjects coming from N01193).  The questionnaire should be filled in at the beginning of 
the Visit.

HADS questionnaire (except if subject mentally impaired and except for all subjects 
coming from N01193).  The questionnaire should be filled in at the beginning of the Visit, 
after the QOLIE-31-P.

Healthcare provider consultation not foreseen by protocol

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject mentally impaired and except for all subjects 
coming from N01193).
11.2.3 Minimal Evaluation Visit

Vital signs including blood pressure and pulse rate.

Retrieval of previous subject DRC.

Recording of seizures.

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home during the first 2 years.

Hospital stay during the first 2 years.

Healthcare provider consultation not foreseen by protocol during the first 2 years.

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.
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.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 47 of 72

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis), 
urine pregnancy test (if applicable).

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 which includes the YEV 
in Year 3.

QOLIE-31-P questionnaire (except if subject mentally impaired and except for all 
subjects coming from N01193).  The questionnaire should be filled in at the beginning of 
the Visit.

HADS questionnaire (except if subject mentally impaired and except for all subjects 
coming from N01193).  The questionnaire should be filled in at the beginning of the Visit, 
after the QOLIE-31-P.

Healthcare provider consultation not foreseen by protocol

Recording of workdays and school days lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject mentally impaired and except for all subjects 
coming from N01193).

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), 
urine pregnancy test (if applicable).

Recording of Adverse Events.

Assessment of suicidality (C-SSRS).

Medical procedures.

Concomitant medications (AED and Non-AED) documentation.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 48 of 72

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 mentally impaired and except for all 
subjects coming from N01193).  The questionnaire should be filled in at the beginning of 
the Visit.

HADS questionnaire (except if subject mentally impaired and except for all subjects 
coming from N01193).  The questionnaire should be filled in at the beginning of the Visit, 
after the QOLIE-31-P.

Healthcare provider consultation not foreseen by protocol

Recording of workdays and schooldays lost and days subject received help from a 
caregiver (paid or not) at home.

Hospital stay.

EQ-5D questionnaire (except if subject mentally impaired and except for all subjects 
coming from N01193).

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 after an EDV when EDV ECG results were normal).

Retrieval of previous subject DRC.

Recording of seizures.

Recording of workdays and school days lost and days subject received help from a 
caregiver (paid or not) at home during the first 2 years.

Hospital stay during the first 2 years.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 49 of 72

Healthcare provider consultation not foreseen by protocol during the first 2 years.

Laboratory assessment including safety (hematology, blood chemistry, and urinalysis), 
urine pregnancy test (if applicable).

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”.
11.2.8 Additional Visit
At any time, the subject may have an additional study visit/phone call if the Investigator or 
the subject deems it necessary. All information, including reason for visit/phone call, any 
information on AEs, etc., should be collected in the source documents and recorded in the 
appropriate section of the CRF.  Study medication can be dispensed if required.
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 11.1.14.
11.4
Other Supplies
Not applicable.
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 patient 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-
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 50 of 72
and post-Treatment Periods required by the protocol, must be reported even if no 
investigational product was taken but specific study procedures were conducted. These 
include all AEs not present prior to the initial visit and all AEs which recurred or worsened 
after the initial visit.
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 
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.
Pattern:
Intermittent
The AE recurs with the same intensity at various 
intervals throughout the entire time period specified. 
There were intervals within the specified time period 
when the AE was not present.
Continuous
The AE is present at the same intensity for the entire 
time period specified. There was no time at which the 
event abated or was not present during the time period 
specified.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 51 of 72
Intensity:
Mild
The subject is aware of the sign or symptom 
(syndrome), but it does not interfere with his/her 
usual activities and/or it is of no clinical consequence.
Moderate
The AE interferes with the usual activities of the 
subject or it is of some clinical consequence.
Severe
The subject is unable to work normally or to carry out 
his/her usual activities, or the AE is of definite 
clinical consequence.
Action taken with investigational product:
Not applicable
For AEs occurring during the study drug free period.
No change
Investigational product dosing remained the same in 
spite of the AE being present.
Dosage increased
Investigational product dose was increased because of 
this AE.
Dosage 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 study drug or the physician felt it 
was in the subject’s best interest to temporarily 
discontinue the investigational product.
Permanently discontinued
Investigational product was permanently discontinued 
because of this AE, either because the subject chose 
to discontinue the study drug or the physician felt it 
was in the subject’s best interest to discontinue the 
investigational product.
Other actions taken:
If action taken other than study drug, the appropriate 
sections should be completed: Medications, Medical 
procedures.
Outcome:
Resolved
The AE is no longer present at any intensity -
completely abated.
Resolved with sequela
The AE is resolved but residual effects are still 
present.
Ongoing
The AE is still present at the last contact with the 
subject. If the AE is marked “ongoing”, the outcome 
date should be blank.
Worsened
The AE is still present but at a heightened intensity. 
The rule of repetition of AE reporting should be 
applied.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 52 of 72
Fatal
This AE caused or directly contributed to the 
subject’s death.
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.  If the AE is marked “ongoing”, 
the outcome date should be blank.
Relationship to study drug:
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 (e.g., a gun shot 
wound).
Unlikely
There are good reasons to think that there is no 
relationship (e.g., the AE is a known adverse drug 
reaction of a concomitant medication).
Possible
Equally valid arguments can be considered for or 
against an implication of the investigational product, 
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 
reducing the dosage of the investigational product.

could not be reasonably explained by the known 
characteristics of the subject’s clinical state.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 53 of 72
Highly probable
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and reappearance on repeated exposure (re-
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12.1.4 Follow-up on Adverse Events
If an AE is still ongoing at the time the CRF is collected, a follow-up report should be 
provided at a later date. If no follow-up report is provided, the Investigator must provide a 
justification.
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplementary measurements and/or evaluations (e.g., re-challenge procedure).
A serious AE or an AE leading to premature discontinuation from the study must always be 
followed up until it has resolved or the Investigator no longer feels it is clinically significant.
12.1.5 Rule for Repetition of an AE
An unexpected 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 Investigator’s original description of the AE being the same for the first and repeated 
AE.
12.1.6 Pregnancy
Should a subject become pregnant during the course of the study, the SP of the Sponsor 
should be informed immediately. The subject should be excluded from the study as soon as 
pregnancy is known (immediate start of down-titration of investigational product intake).
The pregnancy will be documented in the AE section of the CRF. The Investigator must 
inform the subject about the potential risk of malformations that may be caused by any AED, 
and about the available alternatives, eg, voluntary termination with medical indication.  The 
progression of the pregnancy must be followed up using the standard Sponsor Pregnancy 
form. The Investigator has to report on the health of the mother and of the offspring.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 54 of 72
In cases where the partner of a male subject enrolled becomes pregnant, UCB will ask the 
Investigator or designee to contact the subject and his partner to request consent via the 
Partner Pregnancy Consent Form where legally acceptable.  If the partner agrees to provide 
additional information, the Pregnancy Report and Outcome form will be forwarded to the 
subject’s partner for completion.
12.1.7 Overdose of Investigational Product
For this protocol, any daily intake of more than 200 mg/day will be considered as an 
overdose. Symptoms associated with an overdose must be recorded as AEs. Overdose 
without signs or symptoms will be documented in the “Study Medication Intake” section of 
the CRF.
12.2
Serious Adverse Events
12.2.1 Definition of Serious Adverse Event (SAE)
A Serious Adverse Event is any untoward medical occurrence that occurs at any dose:

results in death.

is life threatening, (an immediate risk of death).

requires in-patient hospitalization or prolongation of existing hospitalization.

results in persistent or significant disability/incapacity (any severe or long-lasting inability 
to carry out normal work or normal activities).
or

is a congenital anomaly/birth defect (in a child of a subject/patient who took the 
investigational product, especially of a mother who was pregnant during the study).
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 emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse.
Any event reported by the Investigator to the local authorities will follow the same reporting 
procedures as a “Serious Adverse Event”.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 55 of 72
Cases involving cancer as an Adverse Event could be reported as serious using the criterion 
“medically important”.
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated 
Adverse Event will not be considered as a SAE, except when otherwise required by 
Regulatory Authorities. This also applies to situation of scheduled elective surgery where no 
AE is present.  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.
12.2.2 Procedures for Reporting Serious Adverse Events (SAE)
The Sponsor (or its representatives) must be informed about an SAE within 24 hours of the 
site knowing about the event (see contact details for SAEs listed in Section 2).  The 
Investigator must promptly forward to the Sponsor (or its representatives) a duly completed 
“Investigator SAE report form” provided by the Sponsor, even if the data are incomplete or if 
it is obvious that more data will be needed to make any conclusions.
Additional information (e.g., autopsy or lab reports…) should be provided to the sponsor in a 
timely fashion to ensure accurate follow-up of each case. All documents in the local 
language must be accompanied by a translation in English, or the relevant information 
included in the same document must be summarized in the SAE report form.
The Sponsor (or its representatives) will communicate safety information to the appropriate 
agency(ies) 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. 
Investigators are to provide the Sponsor or its representatives with evidence of such IEC/IRB 
notification.
A copy of the Investigator SAE report form and completion guide will be provided to the 
Investigator. The SAE report form has to be completed in English.
If known by the Investigator, Serious Adverse Events up to 30 days after withdrawal of study 
medication must be reported to the Sponsor, even if the Investigator is certain that they are in 
no way associated with the study drug. Adverse Events that the Investigator thinks may be 
associated with the study medication must be reported to the Sponsor regardless of the time 
between the event and the end of the study.
The reference document for the assessment of the expectedness of the SAEs is the 
Investigator’s Brochure (IB).
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 56 of 72
12.2.3 Anticipated Serious Adverse Events
The following list of Anticipated SAEs has been identified as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure: convulsion.  This original list will remain in effect for the duration of the protocol.
The list does not change the investigator’s obligation to report all serious AEs (including 
Anticipated SAEs) as detailed in Section 12.2.2.
13
STATISTICS
A general description of statistical methods is presented below.  Additional details will be 
described in the Statistical Analysis Plan (SAP).
13.1
Statistical and Analytical Plans
13.1.1 Study Population(s)

Subpopulations
There are 2 mutually exclusive subpopulations.  They are defined based upon enrollment.
1. Partial onset seizure: Subjects enrolled from prior studies N01193, N01252, N01253, 
and subjects from N01254 with a diagnosis of POS at N01254 study entry
2. Primary generalized seizure: Subjects enrolled from prior study N01254 with a 
diagnosis of PGS at N01254 study entry
The Efficacy Population will consist of all subjects who took at least 1 dose of study 
medication and have at least 1 seizure diary during the Evaluation Period.
The Safety Population will consist of all subjects who took at least 1 dose of study 
medication.
13.1.2 Efficacy and Safety Variables
Primary safety variables:

Occurrence of a TEAE

Withdrawal due to an AE

Occurrence of an SAE
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 57 of 72
Other safety variables:

Laboratory tests (hematology, blood chemistry, urinalysis)

Vital signs (systolic blood pressure [SBP]), diastolic blood pressure [DBP], pulse rate) 
and body weight

Electrocardiogram (ECG)

Physical and neurological examinations

Change in Hospital Anxiety and Depression Scale (HADS) scores from the Baseline 
of the previous study to each assessment for the first 2 years and to the last Evaluation 
Period assessment during the first 2 years
Secondary efficacy variables:
POS (type I) frequency per 28 days during the Evaluation Period
Percent reduction in POS (type I)frequency per 28 days from Baseline of the previous 
study to the Evaluation Period
Responder rate for POS (type I) frequency over the Evaluation Period. A responder is
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline 
Period of the previous study
Other efficacy variables:
For subjects with focal-onset epilepsy:
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period
For subjects with generalized epilepsy:
Generalized (type II) seizure days per 28 days during the Evaluation Period
Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period
Responder rate for generalized (type II) seizure days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure days from the 
Baseline Period of the previous study
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 58 of 72
Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at 
least 6 months and at least 12 months during the Evaluation Period
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects
with generalized epilepsy:
Change in 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
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects
with generalized epilepsy:
Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
[ER] visits) during the first 2 years of the Evaluation Period
Indirect costs (work days or school days lost by the subject and days subject received 
help from a caregiver) during the first 2 years of the Evaluation Period
Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
13.1.3 Statistical Evaluation

General considerations:
Summary statistics will consist of frequency tables for categorical variables and descriptive 
statistics (number of available observations, mean, median, standard deviation, minimum, 
maximum, 25th and 75th percentiles) for continuous variables.
The periods considered are: 

Evaluation Period (V1 until the last Evaluation Visit)

Down-Titration Period

Post-Treatment Period
Efficacy summaries will be created separately for the POS and PGS subpopulations within 
the efficacy population, and safety summaries will be created for the safety population.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 59 of 72

Baseline:
Baseline, whether efficacy or safety, will always refer to the original prior study pretreatment 
Baseline value.  Baselines created and validated, as part of the prior study SAPs, will be 
copied and used by this study for all changes from baseline analyses.

Study entry/disposition:
Subjects will be sufficiently described to enable a clear understanding of the populations and 
subpopulations and relevant demographics, disease, medical history, current treatment(s), as 
well as disposition.  Historical and Baseline data will be copied from the prior study as 
required by the SAP.

Seizure efficacy variables:
Analyses will be based upon the Efficacy Population.  Summaries will be over the entire 
Evaluation Period and by 3-month periods over the Evaluation Period.

QOLIE-31-P, HADS, EQ-5D, and socio-professional efficacy variables:
Analyses will be based upon the Efficacy Population and summarized by data collection 
scheduled visits and for the last Evaluation Period assessment during the first 2 years. Data 
collected after Year 2 are not planned to be summarized.

Medical resource and indirect cost efficacy variables:
Analyses will be based upon the Efficacy Population and summarized by 3-month periods.  
Data collected after Year 2 are not planned to be summarized.

Safety variables:
Analyses will be based upon the Safety Population.  Summary tables will be presented over 
the Evaluation Period by time windows, by periods, and by categories of total duration of 
exposure.
Treatment-emergent AEs will be summarized by categories of total duration of exposure, 
period, and Medical Dictionary for Regulatory Activities (MedDRA®) Primary System Organ 
Class (SOC), 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 
for SAEs.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 60 of 72
Laboratory values, vital signs, and weight will be summarized by period and visit.  Possibly 
clinically significant treatment-emergent abnormalities for laboratory values, vital signs, and 
weight will be listed and summarized by period and visit.  Electrocardiogram abnormalities, 
as well as physical and neurological abnormalities, will also be listed by period and visit.
Hospital anxiety and depression scales will be analyzed for the POS and PGS subpopulations.
13.2
Determination of the Sample Size
No sample size calculation has been made. Sample size will depend upon recruitment into 
and completion of preceding studies; approximately 500 - 1000 subjects are expected.
13.3
Statistical and Analytical Issues
13.3.1 Handling of Dropouts of Missing Data
Safety and efficacy variables will be analyzed as they are available. Days with missing 
information will be ignored in the calculation of the seizure frequency and seizure days.  
Since subjects will drop out at different times from the study, results will be presented by 
categories of duration of exposure.
13.3.2 Interim Analysis and Data Monitoring
Due to the single-arm open-label nature of this study, no interim analysis as such will be 
performed. However, interim database snapshots may be performed to allow safety and 
efficacy analyses in support of submission activities or to allow optimization of the 
development program. In addition, an ongoing medical review (Safety Data Review) 
applying to the entire BRV program is organized.
13.3.3
Use of an Efficacy Subset of Subjects
The efficacy population will be a subset of the safety population.  The efficacy population 
will be divided into 2 mutually exclusive groups, the POS and PGS subpopulations.  
Additionally, as needed, the POS and the PGS subjects may be subset into categories that 
group subjects and subject data according to similar BRV exposure times.
13.3.4 Examination of Subgroups
Subgroup analyses, if performed, will be specified in the SAP.
13.4
Criteria for Starting the Analysis
A pre-analysis data review will take place before starting any formal analysis.  A pre-analysis 
data review will follow pertinent UCB Standard Operating Procedures.
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thereof. 


A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 61 of 72
13.5
Dictionaries
Adverse events medical and surgical history will be coded according to the MedDRA.  
Coding of indications of concomitant medication has been stopped during the course of the 
study.
Medications will be coded according to WHO Drug dictionary.
14
ETHICS AND REGULATORY REQUIREMENTS
14.1
Approval
The final protocol and any amendments must be signed by the Principal Investigator of the 
site, the Sponsor Study Physician, the Sponsor Clinical Lead, the Sponsor Clinical Trial 
Manager (CTM) and the Sponsor Statistician.
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, the Study Physician, the Clinical Lead, the 
Statistician, and CTM, and the sponsors’ approvers 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 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.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 62 of 72
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.
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
The original Informed Consent form can be amended as appropriate.  If the Informed Consent 
form is amended during the study, the Investigator (or the Sponsor, if applicable) must follow 
all applicable regulatory requirements pertaining to the approval of the amended Informed 
Consent form by the IRB/IEC and use of the amended form.
All studies conducted at centers in the United States must include the use of a Health 
Insurance Portability and Accountability Act Authorization form.
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. The 
content and process of obtaining informed consent will be in accordance with all applicable 
regulatory and IEC/IRB requirements.
For subjects already ongoing in the study, a new informed consent will be issued and need to 
be signed covering the increased risk of suicidality or suicidal thoughts to comply with the 
warning issued by the FDA subsequent to analysis performed on marketed anti-epileptic 
drugs.  Although data from BRV studies were not included in FDA’s analysis, this risk may 
be expected because BRV belongs to this class of medication.
The Sponsor 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).
The Investigator, or a person designated by the Investigator, should fully inform the subject 
about all pertinent aspects of the study including the fact that the protocol has been granted 
the approval of the IRB/IEC and local regulatory authorities if required.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 63 of 72
Subjects 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 must be 
informed about the main procedures used to guarantee their anonymity, especially during the 
analysis of their personal data. They will receive complete written information in the Subject 
Information Sheet. Subjects should be able to ask any questions about the study and to 
receive relevant answers.
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 or their legal 
representative 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 will receive a copy of the signed and dated consent 
form and the original will be filed in the Investigator’s Study File. The consent form or a 
specific assent form, where required, will be signed and dated by minors.
If the signature of a witness is required, the witness should sign and personally date the 
consent form after the subject has signed. By signing the consent form, the witness attests 
that the information in the consent form and in any other written information was accurately 
explained to, and apparently understood by, the subject and that informed consent was freely 
given by the subject.
The subject may withdraw their consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the informed consent form. A 
Case Report Form must not be started, nor may any study specific procedure be performed 
for a given subject, without obtaining his/her written consent to participate in the study.
If any new information that could influence the subject’s decision to stay in the study 
becomes available, this information will be transmitted to the subject 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 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 the Sponsor (or its 
representative) from Regulatory Authorities and members of the IRB/IEC may inspect 
medical records and Case Report Forms for verification of the accuracy of data. These 
groups are obliged to respect medical confidentiality and to refrain from divulging the 
subject’s identity or any other personal information. Sites will be required to obliterate any 
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 64 of 72
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 (or Pediatrician)
If the subject agrees, the Investigator may inform the subject’s regular physician of his/her 
participation in the study.
15
STUDY MANAGEMENT AND ADMINISTRATION
15.1
Monitoring
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a 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 the Sponsor 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 the sponsor 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.
If the monitoring and/or auditing process identifies serious and/or persistent non-compliance 
by an Investigator/Institution, the Sponsor may terminate the Investigator’s/Institution’s 
participation in the study.
15.2
Direct Access to Source Data/Documents
The Investigator(s)/Institution(s) will permit study-related monitoring, audits by or on behalf 
of the sponsor, IEC/IRB review, and regulatory inspection(s), providing direct access to 
source data/documents.
Source documents 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, etc. Source documents 
should be kept in a secure, limited access area.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 65 of 72
Original laboratory results, ECG tracing and reports, DRC, PRO booklets, etc., will be 
inserted in the CRF and are also to be considered as source data.
All source documents must be, accurate, clear, unambiguous, permanent and capable of being 
audited.  They should be made using 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 investigation product(s), the minimum requirements for source 
documents used in clinical studies are that they should contain the identity of the subject and 
study related identifiers (such as treatment numbers, 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 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 source documents 
verification (SDV) according to the SDV plan prepared for the study.
15.3
Audit and Inspection
The Investigator will permit study-related audits by auditors mandated by the Sponsor and 
inspections by domestic or foreign regulatory authorities, after reasonable notice. The 
purposes of an audit or inspection is 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 the Sponsor.
15.4
Case Report Forms (CRF)
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 66 of 72
Data reflecting participant experience with the drug(s) under investigation will be reported to 
the Sponsor. These data will be recorded on the CRF. The CRF is essentially a data entry 
form and may not routinely constitute the original (or source) medical record. CRFs 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 as indicated.
The Investigator’s or Principal 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:

Draw a single line through the incorrect entry.

Enter the correct data, explain the correction (if necessary), date and initial the change. 
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).
The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must 
be completed. If the data are not available, a straight line should be drawn through all 
applicable fields.
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 must submit to the Sponsor or its representatives a completed CRF for each 
participant exposed to the investigational product.
All supportive documentation submitted to the Sponsor in addition to the CRF, such as 
laboratory results or hospitalization records, must be clearly identified with the study number, 
subject’s number, subject’s initials and visit number where relevant; any personal 
information, including the subject’s name, must be removed or rendered illegible to preserve 
individual confidentiality. All original laboratory reports will remain at the study site.
Copies of the reports will be placed in the CRF binder (where directed) and forwarded to the 
sponsor.
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 should sign 
the protocol to confirm agreement.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 67 of 72
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 the Sponsor, the IRB/IEC and the appropriate regulatory authorities, if 
applicable prior to being implemented.
Any significant protocol deviation will be documented and explained by the Investigator or 
the person designated by the Investigator and will be included in the final 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 and/or auditing by the Sponsor or its designee.
15.7
Data Handling
The Sponsor will be responsible for data processing.
CRF data will be entered in a validated electronic database using a Clinical Data Management 
System (CDMS). Computerized data cleaning checks will be used in addition to manual 
review to check for discrepancies and to ensure consistency of the data. 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 the sponsor or its representatives while maintaining original 
source documents.

Data clarification and/or resolution.

Accountability, reconciliation and arrangements for used and unused study drugs.

Review of site study records for completeness.

Discussion/reminder on archiving responsibilities.

Discussion of IEC/IRB requirements for study termination.

Arrangements for unused CRFs, lab supplies and any other study related supplies.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 68 of 72
15.8.1 Termination of Study by Sponsor
In addition, the Sponsor 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 recurrent non-compliance with respect to quality or quantity.
If the study is prematurely terminated or suspended, the Sponsor 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 study drugs and other material in accordance with the 
Sponsor procedures for the study.
15.9
Clinical Study Report
The Sponsor will prepare a clinical study report in accordance with the relevant ICH 
guidelines. The report will include a thorough description of the clinical laboratory methods, 
a discussion of the results and a list of all measurements as specified in the Statistical 
Analysis Plan. This report may be included in submissions to government drug regulatory 
authorities worldwide, or used for whatever reason considered appropriate by the Sponsor. 
No information contained in the report may be used without written approval of the Sponsor.
15.10
Insurance and Liability
The Sponsor 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. Information as to 
insurance policies held by the Sponsor can be made available to the Investigator and to the 
IEC/IRB upon request.
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.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 69 of 72
All records are to be retained by the Investigator until at least 2 years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with the sponsor (ICH-GCP Guideline-Section 4.9.5).
The Investigator will contact the Sponsor for authorization prior to the destruction of any 
study records or in the event of accidental loss or destruction of any study records. The 
Investigator will also notify the Sponsor should he/she relocate or move the study related files 
to a location other than that specified in the Sponsor’s 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 log of appropriately qualified persons to whom he/she has delegated 
significant study-related duties (“Delegation of Authority” document with name, function, 
signature, initials, and dates of participation in the study conduct and type of tasks delegated). 
The list should be kept up to date.
15.13
Curriculum Vitae (CV)
The Investigators should supply their updated CV (English translation), dated and signed, 
together with a list of their collaborators responsible for the practical conduct of the study.
These collaborators should also provide a recent English version of their CV, dated and 
signed.
Where applicable, a signed and dated FDA Form 1572 (in Canada, a Qualified Investigator
Undertaking Form must also be provided) is 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 from each clinical site for every 
Investigator and Sub-Investigator participating in the study. 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 after study completion/end of study.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 70 of 72
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 the Sponsor to secure compliance. Continued non-compliance may result in the 
termination of the participants’ involvement in the study.
15.16
Publication
Subject to the provisions of the publication article of the agreement with the Investigator or 
his/her legal representative, the Sponsor will be responsible for the publication of the results 
of this study. The site shall not publish or present any research findings resulting from the 
Study or any scientific work with respect to Sponsor’s drug or its development, without the 
Sponsor’s prior written approval of the content of the presentation, manuscript or other 
materials prepared for publication. The Sponsor will respond to requests for presentation or 
publication in a timely manner and will not unreasonably withhold authorization.
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 (EMA) 16 Nov 2000.
CPMP/ICH/2711/99 Note for guidance on clinical investigation of medicinal products in the 
paediatric population (EMA) 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.
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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 71 of 72
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.
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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A
Brivaracetam / N01199
CONFIDENTIAL
Protocol:  RPCE05C2110 / Integrated Amendment 7
Final / 15 Oct 2015 / Page 72 of 72
17
SPONSOR DECLARATION
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to Good Clinical Practice.
REDACTED COPY 
This document cannot be used to support 
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SAP_001.pdf: 
UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 1 of 47
STATISTICAL ANALYSIS PLAN (SAP)
Study: N01199
Product: Brivaracetam
An open-label, multi-center, follow-up trial to evaluate the long-term safety and efficacy of 
brivaracetam (ucb 34714) used as adjunctive treatment at a flexible dose up to a maximum of 
200mg/day in subjects aged 16 years or older suffering from epilepsy
SAP/Amendment Number
Date
Final SAP
SAP Amendment 1
27 January 2014
20 April 2017
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.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 2 of 47
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 ..........................................................................................9
2.2.2.1
Secondary efficacy variables ...............................................................9
2.2.2.2
Other efficacy variables .......................................................................9
2.2.3
Pharmacoeconomic variables ......................................................................10
2.3
Study Design and Conduct.....................................................................................10
2.4
Determination of Sample Size ...............................................................................13
3
DATA ANALYSIS CONSIDERATIONS......................................................................13
3.1
General presentation of summaries and analyses ..................................................13
3.2
Analysis time points...............................................................................................13
3.2.1
First and last dose of BRV...........................................................................13
3.2.2
Relative day .................................................................................................13
3.2.3
Study Entry Visit .........................................................................................14
3.2.4
Study periods ...............................................................................................15
3.2.5
Monthly time intervals.................................................................................16
3.2.6
Last Value on BRV Treatment ....................................................................16
3.2.7
Exposure duration and exposure duration cohorts.......................................17
3.2.8
Study visit cohorts .......................................................................................17
3.3
Definition of Baseline Values................................................................................17
3.4
Protocol deviations.................................................................................................17
3.5
Analysis populations..............................................................................................18
3.5.1
Safety Population.........................................................................................18
3.5.2
Efficacy Populations....................................................................................18
3.6
Treatment Assignment and Treatment Groups......................................................18
3.7
Coding dictionaries ................................................................................................18
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 3 of 47
3.8
Definitions of study-specific derived variables .....................................................18
3.8.1
Calculation of seizure frequency/days.........................................................18
3.8.1.1
Initial seizure data processing............................................................18
3.8.1.2
Calculation of adjusted seizure frequency .........................................19
3.8.1.3
Calculation of adjusted seizure days..................................................19
3.8.2
QOLIE-31-P.................................................................................................19
3.8.3
HADS...........................................................................................................20
3.9
Subject site transfers ..............................................................................................21
4
STATISTICAL/ANALYTICAL ISSUES.......................................................................21
4.1
Adjustments for covariates ....................................................................................21
4.2
Handling of dropouts or missing data....................................................................21
4.3
Interim analyses and data monitoring....................................................................21
4.4
Multicenter studies.................................................................................................21
4.5
Multiple comparisons/multiplicity.........................................................................21
4.6
Use of an “Efficacy Subset” of subjects ................................................................22
4.7
Active-control studies intended to show equivalence............................................22
4.8
Examination of subgroups .....................................................................................22
5
STUDY POPULATION CHARACTERISTICS.............................................................22
5.1
Subject disposition.................................................................................................22
5.2
Protocol Deviations................................................................................................23
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................24
6.1
Demographics ........................................................................................................24
6.2
Medical and procedure history...............................................................................25
6.2.1
Medical history diseases ..............................................................................25
6.2.2
Procedure history and concomitant procedures...........................................25
6.3
History of epilepsy.................................................................................................25
6.3.1
Etiology of epilepsy.....................................................................................25
6.3.2
Epileptic seizure profile...............................................................................25
6.3.3
Classification of epileptic syndrome............................................................25
6.3.4
Focus localization ........................................................................................25
6.3.5
History of epileptic seizures ........................................................................26
6.3.6
Seizure types experienced during baseline of the previous study ...............26
6.4
Medications............................................................................................................26
6.4.1
Non-AEDs taken at study entry...................................................................26
6.4.2
Number of previous AEDs ..........................................................................27
6.4.3
History of previous AED use.......................................................................27
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 4 of 47
6.4.4
AEDs taken at study entry ...........................................................................27
7
MEASUREMENTS OF TREATMENT COMPLIANCE...............................................27
8
EFFICACY ANALYSES ................................................................................................27
8.1
Statistical analyses of secondary efficacy variables ..............................................27
8.1.1
Partial onset seizure frequency ....................................................................27
8.1.2
Percent reduction in POS frequency............................................................28
8.1.3
Responder rate for POS frequency ..............................................................28
8.2
Analysis of other efficacy variables.......................................................................28
8.2.1
Subjects with partial onset seizures .............................................................28
8.2.1.1
Specified Month seizure freedom ......................................................28
8.2.2
Subjects with All Other Seizure Types........................................................29
8.2.2.1
All other type seizure days.................................................................29
8.2.2.2
Percent reduction in All other type seizure days................................29
8.2.2.3
Responder outcome for all other type seizure days ...........................29
8.2.2.4
Specified month seizure freedom.......................................................29
8.2.3
QOLIE-31-P.................................................................................................30
8.2.4
EQ-5D..........................................................................................................30
8.2.5
Direct cost parameters .................................................................................31
8.2.6
Indirect cost parameters...............................................................................31
8.2.7
Socio-professional data................................................................................31
9
PHARMACOKINETICS AND PHARMACODYNAMICS..........................................31
10
IMMUNOLOGICAL PROCEDURES............................................................................31
11
SAFETY ANALYSES.....................................................................................................32
11.1
Extent of exposure .................................................................................................32
11.2
Adverse events.......................................................................................................33
11.2.1
Definition of treatment-emergent AE..........................................................33
11.2.2
General summaries of TEAEs .....................................................................33
11.3
Clinical laboratory evaluations ..............................................................................34
11.3.1
Hematology and blood chemistry parameters .............................................34
11.3.2
Macroscopic urinalysis ................................................................................35
11.3.3
Microscopic urinalysis.................................................................................36
11.4
Vital signs, physical findings, and other observations related to safety................36
11.4.1
Vital signs ....................................................................................................36
11.4.2
Electrocardiograms ......................................................................................36
11.4.3
Physical examination ...................................................................................37
11.4.4
Neurological examination............................................................................37
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 5 of 47
11.4.5
Psychiatric and mental status.......................................................................37
11.4.6
HADS...........................................................................................................37
11.4.7
Columbia-Suicide Severity Rating Scale.....................................................38
12
REFERENCES ................................................................................................................38
13
APPENDICES .................................................................................................................39
13.1
QOLIE-31-P total and subscale score calculations................................................39
13.2
Subject site transfers ..............................................................................................41
13.3
PCST criteria..........................................................................................................42
13.3.1
Hematology parameters ...............................................................................42
13.3.2
Blood chemistry parameters ........................................................................43
13.3.3
Urinalysis.....................................................................................................45
13.3.4
Vital signs and body weight.........................................................................45
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 6 of 47
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
AMD
antimyoclonic drug
ALP
Alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Class
BMI
body mass index
bpm
Beats per minute
BRV
Brivaracetam
BUN
blood urea nitrogen
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
F
Female
FDA
Food and Drug Administration
FEV
Full Evaluation Visit
FV
Final Visit
GGT
Gamma-glutamyl transpeptidase 
HADS
Hospital Anxiety and Depression Scale
HDL
High-density lipoprotein 
HRQoL
Health-Related Quality of Life
ILAE
International League Against Epilepsy
LDL
low-density lipoprotein
MedDRA
Medical Dictionary for Regulatory Activities
M
Male
MEV
Minimal Evaluation Visit
N/A
Not applicable
PBO
Placebo
PCST
potentially clinically significant treatment-emergent
PGS
primary generalized seizures
POS
partial onset seizure
PT
preferred term 
QOLIE-31-P
Patient Weighted Quality of Life in Epilepsy 
Questionnaire
RBC 
Red Blood Cell
SAE
serious adverse event
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 7 of 47
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SEV
Supplemental Entry Visit
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
system organ class
TEAE
treatment-emergent adverse event
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
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 8 of 47
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 N01199.
2
PROTOCOL SUMMARY
2.1
Study objectives
2.1.1
Primary objective
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized 
doses with a maximum of 200mg/day in subjects suffering from epilepsy
2.1.2
Secondary objectives
To evaluate the maintenance of efficacy over time of BRV (for subjects with partial onset 
seizures [POS] and subjects with primary generalized seizures [PGS])
2.1.3
Exploratory objectives
Exploratory objectives for subjects with POS/PGS:

To explore medical resource use and indirect cost parameters for the first 2 years

To obtain a description of the subject’s self-reported health status for the first 2 years

To explore the effects of BRV on the subject’s Health-related Quality of Life (HRQoL), 
anxiety, and depression for the first 2 years

To explore any change in the subject’s socio-professional status for the first 2 years
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 (hematology, blood chemistry, urinalysis)

Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and 
body weight

Electrocardiogram (ECG)

Physical and neurological examinations
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 9 of 47

Change in Hospital Anxiety and Depression Scale (HADS) scores from the Baseline of 
the previous study to each assessment for the first 2 years and to the last Evaluation 
Period assessment during the first 2 years
2.2.2
Efficacy variables
2.2.2.1
Secondary efficacy variables
For subjects with focal-onset epilepsy:

POS (type I) frequency per 28 days during the Evaluation Period

Percent reduction in POS (type I)frequency per 28 days from Baseline of the previous 
study to the Evaluation Period

Responder rate for POS (type I) frequency over the Evaluation Period. A responder is 
defined as a subject with a ≥50% reduction in seizure frequency from the Baseline Period 
of the previous study
2.2.2.2
Other efficacy variables
For subjects with focal-onset epilepsy:

Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period
For subjects with generalized epilepsy:

Generalized (type II) seizure days per 28 days during the Evaluation Period

Percent reduction in generalized (type II) seizure days per 28 days from Baseline of the 
previous study to the Evaluation Period

Responder rate for generalized (type II) seizure days over the Evaluation Period. A 
responder is defined as a subject with a ≥50% reduction in seizure days from the Baseline 
Period of the previous study

Percentage of subjects continuously seizure-free for all seizure types (I+II+III) for at least 
6 months and at least 12 months during the Evaluation Period
The following will be evaluated separately for subjects with focal-onset epilepsy and subjects 
with generalized epilepsy:

Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) 
scores from Baseline of the previous study to each assessment for the first 2 years and to 
the last Evaluation Period assessment during the first 2 years

EuroQol 5 Dimensions (EQ-5D) questionnaire response for each assessment for the first 2 
years for the Evaluation Period and for the last assessment during the first 2 years of the 
Evaluation Period
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 10 of 47
2.2.3
Pharmacoeconomic variables
Due to the inconsistencies in data captured and collection forms across LTFU studies, the 
following variables will be provided in subject data listings only, but will not be evaluated or 
descriptive summarized:

Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent 
medical procedures, concomitant medications, hospitalizations, and emergency room 
[ER] visits) during the first 2 years of the Evaluation Period

Indirect costs (work days or school days lost by the subject and days subject received help 
from a caregiver) during the first 2 years of the Evaluation Period

Socio-professional data for each assessment for the first 2 years and for the last 
assessment during the first 2 years of the Evaluation Period
2.3
Study Design and Conduct
This is an open-label, long-term follow-up, multicenter, noncomparative, single-arm study of 
BRV. The primary objective is to evaluate the long-term safety and tolerability of BRV at 
individualized doses up to a maximum of 200mg/day in subjects with epilepsy. The 
secondary objective is to evaluate the maintenance of efficacy of BRV. Exploratory 
objectives are to assess the effects of BRV on subjects’ HRQoL, obtain information on the 
direct and indirect costs, and explore changes in socio-professional status.
At the time of development of this SAP, the enrollment into N01199 had completed. Study 
N01199 enrolled subjects 16 years of age and older who had completed N01193, N01252, 
N01253, or N01254. Subjects from N01252 and N01254 enrolled into long-term follow-up 
studies, either N01125 or N01199, depending on their country of residence. Studies N01193, 
N01252, and N01253 enrolled subjects with focal-onset seizures with or without secondary 
generalization (designated as “POS subjects”). Study N01254 enrolled subjects with focal-
onset epilepsy and also a smaller number of subjects with generalized epilepsy (designated as 
“PGS subjects”).
Subjects from double-blind, placebo-controlled studies N01193 were to enter N01199 at a 
dose of 20mg/day. Subjects from double-blind, placebo-controlled N01252 were to enter 
N01199 at a dose of 50mg/day. Subjects from double-blind, placebo-controlled N01253 were 
to enter N01199 at a dose of 50mg/day or 20mg/day. The starting doses for subjects from 
double-blind, placebo-controlled, flexible-dose N01254 were based on the blinded dose 
levels achieved during the Maintenance Period of N01254 but were not to exceed 
100mg/day; thus, starting doses for subjects from N01254 were 20mg/day, 50mg/day, or 
100mg/day, with most subjects entering N01199 at a dose of 100mg/day.
Subjects who enrolled in the study entered an Evaluation Period during which treatment with 
BRV was initiated. The dose of BRV could be adjusted based on the individual subject’s 
seizure control and tolerability. Dose increases could be made in increments of 50mg/day on 
a weekly basis up to a maximum of 200mg/day; dose decreases could be made in steps of 
50mg/day on a weekly basis. Subjects who discontinue treatment with BRV enter a Down-
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 11 of 47
Titration Period during which the dose of BRV is decreased in steps of 50mg/day on a 
weekly basis with a last down titration step at 20mg/day for 1 week. Subjects who have 
completed the Down-Titration Period or subjects who discontinue during the Evaluation 
Period without entering the Down-Titration Period enter a Post-Treatment Period for a 
minimum of 2 weeks and a maximum of 4 weeks and subsequently, the final visit will occur.
The maximum allowable daily dose for this study was increased from 150mg/day to 
200mg/day based on amendment 6 to the protocol. It is recommended that the daily dose be 
administered in 2 equal intakes.
Dose adjustment to concomitant AEDs may be made at any time during the study and 
subjects may start new AEDs. Concomitant AEDs may also be discontinued; however, 
special considerations apply if the discontinuation of such AEDs results in the subject 
receiving BRV monotherapy. Previously, in the event of excellent efficacy and tolerability of 
BRV, withdrawal of concomitant AEDs resulting in monotherapy of BRV may have been 
attempted by the Investigator. With protocol amendment 6, conversion to monotherapy was 
no longer permitted; however, subjects already on BRV monotherapy are allowed to continue 
monotherapy treatment.
The visit schedule for this study depends on the previous study from which the subject was 
enrolled and the numbering of study visits differs depending on the previous study. Study 
visits at Months 6, 12, 18, 24, and so forth are either Full Evaluation Visits (FEVs) or Yearly 
Evaluation Visits (YEVs) at which a greater number of assessments are performed for all 
subjects from previous studies. For subjects coming from N01193, study visits at Months 1, 
3, 5, 15, and 21 are minimal Evaluation Visits (MEVs) at which few assessments are 
generally performed. Study visits at Months 2, 4, and 9 are FEVs. For subjects coming from 
N01252, N01253, and N01254, study visits at Months 1, 3, 9, 15, 21 are MEVs. The study 
visit at Month 2 is an FEV. In addition, a phone call is scheduled at the end of the Down-
Titration period and a Drug-Free Final Visit (FV) is scheduled at the end of the Post-
Treatment Period. The study schedule just described is shown in Table 2‒1 .
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 12 of 47
Table 2‒1:
Study Schedule
Subjects coming from Exploratory 
Study (N01193)
Subjects coming from Confirmatory 
Studies (N01252, N01253, N01254)
Month
Visit
Type of Visit
Month
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Type of Visit
1st year Follow-up
1st year Follow-up
M0
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M0
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M1
V2
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MEV
M2
V3
FEV
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FEV
M3
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M3
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M4
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M4
M5
V6
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M5
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M7
M7
M8
M8
M9
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V6
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M10
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M11
M11
2nd and subsequent years Follow-up
2nd and subsequent years Follow-up
M12
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YEV
M15
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MEV1
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MEV1
M18
V11
FEV
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V9
FEV
M21
V12
MEV2
M21
V10
MEV2
FEV=Full Evaluation Visit; MEV=Minimal Evaluation Visit; M=month, V=Visit, YEV=Yearly 
Evaluation Visit
All subjects should have a Visit 1 at the start of N01199. Visit 1 will typically correspond to 
the last visit from the previous study and should be the visit at which study drug is dispensed 
for N01199. However, some subjects had a delay in treatment with study medication after 
completion of the previous study. Such subjects may have had an additional Supplemental 
Entry Visit (SEV) at the time of entry into N01199.
This study will run throughout the duration of the clinical development period of
brivaracetam, and will continue until a marketing authorization is granted by any Health 
Authority in an indication for the adjunctive treatment in adults with refractory POS, whether 
or not secondarily generalized, until the Sponsor decides to close the study, until a managed 
access program, named patient program, compassionate use program, or similar type of 
access program is established as allowed per country-specific requirement in addition to legal 
and regulatory guidelines, or until brivaracetam development is stopped by the Sponsor.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 13 of 47
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 study 
enrollment has been completed; a total of 668 subjects were enrolled into N01199.
3
DATA ANALYSIS CONSIDERATIONS
3.1
General presentation of summaries and analyses
Statistical analysis and generation of tables, figures, subject data listings, and statistical 
output will be carried out using SAS® Version 9.1 or higher.
Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 
75th percentile, minimum value, and maximum value for quantitative variables, and counts 
and percentages for categorical variables, will be provided. Denominators for percentages 
will generally be based on the set of subjects with at least 1 assessment at the time point or at 
least 1 assessment during the time interval being summarized.
All summaries will be descriptive; no statistical hypothesis testing is planned.
Unless otherwise noted, summaries will present BRV overall, which will include all subjects 
exposed to BRV during the study.
Subject data listings will be provided and will present source data and key derived variables 
for statistical analyses.
3.2
Analysis time points
3.2.1
First and last dose of BRV
Unless otherwise noted, all references to the first dose of BRV in this SAP refer to the first 
dose of BRV during N01199 (ie, not the first dose of BRV from the previous study in which 
subjects participated in prior to N01199). 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.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 14 of 47
3.2.3
Study Entry Visit
The study Entry Visit (EV) corresponds to assessments performed at the time of entry into 
N01199. There are 3 groups of subjects to consider:
1. Subjects who immediately entered N01199 after completing the Treatment Periods for 
N01193, N01252, N01253, and N01254.
2. Subjects who entered the Down-Titration Period of the previous study and entered 
N01199 during the Down-Titration Period.
3. Subjects who did not immediately enter N01199 and had a gap in treatment with study 
drug between the previous study and N01199.
Subjects in Categories 1 and 2
Subjects in categories 1 and 2 will generally not have any interruption in study drug dosing 
during the transition to N01199. For such subjects, selected assessments from the following 
visits from the previous study will be summarized at EV:
Study
Visit (Time Point)
N01193
Visit 4 (Week 7)
N01252/N01253
Visit 7 (Week 12)
N01254
Visit 8 (Week 16)
The following assessments were to be performed for all subjects at the above time points: 
laboratory parameters, vital signs, and ECGs; the results for these assessments will be 
summarized at EV. Other assessments were to be performed at the above time points but will 
not be summarized. QOLIE-31-P, HADS, EQ-5D and social-professional data were only 
assessed at the above time points for studies N01252, N01253, and N01254.
The body weight recorded at the above study visits for the previous studies will be 
summarized for EV.
Subjects in Category 3
Some subjects in category 3 have data available from an SEV at the time of entry into 
N01199. Laboratory parameters, vital signs, and ECGs collected at SEV will be summarized 
at EV. If one or more of these assessments were not performed at SEV, or if a subject in 
category 3 does not have an SEV, then the subject will be excluded from EV for the 
assessments that were not performed, regardless of the duration of time the subject was not 
receiving the study drug after the previous study.
QOLIE-31-P, HADS, EQ-5D, and socio-professional data will not be summarized at EV for 
subjects in category 3 regardless of the duration of time the subject was not receiving study 
drug after the previous study.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 15 of 47
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,

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
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 16 of 47
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. 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 17 of 47
3.2.7
Exposure duration and exposure duration cohorts
At the final analysis, the overall duration of exposure (or On Treatment Period) will be 
calculated as the date of last dose of BRV minus the date of first dose of BRV plus 1 day. 
Each subject will be classified into one or more of the following exposure duration cohorts 
based on the duration of BRV exposure as calculated above: 
All subjects 
≥1 day
≥3 months
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≥12 months
≥360 days
This categorization will continue in 6-month increments past 12 months up to a time point 
that will be determined based on cumulative exposure at the time of the database lock.
3.2.8
Study visit cohorts
Study visit cohorts are defined for summaries of QOLIE-31-P, HADS, and EQ-5D. Six-
month, 12-month, 18-month, and 24-month cohorts are defined. Subjects will be classified 
into a study visit cohort if they attend the scheduled visit at the time point defined by the 
cohort. For example, subjects will be included in the 18-month study visit cohort if they 
attend the scheduled visit at 18 months (ie, FEV at Month 18). Subjects may be classified in 
more than 1 cohort. Generally, subjects included in a cohort for a later visit will be included 
in all earlier study visit cohorts (eg, 6-month and 12-month study visit cohorts for subjects in 
the 18-month study visit cohort), although this may not be the case in the event of a missed 
visit or if an unscheduled visit is conducted in lieu of a scheduled visit. 
3.3
Definition of Baseline Values
Baseline for all study outcomes will be based on baseline from the previous studies. For 
assessments performed at scheduled and unscheduled visits, Baseline will generally be the 
last result obtained or prior to the randomization visit of the previous study. Baseline will be 
defined separately for each hematology, blood chemistry, and urinalysis parameter.
Baseline for the evaluation of seizure frequency and seizure days will be calculated from the 
core study seizure diary based on the rules defined in Section 3.8.1.
3.4
Protocol deviations
The criteria for identifying important protocol deviations and the classification of important
protocol deviations will be defined separately in the Specification of Protocol Deviations 
document. Whenever possible, criteria for identifying important protocol deviations will be 
implemented algorithmically to ensure consistency in the classification of important protocol 
deviations across all subjects.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 18 of 47
3.5
Analysis populations
3.5.1
Safety Population
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, , study drug exposure, and safety outcomes will be provided for the Safety Analysis 
Set.
3.5.2
Efficacy Populations
Efficacy Analysis Sets will consist of all subjects who took at least 1 dose of study drug and 
have at least 1 seizure diary day during the Evaluation Period. Separate Efficacy Populations 
are defined for subjects with focal epilepsy from N01193, N01252, N01253, and N01254 and 
subjects with generalized epilepsy from N01254.
A subject will be excluded from the Efficacy Analysis Set for POS or PGS if either they did 
not receive at least 1 dose of BRV, or the clinical database indicates that the daily seizure 
diary was not completed for any days on or after the first dose of BRV and on or prior to the 
end date of the Evaluation Period (see Section 8).
Seizure outcomes will be summarized for either the Efficacy Analysis Set for POS or the 
Efficacy Analysis Set for PGS. Summaries of epilepsy history, QOLIE-31-P, and EQ-5D will 
be provided for the Efficacy Analysis Sets for both POS and PGS. 
3.6
Treatment Assignment and Treatment Groups
This is an uncontrolled study in which all subjects receive BRV in doses that are optimally 
adjusted for each subject. Generally, statistical summaries will present all subjects combined 
as a single treatment arm unless otherwise indicated.
3.7
Coding dictionaries
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Medications will be coded using the World Health Organization Drug 
Reference List (WHO-DRL). Prior and concomitant medical procedures will not be coded.
3.8
Definitions of study-specific derived variables
3.8.1
Calculation of seizure frequency/days
3.8.1.1
Initial seizure data processing
Each seizure code in the clinical database will be mapped to exactly 1 of the following codes 
based on the 1981 International League Against Epilepsy (ILAE) classification: I, IA, IA1, 
IA2, IA3, IA4, IB, IB1, IB2, IC, II, IIA, IIB, IIC, IID, IIE, IIF, or III.
With regard to cluster seizures, investigator sites are to report the number of cluster episodes 
rather than reporting the estimated number of individual seizures. Therefore, no imputation 
will be applied for the seizure counts corresponding to reports of cluster seizures.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 19 of 47
3.8.1.2
Calculation of adjusted seizure frequency
The following derivations apply only to subjects with Partial Onset Seizures.
Baseline POS frequency for seizure types I, IA, IB, IC, and for all seizure types (I+II+III) 
will be obtained from the Baseline Period of the previous double-blind study.
The total number of seizures for seizure types I, IA, IB, and IC, and the total number of 
seizures for all seizure types (I+II+III) will be calculated overall, by 3-month time intervals, 
and over the cohort interval for each exposure duration cohort. 
All seizure diary during evaluation period will be considered for these calculations.
Twenty-eight day adjusted seizure frequency for seizure types I, IA, IB, and IC, and for all 
seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and 
over each exposure duration cohort interval by dividing the total number of seizures for each 
seizure type by the number of days for which the diary was completed overall, within each 
3-month interval, and within each exposure duration cohort interval, and multiplying the 
resulting value by 28.
3.8.1.3
Calculation of adjusted seizure days
The following derivations apply only to subjects with All Other Seizure Types, based on the 
1981 ILAE classification, All Other Seizure Types include the generalized seizure types and 
unclassified seizure types. 
Baseline seizure days for seizure types II, IIA through IIF, and for all seizure types (I+II+III) 
will be obtained from the Baseline Period of the previous study.
The total number of seizure days for seizure types II, IIA through IIF, and the total number of 
seizure days for all seizure types (I+II+III) will be calculated overall, by 3 month time 
intervals, and over the cohort interval for each exposure duration cohort. The same seizure 
diary data defined in the Section 3.8.1.2 for POS frequency will be considered.
Twenty-eight day adjusted seizure days for seizure types II, IIA through IIF, and for all 
seizure types (I+II+III) will be calculated overall, within each 3-month time interval, and 
over each exposure duration cohort interval by dividing the total number of seizure days for 
each seizure type by the number of days for which the diary was completed overall (ie, over 
the periods defined in the Section 3.8.1.2), within each 3-month interval, and within each 
exposure duration cohort interval, and multiplying the resulting value by 28.
3.8.2
QOLIE-31-P
The QOLIE-31-P is an adaptation of the original QOLIE-31 (Cramer et al, 1998). The 
QOLIE-31-P includes 30 items grouped into 7 multi-item subscales (seizure worry [5 items], 
overall quality of life [2 items], emotional well-being [5 items], energy/fatigue [4 items], 
cognitive functioning [6 items], medication effects [3 items], and social function [5 items]) 
and a health status item. The QOLIE-31-P total score, subscale scores, and health status item 
score are calculated according to the scoring algorithm described below, with scores ranging 
from 0 to 100 and higher scores indicating better functioning. In addition to these 31 items, 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 20 of 47
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. 
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 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 21 of 47
anxiety and depression; for example, it may be possible to calculate the depression score in 
cases where the anxiety score is not calculated due to non response.
3.9
Subject site transfers
Subjects may have transferred from one site to another through the course of participation in 
the study. Subjects that transferred from one site to another site, for whatever reason, have 
generally retained their subject number. However, in some cases, the subject number 
changed. When this is true, the most recently assigned subject number will be used for 
analyses and subject data listings. A record of any change in subject numbers will be 
presented in the Section 13.2.
4
STATISTICAL/ANALYTICAL ISSUES
4.1
Adjustments for covariates
No statistical testing is planned; therefore, this section is not applicable.
4.2
Handling of dropouts or missing data
Seizure frequency (subjects with POS) and seizure days (subjects with PGS) will be 
calculated over non missing diary days during each study period or time interval as described 
in Section 3.2.4 and Section 3.2.5 ; diary days for which seizure data were not obtained will 
not be considered in the calculation of seizure frequency or seizure days. Because the 
evaluation of efficacy is not the primary objective of this study, and because this is an 
uncontrolled study in a variable setting, which allows individualized optimization of dosing 
of BRV and concomitant AEDs, no summaries assessing the impact of missing seizure diary 
days are planned.
For subjects who prematurely discontinue during the Evaluation Period, the calculation of 
POS frequency and PGS seizure days will be based on available seizure diary while the 
subject was receiving BRV. The presence of such dropouts may influence the evaluation of 
the long-term outcomes for subjects who either do not discontinue or do not discontinue early 
in the study. Therefore, as described below, selected summaries will be produced by exposure 
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.
4.5
Multiple comparisons/multiplicity
No statistical testing is planned; therefore, this section is not applicable.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 22 of 47
4.6
Use of an “Efficacy Subset” of subjects
All subjects who receive at least 1 dose of study drug and have at least 1 diary record during 
the Evaluation Period will be included in efficacy summaries. No additional efficacy subsets 
are defined for this study.
4.7
Active-control studies intended to show equivalence
This section is not applicable for this study.
4.8
Examination of subgroups
Selected summaries will be provided for the following subgroups as specified within each of 
the following sections;

Seizure type (Partial Onset Seizures, Primary Generalized Seizures)

Geographic region (Latin America, North America, Asia/Pacific/Other). A mapping of 
countries to geographic regions is defined as
Geographic Region
Country
North America
Canada, United States, Puerto Rico
Latin America
Brazil, Mexico
Asia/Pacific/Other
Australia, Hong Kong, India, Israel, Japan, Singapore, 
South Africa, Republic of Korea, Taiwan, Tunisia

Randomized treatment in the previous study (placebo [PBO], BRV) (TEAEs only)
5
STUDY POPULATION CHARACTERISTICS
5.1
Subject disposition
Due to differences in data format across studies, in order to facilitate summary of subject 
disposition, the reasons for discontinuation for individual studies will be collapsed as follows 
for summaries:
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
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 23 of 47
LTFU Category
CRF Reason
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 who have 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”.
Additionally, an overall summary of disposition will present the following for subjects in the 
Safety Analysis Set:

The number of subjects completing the study (final analysis only)

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 and seizure type
for the Safety Analysis Set.
The number of subjects within each geographic region and the number of subjects with each 
seizure type 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 seizure type will be summarized overall and by investigator site. 
Subjects who transferred sites will be summarized according to their original site.
5.2
Protocol Deviations
The number and percentage of subjects with at least 1 important protocol deviation will be 
summarized overall and by category of protocol deviation for the Safety Analysis Set. 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 24 of 47
6
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
6.1
Demographics
Demographics summaries will be based on demographic data from follow-up studies for 
subjects who enrolled in a follow-up study that collected demographic data. Otherwise, 
demographics summaries will be based on demographic data collected in the previous 
double-blind study. 
Age, age category (<17, 17 to <65, and ≥65 years), gender, racial group and overall racial 
group (see below), body weight (kg), height (cm), body mass index (BMI) (kg/m2), and BMI 
category (<18.5, 18.5 to <25, 25 to <30, 30 to <40, ≥40) will be summarized for the Safety 
Analysis Set. Demographic data will be summarized overall and by subgroup for seizure type
and geographic region.
Racial group was not collected in a consistent manner across studies. For this reason, racial 
group will be collapsed as follows for statistical summaries:
•
Category
•
CRF Racial Group
•
American Indian/Alaskan 
Native
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American Indian/Alaskan Native
•
Asian
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Asian, Asian/Pacific Islander, Indian/Pakistani
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•
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•
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•
White
•
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•
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
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Asian 
Asian, Native Hawaiian or Other Pacific Islander, Asian/Pacific Islander, 
Indian/Pakistani
Other
American Indian/Alaskan Native, Other, Other/Mixed
All subjects should be classified into one of the above categories.
Racial group, ethnicity (Hispanic or Latino, Not Hispanic or Latino), and racial subgroup 
(Indian/Pakistani, Japanese, Other) were not collected in a consistent manner across all 
studies; these variables will be provided in subject data listings if available in the clinical data 
from the previous study but will not be summarized.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 25 of 47
6.2
Medical and procedure history
6.2.1
Medical history diseases
The summary of medical history will be based on the medical history at the time of entry into 
the previous study. 
The number and percentage of subjects with a medical history condition, including both 
resolved and ongoing conditions at the time of entry into the previous study, will be 
summarized overall and by primary MedDRA system organ class (SOC) and preferred term 
(PT) for the Safety Analysis Set.
6.2.2
Procedure history and concomitant procedures
Medical procedures are not coded and will only be provided in subject data listings.
6.3
History of epilepsy
All of the following are summarized using data collected at the time of entry into the previous 
studies or from the Baseline Period of the previous studies.
6.3.1
Etiology of epilepsy
The number and percentage of subjects with each type of etiology as specified on the CRF 
(genetic, congenital, etc) from the previous studies will be summarized for the Efficacy 
Analysis Sets for POS and PGS. A subject will be counted as having a particular etiology if 
that etiology was either confirmed or suspected based on the investigator's assessment.
6.3.2
Epileptic seizure profile
The number and percentage of subjects experiencing each seizure type at any time prior to 
study entry will be summarized for the Efficacy Analysis Sets for POS and PGS. The 
following seizure types will be summarized: I, IA, IA1 through IA4, IB, IB1, IB2, IC, II, IIA 
through IIF, III, 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 for POS and PGS. This summary will include the number and 
percentage of subjects within the following categories: localization-related epilepsy; 
idiopathic, symptomatic, and cryptogenic localization-related epilepsy; generalized epilepsy; 
and idiopathic, symptomatic, and cryptogenic generalized epilepsy.
6.3.4
Focus localization
The number and percentage of subjects with each category of focus localization (unknown, 
frontal, temporal, parietal, occipital) will be summarized for the Efficacy Analysis Set for 
POS for subjects from N01252, N01253, and N01254. Subjects may be counted in more than 
1 category of focus localization. Focus localization data was not collected in N01193.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 26 of 47
6.3.5
History of epileptic seizures
History of epileptic seizures, including the number and percentage of subjects with a history 
of status epilepticus and quantitative summaries of epilepsy duration, age at onset of first 
seizure, and percent of life with epilepsy, will be summarized for the Efficacy Analysis Sets 
for POS and PGS
6.3.6
Seizure types experienced during baseline of the previous study
The number and percentage of subjects experiencing each seizure type during the Baseline 
Period will be summarized for the Efficacy Analysis Sets for POS and PGS based on the 
Baseline seizure diary data from the previous studies. The following seizure types will be 
summarized: I, IA, IB, IC, II, and IIA through IIF, and III as well.
Subjects will be counted for all higher levels of seizure type categories corresponding to the 
seizure types or seizure sub-types reported on the CRF.
6.4
Medications
Medications recorded on the Concomitant Medications CRF and the Concomitant 
Medications (AEDs only) CRF will be classified as either AEDs or non-AEDs based on the 
preferred drug name search criteria, which are documented outside of the SAP.

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;


Benzodiazepines (BZD) taken more than once a week (for any indication) will be 
considered as a concomitant 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.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 27 of 47
6.4.2
Number of previous AEDs
The number and percentage of subjects taking an AED within 5 years and discontinued prior 
to entry into the previous double-blind study will be summarized by WHO-DRL preferred 
drug name for the POS and PGS Efficacy Analysis Sets based on the following 
categorization: 0-1 AEDs, 2-4 AEDs, and ≥5 AEDs.
6.4.3
History of previous AED use
The number and percentage of subjects taking an AED within 5 years and discontinued prior 
to entry into the previous double-blind study will be summarized overall and by WHO-DRL
preferred drug name for the POS and PGS Efficacy Analysis Sets.
6.4.4
AEDs taken at study entry
The number and percentage of subjects taking AEDs at study entry for the previous double-
blind study will be summarized by WHO-DRL preferred drug name for the POS and PGS 
Efficacy Analysis Sets.
6.4.5
Concomitant AEDs
A concomitant AED is an AED which was taken during administration of BRV in N01199 
study, regardless of the start and stop date of the AED. The number and percentage of 
subjects taking concomitant AEDs will be summarized by WHO-DRL preferred drug name
for the POS and PGS Efficacy Analysis Sets.
7
MEASUREMENTS OF TREATMENT COMPLIANCE
Study drug compliance will not be assessed due to the complexities associated with the 
calculation and interpretation of study drug compliance for this study. Study drug dosing will 
be provided in subject data listings.
8
EFFICACY ANALYSES
In general, all study outcomes based on seizure frequency will be summarized for the 
Efficacy Analysis Set for POS and all study outcomes based on seizure days will be 
summarized for the Efficacy Analysis Set for PGS. 
The derivations of 28-day adjusted seizure frequency and 28-day adjusted seizure days are 
described in detail in Section 3.8.1.2 and Section 3.8.1.3, respectively.
All summaries of efficacy data are descriptive; no statistical testing will be performed.
8.1
Statistical analyses of secondary efficacy variables
The following variables are summarized for the Efficacy Population for POS.
8.1.1
Partial onset seizure frequency
Twenty-eight day adjusted POS frequency will be summarized with quantitative descriptive 
statistics for all subjects for the Baseline Period, the On Treatment Period, and by 3-month 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 28 of 47
time intervals over the On Treatment Period. The summary over the On Treatment Period 
will include all subjects in the POS Efficacy Analysis Set. Similar summaries will be 
provided for the full cohort interval and by 3-month time intervals for each exposure duration 
cohort.
8.1.2
Percent reduction in POS frequency
Percent reduction in POS frequency from Baseline to the On Treatment Period will be 
calculated as follows, where On Treatment Period Frequency is the 28-day adjusted POS 
frequency during On Treatment Period and Baseline Period Frequency is the 28-day adjusted 
POS frequency during the Baseline Period of the previous study. 
Frequency
Period
Baseline
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Treatment 
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A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort.
Percent reduction from Baseline for POS frequency will be summarized with quantitative 
descriptive statistics for the On Treatment Period, and by 3-month time intervals over the On 
Treatment Period. The summary over the On Treatment Period will include all subjects in the 
POS Efficacy Analysis Set. Similar summaries will be provided for the full cohort interval 
and by 3-month time intervals for each exposure duration cohort. Percent reduction from 
Baseline for POS frequency will be summarized in the same manner by geographic region.
8.1.3
Responder rate for POS frequency
Responders over the On Treatment Period are defined as subjects with a 50% or greater 
reduction in 28-day adjusted POS frequency from Baseline to the On Treatment Period. 
A similar calculation applies to each 3-month time interval over the On Treatment Period and 
for the cohort interval for each exposure duration cohort.
The number and percentage of responders for POS frequency will be summarized for the On 
Treatment Period, and by 3-month time intervals over the On Treatment Period. The 
summary over the On Treatment Period will include all subjects in the POS Efficacy Analysis 
Set. Similar summaries will be provided over the full cohort interval and by 3-month time 
intervals for each exposure duration cohort. Responder rates for POS frequency will be 
summarized in the same manner by geographic region.
8.2
Analysis of other efficacy variables
8.2.1
Subjects with partial onset seizures
All of the following variables are summarized for the Efficacy Analysis Set for POS.
8.2.1.1
Specified Month seizure freedom
The numbers and percentages of subjects who are seizure free for all seizure types for any 
continuous 6-month interval, 12-month interval, 18-month interval, and so forth will be 
summarized overall for the period of time that subjects are being treated with BRV and by 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 29 of 47
Exposure Duration Cohort. The overall summary will present the number and percentage of 
subjects who reported no seizures for the specified duration of seizure freedom and the 
seizure diary was completed for at least 90% of days within the seizure-free interval. Subjects 
whose duration of BRV treatment was less than the specified duration of seizure freedom will 
be considered failures for seizure-freedom. Summaries by exposure duration cohort will 
present the number and percentage of subjects who reported no seizures for the specified 
duration of seizure freedom at any time during the cohort interval (eg, through the end of 
Month 6 for the 6-month cohort) and the seizure diary was completed for at least 90% of days 
within the seizure-free interval. Percentages are relative to the number of subjects within each 
Exposure Duration Cohort. 
A subject is seizure free for a 6-month interval if the subject did not report any seizures in the 
6-month interval and the seizure diary was completed for at least 90% of days within the 
seizure-free interval. The percentage of days for which seizure diary was completed within a 
given 6-month interval will be calculated as follows based on a 30-day month:
% of days diary was done = 100 × 180 −number of days diary was not done in the interval
180
 
A similar calculation applies for 12-month seizure freedom based on 360 days, 18-month 
seizure freedom based on 540 days, and so forth.
8.2.2
Subjects with All Other Seizure Types
The following variables are summarized for the Efficacy Analysis Set for PGS.
8.2.2.1
All other type seizure days
Twenty-eight day adjusted all other type seizure days will be summarized with quantitative 
descriptive statistics in the same manner as 28-day adjusted POS frequency.
8.2.2.2
Percent reduction in All other type seizure days
Percent reduction in all other type seizure days from Baseline will be calculated in the same 
manner as percent reduction in POS frequency as described in Section 8.1.2. This variable 
will be summarized in the same manner as percent reduction in POS frequency.
8.2.2.3
Responder outcome for all other type seizure days
Responder outcome for all other type seizure days will be derived in a manner similar to the 
responder outcome for POS frequency as described in Section 8.1.3. This variable will be 
summarized in the same manner as 50% responder outcome for POS frequency.
8.2.2.4
Specified month seizure freedom
Specified month seizure freedom for subjects in the PGS Efficacy Analysis Set will be 
derived in a manner similar to specified month seizure freedom for the POS Efficacy 
Analysis Set as described in Section 8.2.1.1. This variable will be summarized in the same 
manner as specified month seizure freedom for subjects in the POS Efficacy Analysis Set.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 30 of 47
8.2.3
QOLIE-31-P
The scoring algorithm for QOLIE-31-P is described in Section 13.1. QOLIE-31-P will be 
summarized for the POS and PGS Efficacy Analysis Sets. QOLIE-31-P is assessed at the 
following time points for subjects with POS and subjects with PGS (except for mentally
impaired subjects and subjects coming from N01193): 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. Prior to protocol amendment 6, QOLIE-31-P may 
have been assessed for more than 2 years after study entry for some subjects. These 
additional assessments will not be summarized but will be provided in the subject data 
listings.
Observed values for QOLIE-31-P total score and subscale scores for Seizure Worry, Daily 
Activities/Social Function, Energy/Fatigue, Emotional Well-Being, Cognitive Function, 
Medication Effects, Overall Quality of Life, and Health Status will be summarized for 
Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. 
For each time point, summary statistics will be presented for the baseline scores for subjects 
with a change from baseline at the time point in addition to summaries of the observed values  
and changes from baseline at each time point. Only subjects with a non-missing change from 
baseline will be summarized at each time point.
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, 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 populations for 
POS and PGS. Only observed values will be summarized and only the number of nonmissing 
values and the means for each item will be presented.
8.2.4
EQ-5D
EQ-5D (EuroQol Group, 2000) will be summarized for the POS and PGS Efficacy Analysis 
Sets. EQ-5D is assessed at the following time points (except for mentally impaired subjects 
and subjects coming from N01193): 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. Prior to protocol amendment 6, EQ-5D may have been assessed for more 
than 2 years after study entry for some subjects. These additional assessments will not be 
summarized but will be provided in subject data listings.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 31 of 47
EQ-5D dimensions will be summarized for Months 2, 6, 12, 18, and 24 and Last Value for 
the Efficacy Analysis Sets for POS and PGS. The number and percentage of subjects with 
each response will be summarized for each dimension and time point. Percentages will be 
relative to the number of subjects with a response to the dimension at that time point. 
Additionally, for each dimension and time point, the number and percentage of subjects with 
each response will be summarized for baseline for subjects with an observed response at that 
time point. Additionally, each dimension will be summarized for the 6-Month, 12-Month, 18-
Month, and 24-Month Study Visit Cohorts, including summaries for baseline for all subjects 
within each cohort and summaries of observed responses for all time points for each cohort.
Observed values for the EQ-5D visual analog scale (VAS) score will be summarized for 
Months 2, 6, 12, 18, and 24 and Last Value for the Efficacy Analysis Sets for POS and PGS. 
For each time point, summary statistics will be presented for the baseline VAS score for 
subjects with a change from baseline at the time point in addition to summaries of the 
observed values  and changes from baseline at each time point. Only subjects with a non-
missing change from baseline will be summarized at each time point.
EQ-5D VAS score will also summarized for the 6-Month, 12-Month, 18-Month, and 
24-Month Study Visit Cohorts, including summaries of the baseline scores for all subjects 
within each study visit cohort and summaries of observed values and changes from baseline 
for each time point for each study visit cohort.
8.2.5
Direct cost parameters
Direct costs 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.
8.2.6
Indirect cost parameters
The number of school or working days lost will not be summarized but will be provided in 
subject data listings.
8.2.7
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 for BRV and concomitant AEDs and antimyoclonic drugs (AMDs) will no 
longer be obtained. No summaries of BRV or concomitant AED/AMD plasma levels will be 
provided; plasma levels will only be provided in subject data listings.
10
IMMUNOLOGICAL PROCEDURES
This section is not applicable for this study.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 32 of 47
11
SAFETY ANALYSES
Safety is assessed with AEs, laboratory tests (blood chemistry, hematology, urinalysis, and 
pregnancy test), vital signs, body weight, ECGs, physical examination, neurological 
examination, mental status, and psychiatric status. Summary tables will be provided for AEs; 
blood chemistry, hematology, and urinalysis; vital signs; body weight; and ECGs. No 
summary tables will be provided for pregnancy testing, physical examination, neurological 
examination, mental status, or psychiatric status.
All safety summaries will be based on the Safety Analysis Set.
11.1
Extent of exposure
A daily dose will be calculated for each study day from the day of first dose of BRV to the 
day of last dose of BRV for the purposes of calculating modal dose. Daily dose will be 
calculated as the sum of the AM and PM dose for each day.
Modal daily doses will be calculated across all study days on or after the day of first dose of 
BRV and up to and including the day of last dose of BRV. Modal daily dose is the most 
frequently taken daily dose during this period. In the event of a tie, the modal dose will be set 
to the lower of the tied doses. Modal daily dose will be categorized as follows:
Category
Definition
5 mg/day
<20mg/day
20mg/day        
≥20mg/day to <50mg/day 
50mg/day
≥50mg/day to <100mg/day
100mg/day
≥100mg/day to <150mg/day
150mg/day
≥150mg/day to <200mg/day
200mg/day
≥200mg/day
Subject years of exposure will be calculated by summing the exposure duration in days for all 
subjects being summarized, and dividing the resulting value by 365.25.
Subject years of exposure will be presented overall and by modal dose for the Safety 
Analysis Set. The subject years of exposure presented by modal dose will be the total subject 
years of exposure of subjects with that modal dose.
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, and seizure type (Partial Onset Seizures, All Other Seizure Types).
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 33 of 47
11.2
Adverse events
11.2.1
Definition of treatment-emergent AE
AEs will be classified as either pre-study or treatment-emergent. Pre-study AEs are defined 
as AEs which had onset prior to the date of the first dose of BRV. TEAEs are defined as AEs 
that had onset on or after the day of first BRV dose. AEs with an incomplete onset date will 
be classified as TEAEs if the month and year of onset (when only the month and year are 
specified) is the same as the month and year of the first BRV dose or the year of onset (when 
only year is specified) is the same as the year of first BRV dose.
11.2.2
General summaries of TEAEs
Pre-treatment AEs will be provided in a subject data listing; no summaries of pre treatment 
AEs are planned.
An overall summary of AEs will provide the overall number of TEAEs and the numbers and 
percentages of subjects with at least 1 TEAE, with a TEAE that led to permanent 
discontinuation of study drug, with a drug-related TEAE, with a severe TEAE, with a 
treatment-emergent SAE, and with a drug-related treatment-emergent SAE. The number and 
percentage of subjects who died will also be summarized. This summary will be provided for 
all subjects in the Safety Analysis Set and also by subgroup for geographic region and seizure 
type.
The following summaries of TEAEs will be provided by MedDRA SOC and PT. All 
summaries are for the combined Evaluation, Down-Titration, and Post-Treatment Periods 
unless otherwise indicated.
Overall Incidence Summaries

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, seizure type, and randomized 
treatment from the previous double-blind study.
A subject is included in a 3-month interval if the subject was receiving BRV at any time 
during that interval based on their duration of exposure to BRV (eg, a subject with exposure 
for 91 days is included in the time interval for Months 1-3 and Months 4-6). Summaries of 
AEs by 3-month intervals will include all subjects who are classified into each time interval 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 34 of 47
as defined above. TEAEs which had onset prior to or on the date of the last dose of BRV are 
included in summaries by 3-month time intervals.
Maximum Intensity and Causality

Incidence of TEAEs by maximum intensity

Incidence of drug-related TEAEs
Serious Adverse Events

Incidence of treatment-emergent SAEs
Discontinuations due to TEAE

Incidence of TEAEs leading to permanent discontinuation of study drug
TEAEs of interest
AEs of interest will be identified based on MedDRA search criteria, which are documented 
outside of the SAP.  The following summaries will be provided for AEs of interest:

Incidence of TEAEs of interest

Incidence of TEAEs of interest by 3-month time interval
For the summary by maximum intensity, each subject will be counted at most once per SOC 
or PT according to the maximum intensity of all AEs within that SOC or PT. Severe intensity 
will be assumed for AEs for which intensity is not specified.
Drug-related AEs are AEs for which the relationship to study drug is specified as Related or 
AEs for which relationship is not specified.
11.3
Clinical laboratory evaluations
Clinical laboratory parameters (blood chemistry, hematology, urinalysis) are assessed at all 
FEVs, YEVs, EDVs, and at the 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.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 35 of 47
Additionally, the number and percentage of subjects with a PCST value, PCST low value, 
and PCST high value will be summarized for Baseline, Study Entry, each visit during the 
Evaluation Period for which laboratory parameters were scheduled to be assessed, EDV, Last 
Value, and FV. Percentages for each parameter and time point will be relative to the number 
of subjects with a value at that time point.
PCST criteria (Sections 13.3.1 and 13.3.2) are based on Food and Drug Administration 
(FDA) Division of Neuropharmacologic Drug Products guidelines with some UCB-defined 
additions.
Creatinine clearance, when available from the central laboratory, will be provided in subject 
data listings only and will not be summarized.
11.3.2
Macroscopic urinalysis
Quantitative urinalysis parameters will be summarized in the same manner as hematology 
and blood chemistry parameters. Response categories are negative, 1+, 2+, and 3+ for the 
qualitative urinalysis parameters occult blood, leukocytes, glucose, protein, and ketones and 
negative and positive for nitrates. Outcome values for these parameters are mapped to the 
levels Negative, 1+, 2+, and 3+ as follows for purposes of summary tables and the 
determination of PCST:
Category
Definition
Negative
“Negative”, “NEGATIVE”, or other outcomes that clearly reflect a negative 
finding
1+
“1+”, “+” , “Trace”, “TRACE”, or other outcomes that clearly reflect trace 
amount
2+
“2+” or “++”
3+
“3+”, “+++”, or other outcomes that clearly reflect the data above 3+ (eg, “4+”, 
“5+” etc) or more than 4 plus signs (eg, “++++”, “+++++”etc)
For qualitative urinalysis parameters (occult blood, leukocytes, glucose, protein, ketones, and 
nitrates), the number and percentage of subjects with each response category will be 
summarized for Baseline, Study Entry, each scheduled visit during the Evaluation Period for 
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.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 36 of 47
Additionally, for occult blood, leukocytes, glucose, protein, ketones, and nitrates, the number 
and percentage of subjects with a PCST value, PCST low value, and PCST high value will be 
summarized for Baseline, Study Entry, each visit during the Evaluation Period for which 
laboratory parameters were scheduled to be assessed, EDV, Last Value, and FV. Percentages 
for each parameter and time point will be relative to the number of subjects with a value at 
that time point.
11.3.3
Microscopic urinalysis
In microscopic urinalysis, a small sample of urine is centrifuged to remove the liquid. The 
sediment is then examined under a microscope. In the urinalysis laboratory test group, other 
than urinalysis parameters such as Bilirubin, Blood, Glucose, Ketone, Nitrite, pH, Protein, 
Specific Gravity, Total protein, Hemoglobin, Beta-HCG, Occult Blood, and Leukocytes, a 
listing of microscopic analysis parameters will be provided; no summaries of microscopic 
analysis findings are planned.  
11.4
Vital signs, physical findings, and other observations related 
to safety
11.4.1
Vital signs
Vital signs are assessed at all FEVs, MEVs, YEVs, EDVs, and at FV, and may also be 
assessed at Unscheduled Visits. Body weight is assessed at all FEVs, YEVs, EDVs, and at 
FV, and may also be assessed at Unscheduled Visits.
Observed values for SBP, DBP, pulse rate, and body weight will be summarized for Baseline, 
Study Entry, each visit during the Evaluation Period for which vital signs or body weight 
were assessed, EDV, Last Value, and FV. Changes from Baseline for SBP, DBP, pulse rate, 
and body weight will be summarized for all post-Baseline time points.
The number and percentage of subjects with an on-treatment PCST value, PCST low value, 
and PCST high value will be summarized for SBP, DBP, pulse rate, and body weight. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV. Percentages will be relative to the number of subjects with an on-
treatment assessment.
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.
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 37 of 47
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding will be summarized overall. This 
summary will consider all assessments after the first dose of BRV and prior to or on the date 
of the last dose of BRV. Percentages will be relative to the number of subjects with an on-
treatment assessment.
Additionally, the number and percentage of subjects with no abnormality, an abnormal but 
not clinically significant finding, and a clinically significant finding will be summarized for 
Baseline, Study Entry, each visit during the Evaluation Period for which an ECG is scheduled 
to be performed, Last Value, EDV, and FV. Percentages will be relative to the number of 
subjects with an ECG assessment at each time point. Subjects are counted at most once at 
each time point based on the worst observed outcome across all abnormalities reported at that 
time point.
A subject number listing will be provided that identifies subjects with a clinically significant 
finding after the first dose of BRV for each type of ECG abnormality.
11.4.3
Physical examination
A listing of abnormal physical examination findings will be provided; no summaries of 
physical examination findings are planned.
11.4.4
Neurological examination
A listing of neurological examination findings will be provided; no summaries of 
neurological examination findings are planned.
11.4.5
Psychiatric and mental status
A listing of abnormal Psychiatric and Mental Status findings will be provided; no summaries 
of Psychiatric and Mental Status findings are planned.
11.4.6
HADS
The scoring algorithm for HADS is described in Section 3.8.3.
HADS is assessed at the following time points: Month 2, Month 6, Month 12, Month 18, and 
Month 24. HADS is not assessed for mentally impaired subjects and subjects from N01193. 
HADS is also assessed at EDVs for subjects who discontinue prior to the YEV at the end of 
the second year. Prior to protocol amendment 6, HADS may have been assessed for more 
than 2 years after study entry for some subjects. These additional assessments will not be 
summarized but will be provided in subject data listings.
Observed values for 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 
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UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 38 of 47
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 6 to the protocol, the Columbia-Suicide Severity Rating Scale 
(C-SSRS) was added as an assessment at all study visits. Specific rules are provided to the 
study sites with regard to the identification of AEs or SAEs based on the outcome of this 
assessment. Because clinical events of interest will be recorded as AEs or SAEs, no study 
variable is defined for this assessment and no analyses are planned for the C-SSRS within the 
context of this study. However, subject data listings of the data for the C-SSRS will be 
provided. Additional listings will be provided for the subset of subjects with suicidal ideation 
and the subset of subject with actual suicide attempts.
Suicide ideation includes a “yes” answer to any 1 of the 5 suicidal ideation questions:





 
Suicide attempt includes response of a “yes” answer to any 1 of the 3 suicide attempt 
questions:


 

 
12
REFERENCES
Cramer JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann B. 
Development and cross-cultural translations of a 31-item quality of life in epilepsy inventory. 
Epilepsia 1998, 39(1): 81-88.
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.
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
20 April 2017
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 41 of 47
13.2
Subject site transfers
Subjects listed in this section of the appendix had changes to their subject number as a result 
of site transfer.
CRF#
Initial Site Subject #
Transfer Site Subject #
 
 
 
 
 
 
 
 
 
 
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UCB
8 August 2016
Statistical Analysis Plan
                                                                      Brivaracetam
   N01199
Confidential
                                                              Page 42 of 47
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
8 August 2016
Statistical Analysis Plan
                                                                      Brivaracetam
   N01199
Confidential
                                                              Page 43 of 47
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
8 August 2016
Statistical Analysis Plan
                                                                      Brivaracetam
   N01199
Confidential
                                                              Page 44 of 47
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
8 August2016
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 45 of 47
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
8 August2016
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 46 of 47
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
8 August2016
Statistical Analysis Plan
Brivaracetam
N01199
Confidential
Page 47 of 47
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 8.2.5 Direct cost parameters, Section 8.2.6 Indirect cost parameters, Section 
8.2.7 Socio-professional data
Removed all direct/indirect cost parameters and socio-professional data summary analysis.
Change #3
Removed signature page. Using e-signature approval process through Mikado.
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