Brivaracetam / N01199

A Brivaracetam / N01199 CONFIDENTIALProtocol: RPCE05C2110 / Integrated Amendment 7 Final /15 Oct 2015 / 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 30080Smyrna

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.”

REDACTED

rivaracetam

REDACTED

rivaracetam -

REDACTED

- IN

REDACTED

IN

COPY UNITED STATES

COPY UNITED STATES

Hereafter “UCB”COPY Hereafter “UCB”

This do

cumen

t representative(s) of the clinical study

docu

ment representative(s) of the clinical study

yo

docu

ment your staff, to members of appropriate review committee(s) and/or to persons to whom the

docu

ment ur staff, to members of appropriate review committee(s) and/or to persons to whom the

investigational product may

docu

ment

investigational product may

cann

ot ur agreement that the information contained herein will not be disclosed or in any

cann

ot ur agreement that the information contained herein will not be disclosed or in anycommunicated to an

cann

ot communicated to anrepresentative(s) of the clinical studyca

nnot

representative(s) of the clinical study

be Investigator

be Investigator

ur agreement that the information contained herein will not be disclosed or in anybe

ur agreement that the information contained herein will not be disclosed or in any

used

Confidential Material

used

Confidential Material“The information contained in this document is strictlyus

ed

“The information contained in this document is strictlyInvestigatorus

ed

Investigator

to Confidential Materialto Confidential Materialsu

pport

any m

arketi

ng au

thoriz

ation

Hereafter “UCB”

autho

rizati

on Hereafter “UCB”

IN

autho

rizati

on

IND

autho

rizati

on

D Number

autho

rizati

on

Number

appli

catio

n and

any e

xtens

ions mg

exten

sions

mgor and efficacy

or and efficacy of

or of

mgor mg/dayor /dayva

riatio

ns

of varia

tions

of

thereo

f.


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: _________

REDACTED Phone: __________________________________

REDACTED Phone: __________________________________COPY ________________

COPY __________________________________________________

COPY ____________________________________________________________________

COPY __________________________________

Phone: __________________________________COPY

Phone: __________________________________

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on __________________________________

autho

rizati

on __________________________________

Phone: __________________________________

autho

rizati

on

Phone: __________________________________

appli

catio

n Date:

appli

catio

n Date:

________________

appli

catio

n

__________________________________________________

appli

catio

n

__________________________________

and

contractual obligations towards the Sponsor of the

and

contractual obligations towards the Sponsor of the any able federal, state and/or

any able federal, state and/or

contractual obligations towards the Sponsor of the any

contractual obligations towards the Sponsor of the

exten

sions

110

exten

sions

110 and

exten

sions

and

describ

exten

sions

described therein.

exten

sions

ed therein. Furthermore, I agree to conduct this clinical study in compliance with said Protocol, the I

exten

sions

Furthermore, I agree to conduct this clinical study in compliance with said Protocol, the Iable federal, state and/or ex

tensio

ns

able federal, state and/or

or va

riatio

ns th

ereof.


2 CONTACT INFORMATION

SponsorUCB Pharma Inc.1950 Lake Park DriveUSA - GA 30080SmyrnaUNITED STATES

Study PhysicianName: , MD Phone:

Fax:

Clinical Project ManagerName: Phone:

Fax:

Safety PhysicianName: , MB BCh

BAO, MRCGPPhone:

Fax:

Clinical Trial StatisticianName: Phone:

Fax:

REDACTED Fax:

REDACTED Fax:

MB BCh

REDACTED

MB BCh

COPY Phone:COPY Phone:Fax:C

OPY

Fax:

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on

Fax:

autho

rizati

on

Fax:

Phone:autho

rizati

on

Phone:

appli

catio

n

appli

catio

n and

an

d any

an

y exte

nsion

s or v

ariati

ons t

hereo

f.


SAE Reporting (24h/24), Safety Related Issues (GCSP)

Email: Global: [email protected]

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.

REDACTED COPY nvestigators is maintained in the Trial Mast

COPY nvestigators is maintained in the Trial Mast

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion

nvestigators is maintained in the Trial Mast

appli

catio

n

nvestigators is maintained in the Trial Mast

and a

ny ex

tensio

ns -6949

exten

sions

-6949

exten

sions

-582

exten

sions

-582-8842

exten

sions

-8842

or +1or +1va

riatio

ns

+1varia

tions

+1-varia

tions

-

thereo

f.


3 TABLE OF CONTENTS

1 TITLE..............................................................................................................................1

2 CONTACT INFORMATION .......................................................................................3

3 TABLE OF CONTENTS...............................................................................................5

4 LIST OF ABBREVIATIONS........................................................................................9

5 PROTOCOL SUMMARY...........................................................................................125.1 Study Schedule of Assessments .......................................................................185.2 Schematic Diagram ..........................................................................................21

6 BACKGROUND INFORMATION............................................................................236.1 Background and epidemiology of targeted disease..........................................236.2 Background information regarding product .....................................................246.3 Efficacy with BRV in fixed-dose Phase II/III studies in POS .........................256.4 Safety with BRV ..............................................................................................256.5 Study Rationale ................................................................................................26

6.5.1 Dose Selection....................................................................................266.5.2 Subjects Population............................................................................26

6.5.2.1 Minimal Age...............................................................266.5.3 Duration of Treatment........................................................................26

7 STUDY OBJECTIVES ................................................................................................277.1 Primary Objective ............................................................................................277.2 Secondary Objectives .......................................................................................277.3 Exploratory Objectives.....................................................................................27

8 STUDY DESIGN ..........................................................................................................288.1 Type/Design .....................................................................................................288.2 Subjects/Sites Numbers....................................................................................298.3 Subject Identifier ..............................................................................................298.4 Study Duration .................................................................................................298.5 End of Study.....................................................................................................29

9 SELECTION AND WITHDRAWAL OF SUBJECTS.............................................299.1 Subject Inclusion Criteria.................................................................................299.2 Subject Exclusion Criteria................................................................................309.3 Subject Withdrawal ..........................................................................................30

9.3.1 Withdrawal Criteria............................................................................319.3.2 Subject Replacement Policy...............................................................32

10 TREATMENT OF SUBJECTS (INVESTIGATIONAL PRODUCT AND CONCOMITANT MEDICATIONS) .........................................................................3210.1 Study Investigational Products.........................................................................32

10.1.1 Description of all Investigational Products ........................................32

REDACTED ................................

REDACTED ................................................................

REDACTED ................................

Minimal Age

REDACTED Minimal Age

REDACTED

Duration of Treatment

REDACTED

Duration of Treatment

REDACTED

................................REDACTED

................................

COPY ................................

COPY ................................................................

COPY ................................................................

COPY ................................

................................COPY

................................

This do

cumen

t can

not SELECTION AND WITHDR

cann

ot SELECTION AND WITHDR

cann

ot 9.1

cann

ot 9.1

cann

ot

9.2cann

ot

9.2

be

SELECTION AND WITHDRbe

SELECTION AND WITHDR

used

Subject I

used

Subject I

used

us

ed

Study

used

Study

used

End of Studyus

ed

End of Studyused

to 8.2 Subjects/Sites Numbers................................

to 8.2 Subjects/Sites Numbers................................

Subject Ito Subject Ito su

pport

................................

supp

ort ................................

supp

ort

pe/Design

supp

ort

pe/Design ................................

supp

ort

................................

supp

ort

8.2 Subjects/Sites Numbers................................supp

ort

8.2 Subjects/Sites Numbers................................supp

ort

Subject Isu

pport

Subject Identifiersu

pport

dentifier

any Objectives

any Objectives

any m

arketi

ng

................................

marketi

ng

................................................................

marketi

ng

................................ Objectivesmark

eting

Objectives ................................marketi

ng

................................marketi

ng

Objectivesmarketi

ng

Objectives

autho

rizati

on ................................

autho

rizati

on ................................

................................

autho

rizati

on

................................................................

autho

rizati

on

................................Minimal Age

autho

rizati

on

Minimal Age

autho

rizati

on

Duration of Treatmentautho

rizati

on

Duration of Treatment................................autho

rizati

on

................................autho

rizati

on ap

plica

tion

................................

appli

catio

n ................................

................................

appli

catio

n ................................III studies in POS

appli

catio

n III studies in POS

appli

catio

n

................................ap

plica

tion

................................................................ap

plica

tion

................................

and ................................

and ................................

................................and

................................

any ..........................21

any ..........................21ex

tensio

ns

........................9

exten

sions

........................9

...........................12

exten

sions

...........................12................................ex

tensio

ns

..........................................................21ex

tensio

ns

..........................21

or ...............................5or ...............................5varia

tions

.......................3

varia

tions

.......................3

varia

tions

...............................5varia

tions

...............................5

thereo

f.


10.1.2 Dosing Schedule ................................................................................3210.1.3 Packaging ...........................................................................................3310.1.4 Labeling..............................................................................................3310.1.5 Storage Requirements ........................................................................3310.1.6 Monitoring of Subject Compliance....................................................3410.1.7 Investigational Products Accountability ............................................34

10.2 Concomitant Treatments and Rescue Medications ..........................................3510.2.1 Permitted Concomitant Treatments (Medications and Therapies) ....3510.2.2 Prohibited Concomitant Treatments (Medications and

Therapies)...........................................................................................35

11 STUDY PROCEDURES..............................................................................................3511.1 Description of Procedures ................................................................................35

11.1.1 Informed Consent...............................................................................3511.1.2 Subject Study Card.............................................................................3611.1.3 Demography.......................................................................................3611.1.4 Childbearing Potential and Birth Control ..........................................3611.1.5 General Medical and Procedure History ............................................3611.1.6 Epilepsy History.................................................................................3611.1.7 Antiepileptic Medication History.......................................................3611.1.8 Vital Signs..........................................................................................3611.1.9 Weight and Height .............................................................................3711.1.10 Physical Examination.........................................................................3711.1.11 Neurological Examination .................................................................3711.1.12 ECG....................................................................................................3711.1.13 Daily Record Card (DRC)..................................................................3811.1.14 Laboratory Assessments.....................................................................3811.1.15 Adverse Events (AEs) ........................................................................3911.1.16 Assessment of Suicidality ..................................................................3911.1.17 Medical Procedures............................................................................4011.1.18 Non-Antiepileptic and Antiepileptic Concomitant Medications........4111.1.19 Patient Reported Outcomes................................................................4111.1.20 Quality of Life in Epilepsy Questionnaire (QOLIE-31-P).................4111.1.21 Hospital Anxiety and Depression Scale (HADS) ..............................4211.1.22 EQ-5D Questionnaire.........................................................................4211.1.23 Hospital Stay ......................................................................................4211.1.24 Healthcare Provider Consultation not Foreseen by Protocol .............4311.1.25 Socio-professional Data .....................................................................4311.1.26 End of Study.......................................................................................43

11.2 Description Visit by Visit.................................................................................4411.2.1 Entry Visit ..........................................................................................4411.2.2 Full Evaluation Visit ..........................................................................4511.2.3 Minimal Evaluation Visit...................................................................4611.2.4 Yearly Evaluation Visit (replaces the first FEV of each year)...........46

REDACTED ................................

REDACTED ................................Antiepileptic Medication History

REDACTED Antiepileptic Medication History

REDACTED ................................

REDACTED ................................

Weight and Height

REDACTED

Weight and Height

REDACTED

sical ExaminationREDACTED

sical ExaminationREDACTED

REDACTED

11.1.11 Neurological Examination ................................REDACTED

11.1.11 Neurological Examination ................................

COPY Childbearing Potential and Birth Control

COPY Childbearing Potential and Birth Control

COPY General Medical and Procedure History

COPY General Medical and Procedure History

COPY

................................COPY

................................

This do

cumen

t can

not b

e use

d us

ed 11.1.19 Patient Reported Outcomes................................

used

11.1.19 Patient Reported Outcomes................................

used


used


used

11.1.20us

ed

11.1.20used

us

ed to

11.1.18to 11.1.18to su

pport

Adverse Events (AEs)

supp

ort Adverse Events (AEs)

supp

ort

Asse

supp

ort

Asse

supp

ort

ssment of Suicidality

supp

ort

ssment of Suicidality

supp

ort

11.1.17 supp

ort

11.1.17 Medical Proceduressupp

ort

Medical Proceduressupp

ort

supp

ort

Nonsu

pport

Non

any

Record Card (DRC)

any

Record Card (DRC)

any Laboratory

any Laboratory Assessments

any AssessmentsLaboratory AssessmentsLaboratory

any Laboratory AssessmentsLaboratory

any

Adverse Events (AEs)any

Adverse Events (AEs)

marketi

ng sical Examination

marketi

ng sical Examination

marketi

ng

marketi

ng


marketi

ng


marketi

ng

................................

marketi

ng

................................ Record Card (DRC)mark

eting

Record Card (DRC)marketi

ng

Assessmentsmark

eting

Assessments

autho

rizati

on General Medical and Procedure History

autho

rizati

on General Medical and Procedure History

autho

rizati

on

................................

autho

rizati

on

................................Antiepileptic Medication History

autho

rizati

on

Antiepileptic Medication History

autho

rizati

on

................................

autho

rizati

on

................................................................

autho

rizati

on

................................sical Examinationau

thoriz

ation

sical Examination

appli

catio

n ................................

appli

catio

n ................................................................

appli

catio

n ................................................................

appli

catio

n ................................

Childbearing Potential and Birth Control

appli

catio

n

Childbearing Potential and Birth Control

appli

catio

n

General Medical and Procedure Historyappli

catio

n

General Medical and Procedure Historyappli

catio

n and

................................

and ................................

................................and

................................

any ..............................35

any ..............................35

................................any

................................

exten

sions

..........35

exten

sions

..........3510.2.1 Permitted Concomitant Treatments (Medications and Therapies) ....35

exten

sions

10.2.1 Permitted Concomitant Treatments (Medications and Therapies) ....35

exten

sions

...........................35ex

tensio

ns

...........................35

or ............34

or ............34..........35or ..........35

varia

tions

....................34va

riatio

ns

....................34va

riatio

ns

............34varia

tions

............34

thereo

f.


11.2.5 Early Discontinuation Visit................................................................4711.2.6 Down-Titration Phone Call ................................................................4811.2.7 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..................................................................................4911.3 Handling of Biological Samples ......................................................................4911.4 Other Supplies ..................................................................................................49

12 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................4912.1 Adverse Events.................................................................................................49

12.1.1 Definition of Adverse Event (AE) .....................................................4912.1.2 Procedures for Reporting and Recording Adverse Events.................5012.1.3 Description of AEs.............................................................................5012.1.4 Follow-up on Adverse Events............................................................5312.1.5 Rule for Repetition of an AE .............................................................5312.1.6 Pregnancy...........................................................................................5312.1.7 Overdose of Investigational Product..................................................54

12.2 Serious Adverse Events....................................................................................5412.2.1 Definition of Serious Adverse Event (SAE) ......................................5412.2.2 Procedures for Reporting Serious Adverse Events (SAE).................5512.2.3 Anticipated Serious Adverse Events..................................................56

13 STATISTICS.................................................................................................................5613.1 Statistical and Analytical Plans ........................................................................56

13.1.1 Study Population(s)............................................................................5613.1.2 Efficacy and Safety Variables............................................................5613.1.3 Statistical Evaluation..........................................................................58

13.2 Determination of the Sample Size....................................................................6013.3 Statistical and Analytical Issues .......................................................................60

13.3.1 Handling of Dropouts of Missing Data..............................................6013.3.2 Interim Analysis and Data Monitoring ..............................................6013.3.3 Use of an Efficacy Subset of Subjects ...............................................6013.3.4 Examination of Subgroups.................................................................60

13.4 Criteria for Starting the Analysis .....................................................................6013.5 Dictionaries ......................................................................................................61

14 ETHICS AND REGULATORY REQUIREMENTS................................................6114.1 Approval...........................................................................................................6114.2 Subject Information and Consent.....................................................................6214.3 Subject Confidentiality.....................................................................................6314.4 Informing the General Practitioner (or Pediatrician) .......................................64

15 STUDY MANAGEMENT AND ADMINISTRATION ............................................6415.1 Monitoring........................................................................................................64

REDACTED ................................

REDACTED ................................12.2.1 Definition of Serious Adverse Event (SAE) ................................

REDACTED 12.2.1 Definition of Serious Adverse Event (SAE) ................................

REDACTED Procedures for Reporting Serious Adverse Events (SAE)

REDACTED Procedures for Reporting Serious Adverse Events (SAE)

REDACTED

Anticipated Serious Adverse Events

REDACTED

Anticipated Serious Adverse Events

REDACTED

................................REDACTED

................................

COPY ................................

COPY ................................................................

COPY ................................12.1.7 Overdose of Investigational Product................................

COPY 12.1.7 Overdose of Investigational Product................................

COPY

................................COPY

................................

This do

cumen

t 14 ETHICS AND REGULATOR

docu

ment 14 ETHICS AND REGULATOR

docu

ment c

anno

t 13.4

cann

ot 13.4

cann

ot 13.5

cann

ot 13.5

cann

ot

14 ETHICS AND REGULATORcann

ot

14 ETHICS AND REGULATOR

be us

ed 13.3.2

used

13.3.2

used

13.3.3us

ed

13.3.3us

ed

13.3.4used

13.3.4

to 13.3.1

to 13.3.1

to 13.3.2to 13.3.2su

pport

Statistical Evaluation

supp

ort Statistical Evaluation

supp

ort

Determination of the Sample Size

supp

ort


supp

ort

Statistical asu

pport

Statistical and Analy

supp

ort

nd Analysu

pport

Handling of Dropouts of Missing Datasupp

ort

Handling of Dropouts of Missing Datasupp

ort an

y Efficacy

any Efficacy and Safet

any and Safet

any

Statistical Evaluationany

Statistical Evaluationany

Determination of the Sample Sizean

y


marketi

ng

................................

marketi

ng

................................................................

marketi

ng

................................tical Plans

marketi

ng

tical Plans

marketi

ng

Population(s)mark

eting

Population(s)mark

eting

and Safetmarketi

ng

and Safet

autho

rizati

on 12.1.7 Overdose of Investigational Product................................

autho

rizati

on 12.1.7 Overdose of Investigational Product................................

autho

rizati

on

................................

autho

rizati

on

................................12.2.1 Definition of Serious Adverse Event (SAE) ................................

autho

rizati

on

12.2.1 Definition of Serious Adverse Event (SAE) ................................

autho

rizati

on

Procedures for Reporting Serious Adverse Events (SAE)

autho

rizati

on

Procedures for Reporting Serious Adverse Events (SAE)

autho

rizati

on

Anticipated Serious Adverse Eventsau

thoriz

ation

Anticipated Serious Adverse Eventsau

thoriz

ation

appli

catio

n ................................

appli

catio

n ................................

................................

appli

catio

n ................................12.1.5 Rule for Repetition of an AE ................................

appli

catio

n 12.1.5 Rule for Repetition of an AE ................................

................................

appli

catio

n

................................12.1.7 Overdose of Investigational Product................................ap

plica

tion

12.1.7 Overdose of Investigational Product................................appli

catio

n and

12.1.2 Procedures for Reporting and Recording Adverse Events.................50

and 12.1.2 Procedures for Reporting and Recording Adverse Events.................50

and

................................and

................................

any ................................

any ................................

12.1.2 Procedures for Reporting and Recording Adverse Events.................50any

12.1.2 Procedures for Reporting and Recording Adverse Events.................50

exten

sions

................................

exten

sions

......................................49

exten

sions

......49................................

exten

sions

................................

S................................

exten

sions

S................................................................ex

tensio

ns

................................

or ..................49

or ..................49

......49or ......49va

riatio

ns

.............................48va

riatio

ns

.............................48va

riatio

ns

..................49varia

tions

..................49

thereo

f.


15.2 Direct Access to Source Data/Documents .......................................................6415.3 Audit and Inspection ........................................................................................6515.4 Case Report Forms (CRF)................................................................................6515.5 Adherence to Protocol......................................................................................6615.6 Investigator Site File ........................................................................................6715.7 Data Handling ..................................................................................................6715.8 Termination of Study .......................................................................................67

15.8.1 Termination of Study by Sponsor ......................................................6815.9 Clinical Study Report .......................................................................................6815.10 Insurance and Liability.....................................................................................6815.11 Archiving and Data Retention..........................................................................6815.12 Allocation of Responsibilities ..........................................................................6915.13 Curriculum Vitae (CV).....................................................................................6915.14 Financial Disclosure.........................................................................................6915.15 Good Clinical Practice .....................................................................................7015.16 Publication........................................................................................................70

16 REFERENCES .............................................................................................................70

17 SPONSOR DECLARATION ......................................................................................72

List of TablesTable 5:1 Study Flowchart...........................................................................................18Table 5:2 Visit Schematic Diagrams ...........................................................................22REDACTED ................................

REDACTED ................................

List of Table

REDACTED

List of Table

REDACTED

................................

REDACTED

................................Visit Schematic Diagrams ................................REDACTED

Visit Schematic Diagrams ................................REDACTED COPY ................................

COPY ................................

................................

COPY ................................

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

................................

marketi

ng ................................

Visit Schematic Diagrams ................................

marketi

ng

Visit Schematic Diagrams ................................

marketi

ng au

thoriz

ation

................................

autho

rizati

on ................................

................................

autho

rizati

on

................................

List of Table

autho

rizati

on

List of Table

autho

rizati

on

................................autho

rizati

on

................................

appli

catio

n ................................

appli

catio

n ................................................................

appli

catio

n ................................

appli

catio

n

................................

appli

catio

n

................................

................................appli

catio

n

................................

and

................................

and

................................................................

and ................................

any ................................

any ................................

................................any

................................

exten

sions

.......................67

exten

sions

.......................67......................68

exten

sions

......................68.......................68

exten

sions

.......................68................................

exten

sions

.....................................................68ex

tensio

ns

.....................68

or ................................

or ..................................67

or ..67

.......................67or .......................67va

riatio

ns

........................67va

riatio

ns

........................67va

riatio

ns

..67varia

tions

..67

thereo

f.


4 LIST OF ABBREVIATIONS

AE(s) Adverse Event(s)AED(s) Antiepileptic Drug(s)ALT (ALAT/SGPT)

Alanine Aminotransferase

ASAT/SGOT Aspartate AminotransferaseALP Alkaline PhosphataseAV Additional Visitb.i.d. Twice DailyBRV BrivaracetamBZD BenzodiazepineCBZ CarbamazepineCDMS Clinical Data Management SystemCPMP Committee for Proprietary Medicinal ProductCr Cl Creatinine ClearanceCRF Case Report FormCRO Clinical Research OrganizationC-SSRS Columbia Suicide Severity Rating ScaleCTM Clinical Trial ManagerCV Curriculum VitaeCYP CytochromeDBP Diastolic blood pressureDHHS Department of Health and Human Servicesdl DeciliterDRC Daily Record CardDTP Down-titration Phone CallECG ElectrocardiogramEDV Early Discontinuation VisitEQ-5D EuroQoL 5 Dimensions QuestionnaireER Emergency roomEV Entry VisitFEV Full Evaluation VisitFDA Food and Drug AdministrationFV Final VisitGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilanceGGT Gamma-glutamyltranspeptidaseGMP Good Manufacturing PracticesGP General Practitionerh HourHADS Hospital Anxiety and Depression Scale

REDACTED rganization

REDACTED rganizationColumbia Suicide Severity

REDACTED Columbia Suicide Severity

anager

REDACTED

anagerV

REDACTED

Vitae

REDACTED

itae

COPY Medicinal Product

COPY Medicinal Product

rganizationCOPY

rganization

This do

cumen

t FV

docu

ment FV

GCP

docu

ment GCP

GCSP

docu

ment

GCSP

cann

ot FDA

cann

ot FDAFV ca

nnot

FV

be us

ed to

supp

ort aily

supp

ort aily

Down

supp

ort

Down-

supp

ort

-titration P

supp

ort titration P

Esu

pport

Electrocardiogramsu

pport

lectrocardiogram

Esupp

ort

Earlsupp

ort

arl

any eciliter

any eciliter

Rany

Record any

ecord

marketi

ng

Diastolic blood pressure

marketi

ng

Diastolic blood pressureDepartment of Health and Human Services

marketi

ng

Department of Health and Human Services

autho

rizati

on

rganization

autho

rizati

on

rganizationColumbia Suicide Severity

autho

rizati

on

Columbia Suicide Severity Rating Scale

autho

rizati

on

Rating ScaleColumbia Suicide Severity Rating ScaleColumbia Suicide Severity

autho

rizati

on

Columbia Suicide Severity Rating ScaleColumbia Suicide Severityanager

autho

rizati

on

anager

appli

catio

n

Medicinal Product

appli

catio

n

Medicinal Product

and a

ny ex

tensio

ns or

varia

tions

there

of.


HDPE High Density PolyethyleneIB Investigator BrochureICH International Conference on HarmonizationIEC Independent Ethics CommitteeILAE International League Against EpilepsyIND Investigational New DrugIRB Institutional Review BoardIVRS Interactive voice response systemIWRS Interactive web response systemkg KilogramL LiterLTG Lamotriginem MeterMCH Mean Corpuscular HaemoglobinMCHC Mean Corpuscular Haemoglobin ConcentrationMCV Mean Corpuscular VolumeMedDRA Medical Dictionary for Regulatory Activities

MEV Minimal Evaluation Visitµg Microgrammg Milligrammin Minuteml MilliliterµL MicroliterµM MicromolPBO PlaceboPGS Primary Generalized EpilepsyPK PharmacokineticsPOS Partial Onset SeizurePRO Patient Reported OutcomesQOLIE-31-P Patient Weighted Quality of Life in Epilepsy QuestionnaireRBC Red Blood CellSAE Serious Adverse EventSAP Statistical Analysis PlanSAS Statistical Analysis SystemSBP Systolic blood pressureSDV Source Data VerificationSOC System Organ ClassSOP Standard Operating ProcedureSP Study PhysicianSV2A Synaptic Vesicle Protein 2ATMF Trial Master FileWBC White Blood CellWHO World Health Organization

REDACTED COPY

egulatory

COPY egulatory

isit COPY isit

This do

cumen

t SDV

docu

ment SDV

SOC

docu

ment

SOCca

nnot

SBPca

nnot

SBPSDVca

nnot

SDV

be us

ed to

supp

ort harmacokinetic

supp

ort harmacokinetic

supp

ort

Partial Onset Seizure

supp

ort

Partial Onset SeizurePatient Reported Outcomesu

pport

Patient Reported OutcomePatient Weighted Quality of Lsu

pport

Patient Weighted Quality of L

any Primary

any Primary Generalized Epilepsy

any Generalized EpilepsyPrimary Generalized EpilepsyPrimary

any Primary Generalized EpilepsyPrimary

harmacokineticany

harmacokinetic

marketi

ng

Generalized Epilepsymark

eting

Generalized Epilepsy

autho

rizati

on ap

plica

tion

oncentration

appli

catio

n oncentration

egulatoryappli

catio

n

egulatory Aappli

catio

n

Activitiesappli

catio

n

ctivities

and a

ny ex

tensio

ns or

varia

tions

there

of.


YEV Yearly Evaluation Visit

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or v

ariati

ons t

hereo

f.


5 PROTOCOL SUMMARY

Investigational Product:Brivaracetam (BRV)

Objectives:Primary ObjectiveTo 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 ObjectiveTo 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 EthicsCommittee (IEC)/Institutional Review Board (IRB) approved written informed consent form will be properly executed and documented.

Subject Inclusion Criteria: An IEC/IRB approved written informed consent signed and dated by the subject or by

parent(s) or legally acceptable representative. The consent form or a specific assent form, where required, will be signed and dated by minors.

REDACTED self

REDACTED self-

REDACTED -self-self

REDACTED self-self reported health status

REDACTED reported health statuschange in the subject’s

REDACTED change in the subject’s socio

REDACTED socio

will provide subjects suffering from epilepsyREDACTED

will provide subjects suffering from epilepsyadjunctive treatment, the opportunity REDACTED

adjunctive treatment, the opportunity to receive open label REDACTED

to receive open label adjunctive treatment, the opportunity to receive open label adjunctive treatment, the opportunity REDACTED

adjunctive treatment, the opportunity to receive open label adjunctive treatment, the opportunity

COPY ealth

COPY ealth

medical resource use and indirect cost parametersCOPY medical resource use and indirect cost parameters

reported health statusCOPY

reported health status

This do

cumen

t Before an

docu

ment Before an

Committee (I

docu

ment

Committee (Iwill be properl

docu

ment

will be properl

cann

ot It is estimated that between 100 - 200 sites will participate in this global protocol.

cann

ot It is estimated that between 100 - 200 sites will participate in this global protocol.

Subject ca

nnot

Subject Population and Diagnosis:ca

nnot

Population and Diagnosis:Before anca

nnot

Before an

be It is estimated that between 100 - 200 sites will participate in this global protocol.be It is estimated that between 100 - 200 sites will participate in this global protocol.us

ed atment in epileps

used

atment in epilepsy will roll over into the present

used

y will roll over into the present to assumption that 90% of subjects having completed a previous to assumption that 90% of subjects having completed a previous

y will roll over into the present to

y will roll over into the present

supp

ort

Subjects

supp

ort

SubjectsIt is estimated that approximatelysu

pport

It is estimated that approximatelyassumption that 90% of subjects having completed a previous su

pport

assumption that 90% of subjects having completed a previous

any subjects having completed a previous BRV study

any subjects having completed a previous BRV studymark

eting

will provide subjects suffering from epilepsy

marketi

ng will provide subjects suffering from epilepsy

marketi

ng

to receive open label

marketi

ng

to receive open label is not permitted an

marketi

ng

is not permitted any are allowed to continue BRV monotherapmark

eting

y are allowed to continue BRV monotherapsubjects having completed a previous BRV study

marketi

ng

subjects having completed a previous BRV study

autho

rizati

on medical resource use and indirect cost parameters

autho

rizati

on medical resource use and indirect cost parameters

reported health status

autho

rizati

on

reported health statussocio

autho

rizati

on

socio-

autho

rizati

on

-professional

autho

rizati

on

professional

will provide subjects suffering from epilepsyautho

rizati

on

will provide subjects suffering from epilepsy

appli

catio

n

related

appli

catio

n

related

medical resource use and indirect cost parametersap

plica

tion

medical resource use and indirect cost parameters

and (for POS/PGS subjects)

and (for POS/PGS subjects)

any e

xtens

ions

es with a

exten

sions

es with a

or va

riatio

ns th

ereof.


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

REDACTED understand the proper use of contraceptive methods,

REDACTED understand the proper use of contraceptive methods,y potential change in status

REDACTED y potential change in status. According to the judgment of the

REDACTED . According to the judgment of the might be accepted on a case

REDACTED might be accepted on a case

y acceptable representative considered as reliable and

REDACTED

y acceptable representative considered as reliable and the protocol (e.g. able to understand and complete diaries and questionnaires), visit

REDACTED

the protocol (e.g. able to understand and complete diaries and questionnaires), visit schedule or medication intake according to the judgment of the REDACTED

schedule or medication intake according to the judgment of the

COPY used in conjunction with a barrier method. The subject must understand the consequences

COPY used in conjunction with a barrier method. The subject must understand the consequences y protected sexual activity, be educated about and

COPY y protected sexual activity, be educated about and

understand the proper use of contraceptive methods,COPY understand the proper use of contraceptive methods,

This do

cumen

t that the dai

docu

ment that the dai

be in the evening of the day

docu

ment

be in the evening of the daystarting dose of each subject will be the one defined/reached at the end of the

docu

ment

starting dose of each subject will be the one defined/reached at the end of the

cann

ot Drug Administration:

cann

ot Drug Administration: Subjects

cann

ot Subjects coming from

cann

ot coming from

cann

ot flexible dose of up to a maximum of ca

nnot

flexible dose of up to a maximum of that the daica

nnot

that the dai

be

Drug Administration: be

Drug Administration: us

ed

Pregnant or lactating woman.

used

Pregnant or lactating woman.

to Participation in any

to Participation in anysu

pport

have an impact on the safety

supp

ort have an impact on the safety

Poor compliance with the visit schedule or medication intake in the previous

supp

ort

Poor compliance with the visit schedule or medication intake in the previous Participation in anysu

pport

Participation in any clinical supp

ort

clinical Participation in any clinical Participation in anysupp

ort

Participation in any clinical Participation in any

any Severe medical, neurological and ps

any Severe medical, neurological and ps

have an impact on the safetyany

have an impact on the safety of the subject.any

of the subject.have an impact on the safety of the subject.have an impact on the safetyany

have an impact on the safety of the subject.have an impact on the safety

marketi

ng the protocol (e.g. able to understand and complete diaries and questionnaires), visit

marketi



marketi

ng


Severe medical, neurological and psmark

eting

Severe medical, neurological and ps

autho

rizati

on y protected sexual activity, be educated about and

autho

rizati

on y protected sexual activity, be educated about and

understand the proper use of contraceptive methods,

autho

rizati

on

understand the proper use of contraceptive methods, and undertake to inform the

autho

rizati

on

and undertake to inform the . According to the judgment of the

autho

rizati

on

. According to the judgment of the might be accepted on a case

autho

rizati

on

might be accepted on a casey acceptable representative considered as reliable and

autho

rizati

on

y acceptable representative considered as reliable and the protocol (e.g. able to understand and complete diaries and questionnaires), visit au

thoriz

ation

the protocol (e.g. able to understand and complete diaries and questionnaires), visit

appli

catio

n ligation, bilateral tubal implant, monogamous relationship with vasectomized partner).

appli

catio

n 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

appli

catio

n Oral or depot contraceptive treatment with at least 30 µg [or 50 µg if associated with known as inducers] ethin

appli

catio

n known as inducers] ethinyl

appli

catio

n ylestradiol per intake must be

appli

catio

n estradiol per intake must be

used in conjunction with a barrier method. The subject must understand the consequences

appli

catio

n

used in conjunction with a barrier method. The subject must understand the consequences y protected sexual activity, be educated about and ap

plica

tion

y protected sexual activity, be educated about and and undertake to inform the

appli

catio

n

and undertake to inform the

and oral hormonal contraceptive medi

and oral hormonal contraceptive medication, bilateral tubal

and cation, bilateral tubal

ligation, bilateral tubal implant, monogamous relationship with vasectomized partner). and 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 an

d Oral or depot contraceptive treatment with at least 30 µg [or 50 µg if associated with

any Uterine Device, diaphragm with spermicide, male or female condom with spermicide;


cation, bilateral tubal any

cation, bilateral tubal

exten

sions

ars postmenopausal

exten

sions

ars postmenopausal sterectom

exten

sions

sterectom

tial are eligible

exten

sions

tial are eligible accepted contraceptive method for the duration of ex

tensio

ns

accepted contraceptive method for the duration of the exten

sions

the studyexten

sions

studyUterine Device, diaphragm with spermicide, male or female condom with spermicide;

exten

sions

Uterine Device, diaphragm with spermicide, male or female condom with spermicide;

or ars postmenopausal or ars postmenopausal

varia

tions

there

of.


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 V7and V8).

Second and subsequent years: 1 visit every 3 months; 1 FEV alternating with 1 MEV.

REDACTED y removed.

REDACTED y removed.

Each subject will be informed on how to take the drug and that there is an excess of drug in

REDACTED


COPY BRV

COPY BRV

udies (N01252, N01253, COPY udies (N01252, N01253,

y removed.COPY

y removed.

This do

cumen

t First y

docu

ment First yca

nnot For those subjects coming

cann

ot For those subjects coming

cann

ot follows:

cann

ot follows:First yca

nnot

First y

be

For those subjects coming be

For those subjects coming

used

stages of development. For this reason, the

used

stages of development. For this reason, the studyus

ed

study

to development as well as therapeutic confirmatory

to development as well as therapeutic confirmatorystages of development. For this reason, the to stages of development. For this reason, the

supp

ort

will run throughout the duration of the clinical development period of

supp

ort

will run throughout the duration of the clinical development period of therapeutic explorator

supp

ort

therapeutic exploratordevelopment as well as therapeutic confirmatorysu

pport

development as well as therapeutic confirmatory

any m

arketi

ng

hase III, therapeutic longmark

eting

hase III, therapeutic long-tmark

eting

-term followmark

eting

erm follow

autho

rizati

on udies (N01252, N01253,

autho

rizati

on udies (N01252, N01253,

y removed.

autho

rizati

on

y removed.


autho

rizati

on


appli

catio

n Containers of 80

appli

catio

n Containers of 80

25 mg will be available when appli

catio

n

25 mg will be available when udies (N01252, N01253, ap

plica

tion

udies (N01252, N01253,

and

Brivaracetam 2.5 mg oral tablets were packaged in bottles of 200

and

Brivaracetam 2.5 mg oral tablets were packaged in bottles of 200 ed in bottles of 80 and 200 tablets.

and ed in bottles of 80 and 200 tablets.

Containers of 80and

Containers of 80

any Poly

any Poly

Brivaracetam 2.5 mg oral tablets were packaged in bottles of 200 any

Brivaracetam 2.5 mg oral tablets were packaged in bottles of 200

exten

sions

of 80

exten

sions

of 80 blister cards) and 200 (10 blister cards) tablets were provided and each visit carton had a

exten

sions

blister cards) and 200 (10 blister cards) tablets were provided and each visit carton had a

Polyexten

sions

Polyethexten

sions

eth

or 2.5 mg and

or 2.5 mg and

of 80 or of 80 va

riatio

ns

2.5 mg and varia

tions

2.5 mg and

thereo

f.


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

REDACTED The periods considered in the definition of efficacy variables are the following:

REDACTED The periods considered in the definition of efficacy variables are the following:

-month periods over the Evaluation P

REDACTED

-month periods over the Evaluation Period (V1 until the last evaluation visit).

REDACTED

eriod (V1 until the last evaluation visit).

COPY y the Investigator b

COPY y the Investigator bInvestigator will also confirm on the DRC the number of seizures of each ty

COPY Investigator will also confirm on the DRC the number of seizures of each ty

This do

cumen

t can

not Laboratory

cann

ot Laboratory

ca

nnot

Vital signs (sca

nnot

Vital signs (s

be

Laboratorybe

Laboratoryus

ed

variablesus

ed

variablesus

ed to

Occurrence of an SAEto

Occurrence of an SAEsupp

ort Withdrawal due to an AE

supp

ort Withdrawal due to an AE

Occurrence of an SAEsupp

ort


any

Withdrawal due to an AEan

y


marketi

ng au

thoriz

ation

Investigator will also confirm on the DRC the number of seizures of each ty

autho

rizati

on Investigator will also confirm on the DRC the number of seizures of each ty

The periods considered in the definition of efficacy variables are the following:

autho

rizati

on

The periods considered in the definition of efficacy variables are the following:eriod (V1 until the last evaluation visit).au

thoriz

ation

eriod (V1 until the last evaluation visit).

appli

catio

n using the seizure count informati

appli

catio

n using the seizure count informati

DRC. The subject will be asked to record the date and the number (where possible) of

appli

catio

n DRC. The subject will be asked to record the date and the number (where possible) of ype of seizure (according to individual

appli

catio

n ype of seizure (according to individual

y the Investigator b

appli

catio

n

y the Investigator by

appli

catio

n

y adding the ILAE codes. The

appli

catio

n

adding the ILAE codes. The Investigator will also confirm on the DRC the number of seizures of each tyap

plica

tion

Investigator will also confirm on the DRC the number of seizures of each ty

and

using the seizure count informatiand

using the seizure count informati

any

The YEV will be performed in replacement of the first FEV of each

any

The YEV will be performed in replacement of the first FEV of each exten

sions

The YEV will be performed in replacement of the first FEV of each exten

sions

The YEV will be performed in replacement of the first FEV of each yeexten

sions

ye

or va

riatio

ns th

ereof.


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 isdefined 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


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

REDACTED seizure

REDACTED seizure-

REDACTED -least 6 months and at least 12 months during the Evaluation Period

REDACTED least 6 months and at least 12 months during the Evaluation Period

For subjects with generalized epilepsy

REDACTED


REDACTED

:

COPY

free for all seizure tyCOPY

free for all seizure ty

This do

cumen

t with generalized epileps

docu

ment with generalized epileps

docu

ment c

anno

t least 6 months and at least 12 months during the

cann

ot least 6 months and at least 12 months during the

The following will be evaluated separatelca

nnot

The following will be evaluated separatelca

nnot

with generalized epilepscann

ot

with generalized epileps

be Percentage of subjects continuously

be Percentage of subjects continuously

least 6 months and at least 12 months during thebe

least 6 months and at least 12 months during theus

ed Baseline Period of the previous study

used

Baseline Period of the previous study

Percentage of subjects continuouslyused

Percentage of subjects continuously

to responder is defined as a subject with a

to responder is defined as a subject with a Baseline Period of the previous studyto Baseline Period of the previous study

supp

ort previous study to the Evaluation Period

supp

ort previous study to the Evaluation Period

Responder rate for generalized (ty

supp

ort

Responder rate for generalized (tyresponder is defined as a subject with a su

pport

responder is defined as a subject with a Baseline Period of the previous study

supp

ort

Baseline Period of the previous study

any Percent reduction in generalized (ty

any Percent reduction in generalized (ty

previous study to the Evaluation Periodany previous study to the Evaluation Periodmark

eting

pe II) seizure day

marketi

ng

pe II) seizure days per 28 day

marketi

ng

s per 28 day

Percent reduction in generalized (tymarketi

ng

Percent reduction in generalized (ty

autho

rizati

on

free for all seizure ty

autho

rizati

on

free for all seizure tyleast 6 months and at least 12 months during the Evaluation Period

autho

rizati

on

least 6 months and at least 12 months during the Evaluation Period

appli

catio

n and

from the Baseline

and from the Baseline an

y over the Evaluation Period. A responder isan

y over the Evaluation Period. A responder is from the Baseline an

y from the Baseline

exten

sions

he previous

exten

sions

he previous

over the Evaluation Period. A responder isex

tensio

ns

over the Evaluation Period. A responder is

or va

riatio

ns th

ereof.


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 subjectswith 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

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion

professional data for each assessment for the first 2 y

appli

catio

n professional data for each assessment for the first 2 y

appli

catio

n ears and for the last

appli

catio

n ears and for the last

ears of the Evaluation Period

appli

catio

n


and the subject and d

and the subject and day

and ays subject received

and s subject received

ears of the Evaluation Periodand


any

s subject received any

s subject received

exten

sions

y the protocol, concurrent

exten

sions

y the protocol, concurrent

medical procedures, concomitant medications, hospitalizations, and emergencyex

tensio

ns

medical procedures, concomitant medications, hospitalizations, and emergency

or and subjectsor and subjectsvaria

tions

and subjectsvaria

tions

and subjects

thereo

f.

A Brivaracetam / N01199 CONFIDENTIALProtocol: RPCE05C2110 / Integrated Amendment 7 Final / 15 Oct 2015 / 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

ASSESSMENTSWritten Informed Consent X 11.1.1Clinical Trial Subject Card Dispensing

X 11.1.2

Verification Inclusion/ Exclusion Criteria

X 9.1 and 9.2

Demographic Data X 11.1.3Childbearing 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 11.1.13Daily 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

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED COPY

COPY

COPY

COPY

COPY

COPY

COPY

This do

cumen

t can

not

cann

ot

cann

ot

cann

ot

cann

ot

cann

ot

cann

ot be

X

be X

(c)

be (c)

be us

ed X X

used

X X

used

X X

used

X X

used

us

ed

used

us

ed

(c) used

(c) us

ed to

X Xto X Xto

supp

ort

supp

ort

supp

ort

supp

ort

supp

ort

supp

ort

X

supp

ort

X

supp

ort

supp

ort an

y Xan

y Xan

y an

y mark

eting

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

Xmarketi

ng

Xmarketi

ng au

thoriz

ation

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on ap

plica

tion Discontinuation

appli

catio

n Discontinuation Visit

appli

catio

n Visit

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n and

Early an

d Early

Discontinuation and

Discontinuation and a

ny ex

tensio

ns or

varia

tions

CONFIDENTIAL

varia

tions

CONFIDENTIAL15 Octva

riatio

ns

15 Oct

thereo

f.


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)

Down-Titration 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 11.1.17Concomitant AED X X X X X X X 11.1.18Concomitant Non-AED X X X X X X X 11.1.18

Drug Dispensing X X X X X10.1.2 and

10.1.6

Drug Return/Accountability X X X X X10.1.6 and

10.1.7

End of Study Status(j)

X 11.1.26

REDACTED X

REDACTED X

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED COPY

COPY

COPY

COPY

COPY

COPY

COPY

This do

cumen

t can

not b

e use

d to to

supp

ort

supp

ort

supp

ort

supp

ort

supp

ort

supp

ort

supp

ort an

y Xany Xany

any m

arketi

ng X

marketi

ng X

X

marketi

ng

X

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

marketi

ng

X marketi

ng

X marketi

ng

marketi

ng au

thoriz

ation

X

autho

rizati

on X

X

autho

rizati

on

X

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

X

autho

rizati

on

X

autho

rizati

on

Xautho

rizati

on

Xautho

rizati

on ap

plica

tion (EDV)

appli

catio

n (EDV)

X

appli

catio

n X

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n and

Discontinuation

and

Discontinuation

Visitan

d Visit(a)

and (a)

(EDV)and

(EDV)

any

Discontinuation any

Discontinuation any

any e

xtens

ions

exten

sions

or va

riatio

ns

CONFIDENTIAL

varia

tions


riatio

ns

15 Oct

thereo

f.


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.

REDACTED Recording of seizures

REDACTED Recording of seizures,

REDACTED , Laboratory Assessment including Safety (blood chemistry, hematology

REDACTED Laboratory Assessment including Safety (blood chemistry, hematology

Height will be recorded at Visit 1 (Entry Visit). Height will also be measured at

REDACTED Height will be recorded at Visit 1 (Entry Visit). Height will also be measured at

s an

REDACTED

s an E

REDACTED

Early

REDACTED

arly P and HADS are to be completed at the beginning of the visit by all subjects (except thoREDACTED

P and HADS are to be completed at the beginning of the visit by all subjects (except tho

COPY The following data will be transferred from the database of the baseline visit of the previous

COPY The following data will be transferred from the database of the baseline visit of the previous

The following data will be transferred from the database of the last visit of the previous COPY The following data will be transferred from the database of the last visit of the previous

Laboratory Assessment including Safety (blood chemistry, hematology COPY

Laboratory Assessment including Safety (blood chemistry, hematology

This do

cumen

t can

not For subjects that may transition to another BRV study or a managed access program or similar type of program, the EDV will ne

cann

ot For subjects that may transition to another BRV study or a managed access program or similar type of program, the EDV will ne

cann

ot titration and FV may not be applicable

cann

ot titration and FV may not be applicable

be subjects had completed their Entry Visit. Thus, the C

be subjects had completed their Entry Visit. Thus, the C

For subjects that may transition to another BRV study or a managed access program or similar type of program, the EDV will nebe

For subjects that may transition to another BRV study or a managed access program or similar type of program, the EDV will ne

used

Procedures only performed during the first 2

used

Procedures only performed during the first 2subject discontinues participation within the first 2

used

subject discontinues participation within the first 2SSRS assessment will be implemented by site per IRB/IEC approval and upon completion of required training.us

ed

SSRS assessment will be implemented by site per IRB/IEC approval and upon completion of required training.subjects had completed their Entry Visit. Thus, the Cus

ed

subjects had completed their Entry Visit. Thus, the C

to Procedures only performed during the first 2to Procedures only performed during the first 2 years of to years of subject discontinues participation within the first 2

to subject discontinues participation within the first 2

supp

ort Laboratory assessment is mandatory at Final visit except if Fi

supp

ort Laboratory assessment is mandatory at Final visit except if Fi

status will be completed at the FV for subjects having performed an EDV (discontinued subjects) and for subjects leaving the

supp

ort

status will be completed at the FV for subjects having performed an EDV (discontinued subjects) and for subjects leaving the

years of su

pport

years of

any

professional data will be collected for all subjects except those

any

professional data will be collected for all subjects except those Laboratory assessment includes blood chemistry, hematology and urine analysis; where applicable (w

any Laboratory assessment includes blood chemistry, hematology and urine analysis; where applicable (w

Laboratory assessment is mandatory at Final visit except if Fiany

Laboratory assessment is mandatory at Final visit except if Fi

marketi

ng arly

marketi

ng arly


marketi

ng


5D questionnaire is to be completed by all subjects (except those coming from N01193) who are not mentally impaired.

marketi

ng

5D questionnaire is to be completed by all subjects (except those coming from N01193) who are not mentally impaired.professional data will be collected for all subjects except those mark

eting

professional data will be collected for all subjects except those Laboratory assessment includes blood chemistry, hematology and urine analysis; where applicable (w

marketi

ng

Laboratory assessment includes blood chemistry, hematology and urine analysis; where applicable (w

autho

rizati

on The following data will be transferred from the database of the last visit of the previous

autho

rizati

on The following data will be transferred from the database of the last visit of the previous


autho

rizati

on



autho

rizati

on


arly autho

rizati

on

arly Dautho

rizati

on

Discontinuation Visit where ECG results were normalautho

rizati

on

iscontinuation Visit where ECG results were normal

appli

catio

n =Patient Weighted Quality of life in Epilepsy Questionnaire; YEV=Yearly

appli

catio

n =Patient Weighted Quality of life in Epilepsy Questionnaire; YEV=Yearly

period is mandatory in case the subjects discontinue from more than

appli

catio

n period is mandatory in case the subjects discontinue from more than

The following data will be transferred from the database of the baseline visit of the previous

appli

catio

n

The following data will be transferred from the database of the baseline visit of the previous study

appli

catio

n

study

studyap

plica

tion

study

and Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Vis

and Call; ECG=electrocardiogram; EDV=Early Discontinuation Visit; EV=Entry Visit; FEV=Full Evaluation Vis

=Patient Weighted Quality of life in Epilepsy Questionnaire; YEV=Yearly and

=Patient Weighted Quality of life in Epilepsy Questionnaire; YEV=Yearly

any SSRS=Columbia Suicide Severity Rating Scale; any SSRS=Columbia Suicide Severity Rating Scale;

it; FV=Final Visit; HADS=any

it; FV=Final Visit; HADS=

exten

sions

or va

riatio

ns

CONFIDENTIAL

varia

tions


riatio

ns

15 Oct

thereo

f.


5.2 Schematic Diagram

For subjects coming from the therapeutic exploratory study (N01193), visits will be scheduled as follows: First year:


During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7and 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:


Second and subsequent years: 1 visit/3months: FEV alternating with MEV. The YEV will be performed in replacement of the first FEV of each year.

REDACTED FEV alternating with MEV.

REDACTED FEV alternating with MEV.

1 visit/3 months:

REDACTED 1 visit/3 months:

REDACTED

FEV alternating with MEV.REDACTED

FEV alternating with MEV.

COPY confirmatory

COPY confirmatory

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting


marketi

ng FEV alternating with MEV.


marketi

ng


autho

rizati

on


autho

rizati

on

FEV alternating with MEV.FEV alternating with MEV.

autho

rizati

on


FEV alternating with MEV.au

thoriz

ation


appli

catio

n be performed in replacement of the first

appli

catio

n be performed in replacement of the first

studies

appli

catio

n

studies

and

be performed in replacement of the first and

be performed in replacement of the first

any e

xtens

ions During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit

exten

sions

During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit

months there will be 1 visit every 3 months; 2 FEV (at V7

exten

sions

months there will be 1 visit every 3 months; 2 FEV (at V7

or va

riatio

ns th

ereof.


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-upMonth Visit Type of Visit Month Visit Type of Visit

M0 V1 Entry Visit M0 V1 Entry VisitM1 V2 MEV M1 V2 MEV

M2 V3 FEV M2 V3 FEV

M3 V4 MEV M3 V4 MEV

M4 V5 FEV M4M5 V6 MEV M5M6 V7 FEV M6 V5 FEV

M7 M7M8 M8M9 V8 FEV M9 V6 MEV

M10 M10M11 M112nd and subsequent years follow-up 2nd and subsequent years follow-upM12 V9 YEV M12 V7 YEVM15 V10 MEV1 M15 V8 MEV1M18 V11 FEV M18 V9 FEVM21 V12 MEV2 M21 V10 MEV2

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 of50 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.

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

REDACTED

and subsequent years follow-

REDACTED

and subsequent years follow-up

REDACTED

up

REDACTED

YEVREDACTED

YEVREDACTED

MEV1REDACTED

MEV1REDACTED C

OPY M7

COPY M7M8

COPY M8

COPY

COPY

COPY

This do

cumen

t subsequently

docu

ment subsequently

When the

docu

ment

When the

cann

ot At the end of the down

cann

ot At the end of the downtitrated from doses higher than

cann

ot titrated from doses higher than

cann

ot period free of ca

nnot

period free of subsequentlyca

nnot

subsequently

be

At the end of the downbe

At the end of the downus

ed on a weekl

used

on a weekl

used

included prior to the

used

included prior to the

to titrat

to titrat

on a weeklto on a weekly basis. to y basis. su

pport

In case the subject will not continue with

supp

ort In case the subject will not continue with

y Discontinuation Visit followed by the progressive down

supp

ort

y Discontinuation Visit followed by the progressive downtitrat su

pport

titration period, the dose maysupp

ort

ion period, the dose mayy basis. su

pport

y basis.

any

ME

any

ME

any

any

In case the subject will not continue with an

y In case the subject will not continue with

marketi

ng

marketi

ng

marketi

ng

marketi

ng

FEV

marketi

ng

FEV

marketi

ng

marketi

ng

MEmarketi

ng

MEmarketi

ng

V2marketi

ng

V2marketi

ng

marketi

ng au

thoriz

ation

M8

autho

rizati

on M8

M9

autho

rizati

on

M9

autho

rizati

on

M10

autho

rizati

on

M10

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on

autho

rizati

on ap

plica

tion

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n

appli

catio

n and

an

d an

d any

an

y an

y an

y an

y an

y an

y exte

nsion

s Type of Visit

exten

sions

Type of Visit

exten

sions

Entry

exten

sions

Entry Visit

exten

sions

VisitEntry VisitEntry

exten

sions

Entry VisitEntry

exten

sions

exten

sions

exten

sions

or or va

riatio

ns

varia

tions

there

of.


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

REDACTED (Nasreddine et al, 2010; Kwan and Brodie, 2001).

REDACTED (Nasreddine et al, 2010; Kwan and Brodie, 2001).

y is based on the recurrence of seizures. Seizures may be caused b

REDACTED

y is based on the recurrence of seizures. Seizures may be caused bing brain disorder or lesion or due to genetic conditions. Characterization of the

REDACTED

ing brain disorder or lesion or due to genetic conditions. Characterization of the ndrome has profound implications for treatment and prognosis. The major REDACTED

ndrome has profound implications for treatment and prognosis. The major

COPY y if the seizure disorder remains uncontrolled. The treatment for epilepsy remains

COPY y if the seizure disorder remains uncontrolled. The treatment for epilepsy remains difficult, and there is ongoing medical need for new antiepileptic drugs (AEDs). For

COPY difficult, and there is ongoing medical need for new antiepileptic drugs (AEDs). For

eizure freedom can still not be reached with currentlyCOPY eizure freedom can still not be reached with currently

(Nasreddine et al, 2010; Kwan and Brodie, 2001).COPY

(Nasreddine et al, 2010; Kwan and Brodie, 2001).

This do

cumen

t term video electroencephalograms (EEGs) and high

docu

ment term video electroencephalograms (EEGs) and high

(MRI), providing much more precise knowledge in regard to seizure t

docu

ment (MRI), providing much more precise knowledge in regard to seizure t

epileptic sy

docu

ment

epileptic sy

cann

ot concepts that, for the most part, predate modern technologies and concepts

cann

ot concepts that, for the most part, predate modern technologies and concepts

cann

ot ILAE (

cann

ot ILAE (http://ww

cann

ot http://wwterm video electroencephalograms (EEGs) and highca

nnot

term video electroencephalograms (EEGs) and high

be League Against Epilepsy ([ILAE], 1981 and 1989), these ILAE classifications were based on

be League Against Epilepsy ([ILAE], 1981 and 1989), these ILAE classifications were based on

concepts that, for the most part, predate modern technologies and concepts be

concepts that, for the most part, predate modern technologies and concepts

used

ongoing debate. First published in 1960 and last updated officially

used

ongoing debate. First published in 1960 and last updated officially1989 for epilepsies (Commus

ed

1989 for epilepsies (CommLeague Against Epilepsy ([ILAE], 1981 and 1989), these ILAE classifications were based on us

ed

League Against Epilepsy ([ILAE], 1981 and 1989), these ILAE classifications were based on

to The classification of epileptic sy

to The classification of epileptic syongoing debate. First published in 1960 and last updated officiallyto ongoing debate. First published in 1960 and last updated officially

supp

ort 25 to 30% of all epileps

supp

ort 25 to 30% of all epileps

or the classification remains uncertain.

supp

ort

or the classification remains uncertain.

The classification of epileptic sysupp

ort

The classification of epileptic sy

any 60 to 70% of all cases, and generalized epilepsy

any 60 to 70% of all cases, and generalized epilepsy

25 to 30% of all epilepsany

25 to 30% of all epileps

marketi

ng ing brain disorder or lesion or due to genetic conditions. Characterization of the

marketi

ng ing brain disorder or lesion or due to genetic conditions. Characterization of the

ndrome has profound implications for treatment and prognosis. The major

marketi

ng

ndrome has profound implications for treatment and prognosis. The major for the diagnosis of epilepsy

marketi

ng

for the diagnosis of epilepsy is the differentiation between focal epilepsies (ie,

marketi

ng

is the differentiation between focal epilepsies (ie, for the diagnosis of epilepsy is the differentiation between focal epilepsies (ie, for the diagnosis of epilepsy

marketi

ng

for the diagnosis of epilepsy is the differentiation between focal epilepsies (ie, for the diagnosis of epilepsyction), which are the most frequent and account for

marketi

ng

ction), which are the most frequent and account for 60 to 70% of all cases, and generalized epilepsymark

eting

60 to 70% of all cases, and generalized epilepsy

autho

rizati

on eizure freedom can still not be reached with currently

autho

rizati

on eizure freedom can still not be reached with currently


autho

rizati

on


y is based on the recurrence of seizures. Seizures may be caused b

autho

rizati

on

y is based on the recurrence of seizures. Seizures may be caused bing brain disorder or lesion or due to genetic conditions. Characterization of the au

thoriz

ation

ing brain disorder or lesion or due to genetic conditions. Characterization of the

appli

catio

n yi

appli

catio

n ying cause. Sudden

appli

catio

n ng cause. Sudden s in 1 to

appli

catio

n s in 1 to 5

appli

catio

n 5 per 1000

appli

catio

n per 1000

y if the seizure disorder remains uncontrolled. The treatment for epilepsy remains

appli

catio

n

y if the seizure disorder remains uncontrolled. The treatment for epilepsy remains difficult, and there is ongoing medical need for new antiepileptic drugs (AEDs). For ap

plica

tion

difficult, and there is ongoing medical need for new antiepileptic drugs (AEDs). For eizure freedom can still not be reached with currentlyap

plica

tion

eizure freedom can still not be reached with currently

and

many people, particularl

and

many people, particularlchildren, the condition may remit, although a significant proportion will have epileps

and children, the condition may remit, although a significant proportion will have epileps

ng cause. Sudden and

ng cause. Sudden

any with age, with high rates occurring in childhood, falling to low levels in earl

any with age, with high rates occurring in childhood, falling to low levels in earl

many people, particularlany

many people, particularl

exten

sions

The prevalence of

exten

sions

The prevalence of The annual incidence in developed countries is approximately

exten

sions

The annual incidence in developed countries is approximately 50 to

exten

sions

50 to The annual incidence in developed countries is approximately 50 to The annual incidence in developed countries is approximately

exten

sions

The annual incidence in developed countries is approximately 50 to The annual incidence in developed countries is approximately

70 cases per 100.000. In developing countries, the figure is higher due to more limited

exten

sions

70 cases per 100.000. In developing countries, the figure is higher due to more limited stetric services and the greater likelihood of cerebral infection and trauma.

exten

sions

stetric services and the greater likelihood of cerebral infection and trauma. The incidence ex

tensio

ns

The incidence with age, with high rates occurring in childhood, falling to low levels in earlex

tensio

ns

with age, with high rates occurring in childhood, falling to low levels in earl

or va

riatio

ns th

ereof.


(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®), BRVdisplays 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.

REDACTED s a high and selective interaction with a novel brain

REDACTED s a high and selective interaction with a novel braintein 2A). However, the binding affinity

REDACTED tein 2A). However, the binding affinity

than with LEV

REDACTED

than with LEV. This binding site appears to be the major target

REDACTED

. This binding site appears to be the major target . Unlike LEV,

REDACTED

. Unlike LEV, ivaracetam also reverses the inhibitoryREDACTED

ivaracetam also reverses the inhibitory

COPY 6.2 Background information regarding product

COPY 6.2 Background information regarding product

levetiracetam (COPY levetiracetam (

s a high and selective interaction with a novel brainCOPY

s a high and selective interaction with a novel brain

This do

cumen

t pharmacologically

docu

ment pharmacologically

eliminated primarily

docu

ment eliminated primarily

dose, with less than 9% as unchanged

docu

ment

dose, with less than 9% as unchanged

cann

ot CYP2C19 (with contributions of several other isoenzy

cann

ot CYP2C19 (with contributions of several other isoenzypathway

cann

ot pathway

cann

ot s results in the hy

cann

ot s results in the hypharmacologicallyca

nnot

pharmacologically

be corresponding carbox

be corresponding carbox

CYP2C19 (with contributions of several other isoenzybe

CYP2C19 (with contributions of several other isoenzy

used

water. The plasma half

used

water. The plasma halfadults. The main metabolic pathwayus

ed

adults. The main metabolic pathwaycorresponding carboxus

ed

corresponding carbox

to ≤20%). The volume of distribution is 0.5

to ≤20%). The volume of distribution is 0.5

water. The plasma halfto water. The plasma halfsu

pport

y and completely absorbed throughout the gastrointestinal tract. The

supp

ort y and completely absorbed throughout the gastrointestinal tract. The

absorption is not affected b

supp

ort

absorption is not affected bproportional (at least from 10

supp

ort

proportional (at least from 10≤20%). The volume of distribution is 0.5su

pport

≤20%). The volume of distribution is 0.5

any

y and completely absorbed throughout the gastrointestinal tract. The any

y and completely absorbed throughout the gastrointestinal tract. The

marketi

ng . Unlike LEV,

marketi

ng . Unlike LEV,

ivaracetam also reverses the inhibitory

marketi

ng

ivaracetam also reverses the inhibitoryand gl

marketi

ng

and glycine

marketi

ng

ycinemetabolized, but seizure protection appears to be associated with the parent compound.

marketi

ng

metabolized, but seizure protection appears to be associated with the parent compound.

autho

rizati

on levetiracetam (

autho

rizati

on levetiracetam (

s a high and selective interaction with a novel brain

autho

rizati

on

s a high and selective interaction with a novel braintein 2A). However, the binding affinity

autho

rizati

on

tein 2A). However, the binding affinity. This binding site appears to be the major target

autho

rizati

on

. This binding site appears to be the major target . Unlike LEV, au

thoriz

ation

. Unlike LEV, BRVautho

rizati

on

BRV

appli

catio

n f the ILAE, 1989).

appli

catio

n f the ILAE, 1989).

levetiracetam (appli

catio

n

levetiracetam (

and yndromes will be used according to the 1989 ILAE

and yndromes will be used according to the 1989 ILAE

f the ILAE, 1989).and

f the ILAE, 1989).

any of the ILAE, 1981).

any of the ILAE, 1981).ex

tensio

ns generalized seizures, and on the other

exten

sions

generalized seizures, and on the other cal and at

exten

sions

cal and atypical),

exten

sions

ypical),

-clonic seizures, and atonic seizures.

exten

sions

-clonic seizures, and atonic seizures. impaired from the onset of

exten

sions

impaired from the onset of of the ILAE, 1981).ex

tensio

ns

of the ILAE, 1981).

or classified as simple partial seizures (no alteration of consciousness), complex partial seizures

or classified as simple partial seizures (no alteration of consciousness), complex partial seizures

generalized seizures, and on the other or

generalized seizures, and on the other va

riatio

ns

classified as simple partial seizures (no alteration of consciousness), complex partial seizures varia

tions

classified as simple partial seizures (no alteration of consciousness), complex partial seizures

thereo

f.


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 BRVdoses 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).

REDACTED II studies (N01114

REDACTED II studies (N01114, UCB protocol reference code RPCE05C2201

REDACTED , UCB protocol reference code RPCE05C2201

for the adjunctive treatment of POS. Two adequate

REDACTED

for the adjunctive treatment of POS. Two adequate dose studies (N01252

REDACTED

dose studies (N01252, UCB protocol reference code RPCE06G0705) were conducted to REDACTED

, UCB protocol reference code RPCE06G0705) were conducted to

COPY II/III studies in POS

COPY II/III studies in POS

II studies (N01114COPY

II studies (N01114

This do

cumen

t frequentl

docu

ment frequentl

incidence of serious adverse events (SAEs) was low and similar to PBO. There were no

docu

ment incidence of serious adverse events (SAEs) was low and similar to PBO. There were no

clinically

docu

ment

clinically

cann

ot . The discontinuation rate and the discontinuation rate due to treatment

cann

ot . The discontinuation rate and the discontinuation rate due to treatmentadverse events (TEAEs) were low and s

cann

ot adverse events (TEAEs) were low and s

cann

ot

frequentlcann

ot

frequentl

be /

be /III

be III studies, a favorable safet

be studies, a favorable safet

. The discontinuation rate and the discontinuation rate due to treatmentbe

. The discontinuation rate and the discontinuation rate due to treatment

used

Safety with

used

Safety with

studies, a favorable safetused

studies, a favorable safet

to Safety with to

Safety with BRVto BRVsu

pport

relevant evidence of the efficacy

supp

ort relevant evidence of the efficacy

doses of 20, 50, and 100mg/day

supp

ort

doses of 20, 50, and 100mg/dayevidence for the efficacy

supp

ort

evidence for the efficacy of su

pport

of evidence for the efficacy of evidence for the efficacy

supp

ort

evidence for the efficacy of evidence for the efficacy BRVsu

pport

BRV

any doses of 5, 20, and 50

any doses of 5, 20, and 50

relevant evidence of the efficacyany

relevant evidence of the efficacy

marketi

ng dose studies (N01252

marketi

ng dose studies (N01252

, UCB protocol reference code RPCE06G0705) were conducted to

marketi

ng

, UCB protocol reference code RPCE06G0705) were conducted to across a dose range of 5 to 100

marketi

ng

across a dose range of 5 to 100

doses of 5, 20, and 50marketi

ng

doses of 5, 20, and 50

autho

rizati

on

II studies (N01114

autho

rizati

on

II studies (N01114, UCB protocol reference code

autho

rizati

on

, UCB protocol reference code , UCB protocol reference code RPCE05C2201

autho

rizati

on

, UCB protocol reference code RPCE05C2201for the adjunctive treatment of POS. Two adequate

autho

rizati

on

for the adjunctive treatment of POS. Two adequate dose studies (N01252au

thoriz

ation

dose studies (N01252

appli

catio

n , nearl

appli

catio

n , nearlmg/day

appli

catio

n mg/day.

appli

catio

n .

II/III studies in POSappli

catio

n

II/III studies in POS

and

lamotrigine, LEV, oxcarbamazepine metabolite, p

and

lamotrigine, LEV, oxcarbamazepine metabolite, pine epoxide was significantly

and ine epoxide was significantly

, nearland

, nearl

any related trend was observed for the plasma concentrations of

any related trend was observed for the plasma concentrations of

lamotrigine, LEV, oxcarbamazepine metabolite, p any

lamotrigine, LEV, oxcarbamazepine metabolite, phenobarbital, any

henobarbital,

exten

sions

y rifampicin, a potent

exten

sions

y rifampicin, a potent

udies. No significant ex

tensio

ns

udies. No significant related trend was observed for the plasma concentrations of ex

tensio

ns

related trend was observed for the plasma concentrations of

or but is increased in a nonclinically relevant manner in Japanese subjects possessing

or but is increased in a nonclinically relevant manner in Japanese subjects possessing

y rifampicin, a potent or

y rifampicin, a potent va

riatio

ns

but is increased in a nonclinically relevant manner in Japanese subjects possessing varia

tions

but is increased in a nonclinically relevant manner in Japanese subjects possessing

thereo

f.


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 permittedanymore; however, subjects already on monotherapy are allowed to continue BRVmonotherapy.

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

REDACTED individualized doses up to a maximum of

REDACTED individualized doses up to a maximum of more regular exposure over the

REDACTED more regular exposure over the

was chosen following consultation with regulatory

REDACTED

was chosen following consultation with regulatoryauthorities and is evaluated in more recent BRV studies (eg, N01358 and N01379). REDACTED

authorities and is evaluated in more recent BRV studies (eg, N01358 and N01379).

COPY

individualized doses up to a maximum of COPY

individualized doses up to a maximum of

This do

cumen

t or adults

docu

ment or adults

or legal representative will sign the informed consent form.

docu

ment or legal representative will sign the informed consent form.

assent form, where required, will b

docu

ment

assent form, where required, will b

cann

ot Depending on

cann

ot Depending on or adultsca

nnot

or adults

be (CPMP/EWP/566/98 rev

be (CPMP/EWP/566/98 revus

ed y accepted.

used

y accepted. from the ones of older subjects, and efficacyus

ed

from the ones of older subjects, and efficacy(CPMP/EWP/566/98 revus

ed

(CPMP/EWP/566/98 rev

to Subjects are allowed to participate in this

to Subjects are allowed to participate in this

y accepted. to y accepted. su

pport

Subjects are allowed to participate in this supp

ort

Subjects are allowed to participate in this

any m

arketi

ng was chosen following consultation with regulatory

marketi

ng was chosen following consultation with regulatory

authorities and is evaluated in more recent BRV studies (eg, N01358 and N01379).

marketi

ng

authorities and is evaluated in more recent BRV studies (eg, N01358 and N01379). mg/day

marketi

ng

mg/day doses have been well tolerated.

marketi

ng

doses have been well tolerated.mg/day doses have been well tolerated.mg/day

marketi

ng

mg/day doses have been well tolerated.mg/day

autho

rizati

on

individualized doses up to a maximum of

autho

rizati

on

individualized doses up to a maximum of 200

autho

rizati

on

200more regular exposure over the

autho

rizati

on

more regular exposure over the

was chosen following consultation with regulatoryautho

rizati

on

was chosen following consultation with regulatory

appli

catio

n will explore the long

appli

catio

n will explore the longand

while a minority will present with generalized epileps

and

while a minority will present with generalized epilepsy (subjects coming

and y (subjects coming

The N01252, N01253 and N01254 studies aimed to test the efficacyan

d The N01252, N01253 and N01254 studies aimed to test the efficacywill explore the longan

d will explore the long

any UCB protocol reference code

any UCB protocol reference code

y (subjects coming any

y (subjects coming

exten

sions

suffer from partial onset seizureex

tensio

ns

suffer from partial onset seizureUCB protocol reference code ex

tensio

ns

UCB protocol reference code

or va

riatio

ns

adjunctive va

riatio

ns

adjunctive

thereo

f.


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.

StatementThe 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.

REDACTED

tolerability

REDACTED

tolerabilitymg/day in subjects suffering from epilepsy

REDACTED

mg/day in subjects suffering from epilepsy

COPY

This do

cumen

t can

not To obtain a description of

cann

ot To obtain a description of

explore any

cann

ot explore anybe

explore

be explore

be

To obtain a description of be

To obtain a description of us

ed and depression

used

and depression for the first 2

used

for the first 2explore us

ed

explore medical reused

medical re

to the effects of BRV to the effects of BRV for the first 2to

for the first 2

supp

ort

Exploratory Objectives

supp

ort

Exploratory Objectives

the effects of BRV supp

ort

the effects of BRV

any evaluate the maintenance of efficacy

any evaluate the maintenance of efficacymark

eting


marketi

ng mg/day in subjects suffering from epilepsy

evaluate the maintenance of efficacymark

eting

evaluate the maintenance of efficacy

autho

rizati

on

tolerabilityau

thoriz

ation

tolerability of au

thoriz

ation

of tolerability of tolerabilityau

thoriz

ation

tolerability of tolerabilitymg/day in subjects suffering from epilepsyau

thoriz

ation


appli

catio

n The principles that have their origin in the Declaration of Helsink

appli

catio

n The principles that have their origin in the Declaration of Helsinki.

appli

catio

n i.and

Clinical Practice [CPMP/ICH/135/95] and Code of Federal Regulations on Good Clinical

and


i.an

d i.

any H E6 Note for Guidance on Good

any H E6 Note for Guidance on Good

Clinical Practice [CPMP/ICH/135/95] and Code of Federal Regulations on Good Clinical any


exten

sions

H E6 Note for Guidance on Good exten

sions

H E6 Note for Guidance on Good

or va

riatio

ns th

ereof.


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 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:


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.

REDACTED 3 months; 1 FEV alternating with 1 MEV

REDACTED 3 months; 1 FEV alternating with 1 MEVy Evaluation Visit (YEV) will

REDACTED y Evaluation Visit (YEV) will

For those subjects coming from therapeutic REDACTED

For those subjects coming from therapeutic

COPY During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7

COPY During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7

This do

cumen

t can

not b

e use

d The Yearl

used

The Yearleach

used

each ye

used

ye

to 1 visit/3months:

to 1 visit/3months: The Yearlto The Yearly Evaluation Visit will be performed in replacement of the first FEV of to y Evaluation Visit will be performed in replacement of the first FEV of

supp

ort Next 9 months:

supp

ort Next 9 months: 1 visit/3 months:

supp

ort 1 visit/3 months:

Second and subsequent

supp

ort

Second and subsequent years:

supp

ort

years:

supp

ort

1 visit/3months: supp

ort

1 visit/3months:

any 1 visit/month:any 1 visit/month:

1 visit/3 months:any

1 visit/3 months:

marketi

ng

For those subjects coming from therapeutic

marketi

ng

For those subjects coming from therapeutic confirmatory

marketi

ng

confirmatory

autho

rizati

on

3 months; 1 FEV alternating with 1 MEV

autho

rizati

on

3 months; 1 FEV alternating with 1 MEVy Evaluation Visit (YEV) will

autho

rizati

on

y Evaluation Visit (YEV) will

appli

catio

n During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit

appli

catio

n During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit aluation Visit (MEV)

appli

catio

n aluation Visit (MEV)

During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7

appli

catio

n

During the next 6 months there will be 1 visit every 3 months; 2 FEV (at V7

and

During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit and

During the first 6 months there will be 1 visit/month; 1 Full Evaluation Visit

any (N01193)

any (N01193), visits

any , visitsex

tensio

ns

visits is adapted for the

exten

sions

visits is adapted for the

, visitsexten

sions

, visits

or va

riatio

ns th

ereof.


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 BRVdevelopment 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.

REDACTED will continue until a marketing authorization is granted b

REDACTED will continue until a marketing authorization is granted bdjunctive treatment in adults with refractory

REDACTED djunctive treatment in adults with refractory

generalized, until the Sponsor decides to close the study

REDACTED

generalized, until the Sponsor decides to close the studyuntil a managed access program, named patient program,

REDACTED

until a managed access program, named patient program, e program, or similar tyREDACTED

e program, or similar ty

COPY will run throughout the duration of the clinical development period of COPY will run throughout the duration of the clinical development period of

will continue until a marketing authorization is granted bCOPY

will continue until a marketing authorization is granted b

This do

cumen

t 9.1 Subject Inclusion Criteria

docu

ment 9.1 Subject Inclusion Criteriaca

nnot Committee/I

cann

ot Committee/Iwill be properl

cann

ot will be properl

be y stud

be y stud

Committee/Ibe

Committee/Institutional Review Board (IEC/Ibe

nstitutional Review Board (IEC/I

used


used


y studuse

d

y study procedures are initiated for anused

y procedures are initiated for an

to SELECTION AND WITHDRto SELECTION AND WITHDRsu

pport

y is defined as th

supp

ort

y is defined as th

any m

arketi

ng until a managed access program, named patient program,

marketi

ng until a managed access program, named patient program,

e program, or similar ty

marketi

ng

e program, or similar type of access program is established as allowed per

marketi

ng

pe of access program is established as allowed per e program, or similar type of access program is established as allowed per e program, or similar ty

marketi

ng

e program, or similar type of access program is established as allowed per e program, or similar tyspecific requirement in addition to legal and regulatory

marketi

ng

specific requirement in addition to legal and regulatorydevelopment is stopped by the Sponsor.

marketi

ng

development is stopped by the Sponsor.

autho

rizati

on will run throughout the duration of the clinical development period of

autho

rizati

on will run throughout the duration of the clinical development period of

will continue until a marketing authorization is granted b

autho

rizati

on

will continue until a marketing authorization is granted bdjunctive treatment in adults with refractory

autho

rizati

on

djunctive treatment in adults with refractorygeneralized, until the Sponsor decides to close the study

autho

rizati

on

generalized, until the Sponsor decides to close the studyuntil a managed access program, named patient program, au

thoriz

ation

until a managed access program, named patient program,

appli

catio

n reports and at the level of the database.

appli

catio

n reports and at the level of the database.

will run throughout the duration of the clinical development period of appli

catio

n

will run throughout the duration of the clinical development period of

and

his/her initials and a subject identifier which include the

and

his/her initials and a subject identifier which include the The Master CRF number an

d The Master CRF number reports and at the level of the database.an

d reports and at the level of the database.

any

his/her initials and a subject identifier which include the any

his/her initials and a subject identifier which include the

exten

sions

or va

riatio

ns

as adjunctive va

riatio

ns

as adjunctive

thereo

f.


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

REDACTED the proper use of contraceptive methods, and

REDACTED the proper use of contraceptive methods, andAccording to the judgment of the Investigator, sexual

REDACTED According to the judgment of the Investigator, sexual might be accepted on a case by

REDACTED might be accepted on a case by case basis.

REDACTED case basis. might be accepted on a case by case basis. might be accepted on a case by

REDACTED might be accepted on a case by case basis. might be accepted on a case by

y acceptable representative considered as reliable and capa

REDACTED

y acceptable representative considered as reliable and capathe protocol (e.g. able to understand and complete diaries and questionnaires), visit

REDACTED

the protocol (e.g. able to understand and complete diaries and questionnaires), visit schedule or medication intake according to the judgment of the REDACTED


COPY The subject must understand the consequences and

COPY The subject must understand the consequences and protected sexual activity

COPY protected sexual activity

undertake to inform the Investigator of anCOPY undertake to inform the Investigator of an

This do

cumen

t subject should not be included into

docu

ment subject should not be included into

of doubts concerning the

docu

ment

of doubts concerning the (SP)

docu

ment

(SP)

cann

ot Pregnant or lactating woman.

cann

ot Pregnant or lactating woman.

If the cann

ot If the Investigatorca

nnot

Investigatorsubject should not be included into ca

nnot

subject should not be included into

be

Pregnant or lactating woman.be

Pregnant or lactating woman.us

ed Poor compliance with

used

Poor compliance with Participatio

used

Participation in any

used

n in any

to Poor compliance with to Poor compliance with su

pport

Subjects must be excluded if they

supp

ort Subjects must be excluded if they

Severe medical, neurological and ps

supp

ort

Severe medical, neurological and pst on the safetysu

pport

t on the safetyPoor compliance with

supp

ort

Poor compliance with

any

Subjects must be excluded if theyany

Subjects must be excluded if they

marketi


marketi



marketi

ng


Subject Exclusion Criteriamarketi

ng

Subject Exclusion Criteria

autho

rizati

on protected sexual activity

autho

rizati

on protected sexual activity

undertake to inform the Investigator of an

autho

rizati

on

undertake to inform the Investigator of anAccording to the judgment of the Investigator, sexual

autho

rizati

on

According to the judgment of the Investigator, sexual case basis.

autho

rizati

on

case basis.y acceptable representative considered as reliable and capa

autho

rizati

on

y acceptable representative considered as reliable and capathe protocol (e.g. able to understand and complete diaries and questionnaires), visit au

thoriz

ation

the protocol (e.g. able to understand and complete diaries and questionnaires), visit

appli

catio

n ligation, bilateral tubal implant, monogamous relationship with vasectomized

appli

catio

n ligation, bilateral tubal implant, monogamous relationship with vasectomized Oral or depot contraceptive treatment with at least 30 µg [or 50 µg if associated with

appli

catio

n Oral or depot contraceptive treatment with at least 30 µg [or 50 µg if associated with tradiol per intake must be used in

appli

catio

n tradiol per intake must be used in

The subject must understand the consequences and

appli

catio

n

The subject must understand the consequences and protected sexual activityap

plica

tion

protected sexual activity, be educated about and understand appli

catio

n

, be educated about and understand undertake to inform the Investigator of an

appli

catio

n

undertake to inform the Investigator of an

and edication, bilateral tubal

and edication, bilateral tubal

ligation, bilateral tubal implant, monogamous relationship with vasectomized and ligation, bilateral tubal implant, monogamous relationship with vasectomized

Oral or depot contraceptive treatment with at least 30 µg [or 50 µg if associated with an

d Oral or depot contraceptive treatment with at least 30 µg [or 50 µg if associated with



edication, bilateral tubal any

edication, bilateral tubal

exten

sions

ars postmenopausal

exten

sions

ars postmenopausal sterectom

exten

sions

sterectom

tential are eligible

exten

sions

tential are eligible accepted contraceptive method for the duration of the ex

tensio

ns

accepted contraceptive method for the duration of the studyexten

sions

studyUterine Device, diaphragm with spermicide, male or female condom with spermicide;

exten

sions

Uterine Device, diaphragm with spermicide, male or female condom with spermicide;

or ars postmenopausal or ars postmenopausal

varia

tions

there

of.


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.

REDACTED Investigator

REDACTED Investigatorype of seizure, liver enzy

REDACTED ype of seizure, liver enzy

Subject and/or Investigator does not think that the investigational drug is effective (i.e., REDACTED

Subject and/or Investigator does not think that the investigational drug is effective (i.e.,

COPY Stopping rules and discontinuation criteria for individual subjects mayCOPY Stopping rules and discontinuation criteria for individual subjects may

InvestigatorCOPY

Investigator

This do

cumen

t Sub

docu

ment Subca

nnot

from the study

cann

ot from the study

cann

ot Subject had active suicidal ideation prior to study

cann

ot Subject had active suicidal ideation prior to studya positive response (‘Yes’) to either Question 4 or Question 5 of the “Alreadyca

nnot

a positive response (‘Yes’) to either Question 4 or Question 5 of the “AlreadySubca

nnot

Sub

be Enrolled Subjec

be Enrolled Subjec

from the studybe

from the studyus

ed Subject has a lifetime his

used

Subject has a lifetime his(including an active attempt, interrupted attempt, or aborted attempt) of the “Alread

used

(including an active attempt, interrupted attempt, or aborted attempt) of the “AlreadEnrolled Subjecus

ed

Enrolled Subjec

to Subject has a lifetime histo Subject has a lifetime his(including an active attempt, interrupted attempt, or aborted attempt) of the “Alread

to (including an active attempt, interrupted attempt, or aborted attempt) of the “Alread

supp

ort

Withdrawal criteria for already enrolled subjects who did not complete a C

supp

ort

Withdrawal criteria for already enrolled subjects who did not complete a C

supp

ort

Subject has a lifetime hissupp

ort

Subject has a lifetime his

any Other reason that has to be specified in the CRF.

any Other reason that has to be specified in the CRF.mark

eting


marketi

ng Subject and/or Investigator does not think that the investigational drug is effective (i.e.,

consent for personal reasons; not related to AE or lack/loss of efficacymarketi

ng

consent for personal reasons; not related to AE or lack/loss of efficacyOther reason that has to be specified in the CRF.

marketi

ng

Other reason that has to be specified in the CRF.

autho

rizati

on Stopping rules and discontinuation criteria for individual subjects may

autho

rizati

on Stopping rules and discontinuation criteria for individual subjects may

Investigator

autho

rizati

on

Investigator: occurrence of status epilepticus,

autho

rizati

on

: occurrence of status epilepticus, ype of seizure, liver enzy

autho

rizati

on

ype of seizure, liver enzy

Subject and/or Investigator does not think that the investigational drug is effective (i.e., autho

rizati

on


appli

catio

n time, without prejudice to their continued

appli

catio

n time, without prejudice to their continued

Stopping rules and discontinuation criteria for individual subjects mayappli

catio

n

Stopping rules and discontinuation criteria for individual subjects may

and a

ny y, the Final Visit will occur.

any y, the Final Visit will occur.ex

tensio

ns -titration period,

exten

sions

-titration period, A last

exten

sions

A last

drug free

exten

sions

drug free drugex

tensio

ns

drug of a ex

tensio

ns

of a y, the Final Visit will occur.ex

tensio

ns

y, the Final Visit will occur.

or -titration period, or -titration period, va

riatio

ns th

ereof.


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 willbe 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-

REDACTED y of that site and to the expiry

REDACTED y of that site and to the expiryCOPY or 25

COPY or 25Supply

COPY Supply Department for all subjects.

COPY Department for all subjects.

hich investigational product will be supplied to each individual site will be COPY hich investigational product will be supplied to each individual site will be

y of that site and to the expiryCOPY

y of that site and to the expiry

This do

cumen

t down

docu

ment downca

nnot titration can be made by

cann

ot titration can be made by

cann

ot this to a maximum of 200

cann

ot this to a maximum of 200Dose decreases can be made bca

nnot

Dose decreases can be made b

be each subject visit, if necessary

be each subject visit, if necessary

titration can be made bybe

titration can be made by

used

30 mg, 40 mg, etc. with the implementation of the IVRS

used

30 mg, 40 mg, etc. with the implementation of the IVRS

each subject visit, if necessaryused

each subject visit, if necessary

to It is

to It is recommended that the dosing be done in even increments such

to recommended that the dosing be done in even increments such

30 mg, 40 mg, etc. with the implementation of the IVRSto 30 mg, 40 mg, etc. with the implementation of the IVRSsu

pport

of the di

supp

ort of the di

The individual starting dose of each subject will be the one defined/reached at the end of the su

pport

The individual starting dose of each subject will be the one defined/reached at the end of the

recommended that the dosing be done in even increments such supp

ort

recommended that the dosing be done in even increments such

any dose be divided equall

any dose be divided equall

of the diany

of the di

marketi

ng

studies have the opportunity

marketi

ng

studies have the opportunityflexible dose of up to a maximum of

marketi

ng

flexible dose of up to a maximum of 200mark

eting

200 dose be divided equallm

arketi

ng

dose be divided equally,marketi

ng

y,

autho

rizati

on hich investigational product will be supplied to each individual site will be

autho

rizati

on hich investigational product will be supplied to each individual site will be


autho

rizati

on


appli

catio

n

mg

appli

catio

n

mg BRV

appli

catio

n

BRVDepartment for all subjects.ap

plica

tion

Department for all subjects.hich investigational product will be supplied to each individual site will be ap

plica

tion

hich investigational product will be supplied to each individual site will be

and a

ny ex

tensio

ns

RODUCT AND

exten

sions

RODUCT AND

or va

riatio

ns th

ereof.


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, theInvestigator 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

REDACTED will be packaged in bottles

REDACTED will be packaged in bottles y removed.

REDACTED y removed.

Investigator will be supplied with a sufficient number of containers.

REDACTED Investigator will be supplied with a sufficient number of containers.

-printed identification number.

REDACTED

-printed identification number.

orm each subject on how to take the drug and that an excess of drug REDACTED

orm each subject on how to take the drug and that an excess of drug

COPY

will be packaged in bottles COPY

will be packaged in bottles

This do

cumen

t product package.

docu

ment product package.

docu

ment

manually

docu

ment

manually

cann

ot The label will consist of

cann

ot The label will consist of Case Report Form at the time of visit and the second remains fixed to the investigational

cann

ot Case Report Form at the time of visit and the second remains fixed to the investigational product package. ca

nnot

product package.

be requirements

be requirementsus

ed and the size of the investigational product package

used

and the size of the investigational product package requirementsus

ed

requirements

to su

pport

Clinical drug supplies will be labeled in accordance with the current ICH guidelines on GCP

supp

ort

Clinical drug supplies will be labeled in accordance with the current ICH guidelines on GCP Good Manufacturing Practice su

pport

Good Manufacturing Practice

any m

arketi

ng


marketi

ng


marketi

ng

is present in the investigational product container.

marketi

ng

is present in the investigational product container.

autho

rizati

on

will be packaged in bottles

autho

rizati

on

will be packaged in bottles y removed.

autho

rizati

on

y removed.Investigator will be supplied with a sufficient number of containers.

autho

rizati

on

Investigator will be supplied with a sufficient number of containers.

appli

catio

n ype of access program as allowed per country-

appli

catio

n ype of access program as allowed per country-specific legal and

appli

catio

n specific legal and and

be initiated

and

be initiated m, named patient program, compassionate use

and m, named patient program, compassionate use

specific legal and and

specific legal and

any -titration to commercial BRV, when and where available.

any -titration to commercial BRV, when and where available.

be initiated any

be initiated

exten

sions

subjects will

exten

sions

subjects will will be ex

tensio

ns

will be -titration to commercial BRV, when and where available. ex

tensio

ns

-titration to commercial BRV, when and where available.

or the Final

or the Final va

riatio

ns

a period free va

riatio

ns

a period free the Final va

riatio

ns

the Final

thereo

f.


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 studymedication.

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.

REDACTED At each visit after drug is dispensed, subjects must return all unused medication and

REDACTED At each visit after drug is dispensed, subjects must return all unused medication and (even if empty

REDACTED (even if empty

presence in order to obtain explanations regarding discrepancies in compliance

REDACTED


COPY

At each visit after drug is dispensed, subjects must return all unused medication and COPY

At each visit after drug is dispensed, subjects must return all unused medication and

This do

cumen

t documentation must

docu

ment documentation must

docu

ment review.

docu

ment review.ca

nnot released for subject use.

cann

ot released for subject use.

cann

ot disposed of at the study

cann

ot disposed of at the studydocumentation mustca

nnot

documentation must

be y recording all study drug r

be y recording all study drug r

released for subject use.be

released for subject use.

used

The Sponsor or its representatives will supplyus

ed

The Sponsor or its representatives will supplyy recording all study drug rus

ed

y recording all study drug r

to Investigational Products Accountability

to Investigational Products Accountabilitysu

pport

medication is defined as invest

supp

ort medication is defined as invest

120% of the prescribed dosage.

supp

ort

120% of the prescribed dosage.

Investigational Products Accountabilitysupp

ort

Investigational Products Accountability

any

medication is defined as investany

medication is defined as invest

marketi

ng

as well as explanations of non

marketi

ng

as well as explanations of non

autho

rizati

on

At each visit after drug is dispensed, subjects must return all unused medication and

autho

rizati

on

At each visit after drug is dispensed, subjects must return all unused medication and (even if empty

autho

rizati

on

(even if emptypresence in order to obtain explanations regarding discrepancies in compliance

autho

rizati

on


appli

catio

n specified on the investigational product package label, in a secure place out of t

appli

catio

n specified on the investigational product package label, in a secure place out of tand

The Investigator will instruct

and

The Investigator will instruct acceptable representative to store the medication at the storage temperature

and acceptable representative to store the medication at the storage temperature

specified on the investigational product package label, in a secure place out of tand

specified on the investigational product package label, in a secure place out of t

any The Investigator or the hospital pharmacist is responsible for the appropriate storage and

any The Investigator or the hospital pharmacist is responsible for the appropriate storage and

The Investigator will instruct any

The Investigator will instruct

exten

sions

study

exten

sions

study.

exten

sions

. standard storage statement will appear on each investigational product package label of

exten

sions

standard storage statement will appear on each investigational product package label of study

exten

sions

study

The Investigator or the hospital pharmacist is responsible for the appropriate storage and exten

sions

The Investigator or the hospital pharmacist is responsible for the appropriate storage and

or will be stored

or will be stored

A or A va

riatio

ns

will be stored varia

tions

will be stored

thereo

f.


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).

REDACTED

Prohibited Concomitant Treatments (Medications and Therapies)

REDACTED


COPY adapt the AED drug/dosage for safet

COPY adapt the AED drug/dosage for safety or efficacy reasons.

COPY y or efficacy reasons.

y indication) will be considered as a concomitant COPY y indication) will be considered as a concomitant

This do

cumen

t and benefits of participation in the study

docu

ment and benefits of participation in the study

Where legall

docu

ment

Where legall

cann

ot to them by

cann

ot to them by the

cann

ot the to them by the to them by

cann

ot to them by the to them bywill be given the opportunity

cann

ot will be given the opportunityand benefits of participation in the studyca

nnot

and benefits of participation in the study

be Subjects will be given adequate time to consider anybe Subjects will be given adequate time to consider any

the be

the

used

study

used

study

used

activities, subjects will be asked to read and sign an informed consent form

used

activities, subjects will be asked to read and sign an informed consent form that has been approved by an us

ed

that has been approved by an Subjects will be given adequate time to consider anyus

ed

Subjects will be given adequate time to consider any

to activities, subjects will be asked to read and sign an informed consent form to activities, subjects will be asked to read and sign an informed consent form

supp

ort Description of Procedures

supp

ort Description of Procedures

Informed Consentsu

pport

Informed Consent

any

Description of Proceduresany

Description of Procedures

marketi

ng

STUDY PROCEDURESmarketi

ng

STUDY PROCEDURES

autho

rizati

on y indication) will be considered as a concomitant

autho

rizati

on y indication) will be considered as a concomitant


autho

rizati

on


appli

catio

n 10.2.1 Permitted Concomitant Treatments (Medications and Therapies)

appli

catio

n 10.2.1 Permitted Concomitant Treatments (Medications and Therapies)

y or efficacy reasons.appli

catio

n

y or efficacy reasons.y indication) will be considered as a concomitant

appli

catio

n

y indication) will be considered as a concomitant

and

This record should include the

and

This record should include the the date(s) of administration.an

d the date(s) of administration.an

y accurate record must be kept in the clinic chart (source

any accurate record must be kept in the clinic chart (source

This record should include the any

This record should include the brand any

brand

exten

sions

accurate record must be kept in the clinic chart (source exten

sions

accurate record must be kept in the clinic chart (source

or other purpose

or other purpose va

riatio

ns

) to the Sponsor or designee according to a procedure to be defined at va

riatio

ns

) to the Sponsor or designee according to a procedure to be defined at other purpose va

riatio

ns

other purpose

thereo

f.


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.

REDACTED tudy

REDACTED tudy Fl

REDACTED Fl

General Medical and Procedure History

REDACTED


Medical and Procedure HistoryREDACTED

Medical and Procedure History

COPY At the first visit, information on childbearing potential and contraceptive method used by

COPY At the first visit, information on childbearing potential and contraceptive method used byDuring the course of

COPY During the course of the

COPY the

e that birth control remains optimal should COPY e that birth control remains optimal should the COPY

the owchart (seeCOPY

owchart (see

This do

cumen

t will be recorded on the concomitant AED medication page of the CRF.

docu

ment will be recorded on the concomitant AED medication page of the CRF.

11.1.8 Vital Signs

docu

ment

11.1.8 Vital Signs

cann

ot The AED medication history

cann

ot The AED medication history

cann

ot which the subject was participating.

cann

ot which the subject was participating. will be recorded on the concomitant AED medication page of the CRF.ca

nnot

will be recorded on the concomitant AED medication page of the CRF.

be

The AED medication historybe

The AED medication history

used

Antiepileptic Mus

ed

Antiepileptic M

to electronicall

to electronically transferred from this study

to y transferred from this studysu

pport

reported

supp

ort

reported will be considered as the history

supp

ort

will be considered as the historyy transferred from this studysu

pport

y transferred from this study

any m

arketi

ng


marketi

ng


marketi

ng will be transferred from the database of the

marketi

ng will be transferred from the database of the Medical and Procedure History will be transferred from the database of the Medical and Procedure History

marketi

ng

Medical and Procedure History will be transferred from the database of the Medical and Procedure Historyin which the subject was participating.

marketi

ng

in which the subject was participating.

autho

rizati

on the

autho

rizati

on the subject’s status change.

autho

rizati

on subject’s status change.

owchart (see

autho

rizati

on

owchart (see


autho

rizati

on


appli

catio

n

At the first visit, information on childbearing potential and contraceptive method used by

appli

catio

n

At the first visit, information on childbearing potential and contraceptive method used bythe ap

plica

tion

the studyappli

catio

n

studysubject’s status change. ap

plica

tion

subject’s status change.

and

oup will be recorded.

and

oup will be recorded. any e

xtens

ions will instruct the subject

exten

sions

will instruct the subject or This card

or This card

will instruct the subject or will instruct the subject va

riatio

ns

This card varia

tions

This card

thereo

f.


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.

REDACTED

A standard neurological examination will be performed at the following visits:

REDACTED

A standard neurological examination will be performed at the following visits:y Evaluation VisitREDACTED

y Evaluation Visit

COPY At the Entry Visit, the phy

COPY At the Entry Visit, the phyy from the last Evaluation Visit of the previous study and should not be

COPY y from the last Evaluation Visit of the previous study and should not be

This do

cumen

t normal, no additional ECG has to be performed a

docu

ment normal, no additional ECG has to be performed a

obtained electronicall

docu

ment obtained electronicall

recorded in the CRF.

docu

ment

recorded in the CRF.

cann

ot ECGs will be reduced to once per

cann

ot ECGs will be reduced to once per Discontinuation Visit

cann

ot Discontinuation Visit

cann

ot

normal, no additional ECG has to be performed acann

ot

normal, no additional ECG has to be performed a

be Once the subject has signed the updated Informed Consent, the n

be Once the subject has signed the updated Informed Consent, the n

ECGs will be reduced to once per be

ECGs will be reduced to once per

used

Once the subject has signed the updated Informed Consent, the nused

Once the subject has signed the updated Informed Consent, the n

to su

pport

al sy

supp

ort al sy

be obtained electronically

supp

ort

be obtained electronically from the last Evaluation Visit of the previous study

supp

ort

from the last Evaluation Visit of the previous studybe obtained electronically from the last Evaluation Visit of the previous studybe obtained electronically

supp

ort

be obtained electronically from the last Evaluation Visit of the previous studybe obtained electronicallybe recorded in the CRF.

supp

ort

be recorded in the CRF.

any y recording the presence or absence of ps

any y recording the presence or absence of ps

any

al sy any

al symptomsany

mptomsal symptomsal sy any

al symptomsal sy

marketi

ng A standard neurological examination will be performed at the following visits:

marketi

ng A standard neurological examination will be performed at the following visits:

y Evaluation Visit

marketi

ng

y Evaluation Visitof a brief

marketi

ng

of a briefmotor function, reflex function, sensory

marketi

ng

motor function, reflex function, sensory function, gait and stance. mark

eting

function, gait and stance. motor function, reflex function, sensory function, gait and stance. motor function, reflex function, sensorymark

eting

motor function, reflex function, sensory function, gait and stance. motor function, reflex function, sensoryy recording the presence or absence of psmark

eting

y recording the presence or absence of ps

autho

rizati

on

A standard neurological examination will be performed at the following visits:autho

rizati

on

A standard neurological examination will be performed at the following visits:

appli

catio

n es, ear, nose, throat,

appli

catio

n es, ear, nose, throat, stem, musculoskeletal sy

appli

catio

n stem, musculoskeletal sy

At the Entry Visit, the phy

appli

catio

n

At the Entry Visit, the physical examination will be

appli

catio

n

sical examination will be y from the last Evaluation Visit of the previous study and should not be ap

plica

tion

y from the last Evaluation Visit of the previous study and should not be

and

following visits:

and

following visits:y Evaluation Visit, Early Discontinuation Visit and at the Final

and y Evaluation Visit, Early Discontinuation Visit and at the Final

es, ear, nose, throat, and

es, ear, nose, throat,

any

following visits:any

following visits: everyany

every

exten

sions

will also

exten

sions

will also or Height will

or Height will

will also or will also va

riatio

ns

Height will varia

tions

Height will

thereo

f.


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.

REDACTED the CRF; he/she will also confirm the presence of adverse events (if applicable). The

REDACTED 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

REDACTED concomitant medication changes and adverse events will be reported by

The DRC will be considered part of the CRF as well as source documentation. The subject REDACTED

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 REDACTED

should be educated to complete the DRC on a regular basis (each time that a seizure, an

COPY . As a result of the discussion, the Investigator will asses

COPY . As a result of the discussion, the Investigator will assesepileptic seizures according to the ILAE codes and record the seizure t

COPY epileptic seizures according to the ILAE codes and record the seizure tthe CRF; he/she will also confirm the presence of adverse events (if applicable). The COPY

the CRF; he/she will also confirm the presence of adverse events (if applicable). The

This do

cumen

t Results for hematology

docu

ment

Results for hematologythe

docu

ment

the

cann

ot laboratory

cann

ot laboratory will provide the

cann

ot will provide the laboratory will provide the laboratory

cann

ot laboratory will provide the laboratory(labels, needles, tubes), and a

cann

ot (labels, needles, tubes), and a use the equipment and how to ship the samples back to the central laboratory

cann

ot use the equipment and how to ship the samples back to the central laboratory

be Evaluation Visit of the previous study

be Evaluation Visit of the previous study

will provide the be

will provide the us

ed Visit, and Final Visit,

used

Visit, and Final Visit, central laboratory

used

central laboratory

used

.

used

. At the Entry

used

At the EntryEvaluation Visit of the previous studyus

ed

Evaluation Visit of the previous study

to Visit, and Final Visit, to Visit, and Final Visit, laboratoryto laboratoryAt the Entryto

At the Entry

supp

ort Laboratory Assessments

supp

ort Laboratory Assessments

At the following visits supp

ort

At the following visits,supp

ort

, Full Evaluation Visit, Yearlysupp

ort

Full Evaluation Visit, Yearlylaboratorysu

pport

laboratory

any

Laboratory Assessmentsany

Laboratory Assessments

marketi

ng The DRC will be considered part of the CRF as well as source documentation. The subject

marketi

ng 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

marketi

ng

should be educated to complete the DRC on a regular basis (each time that a seizure, an cation of medication or investigational product, or a medical visit

marketi

ng

cation of medication or investigational product, or a medical visit

autho

rizati

on epileptic seizures according to the ILAE codes and record the seizure t

autho

rizati

on epileptic seizures according to the ILAE codes and record the seizure t

the CRF; he/she will also confirm the presence of adverse events (if applicable). The

autho

rizati

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

autho

rizati

on

concomitant medication changes and adverse events will be reported by

The DRC will be considered part of the CRF as well as source documentation. The subject autho

rizati

on

The DRC will be considered part of the CRF as well as source documentation. The subject

appli

catio

n The written information will be discussed with the subject at each visit in order to ensure

appli

catio

n The written information will be discussed with the subject at each visit in order to ensure

. As a result of the discussion, the Investigator will asses

appli

catio

n

. As a result of the discussion, the Investigator will assesepileptic seizures according to the ILAE codes and record the seizure tap

plica

tion

epileptic seizures according to the ILAE codes and record the seizure t

and a

ny ex

tensio

ns

pe of seizure (according to individual description of epileptic seizures)

exten

sions

pe of seizure (according to individual description of epileptic seizures)

or va

riatio

ns th

ereof.


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).

REDACTED , pH, glucose, bilirubin, ketones, occult blood, protein,

REDACTED , pH, glucose, bilirubin, ketones, occult blood, protein, If the test for protein, blood or leukocy

REDACTED If the test for protein, blood or leukocy

positive, sediment and microscopic anal

REDACTED positive, sediment and microscopic analys

REDACTED yses

REDACTED es

REDACTED

stals, bihy

REDACTED

stals, bihystals, triple phosphate cryREDACTED

stals, triple phosphate crychildbearing potential), a REDACTED

childbearing potential), a

COPY umber, %), neutrophils (number, %), eosinophils (number, %),

COPY umber, %), neutrophils (number, %), eosinophils (number, %),

, pH, glucose, bilirubin, ketones, occult blood, protein, COPY

, pH, glucose, bilirubin, ketones, occult blood, protein,

This do

cumen

t In addition, the

docu

ment In addition, the

cards) used in the

docu

ment

cards) used in the

cann

ot each visit and recorded in the CRF and in the source documents.

cann

ot each visit and recorded in the CRF and in the source documents. be given the

cann

ot be given thedetect AEs, e.g., “Did

cann

ot detect AEs, e.g., “Did In addition, the ca

nnot

In addition, the

be previous

be previous

each visit and recorded in the CRF and in the source documents. be

each visit and recorded in the CRF and in the source documents. us

ed Visit, the

used

Visit, the

used

previous us

ed

previous

to su

pport

11.1.15 Adverse Events (AEs)supp

ort

11.1.15 Adverse Events (AEs)

any BRV

any BRV and concomitant AED plasma concentrations will no longer

any and concomitant AED plasma concentrations will no longer mark

eting

stals, triple phosphate cry

marketi

ng stals, triple phosphate cry


marketi

ng


and concomitant AED plasma concentrations will no longer mark

eting

and concomitant AED plasma concentrations will no longer

autho

rizati

on

, pH, glucose, bilirubin, ketones, occult blood, protein,

autho

rizati

on

, pH, glucose, bilirubin, ketones, occult blood, protein, If the test for protein, blood or leukocy

autho

rizati

on

If the test for protein, blood or leukocyes

autho

rizati

on

es (ery

autho

rizati

on

(ery

autho

rizati

on

stals, bihyau

thoriz

ation

stals, bihydrate calcium oxalate cryau

thoriz

ation

drate calcium oxalate crystals, triple phosphate cryau

thoriz

ation

stals, triple phosphate cry

appli

catio

n white blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit,

appli

catio

n white blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit,

mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean

appli

catio

n mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, lymphocytes (number,

appli

catio

n corpuscular hemoglobin concentration (MCHC), platelet count, lymphocytes (number,

umber, %), neutrophils (number, %), eosinophils (number, %),

appli

catio

n

umber, %), neutrophils (number, %), eosinophils (number, %),

and

white blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit, and

white blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean

and

mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean

any 72 x serum creatinine

any 72 x serum creatinine ex

tensio

ns (only

exten

sions

(only at the

exten

sions

at the (only at the (only

exten

sions

(only at the (only

weight] / (72 x serum creatinin

exten

sions

weight] / (72 x serum creatinin

72 x serum creatinine ex

tensio

ns

72 x serum creatinine

or at the or at the va

riatio

ns th

ereof.


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.

REDACTED COPY

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on ap

plica

tion a

nd an

y exte

nsion

s or page of the CRF but in

or page of the CRF but in va

riatio

ns

page of the CRF but in varia

tions

page of the CRF but in

thereo

f.


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 studymust 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

REDACTED

A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as

REDACTED

A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as The assessment of the Patient Reported Outcomes will be limited to the

REDACTED

The assessment of the Patient Reported Outcomes will be limited to the , which includes the YEV of YearREDACTED

, which includes the YEV of Year

COPY Changes, additions or deletions in the administration of antiepileptic concomitant medications

COPY Changes, additions or deletions in the administration of antiepileptic concomitant medications omitant Medications page of the CRF.

COPY omitant Medications page of the CRF.

This do

cumen

t The PRO booklets will be considered as part of the CRF as well as source documentation.

docu

ment The PRO booklets will be considered as part of the CRF as well as source documentation.

11.1.20

docu

ment

11.1.20

cann

ot the first 2

cann

ot the first 2

cann

ot ye

cann

ot ye

The PRO booklets will be considered as part of the CRF as well as source documentation.cann

ot

The PRO booklets will be considered as part of the CRF as well as source documentation.

be that are not mentally impaired will complete the PR

be that are not mentally impaired will complete the PR

yebe

yearsbe

ars

used

Subjects coming from N01193 will not have to complete the PRO booklet. us

ed

Subjects coming from N01193 will not have to complete the PRO booklet. that are not mentally impaired will complete the PRus

ed

that are not mentally impaired will complete the PR

to su

pport

subjects that are not mentally

supp

ort subjects that are not mentally impaired, at the very beginning of the stud

supp

ort impaired, at the very beginning of the studsubjects that are not mentally impaired, at the very beginning of the studsubjects that are not mentally

supp

ort subjects that are not mentally impaired, at the very beginning of the studsubjects that are not mentally

will be asked to complete the questionnaires on his/her own.

supp

ort

will be asked to complete the questionnaires on his/her own. will hand back the booklet to the I

supp

ort

will hand back the booklet to the I

any -5D self report questionnaire. The PRO booklet is to be provided to

any -5D self report questionnaire. The PRO booklet is to be provided to

impaired, at the very beginning of the studany

impaired, at the very beginning of the stud

marketi

ng The assessment of the Patient Reported Outcomes will be limited to the

marketi

ng The assessment of the Patient Reported Outcomes will be limited to the

, which includes the YEV of Year

marketi

ng

, which includes the YEV of Yearhe Patient Weighted Quality

marketi

ng

he Patient Weighted QualityVersion 2), the Hospital Anxiety

marketi

ng

Version 2), the Hospital Anxiety-5D self report questionnaire. The PRO booklet is to be provided to mark

eting

-5D self report questionnaire. The PRO booklet is to be provided to

autho

rizati

on

A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as

autho

rizati

on

A Patient Reported Outcomes (PRO) booklet per visit will be created for the FEV, YEV as The assessment of the Patient Reported Outcomes will be limited to the au

thoriz

ation

The assessment of the Patient Reported Outcomes will be limited to the

appli

catio

n will contact the monitor immediately

appli

catio

n will contact the monitor immediately.

appli

catio

n .

Changes, additions or deletions in the administration of antiepileptic concomitant medications

appli

catio

n

Changes, additions or deletions in the administration of antiepileptic concomitant medications omitant Medications page of the CRF.ap

plica

tion

omitant Medications page of the CRF.

and

Antiepileptic Concomitant Medications page of the

and

Antiepileptic Concomitant Medications page of the see Section

and see Section

any antiepileptic concomitant

any antiepileptic concomitant

Antiepileptic Concomitant Medications page of the any

Antiepileptic Concomitant Medications page of the

exten

sions

must be documented in the CRF (brand name, indication, dosage, and the dates of start and

exten

sions

must be documented in the CRF (brand name, indication, dosage, and the dates of start and

y being taken will be obtained. ex

tensio

ns

y being taken will be obtained. antiepileptic concomitant ex

tensio

ns

antiepileptic concomitant

or study

or study

must be documented in the CRF (brand name, indication, dosage, and the dates of start and or must be documented in the CRF (brand name, indication, dosage, and the dates of start and va

riatio

ns

study varia

tions

study

thereo

f.


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

REDACTED y Discontinuation Visit occurs within the first 2

REDACTED y Discontinuation Visit occurs within the first 2

is a selfREDACTED

is a self

COPY the authors with each score ranging from 0 to 21 and higher scores indicating higher

COPY the authors with each score ranging from 0 to 21 and higher scores indicating higher The subjects will complete the HADS at every

COPY The subjects will complete the HADS at every

years, and at the EarlCOPY years, and at the Earl

y Discontinuation Visit occurs within the first 2COPY

y Discontinuation Visit occurs within the first 2

This do

cumen

t Discontinuation Visit occurs within the first 2

docu

ment Discontinuation Visit occurs within the first 2

11.1.23

docu

ment

11.1.23

cann

ot The EQ

cann

ot The EQ-

cann

ot -5D questionn

cann

ot 5D questionn

cann

ot Evaluation Visit for the first 2

cann

ot Evaluation Visit for the first 2Discontinuation Visit occurs within the first 2ca

nnot

Discontinuation Visit occurs within the first 2

be

5D questionnbe

5D questionn

used

anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state)

used

anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) to 5D also captures a selfto 5D also captures a selfanchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state) to anchored at 100 (best imaginable health state) at the top and 0 (worst imaginable health state)

supp

ort some or moderate problems = 2

supp

ort some or moderate problems = 2

extreme problems = 3

supp

ort

extreme problems = 3.

supp

ort

.

5D also captures a selfsupp

ort

5D also captures a self

any

some or moderate problems = 2any

some or moderate problems = 2

marketi

ng

is a self

marketi

ng

is a self-

marketi

ng

-is a self-is a self

marketi

ng

is a self-is a self administered qu

marketi

ng administered qu

marketi

ng

5D defines health in terms of 5 dimensions (mobility

marketi

ng

5D defines health in terms of 5 dimensions (mobilityactivities, pain/discomfort and anxiety

marketi

ng

activities, pain/discomfort and anxiety/depression). mark

eting

/depression). activities, pain/discomfort and anxiety/depression). activities, pain/discomfort and anxietymark

eting

activities, pain/discomfort and anxiety/depression). activities, pain/discomfort and anxiety

autho

rizati

on years, and at the Earl

autho

rizati

on years, and at the Earl

y Discontinuation Visit occurs within the first 2

autho

rizati

on

y Discontinuation Visit occurs within the first 2 ye

autho

rizati

on

years.

autho

rizati

on

ars.

appli

catio

n point severit

appli

catio

n point severit, depression) will be calculated as recommended

appli

catio

n , depression) will be calculated as recommended

the authors with each score ranging from 0 to 21 and higher scores indicating higher

appli

catio

n

the authors with each score ranging from 0 to 21 and higher scores indicating higher The subjects will complete the HADS at everyap

plica

tion

The subjects will complete the HADS at everyyears, and at the Earla

pplic

ation

years, and at the Early Discontinuation Visit if the appli

catio

n

y Discontinuation Visit if the

and

The HADS was developed as a self

and

The HADS was developed as a self of both anxiety

and of both anxiety and depression

and and depression of both anxiety and depression of both anxiety

and of both anxiety and depression of both anxiety

point severitand

point severit

any will be used to

any will be used to

The HADS was developed as a self any

The HADS was developed as a self

exten

sions

will be used to exten

sions

will be used to

or va

riatio

ns th

ereof.


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. Itcollects 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 studydrug. 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

REDACTED collects information such as education level, housing status, emplo

REDACTED collects information such as education level, housing status, emploCOPY Evaluation

COPY Evaluation if the Early

COPY if the Early Discontinuation Visit occurs within the

COPY Discontinuation Visit occurs within the

from N01252, N01253 and N01254COPY from N01252, N01253 and N01254

collects information such as education level, housing status, emploCOPY

collects information such as education level, housing status, emplo

This do

cumen

t basis.

docu

ment basis.

docu

ment drug free period.

docu

ment drug free period.

occur for

docu

ment

occur for

cann

ot Discontinuation Visit which will be followed by

cann

ot Discontinuation Visit which will be followed bydrug.

cann

ot drug. The dose decrease can be made by

cann

ot The dose decrease can be made by

basis.cann

ot

basis. A last downcann

ot

A last down

be If a subject will not continue with be If a subject will not continue with

Discontinuation Visit which will be followed bybe

Discontinuation Visit which will be followed by

used

to contact the subject (e.g. b

used

to contact the subject (e.g. b

If a subject will not continue with used

If a subject will not continue with

to A subject will be considered lost to follow-

to A subject will be considered lost to follow-to contact the subject (e.g. bto to contact the subject (e.g. b

supp

ort Whether the subject completed (participated until the

supp

ort Whether the subject completed (participated until the

study

supp

ort

study.

supp

ort

.

A subject will be considered lost to follow-supp

ort

A subject will be considered lost to follow-

any termination) will be recorded.

any termination) will be recorded.

Whether the subject completed (participated until the any

Whether the subject completed (participated until the

marketi

ng

The end of the subject’s participation in

marketi

ng

The end of the subject’s participation in the

marketi

ng

the

marketi

ng

All data about the subject’s status (mark

eting

All data about the subject’s status (termination) will be recorded.mark

eting

termination) will be recorded.

autho

rizati

on from N01252, N01253 and N01254

autho

rizati

on from N01252, N01253 and N01254


autho

rizati

on


appli

catio

n

Evaluation

appli

catio

n

Evaluation Discontinuation Visit occurs within the ap

plica

tion

Discontinuation Visit occurs within the from N01252, N01253 and N01254ap

plica

tion

from N01252, N01253 and N01254

and

ation Visit and the Final Visit if these visits occur within the first 2

and

ation Visit and the Final Visit if these visits occur within the first 2any ars, and at the Early

any ars, and at the Early

ation Visit and the Final Visit if these visits occur within the first 2any

ation Visit and the Final Visit if these visits occur within the first 2

exten

sions

pe of provider [general practitioner

exten

sions

pe of provider [general practitioner hospital, home,

exten

sions

hospital, home,

Healthcare provider

exten

sions

Healthcare provider Full Evaluation Visit,

exten

sions

Full Evaluation Visit, ars, and at the Earlyex

tensio

ns

ars, and at the Early

or protocol will be

or protocol will be

pe of provider [general practitioner or pe of provider [general practitioner va

riatio

ns

protocol will be varia

tions

protocol will be

thereo

f.


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.

REDACTED All information, including the reason for the visit/phone call,

REDACTED All information, including the reason for the visit/phone call, information on adverse events, etc., should be collected in the source documents and

REDACTED information on adverse events, etc., should be collected in the source documents and

recorded in the appropriate section of the CRF.

REDACTED


COPY 7 day

COPY 7 day

studyCOPY study

All information, including the reason for the visit/phone call, COPY

All information, including the reason for the visit/phone call,

This do

cumen

t

docu

ment ECG.

docu

ment ECG.

docu

ment

cann

ot Vital signs

cann

ot Vital signs

cann

ot Bod

cann

ot Body weight and height.

cann

ot y weight and height.Phyca

nnot

Physical and neurological examination.cann

ot sical and neurological examination.

ECG.ca

nnot

ECG.

be AED history

be AED history

Vital signsbe

Vital signsus

ed dical and procedure history

used

dical and procedure history history

used

historyAED historyus

ed

AED history

to dical and procedure historyto dical and procedure historysupp

ort Inclusion

supp

ort Inclusion

date of birth, gender and racial group.

supp

ort

date of birth, gender and racial group.Childbearing potential.su

pport

Childbearing potential.dical and procedure historysu

pport

dical and procedure history

any study

any study

any

Inclusionany

Inclusion/exclusion criteria.any

/exclusion criteria.

marketi

ng

gning and dating of written informed consent.marketi

ng

gning and dating of written informed consent.subject card” (participation in the mark

eting

subject card” (participation in the

autho

rizati

on visit/phone call if the

autho

rizati

on visit/phone call if the

All information, including the reason for the visit/phone call,

autho

rizati

on

All information, including the reason for the visit/phone call, information on adverse events, etc., should be collected in the source documents and

autho

rizati

on

information on adverse events, etc., should be collected in the source documents and recorded in the appropriate section of the CRF.

autho

rizati

on


appli

catio

n

s from the previous visit.

appli

catio

n

s from the previous visit.

visit/phone call if the appli

catio

n

visit/phone call if the

and

representative should be contacted for agreement. The Adverse Events, Medical Procedures,

and

representative should be contacted for agreement. The Adverse Events, Medical Procedures, n belonging to the interim period

and n belonging to the interim period

any tudy

any tudy

representative should be contacted for agreement. The Adverse Events, Medical Procedures, any

representative should be contacted for agreement. The Adverse Events, Medical Procedures,

exten

sions

as the last visit of the previous study in

exten

sions

as the last visit of the previous study in between the

exten

sions

between the tudyex

tensio

ns

tudy Pexten

sions

P

or va

riatio

ns th

ereof.


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.

REDACTED y (hematology, bl

REDACTED y (hematology, blCOPY

y (hematology, blCOPY

y (hematology, bl

This do

cumen

t Drug

docu

ment Drug

docu

ment

cann

ot Assessment of suicidality (C

cann

ot Assessment of suicidality (CMedical procedures.

cann

ot Medical procedures.Concomitant medications (AED and Nonca

nnot

Concomitant medications (AED and NonDrugca

nnot

Drug

be Recording of Adverse Events

be Recording of Adverse Events

Assessment of suicidality (Cbe

Assessment of suicidality (Cus

ed gnancy

used

gnancy test (if applicable)

used

test (if applicable)gnancy test (if applicable)gnancy

used

gnancy test (if applicable)gnancyRecording of Adverse Eventsus

ed

Recording of Adverse Events

to essment including safetto essment including safet test (if applicable)to test (if applicable)

supp

ort sical and neurological examination.

supp

ort sical and neurological examination.

Retrieval of previous subject DRC.

supp

ort

Retrieval of previous subject DRC.Recording of seizures.

supp

ort

Recording of seizures.essment including safetsu

pport

essment including safet

any

sical and neurological examination.any

sical and neurological examination.

marketi

ng

Vital signs including blood pressure and pulse rate.mark

eting

Vital signs including blood pressure and pulse rate.

autho

rizati

on

y (hematology, bl

autho

rizati

on

y (hematology, bl

appli

catio

n and

last evaluation visit o

and last evaluation visit oan

y last evaluation visit oan

y last evaluation visit o

exten

sions

or m the database of the baseline visit of the previous

or m the database of the baseline visit of the previous va

riatio

ns

m the database of the baseline visit of the previous varia

tions

m the database of the baseline visit of the previous

thereo

f.


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.

REDACTED s and schoolday

REDACTED s and schooldays lost and day

REDACTED s lost and day

during the first 2

REDACTED

during the first 2ye REDACTED

yearsREDACTED

ars

COPY Vital signs including blood pressure and pulse rate.

COPY Vital signs including blood pressure and pulse rate.

This do

cumen

t Vital signs including blood pressure and pulse rate.

docu

ment Vital signs including blood pressure and pulse rate.

docu

ment

cann

ot Yearly Evaluation Visit (replaces

cann

ot Yearly Evaluation Visit (replaces

Vital signs including blood pressure and pulse rate.cann

ot

Vital signs including blood pressure and pulse rate.

be Appointment for the next visit according to the schedule described i

be Appointment for the next visit according to the schedule described i

Yearly Evaluation Visit (replaces be

Yearly Evaluation Visit (replaces

used

Dispensation of

used

Dispensation of Appointment for the next visit according to the schedule described ius

ed

Appointment for the next visit according to the schedule described i

to Dispensation of new DRC.to Dispensation of new DRC.studyto study

supp

ort

medications (AED and Non

supp

ort

medications (AED and NonDrug return/accountability

supp

ort

Drug return/accountabilityDispensation of new DRC.su

pport

Dispensation of new DRC.

any Assessment of suicidality (C

any Assessment of suicidality (C-

any -SSRS).

any SSRS).mark

eting

onsultation not

marketi

ng

onsultation not f

marketi

ng

foreseen

marketi

ng

oreseenforeseenf

marketi

ng

foreseenf

SSRS).marketi

ng

SSRS).

autho

rizati

on

s lost and day

autho

rizati

on

s lost and dayduring the first 2au

thoriz

ation

during the first 2

appli

catio

n and

mpaired and except for all subjects

and mpaired and except for all subjects an

y mpaired and except for all subjects an

y mpaired and except for all subjects

exten

sions

s subject received help from a

exten

sions


or coming from N01193). The questionnaire should be filled in at the beginning of the Visit,

or coming from N01193). The questionnaire should be filled in at the beginning of the Visit, va

riatio

ns

coming from N01193). The questionnaire should be filled in at the beginning of the Visit, varia

tions

coming from N01193). The questionnaire should be filled in at the beginning of the Visit,

thereo

f.


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.


Healthcare provider consultation not foreseen by protocol Recording of workdays and school days lost and days subject received help from a


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.

REDACTED The questionnaire should be filled in at the beginning of the Visit,

REDACTED The questionnaire should be filled in at the beginning of the Visit,

Healthcare provider consultation not foreseen b

REDACTED

Healthcare provider consultation not foreseen bs and school day

REDACTED

s and school days lost and day

REDACTED

s lost and day

COPY HADS questionnaire (except if subject mentall

COPY HADS questionnaire (except if subject mentally i

COPY y impaired and except for all subjects COPY

mpaired and except for all subjects The questionnaire should be filled in at the beginning of the Visit, COPY

The questionnaire should be filled in at the beginning of the Visit,

This do

cumen

t Recording of seizures.

docu

ment Recording of seizures.

docu

ment

cann

ot ECG.

cann

ot ECG.Retrieval of previous subject DRC.ca

nnot

Retrieval of previous subject DRC.Recording of seizures.ca

nnot

Recording of seizures.

be sica be sical and neurological examination.be l and neurological examination.us

ed Vital signs including blood pressure and pulse rate.

used

Vital signs including blood pressure and pulse rate.y weight.us

ed

y weight.l and neurological examination.

used

l and neurological examination.

to Vital signs including blood pressure and pulse rate.to Vital signs including blood pressure and pulse rate.

supp

ort

11.2.5 Early Discontinuation Visitsu

pport

11.2.5 Early Discontinuation Visit

any m

arketi

ng s lost and day

marketi

ng s lost and day

5D questionnaire (except if subject mentallmark

eting

5D questionnaire (except if subject mentall

autho

rizati

on mpaired and except for all subjects

autho

rizati

on mpaired and except for all subjects


autho

rizati

on


Healthcare provider consultation not foreseen b

autho

rizati

on

Healthcare provider consultation not foreseen by protocol

autho

rizati

on

y protocols lost and dayau

thoriz

ation

s lost and day

appli

catio

n impaired and except for all

appli

catio

n impaired and except for all The questionnaire should be filled in at the beginning of

appli

catio

n The questionnaire should be filled in at the beginning of

mpaired and except for all subjects appli

catio

n


and ars which includes the YEV

and ars which includes the YEV an

y ars which includes the YEV an

y ars which includes the YEV

exten

sions

medication intake and compliance check.

exten

sions

medication intake and compliance check.

Section exten

sions

Section

or va

riatio

ns th

ereof.


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.


Healthcare provider consultation not foreseen by protocol Recording of workdays and schooldays lost and days subject received help from a


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.

REDACTED 5D questionnaire (except if subject ment

REDACTED 5D questionnaire (except if subject ment

COPY y protocol

COPY y protocols lost and day

COPY s lost and day

This do

cumen

t

docu

ment Phy

docu

ment Phy

docu

ment

cann

ot Vital signs including blood pressure and pulse.

cann

ot Vital signs including blood pressure and pulse.Bodca

nnot

Bod

be upon Sponsor request at the end of the program)

be upon Sponsor request at the end of the program)us

ed

Final Visit us

ed

Final Visit (FVus

ed

(FVupon Sponsor request at the end of the program)us

ed

upon Sponsor request at the end of the program)

to su

pport

Recording of Adverse Events.

supp

ort Recording of Adverse Events.

supp

ort

ppointment for the next visit according to the schedule described in

supp

ort

ppointment for the next visit according to the schedule described in

any Phone Call

any Phone Call

Recording of Adverse Events.an

y

Recording of Adverse Events.

marketi

ng

Phone Callmarketi

ng

Phone Call

autho

rizati

on s lost and day

autho

rizati

on s lost and days subject received help from a

autho

rizati

on s subject received help from a

5D questionnaire (except if subject ment

autho

rizati

on

5D questionnaire (except if subject mentall

autho

rizati

on

ally i

autho

rizati

on

y i

appli

catio

n mpaired and except for all subjects

appli

catio

n mpaired and except for all subjects

The questionnaire should be filled in at the beginning of the Vi

appli

catio

n The questionnaire should be filled in at the beginning of the Vi

y protocol

appli

catio

n

y protocols subject received help from a ap

plica

tion


and

mpaired and except for all subjects and


any The questionnaire should be filled in at the beginning of

any The questionnaire should be filled in at the beginning of ex

tensio

ns

y if the EDV occurs within the first 2

exten

sions

y if the EDV occurs within the first 2 impaired and except for all ex

tensio

ns

impaired and except for all The questionnaire should be filled in at the beginning of

exten

sions

The questionnaire should be filled in at the beginning of

or transition to another BRV studyor transition to another BRV study or or or transition to another BRV study or transition to another BRV studyor transition to another BRV study or transition to another BRV study varia

tions

transition to another BRV study varia

tions

transition to another BRV study or varia

tions

or

thereo

f.


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-

REDACTED

, biochemistry

REDACTED

, biochemistryd and the results sent by fax and letter to the IREDACTED

d and the results sent by fax and letter to the I

COPY information on AEs, etc., should be collected in the source documents and recorded in the

COPY information on AEs, etc., should be collected in the source documents and recorded in the medication can be dispensed if required.

COPY medication can be dispensed if required.

This do

cumen

t subject administered a pharmaceutical product which

docu

ment subject administered a pharmaceutical product which

relationship with this treatment.

docu

ment

relationship with this treatment. unintended sign (including an abnormal laboratory finding), s

docu

ment

unintended sign (including an abnormal laboratory finding), s

cann

ot 12.1.1 Definition of Adverse Event (AE)

cann

ot 12.1.1 Definition of Adverse Event (AE)

An adverse event is ancann

ot An adverse event is ansubject administered a pharmaceutical product which ca

nnot

subject administered a pharmaceutical product which

be

12.1.1 Definition of Adverse Event (AE)be

12.1.1 Definition of Adverse Event (AE)us

ed

Adverse Eventsus

ed

Adverse Eventsto

supp

ort

ADVERSE EVENTS AND Ssupp

ort

ADVERSE EVENTS AND S

any m

arketi

ng d and the results sent by fax and letter to the I

marketi

ng d and the results sent by fax and letter to the Iau

thoriz

ation

medication can be dispensed if required.

autho

rizati

on medication can be dispensed if required.

, biochemistryautho

rizati

on

, biochemistry, urinalyautho

rizati

on

, urinalyd and the results sent by fax and letter to the Iau

thoriz

ation

d and the results sent by fax and letter to the I

appli

catio

n visit/phone call if the

appli

catio

n visit/phone call if the information, including reason for visit/phone call, an

appli

catio

n information, including reason for visit/phone call, an

information on AEs, etc., should be collected in the source documents and recorded in the ap

plica

tion

information on AEs, etc., should be collected in the source documents and recorded in the medication can be dispensed if required.ap

plica

tion

medication can be dispensed if required.

and a

ny ex

tensio

ns

ntake and compliance check.

exten

sions

ntake and compliance check.

or va

riatio

ns th

ereof.


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 AEsThe 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 Investigatormust 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.

REDACTED

The following guidelines and definitions should be used b

REDACTED

The following guidelines and definitions should be used bdescription of an AE when reporting information:REDACTED

description of an AE when reporting information:

COPY our health (since y

COPY our health (since y

elfCOPY elf-COPY

-elf-elfCOPY elf-elf assessment COPY

assessment

This do

cumen

t can

not Date of onset:

cann

ot Date of onset:Pattern:

cann

ot Pattern:

be

Date of onset:be

Date of onset:

used

to su

pport

any m

arketi

ng The following guidelines and definitions should be used b

marketi

ng The following guidelines and definitions should be used b


marketi

ng


Preferablymark

eting

Preferably

autho

rizati

on assessment

autho

rizati

on assessment

The following guidelines and definitions should be used bautho

rizati

on

The following guidelines and definitions should be used b

appli

catio

n A general prompt will also be given to detect adverse events, e.g.,

appli

catio

n A general prompt will also be given to detect adverse events, e.g.,

our health (since y

appli

catio

n

our health (since y

assessment appli

catio

n

assessment

and to report Adverse Events spontaneously

and to report Adverse Events spontaneously

any e

xtens

ions

y significant manner as compared to the clinical

exten

sions

y significant manner as compared to the clinical

or the baseline period.

exten

sions

or the baseline period.

or ptoms of the condition/disease for which the investigational product is being

or ptoms of the condition/disease for which the investigational product is being va

riatio

ns th

ereof.


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.

REDACTED Investigational product was temporaril

REDACTED Investigational product was temporarilbecause of this AE, either because the subject chose

REDACTED because of this AE, either because the subject chose to discontinue the study

REDACTED

to discontinue the studywas in thREDACTED

was in thdiscontinue the investigational product.REDACTED

discontinue the investigational product.

COPY estigational product dose was decreased because

COPY estigational product dose was decreased because

Investigational product was temporarilCOPY

Investigational product was temporaril

This do

cumen

t can

not

Resolved with sequela

cann

ot Resolved with sequela

be Resolvedbe Resolvedu

sed

Resolveduse

d

Resolved

to su

pport

any m

arketi

ng was in th

marketi

ng was in th

discontinue the investigational product.

marketi

ng

discontinue the investigational product.Investigational product was permanently

marketi

ng

Investigational product was permanentlybecause of this AE, either because the subject chose mark

eting

because of this AE, either because the subject chose

autho

rizati

on estigational product dose was decreased because

autho

rizati

on estigational product dose was decreased because

Investigational product was temporaril

autho

rizati

on

Investigational product was temporarilbecause of this AE, either because the subject chose

autho

rizati

on

because of this AE, either because the subject chose to discontinue the study

autho

rizati

on

to discontinue the studywas in thau

thoriz

ation

was in the subject’s best interest to temporarilautho

rizati

on

e subject’s best interest to temporaril

appli

catio

n spite of the AE being present.

appli

catio

n spite of the AE being present.Investigational product dose was increased because of

appli

catio

n Investigational product dose was increased because of

estigational product dose was decreased because appli

catio

n

estigational product dose was decreased because

and

study

and

study drug free period.

and drug free period.study drug free period.study

and

study drug free period.studyInvestigational product dosing remained the same in an

d Investigational product dosing remained the same in an

y drug free period.an

y drug free period.

exten

sions

y or to carry out

exten

sions

y or to carry out

his/her usual activities, or the AE is of definite

exten

sions

his/her usual activities, or the AE is of definite

or va

riatio

ns

usual activities and/or it is of no clinical consequence.va

riatio

ns

usual activities and/or it is of no clinical consequence.

thereo

f.


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


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.

REDACTED Equally

REDACTED Equally valid arguments can be considered for or

REDACTED valid arguments can be considered for or Equally valid arguments can be considered for or Equally

REDACTED Equally valid arguments can be considered for or Equallyagainst an implication of the investigational product,

REDACTED

against an implication of the investigational product, For example, the AE:

REDACTED

For example, the AE:REDACTED

COPY There are good reasons to think that there

COPY There are good reasons to think that thererelationship (e.g., the AE is a known adverse drug

COPY relationship (e.g., the AE is a known adverse drug reaction of a concomitant medication).COPY reaction of a concomitant medication).

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

For example, the AE:

marketi

ng For example, the AE:

follows a reasonable te

marketi

ng

follows a reasonable teadministration of the investigational product

marketi

ng

administration of the investigational productmark

eting

autho

rizati

on reaction of a concomitant medication).

autho

rizati

on reaction of a concomitant medication).

valid arguments can be considered for or

autho

rizati

on

valid arguments can be considered for or against an implication of the investigational product,

autho

rizati

on

against an implication of the investigational product, For example, the AE:au

thoriz

ation

For example, the AE:

appli

catio

n

There are good reasons to think that there

appli

catio

n

There are good reasons to think that thererelationship (e.g., the AE is a known adverse drug ap

plica

tion

relationship (e.g., the AE is a known adverse drug reaction of a concomitant medication).ap

plica

tion

reaction of a concomitant medication).

and

placebo, or when the AE can be ascribed with

and

placebo, or when the AE can be ascribed with to another cause (e.g., a gun shot

and to another cause (e.g., a gun shot

any taken or when the subject is taking single-

any taken or when the subject is taking single-

placebo, or when the AE can be ascribed with any

placebo, or when the AE can be ascribed with

exten

sions

duration of the AE. If the AE is marked “ongoing”,

exten

sions

duration of the AE. If the AE is marked “ongoing”,

plicable when no investigational product was ex

tensio

ns

plicable when no investigational product was taken or when the subject is taking single-ex

tensio

ns

taken or when the subject is taking single-

or duration of the AE. If the AE is marked “ongoing”, or

duration of the AE. If the AE is marked “ongoing”, va

riatio

ns th

ereof.


Highly probable There is a strong relationship. For example, the AE: follows a reasonable temporal sequence from


the investigational product. is confirmed by improvement on stopping or

reducing the dosage of the investigational product, and reappearance on repeated exposure (re-challenge).

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.

REDACTED perform or arrange for the conduct of

REDACTED perform or arrange for the conduct of measurements and/or evaluations (e.g., re-

REDACTED measurements and/or evaluations (e.g., re-

A serious AE or an AE leading to premature discontinuation from the study must alway

REDACTED

A serious AE or an AE leading to premature discontinuation from the study must alwayesolved or the

REDACTED

esolved or the InvestigatorREDACTED

Investigator

COPY perform or arrange for the conduct of COPY perform or arrange for the conduct of

measurements and/or evaluations (e.g., re-COPY

measurements and/or evaluations (e.g., re-

This do

cumen

t should be informed immediatel

docu

ment should be informed immediatel

pregnancy

docu

ment

pregnancyca

nnot

12.1.6 Pregnancy

cann

ot 12.1.6 Pregnancy

Should a subject become pregnant durinca

nnot

Should a subject become pregnant durinshould be informed immediatelca

nnot

should be informed immediatel

be

12.1.6 Pregnancybe

12.1.6 Pregnancyus

ed vestigator

used

vestigator to vestigator to vestigator’s original description of the AE being the same for the first and repeated to ’s original description of the AE being the same for the first and repeated supp

ort

the outcome date of the first AE that is not r

supp

ort

the outcome date of the first AE that is not rbeing the same as the start date of the repeated AE.su

pport

being the same as the start date of the repeated AE.’s original description of the AE being the same for the first and repeated su

pport

’s original description of the AE being the same for the first and repeated

any An unexpected increase in the intensity

any An unexpected increase in the intensitymark

eting

Investigator

marketi

ng Investigator

Rule for Repetition of an AE

marketi

ng

Rule for Repetition of an AE

An unexpected increase in the intensitymark

eting

An unexpected increase in the intensity

autho

rizati

on perform or arrange for the conduct of

autho

rizati

on perform or arrange for the conduct of


autho

rizati

on


A serious AE or an AE leading to premature discontinuation from the study must alwayau

thoriz

ation

A serious AE or an AE leading to premature discontinuation from the study must alwayInvestigatorau

thoriz

ation

Investigator

appli

catio

n If an AE is still ongoing at the time the CRF is collected, a follow

appli

catio

n If an AE is still ongoing at the time the CRF is collected, a follow-up report should be

appli

catio

n -up report should be up report is provided, the

appli

catio

n up report is provided, the Investigator

appli

catio

n Investigator

perform or arrange for the conduct of ap

plica

tion

perform or arrange for the conduct of

and

-up report should be an

d -up report should be

any e

xtens

ions y improvement on stopping or

exten

sions

y improvement on stopping or reducing the dosage of the investigational product,

exten

sions

reducing the dosage of the investigational product, and reappearance on repeated exposure (re-

exten

sions

and reappearance on repeated exposure (re-

or va

riatio

ns th

ereof.


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”.

REDACTED untoward medical occurrence that occurs at any

REDACTED untoward medical occurrence that occurs at any

g, (an immediate risk of death).

REDACTED

g, (an immediate risk of death).patient hospitalization or prolongat

REDACTED

patient hospitalization or prolongatresults in persistent or significant disabilityREDACTED

results in persistent or significant disability

COPY 12.2.1 Definition of Serious Adverse Event (SAE)

COPY 12.2.1 Definition of Serious Adverse Event (SAE)

untoward medical occurrence that occurs at anyCOPY

untoward medical occurrence that occurs at any

This do

cumen

t the definition above should also be reported as a SAE.

docu

ment the definition above should also be reported as a SAE.

treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or

docu

ment

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

docu

ment

convulsions that do not result in hospitalization; or development of drug dependency

cann

ot important medical event that may

cann

ot important medical event that may

or hospitalization but, based upon appropriate medical

cann

ot or hospitalization but, based upon appropriate medical or may

cann

ot or may require medical or surgical intervention to prevent

cann

ot require medical or surgical intervention to prevent or may require medical or surgical intervention to prevent or may

cann

ot or may require medical or surgical intervention to prevent or maythe definition above should also be reported as a SAE. ca

nnot

the definition above should also be reported as a SAE.

be important medical event that maybe important medical event that mayus

ed immediate risk of death at the time of the event; it does NOT refer to an event which might

used

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.

used

have caused death if it would have been more severe.to immediate risk of death at the time of the event; it does NOT refer to an event which might to 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.to

have caused death if it would have been more severe.

supp

ort investigational product, especially

supp

ort investigational product, especially

In this context, the term life threatening refers to an event in whicsupp

ort

In this context, the term life threatening refers to an event in whicimmediate risk of death at the time of the event; it does NOT refer to an event which might su

pport

immediate risk of death at the time of the event; it does NOT refer to an event which might

any birth defect (in a child of a subject/patient who took the

any birth defect (in a child of a subject/patient who took the

investigational product, especiallyany

investigational product, especially

marketi

ng patient hospitalization or prolongat

marketi

ng patient hospitalization or prolongat

results in persistent or significant disability

marketi

ng

results in persistent or significant disability out normal work or norm

marketi

ng

out normal work or normal activitie

marketi

ng

al activitie

birth defect (in a child of a subject/patient who took the mark

eting

birth defect (in a child of a subject/patient who took the

autho

rizati

on


autho

rizati

on


g, (an immediate risk of death).au

thoriz

ation

g, (an immediate risk of death).patient hospitalization or prolongatau

thoriz

ation

patient hospitalization or prolongat

appli

catio

n and

Medication Intake” section of

and

Medication Intake” section of any ptoms associated with an overdose must be recorded as AEs.

any ptoms associated with an overdose must be recorded as AEs. Overdose

any Overdose

Medication Intake” section of any

Medication Intake” section of

exten

sions

will be considered as an ex

tensio

ns

will be considered as an Overdose ex

tensio

ns

Overdose

or va

riatio

ns th

ereof.


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).

REDACTED y or lab reports…) should be provided to

REDACTED y or lab reports…) should be provided to up of each case.

REDACTED up of each case.

y a translation in English, or the relevant information

REDACTED

y a translation in English, or the relevant information

REDACTED

the same document must be summarized in the SAE report form.

REDACTED


COPY ponsor

COPY ponsorit is obvious that more data will be needed to make an

COPY it is obvious that more data will be needed to make any conclusions.

COPY y conclusions.

y or lab reports…) should be provided to COPY

y or lab reports…) should be provided to

This do

cumen

t no way

docu

ment no way

docu

ment associated with the stud

docu

ment associated with the stud

between the event and the end of the stud

docu

ment

between the event and the end of the stud

cann

ot If known b

cann

ot If known by the

cann

ot y the medication must be reported to the Sponsor, even if the

cann

ot medication must be reported to the Sponsor, even if the no wayca

nnot

no way associated with the studycann

ot

associated with the study

be

y the be

y the

used

Investigator

used

Investigator. The SAE report form has to be completed in English.us

ed

. The SAE report form has to be completed in English.

to Investigatorto Investigatorsu

pport

the applicable regulatory

supp

ort the applicable regulatory

Investigators are to provide the Sponsor or its representatives with evidence of such IEC/IRB

supp

ort

Investigators are to provide the Sponsor or its representatives with evidence of such IEC/IRB an

y appropriate IRB/IEC will also be informed b

any appropriate IRB/IEC will also be informed b

the applicable regulatoryany

the applicable regulatory

marketi

ng the same document must be summarized in the SAE report form.

marketi

ng the same document must be summarized in the SAE report form.

(or its representatives) will communicate safet

marketi

ng

(or its representatives) will communicate safetnvestigators, in accordance with applicable regulatory

marketi

ng

nvestigators, in accordance with applicable regulatoryappropriate IRB/IEC will also be informed bmark

eting

appropriate IRB/IEC will also be informed b

autho

rizati

on

y or lab reports…) should be provided to

autho

rizati

on

y or lab reports…) should be provided to up of each case.

autho

rizati

on

up of each case.y a translation in English, or the relevant information

autho

rizati

on

y a translation in English, or the relevant information the same document must be summarized in the SAE report form.au

thoriz

ation


appli

catio

n SAEs listed in

appli

catio

n SAEs listed in S

appli

catio

n Section

appli

catio

n ection (or its representatives) a duly

appli

catio

n (or its representatives) a duly

, even if the data are incomplete or if

appli

catio

n

, even if the data are incomplete or if y conclusions.ap

plica

tion

y conclusions.

and (or its representatives) must be informed about an SAE within 24 hours of the

and (or its representatives) must be informed about an SAE within 24 hours of the

ection and

ection

any e

xtens

ions will not be considered an AE or

exten

sions

will not be considered an AE or However, if a hospitalization is unplanned or is a

exten

sions

However, if a hospitalization is unplanned or is a

or where no

or where no

will not be considered an AE or or will not be considered an AE or va

riatio

ns

where no varia

tions

where no

thereo

f.


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



REDACTED

y exclusive subpopulations. They

REDACTED


Partial onset seizure: Subjects enrolled from prior studies REDACTED

Partial onset seizure: Subjects enrolled from prior studies

COPY

This

Primary

docu

ment Primary

docu

ment Primary

docu

ment Primary

docu

ment c

anno

t 13.1.2 Eff

cann

ot 13.1.2 Efficacy and Safety Variables

cann

ot icacy and Safety Variables13.1.2 Efficacy and Safety Variables13.1.2 Eff

cann

ot 13.1.2 Efficacy and Safety Variables13.1.2 Eff

Primarycann

ot

Primary

be

icacy and Safety Variablesbe

icacy and Safety Variables

used

y Population will consist of all subjects who took at least 1

used

y Population will consist of all subjects who took at least 1to y Population will consist of all subjects who took at least 1to y Population will consist of all subjects who took at least 1

supp

ort

Population will consist of all subjects who took at least 1 dose of study

supp

ort

Population will consist of all subjects who took at least 1 dose of studymedication and have at least 1

supp

ort

medication and have at least 1

any diagnosis of PGS at N01254 study

any diagnosis of PGS at N01254 studymark

eting

Partial onset seizure: Subjects enrolled from prior studies

marketi

ng

Partial onset seizure: Subjects enrolled from prior studies and subjects from N01254 with a diagnosis of POS at N01254 study

marketi

ng

and subjects from N01254 with a diagnosis of POS at N01254 study generalized seizure: Subjects enrolled from prior studymark

eting

generalized seizure: Subjects enrolled from prior studydiagnosis of PGS at N01254 studymark

eting

diagnosis of PGS at N01254 study

autho

rizati

on


autho

rizati

on


appli

catio

n and

A general description of statistical methods is presented below. Additio

and

A general description of statistical methods is presented below. Additional detail

and nal detailan

y nal detailan

y nal detail

exten

sions

serious AEs (including

exten

sions

serious AEs (including or

serious AEs (including or

serious AEs (including va

riatio

ns

exposure: convulsion. This original list will remain in effect for the duration of the protocol.va

riatio

ns

exposure: convulsion. This original list will remain in effect for the duration of the protocol.

thereo

f.


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 isdefined 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:



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

REDACTED I)frequency

REDACTED I)frequency per 28 day

REDACTED per 28 dayI)frequency per 28 dayI)frequency

REDACTED I)frequency per 28 dayI)frequency

pe I) frequency

REDACTED

pe I) frequency≥50% reduction in seizure frequencyREDACTED

≥50% reduction in seizure frequency

COPY s during the Evaluation Period

COPY s during the Evaluation Period

This do

cumen

t can

not Generalized (ty

cann

ot Generalized (ty

cann

ot

Percent reduction in generalized (tycann

ot

Percent reduction in generalized (ty

be For subjects with generalized epilepsy

be For subjects with generalized epilepsyus

ed least 6 months and at least 12 months during the Evaluation Period

used


used

For subjects with generalized epilepsyus

ed

For subjects with generalized epilepsy

to Percentage of subjects continuously

to Percentage of subjects continuouslyleast 6 months and at least 12 months during the Evaluation Periodto least 6 months and at least 12 months during the Evaluation Period

supp

ort onset epilepsy

supp

ort onset epilepsy

Percentage of subjects continuouslysupp

ort

Percentage of subjects continuouslyleast 6 months and at least 12 months during the Evaluation Period

supp

ort


any

onset epilepsyan

y onset epilepsy

marketi

ng pe I) frequency

marketi

ng pe I) frequency

≥50% reduction in seizure frequency

marketi

ng

≥50% reduction in seizure frequencyau

thoriz

ation

s during the Evaluation Period

autho

rizati

on s during the Evaluation Period

per 28 day

autho

rizati

on

per 28 day

pe I) frequencyautho

rizati

on

pe I) frequency

appli

catio

n

s during the Evaluation Periodappli

catio

n

s during the Evaluation Period

and s and to the last Evaluation

and s and to the last Evaluation an

y and Depression Scale (HADS) scores from the Baseline any and Depression Scale (HADS) scores from the Baseline

s and to the last Evaluation any

s and to the last Evaluation

exten

sions

or va

riatio

ns

c blood pressure [DBP], pulse rate)

varia

tions

c blood pressure [DBP], pulse rate)

thereo

f.




Change in Patient Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P)scores from Baseline of the previous study to each assessment for the first 2 years and to the last Evaluation Period assessment during the first 2 years

EuroQol 5 Dimensions (EQ-5D) questionnaire response for each assessment for the first 2 years for the Evaluation Period and for the last assessment during the first 2 years of the Evaluation Period

Pharmacoeconomic variables


Direct costs (healthcare provider consultations not foreseen by the protocol, concurrent medical procedures, concomitant medications, hospitalizations, and emergency room [ER] visits) during the first 2 years of the Evaluation Period

Indirect costs (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.

REDACTED Direct costs (healthcare provider consultations not foreseen b

REDACTED Direct costs (healthcare provider consultations not foreseen bmedical procedures, concomitant medications, hospitalizations, and emergency

REDACTED medical procedures, concomitant medications, hospitalizations, and emergency


REDACTED ears of the Evaluation Period

s or school dayREDACTED

s or school dayhelp from a caregiver) during the first 2 yREDACTED

help from a caregiver) during the first 2 y

COPY y for subjects with focal

COPY y for subjects with focal

Direct costs (healthcare provider consultations not foreseen bCOPY

Direct costs (healthcare provider consultations not foreseen b

This do

cumen

t

docu

ment

cann

ot maximum, 25

cann

ot maximum, 25

The periods considered are: cann

ot The periods considered are:

be statistics (number of available observations, mean, median, standard deviation, minimum,

be statistics (number of available observations, mean, median, standard deviation, minimum,

maximum, 25be

maximum, 25thbe

thus

ed

statistics will consist of frequencyus

ed

statistics will consist of frequencystatistics (number of available observations, mean, median, standard deviation, minimum, us

ed

statistics (number of available observations, mean, median, standard deviation, minimum,

to General considerations:

to General considerations:su

pport

ation

supp

ort ation

General considerations:supp

ort

General considerations:

any

assessment during the first 2 y

any

assessment during the first 2 ymarketi

ng s or school day

marketi

ng s or school day


marketi

ng


professional data for each assessment for the first 2 y

marketi

ng

professional data for each assessment for the first 2 yassessment during the first 2 ymark

eting

assessment during the first 2 years of the Evaluation Periodmarketi

ng


autho

rizati

on

Direct costs (healthcare provider consultations not foreseen b

autho

rizati

on

Direct costs (healthcare provider consultations not foreseen bmedical procedures, concomitant medications, hospitalizations, and emergency

autho

rizati

on

medical procedures, concomitant medications, hospitalizations, and emergencyears of the Evaluation Period

autho

rizati

on


s or school day autho

rizati

on

s or school days lost byautho

rizati

on

s lost by

appli

catio

n

y for subjects with focal

appli

catio

n

y for subjects with focal

and

t assessment during the first 2 y

and

t assessment during the first 2 yany 5D) questionnaire response for each assessment for the first

any 5D) questionnaire response for each assessment for the first

t assessment during the first 2 yany t assessment during the first 2 yex

tensio

ns Questionnaire (QOLIE-31

exten

sions

Questionnaire (QOLIE-31 to each assessment for the first 2 y

exten

sions

to each assessment for the first 2 years and

exten

sions

ears and

5D) questionnaire response for each assessment for the first exten

sions

5D) questionnaire response for each assessment for the first

or -or -P)or P)va

riatio

ns th

ereof.


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.

REDACTED -month periods over the Evaluation Period.

REDACTED -month periods over the Evaluation Period.

5D, and socio

REDACTED 5D, and socio-

REDACTED -professional efficacy

REDACTED professional efficacy

ses will be based upon the EfficacyREDACTED

ses will be based upon the Efficacy Population and summarized byREDACTED

Population and summarized byses will be based upon the Efficacy Population and summarized byses will be based upon the EfficacyREDACTED

ses will be based upon the Efficacy Population and summarized byses will be based upon the Efficacyisits and for the last Evaluation Period assessment during the first 2REDACTED

isits and for the last Evaluation Period assessment during the first 2

COPY Population. Summaries will

COPY Population. Summaries will

-month periods over the Evaluation Period.COPY -month periods over the Evaluation Period.

This do

cumen

t Treatment

docu

ment

Treatmentperiod, and Medical Dictionary

docu

ment

period, and Medical Dictionary

cann

ot ses will be based upon the Safet

cann

ot ses will be based upon the Safet

the Evaluation Period b

cann

ot the Evaluation Period bexposure.

cann

ot exposure.

be

ses will be based upon the Safetbe

ses will be based upon the Safetus

ed Safety variables:

used

Safety variables:to

supp

ort

ses will be based upon the Efficacy

supp

ort

ses will be based upon the EfficacyData collected after Yearsu

pport

Data collected after Year 2 are not planned to be summarized.supp

ort

2 are not planned to be summarized.

any Medical resource and indirect cost efficacy

any Medical resource and indirect cost efficacymark

eting

Population and summarized by

marketi

ng Population and summarized by

isits and for the last Evaluation Period assessment during the first 2

marketi

ng

isits and for the last Evaluation Period assessment during the first 22 are not planned to be summarized.

marketi

ng

2 are not planned to be summarized.

Medical resource and indirect cost efficacymark

eting

Medical resource and indirect cost efficacy

autho

rizati

on Population. Summaries will

autho

rizati

on Population. Summaries will

-month periods over the Evaluation Period.

autho

rizati

on -month periods over the Evaluation Period.

professional efficacy

autho

rizati

on

professional efficacy

Population and summarized byautho

rizati

on

Population and summarized by

appli

catio

n

Population. Summaries willappli

catio

n

Population. Summaries will-month periods over the Evaluation Period.

appli

catio

n

-month periods over the Evaluation Period.

and

well as disposition. Historical and Baseline data will be copied from the prior study

and

well as disposition. Historical and Baseline data will be copied from the prior studyany , current treatment(s), as

any , current treatment(s), as

well as disposition. Historical and Baseline data will be copied from the prior studyany

well as disposition. Historical and Baseline data will be copied from the prior study

exten

sions

described to enable a clear understanding of the populations and exten

sions

described to enable a clear understanding of the populations and , current treatment(s), as ex

tensio

ns

, current treatment(s), as

or va

riatio

ns th

ereof.


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.

REDACTED Since subjects will drop out at different times from the study

REDACTED Since subjects will drop out at different times from the study

and Data Monitoring

REDACTED

and Data Monitoring

label nature of this studyREDACTED

label nature of this study

COPY as they

COPY as they are available.

COPY are available. as they are available. as they

COPY as they are available. as theyin the calculation of the seizure

COPY in the calculation of the seizure

Since subjects will drop out at different times from the studyCOPY

Since subjects will drop out at different times from the study

This do

cumen

t 13.3.4

docu

ment 13.3.4

Subgroup anal

docu

ment

Subgroup anal

cann

ot Additionally

cann

ot Additionally

cann

ot group subjects and subject data according to similar BRV exposure times.

cann

ot group subjects and subject data according to similar BRV exposure times.

13.3.4cann

ot

13.3.4

be ded into 2

be ded into 2

Additionallybe

Additionally, as needed, the POS and the PGS subjects maybe

, as needed, the POS and the PGS subjects mayus

ed population will be a subset of the safety

used

population will be a subset of the safetyded into 2us

ed

ded into 2

to 13.3.3 Use of an Efficacy Subset of Subjects

to 13.3.3 Use of an Efficacy Subset of Subjectssu

pport

ing to the entire BRV program is organized.

supp

ort ing to the entire BRV program is organized.

13.3.3 Use of an Efficacy Subset of Subjectssupp

ort

13.3.3 Use of an Efficacy Subset of Subjects

any

es in support of submission activities or to allow optimization of the

any

es in support of submission activities or to allow optimization of the In addition, an ongoing medical review (Safet

any In addition, an ongoing medical review (Safet

ing to the entire BRV program is organized.any

ing to the entire BRV program is organized.

marketi

ng

label nature of this study

marketi

ng

label nature of this studydatabase

marketi

ng

database snapshots may

marketi

ng

snapshots mayes in support of submission activities or to allow optimization of the mark

eting

es in support of submission activities or to allow optimization of the In addition, an ongoing medical review (Safet

marketi

ng

In addition, an ongoing medical review (Safet

autho

rizati

on in the calculation of the seizure

autho

rizati

on in the calculation of the seizure


autho

rizati

on


and Data Monitoringau

thoriz

ation

and Data Monitoring

appli

catio

n

are available.

appli

catio

n

are available. in the calculation of the seizure ap

plica

tion

in the calculation of the seizure frequencyappli

catio

n

frequency

and a

ny 1000 subjects are expected.

any

1000 subjects are expected.exten

sions

ample size will depend upon recruitment into

exten

sions

ample size will depend upon recruitment into 1000 subjects are expected.ex

tensio

ns

1000 subjects are expected.

or and depression scales will be analyzed for the POS and PGS subpopulations.

or and depression scales will be analyzed for the POS and PGS subpopulations.va

riatio

ns

and depression scales will be analyzed for the POS and PGS subpopulations.varia

tions

and depression scales will be analyzed for the POS and PGS subpopulations.

thereo

f.


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.

REDACTED ndependent Ethics Committee (IEC

REDACTED ndependent Ethics Committee (IEC

Authorities, according to local regulations.

REDACTED


terations to the protocol are required byREDACTED

terations to the protocol are required by

COPY The final protocol must be submitted to and approved byCOPY The final protocol must be submitted to and approved by

ndependent Ethics Committee (IECCOPY

ndependent Ethics Committee (IEC

This do

cumen

t provided to subjects (e.g., ad

docu

ment provided to subjects (e.g., ad

docu

ment

The study

docu

ment

The studyadvertisement, etc.) have received written approval from the IEC/I

docu

ment

advertisement, etc.) have received written approval from the IEC/I

cann

ot Before submission to an IRB/IEC, the consent form and an

cann

ot Before submission to an IRB/IEC, the consent form and anprovided to subjects (e.g., adca

nnot

provided to subjects (e.g., ad

be Compliance should also be forwarded to the CTM.be Compliance should also be forwarded to the CTM.us

ed

e usual composition of the Iused

e usual composition of the ICompliance should also be forwarded to the CTM.

used

Compliance should also be forwarded to the CTM.

to should be forwarded bto should be forwarded by tto y tsupp

ort

y of the IEC/IRB’s written approval

supp

ort

y of the IEC/IRB’s written approval document(s) and a list of members attending the meeting (listed by

supp

ort

document(s) and a list of members attending the meeting (listed byshould be forwarded b su

pport

should be forwarded by tsupp

ort

y the supp

ort

he

any m

arketi

ng

terations to the protocol are required by

marketi

ng

terations to the protocol are required byInvestigator

marketi

ng

Investigatorsponsors’ approversmark

eting

sponsors’ approvers

autho

rizati

on The final protocol must be submitted to and approved by

autho

rizati

on The final protocol must be submitted to and approved by:

autho

rizati

on :


autho

rizati

on


Authorities, according to local regulations.au

thoriz

ation


appli

catio

n the Principal

appli

catio

n the Principal the

appli

catio

n the Sponsor

appli

catio

n Sponsor

and

the Principal and

the Principal

any e

xtens

ions o

r vari

ation

s the

reof.


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.

REDACTED requirements pertaining to the approval of the amended Informed

REDACTED requirements pertaining to the approval of the amended Informed EC and use of the amended form.

REDACTED EC and use of the amended form.

All studies conducted at centers in the United States must include the use of a Health

REDACTED

All studies conducted at centers in the United States must include the use of a Health and Accountability

REDACTED

and Accountability Act Authorization form.REDACTED

Act Authorization form. and Accountability Act Authorization form. and AccountabilityREDACTED

and Accountability Act Authorization form. and Accountability

COPY nsent form can be amended as appropriate. If the I

COPY nsent form can be amended as appropriate. If the IInvestigator (or the Sponsor, if applicable) must follow

COPY Investigator (or the Sponsor, if applicable) must follow

requirements pertaining to the approval of the amended Informed COPY requirements pertaining to the approval of the amended Informed

EC and use of the amended form.COPY

EC and use of the amended form.

This do

cumen

t The final consent form must be approved b

docu

ment The final consent form must be approved b

docu

ment

ICH

docu

ment

ICHca

nnot

The Sponsor mayca

nnot

The Sponsor mayThe final consent form must be approved bca

nnot

The final consent form must be approved b

be drugs. Although data from

be drugs. Although data from

be expected because be be expected because us

ed warning issued b

used

warning issued by the FDA subsequent to anal

used

y the FDA subsequent to anal

used

drugs. Although data from us

ed

drugs. Although data from be expected because

used

be expected because

to be signed covering the increased risk of suicidality or suicidal thoughts to complyto be signed covering the increased risk of suicidality or suicidal thoughts to complyy the FDA subsequent to analto y the FDA subsequent to anal

supp

ort RB requirem

supp

ort RB requirem

y ongoing in the su

pport

y ongoing in the

be signed covering the increased risk of suicidality or suicidal thoughts to complysupp

ort

be signed covering the increased risk of suicidality or suicidal thoughts to comply

any content and process of obtaining informed consent will be in accordance with all applicable

any content and process of obtaining informed consent will be in accordance with all applicable

RB requiremany

RB requirem

marketi

ng Act Authorization form.

marketi

ng Act Authorization form.

marketi

ng

Adequate information will be provided to the subj

marketi

ng

Adequate information will be provided to the subjconsent will be obtained in writing prior to performance of anmark

eting

consent will be obtained in writing prior to performance of ancontent and process of obtaining informed consent will be in accordance with all applicable

marketi

ng

content and process of obtaining informed consent will be in accordance with all applicable

autho

rizati

on Investigator (or the Sponsor, if applicable) must follow

autho

rizati

on Investigator (or the Sponsor, if applicable) must follow

requirements pertaining to the approval of the amended Informed

autho

rizati

on requirements pertaining to the approval of the amended Informed


autho

rizati

on


All studies conducted at centers in the United States must include the use of a Health au

thoriz

ation

All studies conducted at centers in the United States must include the use of a Health Act Authorization form.au

thoriz

ation

Act Authorization form.

appli

catio

n

nsent form can be amended as appropriate. If the I

appli

catio

n

nsent form can be amended as appropriate. If the IInvestigator (or the Sponsor, if applicable) must follow ap

plica

tion

Investigator (or the Sponsor, if applicable) must follow requirements pertaining to the approval of the amended Informed

appli

catio

n

requirements pertaining to the approval of the amended Informed

and a

ny EC/IRB and Regulatory

any EC/IRB and Regulatoryex

tensio

ns

affect subject safety or the conduct of the stu

exten

sions

affect subject safety or the conduct of the study

exten

sions

dy

with the applicable regulatoryexten

sions

with the applicable regulatoryEC/IRB and Regulatoryex

tensio

ns

EC/IRB and Regulatory

or a formal protocol amendment that must be submitted to the IEC/I

or a formal protocol amendment that must be submitted to the IEC/IRB

or RB va

riatio

ns

gnificant changes to the protocol can va

riatio

ns

gnificant changes to the protocol can RB va

riatio

ns

RB

thereo

f.


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 forre-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

REDACTED signing the consent form, the witness attests

REDACTED signing the consent form, the witness attests that the information in the consent form and in any

REDACTED that the information in the consent form and in any

derstood b

REDACTED

derstood by, the subject and that informed consent was freel

REDACTED

y, the subject and that informed consent was freel

COPY specific assent form, where required, will be signed and dated b

COPY specific assent form, where required, will be signed and dated b

If the signature of a witness is required, the witne COPY If the signature of a witness is required, the witness should sign and personally date the COPY

ss should sign and personally date the signing the consent form, the witness attests COPY

signing the consent form, the witness attests

This do

cumen

t 14.3

docu

ment 14.3

Subject confidentiality

docu

ment

Subject confidentiality

cann

ot the study

cann

ot the study from that point forward.

cann

ot from that point forward.the study from that point forward.the study

cann

ot the study from that point forward.the study

14.3 cann

ot

14.3

be consent of all ongoing subjects in the study

be consent of all ongoing subjects in the study

from that point forward.be

from that point forward.

used

addition, the informed consent form must be amended accordingly

used

addition, the informed consent form must be amended accordinglybe created and submitted to the Ius

ed

be created and submitted to the Iconsent of all ongoing subjects in the studyus

ed

consent of all ongoing subjects in the study

to becomes available, this information will be transmitted to the subject without delay

to becomes available, this information will be transmitted to the subject without delayaddition, the informed consent form must be amended accordinglyto addition, the informed consent form must be amended accordingly

supp

ort for a given subject, without obtain

supp

ort for a given subject, without obtain

y new information that could influence the subject’s decissu

pport

y new information that could influence the subject’s decis

becomes available, this information will be transmitted to the subject without delaysupp

ort

becomes available, this information will be transmitted to the subject without delay

any Case Report Form must not be started, nor may

any Case Report Form must not be started, nor may

for a given subject, without obtainany

for a given subject, without obtain

marketi

ng

withdraw their consent to participate in the study

marketi

ng

withdraw their consent to participate in the studyconsidered as enrolled in the study

marketi

ng

considered as enrolled in the study when he/she has signed the informed consemark

eting

when he/she has signed the informed conseconsidered as enrolled in the study when he/she has signed the informed conseconsidered as enrolled in the studymark

eting

considered as enrolled in the study when he/she has signed the informed conseconsidered as enrolled in the studyCase Report Form must not be started, nor maymark

eting

Case Report Form must not be started, nor may

autho

rizati

on ss should sign and personally date the

autho

rizati

on ss should sign and personally date the

signing the consent form, the witness attests

autho

rizati

on

signing the consent form, the witness attests that the information in the consent form and in any

autho

rizati

on

that the information in the consent form and in any other written information was accurately

autho

rizati

on

other written information was accuratelythat the information in the consent form and in any other written information was accuratelythat the information in the consent form and in any

autho

rizati

on

that the information in the consent form and in any other written information was accuratelythat the information in the consent form and in anyy, the subject and that informed consent was freel

autho

rizati

on

y, the subject and that informed consent was freel

appli

catio

n of the signed and dated consent

appli

catio

n of the signed and dated consent File.

appli

catio

n File. The consent form or a

appli

catio

n The consent form or a

specific assent form, where required, will be signed and dated b

appli

catio

n

specific assent form, where required, will be signed and dated by minors.

appli

catio

n

y minors.

ss should sign and personally date the appli

catio

n

ss should sign and personally date the

and

the person who obtained the informed

and

the person who obtained the informed Obtaining of consent will be confirmed i

and Obtaining of consent will be confirmed i

of the signed and dated consent and

of the signed and dated consent

any formed Consent

any formed Consent

the person who obtained the informed any

the person who obtained the informed

exten

sions

After having received extensive information about the purpose and risks of the study

exten

sions

After having received extensive information about the purpose and risks of the study and

exten

sions

and After having received extensive information about the purpose and risks of the study and After having received extensive information about the purpose and risks of the study

exten

sions

After having received extensive information about the purpose and risks of the study and After having received extensive information about the purpose and risks of the studyor their legal

exten

sions

or their legal formed Consent ex

tensio

ns

formed Consent

or va

riatio

ns

will receive complete written information in the Subject va

riatio

ns

will receive complete written information in the Subject

thereo

f.


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.

REDACTED will allow the Sponsor or its representatives to review

REDACTED will allow the Sponsor or its representatives to review

convenient times during the stud

REDACTED

convenient times during the study and after the stud

REDACTED

y and after the studand corresponding source documents (e.g., portions of office, hospital and laboratory

REDACTED

and corresponding source documents (e.g., portions of office, hospital and laboratoryTherefore, the monitorREDACTED

Therefore, the monitor

COPY The Monitor (the individual responsible fo

COPY The Monitor (the individual responsible foregarding the practical conduct of the study

COPY regarding the practical conduct of the study

requirements.COPY requirements.

This do

cumen

t the

docu

ment the

docu

ment source data/documents.

docu

ment source data/documents.ca

nnot Investigator

cann

ot Investigatorthe ca

nnot

the sponsorcann

ot

sponsor

be Direct Access to Source Data/Documentsbe Direct Access to Source Data/Documentsus

ed participation in the study

used

participation in the study

Direct Access to Source Data/Documentsused

Direct Access to Source Data/Documents

to nstitution, the Sponsor mayto

nstitution, the Sponsor mayparticipation in the studyto participation in the study

supp

ort obligations are being fulfilled, and resolve an

supp

ort obligations are being fulfilled, and resolve an

If the monitoring and/or auditing process identifies serious and/or persistent nonsu

pport

If the monitoring and/or auditing process identifies serious and/or persistent non

nstitution, the Sponsor maysupp

ort

nstitution, the Sponsor may

any applicable

any applicable

any

obligations are being fulfilled, and resolve anany

obligations are being fulfilled, and resolve an

marketi

ng and corresponding source documents (e.g., portions of office, hospital and laboratory

marketi

ng and corresponding source documents (e.g., portions of office, hospital and laboratory

Therefore, the monitor

marketi

ng

Therefore, the monitorThe monitoring visits provide the sponsor or its representatives with the opportunity

marketi

ng

The monitoring visits provide the sponsor or its representatives with the opportunity, to verify

marketi

ng

, to verifyapplicable mark

eting

applicable

autho

rizati

on requirements.

autho

rizati

on requirements.

will allow the Sponsor or its representatives to review

autho

rizati

on

will allow the Sponsor or its representatives to reviewy and after the stud

autho

rizati

on

y and after the studand corresponding source documents (e.g., portions of office, hospital and laboratoryau

thoriz

ation

and corresponding source documents (e.g., portions of office, hospital and laboratory

appli

catio

n of the Sponsor and may

appli

catio

n of the Sponsor and may be delegated t

appli

catio

n be delegated t of the Sponsor and may be delegated t of the Sponsor and may

appli

catio

n of the Sponsor and may be delegated t of the Sponsor and may

The Monitor (the individual responsible fo

appli

catio

n

The Monitor (the individual responsible for monitoring) will advise

appli

catio

n

r monitoring) will advise regarding the practical conduct of the studyap

plica

tion

regarding the practical conduct of the study and maintaining compliance with appli

catio

n

and maintaining compliance with regarding the practical conduct of the study and maintaining compliance with regarding the practical conduct of the studyappli

catio

n

regarding the practical conduct of the study and maintaining compliance with regarding the practical conduct of the study requirements.ap

plica

tion

requirements.

and a

ny ex

tensio

ns

physician of his/her

exten

sions

physician of his/her

or va

riatio

ns th

ereof.


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 onnon-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 regulatoryrequirements. 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)

REDACTED documents used in clinical studies are that they

REDACTED documents used in clinical studies are that they should contain the identity

REDACTED should contain the identitydocuments used in clinical studies are that they should contain the identitydocuments used in clinical studies are that they

REDACTED documents used in clinical studies are that they should contain the identitydocuments used in clinical studies are that they related identifiers (such as treatment numbers, CR

REDACTED related identifiers (such as treatment numbers, CR

mention the subject’s participation in the study

REDACTED

mention the subject’s participation in the study should record the obtaining of consent (date of consent), the subject’s medical

REDACTED

should record the obtaining of consent (date of consent), the subject’s medical cation treatments and dates (including contraceptive treatment), REDACTED

cation treatments and dates (including contraceptive treatment),

COPY are consistent.

COPY are consistent.

For subjects exposed to investigation product(s), theCOPY For subjects exposed to investigation product(s), the minimum requirements for source COPY

minimum requirements for source should contain the identityCOPY

should contain the identity

This do

cumen

t the investigational product have been processed and reported in compliance with the planned

docu

ment the investigational product have been processed and reported in compliance with the planned

docu

ment arrangements, the protocol, facility

docu

ment arrangements, the protocol, facility

requirements.

docu

ment

requirements.

cann

ot enrolled have been protected, that enrolled subjects (i.e., signin

cann

ot enrolled have been protected, that enrolled subjects (i.e., signinstudy

cann

ot study procedures) are appropriate for the study

cann

ot procedures) are appropriate for the studystudy procedures) are appropriate for the studystudy

cann

ot study procedures) are appropriate for the studystudythe investigational product have been processed and reported in compliance with the planned ca

nnot

the investigational product have been processed and reported in compliance with the planned

be s of an audit or inspection

be s of an audit or inspection

enrolled have been protected, that enrolled subjects (i.e., signinbe

enrolled have been protected, that enrolled subjects (i.e., signin

used

will permit study

used

will permit studyinspections by us

ed

inspections by domestic or foreign regulatoryused

domestic or foreign regulatoryinspections by domestic or foreign regulatoryinspections by us

ed

inspections by domestic or foreign regulatoryinspections bys of an audit or inspection us

ed

s of an audit or inspection

to will permit studyto will permit studysu

pport

verification (SDV) according to the SDV plan prepared for the study

supp

ort verification (SDV) according to the SDV plan prepared for the study

Audit and Inspectionsu

pport

Audit and Inspection

any tries in the source documents.

any tries in the source documents.

verification (SDV) according to the SDV plan prepared for the studyany

verification (SDV) according to the SDV plan prepared for the study

marketi

ng should record the obtaining of consent (date of consent), the subject’s medical

marketi

ng should record the obtaining of consent (date of consent), the subject’s medical

cation treatments and dates (including contraceptive treatment),

marketi

ng

cation treatments and dates (including contraceptive treatment), e visits.

marketi

ng

e visits. The source documents should provide evidence

marketi

ng

The source documents should provide evidence clusion criteria have been met.

marketi

ng

clusion criteria have been met.tries in the source documents. mark

eting

tries in the source documents.

autho

rizati

on minimum requirements for source

autho

rizati

on minimum requirements for source

should contain the identity

autho

rizati

on

should contain the identity related identifiers (such as treatment numbers, CR

autho

rizati

on

related identifiers (such as treatment numbers, CRmention the subject’s participation in the study

autho

rizati

on

mention the subject’s participation in the study and identification of that study

autho

rizati

on

and identification of that studymention the subject’s participation in the study and identification of that studymention the subject’s participation in the study

autho

rizati

on

mention the subject’s participation in the study and identification of that studymention the subject’s participation in the study should record the obtaining of consent (date of consent), the subject’s medical au

thoriz

ation

should record the obtaining of consent (date of consent), the subject’s medical

appli

catio

n and become a permanent part of the subject’s source documents.

appli

catio

n and become a permanent part of the subject’s source documents. will authorize the monitor to compare the content of the printout and the

appli

catio

n will authorize the monitor to compare the content of the printout and the

minimum requirements for source appli

catio

n

minimum requirements for source

and

y must be printed for

and

y must be printed for copies should be signed and

and copies should be signed and

and become a permanent part of the subject’s source documents. and

and become a permanent part of the subject’s source documents.

any

y must be printed for any

y must be printed for

exten

sions

Photocopies of case report forms are not

exten

sions

Photocopies of case report forms are not be considered as acceptable

exten

sions

be considered as acceptable

ce documents when used to establish permanent documentation of data captured on

exten

sions

ce documents when used to establish permanent documentation of data captured on

or correcting fluid or have temporary

or correcting fluid or have temporary

Photocopies of case report forms are not or Photocopies of case report forms are not va

riatio

ns

correcting fluid or have temporary varia

tions

correcting fluid or have temporary

thereo

f.


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.

REDACTED If the data are not available, a straight line should be drawn through al

REDACTED If the data are not available, a straight line should be drawn through al

Data reported in the CRF, which are derived from source documents, should be consistent REDACTED

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 REDACTED

with the source documents or the discrepancies should be explained in those source

COPY The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must COPY The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must

If the data are not available, a straight line should be drawn through alCOPY

If the data are not available, a straight line should be drawn through al

This do

cumen

t 15.5

docu

ment

15.5ca

nnot Copies of

cann

ot Copies of the

cann

ot the sponsor

cann

ot sponsor.

cann

ot .

be individual confidentiality. be individual confidentiality.

the be

the

used

subject’s number,

used

subject’s number, subject’s

used

subject’sinformation, including the us

ed

information, including the individual confidentiality.

used

individual confidentiality.

to results or hospitalization records, must be clearlyto results or hospitalization records, must be clearlysubject’sto subject’s

supp

ort participant exposed to the investigational product.

supp

ort participant exposed to the investigational product.

All supportive documentation submitted to the Sponsor in addition to the su

pport

All supportive documentation submitted to the Sponsor in addition to the

results or hospitalization records, must be clearlysupp

ort

results or hospitalization records, must be clearly

any must submit to the Sponsor or its

any must submit to the Sponsor or its

participant exposed to the investigational product.any

participant exposed to the investigational product.

marketi

ng Data reported in the CRF, which are derived from source documents, should be consistent

marketi

ng Data reported in the CRF, which are derived from source documents, should be consistent


marketi

ng


must submit to the Sponsor or its marketi

ng

must submit to the Sponsor or its

autho

rizati

on The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must

autho

rizati

on The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must


autho

rizati

on


Data reported in the CRF, which are derived from source documents, should be consistent autho

rizati

on

Data reported in the CRF, which are derived from source documents, should be consistent

appli

catio

n y form of obliteration of data in CRFs is not permitted

appli

catio

n y form of obliteration of data in CRFs is not permitted identify

appli

catio

n identify a subject (i.e., a name

appli

catio

n a subject (i.e., a name identify a subject (i.e., a name identify

appli

catio

n identify a subject (i.e., a name identify

The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must ap

plica

tion

The Sponsor cannot interpret a blank answer as “NONE” or “N/A”; therefore, all fields must

and Enter the correct data, explain the correction (if necessary), date and initial the change. and Enter the correct data, explain the correction (if necessary), date and initial the change.

y form of obliteration of data in CRFs is not permitted and

y form of obliteration of data in CRFs is not permitted

any in a CRF needs to be changed, the correction will be made as follows:

any in a CRF needs to be changed, the correction will be made as follows:ex

tensio

ns

’s signature on the CRF attests to its accuracy

exten

sions

’s signature on the CRF attests to its accuracypoint pen, and must be legible.

exten

sions

point pen, and must be legible. in a CRF needs to be changed, the correction will be made as follows:ex

tensio

ns

in a CRF needs to be changed, the correction will be made as follows:

or the Principal

or the Principal va

riatio

ns

the Principal varia

tions

the Principal

thereo

f.


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 StudyUpon 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.

REDACTED y the Sponsor or its designee.

REDACTED y the Sponsor or its designee.

The Sponsor will be responsible for data processing.REDACTED


COPY All documents required for the conduct of the study

COPY All documents required for the conduct of the study as specified in the I

COPY as specified in the IAll documents required for the conduct of the study as specified in the IAll documents required for the conduct of the study

COPY All documents required for the conduct of the study as specified in the IAll documents required for the conduct of the study

orderlyCOPY orderly manner and made available for COPY

manner and made available for orderly manner and made available for orderlyCOPY orderly manner and made available for orderly

y the Sponsor or its designee.COPY

y the Sponsor or its designee.

This do

cumen

t

docu

ment

D

docu

ment D

docu

ment

cann

ot conjunction with the

cann

ot conjunction with the R

cann

ot Return of all study

cann

ot eturn of all study

source documentscann

ot

source documents

be Upon completion of the studybe Upon completion of the study

conjunction with the be

conjunction with the

used

Terminationus

ed

TerminationUpon completion of the studyus

ed

Upon completion of the study

to is of the data.

to is of the data. Regular back

to Regular backsu

pport

review to check for discrepancies and to ensure consistency

supp

ort review to check for discrepancies and to ensure consistency

be used to track all data changes in the database subsequent to the

supp

ort

be used to track all data changes in the database subsequent to the reconciliation of the double-entered data. The SAS

supp

ort

reconciliation of the double-entered data. The SASRegular backsu

pport

Regular back

any Computerized data cleaning checks will be used in addition to manual

any Computerized data cleaning checks will be used in addition to manual

review to check for discrepancies and to ensure consistencyany

review to check for discrepancies and to ensure consistency

marketi

ng


marketi

ng


idatmark

eting

idated electronic database using a Cmark

eting

ed electronic database using a CComputerized data cleaning checks will be used in addition to manual mark

eting

Computerized data cleaning checks will be used in addition to manual

autho

rizati

on manner and made available for

autho

rizati

on manner and made available for


autho

rizati

on


appli

catio

n

as specified in the Iappli

catio

n

as specified in the I manner and made available for ap

plica

tion

manner and made available for

and

and will be included in the final Clinical Study

and

and will be included in the final Clinical Studyany the

any the Investigator

any Investigator

and will be included in the final Clinical Studyany

and will be included in the final Clinical Study

exten

sions

ficant changes to the protocol will ONLY be made as an amendment to the protocol and

exten

sions

ficant changes to the protocol will ONLY be made as an amendment to the protocol and authorities, if

exten

sions

authorities, if

Investigatorexten

sions

Investigator

or ficant changes to the protocol will ONLY be made as an amendment to the protocol and or ficant changes to the protocol will ONLY be made as an amendment to the protocol and va

riatio

ns

the va

riatio

ns

the

thereo

f.


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.

REDACTED report in accordance with the relevant I

REDACTED report in accordance with the relevant I

The report will include a thorough description of the clinical laboratory

REDACTED

The report will include a thorough description of the clinical laboratorya discussion of the results and a list of all measurements as specified in the Statistical

REDACTED

a discussion of the results and a list of all measurements as specified in the Statistical be included in submissions to governmREDACTED

be included in submissions to governm

COPY

This do

cumen

t 15.11

docu

ment 15.11

The

docu

ment

The

cann

ot IEC/IRB upon request.

cann

ot IEC/IRB upon request.

15.11cann

ot

15.11

be insurance policies held by the Sponsor can be made available to the

be insurance policies held by the Sponsor can be made available to the

IEC/IRB upon request.be

IEC/IRB upon request.

used

or disability

used

or disabilityinform the treating phus

ed

inform the treating phinsurance policies held by the Sponsor can be made available to the us

ed

insurance policies held by the Sponsor can be made available to the

to the subjects, in respect of the risks involved in this study

to the subjects, in respect of the risks involved in this study

or disabilityto or disabilitysu

pport

Insurance and Liability

supp

ort Insurance and Liability

supp

ort

The Sponsor has taken out asu

pport

The Sponsor has taken out an insurance policy

supp

ort

n insurance policythe subjects, in respect of the risks involved in this studysu

pport

the subjects, in respect of the risks involved in this study

any

Insurance and Liabilityany

Insurance and Liability

marketi

ng a discussion of the results and a list of all measurements as specified in the Statistical

marketi

ng a discussion of the results and a list of all measurements as specified in the Statistical

be included in submissions to governm

marketi

ng

be included in submissions to governmauthorities worldwide, or used for whatever reason considered appropriate by

marketi

ng

authorities worldwide, or used for whatever reason considered appropriate byNo information contained in the report may

marketi

ng

No information contained in the report may

autho

rizati

on

report in accordance with the relevant I

autho

rizati

on

report in accordance with the relevant IThe report will include a thorough description of the clinical laboratory

autho

rizati

on

The report will include a thorough description of the clinical laboratorya discussion of the results and a list of all measurements as specified in the Statistical au

thoriz

ation

a discussion of the results and a list of all measurements as specified in the Statistical

appli

catio

n on, arrangements will be

appli

catio

n on, arrangements will be drugs and other material in accordance with

appli

catio

n drugs and other material in accordance with

and

The IEC/IRB should also be informed and provided with

and

The IEC/IRB should also be informed and provided with Investigatoran

d Investigatoron, arrangements will be an

d on, arrangements will be

any suspension and the reason(s) for the termination or suspension, in accordance with

any suspension and the reason(s) for the termination or suspension, in accordance with

The IEC/IRB should also be informed and provided with any

The IEC/IRB should also be informed and provided with

exten

sions

or its representatives will

exten

sions

or its representatives will y(ies) of the termination or

exten

sions

y(ies) of the termination or suspension and the reason(s) for the termination or suspension, in accordance with ex

tensio

ns

suspension and the reason(s) for the termination or suspension, in accordance with

or va

riatio

ns

y time for reasons including, va

riatio

ns

y time for reasons including,

thereo

f.


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 InvestigatorUndertaking 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.

REDACTED signature, initials, and dates of participation in the study

REDACTED signature, initials, and dates of participation in the studyCOPY y possible changes made to it.

COPY y possible changes made to it. y qualified

COPY y qualified persons to whom he/she has delegated

COPY persons to whom he/she has delegated

related duties (“Delegation of AuthorityCOPY related duties (“Delegation of Authority

signature, initials, and dates of participation in the studyCOPY

signature, initials, and dates of participation in the study

This do

cumen

t A

docu

ment A f

docu

ment financial

docu

ment inancial financial f

docu

ment financial f

Investigator

docu

ment

Investigator

cann

ot 15.14 Financial Disclosure

cann

ot 15.14 Financial Disclosure

be the site personnel should be updated on a new FDA Form 1572.

be the site personnel should be updated on a new FDA Form 1572.us

ed current affiliation with

used

current affiliation withForm 1572 should also date and sign a recent English version of their CVs.us

ed

Form 1572 should also date and sign a recent English version of their CVs.the site personnel should be updated on a new FDA Form 1572.us

ed

the site personnel should be updated on a new FDA Form 1572.

to must also be providedto

must also be providedcurrent affiliation withto

current affiliation with

supp

ort

signed and dated FDA Form 1572 (su

pport

signed and dated FDA Form 1572 (

must also be providedsupp

ort

must also be provided

any These collaborators should also provid

any These collaborators should also providmark

eting

their updated CV (

marketi

ng

their updated CV (together with a list of their collaborators responsible for the practical conduct of the study

marketi

ng

together with a list of their collaborators responsible for the practical conduct of the studyThese collaborators should also providmark

eting

These collaborators should also provid

autho

rizati

on related duties (“Delegation of Authority

autho

rizati

on related duties (“Delegation of Authority” document with name, function,

autho

rizati

on ” document with name, function,

signature, initials, and dates of participation in the study

autho

rizati

on

signature, initials, and dates of participation in the study conduct and ty

autho

rizati

on

conduct and tysignature, initials, and dates of participation in the study conduct and tysignature, initials, and dates of participation in the study

autho

rizati

on

signature, initials, and dates of participation in the study conduct and tysignature, initials, and dates of participation in the study

appli

catio

n is responsible for the implementation of the protocol but can de

appli

catio

n is responsible for the implementation of the protocol but can deremains responsible for coordinating and informing

appli

catio

n remains responsible for coordinating and informing

y possible changes made to it.

appli

catio

n

y possible changes made to it. persons to whom he/she has delegated ap

plica

tion

persons to whom he/she has delegated ” document with name, function, ap

plica

tion

” document with name, function,

and

is responsible for the implementation of the protocol but can deand

is responsible for the implementation of the protocol but can de

any e

xtens

ions will contact the Sponsor for authorization prior to the destruction of any

exten

sions

will contact the Sponsor for authorization prior to the destruction of anyThe

exten

sions

The

he Sponsor should he/she relocate or move the study

exten

sions

he Sponsor should he/she relocate or move the study related files

exten

sions

related files he Sponsor should he/she relocate or move the study related files he Sponsor should he/she relocate or move the study

exten

sions

he Sponsor should he/she relocate or move the study related files he Sponsor should he/she relocate or move the study

or will contact the Sponsor for authorization prior to the destruction of anyor will contact the Sponsor for authorization prior to the destruction of anyva

riatio

ns th

ereof.


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.

REDACTED

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised

REDACTED

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised and concepts for organization of seizures and epilepsies: report of th

REDACTED

and concepts for organization of seizures and epilepsies: report of thCommission on Classification and TerminologyREDACTED

Commission on Classification and Terminology

COPY The Sponsor will respond to requests for presentation or

COPY The Sponsor will respond to requests for presentation or manner and will not unreasonably withhold authorization.

COPY manner and will not unreasonably withhold authorization.

This do

cumen

t Cramer JA, Perrine K, Devinsky

docu

ment Cramer JA, Perrine K, Devinsky

Development and cross

docu

ment

Development and crossEpilepsia

docu

ment

Epilepsia

cann

ot CH/2711/99 Note for guidance on clinical investigation of medicinal products in the

cann

ot CH/2711/99 Note for guidance on clinical investigation of medicinal products in the

ediatric population

cann

ot ediatric population

Cramer JA, Perrine K, Devinskycann

ot

Cramer JA, Perrine K, Devinsky

be in the treatment of epileptic disorders

be in the treatment of epileptic disorders

CH/2711/99 Note for guidance on clinical investigation of medicinal products in the be

CH/2711/99 Note for guidance on clinical investigation of medicinal products in the us

ed CPMP/EWP/566/

used

CPMP/EWP/566/98 rev 1

used

98 rev 1in the treatment of epileptic disordersus

ed

in the treatment of epileptic disorders

to 98 rev 1

to 98 rev 1

supp

ort

lassification and

supp

ort

lassification and . Proposal for revised classification of epilepsies and epileptic s

supp

ort

. Proposal for revised classification of epilepsies and epileptic s

any

. Proposal for revised clinical and electroencephalographic classification o

any

. Proposal for revised clinical and electroencephalographic classification o

any 1981;22:489

any 1981;22:489-501.

any -501.

lassification and an

y

lassification and

marketi

ng and concepts for organization of seizures and epilepsies: report of th

marketi

ng and concepts for organization of seizures and epilepsies: report of th


marketi

ng



marketi

ng

Commission on Classification and Terminology. Proposal for revised clinical and electroencephalographic classification omark

eting

. Proposal for revised clinical and electroencephalographic classification o-501.

marketi

ng

-501.

autho

rizati

on

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised

autho

rizati

on

Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised and concepts for organization of seizures and epilepsies: report of thau

thoriz

ation

and concepts for organization of seizures and epilepsies: report of th

appli

catio

n with respect to Sponsor’s drug or its development, without the

appli

catio

n 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

appli

catio

n Sponsor’s prior written approval of the content of the presentation, manuscript or other

The Sponsor will respond to requests for presentation or

appli

catio

n

The Sponsor will respond to requests for presentation or manner and will not unreasonably withhold authorization.ap

plica

tion

manner and will not unreasonably withhold authorization.

and

his/her legal representative, the Sponsor will be responsible for the publication of the results

and

his/her legal representative, the Sponsor will be responsible for the publication of the results research findings resulting from the

and research findings resulting from the

with respect to Sponsor’s drug or its development, without the and

with respect to Sponsor’s drug or its development, without the

any agreement with the

any agreement with the In

any In

his/her legal representative, the Sponsor will be responsible for the publication of the results any

his/her legal representative, the Sponsor will be responsible for the publication of the results

exten

sions

Inexten

sions

Investigatorexten

sions

vestigator

or result in the

or result in the va

riatio

ns th

ereof.


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.

REDACTED 2010;15:415

REDACTED 2010;15:415-31

REDACTED -31

REDACTED of the epilepsies. J Neurol Neurosurg Ps

REDACTED of the epilepsies. J Neurol Neurosurg Ps

COPY Khalil B. Emerging drugs for partial onset COPY Khalil B. Emerging drugs for partial onset

-31COPY

-31

This do

cumen

t can

not b

e use

d to s

uppo

rt any

mark

eting

autho

rizati

on Khalil B. Emerging drugs for partial onset

autho

rizati

on Khalil B. Emerging drugs for partial onset

-31

autho

rizati

on

-31

autho

rizati

on

.

autho

rizati

on

.

of the epilepsies. J Neurol Neurosurg Ps

autho

rizati

on

of the epilepsies. J Neurol Neurosurg Ps

appli

catio

n a J, Alexopoulos A, Baumgartner C, Bautista J, Burgess R, et al. Are

appli

catio

n a J, Alexopoulos A, Baumgartner C, Bautista J, Burgess R, et al. Are yndromes and seizure types outdated? Epileptic

appli

catio

n yndromes and seizure types outdated? Epileptic

Khalil B. Emerging drugs for partial onset ap

plica

tion

Khalil B. Emerging drugs for partial onset

and Survey

and Survey

lepsiaand lepsia.and . 1990;31:391and 1990;31:391

any Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255

any Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255

Surveyany

Survey of seizure disorders any

of seizure disorders Survey of seizure disorders Surveyany

Survey of seizure disorders Survey

exten

sions

and Depression Scale

exten

sions

and Depression Scale

Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255exten

sions

Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255

or va

riatio

ns th

ereof.


17 SPONSOR DECLARATIONI 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 do

cumen

t can

not b

e use

d to s

uppo

rt

supp

ort an

y an

y mark

eting

marketi

ng au

thoriz

ation

appli

catio

n and

any e

xtens

ions o

r vari

ation

s

varia

tions

varia

tions

there

of.

Brivaracetam / N01199

Documents

Transcript of Brivaracetam / N01199