Conditions: Relapsing-Remitting Multiple Sclerosis
Keywords: relapsing multiple sclerosis remitting oral
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1736
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the long-term safety profile of BG00012 (dimethyl fumarate). Secondary objectives of this study are to evaluate the long-term efficacy of BG00012 using clinical endpoints and disability progression, to evaluate further the long-term effects of BG00012 on multiple sclerosis (MS) brain lesions on magnetic resonance imaging (MRI) scans in participants who had MRI scans as part of Studies 109MS301 (NCT00420212) and 109MS302 (NCT00451451) and to evaluate the long-term effects of BG00012 on health economics assessments and the visual function test.

Detailed description:
The initial BG00012 dosage for the extension study (240 mg BID or 240 mg TID) was the same as that used in the Phase 3 Studies 109MS301 (NCT00420212) and 109MS302 (NCT00451451). Subsequent to the initiation of this study, BG00012 was approved in several countries for the treatment of MS at a dose of 240 mg BID. For this reason, all participants continuing in this study will receive the currently marketed dose of 240 mg BID.

Arms:
arm 1: In the first phase, participants will receive BG00012 240 mg (two 120 mg capsules) twice a day (BID) and 2 placebo capsules once a day. In the second phase participants will receive open-label BG00012 240 mg BID, for atleast 8 years. arm 2: In the first phase participants will receive BG00012 240 mg (two 120 mg capsules) three times a day (TID). In the second phase participants will receive open-label BG00012 240 mg BID for atleast 8 years.

Interventions: intervention 1: dimethyl fumarate intervention 2: Placebo
Intervention descriptions: intervention 1: BG00012 capsules intervention 2: Capsules taken to maintain the blind in the 240 mg BID treatment group.

Protocol document:
Prot_000.pdf: 
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
United States
PROTOCOL NUMBER:
109MS303 / NCT00835770
Biogen Idec Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
STUDY PHASE:
3b
PROTOCOL TITLE:
A Dose-Blind, Multicenter, Extension Study to Determine the 
Long-Term Safety and Efficacy of Two Doses of BG00012 
Monotherapy in Subjects with Relapsing-Remitting Multiple 
Sclerosis 
EUDRA CT NO:
2008-004753-14
DATE:
5 February 2018
Version 8
FINAL
Supersedes previous Version 7 dated 07 November 2016.


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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Biogen MA Inc.
2
TABLE OF CONTENTS
1.
CONTACT LIST..........................................................................................................8
1.1.
Biogen Personnel..........................................................................................................8
2.
LIST OF ABBREVIATIONS.....................................................................................11
3.
SYNOPSIS .................................................................................................................13
4.
STUDY ACTIVITIES 109MS303 .............................................................................18
4.1.
Study Activities  (Year 1 Visits).................................................................................18
4.2.
Study Activities  (Years 2 and 3 Treatment Visits)....................................................19
4.3.
Study Activities (Years 4 Through 8 Treatment Visits).............................................20
4.4.
Study Activities for Subjects Who Already Completed Visit 36 ...............................22
4.5.
Study Activities (Hematology and 
Analysis: Year 4 Through 
End of Treatment Visits) ............................................................................................24
4.6.
Study Activities (Unscheduled and Post-Treatment Visits).......................................25
5.
INTRODUCTION......................................................................................................26
5.1.
Overview of Multiple Sclerosis..................................................................................26
5.2.
Profile of Previous Experience with Fumarates .........................................................26
5.3.
Study Rationale...........................................................................................................29
5.4.
Dose Rationale............................................................................................................29
6.
OBJECTIVES.............................................................................................................30
6.1.
Primary Objective.......................................................................................................30
6.2.
Additional Objectives.................................................................................................30
7.
STUDY DESIGN .......................................................................................................31
7.1.
Study Overview ..........................................................................................................31
7.2.
Overall Study Duration and Follow-Up .....................................................................31
7.2.1.
Baseline.......................................................................................................................31
7.2.2.
Treatment Period ........................................................................................................32
7.2.3.
Post-Treatment Period ................................................................................................32
7.3.
Relapses ......................................................................................................................32
7.4.
Disability Progression.................................................................................................33
7.5.
Study Stopping Rules .................................................................................................33
7.6.
End of Study ...............................................................................................................33
8.
STUDY POPULATION.............................................................................................34


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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8.1.
Inclusion Criteria ........................................................................................................34
8.2.
Exclusion Criteria.......................................................................................................34
9.
ENROLLMENT AND RANDOMIZATION PROCEDURES..................................36
9.1.
Enrollment Procedures................................................................................................36
9.2.
Randomization and Registration Procedures..............................................................36
9.3.
Blinding Procedures....................................................................................................36
10.
BG00012 DESCRIPTION AND ALLOCATION .....................................................37
10.1.
BG00012 Packaging...................................................................................................37
10.2.
BG00012 Accountability............................................................................................37
11.
TREATMENT............................................................................................................39
11.1.
Treatment Schedule ....................................................................................................39
11.2.
Modification of Treatment Schedule..........................................................................39
11.2.1.
Abnormal Laboratory Values:  Dosing Interruption and Management......................39
11.2.2.
Dosage Reductions .....................................................................................................41
11.2.3.
Resumption of BG00012 Dosing................................................................................41
11.3.
Monitoring and Management for Subjects with Abnormal Lymphocyte 
Count...........................................................................................................................41
11.4.
Removal of Subjects from Treatment and Withdrawal from Study...........................43
11.5.
Treatment Compliance................................................................................................44
11.6.
Concomitant Therapy and Procedures........................................................................44
11.6.1.
Treatment of Relapses on Scheduled or Unscheduled Visits.....................................45
12.
EFFICACY ASSESSMENTS ....................................................................................46
12.1.
Clinical Efficacy Assessments....................................................................................46
12.2.
Laboratory Efficacy Assessments...............................................................................46
46
12.4.
Additional Assessments..............................................................................................46
13.
SAFETY ASSESSMENTS ........................................................................................47
13.1.
Clinical Safety Assessments.......................................................................................47
13.2.
Laboratory Safety Assessments..................................................................................47
14.
SCHEDULE OF EVENTS.........................................................................................48
14.1.
Site Personnel .............................................................................................................48
14.2.
Subject Management ..................................................................................................49


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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14.3.
Tests and Assessments................................................................................................50
14.3.1.
Year 1..........................................................................................................................50
14.3.1.1.
Baseline Visit (Day 1) ................................................................................................50
14.3.1.2.
Visit 1 (Week 4 ±5 Days) ...........................................................................................51
14.3.1.3.
Visit 2 (Week 8 ±5 Days) ...........................................................................................51
14.3.1.4.
Visit 3 (Week 12 ±5 Days).........................................................................................51
14.3.1.5.
Visit 4 (Week 16 ±5 Days).........................................................................................52
14.3.1.6.
Visit 5 (Week 20 ±5 Days).........................................................................................52
14.3.1.7.
Visit 6 (Week 24 ±5 Days).........................................................................................53
14.3.1.8.
Visit 7 (Week 36 ±7 Days).........................................................................................53
14.3.1.9.
Visit 8 (Week 48 ±7 Days).........................................................................................54
14.3.2.
Years 2 and 3 Treatment Visits ..................................................................................54
14.3.2.1.
Visits 9, 10, 11, 13, 14, and 15 (Weeks 60, 72, 84, 108, 120, and 132 ±7 
Days)...........................................................................................................................54
14.3.2.2.
Visits 12 and 16 (Weeks 96 and 144 ±7 Days) ..........................................................55
14.3.3.
Years 4 through 8 Treatment Visits............................................................................55
14.3.3.1.
Visits 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35 (Weeks 156, 180, 204, 228, 
252, 276, 300, 324, 348, and 372 ±7 Days)................................................................55
14.3.3.2.
Visits 18, 22, 26, 30, and 34 (Weeks 168, 216, 264, 312, and 360 ±7 Days) ............56
14.3.3.3.
Visits 20, 24, 28, 32, and 36 (Weeks 192, 240, 288, 336, and 384 ±7 Days) ............56
14.3.4.
Study Activities for Subjects Who Already Completed Visit 36 ...............................57
14.3.4.1.
Visits 37, 39, 41, 43, 45, 47, 49, and 51 (Weeks 396, 420, 444, 468, 492, 
516, 540, and 564 ±7 Days)........................................................................................57
14.3.4.2.
Visits 38, 42, 46, and 50 (Weeks 408, 456, 504, and 552 ±7 Days) ..........................57
14.3.4.3.
Visits 40, 44, 48, and 52 (Weeks 432, 480, 528, and 576 ±7 Days) ..........................58
14.3.5.
End of Study Visit ......................................................................................................59
14.3.6.
Unscheduled Relapse Assessment Visit.....................................................................59
14.3.7.
Premature Study Treatment Withdrawal Visit ...........................................................60
14.3.8.
Lymphocyte Follow-Up..............................................................................................60
15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................61
15.1.
Definitions ..................................................................................................................61
15.1.1.
Adverse Event.............................................................................................................61
15.1.2.
Serious Adverse Event................................................................................................61


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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15.2.
Monitoring and Recording Events..............................................................................61
15.2.1.
Adverse Events ...........................................................................................................61
15.2.2.
Serious Adverse Events..............................................................................................62
15.2.3.
All Events ...................................................................................................................62
15.2.4.
Immediate Reporting of Serious Adverse Events.......................................................62
15.2.4.1.
Death...........................................................................................................................63
15.3.
Safety Classifications..................................................................................................63
15.3.1.
Relationship of Events to Study Treatment................................................................63
15.3.2.
Severity of Events.......................................................................................................64
15.3.3.
Expectedness of Events ..............................................................................................64
15.4.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................64
15.5.
Procedures for Handling Special Situations ...............................................................65
15.5.1.
Overdose.....................................................................................................................65
15.5.2.
Medical Emergency....................................................................................................65
15.5.3.
Contraception Requirements ......................................................................................65
15.5.4.
Reporting Pregnancy ..................................................................................................66
15.5.5.
Dose Unblinding for Medical Emergencies ...............................................................66
15.5.6.
Regulatory Reporting..................................................................................................66
15.6.
Investigator Responsibilities.......................................................................................66
15.7.
Biogen Responsibilities ..............................................................................................67
16.
STATISTICAL STATEMENT AND ANALYTICAL PLAN ..................................68
16.1.
Description of Objectives and Endpoints ...................................................................68
16.1.1.
Primary Objective and Endpoint ................................................................................68
16.1.2.
Additional Objectives and Endpoints.........................................................................68
16.2.
Demography and Baseline Disease Characteristics....................................................68
16.3.
Efficacy Data ..............................................................................................................68
16.3.1.
Analysis Population....................................................................................................68
16.3.2.
Methods of Analysis...................................................................................................69
16.4.
Safety Data..................................................................................................................70
16.4.1.
Analysis Population....................................................................................................70
16.4.2.
Methods of Analysis...................................................................................................70
71


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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The information contained herein may not be used, disclosed, or published without the written consent of 
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16.6.
Interim Analyses.........................................................................................................71
16.7.
Sample Size Considerations .......................................................................................71
17.
ETHICAL REQUIREMENTS ...................................................................................72
17.1.
Declaration of Helsinki...............................................................................................72
17.2.
Ethics Committee........................................................................................................72
17.3.
Subject Information and Consent ...............................................................................72
17.4.
Subject Data Protection ..............................................................................................73
17.5.
Compensation for Injury.............................................................................................73
17.6.
Conflict of Interest......................................................................................................73
17.7.
Registration of Study and Disclosure of Study Results..............................................73
18.
ADMINISTRATIVE PROCEDURES.......................................................................74
18.1.
Study Site Initiation....................................................................................................74
18.2.
Quality Assurance.......................................................................................................74
18.3.
Monitoring of the Study..............................................................................................74
18.4.
Study Funding.............................................................................................................74
18.5.
Publications.................................................................................................................74
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................75
19.1.
External Contract Organizations.................................................................................75
19.1.1.
Interactive Voice and Web Response System ............................................................75
19.1.2.
Contract Research Organizations ...............................................................................75
19.1.3.
Central Laboratories for Laboratory Assessments .....................................................75
19.1.4.
Central Facility for Other Assessments ......................................................................75
19.2.
Advisory Committee...................................................................................................75
19.3.
Changes to Final Study Protocol ................................................................................76
19.4.
Ethics Committee Notification of Study Completion or Termination........................76
19.5.
Retention of Study Data..............................................................................................76
19.6.
Study Report Signatory...............................................................................................76
20.
REFERENCES ...........................................................................................................77
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................78


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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LIST OF TABLES
Table 1:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
BG00012.....................................................................................................................40
Table 2:
Laboratory Analyses That Require Additional Evaluation ........................................40
Table 3:
Lymphocyte Monitoring and Management for Subjects Who Have a 
Lymphocyte Count <500/mm3 ...................................................................................42
Table 4:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs ...................71


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
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8
1.
CONTACT LIST
Biogen MA Inc.
225 Binney Street
Cambridge, MA 02142
USA
Biogen Idec Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
1.1.
Biogen Personnel
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide for complete contact information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities.






Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
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2.
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine transaminase
ANCOVA
analysis of covariance
ARR
annualized relapse rate
AST
aspartate transaminase
BID
twice a day
CD
cluster of differentiation
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
DCC
Data Coordinating Center
DHA
Directions for Handling and Administration
DMF
dimethyl fumarate
EDSS
Expanded Disability Status Scale
EQ-5D
EuroQol EQ-5D Health Survey
FAE
fumaric acid ester
GA
glatiramer acetate
GCP
Good Clinical Practice
Gd
gadolinium
GGT
gamma-glutamyl-transferase
GI
gastrointestinal
ICF
informed consent form
ICH
International Council for Harmonisation
IFN
interferon
IVMP
intravenous methylprednisolone
IXRS
Interactive Voice and Web Response System
LLN
lower limit of normal
MMF
monomethyl fumarate
MRI
magnetic resonance imaging
MS
multiple sclerosis
MTR
magnetization transfer ratio
PBMC
peripheral blood mononuclear cell
PHI
Protected Health Information
QD
once daily
RRMS
relapsing-remitting MS
SAE
serious adverse event
SF-36®
Short-form 36 Health Survey
SUSAR
suspected unexpected serious adverse reaction
TID
3 times a day


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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TNF
tumor necrosis factor
ULN
upper limit of normal
WBC
white blood cell


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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3.
SYNOPSIS
Protocol Number:
109MS303
Version Number:
8
Protocol Title:
A Dose-Blind, Multicenter, Extension Study to Determine the 
Long-Term Safety and Efficacy of Two Doses of BG00012 
Monotherapy in Subjects with Relapsing-Remitting Multiple 
Sclerosis
Study Phase:
3b
Rationale for the Study:
This study will extend BG00012 therapy from Biogen Studies
109MS301 and 109MS302.  This extension will further evaluate 
the long-term safety and efficacy profile of BG00012 
monotherapy.
Rationale for the Dose and 
Schedule Selection:
The initial BG00012 dosage for the extension study (240 mg 
twice a day [BID] or 240 mg 3 times a day [TID]) was the same 
as that used in the Phase 3 Studies 109MS301 and 109MS302.  
BG00012 has since been approved in several countries for the 
treatment of multiple sclerosis (MS) at a dose of 240 mg BID.  
For this reason, all subjects continuing in this extension study are 
currently receiving the currently marketed dose of 240 mg BID.
Subjects randomized to BG00012 240 mg TID were switched to 
BID dosing following BG00012 approval.
Study Design:
Multicenter parallel-group, randomized, dose-blind, 
dose-comparison phase, followed by an open-label phase.
Duration of Study Participation:
It is intended that eligible subjects from Studies 109MS301 and
109MS302 will be followed for at least 8 years in this extension 
study, assuming BG00012 continues to have a positive 
benefit-risk ratio.
Study Location:
Global; approximately 300 sites


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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Study Objectives:
Primary: 
To evaluate the long-term safety profile of BG00012.
Additional:
To evaluate the long-term efficacy of BG00012 using clinical 
endpoints (including relapse and annualized relapse rate [ARR]) 
and disability progression (Expanded Disability Status Scale 
[EDSS]).
To evaluate further the long-term effects of BG00012 on MS 
brain lesions on magnetic resonance imaging (MRI) scans in 
subjects who had MRI scans as part of Studies 109MS301 and 
109MS302 and in 109MS303 up through and including 
Amendment 6.  The following MRI endpoints will be evaluated in 
the subset of subjects who participated in the MRI scans:  number 
and volume of gadolinium-enhancing lesions, number of new or 
newly-enlarging T2 lesions and volume of total T2 lesions, 
number of new T1 hypointense lesions and volume of T1 
hypointense lesions, brain atrophy, and magnetization transfer 
ratio (MTR).
To evaluate the long-term effects of BG00012 on health 
economics assessments and the visual function test.  The 
endpoints are the Short-form 36 Health Survey (SF-36®) and 
EuroQol EQ-5D Health Survey (EQ-5D) quality of life 
questionnaire, and the visual function test scores.
Number of Planned Subjects:
Approximately 1700 subjects will be enrolled.
Sample Size Determination:
There is no formal sample size calculation.  The number of 
subjects eligible for this study is determined by the number of 
subjects who participated in Studies 109MS301 and 109MS302.
Study Population:
Subjects who participated in and completed as per protocol 
previous BG00012 clinical studies 109MS301 or 109MS302,
including those subjects who received an open-label, approved 
MS therapy and completed the modified visit schedule, are 
eligible to participate in this study.
Reasons for study exclusion include:

Any significant change in medical history in subjects from 
109MS301 or 109MS302, including laboratory tests, or 
current clinically significant condition that in the opinion of 
the Investigator would have excluded the subjects’ 
participation from their previous study.  The Investigator 
must re-review the subject’s medical fitness for participation 
and consider any diseases that would preclude treatment.

Subjects from 109MS301 or 109MS302 who discontinued 
BG00012 due to an adverse event (AE) or due to reasons 
other than protocol-defined relapse/disability progression. 

Subjects from 109MS301 or 109MS302 who discontinued 
BG00012 due to disability progression or relapses and did 
not follow the modified visit schedule up to Week 96.


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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
Alanine transaminase (ALT), aspartate transaminase (AST), 
or gamma-glutamyl-transferase >3 times the upper limit of 
normal (ULN).
Treatment Groups:
At enrollment into the study, all subjects received either:

BG00012 240 mg BID (2 capsules [120 mg each] twice a 
day and 2 placebo capsules once a day).
OR

BG00012 240 mg TID (2 capsules [120 mg each] 3 times a 
day).
Subjects randomized to BG00012 in Study 109MS301 or 
109MS302 continued on the same BG000012 dose in this 
extension study.
Subjects randomized to placebo in Study 109MS301 or 
109MS302 or glatiramer acetate in Study 109MS302 were
randomized to BG00012 in a 1:1 ratio to 240 mg BID or 240 mg 
TID in this extension study.
Subjects who switched to an alternate approved MS therapy in
Study 109MS301 or 109MS302 were randomized in this 
extension study as outlined above according to their original 
treatment group in 109MS301 or 109MS302.
All subjects continuing in this extension study are currently 
receiving the currently marketed dose of BG00012 240 mg BID. 
Subjects randomized to 240 mg TID were switched to BID dosing 
following BG00012 approval.
Visit Schedule:
Eligible subjects will be enrolled at Week 96 (Visit 24) of their 
previous BG00012 study (109MS301 or 109MS302), which will 
serve as the Baseline Visit for this extension study.  If the 
Baseline Visit cannot be combined with Visit 24 of their previous 
BG00012 study, subjects may be randomized within 6 months of 
Visit 24, provided that they are still eligible for enrollment.
Subjects will report to the study site every 4 weeks for the first 
24 weeks (Visit 1 through Visit 6) and every 12 weeks thereafter.

Subjects who reach Week 384 (Visit 36) should complete 
an End of Study Visit 4 weeks later (Week 388).  

Subjects who already completed Visit 36 should complete
an End of Study Visit 4 weeks after their next visit 
(scheduled or unscheduled).

Subjects who permanently discontinue BG00012 prior to 
Week 384 (Visit 36) should complete a Premature Study 
Treatment Withdrawal Visit within 4 weeks of their last 
dose. The Premature Study Treatment Withdrawal Visit 
will serve as the End of Study Visit.
Subjects who complete BG00012 treatment or permanently 
discontinue BG00012 for any reason and who have a lymphocyte 
count less than the lower limit of normal (<LLN) should not be 
withdrawn from the study.  These subjects will be followed 


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
Version 8.0
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according to Section 11.3.  
Discontinuation of Study
Treatment/Withdrawal from 
Study:
A subject must permanently discontinue BG00012 and be 
withdrawn from the study for any of the following reasons:

The subject becomes pregnant.  Treatment must be 
discontinued immediately.  

The subject desires to discontinue treatment and/or to 
discontinue participation under this protocol.

The subject experiences a medical emergency that 
necessitates permanent discontinuation of treatment.

The subject develops >3×ULN elevations in ALT or AST 
that are sustained for 4 consecutive weeks after BG00012
has been withheld. 

The subject experiences more than 1 deviation of the same 
laboratory parameter that requires temporary withholding as
defined in Table 1 at any time during the study. 

The subject experiences more than 2 different deviations of 
laboratory parameters that require temporary withholding as
defined in Table 1 at any time during the study.  On a third 
occasion, the subject must permanently discontinue dosing.

The subject cannot tolerate BG00012.

The subject receives any of the disallowed concomitant 
medications.

The subject is unwilling or unable to comply with the 
protocol.

At the discretion of the Investigator for medical reasons or 
for noncompliance.
NOTE: Subjects who complete BG00012 treatment or 
permanently discontinue BG00012 for any of the aforementioned 
reasons and who have a lymphocyte count <LLN should not be 
withdrawn from the study. These subjects will be followed 
according to Section 11.3.
Efficacy Assessments:
Relapse assessment, EDSS, MRI analysis (on subjects who had 
MRI scans as part of Studies 109MS301 and 109MS302 and in 
109MS303 up through and including Amendment 6), visual 
function as measured by low-contrast Sloan letter charts.
Health Economic Assessments:
SF-36, EQ-5D Quality of Life questionnaire.
Safety Assessments:
Physical examination, including vital signs, blood chemistry, 
hematology, urinalysis, urine cytology, and AE monitoring.
Statistical Analysis:
Efficacy:
ARR will be summarized for the extension study, as well as from 
the original baseline of the Phase 3 studies (i.e., extension study +
2 years in the previous Phase 3 studies).
A negative binomial regression model will be used for the 


Protocol 109MS303
BG00012 Monotherapy Safety and Efficacy Extension Study in MS
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analysis of ARR.  In addition to ARR, disability progression, 
proportion of subjects relapsed, visual function test scores, and 
MRI endpoints will also be analyzed.  The Cox proportional 
hazards model will be used for the analysis of time to 
relapse/proportion relapsed and disability progression.  Visual 
function test will be analyzed by an analysis of covariance 
(ANCOVA) model.  For MRI endpoints, analyses will be 
conducted on all MRI data collected up through and including
Amendment 6 of this protocol:  the number of lesions will be 
analyzed by logit regression, and the volume of lesions, brain 
atrophy, and MTR will be analyzed by ANCOVA models.
Safety:
Safety data will be summarized for the extension study for all 
treatment groups.  Long-term safety data (extension study + 2 
years in the previous Phase 3 studies) will be summarized by 
treatment groups. In addition, analysis by 3- or 6-month intervals 
may also be performed.  Lymphocyte count and lymphocyte 
subset data will be summarized by timepoints on BG00012 as 
well as post-treatment timepoints for subjects who permanently 
discontinue BG00012.
Health Economics:
Actual scores and change from baseline in EQ-5D and SF-36 will 
be analyzed by ANCOVA model. 
Interim Analysis:
Interim analyses may be performed as needed.
End of Study:
The end of study is Last Patient, Last Visit for final collection of 
data for the primary outcome.








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6.
MRI must not be performed within 30 days of receiving a course of steroids.
7.
The date and Study Visit/Week at which subjects are switched to open-label treatment should be recorded on the dosing CRF.




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AE = adverse event; CRF = case report form; 
; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = 
gadolinium; MRI = magnetic resonance imaging;
; SAE = serious adverse event; SF-36 = Short-form 36 Health Survey.
1.
Tests and assessments must be completed prior to BG00012 distribution.
2.
For women of childbearing potential.  Results must be known prior to BG00012 distribution.
3.
If urinalysis is abnormal, see Section 11.2.  
4.
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6.
5.
MRI must not be performed within 30 days of receiving a course of steroids.
6.
The date and Study Visit/Week at which subjects are switched to open-label treatment should be recorded on the dosing CRF.


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4.5.
Study Activities (Hematology 
 Analysis: Year 4 Through End of Treatment Visits)
Tests and Assessments
Subjects With Lymphocyte Count 
≥LLN
Subjects With Lymphocyte Count 
<LLN to ≥500/mm3
Subjects With Lymphocyte Count 
<500/mm3
Hematology
Every 12 weeks
Every 12 weeks
Every 4 or 12 weeks per Table 3
Bone Marrow Biopsy (optional)
Not applicable
Not applicable
Optional procedure6
; LLN = lower limit of normal;
 
 
 
 
 
6.
See Section 11.3 for further details.


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4.6.
Study Activities (Unscheduled and Post-Treatment Visits)
Tests and Assessments
End of Study Visit1
Unscheduled Relapse 
Assessment Visit2
Premature Study 
Treatment Withdrawal 
Visit3
Lymphocyte Follow-Up 
(Up to 96 Weeks After 
Last Dose)4
Physical Examination
X
X
Vital Signs
X
X
X
X
Hematology 
X3
X
X3
X
Blood Chemistry 
X
X
X
Urine Pregnancy Test5
X
X
X
Urinalysis
X6
X6
X6
Brain MRI7 Scan Gd8
Scheduled MRI scans were performed in protocol versions 1 through 6.
EDSS
X
X
Visual Function Test
X
X
SF-36 and EQ-5D
X
X
Relapse Assessment
X
Concomitant Therapy and Procedures Recording
Monitor and record throughout the study as per Section 11.6
AE/SAE Reporting
Monitor and record throughout the study as per Section 15
AE = adverse event; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = gadolinium; LLN = lower limit of normal; MRI = magnetic 
resonance imaging; SAE = serious adverse event; SF-36 = Short-form 36 Health Survey.
1.
For subjects who have already completed Visit 36 or beyond, an End of Study Visit should be completed 4 weeks after their next visit (scheduled or unscheduled).
2.
Unscheduled Relapse Assessment Visit is to be carried out within 5 days of suspected relapse.
3.
Subjects who permanently discontinue BG00012 prior to Week 384 (Visit 36) should complete a Premature Study Treatment Withdrawal Visit within 4 weeks of their 
last dose. The Premature Study Treatment Withdrawal Visit will serve as the End of Study Visit..
4.
Lymphocyte follow-up as per Section 11.3.
5.
For women of childbearing potential.
6.
If urinalysis is abnormal, see Section 11.2.  
7.
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6.
8.
MRI must not be performed within 30 days of receiving a course of steroid.


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5.
INTRODUCTION
5.1.
Overview of Multiple Sclerosis
Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects 
approximately 400,000 persons in North America and 365,000 persons in Europe.  It is 
predominantly a disease of young adults, primarily women, with disease onset typically 
occurring between the ages of 20 and 40.
In most cases, subjects with relapsing-remitting MS (RRMS) experience discrete episodes of 
neurologic dysfunction (referred to as relapses, exacerbations, or attacks), each lasting several 
days to several weeks, which occur intermittently over many years.  Symptoms of such relapses 
include loss of vision or double vision, numbness or tingling sensation in the extremities, muscle 
weakness, slurred speech, difficulty with coordination, and bladder dysfunction.  Early in the 
course of this phase of the disease, these symptoms tend to subside completely after each attack.  
Over time, recovery from attacks tends to be incomplete, leading to the accumulation of 
functional disability.  The majority of patients eventually develop the secondary progressive 
form of MS, which is characterized by the progressive accumulation of disability, with or 
without occasional relapses, minor remissions, and plateaus.  Approximately half of all MS 
patients will be unable to walk without assistance within 15 years of their initial diagnosis 
[Weinshenker 1989].
MS primarily affects myelinated fiber tracts.  Histologically, it is characterized by focal areas of 
demyelination, astrogliosis, the relative preservation of axons, and varying degrees of 
inflammation.  
Although the etiology of MS is uncertain, there is evidence that autoimmunity to myelin 
constituents plays a central role in the development of the MS lesion.  First, myelin breakdown 
products can be detected in macrophages in the MS lesion and in the cerebrospinal fluid (CSF) 
[Cohen 1976; Prineas 1990].  Second, the MS lesion has many features of a delayed-type 
hypersensitivity reaction [Traugott and Lebon 1988; Traugott 1983].  Lymphokines and 
cytokines (interferon [IFN]-gamma, tumor necrosis factor [TNF]-alpha, IL-1), activated cluster 
of differentiation (CD)4+ and CD8+ T cells, mononuclear phagocytes (macrophages, microglia, 
and monocytes) expressing variable levels of class II major histocompatibility complex antigens, 
and upregulation of leukocyte and vascular cell adhesion molecules have all been demonstrated 
within lesions [Ffrench-Constant 1994; Hartung 1995].  Third, CSF from MS patients shows 
intrathecal synthesis of immunoglobulins with restricted heterogeneity [Walsh and Tourtellotte 
1986] and an increased frequency of autoreactive T cells secreting IFN-gamma in response to 
myelin proteins [Soderstrom 1993].  Fourth, agents with immunomodulatory properties, such as 
IFN-beta have been shown to impede the accumulation of lesions, decrease the frequency of 
relapses, and slow the progression of disability in MS.
5.2.
Profile of Previous Experience with Fumarates
Biogen is evaluating BG00012 for the treatment of MS.  BG00012 is a drug product formulated 
as enteric-coated microtablets in gelatin capsules (blue and white) for oral administration.  Each 


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capsule contains 120 mg dimethyl fumarate (DMF).  DMF is an odorless, white, crystalline 
powder.
Fumaric acid and fumaric acid derivatives have been used for over 30 years as topical and oral 
long-term treatments for psoriasis.  Early oral therapies using fumaric acid derivatives were 
based on unapproved formulations.  Doses and modes of preparation varied among pharmacies.  
Clinical studies have demonstrated the efficacy and relative safety of fumaric acid esters (FAEs).  
Two open-label, long-term trials showed significant improvement in psoriasis treated with FAEs, 
including FUMADERM, for up to 3 years [Balasubramaniam 2004].  In 1994, Fumapharm AG 
gained approval in Germany for marketing of the oral compound, FUMADERM, containing 
DMF and ethyl hydrogen fumarate formulated as an enteric-coated, unit-size tablet.  Since then, 
FUMADERMhas become widely used as a systemic anti-psoriatic agent in Germany.
Treatment with FAEs would appear from the trials to be relatively safe compared with the risks 
known to be associated with other systemic treatments for psoriasis [Balasubramaniam 2004].  
The most common side effects observed with FUMADERMare flushing and gastrointestinal 
(GI) disorders.  Changes in liver enzymes and serum creatinine have only rarely been reported 
[Balasubramaniam 2004].  To develop a monosubstance FAE and to potentially improve on the 
overall tolerability versus FUMADERM®, Fumapharm AG developed a new formulation of the 
drug, BG00012.  BG00012 is formulated for oral administration as enteric-coated microtablets 
comprising 120 mg DMF contained in a gelatin capsule.
Function of DMF
The exact mechanism of action by which DMF exerts its effects in MS and psoriasis is still 
unclear.  Nevertheless, the effectiveness of FAEs may be attributed to the following actions of 
DMF and monomethyl fumarate (MMF), its primary metabolite.  FAEs may have both 
anti-inflammatory and neuroprotective effects.  In vitro experiments have shown that FAEs can 
influence the expression of cytokines and adhesion molecules that are thought to be involved in 
the inflammatory cascade (including IL-4, IL-2, TNF-alpha, E-selectin, etc.).  In addition, 
preliminary data have also implicated DMF in the regulation of a novel pathway for MS 
therapeutics:  induction of the expression of Phase II detoxifying enzymes.  This pathway is 
central to protection of cells from metabolic and inflammatory stress.
Clinical Safety in Healthy Volunteers
In Phase 1 clinical studies with FUMADERM® and BG00012, the most common adverse events 
(AEs) were flushing, pruritus, GI disturbance (diarrhea and stomach pain), myalgia, dizziness, 
and headache.  BG00012 produced significantly less GI disturbance than FUMADERM®; this 
improvement was attributed to the formulation of BG00012.  In other clinical studies of 
BG00012, co-administration with food was shown to delay the maximum concentration of MMF 
from approximately 2 hours (fasting) to approximately 5 hours (non-fasting).  The overall 
exposures (area under the curve) remained equivalent.
Clinical Safety in Multiple Sclerosis
BG00012 has been developed as an oral treatment for MS and was previously studied in 
psoriasis and rheumatoid arthritis.  As of September 2013, data were available for reporting from 
2513 subjects with MS who participated in the controlled and/or uncontrolled Phase 2 and 3 


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safety and efficacy studies (Studies C-1900, 109MS301, 109MS302, and 109MS303) and were 
exposed to BG00012 accounting for approximately 6100 subject-years of exposure.  
In a Phase 2, randomized, placebo-controlled study of BG00012 in RRMS (Study C-1900), 
subjects received BG00012 (120 mg once daily [QD] to 240 mg 3 times a day [TID]) or placebo 
for 24 weeks in Part 1 of the study.  In the Part 2 extension phase of the study, subjects who 
received placebo in Part 1 received BG00012 240 mg TID.  Overall, the most commonly 
observed events were flushing, MS relapse, nasopharyngitis, headache, nausea, diarrhea, fatigue, 
pruritus, upper abdominal pain, influenza, and hot flush.  
Study 109MS301 was a Phase 3, double-blind, placebo-controlled, dose-comparison study 
designed to determine the efficacy and safety of BG00012 in subjects with RRMS.  Subjects 
were randomized at a 1:1:1 ratio to receive BG00012 240 mg twice a day (BID; 2 × 120 mg BID 
and 2 placebo capsules QD), BG00012 240 mg TID (2 × 120 mg capsules TID), or placebo 
(2 capsules TID).  
Study 109MS302 was a Phase 3, double-blind, placebo-controlled, dose comparison, active 
reference comparator study in subjects with RRMS.  A total of 1430 subjects were randomized at 
a 1:1:1:1 ratio at 200 sites in 28 countries worldwide, and 363, 359, 345, and 350 subjects 
received at least 1 dose of placebo, BG00012 BID, BG00012 TID, and glatiramer acetate (GA), 
respectively.  
The duration of BG00012 administration in both studies was 96 weeks.  Clinic visits occurred 
every 4 weeks, with the End of Study Visit at Week 96 for subjects who chose to enroll in this 
protocol and at Week 100 for subjects who chose not to enroll in this protocol.  The safety 
profile of BG00012 was similar in Studies 109MS301 and 109MS302.  Across both studies, the 
commonly reported AEs in the BG00012 BID group included flushing and hot flush, GI events 
(diarrhea, nausea, abdominal pain upper, abdominal pain, vomiting, and dyspepsia), skin events 
(pruritus, rash, and erythema), albumin urine present, aspartate transaminase (AST) increased, 
and lymphopenia.
Clinical Efficacy in Multiple Sclerosis
An open-label, investigator-initiated, pilot study of FUMADERMin 10 subjects with RRMS 
demonstrated a robust reduction of the median number of gadolinium (Gd)-enhancing lesions on 
T1 brain magnetic resonance imaging (MRI) from 8 to 2 (p<0.05) at Week 18 of therapy 
(equivalent DMF dose of 720 mg per day).  Pharmacodynamic measures of T-cell function in 
this study demonstrated alterations in TH1/TH2 cytokine ratios and circulating TNF.  All AEs
were reported as mild and reversible.
In Study C-1900, subjects treated with 240 mg TID of BG00012 had a 69% reduction in the 
mean number of new Gd-enhancing lesions versus placebo as measured monthly from Weeks 12 
to 24 of the study.  In addition, subjects treated with BG00012 240 mg TID had a 44% reduction 
in the mean number of new Gd+ lesions versus placebo as measured monthly from Weeks 4 to 
24 of the study.  Subjects treated with BG00012 240 mg TID also demonstrated treatment 
advantages over placebo for other MRI parameters: a 48% reduction in the mean number of new 
or newly enlarging T2-hyperintense lesions versus placebo as measured at Week 24 of the study; 
a 53% reduction in the mean number of new T1-hypointense lesions versus placebo as measured 
at Week 24 of the study.  Although the study was not powered to evaluate the effects of 


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BG00012 on clinical measures, clinical efficacy endpoints of the intent-to-treat population were 
evaluated as exploratory measures.  There was a trend towards a reduction in annualized relapse 
rate (ARR) in the BG00012 240 mg TID group with a 32% reduction in the ARR (240 mg TID
vs. placebo: 0.44 vs. 0.65, which was not statistically significant [the study was not powered to 
detect a difference]). This corresponded to a 24% reduction on the proportion of relapsing 
subjects, but this also failed to reach statistical significance (19% vs. 25%, p=0.524).
A post hoc analysis of the evolution of new Gd-enhancing lesions at Weeks 4, 8, and 12 evolving 
into T1-hypointense lesions on the post-Gd Week 24 scan was performed and showed a reduced 
probability of conversion of Gd lesions into T1-hypointense lesions comparing BG00012 240 mg 
TID with placebo (odds ratio 0.51; 95% CI 0.43–0.61; p<0.0001).
In the placebo-controlled Phase 3 clinical study, Study 109MS301, treatment with BG00012 
240 mg BID and TID over 2 years significantly reduced the occurrence of clinical exacerbations, 
reduced the risk of confirmed (12-week) disability progression, and improved nearly all MRI 
measures of MS disease activity, compared with placebo.  In Study 109MS302, treatment with 
BG00012, administered as 240 mg BID or TID, significantly reduced clinical relapses over the 
2-year treatment period (as assessed by the ARR, the proportion of subjects relapsed, and the 
time to first relapse) and improved nearly all MRI measures of disease activity, compared with 
placebo.  A clinically meaningful, non-statistically significant reduction in disability progression 
was observed in both the BG00012 BID and TID groups, with reductions in the risk of 
confirmed disability progression (as measured by Expanded Disability Status Scale [EDSS]
score).  BG00012 showed efficacy across all prespecified subgroups.  The efficacy of GA 
treatment was consistent with its approved labeling and the results described in the published 
literature [Fox 2012].  
Additional information on BG00012 is found in the BG00012 Investigator’s Brochure and in the 
TECFIDERA prescribing information (where commercially available).
5.3.
Study Rationale
This study will extend BG00012 therapy from Biogen Studies 109MS301 and 109MS302.  This 
extension study will further evaluate the long-term safety and efficacy profile of BG00012 
monotherapy.
5.4.
Dose Rationale
The initial BG00012 dosage for the extension study (240 mg BID or 240 mg TID) was the same 
as that used in the Phase 3 Studies 109MS301 and 109MS302. Subsequent to the initiation of 
this study, BG00012 was approved in several countries for the treatment of MS at a dose of 
240 mg BID.  For this reason, all subjects continuing in this extension study are currently
receiving the currently marketed dose of 240 mg BID.  Subjects randomized to BG00012 240 mg 
TID were switched to BID dosing following BG00012 approval.


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6.
OBJECTIVES
6.1.
Primary Objective
The primary objective of the study is to evaluate the long-term safety profile of BG00012.
6.2.
Additional Objectives
Secondary objectives of this study are as follows:

To evaluate the long-term efficacy of BG00012 using clinical endpoints (including 
relapse and ARR) and disability progression (EDSS).

To evaluate further the long-term effects of BG00012 on MS brain lesions on MRI 
scans in subjects who had MRI scans as part of Studies 109MS301 and 109MS302
and in 109MS303 up through and including Amendment 6.  The following MRI 
endpoints will be evaluated in the subset of subjects who participated in the MRI 
scans:  number and volume of Gd-enhancing lesions, number of new or newly-
enlarging T2 lesions and volume of total T2 lesions, number of new T1 hypointense 
lesions and volume of T1 hypointense lesions, brain atrophy, and magnetization 
transfer ratio (MTR).

To evaluate the long-term effects of BG00012 on health economics assessments and 
the visual function test.  The endpoints are the Short-form 36 Health Survey (SF-36®)
and EuroQol EQ-5D Health Survey (EQ-5D) quality of life questionnaire, and the 
visual function test scores.
Exploratory objectives of this study are as follows:


 
 
 

 


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7.
STUDY DESIGN
7.1.
Study Overview
This first phase of this extension study is a multicenter, parallel-group, randomized, dose-blind, 
dose-comparison.  The second phase of the study is an open-label phase during which all 
subjects receive BG00012 at a dose of 240 mg BID.  Approximately 1700 subjects have been
enrolled at approximately 375 sites in North America, Europe, and the rest of the world.
It is intended that eligible subjects from Studies 109MS301 and 109MS302 will be followed for 
at least 8 years in this extension study, assuming BG00012 continues to have a positive 
benefit-risk ratio.  At enrollment into the study, all subjects received either:

BG00012 240 mg BID (2 capsules [120 mg each] twice a day and 2 placebo capsules 
once a day).
OR

BG00012 240 mg TID (2 capsules [120 mg each] 3 times a day).
Subjects randomized to BG00012 in Study 109MS301 or 109MS302 continued on the same 
BG00012 dose in this extension study.
Subjects randomized to placebo in Study 109MS301 or 109MS302 or to GA in Study 109MS302 
were randomized to BG00012 240 mg BID or 240 mg TID at a 1:1 ratio in this extension study.
Subjects who switched to an alternate approved MS therapy in Study 109MS301 or 109MS302 
were randomized in this extension study as outlined above according to their original treatment 
group in Study 109MS301 or 109MS302.
All subjects continuing in this extension study are currently receiving the currently marketed 
dose of BG00012 240 mg BID (2 capsules [120 mg each] BID).  Subjects randomized to 
BG00012 240 mg TID were switched to BID dosing (2 capsules [120 mg each] BID) following 
BG00012 approval.
Subjects who complete BG00012 treatment or permanently discontinue BG00012 for any reason
and who have a lymphocyte count less than the lower limit of normal (<LLN) should not be 
withdrawn from the study. These subjects will be followed according to Section 11.3.
7.2.
Overall Study Duration and Follow-Up
7.2.1.
Baseline
Eligible subjects will be enrolled at Week 96 (Visit 24) of their previous BG00012 study 
(109MS301 or 109MS302), which will serve as the Baseline Visit for this extension study.  If the 
Baseline Visit cannot be combined with Visit 24 of their previous BG00012 study, subjects may 
be randomized within 6 months of Visit 24, provided that they are still eligible for enrollment.  
Baseline Visit assessments may need to be repeated if there is a gap in BG00012.


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7.2.2.
Treatment Period
Subjects will report to the study site every 4 weeks for the first 24 weeks (Visit 1 through 
Visit 6) and every 12 weeks thereafter.
Premature Study Treatment Withdrawal Visits and Unscheduled Relapse Assessment Visits will 
be performed as necessary.  All efforts should be made to keep the subjects’ visit schedule
relative to their Baseline Visit (Day 1).  Unscheduled Relapse Assessment Visits should not 
modify or replace their regular visit schedule.
7.2.3.
Post-Treatment Period
Subjects who complete the Week 384 visit (Visit 36), regardless of further need to monitor 
lymphocytes on study, will complete an End of Study Visit at Week 388 ± 7 days.  For subjects 
who have already completed Visit 36, an End of Study Visit should be completed 4 weeks after 
their next visit (scheduled or unscheduled), regardless of further need to monitor lymphocytes on 
study. Subjects who permanently discontinue BG00012 prior to Week 384, regardless of further 
need to monitor lymphocytes on study, will complete a Premature Study Treatment Withdrawal 
Visit within 4 weeks after their last dose of BG00012.  Subjects who complete BG00012 
treatment or permanently discontinue BG00012 for any reason and who have a lymphocyte 
count <LLN should not be withdrawn from the study.  These subjects will be followed according 
to Section 11.3.
7.3.
Relapses
Suspected relapses during this study will be reviewed and confirmed according to the protocol by 
the treating neurologist.  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 treating neurologist.  The subject must have 
objective signs on the treating neurologist’s examination confirming the event.  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 
corticosteroid therapy within the protocol.
Subjects who experience new neurologic symptoms must contact the treating nurse or treating 
neurologist within 48 hours of the onset of symptoms to schedule an Unscheduled Relapse 
Assessment Visit.  The subject will then be evaluated in person by the treating neurologist
within 5 days of the onset of the potential relapse.  The treating neurologist is to perform a 
relapse assessment and obtain an EDSS score.  New objective findings on neurological 
examination performed by the treating neurologist are required to determine if a 
protocol-defined relapse has occurred. Subjects may not begin corticosteroid treatment of the 
relapse per protocol until the treating neurologist has examined them.
Treatment of an acute event of relapse as described in Section 11.6.1 may proceed at the 
discretion of the treating neurologist and will not affect the subject’s eligibility to continue in the 
study.


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7.4.
Disability Progression
Disability progression can only be assessed from the EDSS scores performed as per the 
protocol-defined schedule of assessments at regular visits.  The study staff must evaluate EDSS 
scores to determine if a subject experiences at least a 1.0 point increase on the EDSS from a 
baseline EDSS 1.0 that is sustained for 24 weeks or a 1.5 point increase on the EDSS from a 
baseline EDSS = 0 that is sustained for 24 weeks.  In either case, the subject must be informed 
they have experienced a worsening of physical disability.
7.5.
Study Stopping Rules
Biogen MA Inc. may terminate this study, after informing Investigators, at any time.  
Investigators will be notified by Biogen or designee if the study is placed on hold, completed, or 
closed.
7.6.
End of Study
The end of study is defined as the Last Patient, Last Visit for final collection of data for the 
primary outcome.


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8.
STUDY POPULATION
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of the Baseline Visit:
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in 
accordance with national and local subject privacy regulations.
2. Subjects who participated in and completed as per protocol previous BG00012 clinical 
studies 109MS301 or 109MS302, including those subjects who received an open-label, 
approved MS therapy, and completed the modified visit schedule.
3. All male subjects and female subjects of childbearing potential must practice effective 
contraception during the study and be willing and able to continue contraception for 
30 days after their last dose of BG00012.  For further details of contraceptive 
requirements for this study, please refer to Section 15.5.3.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of the Baseline Visit:
1. Any significant change in medical history in subjects from 109MS301 or 109MS302, 
including laboratory tests, or current clinically significant condition that in the opinion of 
the Investigator would have excluded the subjects’ participation from their previous 
study. The Investigator must re-review the subject’s medical fitness for participation and 
consider any diseases that would preclude treatment.
2. Subjects from 109MS301 or 109MS302 who discontinued BG00012 due to an AE or due 
to reasons other than protocol-defined relapse/disability progression.
3. Subjects from 109MS301 or 109MS302 who discontinued BG00012 due to disability 
progression or relapses and did not follow the modified visit schedule up to Week 96.
4. History of malignancy.
5. History of severe allergic or anaphylactic reactions.
6. Alanine transaminase (ALT), AST, or gamma-glutamyl-transferase (GGT) >3 times the 
upper limit of normal (ULN).
7. Female subjects considering becoming pregnant while in the study, currently pregnant, or 
breast feeding.
8. Previous participation in this study (109MS303).
9. Unwillingness or inability to comply with the requirements of the protocol including the 
presence of any condition (physical, mental, or social) that is likely to affect the subject’s 
ability to comply with the protocol.


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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 RANDOMIZATION PROCEDURES
9.1.
Enrollment Procedures
Once the investigational site has been activated for study participation, subjects may be enrolled 
if they have met the inclusion and exclusion criteria.  Subjects will be enrolled at Week 96
(Visit 24) of their previous BG00012 study, which will serve as the Baseline Visit for this
extension study.  
9.2.
Randomization and Registration Procedures
Subjects were randomized after the Investigator verified they were eligible per criteria in 
Sections 8.1 and 8.2.  Subjects who were randomized to BG00012 in Study 109MS301 or 
109MS302 continued in the same dose group for this extension study.  Subjects who were 
randomized to placebo in Study 109MS301 or 109MS302 or to GA in Study 109MS302 were
randomized in this extension study as outlined in Section 7.1 according to their original 
treatment group in Study 109MS301 or 109MS302.
Each subject retained the subject identification number assigned to him/her in the previous 
BG00012 study.  The subject’s identification number was used on all of that subject’s case report 
forms (CRFs).  
9.3.
Blinding Procedures
As sites still had subjects participating in the Phase 3 studies when subjects began to enroll in 
this extension study, measures were taken to preserve the blind for the Phase 3 studies during the 
dose-blind phase of the extension study.  All subjects were to take 1 capsule TID for the first 
week of the extension study and 2 capsules TID from Day 8.
During the dose-blind phase, all study staff and subjects were blinded to subject treatment group, 
except when a subject experienced a medical emergency that required dose unblinding of the 
subject’s randomized treatment assignment.
In addition, separate study personnel were designated to conduct efficacy assessments and to 
treat subjects in order to protect against perceived dose unblinding of treatment assignment.  
Roles and responsibilities of study personnel are described in Section 14.1.
All subjects continuing in this extension study are to receive open-label BG00012 240 mg BID.  
Consequently, subjects and study staff are no longer blinded to dose assignment but will remain 
blinded to the BG00012 dose that subjects were receiving before the open-label treatment, as 
well as to the treatment arm of the subject in the parent study. 


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10.
BG00012 DESCRIPTION AND ALLOCATION
BG00012 is a drug product formulated as enteric-coated microtablets in gelatin capsules (blue 
and white) for oral administration.  Each capsule contains 120 mg DMF.
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, simeticone, sodium laurilsulfate, and polysorbate 80.  
Excipients for the manufacturing of the capsule shell include gelatin, titanium dioxide, and 
indigotine.
The label will include conditions for storage, lot number, and other pertinent information such as 
manufacturer, batch/lot number, and caution statement.  Depending on country requirements, the 
Investigator’s name may also appear on the label.  
BG00012 is to be stored at 15 to 25C in a secure location, preferably a monitored, locked 
cabinet.  Accountability for BG00012 is the responsibility of the Investigator.  More details 
concerning this responsibility are included in Section 10.2.
Study site staff should refer to the Directions for Handling and Administration (DHA) located in 
the Study Reference Guide for specific instructions on the handling and administration of 
BG00012.  The individual dispensing BG00012 should first carefully review the instructions 
provided in the DHA, which supersedes all other references (e.g., Investigator’s Brochure or
commercial product prescribing information).
BG00012 must only be dispensed by qualified study staff and is to be dispensed only to subjects 
enrolled in this study.  Do not use BG00012 after the expiration date unless a written notification 
of an expiration date extension is provided by Biogen.  Once BG00012 is dispensed to a subject, 
it can only be taken by that subject.
10.1.
BG00012 Packaging
The qualified study staff will dispense to subjects at least a 4-week supply of BG00012 at the 
Baseline Visit and at each subsequent study visit (excluding the End of Study Visit, Premature 
Study Treatment Withdrawal Visit, and the Unscheduled Relapse Assessment Visit).
BG00012 is provided in drug wallets identified by kit numbers supplied from an Interactive 
Voice and Web Response System (IXRS) at specific timepoints during the study. 
During the dose-blind phase, BG00012 kits included 6 capsules per day (2 capsules each for the 
morning, noon, and evening doses).  During the open-label treatment, the noon dose is 
eliminated, and the new kit will include 4 capsules per day (2 capsules each for the morning and 
evening doses).
10.2.
BG00012 Accountability
The study site must maintain accurate records demonstrating dates and amount of BG00012
received, to whom dispensed (subject-by-subject accounting), amount returned by subject, and 


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accounts of any BG00012 accidentally or deliberately destroyed.  The date (Study Visit/Week) 
that each subject switched to open-label treatment with 240 mg BID should also be recorded in 
the CRF.
Unless otherwise notified, all capsules both used and unused, must be saved for BG00012
accountability.  At the end of the study, reconciliation must be made between the amount of 
BG00012 supplied, dispensed, and subsequently destroyed or returned to Biogen.  A written 
explanation will be provided for any discrepancies.
The Investigator must return all unused capsules of BG00012 as instructed by Biogen.  If any 
BG00012 supplies are to be destroyed at the site, the institution/Principal Investigator(s) must 
obtain prior approval by Biogen.  After such destruction, the institution/Principal Investigator(s) 
must notify Biogen, in writing, of the method of destruction, the date of destruction, and the 
location of destruction.


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11.
TREATMENT
11.1.
Treatment Schedule
At enrollment into the study, all subjects received either:

BG00012 240 mg BID (2 capsules [120 mg each] twice a day and 2 placebo capsules 
once a day).
OR

BG00012 240 mg TID (2 capsules [120 mg each] 3 times a day).
Subjects randomized to BG00012 in Study 109MS301 or 109MS302 continued on the same 
BG00012 dose in this extension study.
Subjects randomized to placebo in Study 109MS301 or 109MS302 or to GA in Study 109MS302 
were randomized to BG00012 240 mg BID or 240 mg TID at a 1:1 ratio in this extension study.
Subjects who switched to an alternate approved MS therapy in Study 109MS301 or 109MS302 
were randomized in this extension study as outlined above according to their original treatment 
group in Study 109MS301 or 109MS302.
All subjects continuing in the extension study are currently receiving the currently marketed dose 
of BG00012 240 mg BID (2 capsules [120 mg each] BID). Subjects randomized to BG00012 
240 mg TID were switched to BID dosing (2 capsules [120 mg each] BID) following BG00012 
approval.
Subjects who complete BG00012 treatment or permanently discontinue BG00012 for any reason 
and who have a lymphocyte count <LLN should not be withdrawn from the study.  These 
subjects will be followed according to Section 11.3.
11.2.
Modification of Treatment Schedule
11.2.1.
Abnormal Laboratory Values:  Dosing Interruption and Management
BG00012 must be temporarily withheld when any of the following laboratory values meet the 
criteria defined in Table 1.  Subjects are required to have additional evaluation when any of the 
following laboratory values meet the threshold limits defined in Table 2.


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Table 1:
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of BG00012
Laboratory Parameter
Laboratory Result
Required Action
AST or ALT
>3ULN 
The Investigator should repeat the test as soon as 
possible.  If re-test value confirms AST or ALT 
>3ULN, BG00012 must be withheld.  If the value 
remains >3ULN for 4 weeks after discontinuation 
of BG00012, then the subject must permanently
discontinue BG00012.
Lymphocyte counts
<500/mm3
See Table 3.
ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal.
While dosing is withheld, subjects will continue tests and assessments according to the schedule 
defined in the protocol (Section 4), and may also undergo additional assessments to evaluate the 
laboratory abnormality as per the Investigator’s standard practice.  Subjects who have abnormal 
laboratory results other than described in Table 1 must repeat the tests within 2 weeks (repeat 
tests will be run at the central laboratory).  Abnormal laboratory results confirmed on repeat tests 
should be managed per the Investigator’s standard practice.
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 (see Table 1).  However, subjects 
who subsequently experience a different laboratory abnormality can have BG00012 withheld 
again, allowing.  2 dosing interruptions for each subject.  Any subject who experiences 
abnormal laboratory results that require temporary withholding as defined in Table 1 on a third 
occasion must permanently discontinue dosing.
Subjects who complete BG00012 or permanently discontinue BG00012 for any reason and who
have a lymphocyte count <LLN will be followed according to Section 11.3.  
Table 2:
Laboratory Analyses That Require Additional Evaluation 
Laboratory Parameter
Laboratory Result 
Required Action 
Urinalysis
Urinary casts (other 
than hyaline casts)
Repeat test 2 weeks later; if the abnormality persists 
on re-testing, the subject should be followed as per 
standard of care.
Urinalysis
Glycosuria (trace or 
greater)
If occurring in the setting of normal serum glucose, 
repeat test 2 weeks later; if the abnormality persists on 
re-testing, the subject should be followed as per 
standard of care.


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Laboratory Parameter
Laboratory Result 
Required Action 
Urinalysis 
Proteinuria  1+ 
Subjects who demonstrate 1+ proteinuria (and do not 
have a documented history of benign proteinuria)
should be re-tested within 2 weeks of initial abnormal 
finding.  If the abnormality persists on re-testing, the 
subject should be followed as per standard of care.
11.2.2.
Dosage Reductions
Dosage reduction will be allowed only for subjects who are unable to tolerate BG00012 due to 
flushing and/or GI disturbances (dosage reductions will not be allowed for abnormal laboratory 
values; for management of abnormal laboratory values, refer to Section 11.2.1).  Subjects who do 
not tolerate BG00012 will reduce their dosage by taking one 120-mg capsule BID for 4 weeks.  
After 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, the subject must 
discontinue BG00012 and be withdrawn from the study as described in Section 11.2.  
11.2.3.
Resumption of BG00012 Dosing
Subjects who have temporarily withheld BG00012 due to lymphopenia may resume BG00012
according to Section 11.3.
Subjects who are allowed to resume BG00012 dosing following a 2- to 4-week interruption due 
to flushing and/or GI disturbances 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.
11.3.
Monitoring and Management for Subjects with Abnormal 
Lymphocyte Count
Subjects who have a lymphocyte count <500/mm3 at any time should be monitored and managed 
according to Table 3.
All subjects who complete BG00012 treatment or permanently discontinue BG00012 for any 
reason other than those specified in Table 3, and who have a lymphocyte count <LLN, will be 
monitored every 12 weeks until their lymphocyte count is ≥LLN OR for 48 weeks after their last 
dose, whichever is earlier.  






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
The subject develops >3ULN elevations in ALT or AST that are sustained for 
4 consecutive weeks after BG00012 has been withheld. 

The subject experiences more than one 1 deviation of the same laboratory parameter 
that requires temporary withholding as defined in Table 1 at any time during the 
study. 

The subject experiences more than 2 different deviations of laboratory parameters 
that require temporary withholding as defined in Table 1 at any time during the study.  
On a third occasion, the subject must permanently discontinue dosing.

The subject cannot tolerate BG00012.

The subject receives any of the disallowed concomitant medications described in 
Section 11.6.

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Investigator for medical reasons or for noncompliance.
NOTE:  Subjects who complete BG00012 treatment or permanently discontinue BG00012 for 
any of the aforementioned reasons and who have a lymphocyte count <LLN should not be 
withdrawn from the study.  These subjects will be followed according to Section 11.3.
The date(s) and reason(s) for discontinuation of treatment and withdrawal from the study must be 
recorded in the subject’s CRF.  Subjects who permanently discontinue BG00012 prior to 
Week 384, regardless of further need to monitor lymphocytes on study, will complete a 
Premature Study Treatment Withdrawal Visit within 4 weeks of their last dose.
11.5.
Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.  Compliance 
will be monitored by capsule count conducted by study personnel at protocol-scheduled visits.
11.6.
Concomitant Therapy and Procedures
A concomitant therapy is any drug or substance administered from the time of the subject’s 
written consent until the subject’s End of Study Visit.
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed from the 
time the subject is enrolled in the study until the subject’s End of Study Visit, unless the subject 
is being followed for study-related toxicity.
Concomitant treatment with any of the following is not allowed unless otherwise described in 
this protocol:

Any alternative drug treatments directed toward the treatment of MS, such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to, IFN-beta, IFN-alpha, GA, natalizumab, fingolimod, teriflunomide, 
cyclophosphamide, methotrexate, azathioprine, 4-aminopyridine or related products, 
etc.), with the exception of acute management of protocol-defined relapse (as 


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described below) and subjects with prolonged lymphopenia (as described in Section
11.3). 

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 intravenous 
methylprednisolone (IVMP), except for protocol-defined treatment of relapses as 
described below.  Steroids that are administered by non-systemic routes (e.g., topical, 
inhaled) or systemic steroid therapy for limited, short-term treatment of general 
medical conditions are allowed.

Total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any 
therapeutic monoclonal antibody, mitoxantrone, cyclosporine, intravenous
immunoglobulin, plasmapheresis, or cytapheresis.
Subjects who receive any of these restricted medications will be required to discontinue
permanently BG00012 and will be withdrawn from the study unless otherwise described in this 
protocol as outlined in Section 11.2.  
Symptomatic therapy, such as treatment for spasticity, depression, or fatigue is not restricted, but 
should be optimized as early as possible during screening in an attempt to maintain consistent 
treatment for the duration of the study.  Subjects should be instructed not to start taking any new 
medications, including non-prescribed drugs.
The use of concomitant therapies or procedures defined above must be recorded on the subject’s 
CRF, according to instructions for CRF completion.  AEs related to administration of these 
therapies or procedures must be documented on the appropriate CRF.
11.6.1.
Treatment of Relapses on Scheduled or Unscheduled Visits
The protocol-approved treatment for relapse in this study is either 3 to 5 days with IVMP at 
doses of up to 1000 mg/day or a full dose regimen of oral corticosteroids for up to 14 days.  Oral 
corticosteroid taper regimens are not permitted.  IVMP or oral corticosteroids can be given once 
a day or in divided doses.  Subjects may also refuse relapse treatment.  BG00012 dosing is to 
continue uninterrupted during steroid treatment.  New or recurrent neurologic symptoms that 
occur <30 days after the onset of a protocol-defined relapse should be considered part of the 
same relapse and should not be treated with steroid within the protocol.  Steroid retreatment of 
the same relapse is not allowed unless approved by the Medical Monitor.  


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12.
EFFICACY ASSESSMENTS
12.1.
Clinical Efficacy Assessments
The following clinical tests/assessments will be performed to assess the efficacy of BG00012:

Relapse assessment

EDSS [Kurtzke 1983]

Visual function test [Balcer 2000]:  the low-contrast Sloan letter charts (contrast 
sensitivity)
12.2.
Laboratory Efficacy Assessments
The following laboratory tests/assessments will be performed to assess the efficacy of BG00012:

Brain MRI scan with and without Gd parameters (only in subjects who had MRI 
scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and 
including Amendment 6).
 
 
 
  
12.4.
Additional Assessments

The SF-36 is one of the most widely accepted generic health status measures.  It is a 
brief (36-item) scale developed by Steward, Hayes, and Ware.  The SF-36 will be 
available for all subjects for whom a validated translation in the local language is 
available.

EQ-5D:  a self-administered questionnaire consisting of 5 sets of 3 questions 
pertaining to specific health states (i.e., mobility, self-care, pain, usual activities, and 
anxiety), a health status rating scale, and demographic questions.


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13.
SAFETY ASSESSMENTS
13.1.
Clinical Safety Assessments
The following clinical assessments will be performed to assess the safety profile of BG00012:

Physical examination

Vital signs (heart rate, blood pressure, and temperature)

AE monitoring (see Section 15)
13.2.
Laboratory Safety Assessments
The following laboratory tests will be performed to assess the safety profile of BG00012:

Hematology:  hemoglobin, hematocrit, red blood cell count, WBC count (with 
differential), and platelet count.  

Blood chemistry:  sodium, potassium, chloride, total bilirubin, alkaline phosphatase,
ALT, AST, lactate dehydrogenase, GGT, blood urea nitrogen, creatinine, bicarbonate, 
calcium, magnesium, phosphate, uric acid, and glucose.

Urinalysis:  color, specific gravity, pH, protein, glucose, blood, ketones, and 
microscopy.

Urine cytology


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14.
SCHEDULE OF EVENTS
A written, signed informed consent form (ICF) and all authorizations required by local law (e.g., 
PHI in North America) must be obtained prior to performing any tests or assessments under this 
protocol. All tests and assessments scheduled for a particular visit must be completed before 
BG00012 is distributed.  
14.1.
Site Personnel
For each subject, the Principal Investigator of the site will designate the following investigational 
site personnel:

A primary and backup treating neurologist; NOTE:  to preserve the blind prior to 
open-label treatment, an examining neurologist from a Phase 3 study 
(Study 109MS301 or 109MS302) could not serve as the treating neurologist for this 
extension study (109MS303).

An examining neurologist (if the treating neurologist designates EDSS examinations)

A treating nurse (or study coordinator)

An examining technician (if the treating neurologist designates visual function test
examinations)

An MRI technician (only at sites that had MRI scans as part of Study 109MS301 or
109MS302 and in 109MS303 up through and including Amendment 6)
The treating and examining neurologist must have a minimum of 2 years of neurology specialty 
training and be able to make at least a 1-year commitment to the study.
Where specified, evaluations described in this section must be performed only by the personnel 
indicated.
The primary treating neurologist will be responsible for:

Management of the routine neurological care of the subject.

Assessment (including assignment of causality) and treatment of AEs and MS 
relapses.

Review of selected hematology and blood chemistry results from the central 
laboratory to assess whether the subject’s BG00012 should be temporarily withheld 
or permanently discontinued as per the criteria detailed in Sections 11.2 and 11.3.

Obtaining an EDSS score based on a detailed neurological examination at the 
scheduled timepoints required in the protocol. 

Obtaining an EDSS score at every Unscheduled Relapse Assessment Visit when there 
is the possibility of a relapse.
The treating neurologist may designate other medical personnel (i.e., the backup treating 
neurologist, examining neurologist or the treating nurse) at the investigational site to perform 


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some of the tests and evaluations listed under “treating neurologist.”  If there is more than 1 
treating neurologist available at a given site such that each one is assigned to particular subjects, 
then these treating neurologists may act as backup for each other.  All sites, however, should 
attempt to maintain the same treating neurologist for a given subject throughout the study.  The 
same holds true for the treating nurses. The backup treating neurologist will conduct subject 
evaluations ONLY if the primary treating neurologist is unavailable due to illness, vacation, or 
travel.  Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the subject.  
The examining neurologist (if designated by the treating neurologist) will be responsible for:

Obtaining an EDSS score based on a detailed neurological examination at the 
required clinical evaluation visits, at the Unscheduled Relapse Assessment Visit, and 
at the Premature Study Treatment Withdrawal Visit.  
The primary treating nurse (or study coordinator) will be responsible for:

Assisting the treating neurologist in subject management, including the treatment of 
AEs, the treatment and assessment of disease relapses, and the recording of AEs and 
concomitant medications.

Monitoring the EDSS scores (as determined by the treating neurologist) and 
informing the treating neurologist if a subject experiences a 1.0 point increase on the 
EDSS from a baseline EDSS 1.0 that is sustained for 24 weeks or a 1.5 point 
increase on the EDSS from a baseline EDSS = 0 that is sustained for 24 weeks.
The examining technician (or the treating neurologist) will be responsible for:

Administering the visual function test at each scheduled clinical evaluation visit and 
at the End of Study or Premature Study Treatment Withdrawal Visit. 
It is not necessary for the examining technician to be a health care professional as long as he/she 
is qualified, in the opinion of the Principal Investigator, to administer the visual function test.
The MRI technician (only at sites participating in MRI sub-study) will be responsible for:

Performing a brain MRI scan with and without Gd at all protocol-required time points
up through and including Amendment 6 of this protocol.  Study-specific MRI scan 
procedures and protocols will be provided prior to study start and must be followed.
14.2.
Subject Management
Male subjects and female subjects of childbearing potential must practice effective contraception 
during the study and continue contraception for 30 days after their last dose of BG00012.  If a 
female subject becomes pregnant, BG00012 must be discontinued immediately.  For detailed 
information on contraception requirements and pregnancy, please refer to Sections 15.5.3 and 
15.5.4, respectively.
Other than the BG00012 dosing requirements and concomitant medication restrictions described 
in Sections 11.1, 11.2, and 11.6, there are no special subject management procedures.  There are 
no restrictions regarding diet, alcohol use, or activity during this study.


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Subjects should not donate blood until 4 weeks after their last dose of BG00012 in this study.
14.3.
Tests and Assessments
14.3.1.
Year 1
14.3.1.1.
Baseline Visit (Day 1)
Eligible subjects will be enrolled at Week 96 (Visit 24) of their previous BG00012 study 
(109MS301 or 109MS302), which will serve as the Baseline Visit for this extension study.  All 
tests and procedures of the Baseline Visit that are performed at Visit 24 of 109MS301 or 
109MS302 protocol should be performed by the respective personnel of the parent study, unless 
there is a gap in treatment.
Designated Personnel

Randomization by IXRS
Treating Neurologist

Informed consent

Eligibility criteria

Medical history update including review of cardiovascular risk factors

Physical examination

EDSS (If there is a gap in treatment and an examining neurologist is not designated, 
otherwise this exam should be performed by the examining neurologist of the parent 
study.)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

SF-36 and EQ-5D

BG00012 distribution

Recording concomitant medication and AEs


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MRI Technician

Brain MRI scan with and without Gd in subjects who had MRI scans as part of 
Studies 109MS301 and 109MS302 and in 109MS303 up through and including 
Amendment 6.
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.1.2.
Visit 1 (Week 4 ±5 Days)
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
14.3.1.3.
Visit 2 (Week 8 ±5 Days)
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
14.3.1.4.
Visit 3 (Week 12 ±5 Days)
Treating/Examining Neurologist

Monitoring of AEs (treating neurologist)


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
EDSS (To be performed only for subjects who at the Week 96 visit [Visit 24] in 
109MS301 or 109MS302 had a 1.0 point increase in their EDSS score from a 
baseline EDSS 1.0 or a 1.5 point increase in their EDSS from a baseline EDSS = 0.
Since this is to confirm disability progression at the Week 96 visit, this should be 
performed by the examining neurologist of the parent study.)
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
14.3.1.5.
Visit 4 (Week 16 ±5 Days)
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
14.3.1.6.
Visit 5 (Week 20 ±5 Days)
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution


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
Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
14.3.1.7.
Visit 6 (Week 24 ±5 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.1.8.
Visit 7 (Week 36 ±7 Days)
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs


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14.3.1.9.
Visit 8 (Week 48 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

SF-36 and EQ-5D

BG00012 distribution

Recording concomitant medication and AEs
MRI Technician

Brain MRI scan with and without Gd in subjects who had MRI scans as part of 
Studies 109MS301 and 109MS302 and in 109MS303 up through and including 
Amendment 6.  MRI must not be performed within 30 days of receiving a course of 
steroids.
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.2.
Years 2 and 3 Treatment Visits
14.3.2.1.
Visits 9, 10, 11, 13, 14, and 15 (Weeks 60, 72, 84, 108, 120, and 132 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry


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Version 8.0
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
Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.2.2.
Visits 12 and 16 (Weeks 96 and 144 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

SF-36 and EQ-5D

BG00012 distribution

Recording concomitant medication and AEs
MRI Technician

Brain MRI scan with and without Gd in subjects who had MRI scans as part of 
Studies 109MS301 and 109MS302 and in 109MS303 up through and including 
Amendment 6.  MRI must not be performed within 30 days of receiving a course of 
steroids.
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.3.
Years 4 through 8 Treatment Visits
14.3.3.1.
Visits 17, 19, 21, 23, 25, 27, 29, 31, 33, and 35 (Weeks 156, 180, 204, 228, 252, 276, 
300, 324, 348, and 372 ±7 Days)
Treating Neurologist


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
Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis

BG00012 distribution (record the Visit/Week at which subjects are switched to BID 
dosing and/or open-label treatment on the dosing CRF)

Recording concomitant medication and AEs
14.3.3.2.
Visits 18, 22, 26, 30, and 34 (Weeks 168, 216, 264, 312, and 360 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

BG00012 distribution

Recording concomitant medication and AEs
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.3.3.
Visits 20, 24, 28, 32, and 36 (Weeks 192, 240, 288, 336, and 384 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis


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Version 8.0
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
Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

SF-36 and EQ-5D

BG00012 distribution (except at Visit 36)

Recording concomitant medication and AEs
MRI Technician

Brain MRI scan with and without Gd in subjects who had MRI scans as part of 
Studies 109MS301 and 109MS302 and in 109MS303 up through and including 
Amendment 6.  MRI must not be performed within 30 days of receiving a course of 
steroids.
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.4.
Study Activities for Subjects Who Already Completed Visit 36
For subjects who have already completed Visit 36 (or beyond), an End of Study Visit should be 
completed 4 weeks after their next visit (scheduled or unscheduled), regardless of further need to 
monitor lymphocytes on study. For subjects who have not completed Visit 36 prior to Protocol 
Version 8, Visit 36 will serve as the last scheduled Visit and an End of Study Visit should be 
completed 4 weeks after their next Visit (scheduled or unscheduled), regardless of further need 
to monitor lymphocytes on study.
14.3.4.1.
Visits 37, 39, 41, 43, 45, 47, 49, and 51 (Weeks 396, 420, 444, 468, 492, 516, 540, 
and 564 ±7 Days)
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis

Recording concomitant medication and AEs
14.3.4.2.
Visits 38, 42, 46, and 50 (Weeks 408, 456, 504, and 552 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs


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Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential; 
results must be known prior to BG00012 distribution

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.  

Recording concomitant medication and AEs
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.4.3.
Visits 40, 44, 48, and 52 (Weeks 432, 480, 528, and 576 ±7 Days)
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.  

SF-36 and EQ-5D

Recording concomitant medication and AEs
MRI Technician

Brain MRI scan with and without Gd in subjects who had MRI scans as part of 
Studies 109MS301 and 109MS302 and in 109MS303 up through and including 
Amendment 6.  MRI must not be performed within 30 days of receiving a course of 
steroids.
Examining Technician (if designated by treating neurologist)

Visual function test


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14.3.5.
End of Study Visit 
NOTE:  Subjects will complete an End of Study Visit 4 weeks following their last study visit.
For subjects who have already completed Visit 36 (Week 384) or beyond, an End of Study Visit 
should be completed 4 weeks after their next visit (scheduled or unscheduled).  For subjects who 
complete a Premature Study Treatment Withdrawal Visit, this will also be used as the End of 
Study Visit.
Treating Neurologist

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis.  If lymphocyte count is 
<LLN, see Section 11.3.

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential

Collection of urine for urinalysis.

Recording concomitant medication and AEs
14.3.6.
Unscheduled Relapse Assessment Visit
Unscheduled Relapse Assessment Visit to be carried out within 5 days of suspected relapse.
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Relapse assessment

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential

Collection of urine for urinalysis.  If urinalysis is abnormal, see Section 11.2.

SF-36 and EQ-5D

Recording concomitant medication and AEs
Examining Technician (if designated by treating neurologist)


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
Visual function test
14.3.7.
Premature Study Treatment Withdrawal Visit
Subjects who permanently discontinue BG00012 prior to Week 384, regardless of further need to 
monitor lymphocytes on study, will complete a Premature Study Treatment Withdrawal Visit 
within 4 weeks of their last dose.
Treating Neurologist

Physical examination

EDSS (may be performed by the examining neurologist)

Monitoring of AEs
Treating Nurse

Vital signs

Collection of blood for hematology and lymphocyte analysis.  If lymphocyte count is 
<LLN, see Section 11.3.

Collection of blood for blood chemistry

Collection of urine for urine pregnancy test in women of childbearing potential

Collection of urine for urinalysis.

SF-36 and EQ-5D

Recording concomitant medication and AEs
MRI Technician

Brain MRI scan with and without Gd in subjects who had MRI scans as part of 
Studies 109MS301 and 109MS302 and in 109MS303 up through and including 
Amendment 6.  MRI must not be performed within 30 days of receiving a course of 
steroids.
Examining Technician (if designated by treating neurologist)

Visual function test
14.3.8.
Lymphocyte Follow-Up 
Treating Nurse

Vital signs

Collection of blood for hematology as defined in Section 11.3.

Recording concomitant medication and AEs


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15.
SAFETY DEFINITIONS, MONITORING, AND REPORTING
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 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.
15.1.2.
Serious Adverse Event
A serious AE (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 
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.
15.2.
Monitoring and Recording Events
15.2.1.
Adverse Events
Any AE experienced by the subject from the time of first dose of BG00012 until the final study 
visit (including, but not limited to, the lymphocyte follow-up visits [for applicable subjects]) is to 
be recorded on the CRF, regardless of the severity of the event or its relationship to BG00012.


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15.2.2.
Serious Adverse Events
Any SAE experienced by the subject from the time of the first dose of BG00012 until the final 
study visit is to be recorded on an SAE Form, regardless of the severity of the event or its 
relationship to BG00012.  SAEs must be reported to Biogen or designee as detailed in Section
15.2.4.
Any SAE ongoing when the subject completes the study or discontinues the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status.
15.2.3.
All 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 BG00012 as defined in Section 15.3.1.

The severity of the event as defined in Section 15.3.2.
Cardiac events:  subjects who report symptoms suggestive of an underlying cardiac disease or 
condition should be promptly evaluated by the Investigator to determine if further investigations 
are required (e.g., 12-lead electrocardiogram), or whether a referral to a cardiologist may be 
necessary.  For all cardiac SAEs, the Investigator should make every attempt to obtain the full 
details of all relevant investigations and the final diagnosis of the event.  All cardiac SAEs 
should be followed up until the event has been resolved, stabilized, or returned to baseline.
15.2.4.
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 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.


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Reporting Information for SAEs
Any SAE that occurs from the time that the subject has signed the ICF until the final study 
visit must be reported to Biogen or designee within 24 hours of the study site staff becoming 
aware of the event.
A report must be submitted to Biogen or designee regardless of the following:

Whether or not the subject has undergone study-related procedures

Whether or not 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, fax a completed SAE form to the 
following:
Please refer to the Investigator Site File or Study Reference Manual for complete 
information.
15.2.4.1.
Death
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate CRF.  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 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.
Safety Classifications
15.3.1.
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
Unrelated
Any event that does not follow a reasonable temporal sequence from administration of 
study treatment AND that is likely to have been produced by the subject’s clinical 
state or other modes of therapy administered to the subject.
Unlikely
Any event that does not follow a reasonable temporal sequence from administration of 
study treatment OR that is likely to have been produced by the subject’s clinical state 
or other modes of therapy administered to the subject.
Possibly
Any reaction that follows a reasonable temporal sequence from administration of 
study treatment OR that follows a known response pattern to the suspected drug AND
that could not be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject.
Related
Any reaction that follows a reasonable temporal sequence from administration of 
study treatment AND that follows a known response pattern to the suspected drug 
AND that recurs with re-challenge, AND/OR is improved by stopping the drug or 
reducing the dose.
15.3.2.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Severity of Event
Mild
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s) but may be given because of personality of subject.
Moderate
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed.
Severe
Symptom(s) 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 symptom(s) may be given and/or subject hospitalized.
15.3.3.
Expectedness of Events
Expectedness of all AEs will be determined according to the Investigator’s Brochure.
15.4.
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.


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
The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress 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.
15.5.
Procedures for Handling Special Situations
15.5.1.
Overdose
An overdose is any dose of BG00012 given to a subject or taken by a subject that exceeds the 
dose described in the protocol.  Overdoses are not considered AEs, however all overdoses should 
be recorded on an Overdose form and faxed to Biogen or designee within 24 hours of the site 
becoming aware of the overdose.  An overdose should be recorded even if it does not result in an 
AE.  Overdoses do not need to be recorded in the CRF.
15.5.2.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care, and contact the medical monitor.
15.5.3.
Contraception Requirements
All male and female subjects of childbearing potential must practice effective contraception 
during the study and be willing and able to continue contraception for 30 days after their last 
dose of BG00012.
For the purposes of the study, effective contraception is defined as follows:
For females:

Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), intrauterine contraception/device, hormonal 
contraception, or any 2 barrier methods (a combination of male or female condom 
with spermicide; diaphragm, sponge, and cervical cap).

Abstinence can be considered an acceptable method of contraception at the discretion 
of the Investigator.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
and post-ovulation methods) and withdrawal are not considered acceptable methods 
of contraception.
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant, UNLESS they meet the following conditions:

Post-menopausal:  12 months of natural (spontaneous) amenorrhea or 6 weeks 
post-surgical bilateral oophorectomy.
OR

Post-hysterectomy.
For males:


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
Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms with spermicide.
15.5.4.
Reporting Pregnancy 
If a female subject becomes pregnant, BG00012 must be discontinued immediately.
The Investigator must report the pregnancy by faxing the appropriate form to Biogen or designee
within 24 hours of the study site staff becoming aware of the pregnancy.
The Investigator or study site staff must report the outcome of the pregnancy to Biogen or 
designee. 
Please note that congenital abnormalities/birth defects in the offspring of male or female subjects 
should be reported as SAEs when conception occurred during the BG00012 period.
At each routine visit, women of childbearing potential will be asked about their pregnancy status 
and possible pregnancies/spontaneous abortions since the last visit or contact. Spontaneous 
abortions are considered to be SAEs and must be reported as such.
If the partner of a male subject receiving BG00012 becomes pregnant at any time during the 
study, the Investigator should follow the pregnancy outcome and report any congenital anomaly 
or birth defects as an SAE to Biogen or designee. 
15.5.5.
Dose Unblinding for Medical Emergencies
While BG00012 assignment was blinded prior to open-label treatment, emergency decoding was
made available to the Investigator and designated personnel at Biogen or designee through IXRS.
During open-label treatment, all subjects will receive the same dose of BG00012, BG00012 
240 mg BID. While study staff are no longer blinded to dose assignment, they will remain 
blinded to the BG00012 dose subjects were receiving before the open-label treatment, as well as 
to the treatment arm of the subject in the parent study.  
15.5.6.
Regulatory Reporting
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered.
SUSARs will be reported to the appropriate authorities and central ethics committees by 
appropriate personnel in Biogen Drug Safety Risk Management (or designee).  A report will be 
sent to all Investigators.  The subject may remain in the study and continue to receive BG00012
at the Investigator’s discretion.
15.6.
Investigator Responsibilities
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, and severity of each event.


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
Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow-up on the outcome of the pregnancy.

Complete an SAE form for each SAE and fax it to Biogen 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 or designee within 24 hours of the study site staff 
becoming aware of new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Report SAEs to local ethics committees, as required by local law.
15.7.
Biogen Responsibilities
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor or designee 
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 (or designee) 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 STATEMENT AND ANALYTICAL PLAN
16.1.
Description of Objectives and Endpoints
16.1.1.
Primary Objective and Endpoint
The primary objective of the study is to evaluate the long-term safety profile of BG00012.
16.1.2.
Additional Objectives and Endpoints
Secondary objectives of this study are as follows:

To evaluate the long-term efficacy of BG00012 using clinical endpoints (including 
relapse and ARR) and disability progression (EDSS).

To evaluate further the long-term effects of BG00012 on MS brain lesions on MRI 
scans in subjects who had MRI scans as part of Studies 109MS301 and 109MS302
and in 109MS303 up through and including Amendment 6.  The following MRI 
endpoints will be evaluated in the subset of subjects who participated in the MRI 
scans:  number and volume of Gd-enhancing lesions, number of new or newly-
enlarging T2 lesions and volume of total T2 lesions, number of new T1 hypointense 
lesions and volume of T1 hypointense lesions, brain atrophy, and MTR.

To evaluate the long-term effects of BG00012 on health economics assessments and 
the visual function test.  The endpoints are the SF-36 and EQ-5D quality of life 
questionnaire, and the visual function test scores.
Exploratory objectives of this study are as follows:


 
 
 

16.2.
Demography and Baseline Disease Characteristics
Demographics and baseline data will be summarized for each treatment group by presenting 
summary statistics, or frequency distribution.  
16.3.
Efficacy Data
16.3.1.
Analysis Population
The efficacy population is defined as all subjects who received at least 1 dose of BG00012 in the 
study and have at least 1 post-baseline assessment of the efficacy parameter being analyzed.


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16.3.2.
Methods of Analysis
Annualized Relapse Rate
Relapse rate will be summarized for the extension phase as well as starting from the original 
baseline of the Phase 3 studies (109MS301 and 109MS302).  Relapse rate will be presented for 
each of the treatment groups separately (i.e., original 240 mg BID, original 240 mg TID, placebo
or GA later randomized to 240 mg BID, or placebo or GA later randomized to 240 mg TID).  
The following statistical comparisons may be made:

The 2-year ARR in the original Phase 3 studies and the ARR in the extension study in 
the placebo later randomized to 240 mg BID group, and in the placebo later 
randomized to 240 mg TID group.

The ARR in the extension study between the original 240 mg BID and the original 
240 mg TID group.

The ARR in the original Phase 3 studies and the extension study between the original 
240 mg BID and the original 240 mg TID group.

The ARR in the original Phase 3 studies and the extension study between the original 
240 mg BID and the placebo later randomized to 240 mg BID, and the original 
240 mg TID and the placebo later randomized to 240 mg TID.
A negative binomial regression model will be used for the analysis of ARR endpoints. 
In addition to the ARR endpoint, proportion of subjects relapsed will also be analyzed, using the 
Cox proportional hazards model. 
Disability Progression

Progression of disability is defined as 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.  Progression will be 
assessed relative to the baseline EDSS scores in the extension study, as well as from 
the baseline scores in the previous study.  The Cox proportional hazards model will 
be used to analyze disability progression.  
MRI Endpoints
MRI endpoints will be evaluated in the subset of subjects who participated in the MRI scans up 
to and including Amendment 6 of this protocol.

Number and volume of Gd-enhancing lesions

Number of new or newly-enlarging T2 lesions and volume of total T2 lesions

Number of new T1 hypointense lesions and volume of T1 hypointense lesions

Brain atrophy

MTR


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The number of new lesions (Gd-enhancing, T2 or T1 hypointense) will be summarized by 
treatment groups.  Comparison between the treatment groups will be made using multiple logit 
regression. 
The change in the volume of lesions will be compared between the treatment groups using an 
analysis of covariance (ANCOVA) model.
The actual value and change from baseline in brain atrophy will be compared between the 
treatment groups using ANCOVA.
MTR will be compared between treatment groups using ANCOVA.
Health Economics Endpoints: EQ-5D and SF-36
Actual scores and change from baseline in EQ-5D and SF-36 will be summarized for the 
treatment groups separately.  An ANCOVA model will be used to analyze the data.
Visual Function Test
Actual scores and change from baseline in the visual function test scores will be analyzed by an 
ANCOVA model.
16.4.
Safety Data
16.4.1.
Analysis Population
The safety population is defined as subjects who have received at least 1 dose of BG00012 in the 
extension study.
16.4.2.
Methods of Analysis
All AEs, laboratory abnormalities, and vital signs will be evaluated for safety.  Safety analysis 
will focus on the safety data in the extension study.  For subjects who were dosed with BG00012 
in the previous study, long-term safety data (extension study + 2 years in the previous Phase 3 
studies) may also be summarized.
Clinical Adverse Events
Only treatment-emergent AEs will be presented in the summary tables.  Treatment-emergent is 
defined as having onset date which is on or after start of study treatment, or that is worsened 
after the start of study treatment.
The incidence of treatment-emergent AEs will be summarized by treatment group, overall, by 
severity, and by relationship to study treatment.  The summary tables will include incidence 
estimates for overall system organ class as well as for preferred terms within each system organ 
class.
Laboratory Data
Laboratory data will be summarized using shift tables.  Shifts from baseline to high/low status 
for hematology and blood chemistry parameters, and shifts from baseline to high/positive status 
for urinalysis will be presented.  In addition, the shift from baseline to the maximum 
post-baseline value and the shift from baseline to the minimum post-baseline status will be 


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presented for each laboratory test by treatment group.  In addition, summary of laboratory values 
categorized based on Common Toxicity Criteria grade will also be made.  Summary statistics for 
actual values and change from baseline will also be presented, for quantitative laboratory data.  
Additionally, lymphocyte count over time post-treatment 
 will be 
descriptively summarized for subjects who develop decreases in lymphocyte count (<LLN).
Vital Sign 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 by treatment group.  The criteria for clinically 
relevant post-baseline abnormalities are shown in Table 4.  Summary statistics for actual values 
and change from baseline will also be presented.  
Table 4:
Criteria to Determine Clinically Relevant Abnormalities in Vital Signs
Vital Sign
Criteria for Abnormalities
Temperature
>38oC and an increase from pre-dosing of at least 1oC
Pulse
120 beats per minute or an increase from pre-dosing of more than 20 
beats per minute, or
<50 beats per minute or a decrease from pre-dosing of more than 
20 beats per minute
Systolic Blood Pressure
>180 mmHg or an increase from pre-dosing of more than 40 mmHg, 
or 
<90 mmHg or a decrease from pre-dosing of more than 30 mmHg
Diastolic Blood Pressure
>105 mmHg or an increase from pre-dosing of more than 30 mmHg, 
or
<50 mmHg or a decrease from pre-dosing of more than 20 mmHg
 
 
16.6.
Interim Analyses
Interim analyses maybe performed as needed.
16.7.
Sample Size Considerations
There is no formal sample size calculation.  The number of subjects eligible for this study is
determined by the number of subjects who participated in Studies 109MS301 and 109MS302.


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17.
ETHICAL REQUIREMENTS
Biogen, the contract research organizations (CROs), 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
The Investigator, Biogen, and the CROs must adhere to the principles set forth by the 
Declaration of Helsinki dated October 2013.
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 Europe.
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 Investigator(s) 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 any testing under this protocol, including screening tests and assessments, written 
informed consent with the approved ICF must be obtained from the subject 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.
A copy of the signed and dated ICF must be given to the subject.  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 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., PHI authorization in North 
America).
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partner(s) and designee(s), 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) 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 or designee.  This initiation visit will be conducted during a routine Phase 
3 monitoring visit and will include a 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 on-site audits.  The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested.
18.3.
Monitoring of the Study
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
source data and to the subjects’ medical histories.
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the study and 
after the study has completed, as appropriate.
During these visits, CRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.
The monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, BG00012 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 contract(s) 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
19.1.1.
Interactive Voice and Web Response System
For this study, an IXRS supplier will be used.  Before subjects are enrolled, the IXRS will 
provide each study site with appropriate training and a user manual.
19.1.2.
Contract Research Organizations
A CRO will be responsible for all administrative aspects of the study including, but not limited 
to, study initiation, monitoring and management of AE/SAE reporting.  Prior to enrollment of the 
first subject at each site, the CRO will review study responsibilities with the Investigators and 
other site personnel, as appropriate.  
 has been selected by 
Biogen as the Data Coordinating Center (DCC) for this study.  The DCC will be responsible for 
all aspects of data management.
19.1.3.
Central Laboratories for Laboratory Assessments
, Switzerland has been selected by Biogen to 
analyze all hematology, blood chemistry, urine cytology, and urinalysis samples collected for 
this study.
19.1.4.
Central Facility for Other Assessments
MRI Reading Centers
All of the MRI scans with and without Gd will be evaluated at the central MRI reading center.
Original MRI films and digital data on compact disc, DAT tape, or magnetic optical disk are to 
be sent by courier to the respective MRI Reading Center for review (the Clinical Monitor will 
provide specific MRI shipping instructions prior to the start of enrollment at each site).
Additional and more detailed MRI scans with and without Gd procedures and instructions are 
included in the study MRI manual (to be provided under separate cover prior to start of the 
substudy).
19.2.
Advisory Committee
An Advisory Committee will be formed to provide scientific and medical advice on key 
decisions for the study, including: 1) subsequent study protocol amendments; 2) conduct of the 
study, including subject retention and follow-up measures; and 3) review and interpretation of 
key data and implications for patient management.
The Advisory Committee will include the Medical Director, Clinical Trial Manager, and Project 
Statistician from Biogen (and/or their designees) and participating Investigators, as well as 
clinical experts who are not participating as Investigators in this study.  


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19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  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 similar modifications (see 
Sections 17.2 and 17.3).
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 one 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
Balasubramaniam P, Stevenson O, Berth-Jones J. Fumaric acid esters in severe psoriasis, 
including experience of use in combination with other systemic modalities. Br J Dermatol. 
2004;150(4):741-746.
Balcer LJ, Baier ML, Pelak VS, et al. New low-contrast vision charts: reliability and test 
characteristics in patients with multiple sclerosis. Mult Scler. 2000;6(3):163-71.
Cohen SR, Herndon RM, McKhann GM. Radioimmunoassay of myelin basic protein in spinal 
fluid. An index of active demyelination. N Engl J Med. 1976;295(26):1455-7.
Ffrench-Constant C. Pathogenesis of multiple sclerosis. Lancet. 1994;343(8892):271-5.
Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or 
glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-97. Erratum in: N Engl J 
Med. 2012 Oct 25;367(17):1673.
Hartung HP, Archelos JJ, Zielasek J, et al. Circulating adhesion molecules and inflammatory 
mediators in demyelination: a review. Neurology. 1995;45(6 Suppl 6):S22-S32.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983;33(11):1444-52. Epub 1983/11/01.
Prineas J. In: Cook S, editor. Handbook of multiple sclerosis. New York: Marcel Dekker, Inc.; 
1990. p 187.
Soderstrom M, Link H, Sun JB, et al. T cells recognizing multiple peptides of myelin basic 
protein are found in blood and enriched in cerebrospinal fluid in optic neuritis and multiple 
sclerosis. Scand J Immunol. 1993;37(3):355-68.
Traugott U, Lebon P. Multiple sclerosis: involvement of interferons in lesion pathogenesis. Ann 
Neurol. 1988;24(2):243-51.
Traugott U, Reinherz EL, Raine CS. Multiple sclerosis. Distribution of T cells, T cell subsets and 
Ia-positive macrophages in lesions of different ages. J Neuroimmunol. 1983;4(3):201-21.
Walsh MJ, Tourtellotte WW. Temporal invariance and clonal uniformity of brain and 
cerebrospinal IgG, IgA, and IgM in multiple sclerosis. J Exp Med. 1986;163(1):41-53.
Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a 
geographically based study. 2. Predictive value of the early clinical course. Brain. 1989;112 (Pt 
6):1419-28.


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Dose-Blind, Multicenter, Extension Study to Determine 
the Long-Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in 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.
225 Binney Street
Cambridge, MA 02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 109MS303 
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis 
Version 8
Date:  5 February 2018
EUDRA CT Number: 2008-004753-14
Version 8 of the protocol has been prepared for this amendment, which supersedes Version 7.


Protocol 109MS303, Version 8
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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 109MS303 is as follows:

To change the length of the study from 12 years to 8 years
New text is shown in bold type; deleted text is shown with a 
.
Section 7.1, Study Overview
Now reads:
It is intended that Eeligible subjects from Studies 109MS301 and 109MS302 will be followed 
for up t at least 12 8 years in this extension study, assuming BG00012 continues to have a 
positive benefit-risk ratio.  At enrollment into the study, all subjects received either:
Rationale:  
After careful analysis, and agreement with the European Medicines Agency (EMA), it is apparent 
that continuing the study beyond 8 years will not generate additional information about the safety 
and efficacy profile of BG00012 (dimethyl fumarate; DMF). Importantly, the safety and efficacy 
profile of BG00012 has demonstrated a positive benefit/risk profile throughout the duration of 
the trial thus far, up to 12.5 years follow-up, including the parent studies 109MS301 and 
109MS302. The data suggest that long-term exposure to DMF is not associated with any change 
in the known safety profile of DMF. 
 
 Subjects in Study 
109MS303 (ENDORSE) who discontinue treatment for any reason and have an ALC <LLN will 
continue to have follow-up post-treatment until lymphocyte counts return to LLN, or for at least 
48 weeks (whichever is sooner).
This change also affects Section 4.4 Study Activities for Subjects Who Already Completed Visit 
36; Section 4.5, Study Activities (Hematology and Lymphocyte Analysis:  Year 4 Through End 
of Treatment Visits); Section 4.6, Study Activities (Unscheduled and Post-Treatment Visits); 
Section 7.1, Study Overview; Section 7.2.2, Treatment Period; Section 7.2.3, Post-Treatment 
Period; Section 11.4, Removal of Subjects from Treatment and Withdrawal from Study; 
Section 14.3.4, Study Activities for Subjects Who Already Completed Visit 36; Section 14.3.5, 
End of Study Visit; Section 14.3.7, Premature Study Treatment Withdrawal Visit; Section 16.3.2, 
Methods of Analysis; and Section 16.4.2, Methods of Analysis.


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a
.
Section 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 7.2.3, Post-Treatment Period
Change:  A sentence was added to clarify the end of study for those subjects who already have 
completed Visit 36.
Now reads:
Subjects who complete the Week 384 576 visit (Visit 36 52), regardless of further need to 
monitor lymphocytes on study, will complete an End of Study Visit at Week 388 580 ± 7 days.  
For subjects who have already completed Visit 36, an End of Study Visit should be 
completed 4 weeks after their next visit (scheduled or unscheduled), regardless of further 
need to monitor lymphocytes on study. Subjects who permanently discontinue BG00012 prior 
to Week 384 576, regardless of further need to monitor lymphocytes on study, will complete a 
Premature Study Treatment Withdrawal Visit within 4 weeks after their last dose of BG00012.  
Subjects who complete BG00012 treatment or permanently discontinue BG00012 for any reason 
and who have a lymphocyte count <LLN should not be withdrawn from the study.  These 
subjects will be followed according to Section 11.3.
Rationale:  Some subjects have already completed Visit 36; thus, this statement explains how 
sites should address end of study for those subjects.
This change also affects Section 4.3, Study Activities (Years 4 Through 8 Treatment Visits); 
Section 4.4, Study Activities for Subjects Who Already Completed Visit 36); Section 4.6, Study 
Activities (Unscheduled and Post-Treatment Visits); Section 7.2.3, Post-treatment Period, 
Section 14.3.4, Study Activities for Subjects Who Already Completed Visit 36; Section 14.3.5, 
and End of Study Visit.


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

Updated the version number, date, and contact information as appropriate throughout 
the protocol.

Corrected any typographical errors and formatting issues.

In Section 1.1, added the name of the Biogen European Union Qualified Person for 
Pharmacovigilance to the applicable Signature Page.

Updated the name of the medical signatory.

Clarified Footnote 2 in Section 4.6 to state that a Premature Study Treatment 
Withdrawal Visit serves as the End of Study Visit.

In Section 16, stated that the analyses would be conducted on the entirety of the 
extension study as well as all time from start of original Phase 3 studies.

Updated the Biogen United States address.


CONFIDENTIAL 
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Biogen MA Inc. 
1 
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 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 109MS303 
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis  
Version 7 
Date:  07 November 2016 
EUDRA CT Number: 2008-004753-14 
Version 7 of the protocol has been prepared for this amendment, which supersedes Version 6. 


Protocol 109MS303, Version 7 
CONFIDENTIAL 
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Biogen MA Inc. 
2 
PRIMARY REASON FOR AMENDMENT 
The primary reasons for this amendment to Protocol 109MS303 are as follows: 
• To remove the discontinuation criteria of elevated serum creatinine (either >1.2 × 
baseline serum creatinine or >1.2 × upper limit of normal [ULN]), positive urinalysis, 
and low white blood cell (WBC) count. 
New text is shown in bold type; deleted text is shown with a 
. 
Section 11.2.1, Abnormal Laboratory Values:  Dosing Interruption and Management 
Change:  Removed withdrawal criteria of elevated serum creatinine, positive urinalysis, and low 
WBC count from Table 1. 
Table 1: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation 
of BG00012 
Laboratory Parameter 
Laboratory Result 
Required Action 
AST or ALT 
>3×ULN  
The Investigator should repeat the test as soon as 
possible.  If re-test value confirms AST or ALT 
>3×ULN, BG00012 must be withheld.  If the value 
remains >3×ULN for ≥4 weeks after discontinuation of 
BG00012, then the subject must permanently 
discontinue BG00012. 
Lymphocyte counts 
<500/mm3 
See Table 3. 
Serum creatinine 
>1.2 Baseline serum 
 
-test value confirms that creatinine 
>1.2 BSCr
remains >1.2 BSCr for ≥4 weeks after discontinuation 
of BG00012
must 
 
discontinue BG00012. 
 
 
-
must 
 
 


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Laboratory Parameter 
Laboratory Result 
Required Action 
 
 
-
must 
discontinue BG00012.  
 
WBC 
<2000/mm3 
-test value confirms that WBC 
<2000/mm3
remains <2000/mm3 for ≥4 weeks after discontinuation 
must 
 
discontinue BG00012. 
ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal; WBC = white blood cell. 
Rationale:  The removal of elevated serum creatinine from the withdrawal criteria was 
determined through analyses of all 1738 subjects, their laboratory values, renal adverse events, 
and medical interpretation of causation.  The review and analyses of subject data demonstrated 
that an increase in serum creatinine, whether above baseline serum creatinine or above the upper 
limit of normal, were not predictors of a clinical event.   
In addition, removal of elevated serum creatinine, positive urinalysis and low WBC from the 
withdrawal criteria was to align with the guidance provided in the Tecfidera investigator’s 
brochure and all reference safety information for BG00012 where there is no recommendation to 
discontinue treatment based on this criteria.  Elevated creatinine, positive urinalysis and low 
WBC (excluding ALC) were withdrawal criteria during the clinical development of BG00012, 
but no data (i.e., related safety signals) from the clinical studies or in the post-marketing setting 
provide evidence that these should remain as criteria for discontinuation of BG00012.  As of 
April 2015, approximately 5,100 subjects had been treated with BG00012 in completed and 
ongoing clinical studies (see Tecfidera IB, version 10).  As of June 2016, over 215,000 patients 
have been treated with Tecfidera (BG00012) worldwide (in clinical trials and post-marketing), 
representing 285,694 patient-years of exposure (see Fox 2016, ECTRIMS abstract). It should be 
noted that although low WBC is being removed from the withdrawal criteria within the protocol, 
the monitoring of ALC and withdrawal criteria remains.  Additionally, although the automatic 
withdrawal criteria was removed for elevated serum creatinine, low WBC (excluding low ALC) 
and positive urinalyses, the measurement of all safety parameters (short- and long-term) will 
continue and remains an integral part of the protocol to ensure patient safety.   
To date, there is no clinical evidence to suggest an increase incidence of adverse events requiring 
treatment withdrawal as a result of elevated serum creatinine, positive urinalysis, or low WBC. 


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This change also affects Section 11.4, Removal of Subjects from Treatment and Withdrawal 
from Study. 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a 
. 
Section 3, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
Multiple sections 
Change:  Removed requirement for magnetic resonance imaging (MRI) assessments after 
Version 6 of the protocol. 
16.1.2 Additional Objectives and Endpoints 
Secondary objectives of this study are as follows: 
• To evaluate the long-term efficacy of BG00012 using clinical endpoints (including 
relapse and ARR) and disability progression (EDSS). 
• To evaluate further the long-term effects of BG00012 on MS brain lesions on MRI 
scans in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 
and in 109MS303 up through and including Amendment 6.  The following MRI 
endpoints will be evaluated in the subset of subjects who participated in the MRI 
scans:  number and volume of Gd-enhancing lesions, number of new or newly-
enlarging T2 lesions and volume of total T2 lesions, number of new T1 hypointense 
lesions and volume of T1 hypointense lesions, brain atrophy, and MTR. 
Rationale:  MRI assessments are removed from Study 109MS303 because interpretation of the 
data has become limited.  The MRI assessments were performed in Study 109MS303 only in 
subjects who had MRI scans as part of Studies 109MS301 and 109MS302.  Because not all 
subjects in Studies 109MS301 and 109MS302 were part of the MRI assessment cohort, only a 
subpopulation of the 109MS303 had MRI assessments performed.  After a median of 
approximately 7 years on study (2 years in Study 109MS301 or 109MS302 and approximately 5 
years in Study 109MS303), the interpretation of MRI assessment data is considered limited 
because of the diminished number of subjects in the MRI cohort remaining on study.  
Additionally, long-term efficacy of BG00012 is well established by analyses of the data collected 
during these years.  
The wording “up through and including Amendment 6” was added to multiple relevant sections 
throughout the protocol.  The wording “Scheduled MRI scans were performed in protocol 
versions 1 through 6.” was added to multiple tables outlining study activities or schedule of 
assessments. 


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Additional sections affected include Section 14.1, Site Personnel, Section 16.1.2, Additional 
Objectives and Endpoints and Section 16.3.2, Methods of Analysis. 
Section 11.2.1, Abnormal Laboratory Values:  Dosing Interruption and Management 
Change:  Removed an invalid example and changed an incorrect cross-reference. 
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 (see Table 1Section 11.4).  
However, subjects who subsequently experience a different laboratory abnormality can have 
BG00012 withheld again, allowing 
  
 2 dosing interruptions are allowed for each subject.  Any subject 
who experiences abnormal laboratory results that require temporary withholding as defined in 
Table 1 on a third occasion must permanently discontinue dosing. 
Rationale:  The example and cross-reference were no longer valid with the removal of WBC 
count from the withdrawal/dose interruption criteria. 
Section 11.2.1, Abnormal Laboratory Values:  Dosing Interruption and Management 
Change:  Changed nonspecific text under “Required Action” in Table 2 to “followed as per 
standard of care.” 
Table 2: 
Laboratory Analyses That Require Additional Evaluation  
Laboratory Parameter 
Laboratory Result  
Required Action  
Urinalysis 
Urinary casts (other 
than hyaline casts) 
Repeat test 2 weeks later; if the abnormality persists on 
re-testing, the subject should be followed as per 
standard of care
. 
Urinalysis 
 
gGlycosuria (trace or 
greater) 
If occurring in the setting of normal serum glucose, 
repeat test 2 weeks later; if the abnormality persists on 
re-testing, the subject should followed as per 
standard of care
. 
Urinalysis  
pProteinuria  1+  
Subjects who demonstrate 1+ proteinuria on a urine 
 (and do not have a documented history of 
benign proteinuria) should be re-tested within 2 


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Laboratory Parameter 
Laboratory Result  
Required Action  
weeks of initial abnormal finding..
If the 
abnormality persists on re-testing, the subject should 
be followed as per standard of care.
for 
. 
Rationale:  Modified text to specify standard of care in the country in which the assessment is 
performed rather than recommendations that may not be accessible as next steps in the clinical 
care of a subject. 
 
 
 


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number, date, and contact information were updated as appropriate 
throughout the protocol. 
• Typographical errors and formatting were corrected. 
• In Section 1.1, updated the name of one of the Study Medical Directors. 
• Throughout the protocol, multiple cross-references to Section 11.4 were changed to 
Section 11.2 to reflect changes to discontinuation/withdrawal criteria of elevated 
serum creatinine, positive urinalysis, and low WBC count. 


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1 
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 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 109MS303
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis  
Version 6 
Date:  21 January 2016 
EUDRA CT Number: 2008-004753-14 
Version 6 of the protocol has been prepared for this amendment, which supersedes Version 5. 


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PRIMARY REASON FOR AMENDMENT 
The primary reasons for this amendment to Protocol 109MS303 include the following: 
 To extend the study duration by an additional 4 years to collect data on long-term 
efficacy and safety of BG00012. 
 To increase the minimal duration of follow-up for lymphopenic subjects upon 
discontinuation of treatment with BG00012, per Committee for Medicinal Products 
for Human Use (CHMP) recommendations. 
 
New text is shown in bold type; deleted text is shown with a 
. 
 
Section 7.1, Study Overview 
Now reads: 
[...] 
Eligible subjects from Studies 109MS301 and 109MS302 will be followed for up to 812 years in 
this extension study, assuming BG00012 continues to have a positive benefit-risk ratio. 
[...] 
Rationale:  The purpose of the 4-year extension is to collect data on the long-term efficacy and 
safety of BG00012.  The purpose of the longer minimum time of follow-up is to fulfill CHMP 
recommendation.  Study 109MS303 is an important source of data 
 
 
, as it is the only large clinical study with ~1000 ongoing patients having 
more than 4 years of follow-up (up to 6 years for patients continuously treated with BG00012) up 
to 2015.  Extending the study for 4 more years (14-year data on continuously treated patients and 
12-year data on patients who switched from placebo) provides an important point of 
differentiation for BG00012. 
This change also affects Section 3, Synopsis; Section 4.4, Study Activities (Years 9 Through 12 
Treatment Visits); Section 4.5, Study Activities (Hematology and Lymphocyte Analysis: Years 4 
Through 12 Treatment Visits); Section 4.6, Study Activities (Unscheduled and Post-Treatment 
Visits); include Section 7.2.2, Treatment Period; Section 14.3.4, Years 9 through 12 Treatment 
Visits; Section 14.3.5, End of Study Visit (Week 580 ± 7 Days); Section 16.3.2, Methods of 
Analysis; and Section 16.4.2, Methods of Analysis. 


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Section 11.3, Monitoring and Management for Subjects with Abnormal Lymphocyte Count 
Now reads: 
Section 11.3  Treatment Schedule Monitoring and Management for Subjects with Abnormal 
Lymphocyte Count 
11.3.1 
3LLN 
must 
meets the threshold limit defined in Table 2  Subjects who have a lymphocyte count <500/mm3 
at any time should be monitored and managed according to Table 3. 
All subjects who complete BG00012 treatment or permanently discontinue BG00012 for 
any reason other than those specified in Table 3 and who have a lymphocyte count <LLN, 
will be monitored every 12 weeks until their lymphocyte count is ≥LLN OR for 48 weeks 
after their last dose, whichever is earlier. 
Table 2: 
 
 
 
 
 
 
 
<500/mm3 
The Inves
-
<500/mm3
is <500/mm3 
 
-
Section 4.5
3 for 24 weeks aft
 
described in Table 2
count is <500/mm3 
must 
ects who discontinue 
3 should continue tests and assessments 
 4 
 
See 
 1 
3. 
 
3 


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11.3.2 
3 
3 
the schedule defined in Section 4 
  
 11.3.3.  
Table 3: 
Lymphocyte Monitoring and Management for Subjects Who Have a 
Lymphocyte Count <500/mm3 
For subjects who have a lymphocyte count <500/mm3, the Investigator should repeat the test as soon 
as possible.  If re-test confirms that the lymphocyte count remains <500/mm3, lymphocyte counts 
should be monitored every 4 weeks while on BG00012. 
 
 
If subject has lymphocyte counts <500/mm3 for ≥24 weeks, subject meets the Temporary 
Withholding Rule and BG00012 will be temporarily withheld.  If the Temporary Withholding Rule 
is not met, the subject will be monitored every 12 weeks. 


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Lymphocyte Monitoring for Subjects Meeting 
the Temporary Withholding Rule 
Patient Management for Subjects Meeting the 
Temporary Withholding Rule 
The subject will be monitored every 4 weeks for 
24 weeks, then every 12 weeks until the 
lymphocyte count is ≥LLN OR for 96 weeks 
after their last dose, whichever is earlier.  
However, if a subject reaches the end of study 
and their lymphocyte count remains <LLN, the 
subject will be monitored every 12 weeks until 
the lymphocyte count is ≥LLN OR for 48 weeks 
after their last dose, whichever is earlier. 
• 
If lymphocyte count remains <500/mm3 
for 24 weeks after temporary withdrawal, 
BG00012 must be permanently discontinued.  
• 
If lymphocyte count is between ≥500/mm3 
and ≤800/mm3, then BG00012 will continue to 
be temporarily withheld.  
• 
If lymphocyte count recovers to 
>800/mm3 (confirmed by 2 tests, at least 4 
weeks apart), the physician/patient has the 
option to restart BG00012.  If, upon 
resumption of BG00012, the lymphocyte 
count is <500/mm3 on 1 occasion (confirmed 
by repeat testing), then BG00012 must be 
permanently discontinued. 
• 
Alternative disease-modifying treatmenta 
may be considered, at the discretion of the 
treating physician as per standard of care.  
Subjects treated with alternative disease-
modifying treatment will not have the option 
to restart BG00012. 
AE = adverse event; CRF = case report form; LLN = lower limit of normal. 
a The use of concomitant therapies as defined above must be recorded on the subject’s CRF, according to 
instructions for CRF completion.  AEs related to administration of these therapies or procedures must be 
documented on the appropriate CRF. 
 
Optional hematology consult and/or bone marrow biopsy may be considered for subjects 
meeting the Temporary Withholding Rule and whose lymphocyte counts remain <LLN for 
≥48 weeks after discontinuation of BG00012, at the discretion of the Investigator.  Earlier 
hematology consult and/or bone marrow biopsy may be considered in consultation with the 
Medical Monitor. 
Section 11.3.3 
Discontinue 
 
 
11.2
 count <LLN will be followed every 
4 
 


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defined in Section 4 until the 
 
See 
 
 
 
<LLN 
 
 
Rationale:  As a safety measure, management of lymphocyte count is revised to ensure subjects 
with lymphopenia are followed-up for longer than 6 months after drug discontinuation, as 
preliminary evidence suggests full recovery of lymphocyte count to >LLN may take longer than 
6 months following treatment cessation.  Optional hematology consult and/or bone marrow 
biopsy will provide additional safety measures to facilitate patient management.   
This change also affects Section 4.5, Study Activities (Hematology and Lymphocyte Analysis: 
Years 4 Through 12 Treatment Visits); Section 4.6, Study Activities (Unscheduled and 
Post-Treatment Visits); Section 7.1, Study Overview; Section 7.2.3, Post-Treatment Period; 


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Section 11.2, Modification of Treatment Schedule; Section 11.2.1, Abnormal Laboratory Values: 
Dosing Interruption and Management; Section 11.2.2, Resumption of BG00012 Dosing; and 
Section 11.4, Removal of Subjects from Treatment and Withdrawal from Study. 
 
 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a 
. 
Section 3, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
 
Section 6.2, Additional Objectives 
Change:  The secondary objective was revised to be relevant to magnetic resonance imaging 
scans. 
Now reads: 
To evaluate further the long-term effects of BG00012 on MS brain lesions on MRI scans in 
subjects who had MRI scans as part of Studies 109MS301 and 109MS302.  The following MRI 
endpoints will be evaluated in the subset of subjects who participated in the MRI scans:  number 
and volume of Gd-enhancing lesions, number and volume of new or newly-enlarging T2 lesions 
and volume of total T2 lesions, number of new T1 hypointense lesions and volume of T1 
 lesions, brain atrophy, and magnetization transfer ratio (MTR). 
Rationale:  The revision was made to enable measurement of the accumulated burden of the 
disease rather than interval activity. 
This change also affects Section 16.1.2, Additional Objectives and Endpoints and Section 16.3.2, 
Methods of Analysis. 
 
Section 7.2.2, Treatment Period 
Change:  The name of the study visit was updated.  
Now reads: 
Subjects will report to the study site every 4 weeks for the first 24 weeks (Visit 1 through Visit 6) 
and every 12 weeks thereafter for up to 12 years. 
Premature Study Treatment Withdrawal Visits and Unscheduled Relapse Assessment Visits will 
be performed as necessary.  
treatment 
dose.  All efforts should be made to keep the subjects’ visit schedule relative to their Baseline 


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Visit (Day 1).  Unscheduled Relapse Assessment Visits should not modify or replace their 
regular visit schedule. 
Rationale:  The name of the visit was updated to clarify that it is referring to the visit that occurs 
after premature withdrawal of study treatment and not after early withdrawal from the study.  
This change also affects Section 4.6, Study Activities (Unscheduled and Post-Treatment Visits); 
Section 7.2.3, Post-Treatment Period; Section 10.1, BG00012 Packaging; Section 11.4, Removal 
of Subjects from Treatment and Withdrawal from Study; Section 14.1, Site Personnel; Section 
14.3.7, Premature Study Treatment Withdrawal Visit. 
 
Section 9.3, Blinding Procedures 
Change:  Added a phrase to specify blinding status during the extension study. 
Now reads: 
All subjects continuing in this study are to receive open-label BG00012 240 mg BID.  
Consequently, subjects and study staff are no longer blinded to dose assignment but will remain 
blinded to the BG00012 dose that subjects were receiving before the open-label treatment, as 
well as to the treatment arm of the subject in the parent study. 
Rationale:  This change will provide clarification regarding blinding during the study. 
This change also affects Section 15.5.5, Dose Unblinding for Medical Emergencies. 
 
Section 11.2, Modification of Treatment Schedule 
Change:  Changed the heading of Section 11.2.1 for clarification.  In Table 1, rows were 
reordered to be alphabetical, a row was added for lymphocyte count, clarification was provided 
to indicate that creatinine was to be measured using serum, urine cytology was changed to 
urinalysis (to detect hematuria and proteinuria), and language pertaining to monitoring and 
management was updated.  Section 11.2.4, Abnormal Urinalyses that Require Additional 
Evaluation, was removed; the contents of this section were captured in a new table, Table 2, 
which was added to Section 11.2.1.  Section 11.2.3, Subsequent Development of Additional 
Laboratory Abnormalities, was removed and captured in the new text added to Section 11.2.2.  
Dosage Reduction was moved up as Section 11.2.2, prior to Resumption of BG00012 Dosing 
(now Section 11.2.3). 


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Now reads: 
11.2.1 Abnormal Laboratory Values: Dosing Interruption and Management 
BG00012
 must be temporarily withheld when any of the following laboratory 
values meet the threshold limitscriteria defined in Table 1 
 11.4 .  
Subjects are required to have additional evaluation when any of the following laboratory 
values meet the threshold limits defined in Table 2. 
Table 1: 
Laboratory Criteria Requiring Withholding or Permanent Discontinuation of 
BG00012
 
Laboratory Parameter 
Laboratory Result 
Required Action 
AST or ALT 
>3ULN  
The Investigator should repeat the test as soon as 
possible.  If re-test value confirms AST or ALT 
>3ULN, the 
 BG00012 must be 
withheld.  If the value remains >3ULN for 4 weeks 
after discontinuation of 
 BG00012, then 
the subject must permanently discontinue 
treatment BG00012. 
Lymphocyte counts 
<500/mm3 
See Table 3. 
Serum Ccreatinine 
>1.2  ULN 
Baseline serum 
creatinine (BSCr) 
The Investigator should repeat the test as soon as 
possible.  If re-test value confirms that creatinine 
>1.2  ULN BSCr, 
 BG00012 must be 
withheld.  If the value remains >1.2  ULN BSCr for 
4 weeks after discontinuation of 
 
BG00012, then the subject must permanently 
discontinue 
 BG00012. 
 
Positive 
has he
 consecutive 
 
Urinalysis  
Dipstick 
proteinuria (≥2+)  
The Investigator should repeat the test as soon as 
possible.  If re-test confirms proteinuria ≥2+ 
without known etiology, BG00012 must be 
withheld.  If proteinuria ≥2+ persists for ≥4 weeks 
after discontinuation, then the subject must 
permanently discontinue BG00012.  Subjects should 
be referred to a nephrologist for further 
investigation.  


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Laboratory Parameter 
Laboratory Result 
Required Action 
Urinalysis  
Positive dipstick 
hematuria (≥1+) on 
microscopy  
The Investigator should repeat the test as soon as 
possible.  If re-test confirms microscopic hematuria 
≥1+ without known etiology, BG00012 must be 
withheld and urine cytology must be performed.  If 
hematuria persists for ≥4 weeks after 
discontinuation or if cytology is positive, then the 
subject must permanently discontinue BG00012.  
Subjects should be referred to a nephrologist for 
further investigation.  
WBC 
<2000/mm3 
The Investigator should repeat the test as soon as 
possible.  If re-test value confirms that WBC 
2000/mm3, BG00012must be withheld.  If the 
value remains <2000/mm3 for 4 weeks after 
discontinuation of study treatment BG00012, then 
the subject must permanently discontinue study 
treatment BG00012. 
ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal; WBC = white blood cell. 
 
While dosing is withheld, subjects will continue tests and assessments according to the schedule 
defined in the protocol (Section 4), and may also undergo additional assessments to evaluate the 
laboratory abnormality as per the Investigator’s standard practice.  In 
Subjects who have the 
abnormal laboratory results other than described in Table 1 must repeat the tests rechecked at 
within 2 weeks ( checks repeat tests will be run at the central laboratory).  
Abnormal laboratory results confirmed on repeat tests should be managed per the 
investigator’s standard practice 
.  
-
. 
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 (see 
Section 11.4).  However, subjects who subsequently experience a different laboratory 
abnormality can have BG00012 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 white blood cells (WBCs), the 
subject may have BG00012 withheld again.  However, only 2 dosing interruptions are 
allowed for each subject.  Any subject who experiences abnormal laboratory results that 
require temporary withholding as defined in Table 1 on a third occasion must permanently 
discontinue dosing. 


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Subjects who complete BG00012
hhold, or permanently discontinue BG00012 
for any reason and who have a lymphocyte count <LLN will be followed 
 until the 
for 
according to Section 11.3.3 . 
Table 2: 
Laboratory Analyses That Require Additional Evaluation  
Laboratory Parameter 
Laboratory Result  
Required Action  
Urinalysis 
Urinary casts 
(other than hyaline 
casts) 
Repeat test 2 weeks later; if the abnormality 
persists on retesting, the subject should be fully 
investigated for possible causes and referred for 
evaluation by a nephrologist, if appropriate in the 
opinion of the Investigator. 
Urinalysis 
Dipstick glycosuria 
(trace or greater) 
If occurring in the setting of normal serum glucose, 
repeat test 2 weeks later; if the abnormality persists 
on retesting, the subject should be fully investigated 
for possible causes and referred for evaluation by a 
nephrologist, if appropriate in the opinion of the 
Investigator. 
Urinalysis  
Dipstick 
proteinuria 1+  
Subjects who demonstrate 1+ proteinuria on a 
urine dipstick (and do not have a documented 
history of benign proteinuria) should have a spot 
protein/creatinine ratio (on morning void). If spot 
protein/creatinine ratio is >0.3 mg/mg, the subject 
should be fully investigated for possible causes and 
referred for evaluation by a nephrologist, if 
appropriate in the opinion of the Investigator. 
 
11.2.2 Dosage Reductions 
Dosage reduction will be allowed only for subjects who are unable to tolerate BG00012 due 
to flushing and/or GI disturbances (dosage reductions will not be allowed for abnormal 
laboratory values; for management of abnormal laboratory values, refer to Section 11.2.1). 
Subjects who do not tolerate BG00012 will reduce their dosage by taking one 120 mg 
capsule BID for 4 weeks.  After 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, the subject must discontinue BG00012 and be withdrawn from the study as 
described in Section 11.4. 
11.2.3 Resumption of 
 BG00012 Dosing 
with the Medical Monito 


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must per
 
 
Subjects who have temporarily 
 withheld BG00012 due to decreases in 
 lymphopenia may resume 
 BG00012 
when 
 according to Section 11.3 . 
Subjects who are allowed to resume BG00012 dosing following a 2- to 4-week interruption due 
to flushing and/or GI disturbances 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 
 
 BG00012
1 
Section 11.4
 BG00012
 BG00012
criteri
 defined in Table 1 on a third occasion must 
 
 count <LLN will be followed every 
 
[see Section 
. 
11.2.4 
 
 
 
 
 
 
 
 
 


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Rationale:  These changes provide a more concise and specific set of guidelines for the 
monitoring and management of subjects who develop laboratory abnormalities that require 
dosing interruption.   
This change also affects Section 4.1, Study Activities 109MS303 (Year 1 Visits); Section 4.2, 
Study Activities 109MS303 (Years 2 and 3 Treatment Visits); Section 4.3, Study Activities 
(Years 4 Through 8 Treatment Visits); Section 4.4, Study Activities (Years 9 Through 12 
Treatment Visits); Section 4.6, Study Activities (Unscheduled and Post-Treatment Visits); 
Section 11.4, Removal of Subjects from Treatment and Withdrawal from Study; Section 
14.3.1.1, Baseline Visit (Day 1); Section 14.3.1.2, Visit 1 (Week 4 ±5 Days); Section 14.3.1.3, 
Visit 2 (Week 8 ±5 Days); Section 14.3.1.4, Visit 3 (Week 12 ±5 Days); Section 14.3.1.5, Visit 4 
(Week 16 ±5 Days); Section 14.3.1.6, Visit 5 (Week 20 ±5 Days); Section 14.3.1.7, Visit 6 
(Week 24 ±5 Days); Section 14.3.1.8, Visit 7 (Week 36 ±7 Days); Section 14.3.1.9, Visit 8 
(Week 48 ±7 Days); Section 14.3.2.1, Visits 9, 10, 11, 13, 14, and 15 (Weeks 60, 72, 84, 108, 
120, and 132 ±7 Days); Section 14.3.2.2, Visits 12 and 16 (Weeks 96 and 144 ±7 Days); Section 
14.3.3.2, Visits 18, 22, 26, 30, and 34 (Weeks 168, 216, 264, 312, and 360 ±7 Days); Section 
14.3.3.3, Visits 20, 24, 28, 32, and 36 (Weeks 192, 240, 288, 336, and 384 ±7 Days); Section 
14.3.4.2, Visits 38, 42, 46, and 50 (Weeks 408, 456, 504, and 552 ±7 Days); Section 14.3.4.3, 
Visits 40, 44, 48, and 52 (Weeks 432, 480, 528, and 576 ±7 Days); Section 14.3.5, End of Study 
Visit (Week 580 ± 7 Days); Section 14.3.6, Unscheduled Relapse Assessment Visit; and Section 
14.3.7, Premature Study Withdrawal Visit.   
 
Section 11.6, Concomitant Therapy and Procedures 
Change:  Specified the condition in which certain concomitant treatments would be allowed. 
Now reads: 
[...] 
Concomitant treatment with any of the following is not allowed unless otherwise described in 
this protocol: 
 Any alternative drug treatments directed toward the treatment of MS, such as chronic 
immunosuppressant therapy or other immunomodulatory treatments (including, but 
not limited to, IFN-beta, IFN-alpha, GA, natalizumab, fingolimod, teriflunomide, 
cyclophosphamide, methotrexate, azathioprine, 4-aminopyridine or related products, 
etc.), with the exception of acute management of protocol-defined relapse (as 
described below) and subjects with prolonged lymphopenia (as described in 
Section 11.3).  
 Any investigational product, including investigational symptomatic therapies for MS 
and investigational therapies for non-MS indications. 


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 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 below.  Steroids that are administered by 
non-systemic routes (e.g., topical, inhaled) or systemic steroid therapy for limited, 
short-term treatment of general medical conditions are allowed. 
[...] 
Rationale:  This change is to reflect 
 
 that study subject experiencing prolonged and severe lymphopenia in the 
absence of BG00012 treatment has a risk for relapse. 
This change also affects Section 11.2.2, Resumption of BG00012 Dosing and Section 11.3, 
Treatment Schedule for Subjects with Abnormal Lymphocyte Count. 
 
Section 11.6.1, Treatment of Relapses on Scheduled or Unscheduled Visits 
Change:  Added corticosteroid as allowed treatment for relapses 
Now reads: 
The 
 protocol-approved treatment for relapse in this study is either 3 
 to 5 days with 
IVMP at doses of up to 1000 mg/day or a full dose regimen of oral corticosteroids for up to 
14 days.  Oral corticosteroid taper regimens are not permitted.  IVMP or oral 
corticosteroids can be given once a day or in divided doses.  Subjects may also refuse relapse 
treatment.  
 BG00012 dosing is to continue uninterrupted during IVMP steroid 
treatment.  New or recurrent neurologic symptoms that occur less than 30 days after the 
onset of a protocol-defined relapse should be considered part of the same relapse and 
should not be treated with IVMPsteroid within the protocol.  Steroid retreatment of the 
same relapse is not allowed unless approved by the Medical Monitor. 
Rationale:  Oral corticosteroids were added to provide the Neurologist with the option of 
treating relapses with oral corticosteroids and not just intravenous methylprednisolone.   
This change also affects Section 7.3, Relapses. 
 


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Section 14.3.8, Telephone Follow-Up (12 Weeks After Last Study Visit) 
Change:  Removed the section and text pertaining to telephone follow-up 
Now reads: 
14.3.8. 
-
 
-
withdrawal. 
Treating Nurse 
• 
-
 
Rationale:  Telephone follow-up is no longer necessary, given the longer follow-up planned for 
lymphocytes.  
This change also affects Section 4.6, Study Activities (Unscheduled and Post-Treatment Visits); 
Section 10.1, BG00012 Packaging; Section 11.4, Removal of Subjects from Treatment and 
Withdrawal from Study; and Section 15.2.1, Adverse Events. 
Section 19.1.4, Central Facility for Other Assessments 
Change:  Removed text pertaining to the parent studies. 
Now reads: 
MRI Reading Centers 
All of the MRI scans with and without Gd will be evaluated at the central MRI reading center 
used for the s
. 
Original MRI films and digital data on compact disc, DAT tape, or magnetic optical disk are to 
be sent by courier to the respective MRI Reading Center for review (the Clinical Monitor will 
provide specific MRI shipping instructions prior to the start of enrollment at each site) 
. 
Rationale:  Due to the extended duration of the study, the update was made to allow flexibility 
in central MRI reading center.   
 


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Section 19.2, Advisory Committee 
Change:  Revised the information on the advisory committee and deleted all references to Data 
Safety Monitoring Committee. 
Now reads: 
19.2. 
 Advisory Committee  
19.2.1 Advi
 
An Advisory Committee will be formed to provide scientific and medical advice on key 
decisions direction for the study 
, 
including: 1) subsequent study protocol amendments; 2) conduct of the study, including 
subject retention and follow-up measures; and 3) review and interpretation of key data and 
implications for patient management. 
 
The Advisory Committee will include the Medical Director, Clinical Trial Manager, and Project 
Statistician from Biogen (and/or their designees) and participating Investigators, as well as 
clinical experts who are not participating as Investigators in this study.  
and this individual will also 
 
19.2.2 
 
 
 
ished between 
 
Rationale:  This change is to seek and integrate expert advice as part of decision-making during 
the conduct of this trial. 


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
 The version number, date, Biogen logo, company name and address, and contact 
information were updated as appropriate throughout the protocol. 
 Typographical errors and formatting were corrected. 
 All signature pages were deleted in keeping with the current Biogen approval process; 
the Signature page will be added separately. 
 Replaced the words “study treatment” with “BG00012” throughout the protocol and 
synopsis for clarity. 
 Replaced the words “study treatment dose visit” with “study visit” throughout the 
protocol. 
 Changed the number of global study locations in Section 3, Synopsis to more closely 
reflect the total number of sites that participated in the study across time. 
Study Location: 
Global; approximately 375 300 sites  
 Added the names of study medical directors to Section 1.1. 
 There were minor text revisions in Section 5.4, Dose Rationale. 
The initial BG00012 dosage for the extension study (240 mg BID or 240 mg TID) 
was the same as that used in the Phase 3 Studies 109MS301 and 109MS302.  
Subsequent to the initiation of this study, BG00012 was approved in several countries 
for the treatment of MS at a dose of 240 mg BID.  For this reason, all subjects 
continuing in this extension study will receive are receiving the currently marketed 
dose of 240 mg BID.  Subjects 
 randomized to BG00012 240 mg 
TID will be were switched to BID dosing at their next scheduled visit following 
BG00012 approval. 
This change also affects Section 7.1, Study Overview and Section 11.1, Treatment 
Schedule. 
 Changed the timepoint mentioned in Section 6.2, Additional Objectives from 
“months” to “weeks”. 
 
 
 


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This change also affects Section 16.1.2, Additional Objectives and Endpoints. 
 Added a sentence to Section 7.1, Study Overview referring to Section 11.3 for 
lymphocyte monitoring and management. 
Subjects who complete BG00012 treatment or permanently discontinue 
BG00012 for any reason and who have a lymphocyte count <LLN should not be 
withdrawn from the study.  These subjects will be followed according to 
Section 11.3. 
This change also affects Section 7.2.3, Post-Treatment Period; Section 11.1, 
Treatment Schedule; and Section 11.4, Removal of Subjects from Treatment and 
Withdrawal from Study. 
 Added the word “serum” prior to the word creatinine in Section 11.4, Removal of 
Subjects from Treatment and Withdrawal from Study for clarity. 
The subject develops >1.2ULN elevation in serum creatinine that is sustained for 
4 consecutive weeks after 
 BG00012 has been withheld.  


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Biogen Idec Inc. 
14 Cambridge Center 
Cambridge, MA  02142, USA 
Biogen Idec Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Idec Protocol 109MS303
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis  
Version 5 
Date:  16 November 2014 
EUDRA CT Number: 2008-004753-14 
Version 5 of the protocol has been prepared for this amendment, which supersedes Version 4. 


Protocol 109MS303, Version 5 
 
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PRIMARY REASON FOR AMENDMENT 
Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of severe, 
prolonged lymphopenia following BG00012 administration.  Severe, prolonged lymphopenia is a 
known risk factor for PML. In the controlled and uncontrolled BG00012 clinical studies, 2% of 
subjects experienced lymphocyte counts <0.5 x 109/L for at least six months. In these subjects, 
the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy.  The study 
protocol is being amended to enable the early identification of subjects who are at risk for 
developing severe, prolonged lymphopenia, and to provide additional guidance on the 
management of such subjects. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 11.3, Treatment Schedule for Subjects with Abnormal Lymphocyte Count 
Now reads: 
 
11.3.1 Schedule of Subjects with Lymphocyte Count <500/mm3 
 
Table 2: Lymphocyte Count Requiring Withholding of Study Treatment 
Laboratory Parameter 
Laboratory Result 
Required Action 
Lymphocyte count 
 
 
<500/mm3 
The Investigator should repeat the test as soon 
as possible.  If re-test 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 temporarily 
withheld.  
While dosing is withheld, subjects will be followed every 4 weeks until the lymphocyte 
count is ≥LLN or for 24 weeks after the last dose (whichever is sooner) [see Lymphocyte 
Follow-up in Section 4.5].  If lymphocyte count remains <500/mm3 for 24 weeks after the 
last dose, then study treatment must be permanently discontinued.   
Subjects who temporarily withhold  study treatment due to decreases in lymphocyte count 
as described in Table 2, may resume study treatment when lymphocyte counts recover 
(defined as a lymphocyte count ≥LLN on two consecutive occasions at least 4 weeks apart). 
 If the lymphocyte count is <500/mm3 on one occasion (confirmed by repeat testing) on 
resumption of study treatment, then study treatment must be permanently discontinued. 
Subjects who discontinue study treatment due to lymphocyte count <500/mm3 should 
continue tests and assessments according to the schedule defined in Section 4 until the 
lymphocyte count recovers or until the End of Study Visit (whichever is sooner). 
See Figure1 for the treatment schedule of subjects with lymphocyte counts <500/mm3. 


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Figure 1: Schedule for Subjects with Lymphocyte Count <500/mm3 
11.3.2 Schedule for Subjects with Lymphocyte Count <LLN to >500/mm3 
Subjects with lymphocyte count <LLN to ≥500/mm3 will have tests and assessments 
according to the schedule defined in Section 4 (blood draw for hematology and lymphocyte 
analysis every 12 weeks).  If these subjects complete, temporarily withhold, or permanently 
discontinue study treatment for any reason, they will be followed as described in Section 
11.3.3. 
11.3.3 Schedule for Subjects Who Complete, Temporarily Withhold or Permanently 
Discontinue Study Treatment For Any Reason And Also Have Lymphocyte Count <LLN 
Subjects who complete, temporarily withhold, or permanently discontinue BG00012 for 
any other reason (see Section 11.2) 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).  Subjects who permanently discontinue study treatment and 


Protocol 109MS303, Version 5 
 
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have lymphocyte count <LLN should continue tests and assessments according to the 
schedule defined in Section 4 until the lymphocyte count recovers or until the End of Study 
Visit (whichever is sooner). 
See Figure 2 for a schedule of subjects who complete, temporarily withhold or permanently 
discontinue BG00012 for any other reason and who have a lymphocyte count <LLN. 
 
 
Figure 2: Schedule for Subjects Who Complete, Temporarily Withhold or Permanently 
Discontinue Study Treatment Due to Any Reason and Have Lymphocyte Count <LLN 
Rationale:  Severe, prolonged lymphopenia is a known risk factor for PML. The rationale for 
this change is to enable the early identification of subjects who are at risk for developing severe, 
prolonged lymphopenia, and to provide additional guidance on when study treatment should be 
temporarily withheld in these subjects. 
 
This change also affects Section 7.2.3, Post-Treatment Period; Section 11.2.1, Dosing 
Interruption for Abnormal Laboratory Values; Section 11.2.2, Resumption of Study Treatment 


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Dosing; Section 11.2.3, Subsequent Development of Additional Laboratory Abnormalities; and 
Section 11.4 Removal of Subjects from Treatment and Withdrawal from Study. 
 
 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 3, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol.






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Section 4.4, Study Activities (Hematology 
 Analysis, Years 4 Through 8 Treatment Visits) 
Change:  A table has been added. 
Now reads: 
Tests and Assessments 
Subjects with lymphocyte count 
≥LLN 
Subjects with lymphocyte count 
<LLN to ≥500/mm3   
Subjects with lymphocyte count 
<500/mm3  
Hematology 
Every 24 weeks 
Every 12 weeks 
Every 4 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale:  The table has been added to provide guidance on the frequency of collection of blood samples for hematology and 
additional exploratory analyses.  
 


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Section 6.2, Additional Objectives 
Change:  Three exploratory objectives have been added.Now reads: 
Secondary objectives of this study are as follows: 
 To evaluate the long-term efficacy of BG00012 using clinical endpoints (including 
relapse and ARR) and disability progression (EDSS). 
 To evaluate further the long-term effects of BG00012 on MS brain lesions on MRI 
scans in subjects who had MRI scans as part of Studies 109MS301 and 109MS302.  
The following MRI endpoints will be evaluated in the subset of subjects who 
participated in the MRI scans:  number and volume of Gd-enhancing lesions, number 
and volume of new or newly-enlarging T2 lesions, number and volume of T1 
hypointense lesions, brain atrophy, and magnetization transfer ratio (MTR). 
 To evaluate the long-term effects of BG00012 on health economics assessments and 
the visual function test.  The endpoints are the Short-form 36 Health Survey (SF-36®) 
and Euroqol EQ-5D Healthy Survey (EQ-5D) quality of life questionnaire, and the 
visual function test scores. 
Exploratory objectives of this study are as follows: 
 
 
 
 
 
 
 
 
 
Rationale:   
 
 
 
 
 
This change also affects Section 12.3, 
; Section 16.1.2, 
Additional Objectives and Endpoints; Section 16.4.2, Methods of Analysis; and Section 16.5, 
. 
 
 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 


Protocol 109MS303, Version 5 
 
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The following minor changes were made to the protocol: 
 The version number and date were updated throughout the protocol. 
 Signatory information was revised for alignment with current practice. 
 The List of Abbreviations was updated. 
 
 


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Biogen Idec MA Inc. 
1 
Biogen Idec Inc. 
14 Cambridge Center 
Cambridge, MA  02142, USA 
Biogen Idec Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire
SL6 4AY 
United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Idec Protocol 109MS303 
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis  
Version 4 
Date:  02 September 2014 
EUDRA CT Number: 2008-004753-14 
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3. 


Protocol 109MS303, Version 4 
 
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Biogen Idec MA Inc. 
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PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 109MS303 is to update the safety reporting 
information. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 15.2.4, Immediate Reporting of Serious Adverse Events 
Now reads: 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen Idec 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 from the time that the subject has signed the ICF until the final study 
visit must be reported to Biogen Idec or designee 
 within 24 hours of the 
study site staff becoming aware of the event. 
 
A report must be submitted to Biogen Idec or designee 
 regardless of the 
following: 
 
• Whether or not the subject has undergone study-related procedures 
• Whether or not 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, fax a completed SAE form to the 
following: 
 
 
Please refer to the Investigator Site File or Study Reference Manual for complete 
information. 
 


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Rationale:  Study responsibilities for Study 109MS303 have been transferred from 
 
 to 
. This revision reflects this change. 
The change also affects Section 15.2.2, Serious Adverse Events; Section 15.2.4.1, Death; Section 
15.5.1, Overdose; Section 15.5.4 Reporting Pregnancy; and Section 15.6, Investigator 
Responsibilities. 
 


Protocol 109MS303, Version 4 
 
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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol: 
• The version number and date were updated throughout the protocol. 
• With the implementation of Version 4, references to Version 3 in the body text were 
deleted throughout the protocol. 


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
1 
Biogen Idec MA Inc. 
14 Cambridge Center 
Cambridge, MA  02142, USA 
Biogen Idec Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire
SL6 4AY 
United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Idec Protocol 109MS303
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis  
Version 3 
Date:  17 March 2014 
EUDRA CT Number: 2008-004753-14 
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2. 


Protocol 109MS303, Version 3 
 
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PRIMARY REASONS FOR AMENDMENT 
The primary reasons for this amendment to Protocol 109MS303 are to extend the study duration 
for each subject from 5 years to 8 years and to change the dosing regimen from dose-blind 
dosing with BG00012 240 mg twice a day (BID) or three times a day (TID) to open-label dosing 
with BG00012 at a dose of 240 mg BID for all subjects.   
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 7.1, Study Overview 
Now reads: 
The first phase of this extension study This is a multicenter, parallel-group, randomized, dose-
blind, dose-comparison study.  The second phase of the study, implemented with Protocol 
Version 3, is an open-label phase during which all subjects receive BG00012 at a dose of 
240 mg BID. Approximately 1700 subjects will be randomizedhave been enrolled at 
approximately 375 sites in North America, Europe, and the rest of the world. 
Eligible subjects from Studies 109MS301 and 109MS302 will be enrolled in this extension study 
and will be followed for up to 58 years in this extension study, assuming BG00012 continues to 
have a positive benefit-risk ratio.  At enrollment into the study, all subjects received either: 
• BG00012 240 mg BID (2 capsules [120 mg each] twice a day and 2 placebo capsules 
once a day). 
OR 
• BG00012 240 mg TID (2 capsules [120 mg each] three times a day). 
Subjects randomized to BG00012 in Study 109MS301 or 109MS302 will continuecontinued on 
the same BG000012 dose in this extension study. 
Subjects randomized to placebo in Study 109MS301 or 109MS302 or to
GA in 
Study 109MS302 will bewere randomized to BG00012 240 mg BID or 240 mg TID inat a 1:1 
ratio
Subjects who switched to an alternate approved MS therapy in Study 109MS301 or 109MS302 
will bewere randomized in this extension study as outlined above according to their original 
treatment group in Study 109MS301 or 109MS302. 
IfEffective with the resultsapproval
Version
 of the protocol, all subjects are to receive the currently 
marketed dose of 
(2 capsules [120 mg each] BID)
Subjects 
who are receiving BG00012


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extension study will be switched to that dose.BID dosing (2 capsules [120 mg each] BID) at 
their next scheduled visit after the approval of Protocol Version 3. 
 
Rationale:  The risk-benefit of BG00012 continues to be favorable, and treatment of subjects in 
this study for up to 8 years will allow evaluation of the longer-term safety and efficacy of 
BG00012.  Subsequent to the initiation of this study, BG00012 has received marketing approval 
in several countries for the treatment of MS at a dose of 240 mg BID.  For this reason, all 
subjects continuing in this study at the time Protocol Version 3 is implemented will receive the 
currently marketed dose of 240 mg BID.  Subjects currently receiving BG00012 240 mg TID 
will be switched to BID dosing at their next scheduled visit following approval of Protocol 
Version 3. Because all subjects will receive the same dosing regimen, dosing is no longer 
blinded; however, subjects and study personnel will remain blinded to the dose regimen subjects 
were receiving prior to the open-label phase. The change related to the increase in study duration 
from 5 years to 8 years also affects the following sections: 
• Sections 4.2, Study Activities 109MS303 (Years 2 and 3 Treatment Visits) 
• Section, 4.3, Study Activities (Years 4 Through 8 Treatment Visits Effective with 
Protocol Version 3) 
• Section 7.2.2, Treatment Period 
• Section 11.1, Treatment Schedule 
• Section 14.3.2, Years 2 and 3 Treatment Visits 
• Section 14.3.3, Years 4 Through 8 Treatment Visits 
• Section 14.3.4, End of Study Visit (Week 388 ±7 Days) 
• Section 16.3.2, Methods of Analysis 
• Section 16.4.2, Methods of Analysis 
The change related to the switch to open-label dosing with 240 mg BID also affects the 
following sections: 
• Section 5.4, Dose Rationale 
• Section 9.3, Blinding Procedures  
• Section 10.1, Study Treatment Packaging 


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• Section 11.2.2, Resumption of Study Treatment Dosing 
• Section 11.2.5, Dosage Reductions 
• Section 14.1, Site Personnel 
• Section 15.5.5, Dose Unblinding for Medical Emergencies 
 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 3, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol.  
Section 4.3 
Change:  The frequency of some study procedures (clinical chemistry, hematology, urinalysis, 
physical examination, and urine pregnancy testing) was decreased from every 12 weeks to every 
24 weeks during Year 4 through 8 of the treatment period.  The study activities chart (Chart 2 of 
2) was revised and new study activities charts for Years 2 and 3, Years 4 through 8, and 
post-treatment and unscheduled visits were created to reflect the new schedule of assessments as 
well as the extended duration of the study. 










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Rationale:  Because the safety of BG00012 is well established and the dose of BG00012 240 mg 
BID is now approved in several countries, it is considered that the decrease in the frequency of 
certain safety assessments from every 12 weeks to every 24 weeks will be less burdensome for 
subjects while remaining adequate to monitor subject safety.  Subjects will continue to visit the 
clinical site every 12 weeks throughout the study for study drug dispensing and will undergo 
vital signs assessments at these visits.  Monitoring for adverse events and concomitant 
medications continues throughout the study. 
This change also affects the following sections: 
• Section 14.3.2, Years 2 and 3 Treatment Visits 
• Section 14.3.3, Years 4 Through 8 Treatment Visits 
• Section 14.3.4, End of Study Visit (Week 388 ±7 Days) 
Section 7.2.3, Post-Treatment Period 
Change:  Follow-up for subjects with low lymphocyte count at completion or early termination 
of treatment was added. 
Now reads: 
Subjects will complete an End of Study Visit 4 weeks following their last treatment visit.  
Subjects will receive a follow-up telephone call 12 weeks after the last dose of study treatment 
regardless of whether they prematurely withdrew from the study.  Subjects who complete or 
discontinue BG00012 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 
until 24 weeks after the last dose (whichever is sooner; see Section 14.3.8). 
Rationale:  Lymphopenia is a known effect of BG00012 treatment.  Additional follow-up of 
subjects with low lymphocyte counts after the completion or early termination of study treatment 
will provide information regarding the time required for decreased lymphocyte counts to resolve 
following treatment withdrawal.  
This change also affects the following sections: 
• Section 4.4, Study Activities (Unscheduled and Post-Treatment Visits) 
• Section 11.2.1, Dosing Interruption for Abnormal Laboratory Values 
• Section 11.2.3, Subsequent Development of Additional Laboratory Abnormalities 
• Section 11.3, Removal of Subjects from Treatment and Withdrawal from Study 
• Section 14.3.8, Lymphocyte Follow-Up 


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11 
Section 11.2.2, Resumption of Study Treatment Dosing 
Change:  Dosing regimen in the case of dosage interruption was updated. 
Now reads: 
Subjects who are allowed to resume study treatment dosing following a 2 to 4 week interruption 
will restart dosing at a reduced dosage for 1 week.  Subjects will take 1one 120 mg capsule 
TIDBID for 1 week.  After 1 week at the reduced dose, subjects will resume taking 2two 120 mg 
capsules TIDBID. 
Rationale:  The dosing regimen for BG00012 was changed so that all subjects will now receive 
240 mg BID.   
This change also affects Section 11.2.5, Dosage Reductions. 
Section 11.2.4, Abnormal Urinalyses that Require Additional Evaluation 
Change:  Tests for urine beta 2-microglobulin and microalbumin and referral to a nephrologist 
for abnormal urinalysis values are no longer required.   
Now Reads: 
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) 
• Proteinuria (1+ or greater) 
• 
• 
• Glycosuria (trace or greater) in the setting of normal serum glucose. 
Abnormalities detected on urinalysis should be managed as per the local standard of care. 
Rationale:  Abnormal beta 2-microglogulin and microalbumin values have been rarely reported, 
and BG00012 has not been associated with renal dysfunction.  Follow-up as per local standard of 
care for abnormal urinalysis values is considered adequate to ensure patient safety and is 
consistent with other ongoing clinical studies of BG00012. 


Protocol 109MS303, Version 3 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
12 
This change also affects the following sections: 
• Section 11.3, Removal of Subjects from Treatment and Withdrawal from Study 
• Section 13.2, Laboratory Safety Assessments. 


Protocol 109MS303, Version 3 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
13 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were updated throughout the protocol. 
• Section 1.1, Biogen Idec Personnel, was updated. 
• Section 2, List of Abbreviations, was updated.Section 5.2, Profile of Previous 
Experience with Fumarates, was updated with efficacy and safety results from 
recently completed studies.  
• Section 11.6, Continuation of Treatment, was deleted as it no longer applies. 
• Section 15.5.1, Overdose, was changed to indicate that overdoses are to be reported 
on an Overdose Form and faxed to 
. 
• Section 15.5.4, Reporting Pregnancy, was changed for consistency with the protocol 
template and the procedures used in other ongoing BG00012 studies. 
• Section 17, Ethical Requirements; Section 18, Administrative Procedures; and 
Section 19, Further Requirements and General Information, were updated for 
consistency with revisions to the Biogen Idec protocol template and other BG00012 
protocols and to update information related to the roles and responsibilities of clinical 
research organizations and other vendors. 
• Section 20, References, was updated to include a new reference. 
• Minor editorial and formatting changes were made throughout the protocol.  


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
1 
Biogen Idec Inc. 
14 Cambridge Center 
Cambridge, MA  02142, USA 
Biogen Idec Ltd. 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Idec Protocol 109MS303 
A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of 
Two Doses of BG00012 Monotherapy in Subjects with Relapsing-Remitting Multiple Sclerosis  
  Version 2 
Date:  15 September, 2010  
EUDRA CT Number:  2008-004753-14 
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1. 


Protocol 109MS303, Version 2 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
2 
PRIMARY REASON(S) FOR AMENDMENT 
The primary reason for this amendment to Protocol 109MS303 is extension of the duration of the 
study from 2 years to 5 years or marketing authorization (if approved), whichever occurs first.   
 
New text is shown in bold type; deleted text is shown with a strikethrough. 
 
Section 7.1, Study Overview 
 
Now reads: 
This is a multicenter, parallel-group, randomized, dose-blind, dose-comparison study.  
Approximately 1700 subjects will be randomized at approximately 375 sites in North America, 
Europe, and the rest of the world. 
Eligible subjects from Studies 109MS301 and 109MS302 will be enrolled in this extension study 
a
5 years, assuming BG00012 
continues to have a positive benefit/risk ratio. 
 
Rationale:   
Treatment of subjects in this study for up to 5 years or until marketing authorization, whichever 
occurs first, will allow evaluation of BG00012 for longer term safety and efficacy. 
 
This change also affects Sections 3, Synopsis; 4.2, Study Activities 109MS303 (Chart 2 of 2); 
7.2.2 Treatment Period; 7.2.3, Post-Treatment Period; 11.6, Continuation of Treatment; 14.3.13, 
Tests and Assessments; 16.3.2, Methods of Analysis (Efficacy Data); 16.4.2, Methods of 
Analysis (Safety Data). 
 


Protocol 109MS303, Version 2 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec Inc. 
3 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
 
The following minor changes were made to the protocol, as appropriate: 
 The version number and date were updated throughout the protocol. 
 It was clarified that the study personnel may include an examining neurologist to 
perform EDSS evaluations if the treating neurologist does not perform these 
assessments.  This clarification affects Sections 14.1, Site Personnel; 14.3.1, Baseline 
Visit; 14.3.4, Visit 3; 14.3.7, Visit 6; 14.3.9, Visit 8; 14.3.11, Visit 10, 14, 18, 22; 
14.3.12, Visit 12, 16, 20, 24; 14.3.14, Unscheduled Relapse Assessment Visit; 
14.3.15, Premature Study Withdrawal Visit. 
 It was clarified that the study personnel may include an examining technician if the 
treating neurologist designates visual function test examinations.  This change affects 
Sections 14.1, Site Personnel; 14.3.1, Baseline Visit; 14.3.7, Visit 6; 14.3.9, Visit 8; 
14.3.11, Visit 10, 14, 18, 22; 14.3.12, Visit 12, 16, 20, 24; 14.3.14, Unscheduled 
Relapse Assessment Visit; 14.3.15, Premature Study Withdrawal Visit. 
 A window between Visit 24 of the 109MS301 or 109MS302 study and Baseline for 
the 109MS303 study will be allowed.  If the Baseline Visit for 109MS303 cannot be 
combined with Visit 24 of the preceding study, subjects may be randomized within 6 
months of Visit 24.  Language that pertains to continuous dosing has been eliminated. 
This change affects Sections 3, Synopsis; 7.2.1, Baseline; 9.1, Enrollment Procedures; 
14.3.1, Baseline Visit. 
 It was clarified that all tests and procedures of Baseline Visit that are also included in 
the 109MS301 or 109MS302 protocol should be performed by the respective 
personnel of the parent study.  This change affects Section 4.1, Study Activities 
109MS303 (Chart 1 of 2); 14.3.1, Baseline Visit; 14.3.4, Visit 3. 
 Sections 14.3.10 and 14.3.12 in Version 1 were identical; these are now consolidated 
into Section 14.3.10; Section 14.3.12 is deleted; headings have been re-numbered in 
Section 14.3.  This also affects the Table of Contents. 
 Drug Safety and Risk Management signatory updated, page 1. 
 Section 1, Contact List, was updated. 

SAP_001.pdf: 
Study 109MS303 SAP Final Version 
109MS303 / NCT00835770
Biogen - BG00012 in MS 
Statistical Analysis Plan for Clinical Study Report for 
Submission 
BIOGEN 
STATISTICAL ANALYSIS PLAN 






Study 109MS303 Statistical Analysis Plan 
 
  
 3  
Study 109MS303 SAP Final Version 
TABLE OF CONTENTS 
1 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 7 
1.1 
Primary Objective and Endpoint .............................................................................. 7 
1.2 
Secondary Objectives and Endpoints ........................................................................ 7 
1.3 
Exploratory Objectives and Endpoints ...................................................................... 7 
2 
STUDY DESIGN ................................................................................................................. 7 
2.1 
Study Overview........................................................................................................ 7 
2.2 
Overall Study Duration and Follow-Up .................................................................... 8 
2.3 
MRI ......................................................................................................................... 9 
3 
STUDY ACTIVITIES........................................................................................................... 9 
3.1 
Study Activities (Year 1 Visits).............................................................................. 10 
3.2 
Study Activities (Years 2 and 3 Treatment Visits) .................................................. 11 
3.3 
Study Activities (Years 4 Through 8 Treatment Visits) .......................................... 12 
3.4 
Study Activities for Subjects Who Already Completed Visit 36 ............................. 14 
3.5 
Study Activities (Hematology and Lymphocyte Analysis: Year 4 Through End of 
Treatment Visits) ................................................................................................................. 16 
3.6 
Study Activities 109MS303 (Unscheduled and Post-Treatment Visits) .................. 17 
4 
INTERIM ANALYSIS ....................................................................................................... 18 
5 
SAMPLE SIZE JUSTIFICATION ...................................................................................... 18 
6 
STATISTICAL ANALYSIS METHODS............................................................................ 18 
6.1 
Statistical testing procedures .................................................................................. 19 
6.2 
Analysis populations, Treatment groupings, and Datasets ....................................... 19 
6.2.1 Analysis populations............................................................................................... 19 
6.2.2 Treatment Groupings .............................................................................................. 20 
6.2.3 Datasets.................................................................................................................. 21 
6.2.4 Summary of Use of Analysis populations, Treatment groupings, and Datasets ........ 21 
6.3 
Description of Analytic Methods ............................................................................ 22 
6.3.1 Analysis of Baseline Data ...................................................................................... 22 
6.3.2 Accounting of Subjects........................................................................................... 23 
6.3.3 Protocol Deviations ................................................................................................ 23 
6.3.4 Demographic and Baseline Characteristics ............................................................. 23 
6.3.5 Medical History ..................................................................................................... 24 
6.3.6 Study Drug Compliance and Time on Study ........................................................... 24 
6.3.7 Concomitant Medications and Non-drug Therapies ................................................ 24 
6.3.8 Day Ranges for Analyses by Visit .......................................................................... 25 
6.4 
Efficacy Analysis ................................................................................................... 26 
6.4.1 Analysis Population................................................................................................ 26 
6.4.2 Analysis Methods ................................................................................................... 26 
6.4.3 Analysis of Relapse ................................................................................................ 30 
6.4.4 Analysis of Progression .......................................................................................... 32 
6.4.5 Analysis of MRI Endpoints .................................................................................... 33 


4 
 
6.4.6 Analysis Quality of life Assessments (SF-36 and EQ-5D) and Visual Function Test34 
6.5 
Safety Data ............................................................................................................ 36 
6.5.1 Analysis Population................................................................................................ 36 
6.5.2 Analysis Methods ................................................................................................... 36 
6.5.3 Analysis of Adverse Events .................................................................................... 36 
6.5.4 Analysis of Clinical Laboratory Data ..................................................................... 39 
6.5.5 Analysis of Vital Signs Data................................................................................... 40 
6.5.6 Analysis of Absolute Lymphocyte Counts .............................................................. 41 
 41 
6.5.8 Deviations in Analyses from Study Protocol ........................................................... 41 
 
 


5 
 
List of Abbreviations 
AE 
 
 
adverse event 
ALT (SGPT)  
alanine transaminase (serum glutamate pyruvate 
transaminase) 
 
AST (SGOT)  
aspartate transaminase (serum glutamic oxaloacetic 
transaminase) 
 
ARR 
 
 
annualized relapse rate 
BUN 
 
 
blood urea nitrogen 
CRF 
 
 
case report form 
Gd 
 
 
gadolinium 
GGT 
 
 
gamma-glutamyl-transferase 
EDSS 
 
 
Expanded Disability Status Scale 
EQ-5D 
 
 
EQ-5D Health Survey 
GA 
 
 
glatiramer acetate  
HDL 
 
 
high-density lipoprotein 
HLGT 
 
 
high-level group term  
HLT 
 
 
high-level term 
IXRS 
 
 
Interactive Voice and Web Response System 
INEC 
 
 
Independent Neurology Evaluation Committee 
LDL  
 
 
low-density lipoprotein 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
MRI 
 
 
magnetic resonance imaging 
MS 
 
 
multiple sclerosis 
MTR 
 
 
Magnetization Transfer Ratio 
PBVC 
 
 
Percent Brain Volume Change 
PT 
 
 
preferred term 
SAE 
 
 
serious adverse event 
SAP 
 
 
Statistical Analysis Plan 
SOC 
 
 
system organ class 
SF-36 
 
 
SF-36® Health Survey 
ULN 
 
 
upper limit of normal 
VAS 
 
 
Visual Analogue Scale 


6 
 
VFT 
 
 
Visual Function Test 
WBC 
 
 
white blood cell 
WHO 
 
 
World Health Organization 
 
 


7 
 
 
1 
STUDY OBJECTIVES AND ENDPOINTS 
1.1 
Primary Objective and Endpoint 
The primary objective of the study is to evaluate the long-term safety profile of BG00012. 
1.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are as follows: 
• To evaluate the long-term efficacy of BG00012 using clinical endpoints (including 
relapse and ARR) and disability progression (Expanded Disability Status Scale 
[EDSS]). 
• To evaluate further the long-term effects of BG00012 on MS brain lesions on MRI 
scans in subjects who had MRI scans as part of Studies 109MS301 and 
109MS302.  
• To evaluate the long-term effects of BG00012 on health economics assessments 
and the visual function test (VFT). The endpoints are the Short-form 36 Health 
Survey (SF-36) and EuroQol EQ-5D Health Survey (EQ-5D) quality of life 
questionnaires, and the visual function test scores. 
1.3 
Exploratory Objectives and Endpoints 
The exploratory objectives of this study are as follows: 
• 
 
• 
 
 
 
2 
STUDY DESIGN 
2.1 
Study Overview 
The first phase of this extension study is a multicenter, parallel-group, randomized, dose-
blind, dose-comparison study. The second phase of the study is an open-label phase during 
which all subjects receive BG00012 at a dose of 240mg BID. A total of 1738 subjects with 
relapsing-remitting multiple sclerosis have been randomized at approximately 375 sites in 
North America, Europe, and the rest of the world.  
Eligible subjects from Studies 109MS301 and 109MS302 were enrolled in this extension 
study and were followed for up to 8 years, assuming BG00012 continues to have a positive 
benefit/risk ratio. 
All subjects received either: 


8 
 
• BG00012 240 mg BID (2 capsules [120 mg each] twice a day and 2 placebo capsules 
once a day); or 
• BG00012 240 mg TID (2 capsules [120 mg each] 3 times a day). 
Subjects randomized to BG00012 in Study 109MS301 or 109MS302 continued on the 
same BG000012 dose in this extension study. 
Subjects randomized to placebo in Study 109MS301 or 109MS302 or glatiramer acetate 
(GA) in Study 109MS302 were randomized to BG00012 in a 1:1 ratio to 240 mg BID or 
240 mg TID in this extension study. 
With regulatory approval (effective March 2013), all patients receiving BG00012 240 mg 
TID switched to BID (approved dosage) at their next study visit. This study became an open 
label extension study with the approved dosage BG00012 240 mg BID. 
Subjects who switched to an alternate approved MS therapy in Study 109MS301 or 
109MS302 were randomized/enrolled in this extension study as outlined above according to 
their original treatment group in 109MS301 or 109MS302. 
2.2 
Overall Study Duration and Follow-Up 
Eligible subjects were enrolled at Week 96 (Visit 24) of their previous BG00012 study 
(109MS301 or 109MS302), which would serve as the Baseline Visit for this extension 
study. If the Baseline Visit could not be combined with Visit 24 of their previous BG00012 
study, the subjects may have been randomized within 6 months of Visit 24, provided that 
they still were eligible for enrollment. The Baseline visit assessments may have been 
repeated if there was a gap in study treatment. 
Subjects reported to the study site every 4 weeks for the first 24 weeks (Visit 1 through Visit 
6) and every 12 weeks thereafter for up to 8 years.  
Subjects who completed the Week 384 visit (Visit 36), regardless of further need to 
monitor lymphocytes on study, completed an End of Study Visit at Week 388 ± 7 days. For 
subjects who have completed Visit 36, an End of Study Visit was completed 4 weeks after 
their next visit (scheduled or unscheduled), regardless of further need to monitor 
lymphocytes on study. Subjects who permanently discontinued BG00012 prior to Week 
384, regardless of further need to monitor lymphocytes on study, completed a Premature 
Study Treatment Withdrawal Visit within 4 weeks after their last dose of BG00012. 
Subjects who completed BG00012 treatment or permanently discontinued BG00012 for 
any reason and who had a lymphocyte count <LLN were not withdrawn from the study. 
These subjects were followed according to Protocol Section 11.3. 
For subjects who have already completed Visit 36 (or beyond) prior to the Protocol Version 
8, an End of Study Visit was completed 4 weeks after their next visit (scheduled or 
unscheduled), regardless of further need to monitor lymphocytes on study. For subjects who 
have not completed Visit 36 prior to Protocol Version 8, Visit 36 served as the last scheduled 
Visit and an End of Study Visit was completed 4 weeks after their next visit (scheduled or 
unscheduled), regardless of further need to monitor lymphocytes on study. 


9 
 
Premature Study Withdrawal Visits and Unscheduled Relapse Assessment Visits were  
performed as necessary. All efforts were made to keep the subjects’ visit schedule relative to 
their Baseline Visit (Day 1). All subjects who discontinued the study treatment were 
considered to be prematurely withdrawn from the study. 
The end of study is defined as the Last Patient, Last Visit for final collection of data for the 
primary outcome 
2.3 
MRI  
MRI was performed in the same subset of sites/countries as in Studies 109MS301 and 
109MS302, which was based on the availability of MRI equipment at the sites to perform 
the assessments required for the study (e.g., MTR). All subjects at the MRI sites were offered 
the option to participate in Studies 109MS301 and 109MS302, and those subjects 
continuing into Study 109MS303 continued their participation in the MRI cohort. MRI 
scans were performed on a yearly basis in Study 109MS303, as well as at the time of 
premature withdrawal up through and including Amendment 6.  
 
3 
STUDY ACTIVITIES 
The study flowchart for the current version of the protocol is presented below.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 10  
Study 109MS303 SAP Final Version 
3.1 
Study Activities (Year 1 Visits) 
Tests and Assessments1 
Baseline 
Visit 
(Day 1)2 
Visit 1 
(Week 4 
±5 days) 
Visit 2 
(Week 8 
±5 days) 
Visit 3 
(Week 12 
±5 days) 
Visit 4 
(Week 16 
±5 days) 
Visit 5 
(Week 20 
±5 days) 
Visit 6 
(Week 24 
±5 days) 
Visit 7 
(Week 36 
±7 days) 
Visit 8 
(Week 48 
±7 days) 
Informed Consent 
X 
Randomization 
X 
Medical History Update 
X 
Physical Examination 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
Brain MRI5 Scan ± Gd6 
Scheduled MRI scans were performed in protocol versions 1 through 6. 
EDSS 
X 
X7 
X 
X 
Visual Function Test 
X 
X 
X 
SF-36 and EQ-5D 
X 
X 
Dispense Study Treatment (BG00012) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy and Procedures Recording 
Monitor and record throughout the study as per Protocol Section 11.6 
AE/SAE Reporting 
Monitor and record throughout the study as per Protocol Section 15 
AE = adverse event; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = gadolinium; MRI = magnetic resonance imaging; SAE = 
serious 
adverse event; SF-36 = Short-form 36 Health Survey. 
1. 
Tests and assessments must be completed prior to BG00012 distribution. 
2. 
The Week 96 visit (Visit 24) for 109MS301 and 109MS302 will serve as the Baseline Visit for this extension study; activities should be completed (where 
appropriate) by staff of the parent study. 
3. 
For women of childbearing potential. Results must be known prior to BG00012 distribution. 
4. 
If urinalysis is abnormal, see Protocol Section 11.2. 
5. 
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6. 
6. 
MRI must not be performed within 30 days of receiving a course of steroids. 
7. 
rmed only for subjects who at the Week 96 visit (Visit 24) in 109MS301 or 109MS302 had a 1.0 point increase in their EDSS score from a baseline 
EDSS
1.0 or a 1.5 point increase in their EDSS from a baseline EDSS = 0. 


 
 11  
Study 109MS303 SAP Final Version 
3.2 
Study Activities (Years 2 and 3 Treatment Visits) 
 
Year 2 
Year 3 
Visit 
9 
10 
11 
12 
13 
14 
15 
16 
Study Week (±7 days) 
60 
72 
84 
96 
108 
120 
132 
144 
Tests and Assessments1 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test2 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Brain MRI4 
 Gd5 
Scheduled MRI scans were performed in protocol versions 1 through 6. 
EDSS 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Function Test 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 and EQ-5D 
X 
X 
Dispense Study Treatment (BG0012) 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy and Procedures Recording 
Monitor and record throughout the study as per Protocol Section 11.6 
AE/SAE Reporting 
Monitor and record throughout the study as per Protocol Section 15 
AE = adverse event; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = gadolinium; MRI = magnetic resonance imaging; SAE 
= serious adverse event; SF-36 = Short-form 36 Health Survey. 
1. 
Tests and assessments must be completed prior to BG00012 distribution. 
2. 
For women of childbearing potential. Results must be known prior to BG00012 distribution. 
3. 
If urinalysis is abnormal, see Protocol Section 11.2. 
4. 
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6. 
5. 
MRI must not be performed within 30 days of receiving a course of steroids. 
 
 
 
 
 
 
 
 
 
 


 
12 
 
3.3 
Study Activities (Years 4 Through 8 Treatment Visits) 
Year 
Year 4 
Year 5 
Year 6 
Year 7 
Year 8 
Visit 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
361 
Study Week (±7 days) 
156 
168 
180 
192 
204 
216 
228 
240 
252 
264 
276 
288 
300 
312 
324 
336 
348 
360 
372 
384 
Tests and Assessments2 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
See Section 3.5 
Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
Brain MRI5 Scan ± Gd6 
Scheduled MRI scans were performed in protocol versions 1 through 6. 
EDSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Function Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 and EQ-5D 
X 
X 
X 
X 
X 
Dispense Study 
Treatment (BG00012)7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy and 
Procedures Recording 
Monitor and record throughout the study as per Protocol Section 11.6 
AE/SAE Reporting 
Monitor and record throughout the study as per Protocol Section 15 
AE = adverse event; CRF = case report form;
; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = gadolinium; MRI = 
magnetic resonance imaging; 
; SAE = serious adverse event; SF-36 = Short-form 36 Health Survey. 
1. 
For subjects who have already completed Visit 36 (or beyond), an End of Study Visit should be completed 4 weeks after their next visit (scheduled or unscheduled), regardless of 
further need 
to monitor lymphocytes on study. 
2. 
Tests and assessments must be completed prior to BG00012 distribution. 
3. 
For women of childbearing potential. Results must be known prior to BG00012 distribution. 
4. 
If urinalysis is abnormal, see Protocol Section 11.2. 


 
13 
 
5. 
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6. 
6. 
MRI must not be performed within 30 days of receiving a course of steroids. 
7. 
The date and Study Visit/Week at which subjects are switched to open-label treatment should be recorded on the dosing CRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
14 
 
3.4 
Study Activities for Subjects Who Already Completed Visit 36 
For subjects who have already completed Visit 36 (or beyond) prior to Protocol Version 8, an End of Study Visit should be completed 
4 weeks after their next visit (scheduled or unscheduled), regardless of further need to monitor lymphocytes on study. For subjects who have 
not completed Visit 36 prior to Protocol Version 8, Visit 36 will serve as the last scheduled Visit and an End of Study Visit should be 
completed 4 weeks after their next visit (scheduled or unscheduled), regardless of further need to monitor lymphocytes on study. 
 
Year 
Year 9 
Year 10 
Year 11 
Year 12 
Visit 
37 
38 
39 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
Study Week 
7 days) 
396 
408 
420 
432 
444 
456 
468 
480 
492 
504 
516 
528 
540 
552 
564 
576 
Tests and Assessments1 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
                                                 See Protocol Section 4.5 
Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test2 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Brain MRI4 Scan ± Gd5 
Scheduled MRI scans were performed in protocol versions 1 through 6. 
EDSS 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Function Test 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 and EQ-5D 
X 
X 
X 
X 
Dispense Study 
Treatment (BG00012)76 
Concomitant Therapy and 
Procedures Recording 
Monitor and record throughout the study as per Protocol Section 11.6 
AE/SAE Reporting 
Monitor and record throughout the study as per Protocol Section 15 
AE = adverse event; CRF = case report form; 
; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = 


 
15 
 
gadolinium; MRI = magnetic resonance imaging; 
; SAE = serious adverse event; SF-36 = Short-form 36 Health Survey. 
1. 
Tests and assessments must be completed prior to BG00012 distribution. 
2. 
For women of childbearing potential. Results must be known prior to BG00012 distribution. 
3. 
If urinalysis is abnormal, see Protocol Section 11.2. 
4. 
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6. 
5. 
MRI must not be performed within 30 days of receiving a course of steroids. 
6. 
The date and Study Visit/Week at which subjects are switched to open-label treatment should be recorded on the dosing CRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
16 
 
3.5 
Study Activities (Hematology and 
 Analysis: Year 4 Through End of Treatment Visits) 
Tests and Assessments 
Subjects With Lymphocyte Count 
≥LLN 
Subjects With Lymphocyte Count 
<LLN to ≥500/mm3 
Subjects With Lymphocyte Count 
<500/mm3 
Hematology 
Every 12 weeks 
Every 12 weeks 
Every 4 or 12 weeks per Protocol 
Table 3 
Bone Marrow Biopsy (optional) 
Not applicable 
Not applicable 
Optional procedure6 
; LLN = lower limit of normal; 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. 
See Protocol Section 11.3 for further details 
 
 
 
 
 
 
 
 
 
 


 
17 
 
3.6 
Study Activities 109MS303 (Unscheduled and Post-Treatment Visits) 
Tests and Assessments 
End of Study Visit1 
Unscheduled Relapse 
Assessment Visit2 
Premature Study 
Treatment Withdrawal 
Visit3 
Lymphocyte Follow-Up 
(Up to 96 Weeks After 
Last Dose)4 
Physical Examination 
X 
X 
Vital Signs 
X 
X 
X 
X 
Hematology 
X3 
X 
X3 
X 
Blood Chemistry 
X 
X 
X 
Urine Pregnancy Test5 
X 
X 
X 
Urinalysis 
X6 
X6 
X6 
Brain MRI7 Scan ± Gd8 
Scheduled MRI scans were performed in protocol versions 1 through 6. 
EDSS 
X 
X 
Visual Function Test 
X 
X 
SF-36 and EQ-5D 
X 
X 
Relapse Assessment 
X 
Concomitant Therapy and Procedures Recording 
Monitor and record throughout the study as per Protocol Section 11.6 
AE/SAE Reporting 
Monitor and record throughout the study as per Protocol Section 15 
AE = adverse event; EDSS = Expanded Disability Status Scale; EQ-5D = EuroQol EQ-5D Health Survey; Gd = gadolinium; LLN = lower limit of normal; MRI = magnetic 
resonance imaging; SAE = serious adverse event; SF-36 = Short-form 36 Health 
Survey. 
1. 
For subjects who have already completed Visit 36 or beyond, an End of Study Visit should be completed 4 weeks after their next visit (scheduled or 
unscheduled). 
2. 
Unscheduled Relapse Assessment Visit is to be carried out within 5 days of suspected relapse. 
3. 
Subjects who permanently discontinue BG00012 prior to Week 384 (Visit 36) should complete a Premature Study Treatment Withdrawal Visit within 4 weeks 
of their last dose. The Premature Study Treatment Withdrawal Visit will serve as the End of Study Visit. 
4. 
Lymphocyte follow-up as per Protocol Section 11.3. 
5. 
For women of childbearing potential. 
6. 
If urinalysis is abnormal, see Protocol Section 11.2. 
7. 
Only in subjects who had MRI scans as part of Studies 109MS301 and 109MS302 and in 109MS303 up through and including Amendment 6. 
8. 
MRI must not be performed within 30 days of receiving a course of steroid. 
 


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4 
INTERIM ANALYSIS 
This statistical analysis plan (SAP) is intended to describe the planned analysis methods and 
considerations for the final analysis based on data after the database lock. Interim analyses 
were performed as needed for regulatory reporting, safety updates, publications, or as 
otherwise required by the Sponsor. One specific interim analysis was conducted to provide 
an assessment of the long-term safety and efficacy profile of BG00012 at the time of filing 
the MS application. This interim analysis was based on all data collected for subject visits, 
assessments, and evaluations through August 3, 2011. After that, several interim analyses 
were conducted based on data snapshots without formal database lock, and these results were 
presented for publications purposes to assess long-term safety and efficacy profile of 
BG00012. 
 
5 
SAMPLE SIZE JUSTIFICATION 
There is no formal sample size calculation. The number of subjects eligible for this study is 
determined by the number of subjects who participated in and completed Studies 109MS301 
and 109MS302. 
Subjects randomized to BG00012 in Study 109MS301 or 109MS302 continued on the same 
BG000012 dose in this extension study. Subjects randomized to placebo in Study 
109MS301 or 109MS302 or glatiramer acetate in Study 109MS302 were randomized to 
BG00012 in a 1:1 ratio to 240 mg BID or 240 mg TID in this extension study. 
Randomization was stratified by previous study and previous treatment (i.e., 3 strata: Study 
109MS301 placebo, Study 109MS302 placebo, and Study 109MS302 glatiramer acetate).  
All patients receiving BG00012 240 mg TID were switched to BID (approved dosage) at 
their next study visit after regulatory approval (effective March 2013). 
 
6 
STATISTICAL ANALYSIS METHODS 
Descriptive summary statistics will be used throughout. For continuous endpoints and 
parameters, summary statistics will generally include: number of subjects with data, mean, 
standard deviation, median, and range. For categorical endpoints and parameters, summary 
statistics will generally include: number of subjects with data and the number and percentage 
of those with data in each category. 
Summaries will generally include all available data included in the database lock for this 
final analysis. However, as this is an ongoing study, caution must be exercised when 
interpreting analyses at later timepoints for which sample sizes may be relatively sparse. 
Kaplan-Meier curves will display results through timepoints for which a sufficient number of 
subjects at risk exists in each treatment group (e.g., at least 20 subjects at risk per treatment 
group). 
The statistical software, SAS® ,will be used for all statistical analyses. The SAS code for 
efficacy analyses is not provided in this statistical analysis plan, as the code is similar to that 
provided in the statistical analysis plans for Studies 109MS301 and 109MS302. 


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6.1 
Statistical testing procedures 
As this final analysis of a long-term extension study, analyses will generally be descriptive in 
nature and will be based on observed data, without imputation for missing values. For 
relevant efficacy analyses, confidence intervals will be provided for each treatment group 
where appropriate to characterize the variability around the point estimate. Statistical 
hypothesis testing may be completed for selected analyses and will be considered 
exploratory.  
Missing measurements 
In general, no imputation for missing measurements will be performed, unless specified 
otherwise. 
Missing dates 
For start date of adverse events, if all available start date information is the same as that of 
the date of first dose in 109MS303, and the event did not end prior to first dose, the date of 
first dose in 109MS303 will be used as the imputed date. Otherwise for adverse events, and 
always for the start of concomitant medications, the earliest possible start date based on 
available partial information will be used. Namely, if only the day is missing, the 1st of the 
month will be used; if the month is also missing, January 1st will be used. End dates for 
concomitant medications and adverse events will not be imputed. For evaluations other than 
adverse events and concomitant medications, missing or incomplete dates that are needed for 
analysis will also be imputed. If the day is missing for a study procedure or assessment but 
the month and year are present, the day will be imputed as the 15th of the month. Month and 
year will not be imputed for study procedures or assessments. These same rules will be 
applied to missing or incomplete dates for relapses.  
6.2 
Analysis populations, Treatment groupings, and Datasets 
6.2.1 Analysis populations 
The analysis populations of Study 109MS303 that will be utilized are described below.  
• Study 109MS303 Intent-to-Treat (ITT) Population: This analysis population is 
defined to include all subjects who entered Study 109MS303 and received at least 
one dose of study treatment in Study 109MS303. Subjects will be analyzed in the 
treatment groups to which they were randomized/assigned. This will be the primary 
analysis population utilized for the majority of baseline analyses and non-MRI 
analyses addressing long-term efficacy and persistence of efficacy. 
• Study 109MS303 MRI Cohort: This analysis population is defined to include 
subjects in the Study 109MS303 ITT Population who consented to participate in the 
MRI substudy and have any MRI data in Studies 109MS301, 109MS302, or 
109MS303. This will be the primary analysis population utilized for the majority of 
MRI analyses addressing long-term efficacy and persistence of efficacy. 
• Study 109MS303 Safety Population: This analysis population is defined to include 
all subjects who had any post-baseline safety follow-up in Study 109MS303, defined 


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as any treatment emergent AE in Study 109MS303 or any post-baseline laboratory, 
vital signs, or physical exam assessment in Study 109MS303, and received at least 
one dose of study treatment in Study 109MS303. Subjects will be analyzed in the 
treatment groups to which they were randomized/assigned.  
6.2.2 Treatment Groupings 
The analysis populations described above in Section 6.2.1 will be utilized in conjunction 
with the following three sets of treatment groupings as appropriate: 
• Combined Treatment Grouping, indicating the study treatments during Study 
109MS301 or 109MS302 and Study 109MS303 combined: 
o BG00012 240 mg BID -> 240 mg BID (i.e., BG00012 240 mg BID in both 
studies), or, alternatively, BG00012 240 mg BID Previously Treated with 
BG00012 240 mg BID; 
o BG00012 240 mg TID -> 240 mg TID (i.e., BG00012 240 mg TID in both 
studies), or, alternatively, BG00012 240 mg TID Previously Treated with 
BG00012 240 mg TID; 
o Placebo -> BG00012 240 mg BID (i.e., placebo in Studies 109MS301/302 
and BG00012 240 mg BID in Study 109MS303), or, alternatively, 
BG00012 240 mg BID Previously Treated with Placebo; 
o Placebo -> BG00012 240 mg TID (i.e., placebo in Studies 109MS301/302 
and BG00012 240 mg TID in Study 109MS303), or, alternatively, 
BG00012 240 mg TID Previously Treated with Placebo; 
o GA -> BG00012 240 mg BID (i.e., GA in Study 109MS302 and BG00012 
240 mg BID in Study 109MS303), or, alternatively, BG00012 240 mg BID 
Previously Treated with GA;  
o GA -> BG00012 240 mg TID (i.e., GA in Study 109MS302 and BG00012 
240 mg TID in Study 109MS303), or, alternatively, BG00012 240 mg TID 
Previously Treated with GA. 
Analyses utilizing the Study 109MS303 ITT Population, Study 109MS303 MRI 
Cohort, or Study 109MS303 Safety Population may employ Combined Treatment 
Grouping. The first treatment group name in each bullet above (e.g., BG00012 240 
mg BID -> 240 mg BID) will be utilized for relevant efficacy summaries, while the 
second treatment group name in each bullet above (e.g., BG00012 240 mg BID 
Previously Treated with BG00012 240 mg BID) may be utilized for relevant safety 
summaries.   
• Study 109MS303 Treatment Grouping, indicating the study treatment during Study 
109MS303:  
o BG00012 240 mg BID;  


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o BG00012 240 mg TID; and 
o Total BG00012 (i.e., BG00012 240 mg BID and BG00012 240 mg TID 
groups combined). 
Analyses utilizing the Study 109MS303 Safety Population may employ Study 109MS303 
Treatment Grouping. This treatment grouping will be utilized for select safety analyses 
where the incidence of an event or abnormality in Study 109MS303 itself may be of interest. 
Baseline summaries will include both Combined Treatment Grouping and Study 109MS303 
Treatment Grouping. 
6.2.3 Datasets 
The analysis populations and treatment groupings described above in Sections 6.2.1 and 
6.2.2, respectively, will be utilized in conjunction with the following three datasets as 
appropriate: 
• Combined Data, defined as data from Studies 109MS301, 109MS302, and 
109MS303; and 
• Study 109MS303 data only, defined as data from Study 109MS303.  
Analyses utilizing Combined Treatment Grouping may include either Combined Data or 
Study 109MS303 data only. Analyses utilizing Study 109MS303 Treatment Grouping will 
include Study 109MS303 data only. 
6.2.4 Summary of Use of Analysis populations, Treatment groupings, and 
Datasets 
The following table summarizes the use of analysis populations by treatment groupings and 
datasets, with a brief mention of the planned analyses in italicized text in brackets: 


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Table 6.2.4.1: Summary of use of analysis populations by treatment groupings and 
datasets 
 
 
 
Dataset 
Treatment Grouping 
Combined Treatment 
Grouping 
Study 109MS303 Treatment 
Grouping 
 
Combined 
Data 
Study 109MS303 ITT 
Population  
[Majority of Non-MRI 
Efficacy Analyses] 
 
Study 109MS303 MRI 
Cohort  
[Majority of MRI Efficacy 
Analyses] 
 
 
N/A 
 
Study 
109MS303 
data only 
Study 109MS303 ITT 
Population  
[Study 109MS303 ARR 
Analysis] 
 
Study 109MS303 Safety 
Population 
[Majority of Safety 
Analyses] 
 
Study 109MS303 Safety 
Population 
[Selected Safety Analyses] 
Notes: Italicized text in brackets provides a brief description of the analyses planned for the 
particular combination of analysis population, treatment grouping, and dataset. 
Lymphocyte analysis may be utilized with Combined Data and Combined Treatment 
Grouping or Study 109MS303 Treatment Grouping. N/A = Not Applicable. 
6.3 
Description of Analytic Methods  
6.3.1 Analysis of Baseline Data  
Baseline data will be summarized utilizing the Study 109MS303 ITT Population and both 
Combined Treatment Grouping and Study 109MS303 Treatment Grouping. The definition 
of baseline will be dependent on the analysis performed and the study data utilized. 
The following are the various definitions of baseline that may be utilized in analyses: 
• Study 109MS303 Baseline is defined as the latest available value prior to or on the 
date of first dose of study treatment in Study 109MS303;  
• Previous Study Baseline is defined as the latest available value prior to or on the date 
of first dose of study treatment in Study 109MS301 or 109MS302; and 
• BG00012 Treatment Baseline is defined as the latest available value prior to or on 
the date of first exposure to BG00012, specifically: 


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o the latest available value prior to or on the date of first exposure to study 
treatment in Study 109MS301 or 109MS302 for subjects on BG00012 
treatment in Study 109MS301 or 109MS302;  
o the latest available value prior to dosing in Study 109MS303 for subjects in 
the placebo or GA treatment groups in Study 109MS301 or 109MS302. 
6.3.2 Accounting of Subjects 
The following categories of accounting will be summarized for Study 109MS303 using 
numbers and percentages: 
• Subjects who entered the study; 
• Subjects who were dosed; 
• Subjects who discontinued treatment (and therefore withdrew from study), along with 
reasons for discontinuing treatment; and 
• Subjects who have lymphocyte follow up. 
Listings of subjects who discontinued treatment and withdrew from the study and the reasons 
for discontinuation/withdrawal will be presented.     
6.3.3 Protocol Deviations 
Protocol deviations identified in the study will be listed.  
6.3.4 Demographic and Baseline Characteristics 
Demographic characteristics, including age (years), age category (18-19, 20-29, 30-39, 40-
49, 50-55, and >55, as well as <40, 40 ), gender, and race, will be summarized. In addition, 
region, height (cm), weight (kg), and body mass index (kg/m^2) will also be summarized. 
Weight, height, and body mass index will be presented based on the Study 109MS303 
Baseline definition, while age will be presented based on both the Previous Study Baseline 
(corresponding to the age covariate used in efficacy models) and Study 109MS303 Baseline 
definitions. 
Baseline disease characteristics will also be summarized, including MS disease history (time 
since first MS symptoms and time since diagnosis of MS at Study 109MS303 Baseline), 
relapse history (number of relapses in the past 12 months and in the past 3 years at Previous 
Study Baseline), McDonald criteria (at Previous Study Baseline), and EDSS score (at both 
the Previous Study Baseline and Study 109MS303 Baseline). In addition, summary statistics 
for baseline MRI parameters(number and volume of Gd-enhancing lesions, number and 
volume of T2 lesions, number and volume of T1 lesions, normalized whole brain volume, 
and median MTR of whole brain) for the Study 109MS303 MRI cohort will also be 
presented, as applicable, at both the Previous Study Baseline and Study 109MS303 
Baseline. 


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Prior MS treatment history and baseline cardiac risk factors will also be summarized based 
on the Previous Study Baseline definition. 
6.3.5 Medical History 
An updated medical history is collected at the baseline visit of Study 109MS303. A 
summary of this updated medical history will be presented.  
6.3.6 Study Drug Compliance and Time on Study 
Study drug compliance in Study 109MS303 will be summarized.  The number of capsules 
not taken since the previous visit (out of those capsules the subject was expected to take) is 
collected on the study drug accountability CRF page. Using this information, percentage 
compliance will also be calculated as follows: 
Total number of capsules not taken is calculated as the sum of all individual 
values of the number of capsules not taken since the previous visit for a subject, as 
defined above. 
Total number of capsules assigned is calculated based on the number of days on 
study medication for a subject. The calculation of number of days on study 
medication is detailed below. 
Percentage compliance is then calculated as:  
[(Total number of capsules assigned) – (Total number of capsules not taken)] / 
(Total number of capsules assigned) * 100. 
Percentage compliance will be calculated up to the date of last dose in Study 109MS303.  
In addition, the total time on study medication will be summarized as a continuous variable 
and categorized into intervals. Days on study medication is calculated as the number of days 
from date of first dose to date of last dose. Additionally, the total number of subject-years of 
exposure to study medication will be presented. Time on study medication will be 
summarized for Study 109MS303 only and for Combined Data, utilizing the Study 
109MS303 ITT and Safety populations. 
Time on study parameters, including overall time on study and time on study prior to first 
use of alternative MS medication, will be summarized as a continuous variable and 
categorized into intervals. Total number of subject-years for time on study, both overall and 
prior to first use of alternative MS medication, will also be presented with respect to the 
dataset analyzed. The last known date on study will be taken as the last visit/evaluation date 
from relevant data for a subject. Summaries will be performed for Study 109MS303 only 
and for Combined Data, utilizing the Study 109MS303 ITT population. Additionally, 
overall time on study in Study 109MS303 will be summarized utilizing the Study 
109MS303 Safety population. 
6.3.7 Concomitant Medications and Non-drug Therapies 
Concomitant medications are defined as any medications take on or after the day of first dose 
of study treatment and on or before the day of last does of study treatment in the given 


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dataset. This includes medications started prior to the first dose of study treatment in the 
given dataset and continued while on study or started after the first dose of study treatment. 
A windowing rule of +180 days may be applied to these subjects who have completed the 
study without lymphocyte follow-up. The WHO drug dictionary will be used for coding 
concomitant medications. 
Concomitant medications will be summarized using the Study 109MS303 ITT Population 
and Study 109MS303 data only. The number and percent of subjects taking concomitant 
medications will be summarized. The most frequently taken concomitant medications, 
defined as those taken by at least 10% of subjects in any treatment group, will also be 
presented.  
Additionally, summaries of first alternative MS medication used may be performed using the 
following analysis populations, treatment groupings, and datasets: 
• Study 109MS303 ITT Population and Combined Data; and 
• Study 109MS303 ITT Population and Study 109MS303 data only.  
The number and percent of subjects in Study 109MS303 who previously took alternative 
MS medications in Studies 109MS301 or 109MS302 will also be summarized.  
6.3.8 Day Ranges for Analyses by Visit  
 
Subjects do not always strictly adhere to the visit schedule timing in protocols. Therefore, the 
designation of visits (or timepoints) will generally be based on the day of evaluation relative 
to date of first dose of study medication within a given dataset (i.e., with the date of first dose 
of study medication being Study Day 1), rather than the nominal visit recorded in the clinical 
database. 
 
Mutually exclusive visit windows will generally be utilized to assign visits for analysis that 
correspond to post-baseline visits specified in the protocols. In general, for data that are 
summarized by visit, visits for analysis will be assigned by using a windowing scheme as 
described below. 
 
Within a given dataset, the upper bound of the baseline visit window is Day 1, and the lower 
bound of the first post-baseline visit window is Day 2. For all other lower and upper bounds 
of visits, windows will end at the midpoint between scheduled visit timepoints, with the 
midpoint in the latter visit window.   
 
If more than one observation occurs within the same window, data closest to the target day 
for the scheduled visit will be used for analysis. If more than one observation is the same 
distance from the target day, the last observation will be used for analysis.  
 
However, for MRI analyses, visit windowing will only be applied when the nominal visit 
designation is premature withdrawal, with the lower bound of the first post-baseline visit 
window being Day 169 and with all other lower and upper visit bounds defined as above. 


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Otherwise, MRI analyses will not utilize visit windowing and will present results by nominal 
visit designations.  
 
 
6.4 
Efficacy Analysis  
6.4.1 Analysis Population 
Analysis populations, treatment groupings, and datasets are detailed in Section 6.2 above.  
 
The analysis populations, treatment groupings, and datasets for efficacy analyses will be as 
follows: 
 
• Primary efficacy analyses of non-MRI endpoints will utilize the Study 109MS303 
ITT Population with Combined Treatment Grouping and Combined Data;  
• Primary efficacy analyses of MRI endpoints will utilize the Study 109MS303 MRI 
Cohort with Combined Treatment Grouping and Combined Data; 
• The efficacy analysis of Study 109MS303 ARR will utilize the Study 109MS303 
ITT Population with Combined Treatment Grouping and Study 109MS303 data 
only. 
6.4.2 Analysis Methods 
In general, the covariates included in the statistical models for efficacy endpoints are selected 
to be consistent with analysis models in other previously reported Phase 3 MS studies. In 
these studies, the covariates have been demonstrated to be important factors in the analyses 
of the efficacy endpoints. Additionally, the statistical models and the covariates for inclusion 
in these statistical models for the efficacy analyses for Study 109MS303 will generally be the 
same as the corresponding models in Studies 109MS301 and 109MS302. 
 
Consistent with the efficacy analysis conventions in Studies 109MS301 and 109MS302, in 
general, for efficacy analyses of Study 109MS303, observed data after first use of alternative 
MS medications in the given dataset will be excluded, or subjects will be censored at the time 
of first starting alternative MS medication in the given dataset if they have not experienced 
the event of interest. The exceptions to this are: 
 
• Select sensitivity analyses that may be performed which consider all data regardless 
of alternative MS medication usage; and  
• Analysis of disability progression based on EDSS, where EDSS evaluations 
performed after first use of alternative MS medication has been started will be used to 
confirm tentative progression that occurred prior to first use of alternative MS 
medication. 
 
Alternative MS medications may include but are not limited to: interferon beta-1a, 
glatiramer acetate (for those subjects not receiving study-assigned GA), natalizumab, 
interferon beta-1b, mitoxantrone, mycophenolic acid, mycophenoloate mofetil, 
plasmapheresis used for the indication of MS, fingolimod, methotrexate, azathioprine, 


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alemetuzumab, ocrelizumab, teriflunomide, siponimod, daclizumab, cladribine, 
peginterferon beta-1a, cyclophosphamide, and rituximab.   
 
Region as a covariate or in the subgroup analysis is based not only on considerations of 
geography but also on type of health care system and access to health care in each country. 
The categories for regions will be identical to those used in Studies 109MS301 and 
109MS302: 
 
• Region 1: United States (including Puerto Rico); 
• Region 2: Western European countries (including Austria, Belgium, France, 
Germany, Greece, Ireland, Italy, Netherlands, Spain, Switzerland, and United 
Kingdom), plus Australia, Canada, Costa Rica, New Zealand, Israel, and 
South Africa; and 
• Region 3: Eastern European countries (including Belarus, Bosnia And 
Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Latvia, 
Macedonia, Moldova, Poland, Romania, Serbia, Slovakia, and Ukraine), 
India, Guatemala, and Mexico.  
 
The following table includes endpoints, analysis populations, baseline type with a short 
summary of statistical methods for the major efficacy analyses. Sections below include more 
details about these analyses.  
 
 


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6.4.2.1 Table of summary of major efficacy analyses for the 109MS303 ITT population 
Endpoint 
Population 
Data  
Treatment Grouping 
Baseline 
Statistical Methods 
Annualized relapse rate 
 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Unadjusted and adjusted ARR. Adjusted ARR will 
be estimated from the negative binomial model, 
adjusted for baseline EDSS (<=2.0 vs >2.0), baseline 
age (<40 vs >=40), region and number of relapses in 
the 1 year prior to 301/302 study entry. If 
convergence criterion is not met, then Poisson 
regression will be used.  
109MS303 
Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Unadjusted and adjusted ARR. Adjusted ARR will 
be estimated from the negative binomial model, 
adjusted for baseline EDSS (<=2.0 vs >2.0), baseline 
age (<40 vs >=40), region and number of relapses in 
the 1 year prior to 301/302 study entry. If 
convergence criterion is not met, then Poisson 
regression will be used.  
Annualized relapse rate 
by yearly interval 
 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Unadjusted and adjusted ARR. Adjusted ARR will 
be estimated from the negative binomial model, 
adjusted for baseline EDSS (<=2.0 vs >2.0), baseline 
age (<40 vs >=40), region and number of relapses in 
the 1 year prior to 301/302 study entry. If 
convergence criterion is not met, then Poisson 
regression will be used.  
109MS303 
Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Unadjusted and adjusted ARR. Adjusted ARR will 
be estimated from the negative binomial model, 
adjusted for baseline EDSS (<=2.0 vs >2.0), baseline 
age (<40 vs >=40), region and number of relapses in 
the 1 year prior to 301/302 study entry. If 
convergence criterion is not met, then Poisson 
regression will be used.  


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Endpoint 
Population 
Data  
Treatment Grouping 
Baseline 
Statistical Methods 
Proportion of subjects 
who relapsed at selected 
time points 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Kaplan-Meier curve of time to first relapse will be 
used to estimate the proportion at selected time 
points. 
Proportion of subjects 
with 6-month sustained 
disability progression 
measured by EDSS at 
selected time points 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Kaplan Meier analysis of time to the 6-month 
sustained disability progression will be used to 
estimate the proportion at selected time points. 
109MS303 
Data 
Combined Treatment 
Grouping 
109MS303 Baseline 
Kaplan Meier analysis of time to the 6-month 
sustained disability progression will be used to 
estimate the proportion at selected time points. 
EQ-5D: EQ5D VAS, 
EQ-5D index score and 
EQ-5D individual 
questions 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Descriptive statistics by combined treatment group 
and by study visit. 
SF-36 scores 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Descriptive statistics by combined treatment group 
and by study visit. 
Visual function test 
109MS303 
ITT population 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Descriptive statistics by combined treatment group 
and by study visit. 
MRI endpoints  
 
109MS303 
MRI Cohort  
 
Combined Data 
Combined Treatment 
Grouping 
109MS301/109MS302 
Baseline 
Descriptive statistics by combined treatment group 
and by study visit. 
For the total number of new or newly enlarging T2 
lesions, the total number of new T1 lesions, and the 
total number of Gd-enhancing lesions: negative 
binomial models may be used, adjusted for baseline 
characteristics in previous studies.  


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6.4.3 Analysis of Relapse 
Definition of Relapse 
In Study 109MS303, 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 treating (or examining) 
neurologist. The subject must have objective signs on the treating (or examining) 
neurologist’s examination confirming the event (i.e., an objective or protocol-defined 
relapse). New or recurrent neurologic symptoms that evolve gradually over several weeks to 
months are not to be considered an acute relapse. 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. i.e., if 2 relapses have onset days that are 29 days of 
one another, they will be counted only as 1 relapse, and the onset date used in the analysis 
will be the onset date of the first relapse.  
In Studies 109MS301 and 109MS302, 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 examining neurologist. The 
subject must have objective signs on the examining neurologist’s examination confirming 
the event (i.e., an objective or protocol-defined relapse), and additionally must then be 
reviewed and confirmed by the Independent Neurology Evaluation Committee (INEC) 
(INEC-confirmed relapses). New or recurrent neurologic symptoms that evolve gradually 
over several weeks to months were not to be considered an acute relapse. New or recurrent 
neurologic symptoms that occur less than 30 days following the onset of an INEC confirmed 
relapse should be considered part of the same relapse. i.e., if 2 relapses have onset days that 
are 29 days of one another, they will be counted only as 1 relapse, and the onset date used 
in the analysis will be the onset date of the first relapse.  
Therefore, Studies 109MS301, 109MS302, and 109MS303 all utilize essentially the same 
definition for objective (i.e., protocol-defined) relapses, given that there is no Independent 
Neurology Evaluation Committee (INEC) in Study 109MS303. Therefore, analyses of 
relapse for the final analysis of Study 109MS303 will be based primarily on objective (i.e., 
protocol-defined) relapses. 
Annualized Relapse Rate 
Annualized relapse rate (ARR) will be summarized using the following analysis populations, 
treatment grouping, and datasets: 
• Studies 109MS301/302/303 ARR, overall and over time, using the Study 303 ITT 
Population with Combined Treatment Grouping and Combined Data; and 
• Study 109MS303 ARR using the Study 303 ITT Population with Combined 
Treatment Grouping and Study 109MS303 data only.  
The number of subjects with a given number of relapses (categories of 0, 1, 2, 3, and 4 or 
more relapses), total number of relapses, and total number of subject-years of follow-up will 
be summarized by treatment group. The unadjusted ARR will be calculated for each 
treatment group as the total number of relapses divided by the total number of subject-years 


 Statistical Analysis Plan for Study 109MS303 
  
31 
 
of follow-up. Relapses and follow-up time that occur after first use of alternative MS 
medications are excluded from the calculations.  
 
The adjusted ARR and associated 95% confidence interval will be calculated for each 
treatment group by using a negative binomial regression model for unadjusted ARR, 
adjusting for baseline EDSS score (≤2.0 vs. >2.0), baseline age (<40 vs. ≥40 years old), 
region, and baseline relapse rate (i.e., the number of relapses in the year prior to the date of 
first dose in the previous study) as covariates. The baseline definition for these covariates 
will be based on Previous Study Baseline. 
 
The logarithmic transformation of the time on the study will be included in the model as the 
“offset” parameter. If the data are underdispersed, or if the negative binomial regression 
model does not converge, a Poisson regression model with the same covariates will be used 
instead of the negative binomial regression model. Dispersion will be evaluated from the 
Pearson Chi-Square statistic. If the ratio of the Pearson Chi-Square statistic to the degrees of 
freedom is ≤ 1 which indicates no overdispersion, then a Poisson regression model with 
adjustment for underdispersion will be used.  
 
In addition, the subject relapse rate will be calculated as the number of relapses for an 
individual subject divided by follow-up time in years for that subject excluding follow-up 
time after first use of alternative MS medication. Subject relapse rate will be summarized 
descriptively by treatment group. 
 
ARR analyses over time will be presented by various time intervals in order to elucidate 
onset and maintenance of effect over time. For example, time intervals one year in length 
may be considered.  
 
For ARR analyses, data following first use of alternative MS medications in the given dataset 
used for analysis will be excluded. If a subject did not experience a relapse prior to first 
starting an alternative MS medication, the subject’s follow-up time will be censored at the 
time the first alternative MS medication is started. Likewise, if a subject did not experience a 
relapse prior to study withdrawal, the subject’s follow-up time will be censored on the last 
date followed. The start date for calculation of ARR will be date of first dose, and if date of 
first dose is incomplete, date of randomization or enrollment will be used.  
 
Proportion of Subjects Who Relapsed 
The proportion of subjects who relapsed will be summarized using the following analysis 
populations, treatment grouping, and datasets: 
• Studies 109MS301/302/303 proportion relapsed using Study 303 ITT Population 
with Combined Treatment Grouping and Combined Data. 
The proportion of subjects relapsed can be estimated as the probability of relapses from the 
Kaplan-Meier curve of the time to the first relapse (i.e., Kaplan-Meier product-limit 
estimator). If there are no early withdrawals, the Kaplan-Meier estimate of the proportion of 
subjects relapsed is the same as the observed proportion of subjects relapsed. If there are 
early withdrawals, the Kaplan-Meier estimate has the advantage of taking into account the 
length of follow-up for the early withdrawals, without making any assumptions about 
whether those subjects relapsed or not.  


 Statistical Analysis Plan for Study 109MS303 
  
32 
 
Proportion relapsed analyses over time will be presented based on Kaplan-Meier curves. The 
estimated proportion of subjects relapsed at key timepoints from the Kaplan-Meier curves 
will be presented.   
For proportion relapsed analyses, data following first use of alternative MS medications will 
be excluded. If a subject did not experience a relapse prior to first starting an alternative MS 
medication, the subject will be censored at the time the first alternative MS medication is 
started. Likewise, if a subject did not experience a relapse prior to study withdrawal, the 
subject will be censored on the last date followed. The start date for calculation of time to 
relapse will be date of first dose, and if date of first dose is incomplete, date of randomization 
will be used.  
6.4.4 Analysis of Progression 
Definition of Progression 
In Study 109MS303, sustained disability progression will be assessed from the EDSS scores 
performed as per the protocol defined schedule of assessments at regular visits relative to the 
baseline EDSS score in the extension study, and well as from the baseline scores in previous 
study. Sustained disability progression is defined as at least a 1.0 point increase on the EDSS 
from a baseline EDSS ≥1.0 that is sustained for at least 24 weeks or a 1.5 point increase on 
the EDSS from a baseline EDSS = 0 that is sustained for at least 24 weeks. The EDSS 
progression is defined as sustained (or confirmed) when this minimum EDSS change is 
present on the next study visit occurring after 154 days or longer from the initial observation. 
The 154 day interval is based on the visit windows allowed in the protocol around the target 
visit day 
The date of the initial visit at which the minimum increase in the EDSS is met will be the 
date of onset of the progression (tentative progression). 
 
Progression will not be confirmed at a visit where a relapse is also occurring. A subject is 
considered to be having a relapse for at least 29 days after the start date of an objective 
relapse. If a subject meets the defined EDSS criteria of sustained progression and is also 
having a relapse, the subject will be required to meet the defined minimum EDSS criteria at 
the subsequent visit.   
 
Disability progression can be confirmed at the early (premature) study withdrawal visit, 
according to the rules above, as long as the early withdrawal visit is not also a relapse 
assessment visit.  
 
Death due to MS will be counted as progression. If the subject was in the midst of a tentative 
progression at the time of death (e.g. the EDSS evaluation prior to death is a tentative 
progression), the progression date will be the date of the start of the progression. If the 
subject had a confirmed EDSS progression prior to death, the progression date is the start 
date of the tentative progression. Otherwise, the progression date will be the date of death. 
 
In Studies 109MS301 and 109MS302, the same definition of sustained disability 
progression will be used as in Study 109MS303 (i.e., requiring a 24 week confirmation). 
 
Sustained disability progression will be summarized using the following analysis 
populations, treatment groupings, and datasets: 


 Statistical Analysis Plan for Study 109MS303 
  
33 
 
• Studies 109MS301/302/303 time to sustained (24 week) disability progression using 
the Study 303 ITT Population with Combined Treatment Grouping and Combined 
Data with previous study baseline; and 
• Studies 109MS301/302/303 time to sustained (24 week) disability progression using 
the Study 303 ITT Population with Combined Treatment Grouping and Study 
109MS303 data only with 109MS303 baseline. 
Time to sustained disability progression will be presented based on Kaplan-Meier curves. 
The estimated proportion of subjects with sustained disability progression at key timepoints 
based on the Kaplan-Meier curve will be presented.  
For these sustained disability progression analyses, subjects who do not have a sustained 
progression based on the above definition will be censored. The censor date will be the date 
of the last EDSS assessment, or the last EDSS assessment prior to first use of an alternative 
MS medication, unless the subject has a tentative progression at this assessment. For subjects 
with a tentative progression at this assessment, (or at the last EDSS assessment prior to first 
use of alternative MS medication that was subsequently not confirmed) the censor date will 
be the date of the EDSS assessment prior to the last EDSS assessment. Subjects who 
withdraw from the study after the baseline visit but prior to the first scheduled EDSS 
assessment will be censored at baseline. The start date for calculation of time to progression 
will be date of first dose, and if date of first dose is incomplete, date of randomization will be 
used.  
6.4.5 Analysis of MRI Endpoints 
The following MRI endpoints will be analyzed:  
• Lesion parameters: 
o number of Gd-enhancing lesions;  
o number of new or newly-enlarging T2 lesions; and 
o number of new T1 hypointense lesions. 
• Volume parameters: 
o volume of Gd-enhancing lesions; 
o volume of T2 hyperintense lesions; and 
o volume of T1 hypointense lesions. 
• Other parameters: 
o brain atrophy (percent brain volume change [PBVC]); and 
o magnetization transfer ratio (MTR).  
MRI endpoints will be summarized using the following analysis populations, treatment 
grouping, and datasets: 
• Study 109MS303 MRI Cohort with Combined Treatment Grouping and Combined 
Data 
The number of Gd-enhancing lesions will be descriptively summarized, both overall and over 
time, by treatment group, both as a continuous variable and categorically.  


 Statistical Analysis Plan for Study 109MS303 
  
34 
 
The number of new or newly-enlarging T2 lesions will be descriptively summarized, both 
overall and by key time intervals, by treatment group, both as a continuous variable and 
categorically. The negative binomial regression model will be used to estimate adjusted 
means and 95% confidence intervals for each treatment group. The model will adjust for 
region and baseline volume based on the Previous Study Baseline.  
Examples of key time intervals may include, but are not limited to: Previous Study Baseline 
to Week 24 in Previous Study, Week 24 to Week 48 in Previous Study, Week 48 to Week 
96 in Previous Study, Week 96 of Previous Study to Week 48 of Study 109MS303, Week 
48 of Study 109MS303 to Week 96 of Study 109MS303, and up to Week 336 of Study 
109MS303 to Week 384 of Study 109MS303, Previous Study Baseline to Week 48 of 
Previous Study, Previous Study Baseline to Week 96 of Previous Study, Previous Study 
Baseline to Week 48 of Study 109MS303, and up to Previous Study Baseline to Week 384. 
The number of new T1 hypointense lesions will be analyzed in a similar manner as the 
number of new or newly-enlarging T2 lesions. 
The actual value of MRI volume parameters, as well as the change and percentage change in 
these parameters for key time intervals (similar to those used for analysis of T2 lesions), will 
be descriptively summarized by treatment group.  
Brain atrophy (PBVC) and MTR will also be descriptively summarized by treatment group 
for key timepoints and time intervals. 
Analyses utilizing the Studies 109MS301 + 109MS302 MRI Cohort will descriptively 
present the number of new lesions, as well as change in lesion volume for key time intervals 
(e.g., Previous Study Baseline to Week 48 in Previous Study, Week 48 to Week 96 in 
Previous Study, Week 96 in Previous Study to Week 48 in Study 109MS303, Week 48 in 
Study 109MS303 to Week 96 in Study 109MS303, Week 48 in Study 109MS303 to Week 
96 in Study 109MS303, Week 96 in Study 109MS303 to Week 144 in Study 109MS303, 
Week 144 in Study 109MS303 to Week 192 in Study 109MS303, and up to Week 336 in 
Study 109MS303 to Week 384 in Study 109MS303).  
As a result of Study 109MS303 becoming an open label extension with one single arm after 
regulatory approved the dosage of  BG00012 240 mg BID, all patients receiving BG00012 
240 mg TID were switched to BG00012 240 mg BID. Hypothesis tests of comparison 
between treatment groups for MRI endpoints will not be conducted.  
For MRI analyses, data following first use of alternative MS medications will be excluded. 
Some MRI endpoints for Study 109MS303 MRI Cohort with Combined Treatment 
Grouping and 109MS303 Data may be analyzed.  
6.4.6 Analysis Quality of life Assessments (SF-36 and EQ-5D) and Visual 
Function Test 
The quality of life (SF-36 and EQ-5D) and Visual Function Test assessments will be 
summarized using the Study 109MS303 ITT Population with Combined Treatment 
Grouping and Combined Data. For these analyses, data following first use of alternative MS 
medications will be excluded.  


 Statistical Analysis Plan for Study 109MS303 
  
35 
 
SF-36  
Scores for SF-36 will be calculated based on the standard scoring method described in the 
SF-36 Health Survey Manual and Interpretation Guide. This method indicates that for an 
individual domain where 50% or more of the item’s questions are non-missing, the average 
of the non-missing items for that patient in that domain will be calculated, and this average is 
then used to impute the missing item questions response and calculate the domain score. The 
mental and physical component summary measures (MCS and PCS, respectively) are then 
calculated from the imputed domains scores. 
Actual scores and change from Previous Study Baseline over time will be descriptively 
summarized by treatment group for the individual domains and MCS and PCS measures. 
EQ-5D 
The Euroqol (EQ)-5D is a generic health-related quality of life instrument which has been 
extensively validated. There are two components to the EQ-5D, a Health State Profile that 
results in calculation of an EQ-5D index score and a Visual Analog Scale (VAS) that results 
in calculation of the subject assessment of health scale.  
For the Health State Profile, patients record their level of current health for five domains 
comprising a health profile: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Scores of 1, 2, or 3 are possible responses for each of the five questions in 
the Health State Profile (1=no problems, 2=some problems, 3=severe problems). The digits 
for the five dimensions are combined in a 5-digit number describing a person’s health state. 
A scoring formula developed by the EuroQol Group is then used to assign utility values for 
each patient’s Health State Profile. A summary index score (EQ-5D index score) is derived 
from the 5 questions by conversion with this scoring formula and a table of scores.   
For the VAS, patients are asked to rate their current health on a 20 cm scale from 0 to 100 
where 0 represents “worst imaginable health state” and 100 represents “best imaginable 
health state” resulting in the subject assessment of health scale.   
Actual scores and change from Previous Study Baseline over time will be descriptively 
summarized by treatment group for both the EQ-5D index score and subject assessment of 
health scale. Additionally, the scores for each of the five component questions of the EQ-5D 
index score will be summarized categorically.  
Visual Function Test 
The visual function test uses the low-contrast Sloan letter chart as an indicator of disease-
related changes in visual performance. Subjects are tested using the contrast level of 100%, 
2.5% and 1.25% charts, and the scores are defined as the number of letters identified 
correctly for each chart (maximum score is 60).  
Actual scores and change from Previous Study Baseline over time will be descriptively 
summarized by treatment group for the VFT for each of the contrast levels. 
  


 Statistical Analysis Plan for Study 109MS303 
  
36 
 
6.5 
Safety Data 
6.5.1 Analysis Population 
Analysis populations, treatment groupings, and datasets are detailed in Section 6.2 above.  
Study 109MS303 Safety Population is defined to include all subjects who received at least 
one dose of study treatment in Study 109MS303 and had any post-baseline safety follow-up 
in Study 109MS303, defined as any treatment emergent AE in Study 109MS303 or any 
post-baseline laboratory, vital signs, or physical exam assessment in Study 109MS303. This 
definition of the safety population is utilized in order not to inflate the denominator for 
calculation of incidences and percentages (and therefore deflate the incidences and 
percentages themselves) with subjects who were dosed in Study 109MS303 but had no post-
baseline safety follow-up. 
The analysis populations, treatment groupings, and datasets for safety analyses will be as 
follows: 
• Primary safety analyses will utilize the Study 109MS303 Safety Population with 
Combined Treatment Grouping and Study 109MS303 data only; and 
• Select safety analyses (where the incidence in Study 109MS303 itself may be of 
interest) will utilize the Study 109MS303 Safety Population with Study 109MS303 
Treatment Grouping and Study 109MS303 data only. 
6.5.2 Analysis Methods  
Safety analyses will summarize adverse events (AEs), laboratory abnormalities, and vital 
signs.  
6.5.3 Analysis of Adverse Events 
All summary analyses of AEs will be based on the principle of treatment emergence. In a 
given dataset, an event is considered to be treatment emergent if it has an onset date on or 
after the date of first study treatment or if it was present prior to start of study treatment and 
subsequently worsened. Henceforth, whenever an analysis or summary of AEs is mentioned, 
it is intended that this is in reference to the treatment emergent adverse event experience, 
even if not explicitly mentioned. 
In general, analyses of AEs will include all events through the end of a subject’s follow-up in 
a given dataset. 
In general, AEs will be analyzed based on incidence, defined as the proportion of subjects 
who had at least one occurrence of an event out of the number of subjects in the relevant 
safety analysis population.   
The Medical Dictionary for Regulatory Activities (MedDRA) version 13.1 will be utilized to 
code and group AEs by System Organ Class (SOC) and Preferred Term (PT). References to 
summaries of AEs using System Organ Class are intended to refer to the primary SOC.  In 
addition to summaries of incidence by both SOC and PT, incidence of adverse events may 
also be summarized and presented by SOC only or by PT only, as appropriate, depending on 
the nature of the analysis performed. Adverse event summaries may also be provided by 


 Statistical Analysis Plan for Study 109MS303 
  
37 
 
High-Level Group Term (HLGT) or High-Level Term (HLT), if considered appropriate for 
signal detection, in instances where the SOC level of summary is too broad but the PT level 
of summary is too granular. 
A summary analysis of adverse events will be provided including the following numbers and 
incidences/percentages of subjects: in the safety analysis population; with an adverse event; 
with a moderate or severe AE; with a severe AE; with a related AE; with a serious adverse 
event (SAE); with an AE leading to discontinuation of study treatment; and with an AE 
leading to withdrawal from study. 
Summaries of the most frequently reported AEs by PT will also be presented, defined as 
those AEs with an incidence of AEs of at least 5% (at SOC or PT level) in any treatment 
group. Other cutoff values may be explored, as appropriate.   
The incidence of AEs by SOC and PT may also be presented by time intervals (e.g., using a 
12 month time interval). Other time intervals may be explored as well to elucidate trends 
over time. For such analyses, for a given time interval, the number of subjects who were 
followed for adverse events during that time interval will be presented along with the AE 
incidence during that time interval. Therefore, for a given SOC or PT, subjects will be 
counted only once for a given time interval but may be counted more than once across time 
intervals.  
The incidence of AEs by relationship to study treatment will be summarized by SOC and PT. 
For a given SOC or PT, subjects with multiple AEs differing in relatedness will be counted 
once in the most related category. In addition, AEs categorized as “related” (i.e., those where 
the investigator assessment of relationship to study treatment is “possibly” or “related) will 
also be summarized by PT.  
The incidence of AEs by severity will be summarized by SOC and PT using severity 
categories of mild, moderate, and severe. For a given SOC or PT, subjects with multiple AEs 
differing in severity will be counted once in the category of worst severity. The incidence of 
severe AEs will also be summarized by PT.  
Deaths that occur will be described in detail in patient narratives. A listing of deaths will also 
be provided. While the number of deaths is expected to be small, tabulation will be 
performed if appropriate.   
A summary of SAEs by SOC and PT will also be provided. Details of each SAE will also be 
listed, including subject ID, treatment group, system organ class/preferred term, date of 
onset, severity, and relationship to the study drug and action taken. In addition, a summary 
of treatment-related SAEs by SOC and PT will be provided. 
The incidence of adverse events that led to study treatment discontinuation, study 
withdrawal, dose interruption, and dose reduction will each be presented by SOC and PT. 
A listing of AEs leading to study treatment discontinuation and study withdrawal will also be 
presented.  Adverse events that were treatment-emergent to the previous study yet led to 
study treatment discontinuation and study withdrawal in Study 109MS303 will be denoted 
by a negative onset day in the listing. 


 Statistical Analysis Plan for Study 109MS303 
  
38 
 
The incidence of adverse events of special interest will be summarized by SOC and PT. The 
adverse event of special interest categories may include the following: 
• Flushing and other related symptoms; 
• Gastrointestinal tolerability; 
• Infections, including potential opportunistic infections; 
• Ischaemic cardiovascular disorders; 
• Hepatic disorders; 
• Renal disorders; 
• Malignancies; 
• Lymphopenia and Leukopenia.  
Subjects who discontinue study treatment are to have a premature study withdrawal visit 
within four weeks of the last dose of study treatment dose and a telephone follow-up 12 
weeks after the last dose of study treatment. For subjects who have discontinued study 
treatment, a separate summary of adverse events with onset after discontinuation of study 
treatment may be presented.  
Subject narratives will be provided for the following event types in Study 109MS303: 
• Deaths; 
• Serious adverse events (only selected SAEs may be included); 
• AEs leading to study drug discontinuation; 
• AEs leading to study withdrawal; 
• Special interest AE categories of potential opportunistic infections, ischaemic 
cardiovascular disorders, hepatic disorders, and malignancies; 
• ALT or AST values >5xULN at any time post-baseline; and 
• ALT or AST values >=3xULN and concurrently total bilirubin values > 2xULN.  
Select AE analyses utilizing the Study 109MS303 Safety Population with Study 109MS303 
Treatment Grouping and Study 109MS303 data only, mentioned in the second bullet in 
Section 6.5.1 above, may include, but are not limited to: summary analysis of adverse events 
(AEs), incidence of AEs by SOC and PT, incidence of most common AEs, incidence of 
treatment-related AEs, incidence of severe AEs, incidence of serious adverse events (SAEs), 
incidence of treatment-related SAEs, incidence of AEs that led to discontinuation of study 
drug, incidence of AEs that led to study withdrawal, and incidence of AEs of special interest 
such as malignancies, hepatic disorders, GI, opportunistic infections, herpes zoster, etc. 


 Statistical Analysis Plan for Study 109MS303 
  
39 
 
6.5.4 Analysis of Clinical Laboratory Data 
The following clinical laboratory parameters are assessed in the protocol: 
• Hematology: hemoglobin, hematocrit, red blood cell count, WBC count (with 
differential) and platelet count.  
• Blood chemistry: sodium, potassium, chloride, total bilirubin, alkaline phosphatase, 
alanine transaminase/serum glutamate-pyruvate transaminase (ALT/SGPT), 
aspartate transaminase/serum glutamic-oxaloacetic transaminase (AST/SGOT), 
lactate dehydrogenase, gamma-glutamyl-transferase (GGT), blood urea nitrogen 
(BUN), creatinine, bicarbonate, calcium, magnesium, phosphate, uric acid, and 
glucose. 
• Urinalysis: color, specific gravity, pH, protein, glucose, blood, ketones, microscopy, 
2-microglobulin, and microalbumin. 
• Urine cytology 
 
Analyses for laboratory data involving baseline value will be based on BG00012 Treatment 
Baseline (as defined above in Section 6.3.1).  
Shift analyses 
Laboratory data will be summarized using shift tables where appropriate. Each subject’s 
hematology and blood chemistry values will be flagged as “low”, “normal”, or “high” 
relative to the normal ranges of the central laboratory, or as “unknown” if no result is 
available. Each subject’s urinalysis values will be flagged as “positive”, “negative”, or if no 
value is available, “unknown”.  
Shifts from baseline to high/low status for hematology and blood chemistry parameters and 
shifts from baseline to high/positive status for urinalysis will be presented.  Subjects need to 
have at least one post-baseline evaluation in order to be included in the analysis. In addition, 
shifts from baseline to the worst post-baseline value will be presented for relevant laboratory 
tests by treatment group by clinically relevant categories (e.g., <= ULN, >1 - <3 xULN, >=3 
- 5 xULN, >5 – 10 xULN, >10 – 20 x ULN, >20 x ULN, etc.). 
For urine cytology tests results, the number and percentage of subjects with an abnormal 
post-baseline result will be summarized by treatment group. 
 
Summary of laboratory values over time and other analyses  
In addition to the shift analyses, summary of actual values, change from baseline values, and 
percentage change from baseline values will be presented by visit for quantitative laboratory 
parameters.  Graphs showing mean actual values or mean change from baseline values over 
time may be presented as well.  
In addition, summaries of worst post-baseline laboratory values by clinically relevant 
categories may also be presented for selected parameters of interest by treatment group. The 
data may also be presented in graphs. For example, for liver function tests (alkaline 
phosphatase, ALT, AST, GGT and total bilirubin), categories may be defined based on 
cutoff values relative to the upper limit of normal (e.g., <= ULN, > ULN, >=3 x ULN, >5 x 
ULN, >10 xULN, and >20 xULN for ALT, AST, and GGT, and <= ULN, > ULN, > 1.5 


 Statistical Analysis Plan for Study 109MS303 
  
40 
 
xULN, and >2 xULN for total bilirubin).  For hematology parameters, categories may be 
defined based on potentially clinically significant cutoffs (e.g., < 3.0 x 10^9/L and >= 16 x 
10^9/L for WBC and <0.8 x 10^9/L, <0.5 x 10^9/L, and > 12 x 10^9/L for lymphocytes). 
For qualitative urinalysis parameters, categories may be defined based on the qualitative 
categories (e.g., normal/negative, trace, 1+, 2+, 3+, etc.). 
Worst post-baseline laboratory value summaries will comprise those select safety analyses 
utilizing the Study 109MS303 Safety Population with Study 109MS303 Treatment 
Grouping and Study 109MS303 data only, mentioned in the second bullet in Section 6.5.1 
above. 
6.5.5 Analysis of Vital Signs Data 
The analysis of vital signs will focus on the incidence of clinically relevant abnormalities. 
Analyses for vital signs data involving baseline value will be based on BG00012 Treatment 
Baseline (as defined above in Section 6.3.1).  
The number of subjects evaluated and the number and percentage of subjects with clinically 
relevant post-baseline abnormalities will be presented by treatment group. The criteria for 
clinically relevant post-baseline abnormalities (from Table 2 of the protocol) are shown 
below in Table 6.5.5.1 . Summary statistics for actual values and change from baseline will 
also be presented.  
Table 6.5.5.1 Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38oC and an increase from pre-dosing of at least 1oC 
Pulse  
120 beats per minute post-baseline, or 
an increase from pre-dosing of more than 20 beats per minute, or 
<50 beats per minute post-baseline, or 
a decrease from pre-dosing of more than 20 beats per minute 
Systolic Blood Pressure 
>180 mmHg post-baseline, or  
an increase from pre-dosing of more than 40 mmHg, or  
<90 mmHg post-baseline, or  
a decrease from pre-dosing of more than 30 mmHg 
Diastolic Blood Pressure 
>105 mmHg post-baseline, or  
an increase from pre-dosing of more than 30 mmHg, or 
<50 mmHg post-baseline, or  
a decrease from pre-dosing of more than 20 mmHg 
 
Summaries of actual value and change from baseline (based on BG00012 Treatment 
Baseline) by visit for body weight will also be provided. 


 Statistical Analysis Plan for Study 109MS303 
41 
6.5.6 Analysis of Absolute Lymphocyte Counts 
Subjects who temporarily withhold, or permanently discontinue study treatment for any 
reason and have a lymphocyte count <LLN will continue protocol-required visits and 
assessments and will also be followed up every 4 weeks for 24 weeks, then every 12 weeks 
(unless clinically indicated more often or at the Investigator’s discretion) until the 
lymphocyte count is ≥LLN or for up to 48 weeks following drug discontinuation, whichever 
occurs sooner. 
 
 
  
In general, the lymphocyte follow-up analysis may include subjects who have at least one 
ALC < LLN during the treatment period or at the treatment discontinuation and have at least 
one ALC value during the lymphocyte follow-up period. Patients who have any post 
lymphocyte follow-up baseline values may be included in the follow-up analysis. ALCs 
collected during the lymphocyte follow-up period will be analyzed. 
The lymphocyte follow-up period is defined as the time starting from the date of temporary 
dose interruption or study drug discontinuation. The start date of the lymphocyte follow-up 
period is defined as the start date of temporary dose interruption or the treatment end date. 
The last observed value collected on or prior to the date of temporary dose interruption or 
study drug discontinuation will be the reference point (lymphocyte follow-up baseline). Data 
that are collected during the lymphocyte follow-up period will be assigned to an appropriate 
visit by using the mid-point of the two visits windowing scheme. Visits will be mapped every 
4 weeks for 24 weeks and then every 12 weeks afterward.  
The by-visit summary of actual value change and percent change from BG00012 baseline 
and the lymphocyte follow-up baseline in ALC during the lymphocyte follow-up period will 
be presented. The by-visit summary of actual value change and percent change from the 
study baseline in ALC during the whole study period will also be presented. In addition, 
graphical display of median (Q1/Q3) of actual value in ALC in the whole study period will 
be presented; graphical display of median (Q1/Q3) of percent change from BG00012 
baseline and lymphocyte follow-up baseline will be presented. 
  
 
 
  
6.5.8 Deviations in Analyses from Study Protocol 
With regulatory approval (effective March 2013), all patients receiving BG00012 240 mg 
TID switched to BID (approved dosage) at their next study visit. This study becomes an 
open label extension study with a single arm. Following analyses proposed in the protocol 
will not be conducted.  


 Statistical Analysis Plan for Study 109MS303 
  
42 
 
Cox PH analyses for time for first relapse and time to disability progression will not be 
conducted as we only have a single treatment arm.  
ANCOVA models for MRI outcomes will not be conducted as we only have one treatment 
arm.