Clinical trial NCT02555215
Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: Pediatrics
Sponsor: Biogen
Start date: 2016-02-22; Completion date: 2018-09-24
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to evaluate the long-term safety of BG00012 in subjects who completed Study 109MS202 (NCT02410200). Secondary objectives are as follows: To evaluate the long-term efficacy of BG00012 and to describe the long-term Multiple Sclerosis (MS) outcomes in subjects who completed Study 109MS202 (NCT02410200).

Detailed description:

Arms: arm 1: Participants will receive 120 mg capsule(s) taken orally.
Interventions: intervention 1: dimethyl fumarate
Intervention descriptions: intervention 1: administered orally

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER:
109MS311/NCT02555215
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT:
3
PROTOCOL TITLE: A Multicenter Extension Study to Determine the Long-Term Safety 
and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple 
Sclerosis
EUDRA CT NO:
2015-003282-29
DATE:
24 April 2018
Version 3.0
FINAL
Supersedes previous Version 2.0 dated 08 January 2016




Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SPONSOR INFORMATION .......................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................10
3.
SYNOPSIS .................................................................................................................11
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
109MS311...................................................................................................................13
4.1.
Study Schematic .........................................................................................................13
4.2.
Schedule of Activities.................................................................................................14
4.3.
Additional Information ...............................................................................................18
4.3.1.
Blood Volumes...........................................................................................................18
5.
INTRODUCTION......................................................................................................19
5.1.
Overview of Multiple Sclerosis..................................................................................19
5.2.
Current Therapies for Multiple Sclerosis ...................................................................19
5.3.
Profile of Previous Experience With BG00012..........................................................20
5.3.1.
Nonclinical Safety Experience ...................................................................................20
5.3.2.
Clinical Experience.....................................................................................................20
5.4.
Study Rationale...........................................................................................................22
5.5.
Rationale for Dosing Regimen ...................................................................................22
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................23
6.1.
Primary Objective and Endpoint ................................................................................23
6.2.
Secondary Objectives and Endpoints .........................................................................23
7.
STUDY DESIGN .......................................................................................................24
7.1.
Study Overview ..........................................................................................................24
7.2.
Overall Study Duration and Follow-Up .....................................................................24
7.2.1.
Enrollment ..................................................................................................................24
7.2.2.
Treatment....................................................................................................................24
7.2.3.
Follow-Up...................................................................................................................24
7.3.
Relapses ......................................................................................................................25
7.4.
Study Stopping Rules .................................................................................................25
7.5.
End of Study ...............................................................................................................25


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
CONFIDENTIAL
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8.
SELECTION OF SUBJECTS ....................................................................................26
8.1.
Inclusion Criteria ........................................................................................................26
8.2.
Exclusion Criteria.......................................................................................................26
9.
ENROLLMENT AND REGISTRATION .................................................................28
9.1.
Screening and Enrollment...........................................................................................28
9.2.
Registration of Subjects..............................................................................................28
9.3.
Blinding Procedures....................................................................................................28
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................29
10.1.
Discontinuation of Study Treatment...........................................................................29
10.2.
Withdrawal of Subjects From Study...........................................................................29
11.
STUDY TREATMENT USE .....................................................................................30
11.1.
Regimen......................................................................................................................30
11.2.
Modification of Dose and/or Treatment Schedule......................................................30
11.2.1.
Dosing Interruption for Abnormal Laboratory Values...............................................30
11.2.2.
Resumption of Study Treatment Dosing ....................................................................32
11.2.3.
Subsequent Development of Additional Laboratory Abnormalities ..........................33
11.2.4.
Abnormal Urinalyses That Require Additional Evaluation........................................33
11.2.5.
Treatment Schedule for Subjects With Abnormal Lymphocyte Count......................33
11.2.5.1.
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................33
11.2.5.2.
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................34
11.2.6.
Dosage Reductions .....................................................................................................35
11.3.
Precautions..................................................................................................................35
11.4.
Compliance.................................................................................................................36
11.5.
Concomitant Therapy and Procedures........................................................................36
11.5.1.
Concomitant Therapy .................................................................................................36
11.5.1.1.
Allowed Concomitant Therapy...................................................................................36
11.5.1.2.
Disallowed Concomitant Therapy..............................................................................36
11.5.2.
Concomitant Procedures.............................................................................................37
11.5.3.
Treatment of Relapses on Scheduled or Unscheduled Visits.....................................37


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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11.6.
Continuation of Treatment..........................................................................................37
12.
STUDY TREATMENT MANAGEMENT................................................................38
12.1.
BG00012.....................................................................................................................38
12.1.1.
BG00012 Preparation .................................................................................................38
12.1.2.
BG00012 Storage........................................................................................................38
12.1.3.
BG00012 Handling and Disposal...............................................................................38
12.1.4.
BG00012 Accountability............................................................................................39
13.
EFFICACY ASSESSMENTS ....................................................................................40
13.1.
Clinical Efficacy Assessments....................................................................................40
13.2.
MRI Efficacy Assessments.........................................................................................40
14.
SAFETY ASSESSMENTS ........................................................................................41
14.1.
Clinical Safety Assessments.......................................................................................41
14.2.
Laboratory Safety Assessments..................................................................................41
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................42
15.1.
Definitions ..................................................................................................................42
15.1.1.
Adverse Event.............................................................................................................42
15.1.2.
Serious Adverse Event................................................................................................42
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................43
15.2.
Safety Classifications..................................................................................................43
15.2.1.
Investigator Assessment of Events.............................................................................43
15.2.2.
Relationship of Events to Study Treatment................................................................43
15.2.3.
Severity of Events.......................................................................................................44
15.2.4.
Expectedness of Events ..............................................................................................44
15.3.
Monitoring and Recording Events..............................................................................44
15.3.1.
Adverse Events ...........................................................................................................44
15.3.2.
Serious Adverse Events..............................................................................................44
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................45
15.3.3.1.
Deaths .........................................................................................................................45
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................45
15.4.
Procedures for Handling Special Situations ...............................................................46
15.4.1.
Pregnancy ...................................................................................................................46


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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15.4.2.
Overdose.....................................................................................................................46
15.4.3.
Medical Emergency....................................................................................................46
15.4.3.1.
Unblinding for Medical Emergency...........................................................................46
15.5.
Contraception Requirements ......................................................................................46
15.6.
Safety Responsibilities................................................................................................47
15.6.1.
The Investigator..........................................................................................................47
15.6.2.
Biogen.........................................................................................................................48
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........49
16.1.
Efficacy.......................................................................................................................49
16.1.1.
Analysis Population....................................................................................................49
16.1.2.
Methods of Analysis...................................................................................................49
16.1.2.1.
Analysis of the Primary Endpoint...............................................................................49
16.1.2.2.
Analysis of the Secondary Endpoints.........................................................................49
16.2.
Pharmacokinetics........................................................................................................49
16.3.
Pharmacodynamics.....................................................................................................49
16.4.
Biomarker Analyses/Pharmacogenomics ...................................................................49
16.5.
Safety..........................................................................................................................49
16.5.1.
Analysis Population....................................................................................................49
16.5.1.1.
Adverse Events ...........................................................................................................50
16.5.1.2.
Clinical Laboratory Results........................................................................................50
16.5.1.3.
Vital Signs ..................................................................................................................50
16.6.
Antigenicity/Immunogenicity Data ............................................................................50
16.7.
Interim Analyses.........................................................................................................50
16.8.
Sample Size Considerations .......................................................................................50
17.
ETHICAL REQUIREMENTS ...................................................................................51
17.1.
Declaration of Helsinki...............................................................................................51
17.2.
Ethics Committee........................................................................................................51
17.3.
Subject Information and Consent ...............................................................................51
17.4.
Subject Data Protection ..............................................................................................52
17.5.
Compensation for Injury.............................................................................................52
17.6.
Conflict of Interest......................................................................................................52


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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Biogen MA Inc.
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17.7.
Registration of Study and Disclosure of Study Results..............................................52
18.
ADMINISTRATIVE PROCEDURES.......................................................................53
18.1.
Study Site Initiation....................................................................................................53
18.2.
Quality Assurance.......................................................................................................53
18.3.
Monitoring of the Study..............................................................................................53
18.4.
Study Funding.............................................................................................................53
18.5.
Publications.................................................................................................................53
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................54
19.1.
External Contract Organizations.................................................................................54
19.1.1.
Contract Research Organization.................................................................................54
19.1.2.
Electronic Data Capture..............................................................................................54
19.1.3.
Central Laboratories for Laboratory Assessments .....................................................54
19.2.
Study Committees.......................................................................................................54
19.2.1.
Advisory Committee...................................................................................................54
19.2.2.
Independent Data Monitoring Committee..................................................................54
19.3.
Changes to Final Study Protocol ................................................................................55
19.4.
Ethics Committee Notification of Study Completion or Termination........................55
19.5.
Retention of Study Data..............................................................................................55
19.6.
Study Report Signatory...............................................................................................55
20.
REFERENCES ...........................................................................................................56
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................58
LIST OF TABLES
Table 1:
Study Activities for Study 109MS311........................................................................14
Table 2:
Additional Study Activities for Study 109MS311......................................................16
Table 3:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
Treatment....................................................................................................................30
Table 4:
Management of Lymphocyte Count <LLN................................................................32
Table 5:
Lymphocyte Count Criteria Requiring Permanent Discontinuation of 
BG00012 Treatment ...................................................................................................34


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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Biogen MA Inc.
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LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................13
Figure 2:
Schedule for Subjects who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................35


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
9
1.
SPONSOR INFORMATION
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Australia PTY Ltd
Suite 1, Level 3, 
123 Epping Road
North Ryde, NSW 2113
Australia
For urgent medical issues in which the study’s Medical Director should be contacted, please
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities.


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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Biogen MA Inc.
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2.
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine transaminase
ARR
annualized relapse rate
AST
aspartate transaminase
BID
twice daily
BUN
blood urea nitrogen
CNS
central nervous system
CRO
contract research organization
DHA
Directions for Handling and Administration
DMF
dimethyl fumarate
eCRF
electronic case report form
EDSS
Expanded Disability Status Scale
GCP
Good Clinical Practice
GI
gastrointestinal
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IV
intravenous
IVMP
intravenous methylprednisolone
LLN
lower limit of normal
MMF
monomethyl fumarate
MRI
magnetic resonance imaging
MS
multiple sclerosis
PK
pharmacokinetics
PTH
parathyroid hormone
RRMS
relapsing-remitting multiple sclerosis
SABR
Safety and Benefit-Risk Management
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
TID
3 times daily
ULN
upper limit of normal
US
United States
WBC
white blood cell


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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Biogen MA Inc.
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3.
SYNOPSIS
Protocol Number:
109MS311
Protocol Title:
A Multicenter Extension Study to Determine the Long-Term 
Safety and Efficacy of BG00012 in Pediatric Subjects With 
Relapsing-Remitting Multiple Sclerosis
Version Number
3.0
Name of Study Treatment:
BG00012 (Dimethyl Fumarate; Tecfidera®)
Study Indication:
Relapsing-remitting multiple sclerosis (RRMS)
Study Rationale
With no approved multiple sclerosis (MS) therapies in the 
pediatric population, there exists a significant unmet need 
for approved treatment options.  In the adult population, 
BG00012 is a therapeutic option with demonstrated efficacy 
and acceptable tolerability and safety profiles combined 
with the ease of oral administration.  BG00012 was first 
approved (as Tecfidera) in the United States in 2013 for the 
treatment of adult patients with relapsing forms of MS and 
has since been approved in Europe and other regions.  This 
study will extend therapy from the ongoing BG00012 
pediatric Study 109MS202, in which the pharmacokinetics 
and efficacy of BG00012 in pediatric subjects with RRMS 
are being evaluated, in order to further evaluate the 
long-term safety and efficacy of BG00012 in these subjects. 
Phase of Development:
3
Study Objectives and 
Endpoints:
The primary objective of the study is to evaluate the 
long-term safety of BG00012 in subjects who completed 
Study 109MS202.
The primary endpoint that relates to this objective is the 
incidence of adverse events (AEs), serious AEs, and 
discontinuations of study treatment due to an AE
Secondary objectives and endpoints are as follows:
To evaluate the long-term efficacy of BG00012.

The total number of new or newly enlarging T2 
hyperintense lesions on brain magnetic 


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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resonance imaging  scans

The annualized relapse rate

The proportion of subjects who experience 1 or 
more relapses during the study period
To describe the long-term MS outcomes in subjects who 
completed Study 109MS202.

The degree of disability as measured by the 
Expanded Disability Status Scale (EDSS) and 
disability progression (as measured by at least a 
1.0-point increase on the EDSS from baseline 
EDSS ≥1.0 that is sustained for 24 weeks or at 
least a 1.5-point increase on the EDSS from 
baseline EDSS = 0 that is sustained for 
24 weeks)
Study Design:
This is a multicenter, open-label extension of 
Study 109MS202 that is designed to evaluate the long-term 
safety and efficacy of BG00012 in pediatric subjects.
Study Location:
Approximately 20 sites globally are planned.
Number of Planned Subjects:
The number of subjects who are eligible for this study will 
be determined by the number of subjects who have 
completed Study 109MS202 as per protocol.
Study Population:
This study will be conducted in subjects who completed 
Study 109MS202 as per protocol. 
Detailed criteria are described in Section 8.
Treatment Groups:
All subjects will receive BG00012 240 mg twice daily 
(2 capsules of 120 mg).
Duration of Treatment and 
Follow-up:
The treatment period is 96 weeks (2 years) and the 
Follow-Up Safety Visit will take place 4 weeks after the last 
dose of study treatment.


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 109MS311
4.1.
Study Schematic
Figure 1:
Study Design


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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4.2.
Schedule of Activities
Table 1:
Study Activities for Study 109MS311
Tests and Assessments1
Year 1
Year 2
Safety
Follow-Up 
Visit
Baseline 
Visit
(Day 1)2
Visit 1 
(Week 
125d)
Visit 2
(Week 
16 5d)
Visit 3
(Week 
24 5d)
Visit 4
(Week 
36 5d)
Visit 5
(Week 
48 5d)
Visit 6
(Week 
60 5d)
Visit 7
(Week 
64 5d)
Visit 8
(Week 
72 5d)
Visit 9
(Week 
84 5d)
Visit 10
(Week 
96 5d)
Informed Consent and 
Assent3
X
Eligibility Criteria
X
Medical History
X
MS-Related Medical 
History4
X
Physical Examination
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
Vital Signs5
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Blood Chemistry
X
X
X
X
X
X
X
X
Urine Pregnancy Test6
X
X
X
X
X
X
X
X
X
X
Urinalysis7,8
X
X
X
X
X
X
X
X
PTH and Vitamin D Levels
X
X
X
X
Brain MRI Scan9,10
X
X
X
X
X
EDSS
X
X
X
X
X
X
X
Dispense Study Treatment11
X
X
X
X
X
X
X
X
Concomitant Therapy and 
Procedures Recording
Monitor and record throughout the study
AE/SAE Reporting
Monitor and record throughout the study
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
PTH = parathyroid hormone; SAE = serious adverse event.
1 Tests and assessments must be completed prior to study treatment dispensation. 


Protocol 109MS311
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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2 The Final Study Visit for Study 109MS202 will serve as the Baseline Visit for this extension study.  The Final Study Visit from Study 109MS202 can be within 
4 weeks of the Baseline Visit for Study 109MS311 if the 2 visits cannot be combined.
3 Written informed consent from the subject’s parents or legal guardians and assent from the subject, if appropriate, must be obtained prior to performing any 
study-related procedures.
4 MS-related medical history will include complete MS history of disease, MS diagnostic criteria, MS signs and symptoms, and MS treatment history.
5 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements.
6 For females of childbearing potential.  Results must be known prior to study treatment dispensation.
7 Urine cytology must be performed at all visits indicated if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits.  If urine cytology is 
positive for malignant cells, the subject must permanently discontinue study treatment.
8 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol.
9 MRI must not be performed within 30 days of receiving a course of steroids.
10The time between the Week 24 MRI and the Week 16 MRI must be the same as the time between the Day 0 MRI and Week -8 MRI in Study 109MS202 within 
a window of ±3 days.  For example, if the Day 0 and Week -8 MRIs for a particular subject occurred 8 weeks apart in Study 109MS202, then the Week 24 MRI 
in Study 109MS311 should be 8 weeks ± 3 days after the Week 16 MRI.  If necessary, the Week 24 MRI may be conducted separately from the Week 24 clinic 
visit.  Similarly, the time between the Week 72 MRI and the Week 64 MRI must be the same as the time between the Day 0 MRI and Week -8 MRI in Study 
109MS202 within a window of ±3 days. If necessary, the Week 72 MRI may be conducted separately from the Week 72 clinic visit.
11Initial dispensation of study treatment may require an additional visit on or around Day 7.  Laboratory results must be evaluated and eligibility confirmed prior 
to dispensation of study treatment.


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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Table 2:
Additional Study Activities for Study 109MS311
Tests and Assessments
Unscheduled Relapse Assessment 
Visit1
(within 72 hours after symptom onset)
Discontinuation/
Withdrawal Visit2
(as soon as possible but no later than 
4 weeks after last dose of study 
treatment)
Lymphocyte Follow-Up Visit3
Physical Examination
X
X
X
Body Weight
X
X
X
Height
X
Vital Signs4
X
X
X
12-Lead ECG
X
Hematology5,6
X
X
X
Blood Chemistry6
X
X
Urine Pregnancy Test7
X
X
Urinalysis6,8
X
X
PTH and Vitamin D Levels
X
EDSS
X
X
Brain MRI Scan9
X10
Relapse Assessment
X
Concomitant Therapy and 
Procedures
Monitor and record throughout the study 
AE/SAE Recording
Monitor and record throughout the study
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; LLN = lower limit of normal; MRI = magnetic resonance imaging; 
MS = multiple sclerosis; PTH = parathyroid hormone; SAE = serious adverse event.
1 An Unscheduled Relapse Assessment Visit will be conducted within 72 hours of symptom onset of a suspected relapse (i.e., new or recurrent neurologic
symptom[s]).
2 Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from the study.  The Discontinuation/Withdrawal 
Visit should be conducted as soon as possible and no later than 4 weeks after the last dose of study treatment.


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
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3 Subjects who complete, temporarily withhold, or permanently discontinue study treatment for any reason and have a lymphocyte count <LLN will continue 
protocol-required visits and assessments and be followed every 4 weeks for 24 weeks and then every 3 months (unless clinically indicated more often or at 
the Investigator’s discretion) until the lymphocyte count is ≥LLN or for 52 weeks after the last dose, or until one of the following occurs: 1) the subject 
continues on commercial BG00012 following study withdrawal/completion, or 2) the subject is initiated on another MS disease-modifying therapy.  Note:
lymphocyte counts ≥LLN at 2 consecutive visits are required.
4 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements.
5 Hematology testing must be performed every 4 weeks in subjects with lymphocyte count <LLN.
6 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol.
7 For females of childbearing potential.
8 Urine cytology must be performed if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits or at the Unscheduled Relapse Assessment 
Visit or the Discontinuation/Withdrawal Visit.
9 An MRI must not be performed within 30 days of receiving a course of steroids.
10A brain MRI scan will be performed unless assessed in the last 30 days. 


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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4.3.
Additional Information 
4.3.1.
Blood Volumes
Every effort must be made to collect the minimum blood volume needed per protocol.  The 
blood volumes required for this study do not exceed the recommended pediatric blood volume 
limits for sampling, i.e., volumes do not exceed 3% of the total blood volumes during a period of 
4 weeks or 1% at any single visit [European Commission 2008].  For example, in a 30-kg child 
(the lowest weight permitted in this study), it is estimated that 1% of the total volume would be 
approximately 21 mL.  Children weighing more than 30 kg would have higher permitted 
amounts.  The total blood volumes drawn at each visit will be 5 mL or less.  The approximate 
amount of blood to be drawn over the entire study period will be 50 mL.


Protocol 109MS311
Version 3.0
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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5.
INTRODUCTION 
5.1.
Overview of Multiple Sclerosis
Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central 
nervous system (CNS) that is characterized by inflammation, demyelination, and 
oligodendrocyte and neuronal loss.  It is the most common demyelinating disorder of the CNS, 
affecting approximately 2.5 million people worldwide.  MS primarily affects adults, with clinical 
onset occurring most commonly between the ages of 20 and 40 years [O'Connor and Canadian 
Multiple Sclerosis Working Group 2002].  Approximately 2.2% to 4.4% of all MS cases have 
onset during adolescence or childhood [Chitnis 2011], with girls affected more than boys, and 
most cases being relapsing-remitting multiple sclerosis (RRMS).
5.2.
Current Therapies for Multiple Sclerosis
Despite the availability of several therapies approved for the treatment of adult patients with MS, 
there remains an unmet need for safe and effective treatments for pediatric patients with MS.  
Currently, there are no treatments that are approved to treat pediatric MS, and no randomized 
controlled clinical studies have been completed that demonstrate that the agents available for 
treatment of MS in adults are safe and effective in pediatric patients.  Moreover, there are no data 
on the pharmacological characterization of any of the disease-modifying MS therapies in 
pediatric patients.  Thus, current treatment options for pediatric patients with MS are adapted 
from therapeutic paradigms for adult patients, with dosing recommendations based solely on 
adult subject data and expert opinion.
The most commonly used therapies in the pediatric population are interferons and glatiramer 
acetate [Waldman 2011].  Relative to placebo, these agents have been shown to reduce relapse 
rate by approximately 30% and may decrease disease progression [Jacobs 2000; Johnson 1995; 
Paty and Li 1993; PRISMS Study Group 2001; The IFNB Multiple Sclerosis Study Group 1993].
Other therapies currently approved for use in adults with MS include the following:

Natalizumab:  a humanized monoclonal antibody directed against α4 integrins 
[Polman 2006]

Fingolimod:  a selective oral immunosuppressant that is metabolized to a functional 
antagonist of sphingosine 1-phosphate receptors on lymphocytes [Kappos 2010]

Mitoxantrone:  a synthetic antineoplastic anthracenedione that intercalates into DNA, 
interfering with its synthesis and repair [Chitnis 2012]

Teriflunomide:  an immunosuppressive drug inhibiting pyrimidine synthesis by 
blocking dihydroorotate dehydrogenase [O'Connor 2011]

Alemtuzumab:  a monoclonal antibody directed against cluster of differentiation 52 
[Cohen 2012]


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
Tecfidera®:  a dimethyl fumarate (DMF)-containing drug that activates the Nrf2 
antioxidant response pathway to mitigate inflammatory stress [Ghoreschi 2011; 
Nguyen 2003]
5.3.
Profile of Previous Experience With BG00012
5.3.1.
Nonclinical Safety Experience
Nonclinical safety studies were performed to support the development of BG00012 (Tecfidera®) 
for the treatment of MS.  CNS, respiratory, and cardiovascular safety studies demonstrated no 
drug-related adverse effects on those systems, which is consistent with human data.  There were 
no findings of mutagenicity, impaired fertility, or teratogenicity.  Repeat-dose toxicology studies 
were performed in rodents (mouse and rat) and non-rodents (dog and monkey).  Findings in these 
studies in the liver, forestomach, and testis concluded that there is limited concern related to 
human risk.  In the male rat juvenile toxicology study that specifically evaluated the reproductive 
organs, there were no toxicology findings.  Kidney findings seen in animals were not observed in 
humans.  In lifetime carcinogenicity studies, renal tumors were attributed to a rodent-specific 
exacerbation of nephropathy.
See the Investigator’s Brochure for more detailed information on nonclinical studies as well as 
information on nonclinical pharmacology and pharmacokinetic (PK) studies.
5.3.2.
Clinical Experience
BG00012 240 mg twice daily (BID) is currently approved (as Tecfidera) for the treatment of 
adult patients with MS in the United States (US), the European Union, and other countries. 
The efficacy and safety of BG00012 are well established and based on data from Phase 2 and 3 
placebo-controlled safety and efficacy studies (Studies C-1900 Part 1, 109MS301 [DEFINE], 
and 109MS302 [CONFIRM]) and their uncontrolled extensions (Studies C-1900 Part 2 and 
109MS303 [ENDORSE]).  In these studies, over 2500 subjects received treatment with 
BG00012.  The overall exposure to BG00012 in these subjects was approximately 
6100 subject-years as of September 2013.
Results of the Phase 3 clinical studies demonstrate that BG00012 240 mg BID or 3 times daily 
(TID) is an efficacious treatment for RRMS.  In these Phase 3 studies, BG00012 resulted in a 
significant reduction in the risk of relapse and annualized relapse rate (ARR), and the treatment 
had a positive effect on 12-week Expanded Disability Status Scale (EDSS) disability 
progression, with statistical significance achieved in Study 109MS301.  A robust, statistically 
significant effect was also observed on magnetic resonance imaging (MRI) endpoints, including 
the number and volume of new or newly enlarging T2 hyperintense lesions, 
gadolinium-enhancing lesions, and new or newly enlarging T1 hypointense lesions compared 
with placebo.  Efficacy was seen as early as 6 months and maintained over the 2-year span of 
Studies 109MS301 and 109MS302.  In the ongoing Phase 3, uncontrolled extension Study 
109MS303 (ENDORSE), which includes subjects who completed Studies 109MS301 or 
109MS302, sustained efficacy was observed through 5 years of treatment, and the safety profile 
of continued BG00012 treatment was consistent with that observed in the 2-year Phase 3 studies. 


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Overall, safety data from the clinical development program showed that BG00012 was well 
tolerated and has an acceptable safety profile.  In the BG00012 240 mg BID group, the most 
common adverse events (AEs; incidence ≥5%) that also occurred at an incidence of ≥2% higher 
than in the placebo group were flushing and hot flush, gastrointestinal (GI) events (diarrhea, 
nausea, abdominal pain upper, abdominal pain, vomiting, and dyspepsia), skin events (pruritus, 
rash, and erythema), nasopharyngitis, urinary tract infection, upper respiratory tract infection, 
albumin urine present, proteinuria, and microalbuminuria.  The AE profile was similar for 
subjects who received 240 mg TID.
In placebo-controlled studies, decreases in mean white blood cell (WBC) and lymphocyte counts 
were observed over the first year of treatment (approximately 10% and 30%, respectively) with 
both dose regimens of BG00012.  Mean WBC and lymphocyte counts then plateaued and 
remained stable, even during longer periods of observation of approximately 5.25 years.  
Analysis of the data did not show a clear correlation between infections, serious infections, and 
lymphocyte counts.  No increased risk of infection, serious infection, or opportunistic infection 
was observed in subjects treated with BG00012 in the placebo-controlled studies.  With 
open-label and marketed use of BG00012, progressive multifocal leukoencephalopathy has been 
observed in the setting of severe and prolonged lymphopenia.  There has been no other evidence 
of increased risk of infections, serious infections, or other opportunistic infections (in open-label 
and marketed use of BG00012).
BG00012 was also associated with a small increase in the incidence of elevations of liver 
transaminases compared to placebo.  In the controlled studies, this increase was primarily due to 
differences that occurred within the first 6 months of treatment.  The majority of subjects with 
elevations had alanine transaminase (ALT) or aspartate transaminase (AST) levels <3 times the 
upper limit of normal (ULN).  No patients had elevations of ALT or AST ≥3 × ULN associated 
with an elevation in total bilirubin of >2 × ULN.  There were no cases of hepatic failure due to 
BG00012.  During extended treatment with BG00012, ALT and AST levels remained stable 
through 3.5 years of observation.  Based on these data, there appears to be a transient increase in 
liver transaminases with BG00012 relative to placebo that does not appear to be associated with 
any clinically significant liver pathology.
Although the kidney was identified as a target organ of BG00012 toxicity in nonclinical studies, 
subjects treated with BG00012 in the clinical studies did not appear to have a higher risk of renal 
or urinary events.  Small increases in proteinuria were observed, but the increases did not appear 
to be clinically significant.  On laboratory evaluation, there were no clinically relevant changes 
in blood urea nitrogen (BUN), creatinine, electrolytes, calcium, phosphorus, parathyroid 
hormone (PTH), or 1,25-dihydroxyvitamin D.  In the Phase 3 studies (Studies 109MS301 and 
109MS302), there were no differences between placebo and BG00012 BID in the incidence of 
proteinuria on 2 consecutive urinalyses (defined as trace or greater) or of 3+ or 4+ protein, both 
of which are potential indicators of significant proteinuria and renal dysfunction.  In addition, 
there was no evidence of changes over time in β2-microglobulinuria and microalbuminuria, 
which are more sensitive and specific markers of renal tubular dysfunction, even during longer 
periods of observation of approximately 3.5 years.


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In the controlled studies, there was no increased incidence of malignancies in subjects who 
received BG00012 compared with placebo.  The types of malignancies observed and their 
incidence were within expected background rates.  
5.4.
Study Rationale
In adult subjects with RRMS, BG00012 demonstrated efficacy and had an acceptable safety 
profile in 2 Phase 3 studies, Studies 109MS301 and 109MS302.  With no approved therapies, 
there exists a significant unmet need for MS treatment options in the pediatric population.  In the 
adult population, BG00012 is a therapeutic option with demonstrated efficacy and acceptable 
tolerability and safety profiles combined with the ease of oral administration.  This study will 
extend therapy from the ongoing BG00012 pediatric Study 109MS202, in which the PK and 
efficacy of BG00012 in pediatric subjects with RRMS are being evaluated, in order to further 
evaluate the long-term safety and efficacy of BG00012 in these subjects.
5.5.
Rationale for Dosing Regimen
The BG00012 dosage selected for this study (240 mg BID) is the approved BG00012 dosing 
regimen in adult patients with MS.
In adults, after oral administration, DMF is well absorbed and extensively metabolized by 
esterases to its primary active metabolite, monomethyl fumarate (MMF).  As a result, DMF is 
not quantifiable in plasma, and all PK analyses have been performed based on MMF 
concentrations.  Downstream metabolism of DMF/MMF occurs through the tricarboxylic acid 
cycle, with exhalation of carbon dioxide serving as a major route of elimination.  The PK of 
BG00012 has been thoroughly evaluated in adults.  Body weight is a significant covariant for 
BG00012 exposure in that the area under the curve and the maximum concentration are 
decreased by 2% and 1.4%, respectively, for every 1-kg increase in body weight within the 
weight range of 45 to 112 kg.  This translates to a 2-fold increase in exposure levels as body 
weight decreases from 112 to 45 kg.
Despite the effect of body weight changes on the exposure levels of BG00012, data from the 
pivotal Phase 3 studies suggested that the variability in exposure did not affect safety and 
efficacy measures in adult patients.  Notably, the efficacy and tolerability profiles of BG00012 at 
240 mg BID were indistinguishable from those at 240 mg TID, with a wide range of overlapping 
exposures between the 2 dosages.
A Phase 1 PK study (Study 109MS101) revealed no apparent differences in the kinetics of 
BG00012 across the age range of 21 to 51 years once the weight relationship was accounted for.  
Published data [Zhu 2009] indicate that there were no notable differences in the expression and 
activities of esterases in juveniles (12 to 18 years old) when compared with adults.  These 
findings suggest that the disposition of BG00012 is unlikely to change with age for the target 
population (10 to 18 year olds).
Taken together, these data indicate that 240 mg BID, the approved dose in adults, should be 
tolerable in pediatric subjects meeting the inclusion criteria for the parent study (109MS202) and 
the current extension study.  As such, this dose was chosen for the parent and current studies.


Protocol 109MS311
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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Primary Objective and Endpoint
The primary objective of the study is to evaluate the long-term safety of BG00012 in subjects 
who completed Study 109MS202.
The primary endpoint that relates to this objective is the incidence of AEs, serious AEs (SAEs), 
and discontinuations of study treatment due to an AE.
6.2.
Secondary Objectives and Endpoints
A secondary objective is to evaluate the long-term efficacy of BG00012.
The endpoints that relate to this objective are the total number of new or newly enlarging T2 
hyperintense lesions on brain MRI scans, the ARR, and the proportion of subjects who 
experience 1 or more relapses during the study period.
Another secondary objective is to describe the long-term MS outcomes in subjects who 
completed Study 109MS202.
The endpoint that relates to this objective is the degree of disability as measured by the EDSS 
and disability progression (as measured by at least a 1.0-point increase on the EDSS from 
baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS 
from baseline EDSS = 0 that is sustained for 24 weeks).


Protocol 109MS311
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7.
STUDY DESIGN
7.1.
Study Overview
This is a multicenter, open-label extension of Study 109MS202 that is designed to evaluate the 
long-term safety and efficacy of BG00012 in pediatric subjects.
See Figure 1 for a schematic of the study design.
7.2.
Overall Study Duration and Follow-Up
The study period will consist of enrollment, treatment, and follow-up.  The study duration is 
approximately 104 weeks, consisting of a 4-week enrollment period (if the Final Study Visit 
from Study 109MS202 cannot be combined with the Baseline Visit for this study), a 96-week 
treatment period, and a Safety Follow-Up Visit up to 4 weeks after the last dose of study 
treatment.  Unscheduled Relapse Assessment Visits and Lymphocyte Follow-Up Visits will be 
performed as necessary.
7.2.1.
Enrollment
Subject eligibility for the study will be determined at the Final Study Visit for Study 109MS202 
or within 4 weeks prior to study entry.  The Final Study Visit for Study 109MS202 will serve as 
the Baseline Visit for this study.
7.2.2.
Treatment
Eligible subjects will report to the study site to receive study treatment approximately every 
12 weeks for up to 96 weeks (2 years).
7.2.3.
Follow-Up
Subjects are to return to the study site for a follow-up visit 4 weeks after their last treatment visit 
(Visit 10 at Week 96 [±5 days]).
Subjects who withdraw prematurely from the study will complete the Early Withdrawal Visit, 
which should be conducted as soon as possible and no later than 4 weeks after the subject’s last 
dose of study treatment.  Subjects who withdraw prematurely should be encouraged to complete 
the Safety Follow-Up Visit 4 weeks after the last dose of study treatment.
Subjects who complete, temporarily withhold, or permanently discontinue study treatment for 
any reason and have a lymphocyte count less than the lower limit of normal (LLN) will be 
followed every 4 weeks for 24 weeks and then every 3 months (unless clinically indicated more 
often or at the Investigator’s discretion) until the lymphocyte count is ≥LLN or for 52 weeks 
after the last dose, or until one of the following occurs: 1) the subject continues on commercial 
BG00012 following study withdrawal/completion, or 2) the subject is initiated on another MS 
disease-modifying therapy.


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7.3.
Relapses
Suspected relapses during this study will be evaluated and confirmed according to the protocol 
by the Investigator.  Relapses are defined as new or recurrent neurologic symptoms not 
associated with fever or infection, lasting at least 24 hours, and accompanied by new objective 
neurological findings upon examination by the Investigator.  New or recurrent neurologic 
symptoms that evolve gradually over months should be considered disability progression, not an 
acute relapse, and should not be treated with steroids.  New or recurrent neurologic symptoms 
that occur less than 30 days following the onset of a protocol-defined relapse should be 
considered part of the same relapse and would not be treated with intravenous 
methylprednisolone (IVMP) within the protocol.
If a subject experiences new neurologic symptoms, then the subject or caregiver must contact the 
Investigator within 48 hours of the onset of symptoms to complete a Telephone Questionnaire to 
determine the necessity of an Unscheduled Relapse Assessment Visit.  If required, the subject 
will then be evaluated in person by the Investigator within 5 days of the onset of the potential 
relapse.  The Investigator is to perform a relapse assessment and obtain an EDSS score.  To 
ensure consistency across sites, Investigators must undergo a standardized training session on 
EDSS scoring prior to enrollment of subjects at their site.  New objective findings on 
neurological examination performed by the Investigator are required to determine if a 
protocol-defined relapse has occurred.  Subjects may not begin corticosteroid treatment of the 
relapse per protocol until the Investigator has examined them.
Treatment of an acute event of relapse with IVMP may proceed at the discretion of the 
Investigator and will not affect the subject’s eligibility to continue in the study.  If an 
Unscheduled Relapse Assessment Visit occurs within 7 days of a scheduled clinic visit, then the 
2 visits may take place on the same day; however, MRIs must be conducted according to the 
schedule outlined in Section 4.2.
7.4.
Study Stopping Rules
Biogen may terminate this study at any time, after informing the Investigators.  Biogen will 
notify Investigators when the study is to be placed on hold, completed, or terminated.
7.5.
End of Study
The end of study is last subject, last visit for final collection of data. 


Protocol 109MS311
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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Day 1 or at the timepoint specified in the individual eligibility criterion listed:
1. Ability of parents, legal guardians, and/or subjects to understand the purpose and risks of 
the study and provide signed and dated informed consent and authorization to use 
confidential health information in accordance with national and local subject privacy 
regulations.  Subjects will provide assent in addition to the parental or guardian consent, 
as appropriate, per local regulations.
2. Subjects who completed, as per protocol, the previous BG00012 clinical study 
109MS202 and remain on BG00012 treatment at 240 mg BID.
3. All female subjects of childbearing potential and all male subjects must practice effective 
contraception during the study and for at least 30 days after their last dose of study 
treatment.  For further details of contraceptive requirements for this study, please refer to 
Section 15.5.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Day 1 or at the timepoint specified in the individual criterion listed:
1. Unwillingness or inability to comply with study requirements, including the presence of 
any condition (physical, mental, or social) that is likely to affect the subject’s ability to 
comply with the protocol.
2. Any significant changes in medical history occurring after enrollment in the parent Study 
109MS202, including laboratory test abnormalities or current clinically significant 
conditions that in the opinion of the Investigator would have excluded the subject’s 
participation from the parent study.  The Investigator must re-review the subject’s 
medical fitness for participation and consider any factors that would preclude treatment.
3. Subjects from Study 109MS202 who could not tolerate study treatment.
4. History of malignancy.
5. History of severe allergic or anaphylactic reactions or known drug hypersensitivity to 
DMF or fumaric acid esters.
6. Any of the following abnormal blood tests:

ALT >3 times the ULN

AST >3 times the ULN

Gamma-glutamyl-transferase >3 times the ULN


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
Creatinine >1.2 times the ULN

WBC count <2000/mm3

Lymphocyte count <500/mm3
7. Female subjects considering becoming pregnant or breastfeeding while in the study or 
who are pregnant or breastfeeding.
8. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment.


Protocol 109MS311
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9.
ENROLLMENT AND REGISTRATION
9.1.
Screening and Enrollment
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled in the study.  Subjects who have a nonclinically significant out-of-range laboratory 
result may be rescreened 1 time only at the discretion of the Investigator.  Participating study 
sites are required to document all screened candidates initially considered for inclusion in this 
study.  If a subject is excluded from the study, the reasons for exclusion will be documented in 
the subject’s source documents and on the screening log.
9.2.
Registration of Subjects
Subjects will be registered at Day 1, after all baseline assessments have been completed and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  No 
subject may begin treatment prior to assignment of a unique identification number (registration).  
Any subject identification numbers that are assigned will not be reused even if the subject does 
not receive treatment.
Refer to the Study Reference Guide for details on registration.
9.3.
Blinding Procedures
Not applicable.


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10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A subject must permanently discontinue BG00012 for any of the following reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.

The subject has lymphocyte count <500/mm3 for 6 months as outlined in Table 4 and 
Table 5 .

The subject experiences a protocol-specified change in laboratory values that 
necessitates permanent discontinuation of treatment as outlined in Table 3 and 
Table 4.

The subject cannot tolerate study treatment.

The subject receives any of the disallowed concomitant medications for this study.

The subject or subject’s parent/legal guardian desires to discontinue treatment.

At the discretion of the Investigator for medical reasons or for noncompliance.
The reason for discontinuation of study treatment must be recorded in the subject’s eCRF.
Subjects who discontinue treatment may remain in the study and continue protocol-required tests 
and assessments.
10.2.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any one of the following reasons:

The subject or the subject’s parent/guardian withdraws consent.

The subject enrolls into another interventional clinical study.

The subject is unwilling or unable to comply with the protocol.
The reason for the subject’s withdrawal from the study must be recorded in the subject’s eCRF.


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11.
STUDY TREATMENT USE
11.1.
Regimen
BG00012 will be taken orally at a dose of 240 mg BID.
Subjects will be instructed to swallow each BG00012 capsule whole and not chewed.  The 
capsule and its contents are not to be crushed, divided, dissolved, sucked, or chewed since the 
enteric coating of the microtablets in the capsule helps to prevent irritant effects on the stomach.  
If unable to swallow the capsule, the capsule may be opened and the contents mixed with food 
immediately prior to consumption.
Refer to and follow the Directions for Handling and Administration (DHA).
11.2.
Modification of Dose and/or Treatment Schedule
11.2.1.
Dosing Interruption for Abnormal Laboratory Values
BG00012 must be temporarily withheld and/or permanently discontinued when any of the 
following laboratory values meet the threshold limits defined in Table 3 (laboratory 
abnormalities that require immediate and permanent discontinuation of study treatment are also 
specified in Table 3).
Table 3:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of Treatment
Laboratory 
Parameter
Laboratory Result
Required Action
AST (SGOT)
or
ALT (SGPT)
>3 ULN
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms AST or ALT 
>3 ULN, then the study treatment must be withheld.  
If the value remains >3 ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE.
Creatinine
>1.2 ULN
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that creatinine is 
>1.2 ULN, then the study treatment must be withheld.  
If the value remains >1.2 ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE.


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Laboratory 
Parameter
Laboratory Result
Required Action
WBC
2000/mm3
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that WBC count is 
2000/mm3, then the study treatment must be withheld.  
If the value remains <2000/mm3 for ≥4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE.
Urinalysis
Positive hematuria on 
microscopy
The Investigator should repeat the test as soon as 
possible.  If retest confirms microscopic hematuria 
without known etiology, then the study treatment must 
be withheld, and urine cytology performed.  If 
hematuria persists for ≥4 weeks after discontinuation or 
if cytology is positive for malignant cells, then the 
subject must permanently discontinue study 
treatment, and the event must be recorded as an AE.  
Subjects should be referred to a nephrologist for 
further investigation.
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal; 
WBC = white blood cell.
Table 4 describes the management of lymphocytes <LLN for subjects during and after study 
treatment.


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Table 4:
Management of Lymphocyte Count <LLN
Laboratory Parameter
Laboratory Result
Required Action
Lymphocyte count on 
study treatment
<LLN
The Investigator should repeat the test within 
2 weeks.  If retest confirms that lymphocyte count is 
<LLN, lymphocyte count should be closely 
monitored (at least every 4 weeks). 
Lymphocyte count on 
study treatment
<500/mm3
If lymphocyte count is <500/mm3 for more than 
6 months, study treatment must be permanently 
discontinued.
Lymphocyte count in 
subjects who complete, 
temporarily withhold, or 
permanently discontinue 
BG00012 for any reason
<LLN
Subjects will be followed at least every 4 weeks for 
24 weeks and then every 3 months (unless clinically 
indicated more often or at the Investigator’s 
discretion) until the lymphocyte count is ≥LLN1 or 
for 52 weeks after the last dose, or until one of the 
following occurs:  1) the subject continues on 
commercial BG00012 following study 
withdrawal/completion, or 2) the subject is initiated 
on another MS disease-modifying therapy.
LLN = lower limit of normal; MS = multiple sclerosis.
1 Lymphocyte counts ≥LLN at 2 consecutive visits are required.
While dosing is withheld, subjects will continue tests and assessments according to Table 1 (and 
may also undergo additional assessments to evaluate the laboratory abnormality as per the 
Investigator’s standard practice).  In addition, subjects (whether on study treatment, having 
dosing temporarily withheld, or permanently discontinued) must have the abnormal laboratory 
result rechecked at the central laboratory as follows:

For all analytes, with the exception of lymphocytes, results will be rechecked at least 
every 2 weeks until resolution or stabilization of the laboratory value.  Depending on 
the severity and clinical significance of the abnormality, the Investigator may need to 
perform the retests more frequently.

For lymphocytes, results will be rechecked at least every 4 weeks for 24 weeks and 
then every 3 months (unless clinically indicated more often or at the Investigator’s 
discretion) until the lymphocyte count is ≥LLN or for 52 weeks after the last dose, or 
until one of the following occurs:  1) the subject continues on commercial BG00012 
following study withdrawal/completion, or 2) the subject is initiated on another MS 
disease-modifying therapy.  Depending on the severity and clinical significance of the 
abnormality, the Investigator may need to perform the retests more frequently.
11.2.2.
Resumption of Study Treatment Dosing
Resumption of BG00012 treatment is to be considered on a case-by-case basis and must be 
discussed with the Medical Monitor.  


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Resumption of study treatment after an interruption
Subjects who are allowed to resume BG00012 dosing after an interruption of ≥2 weeks will 
restart dosing at a reduced dosage for 1 week.  Subjects will take one 120-mg capsule BID for 
1 week.  After 1 week at the reduced dose, subjects will resume taking two 120-mg capsules 
BID.
11.2.3.
Subsequent Development of Additional Laboratory Abnormalities
Subjects who subsequently develop the same abnormal laboratory value at any other time during 
the study must permanently discontinue dosing with BG00012, i.e., only 1 dosing interruption is 
allowed for each subject for the same laboratory abnormality.  However, subjects who 
subsequently experience a different laboratory abnormality can have study treatment withheld 
again.  For example, if a subject had dosing temporarily withheld for an abnormal ALT, then had 
dosing resume after ALT returned to acceptable limits, and subsequently developed abnormal 
WBCs, then the subject may have BG00012 withheld again.  However, only 2 dosing 
interruptions are allowed for each subject.  
Any subject who experiences abnormal laboratory results (which meet the criteria defined in 
Table 3) on a third occasion must discontinue dosing for the remainder of the study.
11.2.4.
Abnormal Urinalyses That Require Additional Evaluation
Subjects who develop any of the following abnormal urine laboratory values must have the test 
repeated 2 weeks later:

urinary casts (other than hyaline casts)

glycosuria (trace or greater) in the setting of normal serum glucose
If the abnormality persists on retesting, then the subject should be fully investigated for possible 
causes and referred for evaluation by a nephrologist if appropriate in the opinion of the 
Investigator.
Subjects who demonstrate 1+ or greater proteinuria on a urine dipstick (and do not have a 
documented history of prior benign proteinuria) should have a spot protein/creatinine ratio (on 
AM void).  If the spot protein/creatinine ratio is >0.2 mg/mg, then the subject should be fully 
investigated for possible causes and referred for evaluation by a nephrologist if appropriate in the 
opinion of the Investigator.
11.2.5.
Treatment Schedule for Subjects With Abnormal Lymphocyte Count
11.2.5.1.
Schedule for Subjects With Lymphocyte Count <500/mm3
BG00012 must be permanently discontinued when the lymphocyte count meets the threshold 
limits defined in Table 5.


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Table 5:
Lymphocyte Count Criteria Requiring Permanent Discontinuation of 
BG00012 Treatment
Laboratory Parameter
Laboratory Result
Required Action
Lymphocyte count
<500/mm3
The Investigator should repeat the test as soon as 
possible.  If retest confirms that lymphocyte count is 
<500/mm3, lymphocyte count should be closely 
monitored (at least every 4 weeks).  If lymphocyte 
count is <500/mm3 for more than 6 months, study 
treatment must be permanently discontinued. 
If study treatment is permanently discontinued due to lymphocyte count <500/mm3, subjects may 
continue protocol-required tests and assessments and also undergo lymphocyte follow-up every 
4 weeks for 24 weeks and then every 3 months (unless clinically indicated more often or at the 
Investigator’s discretion) until the lymphocyte count is ≥LLN or for 52 weeks after the last 
dose, or until one of the following occurs:  1) the subject continues on commercial BG00012 
following study withdrawal/completion, or 2) the subject is initiated on another MS 
disease-modifying therapy [see Table 2].  During the lymphocyte follow-up, if the lymphocyte 
count does not recover to above LLN after 24 weeks, the treating neurologist should contact the 
Medical Monitor. 
11.2.5.2.
Schedule for Subjects Who Complete, Temporarily Withhold, or Permanently 
Discontinue Study Treatment for Any Reason and Have a Lymphocyte 
Count <LLN
Subjects who complete the 96-week treatment period and who have a lymphocyte count <LLN 
will be followed every 4 weeks for 24 weeks and then every 3 months (unless clinically 
indicated more often or at the Investigator’s discretion) until the lymphocyte count is ≥LLN 
or for 52 weeks after the last dose, or until one of the following occurs:  1) the subject continues 
on commercial BG00012 following study withdrawal/completion, or 2) the subject is initiated on 
another MS disease-modifying therapy.  During the lymphocyte follow-up, if the lymphocyte 
count does not recover to above LLN after 24 weeks, the treating neurologist should contact the 
Medical Monitor.
Subjects who temporarily withhold or permanently discontinue study treatment for any reason 
(see Section 10.1) and who have a lymphocyte count <LLN will continue protocol-required tests 
and assessments and also undergo lymphocyte follow-up every 4 weeks for 24 weeks and then 
every 3 months (unless clinically indicated more often or at the Investigator’s discretion)
until the lymphocyte count is ≥LLN or for 52 weeks after the last dose, or until one of the 
following occurs:  1) the subject continues on commercial BG00012 following study 
withdrawal/completion, or 2) the subject is initiated on another MS disease-modifying therapy
[see Table 4].  During the lymphocyte follow-up, if the lymphocyte count does not recover to 
above LLN after 24 weeks, the treating neurologist should contact the Medical Monitor.


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See Figure 2 for a schedule for subjects who complete, temporarily withhold, or permanently 
discontinue study treatment for any reason and who have a lymphocyte count <LLN.
Figure 2:
Schedule for Subjects who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN
LLN = lower limit of normal.
11.2.6.
Dosage Reductions
Dosage reduction will be allowed only for subjects who are unable to tolerate BG00012 
treatment due to flushing and/or GI disturbances (dosage reductions will not be allowed for 
abnormal laboratory values; for management of abnormal laboratory values, see Sections 11.2.1, 
11.2.2, and 11.2.3).  Subjects who do not tolerate BG00012 treatment will reduce their dosage by 
taking one 120-mg capsule BID for up to 4 weeks.  Within 4 weeks at the reduced dosage, 
subjects will resume taking the full dose of 240 mg (two 120-mg capsules) BID.  If the subject is 
still unable to tolerate BG00012 treatment at the 240-mg BID dose, the subject may continue in 
the study taking the 120-mg BID dose.
11.3.
Precautions
Medications for the treatment of severe hypersensitivity reactions (e.g., epinephrine for 
subcutaneous injections, diphenhydramine for injection) should be available for immediate use.
See the DHA for detailed instructions.


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11.4.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.  Compliance for 
BG00012 will be monitored by capsule count and captured in the eCRF.
11.5.
Concomitant Therapy and Procedures
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the Baseline Visit and the 
Safety Follow-Up Visit.
11.5.1.1.
Allowed Concomitant Therapy
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue, is not restricted but 
should be consistent for the duration of the study.
Subjects should be instructed not to start taking any new medications, including nonprescribed 
drugs, unless they have received permission from the Investigator.
11.5.1.2.
Disallowed Concomitant Therapy
Concomitant treatment with any of the following is not allowed while receiving study treatment, 
unless approved by the Medical Monitor, or as otherwise described in this protocol:

Any alternative drug treatments directed toward the treatment of MS, such as 
immunomodulatory treatments (including but not limited to, interferon-beta, 
glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, 
mitoxantrone, mycophenolate mofetil, laquinimod, cyclophosphamide, methotrexate, 
azathioprine, cyclosporine, etc.) and 4-aminopyridine or related products with the 
exception of acute management of protocol-defined relapse (as described in 
Section 11.5.2 ). 

Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications.

Any systemic steroid therapy including but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IVMP, except for 
protocol-defined treatment of relapses as described in Section 11.5.2.  Steroids that 
are administered by nonsystemic routes (e.g., topical, inhaled) are allowed.

Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, intravenous (IV) immunoglobulin, plasmapheresis, 
or cytapheresis.
Subjects who receive any of these restricted medications without approval from the Biogen 
Medical Director(s) will be required to permanently discontinue study treatment and will be 
withdrawn from the study as outlined in Section 10.2.  


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Use of the concomitant therapies or procedures defined above must be recorded on the subject’s 
eCRF, according to the instructions for eCRF completion.  AEs related to the administration of 
these therapies or procedures must be documented on the appropriate eCRF.
11.5.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the Final Study Visit.
The use of concomitant procedures must be recorded on the subject’s eCRF, according to 
instructions for eCRF completion.  AEs related to the administration of these procedures must be 
documented on the appropriate eCRF.
11.5.3.
Treatment of Relapses on Scheduled or Unscheduled Visits
The only protocol-approved treatment for relapse in this study is either 3 or 5 days with IVMP, 
up to 1000 mg/day.  IVMP can be given once a day or in divided doses.  Subjects may also 
refuse relapse treatment.  Any deviations from this recommended treatment must first be 
discussed with the Biogen Medical Director or designee.
Study treatment dosing is to continue uninterrupted during IVMP treatment.
11.6.
Continuation of Treatment
There is no provision for additional courses of BG00012 provided by Biogen beyond the 
treatment period defined in this protocol.
If and when BG00012 is commercially available at the time the study treatment period is 
completed, subjects will be allowed to take commercial BG00012 during the Safety Follow-Up 
Period if deemed appropriate by product labeling and at the discretion of their treating physician.


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12.
STUDY TREATMENT MANAGEMENT
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study.
12.1.
BG00012
BG00012 is a drug product formulated as enteric-coated microtablets in gelatin capsules (blue 
and white) for oral administration.  Each capsule contains 120 mg BG00012.
Excipients for the manufacturing of the enteric-coated microtablets include microcrystalline 
cellulose, croscarmellose sodium, talc, colloidal anhydrous silica (colloidal silicon dioxide), 
magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer, 
methacrylic acid-ethyl acrylate copolymer, simethicone, sodium lauryl sulfate, and 
polysorbate 80.  Excipients for the manufacturing of the capsule shell include gelatin, titanium 
dioxide, and indigotin.
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  BG00012 should not be used after the expiration date.
12.1.1.
BG00012 Preparation
BG00012 will be provided as capsules.  Drug wallets will be prepared to ensure that the 
appropriate treatment is provided to each subject.  Drug wallets will be supplied from Interactive 
Voice/Web Response System at specific timepoints during the study so that the appropriate 
wallets are correctly dispensed to a subject at the required timepoints throughout the study.
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the drug wallet or study treatment, do not use the study treatment.  The drug wallet in question 
should be quarantined at the study site and the problem immediately reported to Biogen.
12.1.2.
BG00012 Storage
Study treatment must be stored in a secure location.
BG00012 is to be stored at room temperature (15C to 25C or 59F to 77F), in a secured, 
locked cabinet with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA.
12.1.3.
BG00012 Handling and Disposal
The Investigator must return all used and unused drug wallets of BG00012 as instructed by 
Biogen unless approved for onsite destruction.


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If any BG00012 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction.
12.1.4.
BG00012 Accountability
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost.
Unless otherwise notified, all drug wallets, both used and unused, must be saved for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BG00012 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies.


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13.
EFFICACY ASSESSMENTS
See Section 4 for the timing of all assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of BG00012:

Relapse assessment

EDSS
13.2.
MRI Efficacy Assessments
The following MRI efficacy assessments will be performed to evaluate the efficacy of BG00012:

The total number of new or newly enlarging T2 hyperintense lesions from baseline as 
well as from the scan of the previous visit on brain MRI scans 


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14.
SAFETY ASSESSMENTS
Refer to Section 4 for the timing of all safety assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BG00012:

Physical examinations, including body weight and height

Vital sign measurements, including body temperature, pulse rate, and systolic and 
diastolic blood pressure

12-Lead electrocardiograms

Concomitant therapy and procedure recording

AE and SAE recording
14.2.
Laboratory Safety Assessments
The following laboratory assessments will be performed to evaluate the safety profile of 
BG00012:

Hematology:  complete blood count with differential and platelet count

Blood chemistry:  sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphate, BUN, creatinine, uric acid, glucose, albumin, ALT, AST, 
gamma-glutamyl transferase, total bilirubin, and alkaline phosphatase

Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal)

Vitamin D and PTH levels


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15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject or his/her legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE 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.
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Although abnormal laboratory values are typically not considered 
AEs, the following considerations may result in an abnormal laboratory value being considered 
an AE:

A laboratory test result that meets the criteria for an SAE

A laboratory test result that requires the subject to receive specific corrective therapy

A laboratory abnormality that the Investigator considers to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Results in a congenital anomaly/birth defect


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An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
If a subject is hospitalized due to local requirements for administration of the study treatment, 
the hospitalization should not be considered an SAE unless one of the requirements in 
Section 15.1.2 is met.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2 .

The relationship of the event to study treatment as defined in Section 15.2.2.

The severity of the event as defined in Section 15.2.3.
15.2.2.
Relationship of Events to Study Treatment
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment.


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Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
AE, or the presence of a more likely alternative explanation for the AE.
Related
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of an alternative explanation for the AE.
15.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Severity of Event
Mild
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject.
Moderate
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed.
Severe
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of treatment with study treatment; 
treatment for symptoms may be given and/or subject hospitalized.
15.2.4.
Expectedness of Events
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure.  
15.3.
Monitoring and Recording Events
15.3.1.
Adverse Events
Any AE experienced by the subject between the time of first dose of study treatment in the 
extension study and the Safety Follow-Up Visit is to be recorded on the eCRF, regardless of the 
severity of the event or its relationship to study treatment.
15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and the Safety 
Follow-Up Visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to Biogen Safety and Benefit-Risk 


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Management (SABR) or designee within 24 hours as described in Section 15.3.3.  Follow-up 
information regarding an SAE also must be reported with 24 hours. 
Subjects will be followed for all SAEs until the Safety Follow-Up Visit.  Thereafter, the event 
should be reported to Biogen SABR or designee only if the Investigator considers the SAE to be 
related to study treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
15.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen SABR or designee within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately.
Reporting Information for SAEs
Any SAE that occurs between the time that the subject has signed the ICF and the Safety 
Follow-Up Visit must be reported to Biogen SABR or designee within 24 hours of the study site 
staff becoming aware of the event.  Thereafter, the event should be reported only if the 
Investigator considers it related to study treatment.
A report must be submitted to Biogen SABR or designee regardless of the following:

Whether or not the subject has undergone study-related procedures

Whether or not the subject has received study treatment

The severity of the event

The relationship of the event to study treatment
To report initial or follow-up information on an SAE, please fax (please refer to the Study 
Reference Guide) or email 
.
15.3.3.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate eCRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 
death certificates and autopsy reports to Biogen SABR or designee.  The term death should be 
reported as an SAE only if the cause of death is not known and cannot be determined.
15.3.4.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.


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Biogen SABR or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law.
15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Subjects should not become pregnant during the study and for 30 days after their last dose of 
study treatment.  If a female subject becomes pregnant, study treatment must be discontinued 
immediately.
The Investigator must report a pregnancy by faxing or emailing the appropriate form within 
24 hours of the study site staff becoming aware of the pregnancy to Biogen SABR or designee 
(fax: please refer to the Study Reference Guide; email
.  The 
Investigator or study site staff must report the outcome of the pregnancy to Biogen SABR or 
designee.
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen SABR or designee within 24 hours of the site 
becoming aware of the overdose.  An overdose must be reported to Biogen or designee even if 
the overdose does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  
If an overdose results in an SAE, both the SAE and Overdose forms must be completed and 
faxed to Biogen SABR or designee.  All study treatment-related dosing information must be 
recorded on the dosing eCRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will perform appropriate 
medical interventions, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information.
15.4.3.1.
Unblinding for Medical Emergency
Not Applicable
15.5.
Contraception Requirements
Sexually active subjects of reproductive potential must practice effective contraception during 
the study and for at least 30 days after their last dose of study treatment.  Investigators should 
advise subjects of the potential risks associated with pregnancy while taking BG00012 and on 
the appropriate use of contraceptives (as defined below).


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For the purposes of the study, highly effective contraception is defined as use of 1 or more of the 
following:
For females:

Established use of oral, injected, or implanted hormonal methods of contraception.

Placement of an intrauterine device or intrauterine system.

Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide (where approved/applicable).

Female surgical sterilization (e.g., bilateral tubal ligation).
For males:

Effective male contraception includes the use of condoms with spermicide.
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
considered acceptable methods of contraception.
Pregnancy reporting is described in Section 15.4.1.
15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment.

Determine the seriousness, relationship to study treatment, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow up on the outcomes.

Complete an SAE form for each SAE and fax it to Biogen SABR or designee within 
24 hours of the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR or designee within 24 hours of the study site staff 
becoming aware of new information.

Report SAEs to local ethics committees, as required by local law.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.


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
Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.
15.6.2.
Biogen 
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definitions of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames.


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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
16.1.
Efficacy
16.1.1.
Analysis Population
The population for the analysis of efficacy endpoints will be all subjects who have received at 
least 1 dose of BG00012 in this study and who have an evaluation of the efficacy endpoint under 
analysis.
16.1.2.
Methods of Analysis
16.1.2.1.
Analysis of the Primary Endpoint
The primary analysis will be summaries of the incidence of treatment-emergent AEs, SAEs, and 
discontinuations from study treatment due to AEs.
16.1.2.2.
Analysis of the Secondary Endpoints
The number of new or newly enlarging T2 hyperintense lesions on brain MRI scans will be 
summarized over time using descriptive statistics.
ARR will be summarized along with the proportion of subjects relapsing, the rate of relapses 
requiring IV steroid use, and the rate of MS-related hospitalizations.
EDSS scores and changes from baseline will be summarized over time along with the proportion 
of subjects with confirmed disability progression.
16.2.
Pharmacokinetics
Not applicable.
16.3.
Pharmacodynamics
Not applicable.
16.4.
Biomarker Analyses/Pharmacogenomics
Not applicable.
16.5.
Safety
16.5.1.
Analysis Population
The safety population is defined as all subjects who received at least 1 dose of BG00012 in this 
study.


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16.5.1.1.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities.
The primary analysis will be summaries of the incidence of treatment-emergent AEs, SAEs, and 
discontinuations from study treatment due to AEs.
16.5.1.2.
Clinical Laboratory Results
Clinical laboratory evaluations including hematology, blood chemistry, and urinalysis will be 
summarized using the incidence of shifts outside the normal range.  In addition, summary 
statistics for quantitative laboratory values and changes from baseline will be presented.  
Lymphocyte count data will be summarized by timepoints on study treatment.  Additionally, 
lymphocyte count over time post-treatment and the time to recovery will be descriptively 
summarized for subjects who develop decreases in lymphocyte count (<LLN).
16.5.1.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities.  The incidence of 
subjects experiencing these abnormalities will be summarized.
16.6.
Antigenicity/Immunogenicity Data
Not applicable.
16.7.
Interim Analyses
The data from this study will be summarized periodically to support regulatory submissions or 
when further information on the long-term safety and efficacy of BG00012 in the pediatric 
population is required.
16.8.
Sample Size Considerations
Because this study is an extension study, the sample size will be determined by the number of 
eligible subjects who completed Study 109MS202.


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17.
ETHICAL REQUIREMENTS
Biogen, 
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in countries other than the US.
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 


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subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study.
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines.
A copy of the signed and dated ICF and assent if applicable must be given to the subject or the 
subject’s legally authorized representative.  The signed and dated ICF will be retained with the 
study records.  Local regulations must be complied with in respect to the final disposition of the 
original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent and assent if applicable must also be documented in the 
subject’s medical record.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America).
The subject will not be identified by name in the eCRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen or partnering company) with the subject before the subject makes a decision to 
participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not enroll any subjects prior to completion of a study initiation visit 
conducted by Biogen.  This initiation visit will include a detailed review of the protocol and 
study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate.
During these visits, eCRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.
18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.
18.5.
Publications
Details are included in the clinical trial agreement for this study.


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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
Biogen will be responsible for all administrative aspects of this study including but not limited to 
study initiation, monitoring, management of AEs, and data management.
19.1.1.
Contract Research Organization 
A contract research organization (CRO), 
, will be jointly responsible for administrative 
aspects of the study including but not limited to study initiation, monitoring, and management of 
SAE reports and data management.  Before subjects are screened at each study site, the CRO will 
review study responsibilities with the Investigators and other study site staff, as appropriate.
19.1.2.
Electronic Data Capture
Subject information will be captured and managed by study sites on eCRFs by a Web-based 
electronic data capture tool OR remote data capture tool developed and supported by iMedidata 
RAVE and configured by 
.
19.1.3.
Central Laboratories for Laboratory Assessments
A central laboratory has been selected by Biogen to analyze all safety laboratory samples 
collected for this study.
19.2.
Study Committees
19.2.1.
Advisory Committee
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study.  The advisory committee will conduct 
regular reviews to monitor subject accrual and to monitor compliance with the protocol at 
individual study sites.  The advisory committee will determine whether the study should be 
stopped or amended for reasons other than safety.
Members of the advisory committee will include the Medical Director, Clinical Operations Lead, 
and Project Statistician from Biogen, and participating Investigators.  Biogen will designate one 
of the participating Investigators to be the chairperson of the advisory committee.
19.2.2.
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will monitor the progress of the study, 
review interim safety data, and oversee the safety of subjects participating in this study.  The 
specifics regarding the IDMC organization and procedures will be outlined in the IDMC Charter.


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19.3.
Changes to Final Study Protocol
Protocol modifications that affect subject safety, the scope of the investigation, or the scientific 
quality of the study must be approved by the ethics committee before implementation of such 
modifications to the conduct of the study.  If required by local law, such modifications must also 
be approved by the appropriate regulatory agency prior to implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require corresponding modifications (see 
Section 17).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site.
19.6.
Study Report Signatory
Biogen will designate 1 or more of the participating Study Investigators as a signatory for the 
study report.  This determination will be made by several factors, including but not limited to, 
the Investigator’s experience and reputation in the studied indication; the Investigator’s 
contribution to the study in terms of design, management, and/or subject enrollment; or by other 
factors determined to be relevant by Biogen.


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20.
REFERENCES
Chitnis T, Krupp L, Yeh A, et al. Pediatric multiple sclerosis. Neurol Clin. 2011;29(2):481-505.
Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing 
therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-27.
Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line 
treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 
3 trial. Lancet. 2012;380(9856):1819-28.
European Commission. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. 2008.
Ghoreschi K, Brück J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by 
inducing type II dendritic cells. J Exp Med. 2011;208(11):2291-303.
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during 
a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 
2000;343(13):898-904.
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves 
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76.
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Epub 2010 Jan 20.
Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression 
mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003;43:233-60.
O'Connor P, Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and 
treatment of multiple sclerosis. An overview. Neurology. 2002;59(6 Suppl 3):S1-33.
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303.
Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI 
analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC 
MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 
1993;43(4):662-7.
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.
PRISMS Study Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. 
Neurology. 2001;56(12):1628-36.
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61.


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CONFIDENTIAL
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Waldman AT, Gorman MP, Rensel MR, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82.
Zhu HJ, Appel DI, Jiang Y, et al. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37(9):1819-25.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter Extension Study to Determine the Long-Term 
Safety and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple 
Sclerosis,” and agree to conduct the study according to the protocol and the applicable ICH 
guidelines and GCP regulations, and to inform all who assist me in the conduct of this study of 
their responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)


 
 
CONFIDENTIAL 
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Biogen MA Inc. 
1 
 
 
 
 
 
 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
PROTOCOL NUMBER: 
109MS311 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
PHASE OF DEVELOPMENT: 
3 
 
 
PROTOCOL TITLE:  A Multicenter Extension Study to Determine the Long-Term Safety 
and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple 
Sclerosis 
 
 
 
EUDRA CT NO: 
 
2015-003282-29 
 
 
DATE: 
08 January 2016 
Version 2.0 
FINAL 
 
 




Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................8 
2. 
LIST OF ABBREVIATIONS.......................................................................................9 
3. 
SYNOPSIS .................................................................................................................10 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
109MS311...................................................................................................................12 
4.1. 
Study Schematic .........................................................................................................12 
4.2. 
Schedule of Activities .................................................................................................13 
4.3. 
Additional Information ...............................................................................................17 
4.3.1. 
Blood Volumes ...........................................................................................................17 
5. 
INTRODUCTION ......................................................................................................18 
5.1. 
Overview of Multiple Sclerosis ..................................................................................18 
5.2. 
Current Therapies for Multiple Sclerosis ...................................................................18 
5.3. 
Profile of Previous Experience With BG00012 ..........................................................19 
5.3.1. 
Nonclinical Safety Experience ...................................................................................19 
5.3.2. 
Clinical Experience .....................................................................................................19 
5.4. 
Study Rationale ...........................................................................................................21 
5.5. 
Rationale for Dosing Regimen ...................................................................................21 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22 
6.1. 
Primary Objective and Endpoint ................................................................................22 
6.2. 
Secondary Objectives and Endpoints .........................................................................22 
7. 
STUDY DESIGN .......................................................................................................23 
7.1. 
Study Overview ..........................................................................................................23 
7.2. 
Overall Study Duration and Follow-Up .....................................................................23 
7.2.1. 
Enrollment ..................................................................................................................23 
7.2.2. 
Treatment ....................................................................................................................23 
7.2.3. 
Follow-Up ...................................................................................................................23 
7.3. 
Relapses ......................................................................................................................23 
7.4. 
Study Stopping Rules .................................................................................................24 
7.5. 
End of Study ...............................................................................................................24 
8. 
SELECTION OF SUBJECTS ....................................................................................25 


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8.1. 
Inclusion Criteria ........................................................................................................25 
8.2. 
Exclusion Criteria .......................................................................................................25 
9. 
ENROLLMENT AND REGISTRATION .................................................................27 
9.1. 
Screening and Enrollment ...........................................................................................27 
9.2. 
Registration of Subjects ..............................................................................................27 
9.3. 
Blinding Procedures ....................................................................................................27 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................28 
10.1. 
Discontinuation of Study Treatment ...........................................................................28 
10.2. 
Withdrawal of Subjects From Study ...........................................................................28 
11. 
STUDY TREATMENT USE .....................................................................................29 
11.1. 
Regimen ......................................................................................................................29 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................29 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values ...............................................29 
11.2.2. 
Resumption of Study Treatment Dosing ....................................................................31 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities ..........................31 
11.2.4. 
Abnormal Urinalyses That Require Additional Evaluation ........................................31 
11.2.5. 
Treatment Schedule for Subjects With Abnormal Lymphocyte Count ......................32 
11.2.5.1. 
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................32 
11.2.5.2. 
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................32 
11.2.6. 
Dosage Reductions .....................................................................................................33 
11.3. 
Precautions ..................................................................................................................34 
11.4. 
Compliance .................................................................................................................34 
11.5. 
Concomitant Therapy and Procedures ........................................................................34 
11.5.1. 
Concomitant Therapy .................................................................................................34 
11.5.1.1. 
Allowed Concomitant Therapy ...................................................................................34 
11.5.1.2. 
Disallowed Concomitant Therapy ..............................................................................34 
11.5.2. 
Concomitant Procedures .............................................................................................35 
11.5.3. 
Treatment of Relapses on Scheduled or Unscheduled Visits .....................................35 
11.6. 
Continuation of Treatment ..........................................................................................35 


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12. 
STUDY TREATMENT MANAGEMENT ................................................................36 
12.1. 
BG00012 .....................................................................................................................36 
12.1.1. 
BG00012 Preparation .................................................................................................36 
12.1.2. 
BG00012 Storage ........................................................................................................36 
12.1.3. 
BG00012 Handling and Disposal ...............................................................................36 
12.1.4. 
BG00012 Accountability ............................................................................................37 
13. 
EFFICACY ASSESSMENTS ....................................................................................38 
13.1. 
Clinical Efficacy Assessments ....................................................................................38 
13.2. 
MRI Efficacy Assessments .........................................................................................38 
14. 
SAFETY ASSESSMENTS ........................................................................................39 
14.1. 
Clinical Safety Assessments .......................................................................................39 
14.2. 
Laboratory Safety Assessments ..................................................................................39 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................40 
15.1. 
Definitions ..................................................................................................................40 
15.1.1. 
Adverse Event .............................................................................................................40 
15.1.2. 
Serious Adverse Event ................................................................................................40 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................41 
15.2. 
Safety Classifications ..................................................................................................41 
15.2.1. 
Investigator Assessment of Events .............................................................................41 
15.2.2. 
Relationship of Events to Study Treatment ................................................................41 
15.2.3. 
Severity of Events .......................................................................................................42 
15.2.4. 
Expectedness of Events ..............................................................................................42 
15.3. 
Monitoring and Recording Events ..............................................................................42 
15.3.1. 
Adverse Events ...........................................................................................................42 
15.3.2. 
Serious Adverse Events ..............................................................................................42 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................43 
15.3.3.1. 
Deaths .........................................................................................................................43 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................43 
15.4. 
Procedures for Handling Special Situations ...............................................................44 
15.4.1. 
Pregnancy ...................................................................................................................44 
15.4.2. 
Overdose .....................................................................................................................44 


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15.4.3. 
Medical Emergency ....................................................................................................44 
15.4.3.1. 
Unblinding for Medical Emergency ...........................................................................44 
15.5. 
Contraception Requirements ......................................................................................44 
15.6. 
Safety Responsibilities ................................................................................................45 
15.6.1. 
The Investigator ..........................................................................................................45 
15.6.2. 
Biogen .........................................................................................................................46 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........47 
16.1. 
Efficacy .......................................................................................................................47 
16.1.1. 
Analysis Population ....................................................................................................47 
16.1.2. 
Methods of Analysis ...................................................................................................47 
16.1.2.1. 
Analysis of the Primary Endpoint...............................................................................47 
16.1.2.2. 
Analysis of the Secondary Endpoints .........................................................................47 
16.2. 
Pharmacokinetics ........................................................................................................47 
16.3. 
Pharmacodynamics .....................................................................................................47 
16.4. 
Biomarker Analyses/Pharmacogenomics ...................................................................47 
16.5. 
Safety ..........................................................................................................................47 
16.5.1. 
Analysis Population ....................................................................................................47 
16.5.1.1. 
Adverse Events ...........................................................................................................48 
16.5.1.2. 
Clinical Laboratory Results ........................................................................................48 
16.5.1.3. 
Vital Signs ..................................................................................................................48 
16.6. 
Antigenicity/Immunogenicity Data ............................................................................48 
16.7. 
Interim Analyses .........................................................................................................48 
16.8. 
Sample Size Considerations .......................................................................................48 
17. 
ETHICAL REQUIREMENTS ...................................................................................49 
17.1. 
Declaration of Helsinki ...............................................................................................49 
17.2. 
Ethics Committee ........................................................................................................49 
17.3. 
Subject Information and Consent ...............................................................................49 
17.4. 
Subject Data Protection ..............................................................................................50 
17.5. 
Compensation for Injury .............................................................................................50 
17.6. 
Conflict of Interest ......................................................................................................50 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................50 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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18. 
ADMINISTRATIVE PROCEDURES .......................................................................51 
18.1. 
Study Site Initiation ....................................................................................................51 
18.2. 
Quality Assurance .......................................................................................................51 
18.3. 
Monitoring of the Study..............................................................................................51 
18.4. 
Study Funding .............................................................................................................51 
18.5. 
Publications .................................................................................................................51 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................52 
19.1. 
External Contract Organizations .................................................................................52 
19.1.1. 
Contract Research Organization .................................................................................52 
19.1.2. 
Electronic Data Capture ..............................................................................................52 
19.1.3. 
Central Laboratories for Laboratory Assessments .....................................................52 
19.2. 
Study Committees .......................................................................................................52 
19.2.1. 
Advisory Committee ...................................................................................................52 
19.2.2. 
Independent Data Monitoring Committee ..................................................................52 
19.3. 
Changes to Final Study Protocol ................................................................................52 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................53 
19.5. 
Retention of Study Data ..............................................................................................53 
19.6. 
Study Report Signatory...............................................................................................53 
20. 
REFERENCES ...........................................................................................................54 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................56 
 
LIST OF TABLES 
Table 1: 
Study Activities for Study 109MS311 ........................................................................13 
Table 2: 
Additional Study Activities for Study 109MS311......................................................15 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
Treatment ....................................................................................................................29 
Table 4: 
Management of Lymphocyte Count <LLN ................................................................30 
Table 5: 
Lymphocyte Count Criteria Requiring Permanent Discontinuation of 
BG00012 Treatment ...................................................................................................32 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................12 


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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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Figure 2: 
Schedule for Subjects who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................33 
 
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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1. 
SPONSOR INFORMATION 
 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Biogen Australia PTY Ltd 
Suite 1, Level 3,  
123 Epping Road 
North Ryde, NSW 2113 
Australia 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information. 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities. 


Protocol 109MS311 
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2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine transaminase 
ARR 
annualized relapse rate 
AST 
aspartate transaminase 
BID 
twice daily 
BUN 
blood urea nitrogen 
CNS 
central nervous system 
CRO 
contract research organization 
DHA 
Directions for Handling and Administration 
DMF 
dimethyl fumarate 
eCRF 
electronic case report form 
EDSS 
Expanded Disability Status Scale 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IV 
intravenous 
IVMP 
intravenous methylprednisolone 
LLN 
lower limit of normal 
MMF 
monomethyl fumarate 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
PK 
pharmacokinetics 
PTH 
parathyroid hormone 
RRMS 
relapsing-remitting multiple sclerosis 
SABR 
Safety and Benefit-Risk Management 
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reaction 
TID 
3 times daily 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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3. 
SYNOPSIS 
Protocol Number: 
109MS311 
Protocol Title: 
A Multicenter Extension Study to Determine the Long-Term 
Safety and Efficacy of BG00012 in Pediatric Subjects With 
Relapsing-Remitting Multiple Sclerosis 
Version Number 
2.0 
Name of Study Treatment: 
BG00012 (Dimethyl Fumarate; Tecfidera®) 
Study Indication: 
Relapsing-remitting multiple sclerosis (RRMS) 
Study Rationale 
With no approved multiple sclerosis (MS) therapies in the 
pediatric population, there exists a significant unmet need 
for approved treatment options.  In the adult population, 
BG00012 is a therapeutic option with demonstrated efficacy 
and acceptable tolerability and safety profiles combined 
with the ease of oral administration.  BG00012 was first 
approved (as Tecfidera) in the United States in 2013 for the 
treatment of adult patients with relapsing forms of MS and 
has since been approved in Europe and other regions.  This 
study will extend therapy from the ongoing BG00012 
pediatric Study 109MS202, in which the pharmacokinetics 
and efficacy of BG00012 in pediatric subjects with RRMS 
are being evaluated, in order to further evaluate the 
long-term safety and efficacy of BG00012 in these subjects.  
Phase of Development: 
3 
Study Objectives and 
Endpoints: 
The primary objective of the study is to evaluate the 
long-term safety of BG00012 in subjects who completed 
Study 109MS202. 
The primary endpoint that relates to this objective is the 
incidence of adverse events (AEs), serious AEs, and 
discontinuations of study treatment due to an AE 
Secondary objectives and endpoints are as follows: 
To evaluate the long-term efficacy of BG00012. 
 The total number of new or newly enlarging T2 
hyperintense lesions on brain magnetic 


Protocol 109MS311 
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resonance imaging  scans 
 The annualized relapse rate 
 The proportion of subjects who experience 1 or 
more relapses during the study period 
To describe the long-term MS outcomes in subjects who 
completed Study 109MS202. 
 The degree of disability as measured by the 
Expanded Disability Status Scale (EDSS) and 
disability progression (as measured by at least a 
1.0-point increase on the EDSS from baseline 
EDSS ≥1.0 that is sustained for 24 weeks or at 
least a 1.5-point increase on the EDSS from 
baseline EDSS = 0 that is sustained for 
24 weeks) 
Study Design: 
This is a multicenter, open-label extension of 
Study 109MS202 that is designed to evaluate the long-term 
safety and efficacy of BG00012 in pediatric subjects. 
Study Location: 
Approximately 20 sites globally are planned. 
Number of Planned Subjects: 
The number of subjects who are eligible for this study will 
be determined by the number of subjects who have 
completed Study 109MS202 as per protocol. 
Study Population: 
This study will be conducted in subjects who completed 
Study 109MS202 as per protocol.  
Detailed criteria are described in Section 8. 
Treatment Groups: 
All subjects will receive BG00012 240 mg twice daily 
(2 capsules of 120 mg). 
Duration of Treatment and 
Follow-up: 
The treatment period is 96 weeks (2 years) and the 
Follow-Up Safety Visit will take place 4 weeks after the last 
dose of study treatment. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 109MS311 
4.1. 
Study Schematic 
Figure 1: 
Study Design 
  
 


Protocol 109MS311 
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4.2. 
Schedule of Activities 
Table 1: 
Study Activities for Study 109MS311 
Tests and Assessments1 
Year 1 
Year 2 
Safety 
 Follow-Up 
Visit 
Baseline 
Visit 
(Day 1)2 
Visit 1 
(Week 
125d)  
Visit 2 
(Week 
16 5d) 
Visit 3 
(Week 
24 5d) 
Visit 4 
(Week 
36 5d) 
Visit 5 
(Week 
48 5d) 
Visit 6 
(Week 
60 5d) 
Visit 7 
(Week 
64 5d) 
Visit 8 
(Week 
72 5d) 
Visit 9 
(Week 
84 5d) 
Visit 10 
(Week 
96 5d) 
Informed Consent and 
Assent3 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
MS-Related Medical 
History4 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
Body Weight 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Height 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Vital Signs5 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
Urine Pregnancy Test6 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urinalysis78, 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
PTH and Vitamin D Levels 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Brain MRI Scan910 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
EDSS 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
Dispense Study Treatment11 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Concomitant Therapy and 
Procedures Recording 
Monitor and record throughout the study 
AE/SAE Reporting 
Monitor and record throughout the study 
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
PTH = parathyroid hormone; SAE = serious adverse event. 
1 Tests and assessments must be completed prior to study treatment dispensation.  


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2 The Final Study Visit for Study 109MS202 will serve as the Baseline Visit for this extension study.  The Final Study Visit from Study 109MS202 can be within 
4 weeks of the Baseline Visit for Study 109MS311 if the 2 visits cannot be combined. 
3 Written informed consent from the subject’s parents or legal guardians and assent from the subject, if appropriate, must be obtained prior to performing any 
study-related procedures. 
4 MS-related medical history will include complete MS history of disease, MS diagnostic criteria, MS signs and symptoms, and MS treatment history. 
5 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements. 
6 For females of childbearing potential.  Results must be known prior to study treatment dispensation. 
7 Urine cytology must be performed at all visits indicated if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits.  If urine cytology is 
positive for malignant cells, the subject must permanently discontinue study treatment. 
8 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol. 
9 MRI must not be performed within 30 days of receiving a course of steroids. 
10 The time between the Week 24 MRI and the Week 16 MRI must be the same as the time between the Day 0 MRI and Week -8 MRI in Study 109MS202 within 
a window of ±3 days.  For example, if the Day 0 and Week -8 MRIs for a particular subject occurred 8 weeks apart in Study 109MS202, then the Week 24 MRI 
in Study 109MS311 should be 8 weeks ± 3 days after the Week 16 MRI.  If necessary, the Week 24 MRI may be conducted separately from the Week 24 clinic 
visit.  Similarly, the time between the Week 72 MRI and the Week 64 MRI must be the same as the time between the Day 0 MRI and Week -8 MRI in Study 
109MS202 within a window of ±3 days.  If necessary, the Week 72 MRI may be conducted separately from the Week 72 clinic visit. 
11 Initial dispensation of study treatment may require an additional visit on or around Day 7.  Laboratory results must be evaluated and eligibility confirmed prior 
to dispensation of study treatment. 
 


Protocol 109MS311 
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Table 2: 
Additional Study Activities for Study 109MS311 
Tests and Assessments 
Unscheduled Relapse Assessment 
Visit1 
(within 72 hours after symptom onset) 
Discontinuation/ 
Withdrawal Visit2 
(as soon as possible but no later than 
4 weeks after last dose of study 
treatment) 
Lymphocyte Follow-Up Visit3 
Physical Examination 
X 
X 
X 
Body Weight 
X 
X 
X 
Height 
 
X 
 
Vital Signs4 
X 
X 
X 
12-Lead ECG 
 
X 
 
Hematology5,6 
X 
X 
X 
Blood Chemistry6 
X 
X 
 
Urine Pregnancy Test7 
X 
X 
 
Urinalysis6,8 
X 
X 
 
PTH and Vitamin D Levels 
 
X 
 
EDSS 
X 
X 
 
Brain MRI Scan9 
 
X10 
 
Relapse Assessment 
X 
 
 
Concomitant Therapy and 
Procedures 
Monitor and record throughout the study  
AE/SAE Recording 
Monitor and record throughout the study 
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; LLN = lower limit of normal; MRI = magnetic resonance imaging; 
PTH = parathyroid hormone; SAE = serious adverse event. 
1 An Unscheduled Relapse Assessment Visit will be conducted within 72 hours of symptom onset of a suspected relapse (i.e., new or recurrent neurologic 
symptom[s]). 
2 Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from the study.  The Discontinuation/Withdrawal 
Visit should be conducted as soon as possible and no later than 4 weeks after the last dose of study treatment. 


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3 Subjects who complete, temporarily withhold, or permanently discontinue study treatment for any reason and have a lymphocyte count <LLN will continue 
protocol-required visits and assessments and be followed every 4 weeks for 24 weeks and then every 3 months (unless clinically indicated more often or at 
the Investigator’s discretion) until the lymphocyte count is ≥LLN or for 52 weeks after the last dose (whichever is sooner). 
4 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements. 
5 Hematology testing must be performed every 4 weeks in subjects with lymphocyte count <LLN. 
6 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol. 
7 For females of childbearing potential. 
8 Urine cytology must be performed if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits or at the Unscheduled Relapse Assessment 
Visit or the Discontinuation/Withdrawal Visit. 
9 An MRI must not be performed within 30 days of receiving a course of steroids. 
10 A brain MRI scan will be performed unless assessed in the last 30 days.  
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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4.3. 
Additional Information  
4.3.1. 
Blood Volumes 
Every effort must be made to collect the minimum blood volume needed per protocol.  The 
blood volumes required for this study do not exceed the recommended pediatric blood volume 
limits for sampling, i.e., volumes do not exceed 3% of the total blood volumes during a period of 
4 weeks or 1% at any single visit [European Commission 2008].  For example, in a 30-kg child 
(the lowest weight permitted in this study), it is estimated that 1% of the total volume would be 
approximately 21 mL.  Children weighing more than 30 kg would have higher permitted 
amounts.  The total blood volumes drawn at each visit will be 5 mL or less.  The approximate 
amount of blood to be drawn over the entire study period will be 50 mL. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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5. 
INTRODUCTION  
5.1. 
Overview of Multiple Sclerosis 
Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central 
nervous system (CNS) that is characterized by inflammation, demyelination, and 
oligodendrocyte and neuronal loss.  It is the most common demyelinating disorder of the CNS, 
affecting approximately 2.5 million people worldwide.  MS primarily affects adults, with clinical 
onset occurring most commonly between the ages of 20 and 40 years [O'Connor and Canadian 
Multiple Sclerosis Working Group 2002].  Approximately 2.2% to 4.4% of all MS cases have 
onset during adolescence or childhood [Chitnis 2011], with girls affected more than boys, and 
most cases being relapsing-remitting multiple sclerosis (RRMS). 
5.2. 
Current Therapies for Multiple Sclerosis 
Despite the availability of several therapies approved for the treatment of adult patients with MS, 
there remains an unmet need for safe and effective treatments for pediatric patients with MS.  
Currently, there are no treatments that are approved to treat pediatric MS, and no randomized 
controlled clinical studies have been completed that demonstrate that the agents available for 
treatment of MS in adults are safe and effective in pediatric patients.  Moreover, there are no data 
on the pharmacological characterization of any of the disease-modifying MS therapies in 
pediatric patients.  Thus, current treatment options for pediatric patients with MS are adapted 
from therapeutic paradigms for adult patients, with dosing recommendations based solely on 
adult subject data and expert opinion. 
The most commonly used therapies in the pediatric population are interferons and glatiramer 
acetate [Waldman 2011].  Relative to placebo, these agents have been shown to reduce relapse 
rate by approximately 30% and may decrease disease progression [Jacobs 2000; Johnson 1995; 
Paty and Li 1993; PRISMS Study Group 2001; The IFNB Multiple Sclerosis Study Group 1993]. 
Other therapies currently approved for use in adults with MS include the following: 
 Natalizumab:  a humanized monoclonal antibody directed against α4 integrins 
[Polman 2006]  
 Fingolimod:  a selective oral immunosuppressant that is metabolized to a functional 
antagonist of sphingosine 1-phosphate receptors on lymphocytes [Kappos 2010] 
 Mitoxantrone:  a synthetic antineoplastic anthracenedione that intercalates into DNA, 
interfering with its synthesis and repair [Chitnis 2012] 
 Teriflunomide:  an immunosuppressive drug inhibiting pyrimidine synthesis by 
blocking dihydroorotate dehydrogenase [O'Connor 2011] 
 Alemtuzumab:  a monoclonal antibody directed against cluster of differentiation 52 
[Cohen 2012] 


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 Tecfidera®:  a dimethyl fumarate (DMF)-containing drug that activates the Nrf2 
antioxidant response pathway to mitigate inflammatory stress [Ghoreschi 2011; 
Nguyen 2003] 
5.3. 
Profile of Previous Experience With BG00012 
5.3.1. 
Nonclinical Safety Experience 
Nonclinical safety studies were performed to support the development of BG00012 (Tecfidera®) 
for the treatment of MS.  CNS, respiratory, and cardiovascular safety studies demonstrated no 
drug-related adverse effects on those systems, which is consistent with human data.  There were 
no findings of mutagenicity, impaired fertility, or teratogenicity.  Repeat-dose toxicology studies 
were performed in rodents (mouse and rat) and non-rodents (dog and monkey).  Findings in these 
studies in the liver, forestomach, and testis concluded that there is limited concern related to 
human risk.  In the male rat juvenile toxicology study that specifically evaluated the reproductive 
organs, there were no toxicology findings.  Kidney findings seen in animals were not observed in 
humans.  In lifetime carcinogenicity studies, renal tumors were attributed to a rodent-specific 
exacerbation of nephropathy. 
See the Investigator’s Brochure for more detailed information on nonclinical studies as well as 
information on nonclinical pharmacology and pharmacokinetic (PK) studies. 
5.3.2. 
Clinical Experience 
BG00012 240 mg twice daily (BID) is currently approved (as Tecfidera) for the treatment of 
adult patients with MS in the United States (US), the European Union, and other countries.  
The efficacy and safety of BG00012 are well established and based on data from Phase 2 and 3 
placebo-controlled safety and efficacy studies (Studies C-1900 Part 1, 109MS301 [DEFINE], 
and 109MS302 [CONFIRM]) and their uncontrolled extensions (Studies C-1900 Part 2 and 
109MS303 [ENDORSE]).  In these studies, over 2500 subjects received treatment with 
BG00012.  The overall exposure to BG00012 in these subjects was approximately 
6100 subject-years as of September 2013. 
Results of the Phase 3 clinical studies demonstrate that BG00012 240 mg BID or 3 times daily 
(TID) is an efficacious treatment for RRMS.  In these Phase 3 studies, BG00012 resulted in a 
significant reduction in the risk of relapse and annualized relapse rate (ARR), and the treatment 
had a positive effect on 12-week Expanded Disability Status Scale (EDSS) disability 
progression, with statistical significance achieved in Study 109MS301.  A robust, statistically 
significant effect was also observed on magnetic resonance imaging (MRI) endpoints, including 
the number and volume of new or newly enlarging T2 hyperintense lesions, 
gadolinium-enhancing lesions, and new or newly enlarging T1 hypointense lesions compared 
with placebo.  Efficacy was seen as early as 6 months and maintained over the 2-year span of 
Studies 109MS301 and 109MS302.  In the ongoing Phase 3, uncontrolled extension Study 
109MS303 (ENDORSE), which includes subjects who completed Studies 109MS301 or 
109MS302, sustained efficacy was observed through 5 years of treatment, and the safety profile 
of continued BG00012 treatment was consistent with that observed in the 2-year Phase 3 studies.  


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Overall, safety data from the clinical development program showed that BG00012 was well 
tolerated and has an acceptable safety profile.  In the BG00012 240 mg BID group, the most 
common adverse events (AEs; incidence ≥5%) that also occurred at an incidence of ≥2% higher 
than in the placebo group were flushing and hot flush, gastrointestinal (GI) events (diarrhea, 
nausea, abdominal pain upper, abdominal pain, vomiting, and dyspepsia), skin events (pruritus, 
rash, and erythema), nasopharyngitis, urinary tract infection, upper respiratory tract infection, 
albumin urine present, proteinuria, and microalbuminuria.  The AE profile was similar for 
subjects who received 240 mg TID. 
In placebo-controlled studies, decreases in mean white blood cell (WBC) and lymphocyte counts 
were observed over the first year of treatment (approximately 10% and 30%, respectively) with 
both dose regimens of BG00012.  Mean WBC and lymphocyte counts then plateaued and 
remained stable, even during longer periods of observation of approximately 5.25 years.  
Analysis of the data did not show a clear correlation between infections, serious infections, and 
lymphocyte counts.  No increased risk of infection, serious infection, or opportunistic infection 
was observed in subjects treated with BG00012 in the placebo-controlled studies.  With 
open-label and marketed use of BG00012, progressive multifocal leukoencephalopathy has been 
observed in the setting of severe and prolonged lymphopenia.  There has been no other evidence 
of increased risk of infections, serious infections, or other opportunistic infections (in open-label 
and marketed use of BG00012). 
BG00012 was also associated with a small increase in the incidence of elevations of liver 
transaminases compared to placebo.  In the controlled studies, this increase was primarily due to 
differences that occurred within the first 6 months of treatment.  The majority of subjects with 
elevations had alanine transaminase (ALT) or aspartate transaminase (AST) levels <3 times the 
upper limit of normal (ULN).  No patients had elevations of ALT or AST ≥3 × ULN associated 
with an elevation in total bilirubin of >2 × ULN.  There were no cases of hepatic failure due to 
BG00012.  During extended treatment with BG00012, ALT and AST levels remained stable 
through 3.5 years of observation.  Based on these data, there appears to be a transient increase in 
liver transaminases with BG00012 relative to placebo that does not appear to be associated with 
any clinically significant liver pathology. 
Although the kidney was identified as a target organ of BG00012 toxicity in nonclinical studies, 
subjects treated with BG00012 in the clinical studies did not appear to have a higher risk of renal 
or urinary events.  Small increases in proteinuria were observed, but the increases did not appear 
to be clinically significant.  On laboratory evaluation, there were no clinically relevant changes 
in blood urea nitrogen (BUN), creatinine, electrolytes, calcium, phosphorus, parathyroid 
hormone (PTH), or 1,25-dihydroxyvitamin D.  In the Phase 3 studies (Studies 109MS301 and 
109MS302), there were no differences between placebo and BG00012 BID in the incidence of 
proteinuria on 2 consecutive urinalyses (defined as trace or greater) or of 3+ or 4+ protein, both 
of which are potential indicators of significant proteinuria and renal dysfunction.  In addition, 
there was no evidence of changes over time in β2-microglobulinuria and microalbuminuria, 
which are more sensitive and specific markers of renal tubular dysfunction, even during longer 
periods of observation of approximately 3.5 years. 


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In the controlled studies, there was no increased incidence of malignancies in subjects who 
received BG00012 compared with placebo.  The types of malignancies observed and their 
incidence were within expected background rates.   
5.4. 
Study Rationale 
In adult subjects with RRMS, BG00012 demonstrated efficacy and had an acceptable safety 
profile in 2 Phase 3 studies, Studies 109MS301 and 109MS302.  With no approved therapies, 
there exists a significant unmet need for MS treatment options in the pediatric population.  In the 
adult population, BG00012 is a therapeutic option with demonstrated efficacy and acceptable 
tolerability and safety profiles combined with the ease of oral administration.  This study will 
extend therapy from the ongoing BG00012 pediatric Study 109MS202, in which the PK and 
efficacy of BG00012 in pediatric subjects with RRMS are being evaluated, in order to further 
evaluate the long-term safety and efficacy of BG00012 in these subjects. 
5.5. 
Rationale for Dosing Regimen 
The BG00012 dosage selected for this study (240 mg BID) is the approved BG00012 dosing 
regimen in adult patients with MS. 
In adults, after oral administration, DMF is well absorbed and extensively metabolized by 
esterases to its primary active metabolite, monomethyl fumarate (MMF).  As a result, DMF is 
not quantifiable in plasma, and all PK analyses have been performed based on MMF 
concentrations.  Downstream metabolism of DMF/MMF occurs through the tricarboxylic acid 
cycle, with exhalation of carbon dioxide serving as a major route of elimination.  The PK of 
BG00012 has been thoroughly evaluated in adults.  Body weight is a significant covariant for 
BG00012 exposure in that the area under the curve and the maximum concentration are 
decreased by 2% and 1.4%, respectively, for every 1-kg increase in body weight within the 
weight range of 45 to 112 kg.  This translates to a 2-fold increase in exposure levels as body 
weight decreases from 112 to 45 kg. 
Despite the effect of body weight changes on the exposure levels of BG00012, data from the 
pivotal Phase 3 studies suggested that the variability in exposure did not affect safety and 
efficacy measures in adult patients.  Notably, the efficacy and tolerability profiles of BG00012 at 
240 mg BID were indistinguishable from those at 240 mg TID, with a wide range of overlapping 
exposures between the 2 dosages. 
A Phase 1 PK study (Study 109MS101) revealed no apparent differences in the kinetics of 
BG00012 across the age range of 21 to 51 years once the weight relationship was accounted for.   
Published data [Zhu 2009] indicate that there were no notable differences in the expression and 
activities of esterases in juveniles (12 to 18 years old) when compared with adults.  These 
findings suggest that the disposition of BG00012 is unlikely to change with age for the target 
population (10 to 18 year olds). 
Taken together, these data indicate that 240 mg BID, the approved dose in adults, should be 
tolerable in pediatric subjects meeting the inclusion criteria for the parent study (109MS202) and 
the current extension study.  As such, this dose was chosen for the parent and current studies. 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the long-term safety of BG00012 in subjects 
who completed Study 109MS202. 
The primary endpoint that relates to this objective is the incidence of AEs, serious AEs (SAEs), 
and discontinuations of study treatment due to an AE. 
6.2. 
Secondary Objectives and Endpoints 
A secondary objective is to evaluate the long-term efficacy of BG00012. 
The endpoints that relate to this objective are the total number of new or newly enlarging T2 
hyperintense lesions on brain MRI scans, the ARR, and the proportion of subjects who 
experience 1 or more relapses during the study period. 
Another secondary objective is to describe the long-term MS outcomes in subjects who 
completed Study 109MS202. 
The endpoint that relates to this objective is the degree of disability as measured by the EDSS 
and disability progression (as measured by at least a 1.0-point increase on the EDSS from 
baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS 
from baseline EDSS = 0 that is sustained for 24 weeks). 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a multicenter, open-label extension of Study 109MS202 that is designed to evaluate the 
long-term safety and efficacy of BG00012 in pediatric subjects. 
See Figure 1 for a schematic of the study design. 
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of enrollment, treatment, and follow-up.  The study duration is 
approximately 104 weeks, consisting of a 4-week enrollment period (if the Final Study Visit 
from Study 109MS202 cannot be combined with the Baseline Visit for this study), a 96-week 
treatment period, and a Safety Follow-Up Visit up to 4 weeks after the last dose of study 
treatment.  Unscheduled Relapse Assessment Visits and Lymphocyte Follow-Up Visits will be 
performed as necessary. 
7.2.1. 
Enrollment 
Subject eligibility for the study will be determined at the Final Study Visit for Study 109MS202 
or within 4 weeks prior to study entry.  The Final Study Visit for Study 109MS202 will serve as 
the Baseline Visit for this study. 
7.2.2. 
Treatment 
Eligible subjects will report to the study site to receive study treatment approximately every 
12 weeks for up to 96 weeks (2 years). 
7.2.3. 
Follow-Up 
Subjects are to return to the study site for a follow-up visit 4 weeks after their last treatment visit 
(Visit 10 at Week 96 [±5 days]). 
Subjects who withdraw prematurely from the study will complete the Early Withdrawal Visit, 
which should be conducted as soon as possible and no later than 4 weeks after the subject’s last 
dose of study treatment.  Subjects who withdraw prematurely should be encouraged to complete 
the Safety Follow-Up Visit 4 weeks after the last dose of study treatment. 
Subjects who complete, temporarily withhold, or permanently discontinue study treatment for 
any reason and have a lymphocyte count less than the lower limit of normal (LLN) will be 
followed every 4 weeks for 24 weeks and then every 3 months (unless clinically indicated more 
often or at the Investigator’s discretion) until the lymphocyte count is ≥LLN or for 52 weeks 
after the last dose (whichever is sooner). 
7.3. 
Relapses 
Suspected relapses during this study will be evaluated and confirmed according to the protocol 
by the Investigator.  Relapses are defined as new or recurrent neurologic symptoms not 


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associated with fever or infection, lasting at least 24 hours, and accompanied by new objective 
neurological findings upon examination by the Investigator.  New or recurrent neurologic 
symptoms that evolve gradually over months should be considered disability progression, not an 
acute relapse, and should not be treated with steroids.  New or recurrent neurologic symptoms 
that occur less than 30 days following the onset of a protocol-defined relapse should be 
considered part of the same relapse and would not be treated with intravenous 
methylprednisolone (IVMP) within the protocol. 
If a subject experiences new neurologic symptoms, then the subject or caregiver must contact the 
Investigator within 48 hours of the onset of symptoms to complete a Telephone Questionnaire to 
determine the necessity of an Unscheduled Relapse Assessment Visit.  If required, the subject 
will then be evaluated in person by the Investigator within 5 days of the onset of the potential 
relapse.  The Investigator is to perform a relapse assessment and obtain an EDSS score.  To 
ensure consistency across sites, Investigators must undergo a standardized training session on 
EDSS scoring prior to enrollment of subjects at their site.  New objective findings on 
neurological examination performed by the Investigator are required to determine if a 
protocol-defined relapse has occurred.  Subjects may not begin corticosteroid treatment of the 
relapse per protocol until the Investigator has examined them. 
Treatment of an acute event of relapse with IVMP may proceed at the discretion of the 
Investigator and will not affect the subject’s eligibility to continue in the study.  If an 
Unscheduled Relapse Assessment Visit occurs within 7 days of a scheduled clinic visit, then the 
2 visits may take place on the same day; however, MRIs must be conducted according to the 
schedule outlined in Section 4.2. 
7.4. 
Study Stopping Rules 
Biogen may terminate this study at any time, after informing the Investigators.  Biogen will 
notify Investigators when the study is to be placed on hold, completed, or terminated. 
7.5. 
End of Study 
The end of study is last subject, last visit for final collection of data.  


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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Day 1 or at the timepoint specified in the individual eligibility criterion listed: 
1. Ability of parents, legal guardians, and/or subjects to understand the purpose and risks of 
the study and provide signed and dated informed consent and authorization to use 
confidential health information in accordance with national and local subject privacy 
regulations.  Subjects will provide assent in addition to the parental or guardian consent, 
as appropriate, per local regulations. 
2. Subjects who completed, as per protocol, the previous BG00012 clinical study 
109MS202 and remain on BG00012 treatment at 240 mg BID. 
3. All female subjects of childbearing potential and all male subjects must practice effective 
contraception during the study and for at least 30 days after their last dose of study 
treatment.  For further details of contraceptive requirements for this study, please refer to 
Section 15.5. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Day 1 or at the timepoint specified in the individual criterion listed: 
1. Unwillingness or inability to comply with study requirements, including the presence of 
any condition (physical, mental, or social) that is likely to affect the subject’s ability to 
comply with the protocol. 
4. Any significant changes in medical history occurring after enrollment in the parent Study 
109MS202, including laboratory test abnormalities or current clinically significant 
conditions that in the opinion of the Investigator would have excluded the subject’s 
participation from the parent study.  The Investigator must re-review the subject’s 
medical fitness for participation and consider any factors that would preclude treatment. 
5. Subjects from Study 109MS202 who could not tolerate study treatment. 
6. History of malignancy. 
7. History of severe allergic or anaphylactic reactions or known drug hypersensitivity to 
DMF or fumaric acid esters. 
8. Any of the following abnormal blood tests: 
 ALT >3 times the ULN 
 AST >3 times the ULN 
 Gamma-glutamyl-transferase >3 times the ULN 
 Creatinine >1.2 times the ULN 


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 WBC count <2000/mm3 
 Lymphocyte count <500/mm3 
9. Female subjects considering becoming pregnant or breastfeeding while in the study or 
who are pregnant or breastfeeding. 
10. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 
 


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9. 
ENROLLMENT AND REGISTRATION 
9.1. 
Screening and Enrollment 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled in the study.  Subjects who have a nonclinically significant out-of-range laboratory 
result may be rescreened 1 time only at the discretion of the Investigator.  Participating study 
sites are required to document all screened candidates initially considered for inclusion in this 
study.  If a subject is excluded from the study, the reasons for exclusion will be documented in 
the subject’s source documents and on the screening log. 
9.2. 
Registration of Subjects 
Subjects will be registered at Day 1, after all baseline assessments have been completed and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  No 
subject may begin treatment prior to assignment of a unique identification number (registration).  
Any subject identification numbers that are assigned will not be reused even if the subject does 
not receive treatment. 
Refer to the Study Reference Guide for details on registration. 
9.3. 
Blinding Procedures 
Not applicable. 


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue BG00012 for any of the following reasons: 
 The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1. 
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 The subject has lymphocyte count <500/mm3 for 6 months as outlined in Table 4 and 
Table 5 . 
 The subject experiences a protocol-specified change in laboratory values that 
necessitates permanent discontinuation of treatment as outlined in Table 3 and 
Table 4. 
 The subject cannot tolerate study treatment. 
 The subject receives any of the disallowed concomitant medications for this study. 
 The subject or subject’s parent/legal guardian desires to discontinue treatment. 
 At the discretion of the Investigator for medical reasons or for noncompliance. 
The reason for discontinuation of study treatment must be recorded in the subject’s eCRF. 
Subjects who discontinue treatment may remain in the study and continue protocol-required tests 
and assessments. 
10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject or the subject’s parent/guardian withdraws consent. 
 The subject enrolls into another interventional clinical study. 
 The subject is unwilling or unable to comply with the protocol. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s eCRF. 


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11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
BG00012 will be taken orally at a dose of 240 mg BID. 
Subjects will be instructed to swallow each BG00012 capsule whole and not chewed.  The 
capsule and its contents are not to be crushed, divided, dissolved, sucked, or chewed since the 
enteric coating of the microtablets in the capsule helps to prevent irritant effects on the stomach.  
If unable to swallow the capsule, the capsule may be opened and the contents mixed with food 
immediately prior to consumption. 
Refer to and follow the Directions for Handling and Administration (DHA). 
11.2. 
Modification of Dose and/or Treatment Schedule 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values 
BG00012 must be temporarily withheld and/or permanently discontinued when any of the 
following laboratory values meet the threshold limits defined in Table 3 (laboratory 
abnormalities that require immediate and permanent discontinuation of study treatment are also 
specified in Table 3). 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of Treatment 
Laboratory 
Parameter 
Laboratory Result 
Required Action 
AST (SGOT) 
or 
ALT (SGPT) 
 
>3  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms AST or ALT 
>3  ULN, then the study treatment must be withheld.  
If the value remains >3  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Creatinine 
>1.2  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that creatinine is 
>1.2  ULN, then the study treatment must be withheld.  
If the value remains >1.2  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 


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Laboratory 
Parameter 
Laboratory Result 
Required Action 
WBC 
2000/mm3  
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that WBC count is 
2000/mm3, then the study treatment must be withheld.  
If the value remains <2000/mm3 for ≥4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Urinalysis 
Positive hematuria on 
microscopy 
The Investigator should repeat the test as soon as 
possible.  If retest confirms microscopic hematuria 
without known etiology, then the study treatment must 
be withheld, and urine cytology performed.  If 
hematuria persists for ≥4 weeks after discontinuation or 
if cytology is positive for malignant cells, then the 
subject must permanently discontinue study 
treatment, and the event must be recorded as an AE.  
Subjects should be referred to a nephrologist for 
further investigation. 
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal; 
WBC = white blood cell. 
Table 4 describes the management of lymphocytes <LLN for subjects during and after study 
treatment. 
Table 4: 
Management of Lymphocyte Count <LLN 
Laboratory Parameter 
Laboratory Result 
Required Action 
Lymphocyte count on 
study treatment 
<LLN 
The Investigator should repeat the test within 
2 weeks.  If retest confirms that lymphocyte count is 
<LLN, lymphocyte count should be closely 
monitored (at least every 4 weeks).  
Lymphocyte count on 
study treatment 
<500/mm3 
If lymphocyte count is <500/mm3 for more than 
6 months, study treatment must be permanently 
discontinued. 
Lymphocyte count in 
subjects who complete, 
temporarily withhold, or 
permanently discontinue 
BG00012 for any reason 
<LLN 
Subjects will be followed at least every 4 weeks for 
for 24 weeks and then every 3 months (unless 
clinically indicated more often or at the 
Investigator’s discretion) until the lymphocyte 
count is ≥LLN or for 52 weeks after the last dose 
(whichever is sooner). 
LLN = lower limit of normal. 
While dosing is withheld, subjects will continue tests and assessments according to Table 1 (and 
may also undergo additional assessments to evaluate the laboratory abnormality as per the 
Investigator’s standard practice).  In addition, subjects (whether on study treatment, having 


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dosing temporarily withheld, or permanently discontinued) must have the abnormal laboratory 
result rechecked at the central laboratory as follows: 
 For all analytes, with the exception of lymphocytes, results will be rechecked at least 
every 2 weeks until resolution or stabilization of the laboratory value.  Depending on 
the severity and clinical significance of the abnormality, the Investigator may need to 
perform the retests more frequently. 
 For lymphocytes, results will be rechecked at least every 4 weeks for 24 weeks and 
then every 3 months (unless clinically indicated more often or at the Investigator’s 
discretion) until the lymphocyte count is ≥LLN or for 52 weeks after the last dose 
(whichever is sooner).  Depending on the severity and clinical significance of the 
abnormality, the Investigator may need to perform the retests more frequently. 
11.2.2. 
Resumption of Study Treatment Dosing 
Resumption of BG00012 treatment is to be considered on a case-by-case basis and must be 
discussed with the Medical Monitor.   
Resumption of study treatment after an interruption 
Subjects who are allowed to resume BG00012 dosing after an interruption of ≥2 weeks will 
restart dosing at a reduced dosage for 1 week.  Subjects will take one 120-mg capsule BID for 
1 week.  After 1 week at the reduced dose, subjects will resume taking two 120-mg capsules 
BID. 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities 
Subjects who subsequently develop the same abnormal laboratory value at any other time during 
the study must permanently discontinue dosing with BG00012, i.e., only 1 dosing interruption is 
allowed for each subject for the same laboratory abnormality.  However, subjects who 
subsequently experience a different laboratory abnormality can have study treatment withheld 
again.  For example, if a subject had dosing temporarily withheld for an abnormal ALT, then had 
dosing resume after ALT returned to acceptable limits, and subsequently developed abnormal 
WBCs, then the subject may have BG00012 withheld again.  However, only 2 dosing 
interruptions are allowed for each subject.   
Any subject who experiences abnormal laboratory results (which meet the criteria defined in 
Table 3) on a third occasion must discontinue dosing for the remainder of the study. 
11.2.4. 
Abnormal Urinalyses That Require Additional Evaluation 
Subjects who develop any of the following abnormal urine laboratory values must have the test 
repeated 2 weeks later: 
 urinary casts (other than hyaline casts) 
 glycosuria (trace or greater) in the setting of normal serum glucose 
If the abnormality persists on retesting, then the subject should be fully investigated for possible 
causes and referred for evaluation by a nephrologist if appropriate in the opinion of the 
Investigator. 


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Subjects who demonstrate 1+ or greater proteinuria on a urine dipstick (and do not have a 
documented history of prior benign proteinuria) should have a spot protein/creatinine ratio (on 
AM void).  If the spot protein/creatinine ratio is >0.2 mg/mg, then the subject should be fully 
investigated for possible causes and referred for evaluation by a nephrologist if appropriate in the 
opinion of the Investigator. 
11.2.5. 
Treatment Schedule for Subjects With Abnormal Lymphocyte Count 
11.2.5.1. Schedule for Subjects With Lymphocyte Count <500/mm3 
BG00012 must be permanently discontinued when the lymphocyte count meets the threshold 
limits defined in Table 5. 
Table 5: 
Lymphocyte Count Criteria Requiring Permanent Discontinuation of 
BG00012 Treatment 
Laboratory Parameter 
Laboratory Result 
Required Action 
Lymphocyte count 
 
 
<500/mm3 
The Investigator should repeat the test as soon as 
possible.  If retest confirms that lymphocyte count is 
<500/mm3, lymphocyte count should be closely 
monitored (at least every 4 weeks).  If lymphocyte 
count is <500/mm3 for more than 6 months, study 
treatment must be permanently discontinued.  
If study treatment is permanently discontinued due to lymphocyte count <500/mm3, subjects may 
continue protocol-required tests and assessments and also undergo lymphocyte follow-up every 
4 weeks for 24 weeks and then every 3 months (unless clinically indicated more often or at the 
Investigator’s discretion) until weeks after the last dose until the lymphocyte count is ≥LLN or 
for 52 weeks after the last dose (whichever is sooner) [see Table 2].  If the lymphocyte count 
does not recover after 24 weeks, the treating neurologist should contact the Medical Monitor.  
11.2.5.2. Schedule for Subjects Who Complete, Temporarily Withhold, or Permanently 
Discontinue Study Treatment for Any Reason and Have a Lymphocyte 
Count <LLN 
Subjects who complete the 96-week treatment period and who have a lymphocyte count <LLN 
will be followed every 4 weeks for 24 weeks and then every 3 months (unless clinically 
indicated more often or at the Investigator’s discretion) until the lymphocyte count is ≥LLN 
or for 52 weeks after the last dose (whichever is sooner).  If the lymphocyte count does not 
recover after 24 weeks, the treating neurologist should contact the Medical Monitor.   
Subjects who temporarily withhold or permanently discontinue study treatment for any reason 
(see Section 10.1) and who have a lymphocyte count <LLN will continue protocol-required tests 
and assessments and also undergo lymphocyte follow-up every 4 weeks for 24 weeks and then 
every 3 months (unless clinically indicated more often or at the Investigator’s discretion) 
until the lymphocyte count is ≥LLN or for 52 weeks after the last dose (whichever is sooner) [see 


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Table 4].  If the lymphocyte count does not recover after 24 weeks, the treating neurologist 
should contact the Medical Monitor. 
See Figure 2 for a schedule for subjects who complete, temporarily withhold, or permanently 
discontinue study treatment for any reason and who have a lymphocyte count <LLN. 
Figure 2: 
Schedule for Subjects who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN 
 
LLN = lower limit of normal. 
11.2.6. 
Dosage Reductions 
Dosage reduction will be allowed only for subjects who are unable to tolerate BG00012 
treatment due to flushing and/or GI disturbances (dosage reductions will not be allowed for 
abnormal laboratory values; for management of abnormal laboratory values, see Sections 11.2.1, 
11.2.2, and 11.2.3).  Subjects who do not tolerate BG00012 treatment will reduce their dosage by 
taking one 120-mg capsule BID for up to 4 weeks.  Within 4 weeks at the reduced dosage, 
subjects will resume taking the full dose of 240 mg (two 120-mg capsules) BID.  If the subject is 
still unable to tolerate BG00012 treatment at the 240-mg BID dose, the subject may continue in 
the study taking the 120-mg BID dose. 


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11.3. 
Precautions 
Medications for the treatment of severe hypersensitivity reactions (e.g., epinephrine for 
subcutaneous injections, diphenhydramine for injection) should be available for immediate use. 
See the DHA for detailed instructions. 
11.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff.  Compliance for 
BG00012 will be monitored by capsule count and captured in the eCRF. 
11.5. 
Concomitant Therapy and Procedures 
11.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between the Baseline Visit and the 
Safety Follow-Up Visit. 
11.5.1.1. Allowed Concomitant Therapy 
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue, is not restricted but 
should be consistent for the duration of the study. 
Subjects should be instructed not to start taking any new medications, including nonprescribed 
drugs, unless they have received permission from the Investigator. 
11.5.1.2. Disallowed Concomitant Therapy 
Concomitant treatment with any of the following is not allowed while receiving study treatment, 
unless approved by the Medical Monitor, or as otherwise described in this protocol: 
 Any alternative drug treatments directed toward the treatment of MS, such as 
immunomodulatory treatments (including but not limited to, interferon-beta, 
glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, 
mitoxantrone, mycophenolate mofetil, laquinimod, cyclophosphamide, methotrexate, 
azathioprine, cyclosporine, etc.) and 4-aminopyridine or related products with the 
exception of acute management of protocol-defined relapse (as described in 
Section 11.5.2 ).  
 Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications. 
 Any systemic steroid therapy including but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IVMP, except for 
protocol-defined treatment of relapses as described in Section 11.5.2.  Steroids that 
are administered by nonsystemic routes (e.g., topical, inhaled) are allowed. 
 Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, intravenous (IV) immunoglobulin, plasmapheresis, 
or cytapheresis. 


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Subjects who receive any of these restricted medications without approval from the Biogen 
Medical Director(s) will be required to permanently discontinue study treatment and will be 
withdrawn from the study as outlined in Section 10.2.   
Use of the concomitant therapies or procedures defined above must be recorded on the subject’s 
eCRF, according to the instructions for eCRF completion.  AEs related to the administration of 
these therapies or procedures must be documented on the appropriate eCRF. 
11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the Final Study Visit. 
The use of concomitant procedures must be recorded on the subject’s eCRF, according to 
instructions for eCRF completion.  AEs related to the administration of these procedures must be 
documented on the appropriate eCRF. 
11.5.3. 
Treatment of Relapses on Scheduled or Unscheduled Visits 
The only protocol-approved treatment for relapse in this study is either 3 or 5 days with IVMP, 
up to 1000 mg/day.  IVMP can be given once a day or in divided doses.  Subjects may also 
refuse relapse treatment.  Any deviations from this recommended treatment must first be 
discussed with the Biogen Medical Director or designee. 
Study treatment dosing is to continue uninterrupted during IVMP treatment. 
11.6. 
Continuation of Treatment 
There is no provision for additional courses of BG00012 provided by Biogen beyond the 
treatment period defined in this protocol. 
If and when BG00012 is commercially available at the time the study treatment period is 
completed, subjects will be allowed to take commercial BG00012 during the Safety Follow-Up 
Period if deemed appropriate by product labeling and at the discretion of their treating physician. 


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12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol). 
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study. 
12.1. 
BG00012 
BG00012 is a drug product formulated as enteric-coated microtablets in gelatin capsules (blue 
and white) for oral administration.  Each capsule contains 120 mg BG00012. 
Excipients for the manufacturing of the enteric-coated microtablets include microcrystalline 
cellulose, croscarmellose sodium, talc, colloidal anhydrous silica (colloidal silicon dioxide), 
magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer, 
methacrylic acid-ethyl acrylate copolymer, simethicone, sodium lauryl sulfate, and 
polysorbate 80.  Excipients for the manufacturing of the capsule shell include gelatin, titanium 
dioxide, and indigotin. 
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  BG00012 should not be used after the expiration date. 
12.1.1. 
BG00012 Preparation 
BG00012 will be provided as capsules.  Drug wallets will be prepared to ensure that the 
appropriate treatment is provided to each subject.  Drug wallets will be supplied from Interactive 
Voice/Web Response System at specific timepoints during the study so that the appropriate 
wallets are correctly dispensed to a subject at the required timepoints throughout the study. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the drug wallet or study treatment, do not use the study treatment.  The drug wallet in question 
should be quarantined at the study site and the problem immediately reported to Biogen. 
12.1.2. 
BG00012 Storage 
Study treatment must be stored in a secure location. 
BG00012 is to be stored at room temperature (15C to 25C or 59F to 77F), in a secured, 
locked cabinet with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA. 
12.1.3. 
BG00012 Handling and Disposal 
The Investigator must return all used and unused drug wallets of BG00012 as instructed by 
Biogen unless approved for onsite destruction. 
If any BG00012 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen by providing, in writing, the destruction 


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policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction. 
12.1.4. 
BG00012 Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost. 
Unless otherwise notified, all drug wallets, both used and unused, must be saved for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BG00012 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies. 
 


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13. 
EFFICACY ASSESSMENTS 
See Section 4 for the timing of all assessments. 
13.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of BG00012: 
 Relapse assessment 
 EDSS 
13.2. 
MRI Efficacy Assessments 
The following MRI efficacy assessments will be performed to evaluate the efficacy of BG00012: 
 The total number of new or newly enlarging T2 hyperintense lesions from baseline as 
well as from the scan of the previous visit on brain MRI scans  


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14. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of BG00012: 
 Physical examinations, including body weight and height 
 Vital sign measurements, including body temperature, pulse rate, and systolic and 
diastolic blood pressure 
 12-Lead electrocardiograms 
 Concomitant therapy and procedure recording 
 AE and SAE recording 
14.2. 
Laboratory Safety Assessments 
The following laboratory assessments will be performed to evaluate the safety profile of 
BG00012: 
 Hematology:  complete blood count with differential and platelet count 
 Blood chemistry:  sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphate, BUN, creatinine, uric acid, glucose, albumin, ALT, AST, 
gamma-glutamyl transferase, total bilirubin, and alkaline phosphatase 
 Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal) 
 Vitamin D and PTH levels 


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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject or his/her legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE 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. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Although abnormal laboratory values are typically not considered 
AEs, the following considerations may result in an abnormal laboratory value being considered 
an AE: 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject to receive specific corrective therapy 
 A laboratory abnormality that the Investigator considers to be clinically significant 
15.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly/birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 


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listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
If a subject is hospitalized due to local requirements for administration of the study treatment, 
the hospitalization should not be considered an SAE unless one of the requirements in 
Section 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.2 . 
 The relationship of the event to study treatment as defined in Section 15.2.2. 
 The severity of the event as defined in Section 15.2.3. 
15.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment. 


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Relationship of Event to Study Treatment 
Not related 
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
AE, or the presence of a more likely alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of an alternative explanation for the AE. 
15.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject. 
Moderate 
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of treatment with study treatment; 
treatment for symptoms may be given and/or subject hospitalized. 
15.2.4. 
Expectedness of Events 
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure.   
15.3. 
Monitoring and Recording Events 
15.3.1. 
Adverse Events 
Any AE experienced by the subject between the time of first dose of study treatment in the 
extension study and the Safety Follow-Up Visit is to be recorded on the eCRF, regardless of the 
severity of the event or its relationship to study treatment. 
15.3.2. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the signing of the ICF and the Safety 
Follow-Up Visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to Biogen Safety and Benefit-Risk 


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Management (SABR) or designee within 24 hours as described in Section 15.3.3.  Follow-up 
information regarding an SAE also must be reported with 24 hours.  
Subjects will be followed for all SAEs until the Safety Follow-Up Visit.  Thereafter, the event 
should be reported to Biogen SABR or designee only if the Investigator considers the SAE to be 
related to study treatment. 
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
15.3.3. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen SABR or designee within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately. 
Reporting Information for SAEs 
Any SAE that occurs between the time that the subject has signed the ICF and the Safety 
Follow-Up Visit must be reported to Biogen SABR or designee within 24 hours of the study site 
staff becoming aware of the event.  Thereafter, the event should be reported only if the 
Investigator considers it related to study treatment. 
A report must be submitted to Biogen SABR or designee regardless of the following: 
 Whether or not the subject has undergone study-related procedures 
 Whether or not the subject has received study treatment 
 The severity of the event 
 The relationship of the event to study treatment 
To report initial or follow-up information on an SAE, please fax (please refer to the Study 
Reference Guide) or email (
. 
15.3.3.1. Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate eCRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 
death certificates and autopsy reports to Biogen SABR or designee.  The term death should be 
reported as an SAE only if the cause of death is not known and cannot be determined. 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered. 


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Biogen SABR or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
Subjects should not become pregnant during the study and for 30 days after their last dose of 
study treatment.  If a female subject becomes pregnant, study treatment must be discontinued 
immediately. 
The Investigator must report a pregnancy by faxing or emailing the appropriate form within 
24 hours of the study site staff becoming aware of the pregnancy to Biogen SABR or designee 
(fax: please refer to the Study Reference Guide; email:
).  The 
Investigator or study site staff must report the outcome of the pregnancy to Biogen SABR or 
designee. 
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen SABR or designee within 24 hours of the site 
becoming aware of the overdose.  An overdose must be reported to Biogen or designee even if 
the overdose does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  
If an overdose results in an SAE, both the SAE and Overdose forms must be completed and 
faxed to Biogen SABR or designee.  All study treatment-related dosing information must be 
recorded on the dosing eCRF. 
15.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will perform appropriate 
medical interventions, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information. 
15.4.3.1. Unblinding for Medical Emergency 
Not Applicable 
15.5. 
Contraception Requirements 
Sexually active subjects of reproductive potential must practice effective contraception during 
the study and for at least 30 days after their last dose of study treatment.  Investigators should 
advise subjects of the potential risks associated with pregnancy while taking BG00012 and on 
the appropriate use of contraceptives (as defined below). 


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For the purposes of the study, highly effective contraception is defined as use of 1 or more of the 
following: 
For females: 
 Established use of oral, injected, or implanted hormonal methods of contraception. 
 Placement of an intrauterine device or intrauterine system. 
 Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide (where approved/applicable). 
 Female surgical sterilization (e.g., bilateral tubal ligation). 
For males: 
 Effective male contraception includes the use of condoms with spermicide. 
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
considered acceptable methods of contraception. 
Pregnancy reporting is described in Section 15.4.1. 
15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship to study treatment, and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Monitor and record all pregnancies and follow up on the outcomes. 
 Complete an SAE form for each SAE and fax it to Biogen SABR or designee within 
24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR or designee within 24 hours of the study site staff 
becoming aware of new information. 
 Report SAEs to local ethics committees, as required by local law. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 


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 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
15.6.2. 
Biogen  
Biogen’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definitions of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs. 
 Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Efficacy 
16.1.1. 
Analysis Population 
The population for the analysis of efficacy endpoints will be all subjects who have received at 
least 1 dose of BG00012 in this study and who have an evaluation of the efficacy endpoint under 
analysis. 
16.1.2. 
Methods of Analysis 
16.1.2.1. Analysis of the Primary Endpoint 
The primary analysis will be summaries of the incidence of treatment-emergent AEs, SAEs, and 
discontinuations from study treatment due to AEs. 
16.1.2.2. Analysis of the Secondary Endpoints 
The number of new or newly enlarging T2 hyperintense lesions on brain MRI scans will be 
summarized over time using descriptive statistics. 
ARR will be summarized along with the proportion of subjects relapsing, the rate of relapses 
requiring IV steroid use, and the rate of MS-related hospitalizations. 
EDSS scores and changes from baseline will be summarized over time along with the proportion 
of subjects with confirmed disability progression. 
16.2. 
Pharmacokinetics 
Not applicable. 
16.3. 
Pharmacodynamics 
Not applicable. 
16.4. 
Biomarker Analyses/Pharmacogenomics 
Not applicable. 
16.5. 
Safety 
16.5.1. 
Analysis Population 
The safety population is defined as all subjects who received at least 1 dose of BG00012 in this 
study. 


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16.5.1.1. Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. 
The primary analysis will be summaries of the incidence of treatment-emergent AEs, SAEs, and 
discontinuations from study treatment due to AEs. 
16.5.1.2. Clinical Laboratory Results 
Clinical laboratory evaluations including hematology, blood chemistry, and urinalysis will be 
summarized using the incidence of shifts outside the normal range.  In addition, summary 
statistics for quantitative laboratory values and changes from baseline will be presented.  
Lymphocyte count data will be summarized by timepoints on study treatment.  Additionally, 
lymphocyte count over time post-treatment and the time to recovery will be descriptively 
summarized for subjects who develop decreases in lymphocyte count (<LLN). 
16.5.1.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The incidence of 
subjects experiencing these abnormalities will be summarized. 
16.6. 
Antigenicity/Immunogenicity Data 
Not applicable. 
16.7. 
Interim Analyses 
The data from this study will be summarized periodically to support regulatory submissions or 
when further information on the long-term safety and efficacy of BG00012 in the pediatric 
population is required. 
16.8. 
Sample Size Considerations 
Because this study is an extension study, the sample size will be determined by the number of 
eligible subjects who completed Study 109MS202. 


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17. 
ETHICAL REQUIREMENTS 
Biogen, 
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Conference on Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in countries other than the US. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen. 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 


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subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines. 
A copy of the signed and dated ICF and assent if applicable must be given to the subject or the 
subject’s legally authorized representative.  The signed and dated ICF will be retained with the 
study records.  Local regulations must be complied with in respect to the final disposition of the 
original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent and assent if applicable must also be documented in the 
subject’s medical record. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
The subject will not be identified by name in the eCRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen or partnering company) with the subject before the subject makes a decision to 
participate in the study. 
17.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not enroll any subjects prior to completion of a study initiation visit 
conducted by Biogen.  This initiation visit will include a detailed review of the protocol and 
study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate. 
During these visits, eCRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen. 
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
Biogen will be responsible for all administrative aspects of this study including but not limited to 
study initiation, monitoring, management of AEs, and data management. 
19.1.1. 
Contract Research Organization  
A contract research organization (CRO), 
, will be jointly responsible for administrative 
aspects of the study including but not limited to study initiation, monitoring, and management of 
SAE reports and data management.  Before subjects are screened at each study site, the CRO will 
review study responsibilities with the Investigators and other study site staff, as appropriate. 
19.1.2. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on eCRFs by a Web-based 
electronic data capture tool OR remote data capture tool developed and supported by iMedidata 
RAVE and configured by 
. 
19.1.3. 
Central Laboratories for Laboratory Assessments 
A central laboratory has been selected by Biogen to analyze all safety laboratory samples 
collected for this study. 
19.2. 
Study Committees 
19.2.1. 
Advisory Committee 
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study.  The advisory committee will conduct 
regular reviews to monitor subject accrual and to monitor compliance with the protocol at 
individual study sites.  The advisory committee will determine whether the study should be 
stopped or amended for reasons other than safety. 
Members of the advisory committee will include the Medical Director, Clinical Operations Lead, 
and Project Statistician from Biogen, and participating Investigators.  Biogen will designate one 
of the participating Investigators to be the chairperson of the advisory committee. 
19.2.2. 
Independent Data Monitoring Committee  
An Independent Data Monitoring Committee (IDMC) will monitor the progress of the study, 
review interim safety data, and oversee the safety of subjects participating in this study.  The 
specifics regarding the IDMC organization and procedures will be outlined in the IDMC Charter. 
19.3. 
Changes to Final Study Protocol 
Protocol modifications that affect subject safety, the scope of the investigation, or the scientific 
quality of the study must be approved by the ethics committee before implementation of such 


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53 
modifications to the conduct of the study.  If required by local law, such modifications must also 
be approved by the appropriate regulatory agency prior to implementation. 
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require corresponding modifications (see 
Section 17). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site. 
19.6. 
Study Report Signatory 
Biogen will designate 1 or more of the participating Study Investigators as a signatory for the 
study report.  This determination will be made by several factors, including but not limited to, 
the Investigator’s experience and reputation in the studied indication; the Investigator’s 
contribution to the study in terms of design, management, and/or subject enrollment; or by other 
factors determined to be relevant by Biogen. 
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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54 
20. 
REFERENCES 
Chitnis T, Krupp L, Yeh A, et al. Pediatric multiple sclerosis. Neurol Clin. 2011;29(2):481-505. 
Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing 
therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-27. 
Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line 
treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 
3 trial. Lancet. 2012;380(9856):1819-28. 
European Commission. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. 2008. 
Ghoreschi K, Brück J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by 
inducing type II dendritic cells. J Exp Med. 2011;208(11):2291-303. 
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during 
a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 
2000;343(13):898-904. 
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves 
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76. 
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Epub 2010 Jan 20. 
Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression 
mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003;43:233-60. 
O'Connor P, Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and 
treatment of multiple sclerosis. An overview. Neurology. 2002;59(6 Suppl 3):S1-33. 
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303. 
Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI 
analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC 
MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 
1993;43(4):662-7. 
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 
PRISMS Study Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. 
Neurology. 2001;56(12):1628-36. 
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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55 
Waldman AT, Gorman MP, Rensel MR, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82. 
Zhu HJ, Appel DI, Jiang Y, et al. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37(9):1819-25. 
 
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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56 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter Extension Study to Determine the Long-Term 
Safety and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple 
Sclerosis,” and agree to conduct the study according to the protocol and the applicable ICH 
guidelines and GCP regulations, and to inform all who assist me in the conduct of this study of 
their responsibilities and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 


 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
 
 
 
 
 
 
 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
PROTOCOL NUMBER: 
109MS311 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
PHASE OF DEVELOPMENT: 
3 
 
 
PROTOCOL TITLE:  A Multicenter Extension Study to Determine the Long-Term Safety 
and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple 
Sclerosis 
 
 
 
EUDRA CT NO: 
 
2015-003282-29 
 
 
DATE: 
18 August 2015 
Version 1.0 
FINAL 
 
 


Protocol 109MS311 
Phase 3 Extension Study ofBG00012 in Pediatric Subjects With RRMS 
SPONSOR SIGNATURE 
Protocol 1 09MS311 was approved by: 
, MD 
 
 
Biogen MA Inc. 
CONFIDENTIAL 
Version 1.0 
Date 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 


Protocol 109MS311 
Version 1.0 
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
 
TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................9 
2. 
LIST OF ABBREVIATIONS.....................................................................................10 
3. 
SYNOPSIS .................................................................................................................11 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
109MS311...................................................................................................................13 
4.1. 
Study Schematic .........................................................................................................13 
4.2. 
Schedule of Activities .................................................................................................14 
4.3. 
Additional Information ...............................................................................................18 
4.3.1. 
Blood Volumes ...........................................................................................................18 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Overview of Multiple Sclerosis ..................................................................................19 
5.2. 
Current Therapies for Multiple Sclerosis ...................................................................19 
5.3. 
Profile of Previous Experience With BG00012 ..........................................................20 
5.3.1. 
Nonclinical Safety Experience ...................................................................................20 
5.3.2. 
Clinical Experience .....................................................................................................20 
5.4. 
Study Rationale ...........................................................................................................22 
5.5. 
Rationale for Dosing Regimen ...................................................................................22 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
6.1. 
Primary Objective and Endpoint ................................................................................23 
6.2. 
Secondary Objectives and Endpoints .........................................................................23 
7. 
STUDY DESIGN .......................................................................................................24 
7.1. 
Study Overview ..........................................................................................................24 
7.2. 
Overall Study Duration and Follow-Up .....................................................................24 
7.2.1. 
Enrollment ..................................................................................................................24 
7.2.2. 
Treatment ....................................................................................................................24 
7.2.3. 
Follow-Up ...................................................................................................................24 
7.3. 
Relapses ......................................................................................................................24 
7.4. 
Study Stopping Rules .................................................................................................25 
7.5. 
End of Study ...............................................................................................................25 
8. 
SELECTION OF SUBJECTS ....................................................................................26 


Protocol 109MS311 
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8.1. 
Inclusion Criteria ........................................................................................................26 
8.2. 
Exclusion Criteria .......................................................................................................26 
9. 
ENROLLMENT AND REGISTRATION .................................................................28 
9.1. 
Screening and Enrollment ...........................................................................................28 
9.2. 
Registration of Subjects ..............................................................................................28 
9.3. 
Blinding Procedures ....................................................................................................28 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................29 
10.1. 
Discontinuation of Study Treatment ...........................................................................29 
10.2. 
Withdrawal of Subjects From Study ...........................................................................29 
11. 
STUDY TREATMENT USE .....................................................................................30 
11.1. 
Regimen ......................................................................................................................30 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................30 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values ...............................................30 
11.2.2. 
Resumption of Study Treatment Dosing ....................................................................32 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities ..........................32 
11.2.4. 
Abnormal Urinalyses That Require Additional Evaluation ........................................33 
11.2.5. 
Treatment Schedule for Subjects With Abnormal Lymphocyte Count ......................33 
11.2.5.1. 
Schedule for Subjects With Lymphocyte Count <500/mm3.......................................33 
11.2.5.2. 
Schedule for Subjects Who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................34 
11.2.6. 
Dosage Reductions .....................................................................................................35 
11.3. 
Precautions ..................................................................................................................35 
11.4. 
Compliance .................................................................................................................35 
11.5. 
Concomitant Therapy and Procedures ........................................................................35 
11.5.1. 
Concomitant Therapy .................................................................................................35 
11.5.1.1. 
Allowed Concomitant Therapy ...................................................................................35 
11.5.1.2. 
Disallowed Concomitant Therapy ..............................................................................35 
11.5.2. 
Concomitant Procedures .............................................................................................36 
11.5.3. 
Treatment of Relapses on Scheduled or Unscheduled Visits .....................................36 
11.6. 
Continuation of Treatment ..........................................................................................36 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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12. 
STUDY TREATMENT MANAGEMENT ................................................................37 
12.1. 
BG00012 .....................................................................................................................37 
12.1.1. 
BG00012 Preparation .................................................................................................37 
12.1.2. 
BG00012 Storage ........................................................................................................37 
12.1.3. 
BG00012 Handling and Disposal ...............................................................................37 
12.1.4. 
BG00012 Accountability ............................................................................................38 
13. 
EFFICACY ASSESSMENTS ....................................................................................39 
13.1. 
Clinical Efficacy Assessments ....................................................................................39 
13.2. 
MRI Efficacy Assessments .........................................................................................39 
14. 
SAFETY ASSESSMENTS ........................................................................................40 
14.1. 
Clinical Safety Assessments .......................................................................................40 
14.2. 
Laboratory Safety Assessments ..................................................................................40 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................41 
15.1. 
Definitions ..................................................................................................................41 
15.1.1. 
Adverse Event .............................................................................................................41 
15.1.2. 
Serious Adverse Event ................................................................................................41 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................42 
15.2. 
Safety Classifications ..................................................................................................42 
15.2.1. 
Investigator Assessment of Events .............................................................................42 
15.2.2. 
Relationship of Events to Study Treatment ................................................................42 
15.2.3. 
Severity of Events .......................................................................................................43 
15.2.4. 
Expectedness of Events ..............................................................................................43 
15.3. 
Monitoring and Recording Events ..............................................................................43 
15.3.1. 
Adverse Events ...........................................................................................................43 
15.3.2. 
Serious Adverse Events ..............................................................................................43 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................44 
15.3.3.1. 
Deaths .........................................................................................................................44 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................44 
15.4. 
Procedures for Handling Special Situations ...............................................................45 
15.4.1. 
Pregnancy ...................................................................................................................45 
15.4.2. 
Overdose .....................................................................................................................45 


Protocol 109MS311 
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15.4.3. 
Medical Emergency ....................................................................................................45 
15.4.3.1. 
Unblinding for Medical Emergency ...........................................................................45 
15.5. 
Contraception Requirements ......................................................................................45 
15.6. 
Safety Responsibilities ................................................................................................46 
15.6.1. 
The Investigator ..........................................................................................................46 
15.6.2. 
Biogen .........................................................................................................................47 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........48 
16.1. 
Efficacy .......................................................................................................................48 
16.1.1. 
Analysis Population ....................................................................................................48 
16.1.2. 
Methods of Analysis ...................................................................................................48 
16.1.2.1. 
Analysis of the Primary Endpoint...............................................................................48 
16.1.2.2. 
Analysis of the Secondary Endpoints .........................................................................48 
16.2. 
Pharmacokinetics ........................................................................................................48 
16.3. 
Pharmacodynamics .....................................................................................................48 
16.4. 
Biomarker Analyses/Pharmacogenomics ...................................................................48 
16.5. 
Safety ..........................................................................................................................48 
16.5.1. 
Analysis Population ....................................................................................................48 
16.5.1.1. 
Adverse Events ...........................................................................................................49 
16.5.1.2. 
Clinical Laboratory Results ........................................................................................49 
16.5.1.3. 
Vital Signs ..................................................................................................................49 
16.6. 
Antigenicity/Immunogenicity Data ............................................................................49 
16.7. 
Interim Analyses .........................................................................................................49 
16.8. 
Sample Size Considerations .......................................................................................49 
17. 
ETHICAL REQUIREMENTS ...................................................................................50 
17.1. 
Declaration of Helsinki ...............................................................................................50 
17.2. 
Ethics Committee ........................................................................................................50 
17.3. 
Subject Information and Consent ...............................................................................50 
17.4. 
Subject Data Protection ..............................................................................................51 
17.5. 
Compensation for Injury .............................................................................................51 
17.6. 
Conflict of Interest ......................................................................................................51 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................51 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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18. 
ADMINISTRATIVE PROCEDURES .......................................................................52 
18.1. 
Study Site Initiation ....................................................................................................52 
18.2. 
Quality Assurance .......................................................................................................52 
18.3. 
Monitoring of the Study..............................................................................................52 
18.4. 
Study Funding .............................................................................................................52 
18.5. 
Publications .................................................................................................................52 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................53 
19.1. 
External Contract Organizations .................................................................................53 
19.1.1. 
Contract Research Organization .................................................................................53 
19.1.2. 
Electronic Data Capture ..............................................................................................53 
19.1.3. 
Central Laboratories for Laboratory Assessments .....................................................53 
19.1.4. 
Central Facility for Other Assessments ......................................................................53 
19.2. 
Study Committees .......................................................................................................53 
19.2.1. 
Advisory Committee ...................................................................................................53 
19.2.2. 
Independent Data Monitoring Committee ..................................................................54 
19.3. 
Changes to Final Study Protocol ................................................................................54 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................54 
19.5. 
Retention of Study Data ..............................................................................................54 
19.6. 
Study Report Signatory...............................................................................................54 
20. 
REFERENCES ...........................................................................................................55 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................57 
 
LIST OF TABLES 
Table 1: 
Study Activities for Study 109MS311 ........................................................................14 
Table 2: 
Additional Study Activities for Study 109MS311......................................................16 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
Treatment ....................................................................................................................30 
Table 4: 
Management of Lymphocyte Count <LLN ................................................................31 
Table 5: 
Lymphocyte Count Criteria Requiring Permanent Discontinuation of 
BG00012 Treatment ...................................................................................................33 
 
LIST OF FIGURES 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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Figure 1: 
Study Design ...............................................................................................................13 
Figure 2: 
Schedule for Subjects who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN ..........................................................................................34 
 
 


Protocol 109MS311 
Version 1.0 
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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9 
 
1. 
SPONSOR INFORMATION 
 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Biogen Australia PTY Ltd 
Suite 1, Level 5, 123 
Epping Rd 
North Ryde, NSW 2113 
Australia 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information. 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine transaminase 
ARR 
annualized relapse rate 
AST 
aspartate transaminase 
BID 
twice daily 
BUN 
blood urea nitrogen 
CNS 
central nervous system 
CRO 
contract research organization 
DHA 
Directions for Handling and Administration 
DMF 
dimethyl fumarate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDSS 
Expanded Disability Status Scale 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IV 
intravenous 
IVMP 
intravenous methylprednisolone 
LLN 
lower limit of normal 
MMF 
monomethyl fumarate 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
PK 
pharmacokinetics 
PTH 
parathyroid hormone 
RRMS 
relapsing-remitting multiple sclerosis 
SABR 
Safety and Benefit-Risk Management 
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reaction 
TID 
3 times daily 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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3. 
SYNOPSIS 
Protocol Number: 
109MS311 
Protocol Title: 
A Multicenter Extension Study to Determine the Long-Term 
Safety and Efficacy of BG00012 in Pediatric Subjects With 
Relapsing-Remitting Multiple Sclerosis 
Version Number 
1.0 
Name of Study Treatment: 
BG00012 (Dimethyl Fumarate; Tecfidera®) 
Study Indication: 
Relapsing-remitting multiple sclerosis (RRMS) 
Study Rationale 
With no approved multiple sclerosis (MS) therapies in the 
pediatric population, there exists a significant unmet need 
for approved treatment options.  In the adult population, 
BG00012 is a therapeutic option with demonstrated efficacy 
and acceptable tolerability and safety profiles combined 
with the ease of oral administration.  BG00012 was first 
approved (as Tecfidera) in the United States in 2013 for the 
treatment of adult patients with relapsing forms of MS and 
has since been approved in Europe and other regions.  This 
study will extend therapy from the ongoing BG00012 
pediatric Study 109MS202, in which the pharmacokinetics 
and efficacy of BG00012 in pediatric subjects with RRMS 
are being evaluated, in order to further evaluate the 
long-term safety and efficacy of BG00012 in these subjects.  
Phase of Development: 
3 
Study Objectives and 
Endpoints: 
The primary objective of the study is to evaluate the 
long-term safety of BG00012 in subjects who completed 
Study 109MS202. 
The primary endpoint that relates to this objective is the 
incidence of adverse events (AEs), serious AEs, and 
discontinuations of study treatment due to an AE 
Secondary objectives and endpoints are as follows: 
To evaluate the long-term efficacy of BG00012. 
 The total number of new or newly enlarging T2 
hyperintense lesions on brain magnetic 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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resonance imaging (MRI) scans 
 The annualized relapse rate 
 The proportion of subjects who experience 1 or 
more relapses during the study period 
To describe the long-term MS outcomes in subjects who 
completed Study 109MS202. 
 The degree of disability as measured by the 
Expanded Disability Status Scale (EDSS) and 
disability progression (as measured by at least a 
1.0-point increase on the EDSS from baseline 
EDSS ≥1.0 that is sustained for 24 weeks or at 
least a 1.5-point increase on the EDSS from 
baseline EDSS = 0 that is sustained for 
24 weeks) 
Study Design: 
This is a multicenter, open-label extension of 
Study 109MS202 that is designed to evaluate the long-term 
safety and efficacy of BG00012 in pediatric subjects. 
Study Location: 
Approximately 20 sites globally are planned. 
Number of Planned Subjects: 
The number of subjects who are eligible for this study will 
be determined by the number of subjects who have 
completed Study 109MS202 as per protocol. 
Study Population: 
This study will be conducted in subjects who completed 
Study 109MS202 as per protocol.  
Detailed criteria are described in Section 8. 
Treatment Groups: 
All subjects will receive BG00012 240 mg twice daily 
(2 capsules of 120 mg). 
Duration of Treatment and 
Follow-up: 
The treatment period is 96 weeks (2 years) and the 
Follow-Up Safety Visit will take place 4 weeks after the last 
dose of study treatment. 
 
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 109MS311 
4.1. 
Study Schematic 
Figure 1: 
Study Design 
 
 


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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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4.2. 
Schedule of Activities 
Table 1: 
Study Activities for Study 109MS311 
Tests and Assessments1 
Year 1 
Year 2 
Safety 
Follow-
Up Visit 
Baseline 
Visit 
(Day 1)2 
Visit 1 
(Week 16 
5d) 
Visit 2 
(Week 24 
5d) 
Visit 3 
(Week 36 
5d) 
Visit 4 
(Week 48 
5d) 
Visit 5 
(Week 64 
5d) 
Visit 6 
(Week 72 
5d) 
Visit 7 
(Week 84 
5d) 
Visit 8 
(Week 96 
5d) 
Informed Consent and 
Assent3 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
MS-Related Medical 
History4 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
Urine Pregnancy Test6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis7,8 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
PTH and Vitamin D Levels 
X 
 
 
 
X 
 
 
 
X 
X 
Brain MRI Scan9 
X 
X 
X 
 
 
X 
X 
 
 
 
EDSS 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Dispense Study Treatment10 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Therapy and 
Procedures Recording 
Monitor and record throughout the study 
AE/SAE Reporting 
Monitor and record throughout the study 
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
PTH = parathyroid hormone; SAE = serious adverse event. 
1 Tests and assessments must be completed prior to study treatment dispensation. 


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2 The Final Study Visit for Study 109MS202 will serve as the Baseline Visit for this extension study.  The Final Study Visit from Study 109MS202 can be within 
4 weeks of the Baseline Visit for Study 109MS311 if the 2 visits cannot be combined. 
3 Written informed consent from the subject’s parents or legal guardians and assent from the subject, if appropriate, must be obtained prior to performing any 
study-related procedures. 
4 MS-related medical history will include complete MS history of disease, MS diagnostic criteria, MS signs and symptoms, and MS treatment history. 
5 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements. 
6 For females of childbearing potential.  Results must be known prior to study treatment dispensation. 
7 Urine cytology must be performed at all visits indicated if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits.  If urine cytology is 
positive for malignant cells, the subject must permanently discontinue study treatment. 
,8 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol. 
9 MRI must not be performed within 30 days of receiving a course of steroids. 
10 Initial dispensation of study treatment may require an additional visit on or around Day 7.  Laboratory results must be evaluated and eligibility confirmed prior 
to dispensation of study treatment. 
 
 


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Table 2: 
Additional Study Activities for Study 109MS311 
Tests and Assessments 
Unscheduled Relapse Assessment 
Visit1 
(within 72 hours after symptom onset) 
Discontinuation/ 
Withdrawal Visit2 
(as soon as possible but no later than 
4 weeks after last dose of study 
treatment) 
Lymphocyte Follow-Up Visit3 
Physical Examination 
X 
X 
X 
Body Weight 
X 
X 
X 
Height 
 
X 
 
Vital Signs4 
X 
X 
X 
12-Lead ECG 
 
X 
 
Hematology5,6 
X 
X 
X 
Blood Chemistry6 
X 
X 
 
Urine Pregnancy Test7 
X 
X 
 
Urinalysis6,8 
X 
X 
 
PTH and Vitamin D Levels 
 
X 
 
EDSS 
X 
X 
 
Brain MRI Scan9 
 
X10 
 
Relapse Assessment 
X 
 
 
Concomitant Therapy and 
Procedures 
Monitor and record throughout the study 
AE/SAE Recording 
Monitor and record throughout the study 
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; LLN = lower limit of normal; MRI = magnetic resonance imaging; 
PTH = parathyroid hormone; SAE = serious adverse event. 
1 An Unscheduled Relapse Assessment Visit will be conducted within 72 hours of symptom onset of a suspected relapse (i.e., new or recurrent neurologic 
symptom[s]). 
2 Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from the study.  The Discontinuation/Withdrawal 
Visit should be conducted as soon as possible and no later than 4 weeks after the last dose of study treatment. 


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3 Subjects who complete, temporarily withhold, or permanently discontinue study treatment for any reason and have a lymphocyte count <LLN will continue 
protocol-required visits and assessments and be followed every 4 weeks until the lymphocyte count is ≥LLN or for 24 weeks after the last dose (whichever is 
sooner). 
4 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements. 
5 Hematology testing must be performed every 4 weeks in subjects with lymphocyte count <500/mm3. 
6 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol. 
7 For females of childbearing potential. 
8 Urine cytology must be performed if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits or at the Unscheduled Relapse Assessment 
Visit or the Discontinuation/Withdrawal Visit. 
9 An MRI must not be performed within 30 days of receiving a course of steroids. 
10 A brain MRI scan will be performed unless assessed in the last 30 days. 
 


Protocol 109MS311 
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4.3. 
Additional Information  
4.3.1. 
Blood Volumes 
Every effort must be made to collect the minimum blood volume needed per protocol.  The 
blood volumes required for this study do not exceed the recommended pediatric blood volume 
limits for sampling, i.e., volumes do not exceed 3% of the total blood volumes during a period of 
4 weeks or 1% at any single visit [European Commission 2008].  For example, in a 30-kg child 
(the lowest weight permitted in this study), it is estimated that 1% of the total volume would be 
approximately 21 mL.  Children weighing more than 30 kg would have higher permitted 
amounts.  The total blood volumes drawn at each visit will be 5 mL or less.  The approximate 
amount of blood to be drawn over the entire study period will be 50 mL.


Protocol 109MS311 
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5. 
INTRODUCTION  
5.1. 
Overview of Multiple Sclerosis 
Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central 
nervous system (CNS) that is characterized by inflammation, demyelination, and 
oligodendrocyte and neuronal loss.  It is the most common demyelinating disorder of the CNS, 
affecting approximately 2.5 million people worldwide.  MS primarily affects adults, with clinical 
onset occurring most commonly between the ages of 20 and 40 years [O'Connor and Canadian 
Multiple Sclerosis Working Group 2002].  Approximately 2.2% to 4.4% of all MS cases have 
onset during adolescence or childhood [Chitnis 2011], with girls affected more than boys, and 
most cases being relapsing-remitting multiple sclerosis (RRMS). 
5.2. 
Current Therapies for Multiple Sclerosis 
Despite the availability of several therapies approved for the treatment of adult patients with MS, 
there remains an unmet need for safe and effective treatments for pediatric patients with MS.  
Currently, there are no treatments that are approved to treat pediatric MS, and no randomized 
controlled clinical studies have been completed that demonstrate that the agents available for 
treatment of MS in adults are safe and effective in pediatric patients.  Moreover, there are no data 
on the pharmacological characterization of any of the disease-modifying MS therapies in 
pediatric patients.  Thus, current treatment options for pediatric patients with MS are adapted 
from therapeutic paradigms for adult patients, with dosing recommendations based solely on 
adult subject data and expert opinion. 
The most commonly used therapies in the pediatric population are interferons and glatiramer 
acetate [Waldman 2011].  Relative to placebo, these agents have been shown to reduce relapse 
rate by approximately 30% and may decrease disease progression [Jacobs 2000; Johnson 1995; 
Paty and Li 1993; PRISMS Study Group 2001; The IFNB Multiple Sclerosis Study Group 1993]. 
Other therapies currently approved for use in adults with MS include the following: 
 Natalizumab:  a humanized monoclonal antibody directed against α4 integrins 
[Polman 2006]  
 Fingolimod:  a selective oral immunosuppressant that is metabolized to a functional 
antagonist of sphingosine 1-phosphate receptors on lymphocytes [Kappos 2010] 
 Mitoxantrone:  a synthetic antineoplastic anthracenedione that intercalates into DNA, 
interfering with its synthesis and repair [Chitnis 2012] 
 Teriflunomide:  an immunosuppressive drug inhibiting pyrimidine synthesis by 
blocking dihydroorotate dehydrogenase [O'Connor 2011] 
 Alemtuzumab:  a monoclonal antibody directed against cluster of differentiation 52 
[Cohen 2012] 


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 Tecfidera®:  a dimethyl fumarate (DMF)-containing drug that activates the Nrf2 
antioxidant response pathway to mitigate inflammatory stress [Ghoreschi 2011; 
Nguyen 2003] 
5.3. 
Profile of Previous Experience With BG00012 
5.3.1. 
Nonclinical Safety Experience 
Nonclinical safety studies were performed to support the development of BG00012 (Tecfidera®) 
for the treatment of MS.  CNS, respiratory, and cardiovascular safety studies demonstrated no 
drug-related adverse effects on those systems, which is consistent with human data.  There were 
no findings of mutagenicity, impaired fertility, or teratogenicity.  Repeat-dose toxicology studies 
were performed in rodents (mouse and rat) and non-rodents (dog and monkey).  Findings in these 
studies in the liver, forestomach, and testis concluded that there is limited concern related to 
human risk.  In the male rat juvenile toxicology study that specifically evaluated the reproductive 
organs, there were no toxicology findings.  Kidney findings seen in animals were not observed in 
humans.  In lifetime carcinogenicity studies, renal tumors were attributed to a rodent-specific 
exacerbation of nephropathy. 
See the Investigator’s Brochure for more detailed information on nonclinical studies as well as 
information on nonclinical pharmacology and pharmacokinetic (PK) studies. 
5.3.2. 
Clinical Experience 
BG00012 240 mg twice daily (BID) is currently approved (as Tecfidera) for the treatment of 
adult patients with MS in the United States (US), the European Union, and other countries.  
The efficacy and safety of BG00012 are well established and based on data from Phase 2 and 3 
placebo-controlled safety and efficacy studies (Studies C-1900 Part 1, 109MS301 [DEFINE], 
and 109MS302 [CONFIRM]) and their uncontrolled extensions (Studies C-1900 Part 2 and 
109MS303 [ENDORSE]).  In these studies, over 2500 subjects received treatment with 
BG00012.  The overall exposure to BG00012 in these subjects was approximately 
6100 subject-years as of September 2013. 
Results of the Phase 3 clinical studies demonstrate that BG00012 240 mg BID or 3 times daily 
(TID) is an efficacious treatment for RRMS.  In these Phase 3 studies, BG00012 resulted in a 
significant reduction in the risk of relapse and annualized relapse rate (ARR), and the treatment 
had a positive effect on 12-week Expanded Disability Status Scale (EDSS) disability 
progression, with statistical significance achieved in Study 109MS301.  A robust, statistically 
significant effect was also observed on magnetic resonance imaging (MRI) endpoints, including 
the number and volume of new or newly enlarging T2 hyperintense lesions, 
gadolinium-enhancing lesions, and new or newly enlarging T1 hypointense lesions compared 
with placebo.  Efficacy was seen as early as 6 months and maintained over the 2-year span of 
Studies 109MS301 and 109MS302.  In the ongoing Phase 3, uncontrolled extension Study 
109MS303 (ENDORSE), which includes subjects who completed Studies 109MS301 or 
109MS302, sustained efficacy was observed through 5 years of treatment, and the safety profile 
of continued BG00012 treatment was consistent with that observed in the 2-year Phase 3 studies. 


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Overall, safety data from the clinical development program showed that BG00012 was well 
tolerated and has an acceptable safety profile.  In the BG00012 240 mg BID group, the most 
common adverse events (AEs; incidence ≥5%) that also occurred at an incidence of ≥2% higher 
than in the placebo group were flushing and hot flush, gastrointestinal (GI) events (diarrhea, 
nausea, abdominal pain upper, abdominal pain, vomiting, and dyspepsia), skin events (pruritus, 
rash, and erythema), nasopharyngitis, urinary tract infection, upper respiratory tract infection, 
albumin urine present, proteinuria, and microalbuminuria.  The AE profile was similar for 
subjects who received 240 mg TID. 
In placebo-controlled studies, decreases in mean white blood cell (WBC) and lymphocyte counts 
were observed over the first year of treatment (approximately 10% and 30%, respectively) with 
both dose regimens of BG00012.  Mean WBC and lymphocyte counts then plateaued and 
remained stable, even during longer periods of observation of approximately 5.25 years.  
Analysis of the data did not show a clear correlation between infections, serious infections, and 
lymphocyte counts.  No increased risk of infection, serious infection, or opportunistic infection 
was observed in subjects treated with BG00012 in the placebo-controlled studies.  With 
open-label and marketed use of BG00012, progressive multifocal leukoencephalopathy has been 
observed in the setting of severe and prolonged lymphopenia.  There has been no other evidence 
of increased risk of infections, serious infections, or other opportunistic infections (in open-label 
and marketed use of BG00012). 
BG00012 was also associated with a small increase in the incidence of elevations of liver 
transaminases compared to placebo.  In the controlled studies, this increase was primarily due to 
differences that occurred within the first 6 months of treatment.  The majority of subjects with 
elevations had alanine transaminase (ALT) or aspartate transaminase (AST) levels <3 times the 
upper limit of normal (ULN).  No patients had elevations of ALT or AST ≥3 × ULN associated 
with an elevation in total bilirubin of >2 × ULN.  There were no cases of hepatic failure due to 
BG00012.  During extended treatment with BG00012, ALT and AST levels remained stable 
through 3.5 years of observation.  Based on these data, there appears to be a transient increase in 
liver transaminases with BG00012 relative to placebo that does not appear to be associated with 
any clinically significant liver pathology. 
Although the kidney was identified as a target organ of BG00012 toxicity in nonclinical studies, 
subjects treated with BG00012 in the clinical studies did not appear to have a higher risk of renal 
or urinary events.  Small increases in proteinuria were observed, but the increases did not appear 
to be clinically significant.  On laboratory evaluation, there were no clinically relevant changes 
in blood urea nitrogen (BUN), creatinine, electrolytes, calcium, phosphorus, parathyroid 
hormone (PTH), or 1,25-dihydroxyvitamin D.  In the Phase 3 studies (Studies 109MS301 and 
109MS302), there were no differences between placebo and BG00012 BID in the incidence of 
proteinuria on 2 consecutive urinalyses (defined as trace or greater) or of 3+ or 4+ protein, both 
of which are potential indicators of significant proteinuria and renal dysfunction.  In addition, 
there was no evidence of changes over time in β2-microglobulinuria and microalbuminuria, 
which are more sensitive and specific markers of renal tubular dysfunction, even during longer 
periods of observation of approximately 3.5 years. 


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In the controlled studies, there was no increased incidence of malignancies in subjects who 
received BG00012 compared with placebo.  The types of malignancies observed and their 
incidence were within expected background rates.   
5.4. 
Study Rationale 
In adult subjects with RRMS, BG00012 demonstrated efficacy and had an acceptable safety 
profile in 2 Phase 3 studies, Studies 109MS301 and 109MS302.  With no approved therapies, 
there exists a significant unmet need for MS treatment options in the pediatric population.  In the 
adult population, BG00012 is a therapeutic option with demonstrated efficacy and acceptable 
tolerability and safety profiles combined with the ease of oral administration.  This study will 
extend therapy from the ongoing BG00012 pediatric Study 109MS202, in which the PK and 
efficacy of BG00012 in pediatric subjects with RRMS are being evaluated, in order to further 
evaluate the long-term safety and efficacy of BG00012 in these subjects. 
5.5. 
Rationale for Dosing Regimen 
The BG00012 dosage selected for this study (240 mg BID) is the approved BG00012 dosing 
regimen in adult patients with MS. 
In adults, after oral administration, DMF is well absorbed and extensively metabolized by 
esterases to its primary active metabolite, monomethyl fumarate (MMF).  As a result, DMF is 
not quantifiable in plasma, and all PK analyses have been performed based on MMF 
concentrations.  Downstream metabolism of DMF/MMF occurs through the tricarboxylic acid 
cycle, with exhalation of carbon dioxide serving as a major route of elimination.  The PK of 
BG00012 has been thoroughly evaluated in adults.  Body weight is a significant covariant for 
BG00012 exposure in that the area under the curve and the maximum concentration are 
decreased by 2% and 1.4%, respectively, for every 1-kg increase in body weight within the 
weight range of 45 to 112 kg.  This translates to a 2-fold increase in exposure levels as body 
weight decreases from 112 to 45 kg. 
Despite the effect of body weight changes on the exposure levels of BG00012, data from the 
pivotal Phase 3 studies suggested that the variability in exposure did not affect safety and 
efficacy measures in adult patients.  Notably, the efficacy and tolerability profiles of BG00012 at 
240 mg BID were indistinguishable from those at 240 mg TID, with a wide range of overlapping 
exposures between the 2 dosages. 
A Phase 1 PK study (Study 109MS101) revealed no apparent differences in the kinetics of 
BG00012 across the age range of 21 to 51 years once the weight relationship was accounted for.   
Published data [Zhu 2009] indicate that there were no notable differences in the expression and 
activities of esterases in juveniles (12 to 18 years old) when compared with adults.  These 
findings suggest that the disposition of BG00012 is unlikely to change with age for the target 
population (10 to 18 year olds). 
Taken together, these data indicate that 240 mg BID, the approved dose in adults, should be 
tolerable in pediatric subjects meeting the inclusion criteria for the parent study (109MS202) and 
the current extension study.  As such, this dose was chosen for the parent and current studies. 


Protocol 109MS311 
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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the long-term safety of BG00012 in subjects 
who completed Study 109MS202. 
The primary endpoint that relates to this objective is the incidence of AEs, serious AEs (SAEs), 
and discontinuations of study treatment due to an AE. 
6.2. 
Secondary Objectives and Endpoints 
A secondary objective is to evaluate the long-term efficacy of BG00012. 
The endpoints that relate to this objective are the total number of new or newly enlarging T2 
hyperintense lesions on brain MRI scans, the ARR, and the proportion of subjects who 
experience 1 or more relapses during the study period. 
Another secondary objective is to describe the long-term MS outcomes in subjects who 
completed Study 109MS202. 
The endpoint that relates to this objective is the degree of disability as measured by the EDSS 
and disability progression (as measured by at least a 1.0-point increase on the EDSS from 
baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS 
from baseline EDSS = 0 that is sustained for 24 weeks). 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a multicenter, open-label extension of Study 109MS202 that is designed to evaluate the 
long-term safety and efficacy of BG00012 in pediatric subjects. 
See Figure 1 for a schematic of the study design. 
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of enrollment, treatment, and follow-up.  The study duration is 
approximately 104 weeks, consisting of a 4-week enrollment period (if the Final Study Visit 
from Study 109MS202 cannot be combined with the Baseline Visit for this study), a 96-week 
treatment period, and a Safety Follow-Up Visit up to 4 weeks after the last dose of study 
treatment.  Unscheduled Relapse Assessment Visits and Lymphocyte Follow-Up Visits will be 
performed as necessary. 
7.2.1. 
Enrollment 
Subject eligibility for the study will be determined at the Final Study Visit for Study 109MS202 
or within 4 weeks prior to study entry.  The Final Study Visit for Study 109MS202 will serve as 
the Baseline Visit for this study. 
7.2.2. 
Treatment 
Eligible subjects will report to the study site to receive study treatment approximately every 
12 weeks for up to 96 weeks (2 years). 
7.2.3. 
Follow-Up 
Subjects are to return to the study site for a follow-up visit 4 weeks after their last treatment visit 
(Visit 8 at Week 96 [±5 days]). 
Subjects who withdraw prematurely from the study will complete the Early Withdrawal Visit, 
which should be conducted as soon as possible and no later than 4 weeks after the subject’s last 
dose of study treatment.  Subjects who withdraw prematurely should be encouraged to complete 
the Safety Follow-Up Visit 4 weeks after the last dose of study treatment. 
Subjects who complete, temporarily withhold, or permanently discontinue study treatment for 
any reason and have a lymphocyte count less than the lower limit of normal (LLN) will be 
followed every 4 weeks until the lymphocyte count is ≥LLN or for 24 weeks after the last dose 
(whichever is sooner). 
7.3. 
Relapses 
Suspected relapses during this study will be evaluated and confirmed according to the protocol 
by the Investigator.  Relapses are defined as new or recurrent neurologic symptoms not 


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associated with fever or infection, lasting at least 24 hours, and accompanied by new objective 
neurological findings upon examination by the Investigator.  New or recurrent neurologic 
symptoms that evolve gradually over months should be considered disability progression, not an 
acute relapse, and should not be treated with steroids.  New or recurrent neurologic symptoms 
that occur less than 30 days following the onset of a protocol-defined relapse should be 
considered part of the same relapse and would not be treated with intravenous 
methylprednisolone (IVMP) within the protocol. 
If a subject experiences new neurologic symptoms, then the subject or caregiver must contact the 
Investigator within 48 hours of the onset of symptoms to complete a Telephone Questionnaire to 
determine the necessity of an Unscheduled Relapse Assessment Visit.  If required, the subject 
will then be evaluated in person by the Investigator within 5 days of the onset of the potential 
relapse.  The Investigator is to perform a relapse assessment and obtain an EDSS score.  To 
ensure consistency across sites, Investigators must undergo a standardized training session on 
EDSS scoring prior to enrollment of subjects at their site.  New objective findings on 
neurological examination performed by the Investigator are required to determine if a 
protocol-defined relapse has occurred.  Subjects may not begin corticosteroid treatment of the 
relapse per protocol until the Investigator has examined them. 
Treatment of an acute event of relapse with IVMP may proceed at the discretion of the 
Investigator and will not affect the subject’s eligibility to continue in the study.  If an 
Unscheduled Relapse Assessment Visit occurs within 7 days of a scheduled clinic visit, then the 
2 visits may take place on the same day; however, MRIs must be conducted according to the 
schedule outlined in Section 4.2. 
7.4. 
Study Stopping Rules 
Biogen may terminate this study at any time, after informing the Investigators.  Biogen will 
notify Investigators when the study is to be placed on hold, completed, or terminated. 
7.5. 
End of Study 
The end of study is last subject, last visit for final collection of data. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Day 1 or at the timepoint specified in the individual eligibility criterion listed: 
1. Ability of parents, legal guardians, and/or subjects to understand the purpose and risks of 
the study and provide signed and dated informed consent and authorization to use 
confidential health information in accordance with national and local subject privacy 
regulations.  Subjects will provide assent in addition to the parental or guardian consent, 
as appropriate, per local regulations. 
2. Subjects who completed, as per protocol, the previous BG00012 clinical study 
109MS202 and remain on BG00012 treatment at 240 mg BID. 
3. All female subjects of childbearing potential and all male subjects must practice effective 
contraception during the study and for at least 30 days after their last dose of study 
treatment.  For further details of contraceptive requirements for this study, please refer to 
Section 15.5. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Day 1 or at the timepoint specified in the individual criterion listed: 
1. Unwillingness or inability to comply with study requirements, including the presence of 
any condition (physical, mental, or social) that is likely to affect the subject’s ability to 
comply with the protocol. 
4. Any significant changes in medical history occurring after enrollment in the parent Study 
109MS202, including laboratory test abnormalities or current clinically significant 
conditions that in the opinion of the Investigator would have excluded the subject’s 
participation from the parent study.  The Investigator must re-review the subject’s 
medical fitness for participation and consider any factors that would preclude treatment. 
5. Subjects from Study 109MS202 who could not tolerate study treatment. 
6. History of malignancy. 
7. History of severe allergic or anaphylactic reactions or known drug hypersensitivity to 
DMF or fumaric acid esters. 
8. Any of the following abnormal blood tests: 
 ALT >3 times the ULN 
 AST >3 times the ULN 
 Gamma-glutamyl-transferase >3 times the ULN 


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 Creatinine >1.2 times the ULN 
 WBC count <2000/mm3 
 Lymphocyte count <500/mm3 
9. Female subjects considering becoming pregnant or breastfeeding while in the study or 
who are pregnant or breastfeeding. 
10. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 
 


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9. 
ENROLLMENT AND REGISTRATION 
9.1. 
Screening and Enrollment 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the informed consent form (ICF), that subject is considered 
to be enrolled in the study.  Subjects who have a nonclinically significant out-of-range laboratory 
result may be rescreened 1 time only at the discretion of the Investigator.  Participating study 
sites are required to document all screened candidates initially considered for inclusion in this 
study.  If a subject is excluded from the study, the reasons for exclusion will be documented in 
the subject’s source documents and on the screening log. 
9.2. 
Registration of Subjects 
Subjects will be registered at Day 1, after all baseline assessments have been completed and after 
the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  No 
subject may begin treatment prior to assignment of a unique identification number (registration).  
Any subject identification numbers that are assigned will not be reused even if the subject does 
not receive treatment. 
Refer to the Study Reference Guide for details on registration. 
9.3. 
Blinding Procedures 
Not applicable. 


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue BG00012 for any of the following reasons: 
 The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1. 
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
 The subject has lymphocyte count <500/mm3 for 6 months as outlined in Table 4 and 
Table 5 . 
 The subject experiences a protocol-specified change in laboratory values that 
necessitates permanent discontinuation of treatment as outlined in Table 3 and 
Table 4. 
 The subject cannot tolerate study treatment. 
 The subject receives any of the disallowed concomitant medications for this study. 
 The subject or subject’s parent/legal guardian desires to discontinue treatment. 
 At the discretion of the Investigator for medical reasons or for noncompliance. 
The reason for discontinuation of study treatment must be recorded in the subject’s eCRF. 
Subjects who discontinue treatment may remain in the study and continue protocol-required tests 
and assessments. 
10.2. 
Withdrawal of Subjects From Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject or the subject’s parent/guardian withdraws consent. 
 The subject enrolls into another interventional clinical study. 
 The subject is unwilling or unable to comply with the protocol. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s eCRF. 


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11. 
STUDY TREATMENT USE 
11.1. 
Regimen 
BG00012 will be taken orally at a dose of 240 mg BID. 
Subjects will be instructed to swallow each BG00012 capsule whole and not chewed.  The 
capsule and its contents are not to be crushed, divided, dissolved, sucked, or chewed since the 
enteric coating of the microtablets in the capsule helps to prevent irritant effects on the stomach.  
If unable to swallow the capsule, the capsule may be opened and the contents mixed with food 
immediately prior to consumption. 
Refer to and follow the Directions for Handling and Administration (DHA). 
11.2. 
Modification of Dose and/or Treatment Schedule 
11.2.1. 
Dosing Interruption for Abnormal Laboratory Values 
BG00012 must be temporarily withheld and/or permanently discontinued when any of the 
following laboratory values meet the threshold limits defined in Table 3 (laboratory 
abnormalities that require immediate and permanent discontinuation of study treatment are also 
specified in Table 3). 
Table 3: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of Treatment 
Laboratory 
Parameter 
Laboratory Result 
Required Action 
AST (SGOT) 
or 
ALT (SGPT) 
 
>3  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms AST or ALT 
>3  ULN, then the study treatment must be withheld.  
If the value remains >3  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Creatinine 
>1.2  ULN 
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that creatinine is 
>1.2  ULN, then the study treatment must be withheld.  
If the value remains >1.2  ULN for 4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 


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Laboratory 
Parameter 
Laboratory Result 
Required Action 
WBC 
2000/mm3  
The Investigator should repeat the test as soon as 
possible.  If the retest value confirms that WBC count is 
2000/mm3, then the study treatment must be withheld.  
If the value remains <2000/mm3 for ≥4 weeks after 
discontinuation of study treatment, then the subject 
must permanently discontinue study treatment, and 
the event must be recorded as an AE. 
Urinalysis 
Positive hematuria on 
microscopy 
The Investigator should repeat the test as soon as 
possible.  If retest confirms microscopic hematuria 
without known etiology, then the study treatment must 
be withheld, and urine cytology performed.  If 
hematuria persists for ≥4 weeks after discontinuation or 
if cytology is positive for malignant cells, then the 
subject must permanently discontinue study 
treatment, and the event must be recorded as an AE.  
Subjects should be referred to a nephrologist for 
further investigation. 
Urinalysis 
Proteinuria ≥2+ 
The Investigator should repeat the test as soon as 
possible.  If retest confirms proteinuria ≥2+ without 
known etiology, then the study treatment must be 
withheld.  If proteinuria ≥2+ persists for ≥4 weeks after 
discontinuation, then the subject must permanently 
discontinue study treatment, and the event must be 
recorded as an AE.  Subjects should be referred to a 
nephrologist for further investigation. 
AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; SGOT = serum glutamic 
oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal; 
WBC = white blood cell. 
Table 4 describes the management of lymphocytes <LLN for subjects during and after study 
treatment. 
Table 4: 
Management of Lymphocyte Count <LLN 
Laboratory Parameter 
Laboratory Result 
Required Action 
Lymphocyte count on 
study treatment 
<LLN 
The Investigator should repeat the test within 
2 weeks.  If retest confirms that lymphocyte count is 
<LLN, lymphocyte count should be closely 
monitored (at least every 4 weeks). 
Lymphocyte count on 
study treatment 
<500/mm3 
If lymphocyte count is <500/mm3 for more than 
6 months, study treatment must be permanently 
discontinued. 


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Laboratory Parameter 
Laboratory Result 
Required Action 
Lymphocyte count in 
subjects who complete or 
permanently discontinue 
BG00012 for any reason 
<LLN 
Subjects will be followed at least every 4 weeks 
until the lymphocyte count is ≥LLN or for 24 weeks 
after the last dose (whichever is sooner). 
LLN = lower limit of normal. 
While dosing is withheld, subjects will continue tests and assessments according to Table 1 (and 
may also undergo additional assessments to evaluate the laboratory abnormality as per the 
Investigator’s standard practice).  In addition, subjects (whether on study treatment, having 
dosing temporarily withheld, or permanently discontinued) must have the abnormal laboratory 
result rechecked at the central laboratory as follows: 
 For all analytes, with the exception of lymphocytes, results will be rechecked at least 
every 2 weeks until resolution or stabilization of the laboratory value.  Depending on 
the severity and clinical significance of the abnormality, the Investigator may need to 
perform the retests more frequently. 
 For lymphocytes, results will be rechecked at least every 4 weeks until the 
lymphocyte count is ≥LLN or for 24 weeks after the last dose (whichever is sooner).  
Depending on the severity and clinical significance of the abnormality, the 
Investigator may need to perform the retests more frequently. 
11.2.2. 
Resumption of Study Treatment Dosing 
Resumption of BG00012 treatment is to be considered on a case-by-case basis and must be 
discussed with the Medical Monitor.   
Subjects with lymphocyte <LLN  
Subjects who temporarily withhold study treatment due to decreases in lymphocyte count (at the 
discretion of the Investigator) may resume study treatment when lymphocyte counts recover 
(defined as a lymphocyte count ≥LLN on 2 consecutive occasions at least 4 weeks apart).   
Resumption of study treatment after an interruption 
Subjects who are allowed to resume BG00012 dosing after an interruption of ≥2 weeks will 
restart dosing at a reduced dosage for 1 week.  Subjects will take one 120-mg capsule BID for 
1 week.  After 1 week at the reduced dose, subjects will resume taking two 120-mg capsules 
BID. 
11.2.3. 
Subsequent Development of Additional Laboratory Abnormalities 
Subjects who subsequently develop the same abnormal laboratory value at any other time during 
the study must permanently discontinue dosing with BG00012, i.e., only 1 dosing interruption is 
allowed for each subject for the same laboratory abnormality.  However, subjects who 
subsequently experience a different laboratory abnormality can have study treatment withheld 
again.  For example, if a subject had dosing temporarily withheld for an abnormal ALT, then had 
dosing resume after ALT returned to acceptable limits, and subsequently developed abnormal 


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WBCs, then the subject may have BG00012 withheld again.  However, only 2 dosing 
interruptions are allowed for each subject.   
Any subject who experiences abnormal laboratory results (which meet the criteria defined in 
Table 3) on a third occasion must discontinue dosing for the remainder of the study. 
11.2.4. 
Abnormal Urinalyses That Require Additional Evaluation 
Subjects who develop any of the following abnormal urine laboratory values must have the test 
repeated 2 weeks later: 
 urinary casts (other than hyaline casts) 
 glycosuria (trace or greater) in the setting of normal serum glucose 
If the abnormality persists on retesting, then the subject should be fully investigated for possible 
causes and referred for evaluation by a nephrologist if appropriate in the opinion of the 
Investigator. 
Subjects who demonstrate 1+ or greater proteinuria on a urine dipstick (and do not have a 
documented history of prior benign proteinuria) should have a spot protein/creatinine ratio (on 
AM void).  If the spot protein/creatinine ratio is >0.2 mg/mg, then the subject should be fully 
investigated for possible causes and referred for evaluation by a nephrologist if appropriate in the 
opinion of the Investigator. 
11.2.5. 
Treatment Schedule for Subjects With Abnormal Lymphocyte Count 
11.2.5.1. Schedule for Subjects With Lymphocyte Count <500/mm3 
BG00012 must be permanently discontinued when the lymphocyte count meets the threshold 
limits defined in Table 5. 
Table 5: 
Lymphocyte Count Criteria Requiring Permanent Discontinuation of 
BG00012 Treatment 
Laboratory Parameter 
Laboratory Result 
Required Action 
Lymphocyte count 
 
 
<500/mm3 
The Investigator should repeat the test as soon as 
possible.  If retest confirms that lymphocyte count is 
<500/mm3, lymphocyte count should be closely 
monitored (at least every 4 weeks).  If lymphocyte 
count is <500/mm3 for more than 6 months, study 
treatment must be permanently discontinued.  
If study treatment is permanently discontinued due to lymphocyte count <500/mm3, subjects may 
continue protocol-required tests and assessments and also undergo lymphocyte follow-up every 
4 weeks until the lymphocyte count is ≥LLN or for 24 weeks after the last dose (whichever is 
sooner) [see Table 2].  If the lymphocyte count does not recover, the treating neurologist should 
contact the Medical Monitor.  


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11.2.5.2. Schedule for Subjects Who Complete, Temporarily Withhold, or Permanently 
Discontinue Study Treatment for Any Reason and Have a Lymphocyte 
Count <LLN 
Subjects who complete the 96-week treatment period and who have a lymphocyte count <LLN 
will be followed every 4 weeks until the lymphocyte count is ≥LLN or for 24 weeks after the last 
dose (whichever is sooner).  If the lymphocyte count does not recover after 24 weeks, the 
treating neurologist should contact the Medical Monitor.   
Subjects who temporarily withhold or permanently discontinue study treatment for any reason 
(see Section 10.1) and who have a lymphocyte count <LLN will continue protocol-required tests 
and assessments and also undergo lymphocyte follow-up every 4 weeks until the lymphocyte 
count is ≥LLN or for 24 weeks after the last dose (whichever is sooner) [see Table 4].  If the 
lymphocyte count does not recover after 24 weeks, the treating neurologist should contact the 
Medical Monitor. 
See Figure 2 for a schedule for subjects who complete, temporarily withhold, or permanently 
discontinue study treatment for any reason and who have a lymphocyte count <LLN. 
Figure 2: 
Schedule for Subjects who Complete, Temporarily Withhold, or 
Permanently Discontinue Study Treatment for Any Reason and Have a 
Lymphocyte Count <LLN 
 


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LLN = lower limit of normal. 
11.2.6. 
Dosage Reductions 
Dosage reduction will be allowed only for subjects who are unable to tolerate BG00012 
treatment due to flushing and/or GI disturbances (dosage reductions will not be allowed for 
abnormal laboratory values; for management of abnormal laboratory values, see Sections 11.2.1, 
11.2.2, and 11.2.3).  Subjects who do not tolerate BG00012 treatment will reduce their dosage by 
taking one 120-mg capsule BID for up to 4 weeks.  Within 4 weeks at the reduced dosage, 
subjects will resume taking the full dose of 240 mg (two 120-mg capsules) BID.  If the subject is 
still unable to tolerate BG00012 treatment at the 240-mg BID dose, the subject may continue in 
the study taking the 120-mg BID dose. 
11.3. 
Precautions 
Medications for the treatment of severe hypersensitivity reactions (e.g., epinephrine for 
subcutaneous injections, diphenhydramine for injection) should be available for immediate use. 
See the DHA for detailed instructions. 
11.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff.  Compliance for 
BG00012 will be monitored by capsule count and captured in the eCRF. 
11.5. 
Concomitant Therapy and Procedures 
11.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between the Baseline Visit and the 
Safety Follow-Up Visit. 
11.5.1.1. Allowed Concomitant Therapy 
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue, is not restricted but 
should be consistent for the duration of the study. 
Subjects should be instructed not to start taking any new medications, including nonprescribed 
drugs, unless they have received permission from the Investigator. 
11.5.1.2. Disallowed Concomitant Therapy 
Concomitant treatment with any of the following is not allowed while receiving study treatment, 
unless approved by the Medical Monitor, or as otherwise described in this protocol: 
 Any alternative drug treatments directed toward the treatment of MS, such as 
immunomodulatory treatments (including but not limited to, interferon-beta, 
glatiramer acetate, natalizumab, fingolimod, teriflunomide, alemtuzumab, 
mitoxantrone, mycophenolate mofetil, laquinimod, cyclophosphamide, methotrexate, 
azathioprine, cyclosporine, etc.) and 4-aminopyridine or related products with the 


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exception of acute management of protocol-defined relapse (as described in 
Section 11.5.2 ).  
 Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications. 
 Any systemic steroid therapy including but not limited to, oral corticosteroids 
(e.g., prednisone) or periodic (e.g., monthly) treatment with IVMP, except for 
protocol-defined treatment of relapses as described in Section 11.5.2.  Steroids that 
are administered by nonsystemic routes (e.g., topical, inhaled) are allowed. 
 Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, intravenous (IV) immunoglobulin, plasmapheresis, 
or cytapheresis. 
Subjects who receive any of these restricted medications without approval from the Biogen 
Medical Director(s) will be required to permanently discontinue study treatment and will be 
withdrawn from the study as outlined in Section 10.2.   
Use of the concomitant therapies or procedures defined above must be recorded on the subject’s 
eCRF, according to the instructions for eCRF completion.  AEs related to the administration of 
these therapies or procedures must be documented on the appropriate eCRF. 
11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the Final Study Visit. 
The use of concomitant procedures must be recorded on the subject’s eCRF, according to 
instructions for eCRF completion.  AEs related to the administration of these procedures must be 
documented on the appropriate eCRF. 
11.5.3. 
Treatment of Relapses on Scheduled or Unscheduled Visits 
The only protocol-approved treatment for relapse in this study is either 3 or 5 days with IVMP, 
up to 1000 mg/day.  IVMP can be given once a day or in divided doses.  Subjects may also 
refuse relapse treatment.  Any deviations from this recommended treatment must first be 
discussed with the Biogen Medical Director or designee. 
Study treatment dosing is to continue uninterrupted during IVMP treatment. 
11.6. 
Continuation of Treatment 
There is no provision for additional courses of BG00012 provided by Biogen beyond the 
treatment period defined in this protocol. 
If and when BG00012 is commercially available at the time the study treatment period is 
completed, subjects will be allowed to take commercial BG00012 during the Safety Follow-Up 
Period if deemed appropriate by product labeling and at the discretion of their treating physician. 


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12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol). 
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study. 
12.1. 
BG00012 
BG00012 is a drug product formulated as enteric-coated microtablets in gelatin capsules (blue 
and white) for oral administration.  Each capsule contains 120 mg BG00012. 
Excipients for the manufacturing of the enteric-coated microtablets include microcrystalline 
cellulose, croscarmellose sodium, talc, colloidal anhydrous silica (colloidal silicon dioxide), 
magnesium stearate, triethyl citrate, methacrylic acid-methyl methacrylate copolymer, 
methacrylic acid-ethyl acrylate copolymer, simethicone, sodium lauryl sulfate, and 
polysorbate 80.  Excipients for the manufacturing of the capsule shell include gelatin, titanium 
dioxide, and indigotin. 
The contents of the study treatment label will be in accordance with all applicable regulatory 
requirements.  BG00012 should not be used after the expiration date. 
12.1.1. 
BG00012 Preparation 
BG00012 will be provided as capsules.  Drug wallets will be prepared to ensure that the 
appropriate treatment is provided to each subject.  Drug wallets will be supplied from Interactive 
Voice/Web Response System at specific timepoints during the study so that the appropriate 
wallets are correctly dispensed to a subject at the required timepoints throughout the study. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the drug wallet or study treatment, do not use the study treatment.  The drug wallet in question 
should be quarantined at the study site and the problem immediately reported to Biogen. 
12.1.2. 
BG00012 Storage 
Study treatment must be stored in a secure location. 
BG00012 is to be stored at room temperature (15C to 25C or 59F to 77F), in a secured, 
locked cabinet with limited access.  For the most up-to-date storage requirements, follow the 
instructions provided in the DHA. 
12.1.3. 
BG00012 Handling and Disposal 
The Investigator must return all used and unused drug wallets of BG00012 as instructed by 
Biogen unless approved for onsite destruction. 


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If any BG00012 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction. 
12.1.4. 
BG00012 Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed or lost. 
Unless otherwise notified, all drug wallets, both used and unused, must be saved for study 
treatment accountability.  At the end of the study, reconciliation must be made between the 
amount of BG00012 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Biogen.  A written explanation must be provided for any discrepancies. 
 


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13. 
EFFICACY ASSESSMENTS 
See Section 4 for the timing of all assessments. 
13.1. 
Clinical Efficacy Assessments 
The following clinical assessments will be performed to evaluate the efficacy of BG00012: 
 Relapse assessment 
 EDSS 
13.2. 
MRI Efficacy Assessments 
The following MRI efficacy assessments will be performed to evaluate the efficacy of BG00012: 
 The total number of new or newly enlarging T2 hyperintense lesions from baseline as 
well as from the scan of the previous visit on brain MRI scans  


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14. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of BG00012: 
 Physical examinations, including body weight and height 
 Vital sign measurements, including body temperature, pulse rate, and systolic and 
diastolic blood pressure 
 12-Lead electrocardiograms 
 Concomitant therapy and procedure recording 
 AE and SAE recording 
14.2. 
Laboratory Safety Assessments 
The following laboratory assessments will be performed to evaluate the safety profile of 
BG00012: 
 Hematology:  complete blood count with differential and platelet count 
 Blood chemistry:  sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphate, BUN, creatinine, uric acid, glucose, albumin, ALT, AST, 
gamma-glutamyl transferase, total bilirubin, and alkaline phosphatase 
 Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination, if 
abnormal) 
 Vitamin D and PTH levels 


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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject or his/her legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE 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. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator.  Although abnormal laboratory values are typically not considered 
AEs, the following considerations may result in an abnormal laboratory value being considered 
an AE: 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject to receive specific corrective therapy 
 A laboratory abnormality that the Investigator considers to be clinically significant 
15.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly/birth defect 


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An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission. 
If a subject is hospitalized due to local requirements for administration of the study treatment, 
the hospitalization should not be considered an SAE unless one of the requirements in 
Section 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.2 . 
 The relationship of the event to study treatment as defined in Section 15.2.2. 
 The severity of the event as defined in Section 15.2.3. 
15.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment. 


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Relationship of Event to Study Treatment 
Not related 
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
AE, or the presence of a more likely alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the AE, or a lack of an alternative explanation for the AE. 
15.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject. 
Moderate 
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of treatment with study treatment; 
treatment for symptoms may be given and/or subject hospitalized. 
15.2.4. 
Expectedness of Events 
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure.   
15.3. 
Monitoring and Recording Events 
15.3.1. 
Adverse Events 
Any AE experienced by the subject between the time of first dose of study treatment in the 
extension study and the Safety Follow-Up Visit is to be recorded on the eCRF, regardless of the 
severity of the event or its relationship to study treatment. 
15.3.2. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of the signing of the ICF and the Safety 
Follow-Up Visit is to be recorded on an SAE form, regardless of the severity of the event or its 
relationship to study treatment.  SAEs must be reported to Biogen Safety and Benefit-Risk 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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44 
 
Management (SABR) or designee within 24 hours as described in Section 15.3.3.  Follow-up 
information regarding an SAE also must be reported with 24 hours.  
Subjects will be followed for all SAEs until the Safety Follow-Up Visit.  Thereafter, the event 
should be reported to Biogen SABR or designee only if the Investigator considers the SAE to be 
related to study treatment. 
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
15.3.3. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen SABR or designee within 24 hours of the study site staff becoming aware 
of the SAE.  It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately. 
Reporting Information for SAEs 
Any SAE that occurs between the time that the subject has signed the ICF and the Safety 
Follow-Up Visit must be reported to Biogen SABR or designee within 24 hours of the study site 
staff becoming aware of the event.  Thereafter, the event should be reported only if the 
Investigator considers it related to study treatment. 
A report must be submitted to Biogen SABR or designee regardless of the following: 
 Whether or not the subject has undergone study-related procedures 
 Whether or not the subject has received study treatment 
 The severity of the event 
 The relationship of the event to study treatment 
To report initial or follow-up information on an SAE, please fax (please refer to the Study 
Reference Guide) or email 
. 
15.3.3.1. Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate eCRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 
death certificates and autopsy reports to Biogen SABR or designee.  The term death should be 
reported as an SAE only if the cause of death is not known and cannot be determined. 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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45 
 
Biogen SABR or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
Subjects should not become pregnant during the study and for 30 days after their last dose of 
study treatment.  If a female subject becomes pregnant, study treatment must be discontinued 
immediately. 
The Investigator must report a pregnancy by faxing or emailing the appropriate form within 
24 hours of the study site staff becoming aware of the pregnancy to Biogen SABR or designee 
(fax: please refer to the Study Reference Guide; email:
.  The 
Investigator or study site staff must report the outcome of the pregnancy to Biogen SABR or 
designee. 
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen SABR or designee within 24 hours of the site 
becoming aware of the overdose.  An overdose must be reported to Biogen or designee even if 
the overdose does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  
If an overdose results in an SAE, both the SAE and Overdose forms must be completed and 
faxed to Biogen SABR or designee.  All study treatment-related dosing information must be 
recorded on the dosing eCRF. 
15.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will perform appropriate 
medical interventions, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information. 
15.4.3.1. Unblinding for Medical Emergency 
Not Applicable 
15.5. 
Contraception Requirements 
Sexually active subjects of reproductive potential must practice effective contraception during 
the study and for at least 30 days after their last dose of study treatment.  Investigators should 
advise subjects of the potential risks associated with pregnancy while taking BG00012 and on 
the appropriate use of contraceptives (as defined below). 


Protocol 109MS311 
Version 1.0 
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
46 
 
For the purposes of the study, highly effective contraception is defined as use of 1 or more of the 
following: 
For females: 
 Established use of oral, injected, or implanted hormonal methods of contraception. 
 Placement of an intrauterine device or intrauterine system. 
 Barrier methods of contraception with use of a spermicide:  condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository.  
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide (where approved/applicable). 
 Female surgical sterilization (e.g., bilateral tubal ligation). 
For males: 
 Effective male contraception includes the use of condoms with spermicide. 
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
considered acceptable methods of contraception. 
Pregnancy reporting is described in Section 15.4.1. 
15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship to study treatment, and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Monitor and record all pregnancies and follow up on the outcomes. 
 Complete an SAE form for each SAE and fax it to Biogen SABR or designee within 
24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR or designee within 24 hours of the study site staff 
becoming aware of new information. 
 Report SAEs to local ethics committees, as required by local law. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
15.6.2. 
Biogen  
Biogen’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor is 
responsible for reviewing with study site staff the definitions of AE and SAE, as well 
as the instructions for monitoring, recording, and reporting AEs and SAEs. 
 Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames. 


Protocol 109MS311 
Version 1.0 
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
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Biogen MA Inc. 
48 
 
16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
16.1. 
Efficacy 
16.1.1. 
Analysis Population 
The population for the analysis of efficacy endpoints will be all subjects who have received at 
least 1 dose of BG00012 in this study and who have an evaluation of the efficacy endpoint under 
analysis. 
16.1.2. 
Methods of Analysis 
16.1.2.1. Analysis of the Primary Endpoint 
The primary analysis will be summaries of the incidence of treatment-emergent AEs, SAEs, and 
discontinuations from study treatment due to AEs. 
16.1.2.2. Analysis of the Secondary Endpoints 
The number of new or newly enlarging T2 hyperintense lesions on brain MRI scans will be 
summarized over time using descriptive statistics. 
ARR will be summarized along with the proportion of subjects relapsing, the rate of relapses 
requiring IV steroid use, and the rate of MS-related hospitalizations. 
EDSS scores and changes from baseline will be summarized over time along with the proportion 
of subjects with confirmed disability progression. 
16.2. 
Pharmacokinetics 
Not applicable. 
16.3. 
Pharmacodynamics 
Not applicable. 
16.4. 
Biomarker Analyses/Pharmacogenomics 
Not applicable. 
16.5. 
Safety 
16.5.1. 
Analysis Population 
The safety population is defined as all subjects who received at least 1 dose of BG00012 in this 
study. 


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16.5.1.1. Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. 
The primary analysis will be summaries of the incidence of treatment-emergent AEs, SAEs, and 
discontinuations from study treatment due to AEs. 
16.5.1.2. Clinical Laboratory Results 
Clinical laboratory evaluations including hematology, blood chemistry, and urinalysis will be 
summarized using the incidence of shifts outside the normal range.  In addition, summary 
statistics for quantitative laboratory values and changes from baseline will be presented.  
Lymphocyte count data will be summarized by timepoints on study treatment.  Additionally, 
lymphocyte count over time post-treatment and the time to recovery will be descriptively 
summarized for subjects who develop decreases in lymphocyte count (<LLN). 
16.5.1.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities.  The incidence of 
subjects experiencing these abnormalities will be summarized. 
16.6. 
Antigenicity/Immunogenicity Data 
Not applicable. 
16.7. 
Interim Analyses 
The data from this study will be summarized periodically to support regulatory submissions or 
when further information on the long-term safety and efficacy of BG00012 in the pediatric 
population is required. 
16.8. 
Sample Size Considerations 
Because this study is an extension study, the sample size will be determined by the number of 
eligible subjects who completed Study 109MS202. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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17. 
ETHICAL REQUIREMENTS 
Biogen, 
, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Conference on Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
investigational sites in countries other than the US. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen. 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
51 
 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines. 
A copy of the signed and dated ICF and assent if applicable must be given to the subject or the 
subject’s legally authorized representative.  The signed and dated ICF will be retained with the 
study records.  Local regulations must be complied with in respect to the final disposition of the 
original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent and assent if applicable must also be documented in the 
subject’s medical record. 
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
The subject will not be identified by name in the eCRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partners and designees, ethics committees, 
and various government health agencies may inspect the records of this study.  Every effort will 
be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen or partnering company) with the subject before the subject makes a decision to 
participate in the study. 
17.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
52 
 
18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not enroll any subjects prior to completion of a study initiation visit 
conducted by Biogen.  This initiation visit will include a detailed review of the protocol and 
study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor will visit the Investigator at regular intervals during the study and after the 
study has completed, as appropriate. 
During these visits, eCRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen. 
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
53 
 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
Biogen will be responsible for all administrative aspects of this study including but not limited to 
study initiation, monitoring, management of AEs, and data management. 
19.1.1. 
Contract Research Organization  
A contract research organization (CRO), 
, will be jointly responsible for administrative 
aspects of the study including but not limited to study initiation, monitoring, and management of 
SAE reports and data management.  Before subjects are screened at each study site, the CRO will 
review study responsibilities with the Investigators and other study site staff, as appropriate. 
19.1.2. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on eCRFs by a Web-based 
electronic data capture tool OR remote data capture tool developed and supported by iMedidata 
RAVE and configured by 
. 
19.1.3. 
Central Laboratories for Laboratory Assessments 
A central laboratory has been selected by Biogen to analyze all safety laboratory samples 
collected for this study. 
19.1.4. 
Central Facility for Other Assessments 
Central and specialty facilities have been selected by Biogen to read and interpret all MRI scans 
for this study. 
19.2. 
Study Committees 
19.2.1. 
Advisory Committee 
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study.  The advisory committee will conduct 
regular reviews to monitor subject accrual and to monitor compliance with the protocol at 
individual study sites.  The advisory committee will determine whether the study should be 
stopped or amended for reasons other than safety. 
Members of the advisory committee will include the Medical Director, Clinical Operations Lead, 
and Project Statistician from Biogen, and participating Investigators.  Biogen will designate one 
of the participating Investigators to be the chairperson of the advisory committee. 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
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19.2.2. 
Independent Data Monitoring Committee  
An Independent Data Monitoring Committee (IDMC) will monitor the progress of the study, 
review interim safety data, and oversee the safety of subjects participating in this study.  The 
specifics regarding the IDMC organization and procedures will be outlined in the IDMC Charter. 
19.3. 
Changes to Final Study Protocol 
Protocol modifications that affect subject safety, the scope of the investigation, or the scientific 
quality of the study must be approved by the ethics committee before implementation of such 
modifications to the conduct of the study.  If required by local law, such modifications must also 
be approved by the appropriate regulatory agency prior to implementation. 
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require corresponding modifications (see 
Section 17). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site. 
19.6. 
Study Report Signatory 
Biogen will designate 1 or more of the participating Study Investigators as a signatory for the 
study report.  This determination will be made by several factors, including but not limited to, 
the Investigator’s experience and reputation in the studied indication; the Investigator’s 
contribution to the study in terms of design, management, and/or subject enrollment; or by other 
factors determined to be relevant by Biogen. 
 


Protocol 109MS311 
Version 1.0 
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
55 
 
20. 
REFERENCES 
Chitnis T, Krupp L, Yeh A, et al. Pediatric multiple sclerosis. Neurol Clin. 2011;29(2):481-505. 
Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing 
therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18(1):116-27. 
Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line 
treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 
3 trial. Lancet. 2012;380(9856):1819-28. 
European Commission. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. 2008. 
Ghoreschi K, Brück J, Kellerer C, et al. Fumarates improve psoriasis and multiple sclerosis by 
inducing type II dendritic cells. J Exp Med. 2011;208(11):2291-303. 
Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during 
a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 
2000;343(13):898-904. 
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves 
disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-
blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 
1995;45(7):1268-76. 
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in 
relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. Epub 2010 Jan 20. 
Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression 
mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003;43:233-60. 
O'Connor P, Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and 
treatment of multiple sclerosis. An overview. Neurology. 2002;59(6 Suppl 3):S1-33. 
O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for 
relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303. 
Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI 
analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC 
MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 
1993;43(4):662-7. 
Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 
PRISMS Study Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. 
Neurology. 2001;56(12):1628-36. 
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting 
multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-
controlled trial. Neurology. 1993;43(4):655-61. 


Protocol 109MS311 
Version 1.0 
Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
56 
 
Waldman AT, Gorman MP, Rensel MR, et al. Management of pediatric central nervous system 
demyelinating disorders: consensus of United States neurologists. J Child Neurol. 
2011;26(6):675-82. 
Zhu HJ, Appel DI, Jiang Y, et al. Age- and sex-related expression and activity of 
carboxylesterase 1 and 2 in mouse and human liver. Drug Metab Dispos. 2009;37(9):1819-25. 
 
 


Protocol 109MS311 
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Phase 3 Extension Study of BG00012 in Pediatric Subjects With RRMS 
 
CONFIDENTIAL 
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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Multicenter Extension Study to Determine the Long-Term 
Safety and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple 
Sclerosis,” and agree to conduct the study according to the protocol and the applicable ICH 
guidelines and GCP regulations, and to inform all who assist me in the conduct of this study of 
their responsibilities and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 

SAP_001.pdf: 
Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
V1.0 dated 9-Jul-18 
109MS311/
NCT02555215 
Biogen Idec - BG00012 in MS 
Statistical Analysis Plan 
BIOGEN  
STATISTICAL ANALYSIS PLAN 
A Multicenter Extension Study to Determine the Long-Term Safety and Efficacy of 
BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple Sclerosis 
________________________________________________________________ 




Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
V1.0 dated 9-Jul-18 
 
 
  
 3  
TABLE OF CONTENTS 
 
1 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 5 
1.1 
Primary Objective and Endpoint ................................................................................... 5 
1.2 
Secondary Objectives and Endpoints ............................................................................ 5 
2 
STUDY DESIGN ...................................................................................................................... 5 
2.1 
Study Overview ............................................................................................................ 5 
2.2 
Overall Study Duration and Follow-Up ........................................................................ 5 
3 
STUDY ACTIVITIES ............................................................................................................... 7 
4 
INTERIM ANALYSIS ............................................................................................................ 11 
5 
SAMPLE SIZE JUSTIFICATION .......................................................................................... 11 
6 
STATISTICAL ANALYSIS METHODS ............................................................................... 11 
6.1 
Description of Analytic Methods ................................................................................ 11 
6.1.1 Summary of Baseline Data ......................................................................................... 11 
6.1.2 Accounting of Subjects ............................................................................................... 11 
6.1.3 Protocol Deviations ..................................................................................................... 11 
6.1.4 Demographic and Baseline Characteristics ................................................................ 12 
6.1.5 Concomitant Medications and Non-drug Therapies ................................................... 12 
6.1.6 Exposure to study drug ............................................................................................... 12 
6.1.7 Visit Windows  
 ....................................................................................................... 13 
6.2 
Efficacy Analysis ........................................................................................................ 13 
6.2.1 Analysis Population .................................................................................................... 13 
6.2.2 Analysis Methods  ....................................................................................................... 13 
6.3 
Safety Data .................................................................................................................. 13 
6.3.1 Analysis Population .................................................................................................... 13 
6.3.2 Analysis Methods  ....................................................................................................... 13 
6.3.2.1 Definition of Baseline Value and Visit Windows.................13 
6.3.2.2 Clinical Adverse Events ........................................................14 
6.3.2.3 Clinical Laboratory Data.......................................................14 
6.3.2.4 Vital Signs Data ....................................................................15 
6.3.2.5 12-Lead ECG ........................................................................15 
6.3.2.6 Height and Weight ................................................................15 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
V1.0 dated 9-Jul-18 
 4  
 
List of Abbreviations 
AE 
adverse event 
BID 
twice daily 
CDT 
Clinical Development Team 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DMF 
dimethyl fumarate 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IFN 
interferon 
IgG 
immunoglobulin G 
IXRS 
Interactive Voice/Web Response System 
MCV4 
meningococcal polysaccharide diphtheria conjugate vaccine 
(quadrivalent) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MS 
multiple sclerosis 
PHI 
protected health information 
PPSV23 
23-valent pneumococcal polysaccharide vaccine 
RRMS 
relapsing-remitting multiple sclerosis 
SAE 
serious adverse event 
SMT 
Study Management Team 
SUSAR 
suspected unexpected serious adverse reaction 
Td 
tetanus diphtheria toxoids vaccine 
US 
United States 
WHO 
World Health Organization 
 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
V1.0 dated 9-Jul-18 
 
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109MS311 SAP_v1_Final_09JUL2018.docx 
1 
STUDY OBJECTIVES AND ENDPOINTS 
 
1.1 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the long-term safety of BG00012 in 
pediatric subjects who completed Study 109MS202. 
Primary endpoint: 
incidence of AEs, serious AEs (SAEs), and discontinuations of study treatment 
due to an AE 
1.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are as follows: 
 to evaluate the long-term efficacy of BG00012 
 describe the long-term MS outcomes in subjects who completed Study 109MS202 
The secondary endpoints are: 
 The total number of new or newly enlarging T2 hyperintense lesions on brain 
MRI scans, the ARR, and the proportion of subjects who experience 1 or more 
relapses during the study period. 
 The degree of disability as measured by the EDSS and disability progression (as 
measured by at least a 1.0-point increase on the EDSS from baseline EDSS ≥1.0 
that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from 
baseline EDSS = 0 that is sustained for 24 weeks). 
 
2 
STUDY DESIGN 
2.1 
Study Overview 
This is a multicenter, open-label extension of Study 109MS202 that is designed to evaluate 
the long-term safety and efficacy of BG00012 in pediatric subjects. 
 
2.2 
Overall Study Duration and Follow-Up 
The study period will consist of enrollment, treatment, and follow-up.  The study duration is 
approximately 104 weeks, consisting of a 4-week enrollment period (if the Final Study Visit 
from Study 109MS202 cannot be combined with the Baseline Visit for this study), a 96-week 
treatment period, and a Safety Follow-Up Visit up to 4 weeks after the last dose of study 
treatment.  Unscheduled Relapse Assessment Visits and Lymphocyte Follow-Up Visits will 
be performed as necessary. 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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109MS311 SAP_v1_Final_09JUL2018.docx 
End of Study for Subjects 
The end of the study is the last subject, last visit for final collection of data, which is the 
Safety Follow-Up Visit.  This visit is up to 4 weeks after the last dose of study treatment.   
 
 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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109MS311 SAP_v1_Final_09JUL2018.docx 
 
3 
STUDY ACTIVITIES  
 
Table 1: Schedule of Activities for 109MS311 
Tests and Assessments1 
Year 1 
Year 2 
Safety 
 Follow-Up 
Visit 
Baseline 
Visit 
(Day 1)2 
 
Visit 1 
(Week 
125d)  
Visit 2 
(Week 
16 5d) 
Visit 3 
(Week 
24 5d) 
Visit 4 
(Week 
36 5d) 
Visit 5 
(Week 
48 5d) 
 
Visit 6 
(Week 
60 5d) 
Visit 7 
(Week 
64 5d) 
Visit 8 
(Week 
72 5d) 
Visit 9 
(Week 
84 5d) 
Visit 10 
(Week 
96 5d) 
Informed Consent and 
Assent3 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
MS-Related Medical 
History4 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
Body Weight 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Height 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
Vital Signs5 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
Urine Pregnancy Test6 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urinalysis 78 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
PTH and Vitamin D Levels 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Brain MRI Scan
a)910 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
EDSS 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
Dispense Study 
Treatment11b) 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
Concomitant Therapy and 
Procedures Recording 
Monitor and record throughout the study 
AE/SAE Reporting 
Monitor and record throughout the study 
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; MS = multiple sclerosis; 
PTH = parathyroid hormone; SAE = serious adverse event. 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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1 Tests and assessments must be completed prior to study treatment dispensation. 
2 The Final Study Visit for Study 109MS202 will serve as the Baseline Visit for this extension study.  The Final Study Visit from Study 109MS202 can be within 
4 weeks of the Baseline Visit for Study 109MS311 if the 2 visits cannot be combined. 
3 Written informed consent from the subject’s parents or legal guardians and assent from the subject, if appropriate, must be obtained prior to performing any 
study-related procedures. 
4 MS-related medical history will include complete MS history of disease, MS diagnostic criteria, MS signs and symptoms, and MS treatment history. 
5 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements. 
6 For females of child bearing potential.  Results must be known prior to study treatment dispensation. 
7 Urine cytology must be performed at all visits indicated if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits.  If urine cytology is 
positive for malignant cells, the subject must permanently discontinue study treatment. 
8 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol. 
9 MRI must not be performed within 30 days of receiving a course of steroids. 
10 The time between the Week 24 MRI and the Week 16 MRI must be the same as the time between the Day 0 MRI and Week -8 MRI in Study 109MS202 
within a window of ±3 days.  For example, if the Day 0 and Week -8 MRIs for a particular subject occurred 8 weeks apart in Study 109MS202, then the Week 
24 MRI in Study 109MS311 should be 8 weeks ± 3 days after the Week 16 MRI.  If necessary, the Week 24 MRI may be conducted separately from the Week 
24 clinic visit.  Similarly, the time between the Week 72 MRI and the Week 64 MRI must be the same as the time between the Day 0 MRI and Week -8 MRI in 
Study 109MS202 within a window of ±3 days.  If necessary, the Week 72 MRI may be conducted separately from the Week 72 clinic visit. 
11 Initial dispensation of study treatment may require an additional visit on or around Day 7.  Laboratory results must be evaluated and eligibility confirmed prior 
to dispensation of study treatment. 
 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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Table 2: Additional Study Activities for Study 109MS311 
Tests and Assessments 
Unscheduled Relapse Assessment 
Visit1 
(within 72 hours after symptom 
onset) 
Discontinuation/ 
Withdrawal Visit2 
(as soon as possible but no later than 
4 weeks after last dose of study 
treatment) 
Lymphocyte Follow-Up Visit3 
Physical Examination 
X 
X 
X 
Body Weight 
X 
X 
X 
Height 
 
X 
 
Vital Signs4 
X 
X 
X 
12-Lead ECG 
 
X 
 
Hematology5,6 
X 
X 
X 
Blood Chemistry6 
X 
X 
 
Urine Pregnancy Test7 
X 
X 
 
Urinalysis6,8 
X 
X 
 
PTH and Vitamin D Levels 
 
X 
 
EDSS 
X 
X 
 
Brain MRI Scan9 
 
X10 
 
Relapse Assessment 
X 
 
 
Concomitant Therapy and 
Procedures 
Monitor and record throughout the study  
AE/SAE Recording 
Monitor and record throughout the study 
AE = adverse event; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; LLN = lower limit of normal; MRI = magnetic resonance imaging; 
PTH = parathyroid hormone; SAE = serious adverse event. 
1 An Unscheduled Relapse Assessment Visit will be conducted within 72 hours of symptom onset of a suspected relapse (i.e., new or recurrent neurologic 
symptom[s]). 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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2 Discontinuation refers to discontinuation of study treatment.  Withdrawal refers to withdrawal of subjects from the study.  The Discontinuation/Withdrawal 
Visit should be conducted as soon as possible and no later than 4 weeks after the last dose of study treatment. 
3 Subjects who complete, temporarily withhold, or permanently discontinue study treatment for any reason and have a lymphocyte count <LLN will continue 
protocol-required visits and assessments and be followed every 4 weeks for 24 weeks and then every 3 months (unless clinically indicated more often or at the 
Investigator’s discretion) until the lymphocyte count is ≥LLN or for 52 weeks after the last dose (whichever is sooner). 
4 Vital signs include body temperature, pulse rate, and systolic/diastolic blood pressure measurements. 
5 Hematology testing must be performed every 4 weeks in subjects with lymphocyte count <LLN 
6 Study treatment must be temporarily withheld or permanently discontinued if any of the laboratory values meet the criteria defined in the protocol. 
7 For females of childbearing potential. 
8 Urine cytology must be performed if a subject experiences hematuria (of unknown etiology) at 2 consecutive visits or at the Unscheduled Relapse Assessment 
Visit or the Discontinuation/Withdrawal Visit. 
9 An MRI must not be performed within 30 days of receiving a course of steroids. 
10 A brain MRI scan will be performed unless assessed in the last 30 days.  
 
 
 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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4 
INTERIM ANALYSIS 
The data from this study will be summarized periodically to support regulatory submissions, or 
when further information on the long-term safety and efficacy of BG00012 in the pediatric 
population is required. 
5 
SAMPLE SIZE JUSTIFICATION 
Because this study is an extension study, the sample size was be determined by the number of 
eligible subjects who completed Study 109MS202. 
 
6 
STATISTICAL ANALYSIS METHODS 
The statistical software, SAS® ,will be used for all summaries and statistical analyses.  
Statistical analyses will be descriptive in nature with appropriate measures of variation provided 
where applicable.  For continuous endpoints, summary statistics will generally include the 
following:  number of subjects with data, mean, standard deviation, median, and range.  For 
categorical endpoints, summary statistics will generally include the frequency distribution of the 
analysis population. 
6.1 
Description of Analytic Methods 
As the study contains a single treatment group, descriptive statistics will be the primary approach 
to analyze the data. 
6.1.1 Summary of Baseline Data 
Baseline data are defined as data collected prior to the administration of BG00012 on Day 1 on 
study 109MS311, which should be the final visit in study 109MS202.  If the final visit in study 
109MS202 cannot be used as baseline, Day 1 on study 109MS311 will be considered baseline.  
Baseline demographics from study 109MS202 will be summarized using only those subjects that 
continue into study109MS311.  Age will be recalculated based on the date informed consent was 
signed for study 109MS311. 
6.1.2 Accounting of Subjects 
Number of subjects who enrolled into 109MS311 from the previous study, number who received 
at least one dose of BG00012, number completing treatment, number completing the study, 
number discontinuing prior to Week 96 and reason for early withdrawal, will be summarized.   
 
6.1.3 Protocol Deviations 
Major and minor protocol deviations identified in the study will be listed. 


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6.1.4 Demographic and Baseline Characteristics 
Demographic data, including age (in years, at the time of consent to study 109MS311), gender 
and race category will be summarized for the subjects that enroll into study 109MS311.  In 
addition, baseline height (cm) and weight (kg) will also be presented.  
Medical history will be summarized for just those subjects who enrolled in 109MS311 by 
category using number and percentage of subjects that had experienced certain maladies prior to 
entering the study.  Medical history will include information collected in 109MS202, but for only 
those subjects who entered 109MS311.  Included will be the number of subjects with ongoing or 
resolved medical/surgical history that have occurred since the subject enrolled in 109MS202.  
The MS Pediatric Diagnostic Criteria as defined by Krupp (2013), obtained at screening of study 
109MS202, will be summarized for those subjects who enrolled into 109MS311.   
MS signs considered typical MS signs and symptoms will be summarized for each area: vision, 
cognition, coordination/balance, bladder control, bowel, sexual function, and general.  In 
addition, MS signs related to sensory disturbances, motor disturbances, and other will be 
presented for the population and summarized.  Only those subjects who entered 109MS311 will 
be included in the summaries. 
History of MS for the subjects enrolled in 109MS311 will be summarized using information 
collected prior to study 109MS202.  This includes time since first MS diagnosis, time since first 
symptoms, number of relapses prior to screening in study 109MS202 (prior 12 months, 2 years, 
and 3 years) and the time since the last relapse prior to 109MS202.  In addition, the MS 
treatment history will be summarized for these subjects in 109MS311 prior to receiving 
BG00012 in the 109MS202 study. 
6.1.5 Concomitant Medications and Non-drug Therapies 
Concomitant medication is defined as prescribed or over-the-counter medications used during 
the study (on or after Day 1 of 109MS311).  The World Health Organization (WHO) Drug 
Dictionary will be used for coding concomitant medications.  The Medical Dictionary for 
Regulatory Activities  (MedDRA) will be used for coding concomitant non-drug therapies.   
The number and percentage of subjects taking concomitant medication and receiving non-drug 
treatments will be summarized.   
As the study progresses, a listing of all medications will be periodically reviewed by clinical 
personnel so as to properly classify concomitant medications as allowed or prohibited. 
6.1.6 Exposure to study drug 
Number of days exposed to BG00012 during study 109MS311, total amount of BG00012 
received and overall compliance will be summarized.   Compliance for each subject is defined as 
the total amount of BG00012 received divided by the number of days on treatment. 


Statistical Analysis Plan for 109MS311 (Pediatric extension study) 
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6.1.7 Visit Windows 
If a subject withdraws after receiving at least one dose of BG00012, but prior to the Week 96 
scheduled visit, data from the early withdrawal visit will be assigned as the next scheduled visit 
if it has occurred within a visit window.   Scheduled visits have a window of ±5 days. 
 
If more than one observation is within the same window, data closest to the target regular 
scheduled visit will be used in the summary statistics.  If more than one observation falls in the 
same distance from the target regular scheduled visit day, the later observation will be used in 
the summary statistics.  
 
6.2 
Efficacy Analysis  
6.2.1 Analysis Population 
The population for the analysis of efficacy endpoints will be all subjects who have received at 
least 1 dose of BG00012 in this study and who have an evaluation of the efficacy endpoint under 
analysis. 
6.2.2 Analysis Methods   
Summary statistics will be presented for MRI data (number of new or newly enlarging T2 
hyperintense lesions) over time 
 
ARR will be summarized, along with the proportion of subjects relapsing, the rate of relapses 
requiring IV steroid use, and the rate of MS-related hospitalizations. 
EDSS scores and changes from baseline will be summarized over time along with the proportion 
of subjects with confirmed disability progression. 
 
6.3 
Safety Data 
6.3.1 Analysis Population 
The analysis population for safety summaries will be all subjects who received at least 1 dose of 
BG00012. 
6.3.2 Analysis Methods  
Summaries of safety data will include descriptive statistics for continuous variables and 
frequency distributions for categorical variables. 
6.3.2.1 Definition of Baseline Value and Visit Windows 
Baseline values and visit windows for safety summaries are defined in the same way as they are 
for efficacy analyses (see Section 6.1.1 and 6.1.7, respectively).  


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6.3.2.2 Clinical Adverse Events 
Treatment (BG00012)-emergent AEs are defined as AEs occurring or worsening after beginning 
study treatment (after the first dose in study 109MS311). 
Incidence of AEs will be summarized using frequency distribution tables; overall, by severity, 
and by relationship to BG00012.  The summary tables will include incidences for system organ 
class as well as for preferred terms within each system organ class.  Similar incidence analyses 
will be summarized for SAEs and for the most common AEs. 
AEs will be coded using the MedDRA dictionary (version 20.1).  This coding system provides 
five levels to classify AEs.  In general, AEs will be presented by system organ class and 
preferred term.    
The summary tables will include incidence estimates for overall system organ class as well as for 
preferred terms within each system organ class.  AEs will be presented in the order of decreasing 
incidence of system organ class and then by preferred term within system organ class.  
If a subject experiences an event more than once during the study, he/she will be counted only 
once using the maximum severity if more than one severity is reported, within each system organ 
class/preferred term. 
AEs will be classified by severity (mild, moderate and severe) and by relationship to BG00012. 
The incidence of  SAEs will be presented by system organ class and preferred term.  Details of 
each SAE will be listed, including subject ID, system organ class/preferred term, date of onset, 
severity, relationship to BG00012 and action taken.  Subject narratives will also be provided.  
The incidence of AEs that led to early withdrawal from the study will be presented separately.  A 
listing of the individual subjects with these AEs will also be presented. 
The incidence of AEs that led to treatment discontinuation during the study will be presented in a 
separate table, along with a listing of these individual subjects who experienced AEs leading to 
treatment discontinuation. 
6.3.2.3 Clinical Laboratory Data 
The following clinical laboratory parameters are assessed per the protocol: 
 Hematology:  hemoglobin, hematocrit, red blood cell count, WBC count (with 
differential) and platelet count.   
 Blood chemistry:  albumin, sodium, potassium, chloride, total bilirubin, alkaline 
phosphatase, ALT, AST, GGT, blood urea nitrogen, creatinine, bicarbonate, calcium, 
magnesium, phosphate, uric acid, and glucose 
 Vitamin D and PTH (Day 1 and Week 96 only) 
 Urine and serum pregnancy tests 


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Each laboratory value for each subject will be flagged as ‘low’, ‘normal’, or ‘high’, relative to 
the parameter’s normal range.  Each subject’s urinalysis values will be flagged as “positive”, 
“negative”, or if no value is available, “unknown”.   
Shifts from baseline to post baseline (Week 4/early withdrawal) high/low status for all  
hematology and blood chemistry parameters, and shifts from baseline to high/positive status for 
urinalysis will be presented.   
Summary statistics will also be provided for all absolute laboratory values as well as change 
from baseline. The summaries for laboratory data will be data from baseline to each time point, 
including early withdrawal.  Graphs showing the mean or change from baseline values may be 
presented as well.  
In addition to lymphocyte count data summarized at each timepoint on study treatment, 
lymphocyte count over time post-treatment and the time to recovery will be descriptively 
summarized for subjects who develop decreases in lymphocyte count (<LLN). 
 
6.3.2.4 Vital Signs Data 
The analysis of vital signs will focus on the incidence of clinically relevant abnormalities. The 
number of subjects evaluated and the number and percentage of subjects with clinically relevant 
post-baseline abnormalities will be presented.  The criteria for clinically relevant post-baseline 
abnormalities are shown in the following table (Table 2).  Summary statistics for actual values 
and change from baseline will also be presented.   
 
Table 2  Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38oC or an increase from baseline of at least 1oC 
Pulse  
120 beats per minute (bpm) or an increase from baseline of >20 bpm 
<50 bpm or a decrease from baseline of >20 bpm 
Systolic Blood Pressure 
>180 mmHg  or an increase from baseline of >40 mmHg  
<90 mmHg or a decrease from baseline of >30 mmHg 
Diastolic Blood Pressure 
>105 mmHg or an increase from baseline of >30 mmHg 
<50 mmHg or a decrease from baseline of >20 mmHg 
 
6.3.2.5 12-Lead ECG 
The analysis of ECG will be summarized at each timepoint, presenting only frequencies of 
Normal, Abnormal – no adverse event, and Abnormal – adverse event. 
6.3.2.6 Height and Weight 
The analysis of height and weight will be summarized at each timepoint, presenting descriptive 
statistics for both.